6:00am - 8:00am Saturday morning 1/31/15
Recent Stanford Publications in PubMed
- Modeling stochastic noise in gene regulatory systems.Meister A, Du C, Li YH, Wong WHQuant Biol
- A time-indexed reference standard of adverse drug reactions.Harpaz R, Odgers D, Gaskin G, DuMouchel W, Winnenburg R, Bodenreider O, Ripple A, Szarfman A, Sorbello A, Horvitz E, White RW, Shah NHSci Data
- Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors†Dedicated to Max Malacria, a friend and scholar whose science and creative contributions to step-economical synthesis have inspired us all and moved the field closer to the ideal.‡Electronic supplementary information (ESI) available: Synthetic procedures and spectral data. See DOI: 10.1039/c4qo00228hClick here for additional data file.Wender PA, Axtman AD, Golden JE, Kee JM, Sirois LE, Quiroz RV, Stevens MCOrg Chem Front
- A Modified Retromaxillary Approach to the Infratemporal Fossa: Three Case Studies.Woodford R, Chaudhary N, Wolf A, Lownie S, Armstrong JEJ Oral Maxillofac Surg
- Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, Moreau R, Jalan R, Sarin SK, Piano S, Moore K, Lee SS, Durand F, Salerno F, Caraceni P, Kim WR, Arroyo V, Garcia-Tsao GGut
- In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals.Ahmed SA, de Hoog GS, Stevens DA, Fahal AH, van de Sande WWMed Mycol
- Genomics: CRISPR engineering turns on genes.Cho SW, Chang HYNature
- (13)C NMR detects conformational change in the 100-kD membrane transporter ClC-ec1.Abraham SJ, Cheng RC, Chew TA, Khantwal CM, Liu CW, Gong S, Nakamoto RK, Maduke MJ Biomol NMR
- The ER membrane J protein C18 executes a distinct role in promoting SV40 membrane penetration.Bagchi P, Walczak CP, Tsai BJ Virol
- A recurrent regulatory change underlying altered expression and Wnt response of the stickleback armor plates gene EDA.O'Brown NM, Summers BR, Jones FC, Brady SD, Kingsley DMElife
- Alzheimer's pantoum.Stanford EAm J Nurs
- Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes.Burridge PW, Metzler SA, Nakayama KH, Abilez OJ, Simmons CS, Bruce MA, Matsuura Y, Kim P, Wu JC, Butte M, Huang NF, Yang PCAm J Transl Res
- Cancer Cell Gene Expression Modulated from Plasma Membrane Integrin αvβ3 by Thyroid Hormone and Nanoparticulate Tetrac.Davis PJ, Glinsky GV, Lin HY, Leith JT, Hercbergs A, Tang HY, Ashur-Fabian O, Incerpi S, Mousa SAFront Endocrinol (Lausanne)
- Transient global amnesia associated with a unilateral infarction of the fornix: case report and review of the literature.Gupta M, Kantor MA, Tung CE, Zhang N, Albers GWFront Neurol
- Diagnostic Yield of Extended Cardiac Patch Monitoring in Patients with Stroke or TIA.Tung CE, Su D, Turakhia MP, Lansberg MGFront Neurol
- The brain, amphotericin B, and p-glycoprotein.Stevens DA, Clemons KV, Martinez M, Chen VAntimicrob Agents Chemother
- Multiscale Analyses of the Bone-implant Interface.Cha JY, Pereira MD, Smith AA, Houschyar KS, Yin X, Mouraret S, Brunski JB, Helms JAJ Dent Res
- Novel codon-optimized mini-intronic plasmid for efficient, inexpensive, and xeno-free induction of pluripotency.Diecke S, Lu J, Lee J, Termglinchan V, Kooreman NG, Burridge PW, Ebert AD, Churko JM, Sharma A, Kay MA, Wu JCSci Rep
- Long-range ion-water and ion-ion interactions in aqueous solutions.Chen C, Huang C, Waluyo I, Weiss T, Pettersson LG, Nilsson APhys Chem Chem Phys
- More hippocrates, less hypocrisy: eliminate sugar-sweetened beverages from residency lunches.Nagata JM, Chamberlain LJ, Robinson TNAcad Med
- Menopausal symptoms in women with chronic kidney disease.Cheung KL, Stefanick ML, Allison MA, LeBlanc ES, Vitolins MZ, Shara N, Chertow GM, Winkelmayer WC, Tamura MKMenopause
- Dewetting and deposition of thin films with insoluble surfactants from curved silicone hydrogel substrates.Bhamla MS, Balemans C, Fuller GGJ Colloid Interface Sci
- Using iPSCs and genomics to catch CNVs in the act.Urban AE, Purmann CNat Genet
- Impact of surgical innovation on tissue repair in the surgical patient.Tevlin R, Atashroo D, Duscher D, Mc Ardle A, Gurtner GC, Wan DC, Longaker MTBr J Surg
- Reply: Studies in Fat Grafting: Part I. Effects of Injection Technique on In Vitro Fat Viability and In Vivo Volume Retention; and Studies in Fat Grafting: Part II. Effects of Injection Mechanics on Material Properties of Fat.Wan DC, Gurtner GC, Longaker MTPlast Reconstr Surg
- Exercise induces stromal cell-derived factor-1α-mediated release of endothelial progenitor cells with increased vasculogenic function.Chang E, Paterno J, Duscher D, Maan ZN, Chen JS, Januszyk M, Rodrigues M, Rennert RC, Bishop S, Whitmore AJ, Whittam AJ, Longaker MT, Gurtner GCPlast Reconstr Surg
- Microchip ELISA Coupled with Cell Phone to Detect Ovarian Cancer HE4 Biomarker in Urine.Wang S, Akbas R, Demirci UMethods Mol Biol
- OPTN/SRTR 2013 Annual Data Report: Liver.Kim WR, Lake JR, Smith JM, Skeans MA, Schladt DP, Edwards EB, Harper AM, Wainright JL, Snyder JJ, Israni AK, Kasiske BLAm J Transplant
- Causes and timing of death in extremely premature infants from 2000 through 2011.Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, Sánchez PJ, Shankaran S, Van Meurs KP, Ball MB, Hale EC, Newman NS, Das A, Higgins RD, Stoll BJ, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research NetworkN Engl J Med
- Posttraumatic stress disorder and risk of spontaneous preterm birth.Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CSObstet Gynecol
- Pregnancy outcomes in the super obese, stratified by weight gain above and below institute of medicine guidelines.Swank ML, Marshall NE, Caughey AB, Main EK, Gilbert WM, Melsop KA, Chung JHObstet Gynecol
- Commentary: Operational Definition of Epilepsy survey.Fisher RSEpilepsia
- Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays.Light JG, Fransen JW, Adekunle AN, Adkins A, Pangeni G, Loudin J, Mathieson K, Palanker DV, McCall MA, Pardue MTExp Eye Res
- Cross-kingdom chemical communication drives a heritable, mutually beneficial prion-based transformation of metabolism.Jarosz DF, Brown JC, Walker GA, Datta MS, Ung WL, Lancaster AK, Rotem A, Chang A, Newby GA, Weitz DA, Bisson LF, Lindquist SCell
- An evolutionarily conserved prion-like element converts wild fungi from metabolic specialists to generalists.Jarosz DF, Lancaster AK, Brown JC, Lindquist SCell
- Robust expansion of dendritic cells in vivo by hydrodynamic FLT3L-FC gene transfer.Tu H, Burke TM, Oderup C, Huang K, Wong K, Lewén S, LaJevic M, Zabel BAJ Immunol Methods
- Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial.Koenekoop RK, Sui R, Sallum J, van den Born LI, Ajlan R, Khan A, den Hollander AI, Cremers FP, Mendola JD, Bittner AK, Dagnelie G, Schuchard RA, Saperstein DALancet
- Cryoprecipitate therapy.Nascimento B, Goodnough LT, Levy JHBr J Anaesth
- Five strategies to effectively use online resources in emergency medicine.Thoma B, Joshi N, Trueger NS, Chan TM, Lin MAnn Emerg Med
- Risk of selected structural abnormalities in infants after increased nuchal translucency measurement.Baer RJ, Norton ME, Shaw GM, Flessel MC, Goldman S, Currier RJ, Jelliffe-Pawlowski LLAm J Obstet Gynecol
- Nanocones to study initial steps of endocytosis.Jeong S, Galic MMethods Mol Biol
- Anti-asialo GM1 NK cell depleting antibody does not alter the development of bleomycin induced pulmonary fibrosis.Monnier J, Zabel BAPLoS One
- Age-dependent transcriptome and proteome following transection of neonatal spinal cord of Monodelphis domestica (South American grey short-tailed opossum).Saunders NR, Noor NM, Dziegielewska KM, Wheaton BJ, Liddelow SA, Steer DL, Ek CJ, Habgood MD, Wakefield MJ, Lindsay H, Truettner J, Miller RD, Smith AI, Dietrich WDPLoS One
- Human stem cells for modeling heart disease and for drug discovery.Matsa E, Burridge PW, Wu JCSci Transl Med
- As the egg turns: monitoring egg attendance behavior in wild birds using novel data logging technology.Shaffer SA, Clatterbuck CA, Kelsey EC, Naiman AD, Young LC, VanderWerf EA, Warzybok P, Bradley R, Jahncke J, Bower GCPLoS One
- Insulin resistance: regression and clustering.Yoon S, Assimes TL, Quertermous T, Hsiao CF, Chuang LM, Hwu CM, Rajaratnam B, Olshen RAPLoS One
- Functional genomics with a comprehensive library of transposon mutants for the sulfate-reducing bacterium Desulfovibrio alaskensis G20.Kuehl JV, Price MN, Ray J, Wetmore KM, Esquivel Z, Kazakov AE, Nguyen M, Kuehn R, Davis RW, Hazen TC, Arkin AP, Deutschbauer AMBio
- Adipose-derived stem cells: a review of signaling networks governing cell fate and regenerative potential in the context of craniofacial and long bone skeletal repair.Senarath-Yapa K, McArdle A, Renda A, Longaker MT, Quarto NInt J Mol Sci
- Invasion and proliferation kinetics in enhancing gliomas predict IDH1 mutation status.Baldock AL, Yagle K, Born DE, Ahn S, Trister AD, Neal M, Johnston SK, Bridge CA, Basanta D, Scott J, Malone H, Sonabend AM, Canoll P, Mrugala MM, Rockhill JK, Rockne RC, Swanson KRNeuro Oncol
- Enhanced decolorization of azo dye in a small pilot-scale anaerobic baffled reactor coupled with biocatalyzed electrolysis system (ABR-BES): a design suitable for scaling-up.Cui D, Guo YQ, Lee HS, Wu WM, Liang B, Wang AJ, Cheng HYBioresour Technol
- Mast cells: potential positive and negative roles in tumor biology.Marichal T, Tsai M, Galli SJCancer Immunol Res
- Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal.Cheng JC, Bazan JG, Wu JK, Koong AC, Chang DTPract Radiat Oncol
- The effect of arm position on the dosimetry of thoracic stereotactic ablative radiation therapy using volumetric modulated arc therapy.Shultz DB, Jang SS, Hanlon AL, Diehn M, Loo BW, Maxim PGPract Radiat Oncol
- Updating emotional content in working memory: a depression-specific deficit?Yoon KL, LeMoult J, Joormann JJ Behav Ther Exp Psychiatry
- Α-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion.Aguilar A, Becker L, Tedeschi T, Heller S, Iomini C, Nachury MVMol Biol Cell
- Case report of a transfusion-associated hepatitis A infection.Hughes JA, Fontaine MJ, Gonzalez CL, Layon AG, Goodnough LT, Galel SATransfusion
- Executive function is associated with social competence in preschool-aged children born preterm or full term.Alduncin N, Huffman LC, Feldman HM, Loe IMEarly Hum Dev
- Cardiac rehabilitation exercise and self-care for chronic heart failure.Ades PA, Keteyian SJ, Balady GJ, Houston-Miller N, Kitzman DW, Mancini DM, Rich MWJACC Heart Fail
- Whole-genome haplotyping using long reads and statistical methods.Kuleshov V, Xie D, Chen R, Pushkarev D, Ma Z, Blauwkamp T, Kertesz M, Snyder MNat Biotechnol
- Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice.Iyer SM, Montgomery KL, Towne C, Lee SY, Ramakrishnan C, Deisseroth K, Delp SLNat Biotechnol
- Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404).Ganjoo K, Hong F, Horning SJ, Gascoyne RD, Natkunam Y, Swinnen LJ, Habermann TM, Kahl BS, Advani RHLeuk Lymphoma
Modeling stochastic noise in gene regulatory systems.
