Recent Stanford Publications in PubMedSubscribe to Recent Stanford Publications in PubMed
- Resource allocation as a driver of senescence: Life history tradeoffs produce age patterns of mortality.Davison R, Boggs CL, Baudisch AJ Theor Biol
- Novel celastrol derivatives inhibit the growth of hepatocellular carcinoma patient-derived xenografts.Wei W, Wu S, Wang X, Sun CK, Yang X, Yan X, Chua MS, So SOncotarget
- Docking Interactions: Cell-Cycle Regulation and Beyond.Kõivomägi M, Skotheim JMCurr Biol
- Hypocretin (orexin) neuromodulation of stress and reward pathways.Giardino WJ, de Lecea LCurr Opin Neurobiol
- Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome-Spectrum Cancers.Park DJ, Tao K, Le Calvez-Kelm F, Nguyen-Dumont T, Robinot N, Hammet F, Odefrey F, Tsimiklis H, Teo ZL, Thingholm LB, Young EL, Voegele C, Lonie A, Pope BJ, Roane TC, Bell R, Hu H, Shankaracharya, Huff CD, Ellis J, Li J, Makunin IV, John EM, Andrulis IL, Terry MB, Daly M, Buys SS, Snyder C, Lynch HT, Devilee P, Giles GG, Hopper JL, Feng BJ, Lesueur F, Tavtigian SV, Southey MC, Goldgar DECancer Discov
- In Reply.Schmidt PC, Ruchelli G, Mackey SC, Carroll IRAnesthesiology
- Prevention of Traumatic Stress in Mothers of Preterms: 6-Month Outcomes.Shaw RJ, St John N, Lilo E, Jo B, Benitz W, Stevenson DK, Horwitz SMPediatrics
- The global burden of neurologic diseases.Chin JH, Vora NNeurology
- Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.Melhorn SJ, Tyagi V, Smeraglio A, Roth CL, Schur EAAppetite
- Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells.Hew KM, Walker AI, Kohli A, Garcia M, Syed A, McDonald-Hyman C, Noth EM, Mann JK, Pratt B, Balmes J, Hammond SK, Eisen EA, Nadeau KCClin Exp Allergy
- Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease and type 2 diabetes.Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Walker M, Borecki IB, Knowles JW, Yerges-Armstrong L, Ohlsson C, Perry JR, Chambers JC, Kooner JS, Franceschini N, Langenberg C, Hivert MF, Dastani Z, Richards JB, Semple RK, Frayling TMDiabetes
- When It Hurts (and Helps) to Try: The Role of Effort in Language Learning.Finn AS, Lee T, Kraus A, Hudson Kam CLPLoS One
- Collateral vessel number, plaque burden, and functional decline in peripheral artery disease.McDermott MM, Carr J, Liu K, Kramer CM, Yuan C, Tian L, Criqui MH, Guralnik JM, Ferrucci L, Zhao L, Xu D, Kibbe M, Berry J, Carroll TJVasc Med
- Electronic Readout Enzyme-Linked Immunosorbent Assay with Organic Field-Effect Transistors as a Preeclampsia Prognostic.Hammock ML, Knopfmacher O, Ng TN, Tok JB, Bao ZAdv Mater
- Influence of the stiffness of three-dimensional alginate/collagen-I interpenetrating networks on fibroblast biology.Branco da Cunha C, Klumpers DD, Li WA, Koshy ST, Weaver JC, Chaudhuri O, Granja PL, Mooney DJBiomaterials
- How do cilia organize signalling cascades?Nachury MVPhilos Trans R Soc Lond B Biol Sci
- The centriole duplication cycle.Fırat-Karalar EN, Stearns TPhilos Trans R Soc Lond B Biol Sci
- Top-Down Patterning and Self-Assembly for Regular Arrays of Semiconducting Single-Walled Carbon Nanotubes.Wu J, Antaris A, Gong M, Dai HAdv Mater
- Bio-Inspired Cryo-Ink Preserves Red Blood Cell Phenotype and Function During Nanoliter Vitrification.El Assal R, Guven S, Gurkan UA, Gozen I, Shafiee H, Dalbeyler S, Abdalla N, Thomas G, Fuld W, Illigens BM, Estanislau J, Khoory J, Kaufman R, Zylberberg C, Lindeman N, Wen Q, Ghiran I, Demirci UAdv Mater
- The sports bra, the ACL, and Title IX--the game in play.Ladd ALClin Orthop Relat Res
- JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside.Gotlib JHematology Am Soc Hematol Educ Program
- A decade of Clinical Trials.Goodman SNClin Trials
- Growing matter: a review of growth in living systems.Kuhl EJ Mech Behav Biomed Mater
- GCY-8, PDE-2, and NCS-1 are critical elements of the cGMP-dependent thermotransduction cascade in the AFD neurons responsible for C. elegans thermotaxis.Wang D, O'Halloran D, Goodman MBJ Gen Physiol
Resource allocation as a driver of senescence: Life history tradeoffs produce age patterns of mortality.
