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  • Article
    Li QQ, Zhang L, Wan HY, Liu M, Li X, Tang H.
    Oncotarget. 2015 Oct 27;6(33):34924-40.
    The altered expression of miRNAs in response to stresses contributes to cancer pathogenesis. However, little is known regarding the mechanism by which cellular stresses drive alterations in miRNA expression. Here, we found that serum starvation enhanced mitophagy by downregulating the mitophagy-associated protein voltage-dependent anion channel 1 (VDAC1) and by inducing the expression of miR-320a and the transcription factor cAMP responsive element binding protein 1(CREB1). Furthermore, we cloned the promoter of miR-320a and identified the core promoter of miR-320a in the upstream -16 to -130 region of pre-miR-320a. Moreover, CREB1 was found to bind to the promoter of miR-320a to activate its expression and to induce mitophagy during serum starvation. Collectively, our results reveal a new mechanism underlying serum starvation-induced mitophagy in which serum starvation induces CREB1 expression, in turn activating miR-320a expression, which then down-regulates VDAC1 expression to facilitate mitophagy. These findings may provide new insights into cancer cell survival in response to environmental stresses.
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  • Article
    Goyal M, Singh N, Kapoor R, Verma A, Gedam P.
    Cureus. 2023 Feb;15(2):e34924.
    Introduction Malnutrition among children continues to be a severe public health problem worldwide, whether in a developing country like India or a developed nation. Correct estimation of the problem is a prerequisite to planning the measures to control it. Objective To estimate the prevalence of undernutrition among children under five years of age by utilizing the Composite Index of Anthropometric Failure and the WHO growth charts. Methods From January to March 2020, 1332 children under the age of five years participated in a facility-based, descriptive, cross-sectional study at Fatehpur Beri, Urban Primary Health Center. An anthropometric assessment for each participant was done as per the WHO criteria. The data were entered into a Microsoft Office Excel spreadsheet (Microsoft Corporation, Redmond, WA) and analyzed with WHO Anthro software (WHO, Geneva, Switzerland) and a licensed version of SPSS 21 (IBM Corp., Armonk, NY). Continuous data were expressed using appropriate measures of central tendency, while categorical data were expressed in either frequency or proportions. Results The mean age of the study participants was 23.04 ± 18.24 months, and males (53.3%) were more than (46.7%) females. The prevalence of being underweight was 24.5% (327/1332), of which 24.1% (79/327) of children were severely underweight. Of the total study participants, 27.3% (362/1332) were stunted, and 17.8% (237/1332) were wasted, of which 29.1% (69/237) were severely wasted. The prevalence of anthropometric failure was 45%. Conclusions According to the findings of this study, the prevalence of undernutrition among the study participants was substantial. Furthermore, considering weight for age as the sole criterion may underestimate the true prevalence of malnutrition. The findings have critical implications for future interventions and initiatives among children in India.
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  • Article
    Xu H, Pasini D.
    Sci Rep. 2016 10 10;6:34924.
    The coefficient of thermal expansion (CTE) of architected materials, as opposed to that of conventional solids, can be tuned to zero by intentionally altering the geometry of their structural layout. Existing material architectures, however, achieve CTE tunability only with a sacrifice in structural efficiency, i.e. a drop in both their stiffness to mass ratio and strength to mass ratio. In this work, we elucidate how to resolve the trade-off between CTE tunability and structural efficiency and present a lightweight bi-material architecture that not only is stiffer and stronger than other 3D architected materials, but also has a highly tunable CTE. Via a combination of physical experiments on 3D fabricated prototypes and numeric simulations, we demonstrate how two distinct mechanisms of thermal expansion appearing in a tetrahedron, can be exploited in an Octet lattice to generate a large range of CTE values, including negative, zero, or positive, with no loss in structural efficiency. The novelty and simplicity of the proposed design as well as the ease in fabrication, make this bi-material architecture well-suited for a wide range of applications, including satellite antennas, space optical systems, precision instruments, thermal actuators, and MEMS.
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  • Article
    Yu OC, Jung B, Go H, Park M, Ha IH.
    BMJ Open. 2020 10 05;10(10):e034924.
    OBJECTIVES: Dementia is common in people over the age of 65 years, with 80% of people with dementia older than 75 years. Previous studies have linked dementia to late-life depression, but the association between dementia and mid-life depression is poorly understood. Depression is a preventable and treatable medical condition, which means it is a modifiable factor that can potentially prevent or delay dementia. This study aimed to identify the association between dementia and depression within the life course.
    DESIGN: A nationwide, retrospective propensity score matched cohort study associating dementia with depression. Depression diagnosed between the ages of 45 and 64 years was classified as 'mid-life' and 'late-life' if diagnosed at 65 years or older. Patients were considered to have depression when one or more International Statistical Classification of Diseases and Related Health Problems, 10th revision codes for depression were recorded as primary or secondary diagnosis.