Quant Biol. 2014 Mar;2(1):1-29
Authors: Meister A, Du C, Li YH, Wong WH
The Master equation is considered the gold standard for modeling the stochastic mechanisms of gene regulation in molecular detail, but it is too complex to solve exactly in most cases, so approximation and simulation methods are essential. However, there is still a lack of consensus about the best way to carry these out. To help clarify the situation, we review Master equation models of gene regulation, theoretical approximations based on an expansion method due to N.G. van Kampen and R. Kubo, and simulation algorithms due to D.T. Gillespie and P. Langevin. Expansion of the Master equation shows that for systems with a single stable steady-state, the stochastic model reduces to a deterministic model in a first-order approximation. Additional theory, also due to van Kampen, describes the asymptotic behavior of multistable systems. To support and illustrate the theory and provide further insight into the complex behavior of multistable systems, we perform a detailed simulation study comparing the various approximation and simulation methods applied to synthetic gene regulatory systems with various qualitative characteristics. The simulation studies show that for large stochastic systems with a single steady-state, deterministic models are quite accurate, since the probability distribution of the solution has a single peak tracking the deterministic trajectory whose variance is inversely proportional to the system size. In multistable stochastic systems, large fluctuations can cause individual trajectories to escape from the domain of attraction of one steady-state and be attracted to another, so the system eventually reaches a multimodal probability distribution in which all stable steady-states are represented proportional to their relative stability. However, since the escape time scales exponentially with system size, this process can take a very long time in large systems.
PMID: 25632368 [PubMed - as supplied by publisher]
A time-indexed reference standard of adverse drug reactions.
Sci Data. 2014 Nov 11;1:140043
Authors: Harpaz R, Odgers D, Gaskin G, DuMouchel W, Winnenburg R, Bodenreider O, Ripple A, Szarfman A, Sorbello A, Horvitz E, White RW, Shah NH
Undetected adverse drug reactions (ADRs) pose a major burden on the health system. Data mining methodologies designed to identify signals of novel ADRs are of deep importance for drug safety surveillance. The development and evaluation of these methodologies requires proper reference benchmarks. While progress has recently been made in developing such benchmarks, our understanding of the performance characteristics of the data mining methodologies is limited because existing benchmarks do not support prospective performance evaluations. We address this shortcoming by providing a reference standard to support prospective performance evaluations. The reference standard was systematically curated from drug labeling revisions, such as new warnings, which were issued and communicated by the US Food and Drug Administration in 2013. The reference standard includes 62 positive test cases and 75 negative controls, and covers 44 drugs and 38 events. We provide usage guidance and empirical support for the reference standard by applying it to analyze two data sources commonly mined for drug safety surveillance.
PMID: 25632348 [PubMed - as supplied by publisher]
Function through bio-inspired, synthesis-informed design: step-economical syntheses of designed kinase inhibitors†Dedicated to Max Malacria, a friend and scholar whose science and creative contributions to step-economical synthesis have inspired us all and moved the field closer to the ideal.‡Electronic supplementary information (ESI) available: Synthetic procedures and spectral data. See DOI: 10.1039/c4qo00228hClick here for additional data file.
Org Chem Front. 2014 Dec 29;1(10):1166-1171
Authors: Wender PA, Axtman AD, Golden JE, Kee JM, Sirois LE, Quiroz RV, Stevens MC
The human kinome comprises over 500 protein kinases. When mutated or over-expressed, many play critical roles in abnormal cellular functions associated with cancer, cardiovascular disease and neurological disorders. Here we report a step-economical approach to designed kinase inhibitors inspired by the potent, but non-selective, natural product staurosporine, and synthetically enabled by a novel, complexity-increasing, serialized [5 + 2]/[4 + 2] cycloaddition strategy. This function-oriented synthesis approach rapidly affords tunable scaffolds, and produced a low nanomolar inhibitor of protein kinase C.
PMID: 25632347 [PubMed - as supplied by publisher]
A Modified Retromaxillary Approach to the Infratemporal Fossa: Three Case Studies.
J Oral Maxillofac Surg. 2014 Oct 31;
Authors: Woodford R, Chaudhary N, Wolf A, Lownie S, Armstrong JE
The infratemporal fossa (ITF) is an anatomically complex region with multiple neural and vascular structures entering and exiting through foramina in the skull base. The main obstacles to approaching the ITF are the zygomatic arch, the parotid gland, the facial nerve, and the ascending ramus AND condylar head of the mandible. Different surgical approaches to the ITF exist and the best approach should provide optimal visibility, minimal impairment of temporomandibular joint function, and preservation of motor and sensory nerve integrity. This report describes a modified Obwegeser retromaxillary approach to access lesions within the ITF. A multidisciplinary team was involved, which included an oral and maxillofacial surgery team, a neurosurgery team, and an otolaryngology team. Three patients with large skull base lesions, including an aneurysmal bone cyst, a giant cell tumor of the bone, and an invasive melanoma, underwent resection using this approach and were followed postoperatively. Excellent exposure of the floor of the middle cranial fossa and ITF was achieved with this approach. Functional status remained unchanged with respect to mastication, speech, swallowing, and cosmesis. Given the severity of the patients' conditions and extent of involvement of the skull base, outcomes were favorable, with minimal morbidity. This experience suggests that this approach provides safe access to an anatomically complex region and lessens challenges associated with more conventional approaches.
PMID: 25631866 [PubMed - as supplied by publisher]
Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.
Gut. 2015 Jan 28;
Authors: Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, Moreau R, Jalan R, Sarin SK, Piano S, Moore K, Lee SS, Durand F, Salerno F, Caraceni P, Kim WR, Arroyo V, Garcia-Tsao G
PMID: 25631669 [PubMed - as supplied by publisher]
In vitro antifungal susceptibility of coelomycete agents of black grain eumycetoma to eight antifungals.
Med Mycol. 2015 Jan 28;
Authors: Ahmed SA, de Hoog GS, Stevens DA, Fahal AH, van de Sande WW
Fungal mycetoma (eumycetoma) represents one of the most difficult infections to appropriately manage. The current recommended treatment is based on extensive surgical debridement combined with prolonged antifungal therapy with ketoconazole or itraconazole. Despite the different phylogenetic positions of black-grain eumycetoma species, they are all treated with the same antifungal agents. The in vitro antifungal susceptibility of coelomycetous eumycetoma agents in the order of Pleosporales presently is largely unknown. Here we determined the in vitro activity of eight antifungal agents against seven species causing human eumycetoma using the Sensititre YeastOne method. High minimum inhibitory concentrations (MICs) were found with fluconazole, caspofungin, flucytosine, and amphotericin B. Voriconazole and posaconazole were found to be active against all species tested. Of the species included in the investigation, MICs of Medicopsis romeroi differed from the rest of the mycetoma causative agents belonging to the order of the Pleosporales. We found significantly lower MICs for amphotericin B and significantly higher MICs for fluconazole, ketoconazole, and itraconazole against this species. Our results emphasised that identification of black grain mycetoma agent is important as well as performing susceptibility testing before starting of antifungal treatment.
PMID: 25631481 [PubMed - as supplied by publisher]
Genomics: CRISPR engineering turns on genes.
Nature. 2015 Jan 29;517(7536):560-2
Authors: Cho SW, Chang HY
PMID: 25631441 [PubMed - in process]
(13)C NMR detects conformational change in the 100-kD membrane transporter ClC-ec1.
J Biomol NMR. 2015 Jan 29;
Authors: Abraham SJ, Cheng RC, Chew TA, Khantwal CM, Liu CW, Gong S, Nakamoto RK, Maduke M
CLC transporters catalyze the exchange of Cl(-) for H(+) across cellular membranes. To do so, they must couple Cl(-) and H(+) binding and unbinding to protein conformational change. However, the sole conformational changes distinguished crystallographically are small movements of a glutamate side chain that locally gates the ion-transport pathways. Therefore, our understanding of whether and how global protein dynamics contribute to the exchange mechanism has been severely limited. To overcome the limitations of crystallography, we used solution-state (13)C-methyl NMR with labels on methionine, lysine, and engineered cysteine residues to investigate substrate (H(+)) dependent conformational change outside the restraints of crystallization. We show that methyl labels in several regions report H(+)-dependent spectral changes. We identify one of these regions as Helix R, a helix that extends from the center of the protein, where it forms the part of the inner gate to the Cl(-)-permeation pathway, to the extracellular solution. The H(+)-dependent spectral change does not occur when a label is positioned just beyond Helix R, on the unstructured C-terminus of the protein. Together, the results suggest that H(+) binding is mechanistically coupled to closing of the intracellular access-pathway for Cl(-).
PMID: 25631353 [PubMed - as supplied by publisher]
The ER membrane J protein C18 executes a distinct role in promoting SV40 membrane penetration.
J Virol. 2015 Jan 28;
Authors: Bagchi P, Walczak CP, Tsai B
The non-enveloped SV40 hijacks the three endoplasmic reticulum (ER) membrane-bound J proteins B12, B14, and C18 to escape from the ER into the cytosol en route for successful infection. How C18 controls SV40 ER-to-cytosol membrane penetration is the least understood. We previously found that SV40 triggers B12 and B14 to reorganize into discrete puncta in the ER membrane called foci, a structure postulated to represent the cytosol entry site. We now find that SV40 also recruits C18 to the virus-induced B12/B14 foci. Importantly, the C18 foci harbor membrane penetration-competent SV40, further implicating this structure as the membrane penetration site. Consistent with this, a mutant SV40 that cannot penetrate the ER membrane and promote infection fails to induce C18 foci. C18 also regulates the recruitment of B12/B14 into the foci. By contrast to B14, C18's cytosolic Hsc70-binding J- but not lumenal domain is essential for its targeting to the foci; this J-domain is likewise necessary to support SV40 infection. Knockdown-rescue experiments reveal that C18 executes a nonredundant role from B12/B14 during SV40 infection. Collectively, our data illuminate C18's contribution to SV40 ER membrane penetration, strengthening the idea that SV40-triggered foci is critical for cytosol entry.
IMPORTANCE: Polyomaviruses (PyVs) cause devastating human diseases, particularly in immunocompromised patients. As this virus family continues to be a significant human pathogen, clarifying the molecular basis of their cellular entry pathway remains a high priority. To infect cells, PyV traffics from the cell surface to the ER where it penetrates the ER membrane to reach the cytosol. In the cytosol, the virus moves to the nucleus to cause infection. ER-to-cytosol membrane penetration is a critical yet mysterious infection step. In this study, we clarify the role of an ER membrane protein called C18 in mobilizing the simian PyV SV40, a PyV archetype, from the ER into the cytosol. Our findings also support the hypothesis that SV40 induces the formation of a punctate structure in the ER membrane called foci that serve as the portal for cytosol entry of the virus.