J Theor Biol. 2014 Jul 19;
Authors: Davison R, Boggs CL, Baudisch A
We investigate the effects of optimal time and resource allocation on age patterns of fertility and mortality for a model organism with (1) fixed maximum lifespan, (2) distinct juvenile and adult diets, and (3) reliance on nonrenewable resources for reproduction. We ask when it is optimal to tolerate starvation vs. conserve resources and then examine the effects of these decisions on adult mortality rates. We find that (1) age-related changes in tradeoffs partition the life cycle into as many as four discrete phases with different optimal behavior and mortality patterns, and (2) given a cost of reproduction, terminal investment can produce a signal of actuarial senescence. Also, given limitations imposed by non-replenishable resources, individuals beginning adult life with more replenishable resources do not necessarily live longer, since they can engage in capital breeding and need not defer reproduction to forage; low reproductive overheads and low costs of starvation also encourage capital breeding and may lead to earlier terminal investment and earlier senescence. We conclude that, even for species with qualitatively similar life histories, differences in physiological, behavioral and environmental tradeoffs or constraints may strongly influence optimal allocation schedules and produce variation in mortality patterns and life expectancy.
PMID: 25051533 [PubMed - as supplied by publisher]
Novel celastrol derivatives inhibit the growth of hepatocellular carcinoma patient-derived xenografts.
Oncotarget. 2014 Jul 10;
Authors: Wei W, Wu S, Wang X, Sun CK, Yang X, Yan X, Chua MS, So S
The molecular co-chaperone CDC37 is over-expressed in hepatocellular carcinoma (HCC) cells, where it functions with HSP90 to regulate the activity of protein kinases in multiple oncogenic signaling pathways that contribute towards hepatocarcinogenesis. Disruption of these signaling pathways via inhibition of HSP90/CDC37 interaction is therefore a rational therapeutic approach. We evaluated the anti-tumor effects of celastrol, pristimerin, and two novel derivatives (cel-D2, and cel-D7) on HCC cell lines in vitro and on orthotopic HCC patient-derived xenografts in vivo. All four compounds preferentially inhibited viability of HCC cells in vitro,and significantly inhibited the growth of three orthotopic HCC patient-derived xenografts in vivo; with the novel derivatives cel-D2 and cel-D7 exhibiting lower toxicity. All four compounds also induced cell apoptosis; and promoted degradation and inhibited phosphorylation of protein kinases in the Raf/MEK/ERK and PI3K/AKT/mTOR signaling pathways. We demonstrated that HSP90/CDC37 antagonists are potentially broad spectrum agents that might be beneficial for treating the heterogeneous subtypes of HCC, either as monotherapy, or in combination with other chemotherapeutic agents.
PMID: 25051375 [PubMed - as supplied by publisher]
Docking Interactions: Cell-Cycle Regulation and Beyond.
Curr Biol. 2014 Jul 21;24(14):R647-R649
Authors: Kõivomägi M, Skotheim JM
In budding yeast, the mating pathway activates Far1 to inhibit G1 cyclins in complex with the cyclin-dependent kinase (Cln-Cdk). Yet, the molecular mechanism has remained largely unclear for over 20 years. A recent report helps shed light on this regulation.
PMID: 25050961 [PubMed - as supplied by publisher]
Hypocretin (orexin) neuromodulation of stress and reward pathways.
Curr Opin Neurobiol. 2014 Jul 19;29C:103-108
Authors: Giardino WJ, de Lecea L
Hypocretin (also known as orexin) is a peptide neuromodulator that is expressed exclusively in the lateral hypothalamic area and plays a fundamental role in wakefulness and arousal. Chronic stress and compulsive drug-seeking are two examples of dysregulated states of hyperarousal that are influenced by hypocretin transmission throughout hypothalamic, extended amygdala, brainstem, and mesolimbic pathways. Here, we review current advances in the understanding of hypocretin's modulatory actions underlying conditions of negative and positive emotional valence, focusing particularly on mechanisms that facilitate adaptive (and maladaptive) responses to stressful or rewarding environmental stimuli. We conclude by discussing progress toward integrated theories for hypocretin modulation of divergent behavioral domains.
PMID: 25050887 [PubMed - as supplied by publisher]
Rare Mutations in RINT1 Predispose Carriers to Breast and Lynch Syndrome-Spectrum Cancers.
Cancer Discov. 2014 Jul;4(7):804-815
Authors: Park DJ, Tao K, Le Calvez-Kelm F, Nguyen-Dumont T, Robinot N, Hammet F, Odefrey F, Tsimiklis H, Teo ZL, Thingholm LB, Young EL, Voegele C, Lonie A, Pope BJ, Roane TC, Bell R, Hu H, Shankaracharya, Huff CD, Ellis J, Li J, Makunin IV, John EM, Andrulis IL, Terry MB, Daly M, Buys SS, Snyder C, Lynch HT, Devilee P, Giles GG, Hopper JL, Feng BJ, Lesueur F, Tavtigian SV, Southey MC, Goldgar DE
Approximately half of the familial aggregation of breast cancer remains unexplained. A multiple-case breast cancer family exome-sequencing study identified three likely pathogenic mutations in RINT1 (NM_021930.4) not present in public sequencing databases: RINT1 c.343C>T (p.Q115X), c.1132_1134del (p.M378del), and c.1207G>T (p.D403Y). On the basis of this finding, a population-based case-control mutation-screening study was conducted that identified 29 carriers of rare (minor allele frequency < 0.5%), likely pathogenic variants: 23 in 1,313 early-onset breast cancer cases and six in 1,123 frequency-matched controls [OR, 3.24; 95% confidence interval (CI), 1.29-8.17; P = 0.013]. RINT1 mutation screening of probands from 798 multiple-case breast cancer families identified four additional carriers of rare genetic variants. Analysis of the incidence of first primary cancers in families of women carrying RINT1 mutations estimated that carriers were at increased risk of Lynch syndrome-spectrum cancers [standardized incidence ratio (SIR), 3.35; 95% CI, 1.7-6.0; P = 0.005], particularly for relatives diagnosed with cancer under the age of 60 years (SIR, 10.9; 95% CI, 4.7-21; P = 0.0003).
SIGNIFICANCE: The work described in this study adds RINT1 to the growing list of genes in which rare sequence variants are associated with intermediate levels of breast cancer risk. Given that RINT1 is also associated with a spectrum of cancers with mismatch repair defects, these findings have clinical applications and raise interesting biological questions. Cancer Discov; 4(7); 804-15. ©2014 AACR. See related commentary by Ngeow and Eng, p. 762 This article is highlighted in the In This Issue feature, p. 745.
PMID: 25050558 [PubMed - as supplied by publisher]
Anesthesiology. 2014 Aug;121(2):424-426
Authors: Schmidt PC, Ruchelli G, Mackey SC, Carroll IR
PMID: 25050501 [PubMed - as supplied by publisher]
Prevention of Traumatic Stress in Mothers of Preterms: 6-Month Outcomes.
Pediatrics. 2014 Jul 21;
Authors: Shaw RJ, St John N, Lilo E, Jo B, Benitz W, Stevenson DK, Horwitz SM
OBJECTIVE: Symptoms of posttraumatic stress disorder are a well-recognized phenomenon in mothers of preterm infants, with implications for maternal health and infant outcomes. This randomized controlled trial evaluated 6-month outcomes from a skills-based intervention developed to reduce symptoms of posttraumatic stress disorder, anxiety, and depression.METHODS: One hundred five mothers of preterm infants were randomly assigned to (1) a 6- or 9-session intervention based on principles of trauma-focused cognitive behavior therapy with infant redefinition or (2) a 1-session active comparison intervention based on education about the NICU and parenting of the premature infant. Outcome measures included the Davidson Trauma Scale, the Beck Depression Inventory II, and the Beck Anxiety Inventory. Participants were assessed at baseline, 4 to 5 weeks after birth, and 6 months after the birth of the infant.RESULTS: At the 6-month assessment, the differences between the intervention and comparison condition were all significant and sizable and became more pronounced when compared with the 4- to 5-week outcomes: Davidson Trauma Scale (Cohen's d = -0.74, P < .001), Beck Anxiety Inventory (Cohen's d = -0.627, P = .001), Beck Depression Inventory II (Cohen's d = -0.638, P = .002). However, there were no differences in the effect sizes between the 6- and 9-session interventions.CONCLUSIONS: A brief 6-session intervention based on principles of trauma-focused cognitive behavior therapy was effective at reducing symptoms of trauma, anxiety, and depression in mothers of preterm infants. Mothers showed increased benefits at the 6-month follow-up, suggesting that they continue to make use of techniques acquired during the intervention phase.