PMID: 25631089 [PubMed - as supplied by publisher]
A recurrent regulatory change underlying altered expression and Wnt response of the stickleback armor plates gene EDA.
Elife. 2015 Jan 28;4
Authors: O'Brown NM, Summers BR, Jones FC, Brady SD, Kingsley DM
Armor plate changes in sticklebacks are a classic example of repeated adaptive evolution. Previous studies identified ectodysplasin (EDA) gene as the major locus controlling recurrent plate loss in freshwater fish, though the causative DNA alterations were not known. Here we show that freshwater EDA alleles have cis-acting regulatory changes that reduce expression in developing plates and spines. An identical T->G base pair change is found in EDA enhancers of divergent low-plated fish. Recreation of the T->G change in a marine enhancer strongly reduces expression in posterior armor plates. Bead implantation and cell culture experiments show that Wnt signaling strongly activates the marine EDA enhancer, and the freshwater T->G change reduces Wnt responsiveness. Thus parallel evolution of low-plated sticklebacks has occurred through a shared DNA regulatory change, which reduces the sensitivity of an EDA enhancer to Wnt signaling, and alters expression in developing armor plates while preserving expression in other tissues.
PMID: 25629660 [PubMed - as supplied by publisher]
Am J Nurs. 2015 Feb;115(2):48
Authors: Stanford E
PMID: 25629192 [PubMed - in process]
Multi-cellular interactions sustain long-term contractility of human pluripotent stem cell-derived cardiomyocytes.
Am J Transl Res. 2014;6(6):724-35
Authors: Burridge PW, Metzler SA, Nakayama KH, Abilez OJ, Simmons CS, Bruce MA, Matsuura Y, Kim P, Wu JC, Butte M, Huang NF, Yang PC
Therapeutic delivery of cardiomyocytes derived from human pluripotent stem cells (hPSC-CMs) represents a novel clinical approach to regenerate the injured myocardium. However, poor survival and contractility of these cells are a significant bottleneck to their clinical use. To better understand the role of cell-cell communication in enhancing the phenotype and contractile properties of hPSC-CMs, we developed a three-dimensional (3D) hydrogel composed of hPSC-CMs, human pluripotent stem cell-derived endothelial cells (hPSC-ECs), and/or human amniotic mesenchymal stem cells (hAMSCs). The objective of this study was to examine the role of multi-cellular interactions among hPSC-ECs and hAMSCs on the survival and long-term contractile phenotype of hPSC-CMs in a 3D hydrogel. Quantification of spontaneous contractility of hPSC-CMs in tri-culture demonstrated a 6-fold increase in the area of contractile motion after 6 weeks with characteristic rhythmic contraction frequency, when compared to hPSC-CMs alone (P < 0.05). This finding was supported by a statistically significant increase in cardiac troponin T protein expression in the tri-culture hydrogel construct at 6 weeks, when compared to hPSC-CMs alone (P < 0.001). The sustained hPSC-CM survival and contractility in tri-culture was associated with a significant upregulation in the gene expression of L-type Ca(2+) ion channel, Cav1.2, and the inward-rectifier potassium channel, Kir2.1 (P < 0.05), suggesting a role of ion channels in mediating these processes. These findings demonstrate that multi-cellular interactions modulate hPSC-CM phenotype, function, and survival, and they will have important implications in engineering cardiac tissues for treatment of cardiovascular diseases.
PMID: 25628783 [PubMed]
Cancer Cell Gene Expression Modulated from Plasma Membrane Integrin αvβ3 by Thyroid Hormone and Nanoparticulate Tetrac.
Front Endocrinol (Lausanne). 2014;5:240
Authors: Davis PJ, Glinsky GV, Lin HY, Leith JT, Hercbergs A, Tang HY, Ashur-Fabian O, Incerpi S, Mousa SA
Integrin αvβ3 is generously expressed by cancer cells and rapidly dividing endothelial cells. The principal ligands of the integrin are extracellular matrix proteins, but we have described a cell surface small molecule receptor on αvβ3 that specifically binds thyroid hormone and thyroid hormone analogs. From this receptor, thyroid hormone (l-thyroxine, T4; 3,5,3'-triiodo-l-thyronine, T3) and tetraiodothyroacetic acid (tetrac) regulate expression of specific genes by a mechanism that is initiated non-genomically. At the integrin, T4 and T3 at physiological concentrations are pro-angiogenic by multiple mechanisms that include gene expression, and T4 supports tumor cell proliferation. Tetrac blocks the transcriptional activities directed by T4 and T3 at αvβ3, but, independently of T4 and T3, tetrac modulates transcription of cancer cell genes that are important to cell survival pathways, control of the cell cycle, angiogenesis, apoptosis, cell export of chemotherapeutic agents, and repair of double-strand DNA breaks. We have covalently bound tetrac to a 200 nm biodegradable nanoparticle that prohibits cell entry of tetrac and limits its action to the hormone receptor on the extracellular domain of plasma membrane αvβ3. This reformulation has greater potency than unmodified tetrac at the integrin and affects a broader range of cancer-relevant genes. In addition to these actions on intra-cellular kinase-mediated regulation of gene expression, hormone analogs at αvβ3 have additional effects on intra-cellular protein-trafficking (cytosol compartment to nucleus), nucleoprotein phosphorylation, and generation of nuclear coactivator complexes that are relevant to traditional genomic actions of T3. Thus, previously unrecognized cell surface-initiated actions of thyroid hormone and tetrac formulations at αvβ3 offer opportunities to regulate angiogenesis and multiple aspects of cancer cell behavior.
PMID: 25628605 [PubMed]
Transient global amnesia associated with a unilateral infarction of the fornix: case report and review of the literature.
Front Neurol. 2014;5:291
Authors: Gupta M, Kantor MA, Tung CE, Zhang N, Albers GW
Stroke is an extremely uncommon cause of transient global amnesia (TGA). Unilateral lesions of the fornix rarely cause amnesia and have not previously been reported to be associated with the distinctive amnesic picture of TGA. We describe the case of a 60-year-old woman who presented with acute onset, recent retrograde, and anterograde amnesia characteristic of TGA. Serial magnetic resonance imaging showed a persistent focal infarction of the body and left column of the fornix, without acute lesions in the hippocampus or other structures. Amnesia resolved in 6 h. Infarction of the fornix should thus be included in the differential diagnosis of TGA, as it changes the management of this otherwise self-limited syndrome.
PMID: 25628601 [PubMed]
Diagnostic Yield of Extended Cardiac Patch Monitoring in Patients with Stroke or TIA.
Front Neurol. 2014;5:266
Authors: Tung CE, Su D, Turakhia MP, Lansberg MG
BACKGROUND: It is important to evaluate patients with transient ischemic attack (TIA) or stroke for atrial fibrillation (AF) because the detection of AF changes the recommended anti-thrombotic regimen from treatment with an antiplatelet agent to oral anticoagulation. This study describes the diagnostic yield of a patch-based, single-use, and water-resistant 14-day continuous cardiac rhythm monitor (ZIO Patch) in patients with stroke or TIA.
METHODS: We obtained data from the manufacturer and servicer of the ZIO Patch (iRhythm Technologies). Patients who were monitored between January 2012 and June 2013 and whose indication for monitoring was TIA or stroke were included. The duration of monitoring, the number and type of arrhythmias, and the time to first arrhythmia were documented.
RESULTS: One thousand one hundred seventy-one monitoring reports were analyzed. The mean monitor wear time was 10.9 days and the median wear time was 13.0 days (interquartile range 7.2-14.0). The median analyzable time relative to the total wear time was 98.7% (IQR 96.0-99.5%). AF was present in 5.0% of all reports. The mean duration before the first episode of paroxysmal AF (PAF) was 1.5 days and the median duration was 0.4 days. 14.3% of first PAF episodes occurred after 48 h. The mean PAF burden was 12.7% of the total monitoring duration.
CONCLUSION: Excellent quality of the recordings and very good patient compliance coupled with a substantial proportion of AF detection beyond the first 48 h of monitoring suggest that the cardiac patch is superior to conventional 48-h Holter monitors for AF detection in patients with stroke or TIA.
PMID: 25628595 [PubMed]
The brain, amphotericin B, and p-glycoprotein.
Antimicrob Agents Chemother. 2015 Feb;59(2):1386
Authors: Stevens DA, Clemons KV, Martinez M, Chen V
PMID: 25628395 [PubMed - in process]
Multiscale Analyses of the Bone-implant Interface.
J Dent Res. 2015 Jan 27;
Authors: Cha JY, Pereira MD, Smith AA, Houschyar KS, Yin X, Mouraret S, Brunski JB, Helms JA
Implants placed with high insertion torque (IT) typically exhibit primary stability, which enables early loading. Whether high IT has a negative impact on peri-implant bone health, however, remains to be determined. The purpose of this study was to ascertain how peri-implant bone responds to strains and stresses created when implants are placed with low and high IT. Titanium micro-implants were inserted into murine femurs with low and high IT using torque values that were scaled to approximate those used to place clinically sized implants. Torque created in peri-implant tissues a distribution and magnitude of strains, which were calculated through finite element modeling. Stiffness tests quantified primary and secondary implant stability. At multiple time points, molecular, cellular, and histomorphometric analyses were performed to quantitatively determine the effect of high and low strains on apoptosis, mineralization, resorption, and collagen matrix deposition in peri-implant bone. Preparation of an osteotomy results in a narrow zone of dead and dying osteocytes in peri-implant bone that is not significantly enlarged in response to implants placed with low IT. Placing implants with high IT more than doubles this zone of dead and dying osteocytes. As a result, peri-implant bone develops micro-fractures, bone resorption is increased, and bone formation is decreased. Using high IT to place an implant creates high interfacial stress and strain that are associated with damage to peri-implant bone and therefore should be avoided to best preserve the viability of this tissue.
PMID: 25628271 [PubMed - as supplied by publisher]
Novel codon-optimized mini-intronic plasmid for efficient, inexpensive, and xeno-free induction of pluripotency.
Sci Rep. 2015;5:8081
Authors: Diecke S, Lu J, Lee J, Termglinchan V, Kooreman NG, Burridge PW, Ebert AD, Churko JM, Sharma A, Kay MA, Wu JC
The development of human induced pluripotent stem cell (iPSC) technology has revolutionized the regenerative medicine field. This technology provides a powerful tool for disease modeling and drug screening approaches. To circumvent the risk of random integration into the host genome caused by retroviruses, non-integrating reprogramming methods have been developed. However, these techniques are relatively inefficient or expensive. The mini-intronic plasmid (MIP) is an alternative, robust transgene expression vector for reprogramming. Here we developed a single plasmid reprogramming system which carries codon-optimized (Co) sequences of the canonical reprogramming factors (Oct4, Klf4, Sox2, and c-Myc) and short hairpin RNA against p53 ("4-in-1 CoMiP"). We have derived human and mouse iPSC lines from fibroblasts by performing a single transfection. Either independently or together with an additional vector encoding for LIN28, NANOG, and GFP, we were also able to reprogram blood-derived peripheral blood mononuclear cells (PBMCs) into iPSCs. Taken together, the CoMiP system offers a new highly efficient, integration-free, easy to use, and inexpensive methodology for reprogramming. Furthermore, the CoMIP construct is color-labeled, free of any antibiotic selection cassettes, and independent of the requirement for expression of the Epstein-Barr Virus nuclear antigen (EBNA), making it particularly beneficial for future applications in regenerative medicine.
PMID: 25628230 [PubMed - in process]
Long-range ion-water and ion-ion interactions in aqueous solutions.
Phys Chem Chem Phys. 2015 Jan 28;
Authors: Chen C, Huang C, Waluyo I, Weiss T, Pettersson LG, Nilsson A
Using small-angle X-ray scattering (SAXS), we obtained direct experimental evidence on the structure of hydrated polyatomic anions, with hydration effects starkly different from those of cations (J. Chem. Phys., 2011, 134, 064513). We propose that the size and charge density of the naked ions do not sufficiently account for the differences in the SAXS curves. For cations, the ion-ion contribution gives a prominent first-order diffraction peak, whereas for anions, the low-Q enhancement in the SAXS curves indicates density inhomogeneities as a result of ion-water interactions.
PMID: 25628145 [PubMed - as supplied by publisher]
More hippocrates, less hypocrisy: eliminate sugar-sweetened beverages from residency lunches.
Acad Med. 2015 Feb;90(2):127-8
Authors: Nagata JM, Chamberlain LJ, Robinson TN
PMID: 25628132 [PubMed - in process]
Menopausal symptoms in women with chronic kidney disease.
Menopause. 2015 Jan 26;
Authors: Cheung KL, Stefanick ML, Allison MA, LeBlanc ES, Vitolins MZ, Shara N, Chertow GM, Winkelmayer WC, Tamura MK
OBJECTIVE: This study aims to determine whether menopausal symptoms differed between women with chronic kidney disease (CKD) and women without CKD, and whether CKD modified associations of late vasomotor symptoms (VMS) with mortality and/or cardiovascular events.
METHODS: CKD, defined as estimated glomerular filtration rate lower than 60 mL/minute/1.73 m (using the Chronic Kidney Disease Epidemiology Collaboration equation), was determined in 17,891 postmenopausal women, aged 50 to 79 years at baseline, in the multiethnic Women's Health Initiative cohort. Primary outcomes were presence, severity, and timing/duration of VMS (self-reported hot flashes and night sweats) at baseline. We used polytomous logistic regression to test for associations among CKD and four VMS categories (no VMS; early VMS-present before menopause but not at study baseline; late VMS-'present only at study baseline; persistent VMS-'present before menopause and study baseline) and Cox regression to determine whether CKD modified associations between late VMS and mortality or cardiovascular events.
RESULTS: Women with CKD (1,017 of 17,891; mean estimated glomerular filtration rate, 50.7 mL/min/1.73 m) were more likely to have had menopause before age 45 years (26% vs 23%, P = 0.02) but were less likely to experience VMS (38% vs 46%, P < 0.001) than women without CKD. Women with CKD were not more likely than women without CKD to experience late VMS. Late VMS (hazard ratio, 1.16; 95% CI, 1.04-1.29) and CKD (hazard ratio, 1.74; 95% CI, 1.54-1.97) were each independently associated with increased risk for mortality, but CKD did not modify the association of late VMS with mortality (Pinteraction = 0.53), coronary heart disease (Pinteraction = 0.12), or stroke (Pinteraction = 0.68).
CONCLUSIONS: Women with mild CKD experience earlier menopause and fewer VMS than women without CKD.
PMID: 25628057 [PubMed - as supplied by publisher]
Dewetting and deposition of thin films with insoluble surfactants from curved silicone hydrogel substrates.
J Colloid Interface Sci. 2015 Jan 14;
Authors: Bhamla MS, Balemans C, Fuller GG
We investigate the stabilizing effect of insoluble surfactant monolayers on thin aqueous films. We first describe an experimental platform that enables the formation of aqueous films laden with dipalmitoylphosphatidylcholine (DPPC) monolayers on curved silicone hydrogel (SiHy) substrates. We show that these surfactant layers extend the lifetime of the aqueous films. The films eventually "dewet" by the nucleation and growth of dry areas and the onset of this dewetting can be controlled by the surface rheology of the DPPC layer. We thus demonstrate that increasing the interfacial rheology of the DPPC layer leads to stable films that delay dewetting. We also show that dewetting can be exploited to controllably pattern the underlying curved SiHy substrates with DPPC layers.
PMID: 25628055 [PubMed - as supplied by publisher]
Using iPSCs and genomics to catch CNVs in the act.
Nat Genet. 2015 Jan 28;47(2):100-1
Authors: Urban AE, Purmann C
Large copy number variants (CNVs) are strongly associated with morphogenetic processes and common neurodevelopmental disorders. A new study uses the example of Williams-Beuren syndrome (WBS) and Williams-Beuren region duplication syndrome to illustrate how induced pluripotent stem cells (iPSCs) and next-generation genomics can lead to a better understanding of complex genetics.
PMID: 25627897 [PubMed - in process]
Impact of surgical innovation on tissue repair in the surgical patient.
Br J Surg. 2015 Jan;102(2):e41-55
Authors: Tevlin R, Atashroo D, Duscher D, Mc Ardle A, Gurtner GC, Wan DC, Longaker MT
BACKGROUND: Throughout history, surgeons have been prolific innovators, which is hardly surprising as most surgeons innovate daily, tailoring their intervention to the intrinsic uniqueness of each operation, each patient and each disease. Innovation can be defined as the application of better solutions that meet new requirements, unarticulated needs or existing market needs. In the past two decades, surgical innovation has significantly improved patient outcomes, complication rates and length of hospital stay. There is one key area that has great potential to change the face of surgical practice and which is still in its infancy: the realm of regenerative medicine and tissue engineering.
METHODS: A literature review was performed using PubMed; peer-reviewed publications were screened for relevance in order to identify key surgical innovations influencing regenerative medicine, with a focus on osseous, cutaneous and soft tissue reconstruction.
RESULTS: This review describes recent advances in regenerative medicine, documenting key innovations in osseous, cutaneous and soft tissue regeneration that have brought regenerative medicine to the forefront of the surgical imagination.
CONCLUSION: Surgical innovation in the emerging field of regenerative medicine has the ability to make a major impact on surgery on a daily basis.
PMID: 25627135 [PubMed - in process]
Reply: Studies in Fat Grafting: Part I. Effects of Injection Technique on In Vitro Fat Viability and In Vivo Volume Retention; and Studies in Fat Grafting: Part II. Effects of Injection Mechanics on Material Properties of Fat.
Plast Reconstr Surg. 2015 Feb;135(2):448e-9e
Authors: Wan DC, Gurtner GC, Longaker MT
PMID: 25626833 [PubMed - in process]
Exercise induces stromal cell-derived factor-1α-mediated release of endothelial progenitor cells with increased vasculogenic function.
Plast Reconstr Surg. 2015 Feb;135(2):340e-50e
Authors: Chang E, Paterno J, Duscher D, Maan ZN, Chen JS, Januszyk M, Rodrigues M, Rennert RC, Bishop S, Whitmore AJ, Whittam AJ, Longaker MT, Gurtner GC
BACKGROUND: Endothelial progenitor cells have been shown to traffic to and incorporate into ischemic tissues, where they participate in new blood vessel formation, a process termed vasculogenesis. Previous investigation has demonstrated that endothelial progenitor cells appear to mobilize from bone marrow to the peripheral circulation after exercise. In this study, the authors investigate potential etiologic factors driving this mobilization and investigate whether the mobilized endothelial progenitor cells are the same as those present at baseline.
METHODS: Healthy volunteers (n = 5) performed a monitored 30-minute run to maintain a heart rate greater than 140 beats/min. Venous blood samples were collected before, 10 minutes after, and 24 hours after exercise. Endothelial progenitor cells were isolated and evaluated.
RESULTS: Plasma levels of stromal cell-derived factor-1α significantly increased nearly two-fold immediately after exercise, with a nearly four-fold increase in circulating endothelial progenitor cells 24 hours later. The endothelial progenitor cells isolated following exercise demonstrated increased colony formation, proliferation, differentiation, and secretion of angiogenic cytokines. Postexercise endothelial progenitor cells also exhibited a more robust response to hypoxic stimulation.
CONCLUSIONS: Exercise appears to mobilize endothelial progenitor cells and augment their function by means of stromal cell-derived factor 1α-dependent signaling. The population of endothelial progenitor cells mobilized following exercise is primed for vasculogenesis with increased capacity for proliferation, differentiation, secretion of cytokines, and responsiveness to hypoxia. Given the evidence demonstrating positive regenerative effects of exercise, this may be one possible mechanism for its benefits.
PMID: 25626819 [PubMed - in process]
Microchip ELISA Coupled with Cell Phone to Detect Ovarian Cancer HE4 Biomarker in Urine.
Methods Mol Biol. 2015;1256:111-21
Authors: Wang S, Akbas R, Demirci U
Ovarian cancer is a leading cause of death from gynecologic cancers in the USA, and early diagnosis can potentially increase 5-year survival rate. Detection of biomarkers derived from hyperplasia of epithelial tissue by enzyme-linked immunosorbent assay (ELISA) proves to be a practical way of early diagnosis of ovarian cancer. However, ELISA is commonly performed in a laboratory setting, and it cannot be used in a clinical setting for on-site consultation. We have shown a microchip ELISA that detects HE4, an ovarian cancer biomarker, from urine using a cell phone integrated with a mobile application for imaging and data analysis. In microchip ELISA, HE4 from urine was first absorbed on the surface; the primary and secondary antibodies were subsequently anchored on the surface via immuno-reaction; and addition of substrate led to color development because of enzymatic labeling. The microchip after color development was imaged using a cell phone, and the color intensity was analyzed by an integrated mobile application. By comparing with an ELISA standard curve, the concentration of HE4 was reported on the cell phone screen. The presented microchip ELISA coupled with a cell phone is portable as opposed to traditional ELISA, and this method can facilitate the detection of ovarian cancer at the point-of-care (POC).
PMID: 25626535 [PubMed - in process]
OPTN/SRTR 2013 Annual Data Report: Liver.
Am J Transplant. 2015 Jan;15 Suppl 2:1-28
Authors: Kim WR, Lake JR, Smith JM, Skeans MA, Schladt DP, Edwards EB, Harper AM, Wainright JL, Snyder JJ, Israni AK, Kasiske BL
During 2013, 10,479 adult candidates were added to the liver transplant waiting list, compared with 10,185 in 2012; 5921 liver transplants were performed, and 211 of the transplanted organs were from living donors. As of December 31, 2013, 15,027 candidates were registered on the waiting list, including 12,407 in active status. The most significant change in allocation policy affecting liver waitlist trends in 2013 was the Share 35 policy, whereby organs from an entire region are available to candidates with model for end-stage liver disease scores of 35 or higher. Median waiting time for such candidates decreased dramatically, from 14.0 months in 2012 to 1.4 months in 2013, but the effect on waitlist mortality is unknown. The number of new active pediatric candidates added to the liver transplant waiting list increased to 693 in 2013. Transplant rates were highest for candidates aged younger than 1 year (275.6 per 100 waitlist years) and lowest for candidates aged 11 to 17 years (97.0 per 100 waitlist years). Five-year graft survival was 71.7% for recipients aged younger than 1 year, 74.9% for ages 1 to 5 years, 78.9% ages 6 to 10 years, and 77.4% for ages 11 to 17 years.
PMID: 25626341 [PubMed - in process]
Causes and timing of death in extremely premature infants from 2000 through 2011.
N Engl J Med. 2015 Jan 22;372(4):331-40
Authors: Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, Sánchez PJ, Shankaran S, Van Meurs KP, Ball MB, Hale EC, Newman NS, Das A, Higgins RD, Stoll BJ, Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network
BACKGROUND: Understanding the causes and timing of death in extremely premature infants may guide research efforts and inform the counseling of families.
METHODS: We analyzed prospectively collected data on 6075 deaths among 22,248 live births, with gestational ages of 22 0/7 to 28 6/7 weeks, among infants born in study hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. We compared overall and cause-specific in-hospital mortality across three periods from 2000 through 2011, with adjustment for baseline differences.