PMID: 25049338 [PubMed - as supplied by publisher]
The global burden of neurologic diseases.
Neurology. 2014 Jul 22;83(4):349-51
Authors: Chin JH, Vora N
PMID: 25049303 [PubMed - in process]
Initial evidence that GLP-1 receptor blockade fails to suppress postprandial satiety or promote food intake in humans.
Appetite. 2014 Jul 15;
Authors: Melhorn SJ, Tyagi V, Smeraglio A, Roth CL, Schur EA
Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, 8 normal weight participants (7 men, BMI 19-24.7 kg/m(2), age 19-29 yr) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 minutes later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62±5 Placebo -41±9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.
PMID: 25049134 [PubMed - as supplied by publisher]
Childhood exposure to ambient polycyclic aromatic hydrocarbons is linked to epigenetic modifications and impaired systemic immunity in T cells.
Clin Exp Allergy. 2014 Jul 22;
Authors: Hew KM, Walker AI, Kohli A, Garcia M, Syed A, McDonald-Hyman C, Noth EM, Mann JK, Pratt B, Balmes J, Hammond SK, Eisen EA, Nadeau KC
BACKGROUND: Evidence suggests that exposure to polycyclic aromatic hydrocarbons (PAHs) increases atopy; it is unclear how PAH exposure is linked to increased severity of atopic diseases.
OBJECTIVE: We hypothesized that ambient PAH exposure is linked to impairment of immunity in atopic children (defined as children with asthma and/or allergic rhinitis) from Fresno, California, an area with elevated ambient PAHs.
METHODS: We recruited 256 subjects from Fresno, CA. Ambient PAH concentrations (ng/m(3) ) were measured using a spatial-temporal regression model over multiple time periods. Asthma diagnosis was determined by current NHLBI criteria. Phenotyping and functional immune measurements were performed from isolated cells. For epigenetic measurements DNA was isolated and pyrosequenced.
RESULTS: We show that higher average PAH exposure was significantly associated with impaired Treg function and increased methylation in the forkhead box protein 3 (FOXP3) (p<0.05), conditional on atopic status. These epigenetic modifications were significantly linked to differential protein expression of FOXP3 (p<0.001). Methylation was associated with cellular functional changes, specifically Treg dysfunction, and an increase in total plasma IgE levels. Protein expression of IL-10 decreased and IFN-γ increased as the extent of PAH exposure increased. The strength of the associations generally increased as the time window for average PAH exposure increased from 24 hrs to 1 year, suggesting more of a chronic response. Significant associations with chronic PAH exposure and immune outcomes were also observed in subjects with allergic rhinitis.
CONCLUSIONS & CLINICAL RELEVANCE: Collectively, these results demonstrate increased ambient PAH exposure is associated with impaired systemic immunity and epigenetic modifications in a key locus involved in atopy: FOXP3, with a higher impact on atopic children. The results suggest that increased atopic clinical symptoms in children could be linked to increased PAH exposure in air pollution. This article is protected by copyright. All rights reserved.
PMID: 25048800 [PubMed - as supplied by publisher]
Genetic evidence for a normal-weight "metabolically obese" phenotype linking insulin resistance, hypertension, coronary artery disease and type 2 diabetes.
Diabetes. 2014 Jul 21;
Authors: Yaghootkar H, Scott RA, White CC, Zhang W, Speliotes E, Munroe PB, Ehret GB, Bis JC, Fox CS, Walker M, Borecki IB, Knowles JW, Yerges-Armstrong L, Ohlsson C, Perry JR, Chambers JC, Kooner JS, Franceschini N, Langenberg C, Hivert MF, Dastani Z, Richards JB, Semple RK, Frayling TM
The mechanisms that predispose to hypertension, coronary artery disease (CAD) and type 2 diabetes (T2D) in individuals of normal weight are poorly understood. In contrast, in monogenic primary lipodystrophy - a reduction in subcutaneous adipose tissue - it is clear that it is adipose dysfunction that causes severe insulin resistance (IR), hypertension, coronary artery disease and type 2 diabetes. We aimed to test the hypothesis that common alleles associated with insulin resistance also influence the wider clinical and biochemical profile of monogenic insulin resistance. We selected 19 common genetic variants associated with fasting insulin based measures of insulin resistance. We used hierarchical clustering and results from genome wide association studies of 8 non-disease outcomes of monogenic insulin resistance, to group these variants. We analysed genetic risk scores against disease outcomes including 12,171 T2D cases, 40,365 CAD cases and 69,828 individuals with blood pressure measurements. Hierarchical clustering identified 11 variants associated with a metabolic profile consistent with a common, subtle, form of lipodystrophy. A genetic risk score consisting of these 11 IR risk alleles was associated with higher triglycerides (ß=0.018; p=4x10(-29)), lower HDL cholesterol (ß=-0.020; p=7x10(-37)), greater hepatic steatosis (ß=0.021; p=3x10(-4)) higher alanine transaminase (ß=0.002; p=3x10(-5)), lower SHBG (ß=-0.010; p=9x10(-13)) and lower adiponectin (ß=-0.015; p=2x10(-26)). The same risk alleles were associated with lower BMI (per-allele ß=-0.008; p=7x10(-8)), and increased visceral-to-subcutaneous adipose tissue ratio (ß=-0.015; p=6x10(-7)). Individuals carrying >= 17 fasting insulin raising alleles (5.5% population) were slimmer (0.30 kgm(-2)) but at increased risk of T2D (odds ratio [OR] 1.46, per-allele p=5x10(-13)), CAD (OR 1.12, per-allele p=1x10(-5)), and increased blood pressure (systolic and diastolic blood pressure of 1.21 mmHg (per-allele p=2x10(-5)), and 0.67 mmHg (per-allele p=2x10(-4)), respectively, compared to individuals carrying <=9 risk alleles (5.5% population). Our results provide genetic evidence for a link between the three diseases of the "metabolic syndrome" and point to reduced subcutaneous adiposity as a central mechanism.
PMID: 25048195 [PubMed - as supplied by publisher]
When It Hurts (and Helps) to Try: The Role of Effort in Language Learning.
PLoS One. 2014;9(7):e101806
Authors: Finn AS, Lee T, Kraus A, Hudson Kam CL
Compared to children, adults are bad at learning language. This is counterintuitive; adults outperform children on most measures of cognition, especially those that involve effort (which continue to mature into early adulthood). The present study asks whether these mature effortful abilities interfere with language learning in adults and further, whether interference occurs equally for aspects of language that adults are good (word-segmentation) versus bad (grammar) at learning. Learners were exposed to an artificial language comprised of statistically defined words that belong to phonologically defined categories (grammar). Exposure occurred under passive or effortful conditions. Passive learners were told to listen while effortful learners were instructed to try to 1) learn the words, 2) learn the categories, or 3) learn the category-order. Effortful learners showed an advantage for learning words while passive learners showed an advantage for learning the categories. Effort can therefore hurt the learning of categories.
PMID: 25047901 [PubMed - as supplied by publisher]
Collateral vessel number, plaque burden, and functional decline in peripheral artery disease.