RESULTS: The number of deaths per 1000 live births was 275 (95% confidence interval [CI], 264 to 285) from 2000 through 2003 and 285 (95% CI, 275 to 295) from 2004 through 2007; the number decreased to 258 (95% CI, 248 to 268) in the 2008-2011 period (P=0.003 for the comparison across three periods). There were fewer pulmonary-related deaths attributed to the respiratory distress syndrome and bronchopulmonary dysplasia in 2008-2011 than in 2000-2003 and 2004-2007 (68 [95% CI, 63 to 74] vs. 83 [95% CI, 77 to 90] and 84 [95% CI, 78 to 90] per 1000 live births, respectively; P=0.002). Similarly, in 2008-2011, as compared with 2000-2003, there were decreases in deaths attributed to immaturity (P=0.05) and deaths complicated by infection (P=0.04) or central nervous system injury (P<0.001); however, there were increases in deaths attributed to necrotizing enterocolitis (30 [95% CI, 27 to 34] vs. 23 [95% CI, 20 to 27], P=0.03). Overall, 40.4% of deaths occurred within 12 hours after birth, and 17.3% occurred after 28 days.
CONCLUSIONS: We found that from 2000 through 2011, overall mortality declined among extremely premature infants. Deaths related to pulmonary causes, immaturity, infection, and central nervous system injury decreased, while necrotizing enterocolitis-related deaths increased. (Funded by the National Institutes of Health.).
PMID: 25607427 [PubMed - indexed for MEDLINE]
Posttraumatic stress disorder and risk of spontaneous preterm birth.
Obstet Gynecol. 2014 Dec;124(6):1111-9
Authors: Shaw JG, Asch SM, Kimerling R, Frayne SM, Shaw KA, Phibbs CS
OBJECTIVE: To evaluate the association between antenatal posttraumatic stress disorder (PTSD) and spontaneous preterm delivery.
METHODS: We identified antenatal PTSD status and spontaneous preterm delivery in a retrospective cohort of 16,334 deliveries covered by the Veterans Health Administration from 2000 to 2012. We divided mothers with PTSD into those with diagnoses present the year before delivery (active PTSD) and those only with earlier diagnoses (historical PTSD). We identified spontaneous preterm birth and potential confounders including age, race, military deployment, twins, hypertension, substance use, depression, and results of military sexual trauma screening and then performed multivariate regression to estimate adjusted odds ratio (OR) of spontaneous preterm delivery as a function of PTSD status.
RESULTS: Of 16,334 births, 3,049 (19%) were to mothers with PTSD diagnoses, of whom 1,921 (12%) had active PTSD. Spontaneous preterm delivery was higher in those with active PTSD (9.2%, n=176) than those with historical (8.0%, n=90) or no PTSD (7.4%, n=982) before adjustment (P=.02). The association between PTSD and preterm birth persisted, when adjusting for covariates, only in those with active PTSD (adjusted OR 1.35, 95% confidence interval [CI] 1.14-1.61). Analyses adjusting for comorbid psychiatric and medical diagnoses revealed the association with active PTSD to be robust.
CONCLUSION: In this cohort, containing an unprecedented number of PTSD-affected pregnancies, mothers with active PTSD were significantly more likely to suffer spontaneous preterm birth with an attributable two excess preterm births per 100 deliveries (95% CI 1-4). Posttraumatic stress disorder's health effects may extend, through birth outcomes, into the next generation.
PMID: 25415162 [PubMed - indexed for MEDLINE]
Pregnancy outcomes in the super obese, stratified by weight gain above and below institute of medicine guidelines.
Obstet Gynecol. 2014 Dec;124(6):1105-10
Authors: Swank ML, Marshall NE, Caughey AB, Main EK, Gilbert WM, Melsop KA, Chung JH
OBJECTIVE: To examine the association of antenatal weight gain above and below the 2009 Institute of Medicine (IOM) guidelines in the super-obese population (body mass index [BMI] of 50 or higher) on the maternal and neonatal morbidities of gestational hypertension or preeclampsia (pregnancy-induced hypertension), gestational diabetes mellitus, cesarean delivery, birth weight more than 4,000 g and more than 4,500 g, low birth weight, and preterm birth.
METHODS: The effect of gestational weight gain was assessed in this retrospective cohort study using California birth certificate and patient discharge diagnosis data. Unconditional logistic regression was used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) as a function of antenatal weight gain. Weight gain within 2009 IOM guidelines (11-20 pounds) served as the reference group.
RESULTS: The study population consisted of 1,034 women. Women gaining below, within, and above IOM guidelines accounted for 38.3, 23.5, and 38.2%, respectively. Weight gain below IOM guidelines was not associated with a statistically increased odds of preterm birth (OR 1.82, 95% CI 0.60-5.59) or low birth weight (OR 1.20, 95% CI 0.57-2.49); however, birth weight more than 4,000 g was significantly reduced (OR 0.50, 95% CI 0.32-0.77). Excessive weight gain statistically increased the odds of pregnancy-induced hypertension (OR 1.96, 95% CI 1.26-3.03) and cesarean delivery (OR 1.40, 95% CI 1.00-1.97) while not appearing to protect against the delivery of low-birth-weight neonates (OR 0.84, 95% CI 0.40-1.78).
CONCLUSION: Weight gain below the current guidelines in the super-obese cohort is not associated with an increase in maternal or neonatal risk while decreasing the odds of delivering a macrosomic neonate. Women with BMIs of 50 or higher may warrant separate gestational weight gain recommendations.
PMID: 25415161 [PubMed - indexed for MEDLINE]
Commentary: Operational Definition of Epilepsy survey.
Epilepsia. 2014 Nov;55(11):1688
Authors: Fisher RS
PMID: 25382823 [PubMed - indexed for MEDLINE]
Inner retinal preservation in rat models of retinal degeneration implanted with subretinal photovoltaic arrays.
Exp Eye Res. 2014 Nov;128:34-42
Authors: Light JG, Fransen JW, Adekunle AN, Adkins A, Pangeni G, Loudin J, Mathieson K, Palanker DV, McCall MA, Pardue MT
Photovoltaic arrays (PVA) implanted into the subretinal space of patients with retinitis pigmentosa (RP) are designed to electrically stimulate the remaining inner retinal circuitry in response to incident light, thereby recreating a visual signal when photoreceptor function declines or is lost. Preservation of inner retinal circuitry is critical to the fidelity of this transmitted signal to ganglion cells and beyond to higher visual targets. Post-implantation loss of retinal interneurons or excessive glial scarring could diminish and/or eliminate PVA-evoked signal transmission. As such, assessing the morphology of the inner retina in RP animal models with subretinal PVAs is an important step in defining biocompatibility and predicting success of signal transmission. In this study, we used immunohistochemical methods to qualitatively and quantitatively compare inner retinal morphology after the implantation of a PVA in two RP models: the Royal College of Surgeons (RCS) or transgenic S334ter-line 3 (S334ter-3) rhodopsin mutant rat. Two PVA designs were compared. In the RCS rat, we implanted devices in the subretinal space at 4 weeks of age and histologically examined them at 8 weeks of age and found inner retinal morphology preservation with both PVA devices. In the S334ter-3 rat, we implanted devices at 6-12 weeks of age and again, inner retinal morphology was generally preserved with either PVA design 16-26 weeks post-implantation. Specifically, the length of rod bipolar cells and numbers of cholinergic amacrine cells were maintained along with their characteristic inner plexiform lamination patterns. Throughout the implanted retinas we found nonspecific glial reaction, but none showed additional glial scarring at the implant site. Our results indicate that subretinally implanted PVAs are well-tolerated in rodent RP models and that the inner retinal circuitry is preserved, consistent with our published results showing implant-evoked signal transmission.
PMID: 25224340 [PubMed - indexed for MEDLINE]
Cross-kingdom chemical communication drives a heritable, mutually beneficial prion-based transformation of metabolism.
Cell. 2014 Aug 28;158(5):1083-93
Authors: Jarosz DF, Brown JC, Walker GA, Datta MS, Ung WL, Lancaster AK, Rotem A, Chang A, Newby GA, Weitz DA, Bisson LF, Lindquist S
In experimental science, organisms are usually studied in isolation, but in the wild, they compete and cooperate in complex communities. We report a system for cross-kingdom communication by which bacteria heritably transform yeast metabolism. An ancient biological circuit blocks yeast from using other carbon sources in the presence of glucose. [GAR(+)], a protein-based epigenetic element, allows yeast to circumvent this "glucose repression" and use multiple carbon sources in the presence of glucose. Some bacteria secrete a chemical factor that induces [GAR(+)]. [GAR(+)] is advantageous to bacteria because yeast cells make less ethanol and is advantageous to yeast because their growth and long-term viability is improved in complex carbon sources. This cross-kingdom communication is broadly conserved, providing a compelling argument for its adaptive value. By heritably transforming growth and survival strategies in response to the selective pressures of life in a biological community, [GAR(+)] presents a unique example of Lamarckian inheritance.
PMID: 25171409 [PubMed - indexed for MEDLINE]
An evolutionarily conserved prion-like element converts wild fungi from metabolic specialists to generalists.
Cell. 2014 Aug 28;158(5):1072-82
Authors: Jarosz DF, Lancaster AK, Brown JC, Lindquist S
[GAR(+)] is a protein-based element of inheritance that allows yeast (Saccharomyces cerevisiae) to circumvent a hallmark of their biology: extreme metabolic specialization for glucose fermentation. When glucose is present, yeast will not use other carbon sources. [GAR(+)] allows cells to circumvent this "glucose repression." [GAR(+)] is induced in yeast by a factor secreted by bacteria inhabiting their environment. We report that de novo rates of [GAR(+)] appearance correlate with the yeast's ecological niche. Evolutionarily distant fungi possess similar epigenetic elements that are also induced by bacteria. As expected for a mechanism whose adaptive value originates from the selective pressures of life in biological communities, the ability of bacteria to induce [GAR(+)] and the ability of yeast to respond to bacterial signals have been extinguished repeatedly during the extended monoculture of domestication. Thus, [GAR(+)] is a broadly conserved adaptive strategy that links environmental and social cues to heritable changes in metabolism.
PMID: 25171408 [PubMed - indexed for MEDLINE]
Robust expansion of dendritic cells in vivo by hydrodynamic FLT3L-FC gene transfer.
J Immunol Methods. 2014 Nov;413:69-73
Authors: Tu H, Burke TM, Oderup C, Huang K, Wong K, Lewén S, LaJevic M, Zabel BA
Due to low numbers of endogenous dendritic cells (DCs) in vivo, exogenous DC-poietin Fms-like tyrosine kinase 3-ligand (FLT3L) is routinely used to generate DC for subsequent studies. We engineered a novel FLT3L-FC DNA construct that, when combined with hydrodynamic gene transfer (HDT), induced robust DC expansion in mice. DC generated in vivo by FLT3L-FC HDT produced cytokines in response to stimulation by an array of TLR agonists and promoted T cell proliferation. The FLT3L-FC protein produced in vivo spontaneously homodimerized to enable effective FLT signaling and the FC-domain enhanced its plasma half-life, providing an improved reagent and method to boost DC numbers.
PMID: 25066631 [PubMed - indexed for MEDLINE]
Oral 9-cis retinoid for childhood blindness due to Leber congenital amaurosis caused by RPE65 or LRAT mutations: an open-label phase 1b trial.