Vasc Med. 2014 Jul 21;19(4):281-288
Authors: McDermott MM, Carr J, Liu K, Kramer CM, Yuan C, Tian L, Criqui MH, Guralnik JM, Ferrucci L, Zhao L, Xu D, Kibbe M, Berry J, Carroll TJ
Associations of collateral vessels and lower extremity plaque with functional decline are unknown. Among people with peripheral artery disease (PAD), we determined whether greater superficial femoral artery (SFA) plaque burden combined with fewer lower extremity collateral vessels was associated with faster functional decline, compared to less plaque and/or more numerous collateral vessels. A total of 226 participants with ankle-brachial index (ABI) <1.00 underwent magnetic resonance imaging of lower extremity collateral vessels and cross-sectional imaging of the proximal SFA. Participants were categorized as follows: Group 1 (best), maximum plaque area < median and collateral vessel number ≥6 (median); Group 2, maximum plaque area < median and collateral vessel number <6; Group 3, maximum plaque area > median and collateral vessel number ≥6; Group 4 (worst), maximum plaque area > median and collateral vessel number <6. Functional measures were performed at baseline and annually for 2 years. Analyses adjust for age, sex, race, comorbidities, and other confounders. Annual changes in usual-paced walking velocity were: Group 1, +0.01 m/s; Group 2, -0.02 m/s; Group 3, -0.01 m/s; Group 4, -0.05 m/s (p-trend=0.008). Group 4 had greater decline than Group 1 (p<0.001), Group 2 (p=0.029), and Group 3 (p=0.010). Similar trends were observed for fastest-paced 4-meter walking velocity (p-trend=0.018). Results were not substantially changed when analyses were repeated with additional adjustment for ABI. However, there were no associations of SFA plaque burden and collateral vessel number with decline in 6-minute walk. In summary, a larger SFA plaque burden combined with fewer collateral vessels is associated with a faster decline in usual and fastest-paced walking velocity in PAD.
PMID: 25047855 [PubMed - as supplied by publisher]
Electronic Readout Enzyme-Linked Immunosorbent Assay with Organic Field-Effect Transistors as a Preeclampsia Prognostic.
Adv Mater. 2014 Jul 22;
Authors: Hammock ML, Knopfmacher O, Ng TN, Tok JB, Bao Z
Organic field-effect transistor (OFET) sensors can meet the need for portable and real-time diagnostics. We demonstrate an electronic readout enzyme-linked immunosorbent assay using OFETs for the detection of a panel of three biomarkers in complex media to create a pre-eclampsia prognostic. We also demonstrate biodetection utilizing a fully inkjet printed and flexible OFET to underscore our ability to produce disposable devices.
PMID: 25047764 [PubMed - as supplied by publisher]
Influence of the stiffness of three-dimensional alginate/collagen-I interpenetrating networks on fibroblast biology.
Biomaterials. 2014 Jul 18;
Authors: Branco da Cunha C, Klumpers DD, Li WA, Koshy ST, Weaver JC, Chaudhuri O, Granja PL, Mooney DJ
Wound dressing biomaterials are increasingly being designed to incorporate bioactive molecules to promote healing, but the impact of matrix mechanical properties on the biology of resident cells orchestrating skin repair and regeneration remains to be fully understood. This study investigated whether tuning the stiffness of a model wound dressing biomaterial could control the behavior of dermal fibroblasts. Fully interpenetrating networks (IPNs) of collagen-I and alginate were fabricated to enable gel stiffness to be tuned independently of gel architecture, polymer concentration or adhesion ligand density. Three-dimensional cultures of dermal fibroblasts encapsulated within matrices of different stiffness were shown to promote dramatically different cell morphologies, and enhanced stiffness resulted in upregulation of key-mediators of inflammation such as IL-10 and COX-2. These findings suggest that simply modulating the matrix mechanical properties of a given wound dressing biomaterial deposited at the wound site could regulate the progression of wound healing.
PMID: 25047628 [PubMed - as supplied by publisher]
How do cilia organize signalling cascades?
Philos Trans R Soc Lond B Biol Sci. 2014 Sep 5;369(1650)
Authors: Nachury MV
Cilia and flagella are closely related centriole-nucleated protrusions of the cell with roles in motility and signal transduction. Two of the best-studied signalling pathways organized by cilia are the transduction cascade for the morphogen Hedgehog in vertebrates and the mating pathway that initiates gamete fusion in the unicellular green alga Chlamydomonas reinhardtii. What is the role of cilia in these signalling transduction cascades? In both Hedgehog and mating pathways, all signalling intermediates have been found to localize to cilia, and, for some signalling factors, ciliary localization is regulated by pathway activation. Given a concentration factor of three orders of magnitude provided by translocating a protein into the cilium, the compartment model proposes that cilia act as miniaturized reaction tubes bringing signalling factors and processing enzymes in close proximity. On the other hand, the scaffolding model views the intraflagellar transport machinery, whose primary function is to build cilia and flagella, as a molecular scaffold for the mating transduction cascade at the flagellar membrane. While these models may coexist, it is hoped that a precise understanding of the mechanisms that govern signalling inside cilia will provide a satisfying answer to the question 'how do cilia organize signalling?'. This review covers the evidence supporting each model of signalling and outlines future directions that may address which model applies in given biological settings.
PMID: 25047619 [PubMed - as supplied by publisher]
The centriole duplication cycle.
Philos Trans R Soc Lond B Biol Sci. 2014 Sep 5;369(1650)
Authors: Fırat-Karalar EN, Stearns T
Centrosomes are the main microtubule-organizing centre of animal cells and are important for many critical cellular and developmental processes from cell polarization to cell division. At the core of the centrosome are centrioles, which recruit pericentriolar material to form the centrosome and act as basal bodies to nucleate formation of cilia and flagella. Defects in centriole structure, function and number are associated with a variety of human diseases, including cancer, brain diseases and ciliopathies. In this review, we discuss recent advances in our understanding of how new centrioles are assembled and how centriole number is controlled. We propose a general model for centriole duplication control in which cooperative binding of duplication factors defines a centriole 'origin of duplication' that initiates duplication, and passage through mitosis effects changes that license the centriole for a new round of duplication in the next cell cycle. We also focus on variations on the general theme in which many centrioles are created in a single cell cycle, including the specialized structures associated with these variations, the deuterosome in animal cells and the blepharoplast in lower plant cells.
PMID: 25047614 [PubMed - as supplied by publisher]
Top-Down Patterning and Self-Assembly for Regular Arrays of Semiconducting Single-Walled Carbon Nanotubes.
Adv Mater. 2014 Jul 22;
Authors: Wu J, Antaris A, Gong M, Dai H
Highly pure semiconducting single-walled carbon nanotubes (SWNTs), sorted by density gradient ultracentrifugation, undergo self-assembly using depletion attraction forces into rafts along lithographically defined patterns of narrow pitch (100 or 200 nm). The arrays demonstrate high pattern fidelity and channel filling, along with large-scale homogeneity. Field-effect transistors made from these arrays exhibit high performance at on/off ratios > 1000.
PMID: 25047392 [PubMed - as supplied by publisher]
Bio-Inspired Cryo-Ink Preserves Red Blood Cell Phenotype and Function During Nanoliter Vitrification.
Adv Mater. 2014 Jul 22;
Authors: El Assal R, Guven S, Gurkan UA, Gozen I, Shafiee H, Dalbeyler S, Abdalla N, Thomas G, Fuld W, Illigens BM, Estanislau J, Khoory J, Kaufman R, Zylberberg C, Lindeman N, Wen Q, Ghiran I, Demirci U
Current red blood cell cryopreservation methods utilize bulk volumes, causing cryo-injury of cells, which results in irreversible disruption of cell morphology, mechanics, and function. An innovative approach to preserve human red blood cell morphology, mechanics, and function following vitrification in nanoliter volumes is developed using a novel cryo-ink integrated with a bio-printing approach.
PMID: 25047246 [PubMed - as supplied by publisher]
The sports bra, the ACL, and Title IX--the game in play.
Clin Orthop Relat Res. 2014 Jun;472(6):1681-4
Authors: Ladd AL
PMID: 24723143 [PubMed - indexed for MEDLINE]
JAK inhibition in the myeloproliferative neoplasms: lessons learned from the bench and bedside.
Hematology Am Soc Hematol Educ Program. 2013;2013:529-37
Authors: Gotlib J
The discovery of the JAK2 V617F mutation in the classic BCR-ABL1-negative myeloproliferative neoplasms in 2005 catalyzed a burst of research efforts that have culminated in substantial dividends for patients. Beyond JAK2 V617F, a more detailed picture of the pathobiologic basis for activated JAK-STAT signaling has emerged. In some patients with myelofibrosis (MF), next-generation sequencing technologies have revealed a complex clonal architecture affecting both genetic and epigenetic regulators of cell growth and differentiation. Although these bench-top findings have informed the clinical development of JAK inhibitors in MF, they have also provided scientific context for some of their limitations. The JAK1/JAK2 inhibitor ruxolitinib is approved for treatment of MF in North America and Europe and other lead JAK inhibitors discussed herein (fedratinib [SAR302503], momelotinib [CYT387], and pacritinib [SB1518]), have entered advanced phases of trial investigation. Uniformly, these agents share the ability to reduce spleen size and symptom burden. A major challenge for practitioners is how to optimize dosing of these agents to secure clinically relevant and durable benefits while minimizing myelosuppression. Suboptimal responses have spurred a "return to the bench" to characterize the basis for disease persistence and to inform new avenues of drug therapy.