Lancet. 2014 Oct 25;384(9953):1513-20
Authors: Koenekoop RK, Sui R, Sallum J, van den Born LI, Ajlan R, Khan A, den Hollander AI, Cremers FP, Mendola JD, Bittner AK, Dagnelie G, Schuchard RA, Saperstein DA
BACKGROUND: Leber congenital amaurosis, caused by mutations in RPE65 and LRAT, is a severe form of inherited retinal degeneration leading to blindness. We aimed to assess replacement of the missing chromophore 11-cis retinal with oral QLT091001 (synthetic 9-cis-retinyl acetate) in these patients.
METHODS: In our open-label, prospective, phase 1b trial, we enrolled patients (aged ≥6 years) with Leber congenital amaurosis and RPE65 or LRAT mutations at McGill University's Montreal Children's Hospital. Patients received 7 days of oral QLT091001 (10-40 mg/m(2) per day). We assessed patients at baseline and days 7, 9, 14, and 30, and then 2 months and every 2 months thereafter for up to 2·2 years for safety outcomes and visual function endpoints including Goldmann visual fields (GVF), visual acuity, and functional MRI assessment. We regarded patients as having an improvement in vision if we noted at least a 20% improvement in retinal area on GVF compared with baseline or a visual acuity improvement of five or more letters compared with baseline in two consecutive study visits (or any improvement from no vision at baseline). This study is registered with ClinicalTrials.gov, number NCT01014052.
FINDINGS: Between December, 2009, and June, 2011, we enrolled and treated 14 patients aged 6-38 years who were followed up until March, 2012. Ten (71%) of 14 patients had an improvement in GVF areas (mean increase in retinal area of 28-683%). Six (43%) patients had an improvement in visual acuity (mean increase of 2-30 letters). Self-reported or parent-reported improvements in activities of daily living supported these findings. After 2 years, 11 (79%) patients had returned to their baseline GVF retinal area and ten (71%) had returned to baseline visual acuity letter values. Thus, three (21%) patients had a sustained GVF response and four (30%) had a sustained visual acuity response. Four patients had functional MRI scans, which correlated with visual response or absence of response to treatment. No serious adverse events occurred, although we noted transient headaches (11 patients), photophobia (11 patients), reduction in serum HDL concentrations (four patients), and increases in serum triglycerides (eight patients) and aspartate aminotransferase concentrations (two patients).
INTERPRETATION: Non-invasive oral QLT091001 therapy is well tolerated, and can rapidly improve visual function in some patients with Leber congenital amaurosis and RPE65 and LRAT mutations.
FUNDING: QLT, Foundation Fighting Blindness Canada, CIHR, FRSQ, Reseau Vision.
PMID: 25030840 [PubMed - indexed for MEDLINE]
Br J Anaesth. 2014 Dec;113(6):922-34
Authors: Nascimento B, Goodnough LT, Levy JH
Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.
PMID: 24972790 [PubMed - indexed for MEDLINE]
Five strategies to effectively use online resources in emergency medicine.
Ann Emerg Med. 2014 Oct;64(4):392-5
Authors: Thoma B, Joshi N, Trueger NS, Chan TM, Lin M
PMID: 24962889 [PubMed - indexed for MEDLINE]
Risk of selected structural abnormalities in infants after increased nuchal translucency measurement.
Am J Obstet Gynecol. 2014 Dec;211(6):675.e1-19
Authors: Baer RJ, Norton ME, Shaw GM, Flessel MC, Goldman S, Currier RJ, Jelliffe-Pawlowski LL
OBJECTIVE: We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants.
STUDY DESIGN: Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL).
RESULTS: When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4).
CONCLUSION: Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.
PMID: 24949541 [PubMed - indexed for MEDLINE]
Nanocones to study initial steps of endocytosis.
Methods Mol Biol. 2014;1174:275-84
Authors: Jeong S, Galic M
Vesicle endocytosis at the plasma membrane is associated with a precise temporal choreography in the recruitment of cytosolic proteins that sense, generate, or stabilize locally curved membrane regions. To dissect the role of membrane curvature sensing from other co-occurring events during the initial steps of endocytosis, we developed a method to artificially induce nanoscale deformations of the PM in living cells that is based on cone-shaped nanostructures (i.e., Nanocones). When cultured on Nanocones, cells create stable inward plasma membrane deformations to which curvature-sensing proteins are recruited. Here, we provide a detailed protocol how to use Nanocones to study recruitment during the initial steps of endocytosis in cells by fluorescence and electron microscopy.
PMID: 24947389 [PubMed - indexed for MEDLINE]
Anti-asialo GM1 NK cell depleting antibody does not alter the development of bleomycin induced pulmonary fibrosis.
PLoS One. 2014;9(6):e99350
Authors: Monnier J, Zabel BA
Despite circumstantial evidence postulating a protective role for NK cells in many fibrotic conditions, their contribution to the development of pulmonary fibrosis has yet to be tested. Lung-migrating NK cells are thought to attenuate the development of bleomycin induced pulmonary fibrosis (BIPF) by providing anti-fibrotic mediators and cytokines, such as IFN-γ. If true, we reasoned that depletion of NK cells during experimentally-induced fibrotic disease would lead to exacerbated fibrosis. To test this, we treated mice with NK cell-depleting antisera (anti-asialo GM1) and evaluated lung inflammation and fibrosis in the BIPF model. While NK cell infiltration into the airways was maximal at day 10 after bleomycin injection, NK cells represented a minor portion (1-3%) of the total leukocytes in BAL fluid. Anti-asialo GM1 significantly abrogated NK cell numbers over the course of the disease. Depletion of NK cells with anti-asialo GM1 before and throughout the BIPF model, or during just the fibrotic phase did not alter fibrosis development or affect the levels of any of the pro-inflammatory/pro-fibrotic cytokines measured (IL-1β, IL-17, IFN-γ, TGF-β and TNF-α). In addition, adoptively transferred NK cells, which were detectable systemically and in the airways throughout BIPF, failed to impact lung fibrosis. These findings indicate that NK cells likely do not play an essential protective role in controlling pulmonary fibrosis development.
PMID: 24922516 [PubMed - indexed for MEDLINE]
Age-dependent transcriptome and proteome following transection of neonatal spinal cord of Monodelphis domestica (South American grey short-tailed opossum).
PLoS One. 2014;9(6):e99080
Authors: Saunders NR, Noor NM, Dziegielewska KM, Wheaton BJ, Liddelow SA, Steer DL, Ek CJ, Habgood MD, Wakefield MJ, Lindsay H, Truettner J, Miller RD, Smith AI, Dietrich WD
This study describes a combined transcriptome and proteome analysis of Monodelphis domestica response to spinal cord injury at two different postnatal ages. Previously we showed that complete transection at postnatal day 7 (P7) is followed by profuse axon growth across the lesion with near-normal locomotion and swimming when adult. In contrast, at P28 there is no axon growth across the lesion, the animals exhibit weight-bearing locomotion, but cannot use hind limbs when swimming. Here we examined changes in gene and protein expression in the segment of spinal cord rostral to the lesion at 24 h after transection at P7 and at P28. Following injury at P7 only forty genes changed (all increased expression); most were immune/inflammatory genes. Following injury at P28 many more genes changed their expression and the magnitude of change for some genes was strikingly greater. Again many were associated with the immune/inflammation response. In functional groups known to be inhibitory to regeneration in adult cords the expression changes were generally muted, in some cases opposite to that required to account for neurite inhibition. For example myelin basic protein expression was reduced following injury at P28 both at the gene and protein levels. Only four genes from families with extracellular matrix functions thought to influence neurite outgrowth in adult injured cords showed substantial changes in expression following injury at P28: Olfactomedin 4 (Olfm4, 480 fold compared to controls), matrix metallopeptidase (Mmp1, 104 fold), papilin (Papln, 152 fold) and integrin α4 (Itga4, 57 fold). These data provide a resource for investigation of a priori hypotheses in future studies of mechanisms of spinal cord regeneration in immature animals compared to lack of regeneration at more mature stages.
PMID: 24914927 [PubMed - indexed for MEDLINE]
Human stem cells for modeling heart disease and for drug discovery.
Sci Transl Med. 2014 Jun 4;6(239):239ps6
Authors: Matsa E, Burridge PW, Wu JC
A major research focus in the field of cardiovascular medicine is the prospect of using stem cells and progenitor cells for cardiac regeneration. With the advent of induced pluripotent stem cell (iPSC) technology, major efforts are also underway to use iPSCs to model heart disease, to screen for new drugs, and to test candidate drugs for cardiotoxicity. Here, we discuss recent advances in the exciting fields of stem cells and cardiovascular disease.
PMID: 24898747 [PubMed - indexed for MEDLINE]
As the egg turns: monitoring egg attendance behavior in wild birds using novel data logging technology.
PLoS One. 2014;9(6):e97898
Authors: Shaffer SA, Clatterbuck CA, Kelsey EC, Naiman AD, Young LC, VanderWerf EA, Warzybok P, Bradley R, Jahncke J, Bower GC
Egg turning is unique to birds and critical for embryonic development in most avian species. Technology that can measure changes in egg orientation and temperature at fine temporal scales (1 Hz) was neither readily available nor small enough to fit into artificial eggs until recently. Here we show the utility of novel miniature data loggers equipped with 3-axis (i.e., triaxial) accelerometers, magnetometers, and a temperature thermistor to study egg turning behavior in free-ranging birds. Artificial eggs containing egg loggers were deployed in the nests of three seabird species for 1-7 days of continuous monitoring. These species (1) turned their eggs more frequently (up to 6.5 turns h(-1)) than previously reported for other species, but angular changes were often small (1-10° most common), (2) displayed similar mean turning rates (ca. 2 turns h(-1)) despite major differences in reproductive ecology, and (3) demonstrated distinct diurnal cycling in egg temperatures that varied between 1.4 and 2.4 °C. These novel egg loggers revealed high-resolution, three-dimensional egg turning behavior heretofore never measured in wild birds. This new form of biotechnology has broad applicability for addressing fundamental questions in avian breeding ecology, life history, and development, and can be used as a tool to monitor birds that are sensitive to disturbance while breeding.
PMID: 24887441 [PubMed - indexed for MEDLINE]
Insulin resistance: regression and clustering.
PLoS One. 2014;9(6):e94129
Authors: Yoon S, Assimes TL, Quertermous T, Hsiao CF, Chuang LM, Hwu CM, Rajaratnam B, Olshen RA
In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be.
PMID: 24887437 [PubMed - indexed for MEDLINE]
Functional genomics with a comprehensive library of transposon mutants for the sulfate-reducing bacterium Desulfovibrio alaskensis G20.
Authors: Kuehl JV, Price MN, Ray J, Wetmore KM, Esquivel Z, Kazakov AE, Nguyen M, Kuehn R, Davis RW, Hazen TC, Arkin AP, Deutschbauer A
UNLABELLED: The genomes of sulfate-reducing bacteria remain poorly characterized, largely due to a paucity of experimental data and genetic tools. To meet this challenge, we generated an archived library of 15,477 mapped transposon insertion mutants in the sulfate-reducing bacterium Desulfovibrio alaskensis G20. To demonstrate the utility of the individual mutants, we profiled gene expression in mutants of six regulatory genes and used these data, together with 1,313 high-confidence transcription start sites identified by tiling microarrays and transcriptome sequencing (5' RNA-Seq), to update the regulons of Fur and Rex and to confirm the predicted regulons of LysX, PhnF, PerR, and Dde_3000, a histidine kinase. In addition to enabling single mutant investigations, the D. alaskensis G20 transposon mutants also contain DNA bar codes, which enables the pooling and analysis of mutant fitness for thousands of strains simultaneously. Using two pools of mutants that represent insertions in 2,369 unique protein-coding genes, we demonstrate that the hypothetical gene Dde_3007 is required for methionine biosynthesis. Using comparative genomics, we propose that Dde_3007 performs a missing step in methionine biosynthesis by transferring a sulfur group to O-phosphohomoserine to form homocysteine. Additionally, we show that the entire choline utilization cluster is important for fitness in choline sulfate medium, which confirms that a functional microcompartment is required for choline oxidation. Finally, we demonstrate that Dde_3291, a MerR-like transcription factor, is a choline-dependent activator of the choline utilization cluster. Taken together, our data set and genetic resources provide a foundation for systems-level investigation of a poorly studied group of bacteria of environmental and industrial importance.
IMPORTANCE: Sulfate-reducing bacteria contribute to global nutrient cycles and are a nuisance for the petroleum industry. Despite their environmental and industrial significance, the genomes of sulfate-reducing bacteria remain poorly characterized. Here, we describe a genetic approach to fill gaps in our knowledge of sulfate-reducing bacteria. We generated a large collection of archived, transposon mutants in Desulfovibrio alaskensis G20 and used the phenotypes of these mutant strains to infer the function of genes involved in gene regulation, methionine biosynthesis, and choline utilization. Our findings and mutant resources will enable systematic investigations into gene function, energy generation, stress response, and metabolism for this important group of bacteria.
PMID: 24865553 [PubMed - indexed for MEDLINE]
Adipose-derived stem cells: a review of signaling networks governing cell fate and regenerative potential in the context of craniofacial and long bone skeletal repair.
Int J Mol Sci. 2014;15(6):9314-30
Authors: Senarath-Yapa K, McArdle A, Renda A, Longaker MT, Quarto N
Improvements in medical care, nutrition and social care are resulting in a commendable change in world population demographics with an ever increasing skew towards an aging population. As the proportion of the world's population that is considered elderly increases, so does the incidence of osteodegenerative disease and the resultant burden on healthcare. The increasing demand coupled with the limitations of contemporary approaches, have provided the impetus to develop novel tissue regeneration therapies. The use of stem cells, with their potential for self-renewal and differentiation, is one potential solution. Adipose-derived stem cells (ASCs), which are relatively easy to harvest and readily available have emerged as an ideal candidate. In this review, we explore the potential for ASCs to provide tangible therapies for craniofacial and long bone skeletal defects, outline key signaling pathways that direct these cells and describe how the developmental signaling program may provide clues on how to guide these cells in vivo. This review also provides an overview of the importance of establishing an osteogenic microniche using appropriately customized scaffolds and delineates some of the key challenges that still need to be overcome for adult stem cell skeletal regenerative therapy to become a clinical reality.
PMID: 24865492 [PubMed - indexed for MEDLINE]
Invasion and proliferation kinetics in enhancing gliomas predict IDH1 mutation status.
Neuro Oncol. 2014 Jun;16(6):779-86
Authors: Baldock AL, Yagle K, Born DE, Ahn S, Trister AD, Neal M, Johnston SK, Bridge CA, Basanta D, Scott J, Malone H, Sonabend AM, Canoll P, Mrugala MM, Rockhill JK, Rockne RC, Swanson KR
BACKGROUND: Glioblastomas with a specific mutation in the isocitrate dehydrogenase 1 (IDH1) gene have a better prognosis than gliomas with wild-type IDH1.
METHODS: Here we compare the IDH1 mutational status in 172 contrast-enhancing glioma patients with the invasion profile generated by a patient-specific mathematical model we developed based on MR imaging.
RESULTS: We show that IDH1-mutated contrast-enhancing gliomas were relatively more invasive than wild-type IDH1 for all 172 contrast-enhancing gliomas as well as the subset of 158 histologically confirmed glioblastomas. The appearance of this relatively increased, model-predicted invasive profile appears to be determined more by a lower model-predicted net proliferation rate rather than an increased model-predicted dispersal rate of the glioma cells. Receiver operator curve analysis of the model-predicted MRI-based invasion profile revealed an area under the curve of 0.91, indicative of a predictive relationship. The robustness of this relationship was tested by cross-validation analysis of the invasion profile as a predictive metric for IDH1 status.
CONCLUSIONS: The strong correlation between IDH1 mutation status and the MRI-based invasion profile suggests that use of our tumor growth model may lead to noninvasive clinical detection of IDH1 mutation status and thus lead to better treatment planning, particularly prior to surgical resection, for contrast-enhancing gliomas.
PMID: 24832620 [PubMed - indexed for MEDLINE]
Enhanced decolorization of azo dye in a small pilot-scale anaerobic baffled reactor coupled with biocatalyzed electrolysis system (ABR-BES): a design suitable for scaling-up.
Bioresour Technol. 2014 Jul;163:254-61
Authors: Cui D, Guo YQ, Lee HS, Wu WM, Liang B, Wang AJ, Cheng HY
A four-compartment anaerobic baffled reactor (ABR) incorporated with membrane-less biocatalyzed electrolysis system (BES) was tested for the treatment of azo dye (alizarin yellow R, AYR) wastewater (AYR, 200 mg L(-1); glucose, 1000 mg L(-1)). The ABR-BES was operated without and with external power supply to examine AYR reduction process and reductive intermediates with different external voltages (0.3, 0.5 and 0.7 V) and hydraulic retention times (HRT: 8, 6 and 4h). The decolorization efficiency in the ABR-BES (8h HRT, 0.5 V) was higher than that in ABR-BES without electrolysis, i.e. 95.1 ± 1.5% versus 86.9 ± 6.3%. Incorporation of BES with ABR accelerated the consumption of VFAs (mainly acetate) and attenuated biogas (methane) production. Higher power supply (0.7 V) enhanced AYR decolorization efficiency (96.4 ± 1.8%), VFAs removal, and current density (24.1 Am(-3) TCV). Shorter HRT increased volumetric AYR decolorization rates, but decreased AYR decolorization efficiency.
PMID: 24821204 [PubMed - indexed for MEDLINE]
Mast cells: potential positive and negative roles in tumor biology.
Cancer Immunol Res. 2013 Nov;1(5):269-79
Authors: Marichal T, Tsai M, Galli SJ
Mast cells are immune cells that reside in virtually all vascularized tissues. Upon activation by diverse mechanisms, mast cells can secrete a broad array of biologically active products that either are stored in the cytoplasmic granules of the cells (e.g., histamine, heparin, various proteases) or are produced de novo upon cell stimulation (e.g., prostaglandins, leukotrienes, cytokines, chemokines, and growth factors). Mast cells are best known for their effector functions during anaphylaxis and acute IgE-associated allergic reactions, but they also have been implicated in a wide variety of processes that maintain health or contribute to disease. There has been particular interest in the possible roles of mast cells in tumor biology. In vitro studies have shown that mast cells have the potential to influence many aspects of tumor biology, including tumor development, tumor-induced angiogenesis, and tissue remodeling, and the shaping of adaptive immune responses to tumors. Yet, the actual contributions of mast cells to tumor biology in vivo remain controversial. Here, we review some basic features of mast cell biology with a special emphasis on those relevant to their potential roles in tumors. We discuss how using in vivo tumor models in combination with models in which mast cell function can be modulated has implicated mast cells in the regulation of host responses to tumors. Finally, we summarize data from studies of human tumors that suggest either beneficial or detrimental roles for mast cells in tumors.
PMID: 24777963 [PubMed - indexed for MEDLINE]
Lumbosacral spine and marrow cavity modeling of acute hematologic toxicity in patients treated with intensity modulated radiation therapy for squamous cell carcinoma of the anal canal.
Pract Radiat Oncol. 2014 May-Jun;4(3):198-206
Authors: Cheng JC, Bazan JG, Wu JK, Koong AC, Chang DT
PURPOSE: To identify various dosimetric parameters of bone marrow cavity that correlate with acute hematologic toxicity (HT) in patients with anal squamous cell carcinoma treated with definitive chemoradiation therapy (CRT).
METHODS AND MATERIALS: We analyzed 32 patients receiving CRT. The whole pelvic bone marrow (PBM) and the lumbosacral spine (LSS) subregion were contoured for each patient. Marrow cavities were contoured using the Hounsfield units (HUs) of 100, 150, 200, and 250 as maximum density threshold levels. The volume of each region receiving at least 5, 10, 15, 20, 30, and 40 Gy was calculated. The endpoint was grade ≥3 HT (HT3+). Normal-tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Maximal likelihood estimate was used to compare the parameter set. Logistic regression was used to test associations between HT and both dosimetric and clinical parameters.
RESULTS: Ten patients (31%) experienced HT3+. While dose to both LSS and PBM significantly predicted for HT3+, LSS was superior to PBM by logistic regression and LKB modeling. Constrained optimization of the LKB model for HT3+ yielded the parameters m = 0.21, n = 1, and TD50 = 32 Gy for LSS. The NTCP fits were better with the whole bone than with marrow cavity using any HU threshold. Mean LSS doses of 21 Gy and 23.5 Gy result in a 5% and 10% risk of HT3+, respectively. Mean dose and low-dose radiation parameters (V5, V10, V15, V20) of whole bone or bone cavities of LSS were correlated most significantly with HT3+.
CONCLUSIONS: For predicting the risk of HT3+, whole-bone contours were superior to marrow cavity and LSS was superior to PBM by LKB modeling. The results confirm PBM and LSS as parallel organs when predicting hematologic toxicity. Recommended dose constraints to the LSS are V10 ≤80%. An LSS mean dose of 23.5 Gy is associated with a 10% risk of HT.
PMID: 24766688 [PubMed - indexed for MEDLINE]
The effect of arm position on the dosimetry of thoracic stereotactic ablative radiation therapy using volumetric modulated arc therapy.
Pract Radiat Oncol. 2014 May-Jun;4(3):192-7
Authors: Shultz DB, Jang SS, Hanlon AL, Diehn M, Loo BW, Maxim PG
PURPOSE: Patient comfort and positioning stability may be improved in the arms down (AD) compared with the typical arms up (AU) position in thoracic stereotactic ablative radiation therapy (SABR). We compared plan quality for AD vs AU when using volumetric modulated arc therapy (VMAT), and evaluated the sensitivity of AD plans to arm positioning variability.
METHODS AND MATERIALS: We took plans of 14 patients with 17 lung tumors treated with thoracic SABR using VMAT in the AD position and simulated the same treatments in the AU position by re-optimizing after digitally removing the ipsilateral arm. To evaluate the sensitivity of AD plans to arm positioning variability, all plans were recalculated without re-optimization after assigning water density to the ipsilateral arm (AD-W) and then digitally shifting the arm 2.5 cm anterolaterally (AD-WS).
RESULTS: Between AD and AU plans, statistically significant but clinically insignificant (all original planning constraints met) differences were found for the following parameters: mean planning target volume maximum dose, difference of 2.3% of prescription dose (P = .049); mean intermediate dose conformity index, difference of 0.27 (P = .012); median percent lung volume receiving a minimum of 10, 20, and 30 Gy (V10, V20, and V30), differences of 0.5%, 0.2%, and 0.1%, respectively (P = .040, .007, and .001); and median spinal cord maximum dose, difference of 33.5 cGy (P = .017). Similarly, between AD-W and AD-WS plans, statistically significant but clinically insignificant differences were found for median lung V20 and V30, difference of 0.0% for both (P = .034 and .016, by matched pair analysis).
CONCLUSIONS: Our exploratory planning study suggests that when using VMAT for lung tumor SABR, AD and AU positioning achieve clinically equivalent plan quality, and AD plans are insensitive to relatively large variability in arm position.
PMID: 24766687 [PubMed - indexed for MEDLINE]
Updating emotional content in working memory: a depression-specific deficit?