PMID: 24319228 [PubMed - indexed for MEDLINE]
A decade of Clinical Trials.
Clin Trials. 2013;10(6):837-9
Authors: Goodman SN
PMID: 24287131 [PubMed - indexed for MEDLINE]
Growing matter: a review of growth in living systems.
J Mech Behav Biomed Mater. 2014 Jan;29:529-43
Authors: Kuhl E
Living systems can grow, develop, adapt, and evolve. These phenomena are non-intuitive to traditional engineers and often difficult to understand. Yet, classical engineering tools can provide valuable insight into the mechanisms of growth in health and disease. Within the past decade, the concept of incompatible configurations has evolved as a powerful tool to model growing systems within the framework of nonlinear continuum mechanics. However, there is still a substantial disconnect between the individual disciplines, which explore the phenomenon of growth from different angles. Here we show that the nonlinear field theories of mechanics provide a unified concept to model finite growth by means of a single tensorial internal variable, the second order growth tensor. We review the literature and categorize existing growth models by means of two criteria: the microstructural appearance of growth, either isotropic or anisotropic; and the microenvironmental cues that drive the growth process, either chemical or mechanical. We demonstrate that this generic concept is applicable to a broad range of phenomena such as growing arteries, growing tumors, growing skin, growing airway walls, growing heart valve leaflets, growing skeletal muscle, growing plant stems, growing heart valve annuli, and growing cardiac muscle. The proposed approach has important biological and clinical applications in atherosclerosis, in-stent restenosis, tumor invasion, tissue expansion, chronic bronchitis, mitral regurgitation, limb lengthening, tendon tear, plant physiology, dilated and hypertrophic cardiomyopathy, and heart failure. Understanding the mechanisms of growth in these chronic conditions may open new avenues in medical device design and personalized medicine to surgically or pharmacologically manipulate development and alter, control, or revert disease progression.
PMID: 24239171 [PubMed - indexed for MEDLINE]
GCY-8, PDE-2, and NCS-1 are critical elements of the cGMP-dependent thermotransduction cascade in the AFD neurons responsible for C. elegans thermotaxis.
J Gen Physiol. 2013 Oct;142(4):437-49
Authors: Wang D, O'Halloran D, Goodman MB
Certain thermoreceptor neurons are sensitive to tiny thermal fluctuations (0.01°C or less) and maintain their sensitivity across a wide range of ambient temperatures through a process of adaptation, but understanding of the biochemical basis for this performance is rudimentary. Prior studies of the AFD thermoreceptor in Caenorhabditis elegans revealed a signaling cascade that depends on a trio of receptor guanylate cyclases (rGCs), GCY-8, GCY-18, and GCY-23, and gives rise to warming-activated thermoreceptor currents (ThRCs) carried by cyclic GMP-gated ion channels. The threshold for ThRC activation adapts to the ambient temperature through an unknown calcium-dependent process. Here, we use in vivo whole-cell patch-clamp recording from AFD to show that loss of GCY-8, but not of GCY-18 or GCY-23, reduces or eliminates ThRCs, identifying this rGC as a crucial signaling element. To learn more about thermotransduction and adaptation, we used behavioral screens and analysis of gene expression patterns to identify phosphodiesterases (PDEs) likely to contribute to thermotransduction. Deleting PDE-2 decouples the threshold for ThRC activation from ambient temperature, altering adaptation. We provide evidence that the conserved neuronal calcium sensor 1 protein also regulates the threshold for ThRC activation and propose a signaling network to account for ThRC activation and adaptation. Because PDEs play essential roles in diverse biological processes, including vertebrate phototransduction and olfaction, and regulation of smooth muscle contractility and cardiovascular function, this study has broad implications for understanding how extraordinary sensitivity and dynamic range is achieved in cyclic nucleotide-based signaling networks.
PMID: 24081984 [PubMed - indexed for MEDLINE]
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