J Behav Ther Exp Psychiatry. 2014 Sep;45(3):368-74
Authors: Yoon KL, LeMoult J, Joormann J
BACKGROUND AND OBJECTIVES: Interference from irrelevant negative material might be a key mechanism underlying intrusive ruminative thoughts in depression. Considering commonalities between depression and social anxiety and the presence of similar intrusive thoughts in social anxiety, the current study was designed to assess whether interference from irrelevant material in working memory is specific to depression or is also present in social anxiety disorder.
METHODS: To examine the effects of irrelevant emotional material on working memory performance, participants memorized two lists of words on each trial and were subsequently instructed to ignore one of the lists. Participants were then asked to indicate whether a probe word belonged to the relevant list or not.
RESULTS: Compared to control and social anxiety groups, the depression groups (both pure and comorbid with social anxiety disorder) exhibited greater difficulties removing irrelevant emotional material from working memory (i.e., greater intrusion effects). Greater intrusion effects were also associated with increased rumination.
LIMITATIONS: Although we included three clinical groups (depression, social anxiety, and the comorbid groups), the results are based on a relatively small number of participants.
CONCLUSIONS: The results indicate that difficulties removing irrelevant material from working memory might be unique to depression, and the ability to inhibit irrelevant information is relatively preserved in social anxiety disorder.
PMID: 24747511 [PubMed - indexed for MEDLINE]
Α-tubulin K40 acetylation is required for contact inhibition of proliferation and cell-substrate adhesion.
Mol Biol Cell. 2014 Jun 15;25(12):1854-66
Authors: Aguilar A, Becker L, Tedeschi T, Heller S, Iomini C, Nachury MV
Acetylation of α-tubulin on lysine 40 marks long-lived microtubules in structures such as axons and cilia, and yet the physiological role of α-tubulin K40 acetylation is elusive. Although genetic ablation of the α-tubulin K40 acetyltransferase αTat1 in mice did not lead to detectable phenotypes in the developing animals, contact inhibition of proliferation and cell-substrate adhesion were significantly compromised in cultured αTat1(-/-) fibroblasts. First, αTat1(-/-) fibroblasts kept proliferating beyond the confluent monolayer stage. Congruently, αTat1(-/-) cells failed to activate Hippo signaling in response to increased cell density, and the microtubule association of the Hippo regulator Merlin was disrupted. Second, αTat1(-/-) cells contained very few focal adhesions, and their ability to adhere to growth surfaces was greatly impaired. Whereas the catalytic activity of αTAT1 was dispensable for monolayer formation, it was necessary for cell adhesion and restrained cell proliferation and activation of the Hippo pathway at elevated cell density. Because α-tubulin K40 acetylation is largely eliminated by deletion of αTAT1, we propose that acetylated microtubules regulate contact inhibition of proliferation through the Hippo pathway.
PMID: 24743598 [PubMed - indexed for MEDLINE]
Case report of a transfusion-associated hepatitis A infection.
Transfusion. 2014 Sep;54(9):2202-6
Authors: Hughes JA, Fontaine MJ, Gonzalez CL, Layon AG, Goodnough LT, Galel SA
BACKGROUND: Documented transfusion-associated hepatitis A (TAHA) is rare, and blood donors in the United States are not routinely screened for this infection. We report a case of TAHA associated with a donation made 8 days after a donor returned from a trip to South America.
STUDY DESIGN AND METHODS: This is a review of donor and recipient records and a review of the literature.
RESULTS: A donor developed symptoms of hepatitis 20 days after donation (28 days after returning from South America). The donor reported the illness 56 days after donation when contacted to schedule another visit. By this time, the red blood cell and frozen plasma components had been transfused. The recipient of the plasma, a 15-month-old female, tested positive for immunoglobulin M antibody to hepatitis A virus 43 days after transfusion. The recipient had displayed mild, nonspecific symptoms approximately 2 weeks after transfusion. Hospital infection control investigated the potential for further spread within the hospital because the recipient had been an inpatient for most of the posttransfusion period. The risk of transmission to other patients was determined to be negligible because the patient had been in isolation for other reasons. Family members, who included a health care professional, were counseled and offered prophylaxis.
CONCLUSION: TAHA may be underrecognized. This case was identified only because of a donor report at the time of recruitment. Asymptomatic donor viremia has been documented in plasma donors. Although TAHA rarely results in severe disease, the risk it creates of secondary transmission especially within the hospital setting is not inconsequential.
PMID: 24689888 [PubMed - indexed for MEDLINE]
Executive function is associated with social competence in preschool-aged children born preterm or full term.
Early Hum Dev. 2014 Jun;90(6):299-306
Authors: Alduncin N, Huffman LC, Feldman HM, Loe IM
BACKGROUND: Executive function (EF), defined as higher-order cognitive processes used in planning and organizing actions and emotions, is often impaired in children born preterm. Few studies have assessed social competence, the processes and resources required to meet social demands and achieve social goals, in children born preterm. The relations between EF and social competence in preterm and full term preschoolers have not been well characterized.
AIMS: To characterize social competence and assess the relationship between EF and social competence in preschool-aged children born preterm or full term.
STUDY DESIGN: Cross-sectional study.
SUBJECTS: Study subjects had a history of preterm birth (≤34weeks of gestation) and birth weight <2500g (n=70). Controls were born full term (≥37weeks) (n=79).
OUTCOME MEASURES: Children completed a battery of EF tasks; a mean age-adjusted z-score for the battery was generated for each child. Parents rated child EF on one scale and child social competence on two standardized scales.
RESULTS: Compared to full term children, preterm children showed a lower mean EF battery z-score, poorer parent-rated EF, and poorer scores on the two social competence scales. In hierarchical multiple regression models, EF battery z-score and parent-rated EF made independent contributions to both measures of social competence. Preterm birth explained additional variance for one measure of social competence.
CONCLUSIONS: Standard assessment of EF skills and social competence in young preschool children, including children born preterm, may identify at-risk children for long-term social difficulties and may also provide targets for intervention.
PMID: 24661446 [PubMed - indexed for MEDLINE]
Cardiac rehabilitation exercise and self-care for chronic heart failure.
JACC Heart Fail. 2013 Dec;1(6):540-7
Authors: Ades PA, Keteyian SJ, Balady GJ, Houston-Miller N, Kitzman DW, Mancini DM, Rich MW
Chronic heart failure (CHF) is highly prevalent in older individuals and is a major cause of morbidity, mortality, hospitalizations, and disability. Cardiac rehabilitation (CR) exercise training and CHF self-care counseling have each been shown to improve clinical status and clinical outcomes in CHF. Systematic reviews and meta-analyses of CR exercise training alone (without counseling) have demonstrated consistent improvements in CHF symptoms in addition to reductions in cardiac mortality and number of hospitalizations, although individual trials have been less conclusive of the latter 2 findings. The largest single trial, HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training), showed a reduction in the adjusted risk for the combined endpoint of all-cause mortality or hospitalization (hazard ratio: 0.89, 95% confidence interval: 0.81 to 0.99; p = 0.03). Quality of life and mental depression also improved. CHF-related counseling, whether provided in isolation or in combination with CR exercise training, improves clinical outcomes and reduces CHF-related hospitalizations. We review current evidence on the benefits and risks of CR and self-care counseling in patients with CHF, provide recommendations for patient selection for third-party payers, and discuss the role of CR in promoting self-care and behavioral changes.
PMID: 24622007 [PubMed - indexed for MEDLINE]
Whole-genome haplotyping using long reads and statistical methods.
Nat Biotechnol. 2014 Mar;32(3):261-6
Authors: Kuleshov V, Xie D, Chen R, Pushkarev D, Ma Z, Blauwkamp T, Kertesz M, Snyder M
The rapid growth of sequencing technologies has greatly contributed to our understanding of human genetics. Yet, despite this growth, mainstream technologies have not been fully able to resolve the diploid nature of the human genome. Here we describe statistically aided, long-read haplotyping (SLRH), a rapid, accurate method that uses a statistical algorithm to take advantage of the partially phased information contained in long genomic fragments analyzed by short-read sequencing. For a human sample, as little as 30 Gbp of additional sequencing data are needed to phase genotypes identified by 50× coverage whole-genome sequencing. Using SLRH, we phase 99% of single-nucleotide variants in three human genomes into long haplotype blocks 0.2-1 Mbp in length. We apply our method to determine allele-specific methylation patterns in a human genome and identify hundreds of differentially methylated regions that were previously unknown. SLRH should facilitate population-scale haplotyping of human genomes.
PMID: 24561555 [PubMed - indexed for MEDLINE]
Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice.
Nat Biotechnol. 2014 Mar;32(3):274-8
Authors: Iyer SM, Montgomery KL, Towne C, Lee SY, Ramakrishnan C, Deisseroth K, Delp SL
Primary nociceptors are the first neurons involved in the complex processing system that regulates normal and pathological pain. Because of constraints on pharmacological and electrical stimulation, noninvasive excitation and inhibition of these neurons in freely moving nontransgenic animals has not been possible. Here we use an optogenetic strategy to bidirectionally control nociceptors of nontransgenic mice. Intrasciatic nerve injection of adeno-associated viruses encoding an excitatory opsin enabled light-inducible stimulation of acute pain, place aversion and optogenetically mediated reductions in withdrawal thresholds to mechanical and thermal stimuli. In contrast, viral delivery of an inhibitory opsin enabled light-inducible inhibition of acute pain perception, and reversed mechanical allodynia and thermal hyperalgesia in a model of neuropathic pain. Light was delivered transdermally, allowing these behaviors to be induced in freely moving animals. This approach may have utility in basic and translational pain research, and enable rapid drug screening and testing of newly engineered opsins.
PMID: 24531797 [PubMed - indexed for MEDLINE]
Bevacizumab and cyclosphosphamide, doxorubicin, vincristine and prednisone in combination for patients with peripheral T-cell or natural killer cell neoplasms: an Eastern Cooperative Oncology Group study (E2404).
Leuk Lymphoma. 2014 Apr;55(4):768-72
Authors: Ganjoo K, Hong F, Horning SJ, Gascoyne RD, Natkunam Y, Swinnen LJ, Habermann TM, Kahl BS, Advani RH
Peripheral T-cell lymphoma (PTCL) and natural killer (NK) cell lymphoma have poor survival with conventional cytotoxic chemotherapy. Because angiogenesis plays an important role in the biology of PTCL, a fully humanized anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab (A), was studied in combination with standard cyclosphosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy (ACHOP) to evaluate its potential to improve outcome in these patients. Patients were treated with 6-8 cycles of ACHOP followed by eight doses of maintenance A (15 mg/kg every 21 days). Forty-six patients were enrolled on this phase 2 study from July 2006 through March 2009. Forty-four patients were evaluable for toxicity and 39 were evaluable for response, progression and survival. A total of 324 cycles (range: 2-16, median 7) were administered to 39 evaluable patients and only nine completed all planned treatment. The overall response rate was 90% with 19 (49%) complete response/complete response unconfirmed (CR/CRu) and 16 (41%) a partial response (PR). The 1-year progression-free survival (PFS) rate was 44% at a median follow-up of 3 years. The median PFS and overall survival (OS) rates were 7.7 and 22 months, respectively. Twenty-three patients died (21 from lymphoma, two while in remission). Grade 3 or 4 toxicities included febrile neutropenia (n = 8), anemia (n = 3), thrombocytopenia (n = 5), congestive heart failure (n = 4), venous thrombosis (n = 3), gastrointestinal hemorrhage/perforation (n = 2), infection (n = 8) and fatigue (n = 6). Despite a high overall response rate, the ACHOP regimen failed to result in durable remissions and was associated with significant toxicities. Studies of novel therapeutics are needed for this patient population, whose clinical outcome remains poor.
PMID: 23786456 [PubMed - indexed for MEDLINE]
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