    SETTING: National Health Insurance Service-National Sample Cohort database of the National Health Insurance Service in South Korea, containing patient data from 2002 to 2013.
    PARTICIPANTS: The study included 1824 and 374 852 patients in the case and control groups, respectively. A logistic regression analysis with complex sampling design was performed after adjusting for covariates, using the propensity score matching method without callipers, with a 1:1 nearest neighbour matching algorithm.
    PRIMARY AND SECONDARY OUTCOME MEASURES: The association of mid-onset and late-onset depression with dementia in terms of sociodemographic characteristics, such as sex and age, within the Korean population.
    RESULTS: Dementia was significantly associated with the presence of depression (OR=2.20, 95% CI=1.53-3.14); in particular, female patients with depression and patients aged 45-64 years with depression had increased odds of dementia (OR=2.65, 95% CI=1.78-3.93 and OR=2.72, 95% CI=1.41-5.24, respectively) CONCLUSION: Depression is an associated factor for dementia, especially among people aged 45-64 years (mid-life).
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  • Article
    Wang F, Wang Y, Liu J.
    Medicine (Baltimore). 2023 Sep 29;102(39):e34924.
    To explore the risk factors for peripherally inserted central venous catheter (PICC)-related complications in children. This retrospective study analyzed data collected from electronic medical records. A total of 584 patients with indwelling PICC treated between January 2019 and August 2021 were included in this study. According to the occurrence of PICC-related complications, the patients without PICC-related complications were included in the control group (n = 538) and those with PICC-related complications were included the observation group (n = 46). The risk factors for PICC-related complications were analyzed. Of the 584 patients with PICCs, 46 (7.88%) had PICC-related complications. Univariate analysis revealed significant differences in venipuncture (P < .001), oozing of blood from the puncture point (P < .001), indwelling time (P < .001), intravenous nutrient solution (P < .001), and catheter type (P = .003). Complications were used as dependent variables. The independent variables were vein puncture, blood oozing at the puncture point, indwelling time, intravenous nutrient solution, and catheter type. Multivariate logistic regression analysis revealed that the vein puncture (odds ratio [OR] 10.115, 95% confidence interval [CI] 5.034-20.323, P < .001), puncture point blood oozing (OR 9.217, 95% CI 3.860-22.004, P < .001), indwelling time (OR 6.390, 95% CI 3.527-10.972, P = .005), intravenous nutrient solution (OR 2.593, 95% CI 1.675-4.015, P < .001), and catheter type (OR 8.588, 95% CI 2.048-19.095, P = .013) were all risk factors for PICC-related complications in children. Venipuncture, oozing of blood from the puncture point, indwelling time, intravenous nutrient solution, and catheter type are risk factors for PICC-related complications in children. Significant attention should be paid to whether the puncture point is bleeding, the presence or absence of an intravenous nutrient solution, duration of catheterization, type of catheterization, and venipuncture. Additionally, preventive nursing measures should be implemented as soon as possible to reduce the risk of complications related to peripheral PICC.
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  • Article
    Han Y, Yuan Z, Yi Z.
    J Virol. 2024 Apr 19:e0034924.
    The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), has rapidly spread worldwide since its emergence in late 2019. Its ongoing evolution poses challenges for antiviral drug development. Coronavirus nsp6, a multiple-spanning transmembrane protein, participates in the biogenesis of the viral replication complex, which accommodates the viral replication-transcription complex. The roles of its structural domains in viral replication are not well studied. Herein, we predicted the structure of the SARS-CoV-2 nsp6 protein using AlphaFold2 and identified a highly folded C-terminal region (nsp6C) downstream of the transmembrane helices. The enhanced green fluorescent protein (EGFP)-fused nsp6C was found to cluster in the cytoplasm and associate with membranes. Functional mapping identified a minimal membrane-associated element (MAE) as the region from amino acids 237 to 276 (LGV-KLL), which is mainly composed of the α-helix H1 and the α-helix H2; the latter exhibits characteristics of an amphipathic helix (AH). Mutagenesis studies and membrane flotation experiments demonstrate that AH-like H2 is required for MAE-mediated membrane association. This MAE was functionally conserved across MERS-CoV, HCoV-OC43, HCoV-229E, HCoV-HKU1, and HCoV-NL63, all capable of mediating membrane association. In a SARS-CoV-2 replicon system, mutagenesis studies of H2 and replacements of H1 and H2 with their homologous counterparts demonstrated requirements of residues on both sides of the H2 and properly paired H1-H2 for MAE-mediated membrane association and viral replication. Notably, mutations I266A and K274A significantly attenuated viral replication without dramatically affecting membrane association, suggesting a dual role of the MAE in viral replication: mediating membrane association as well as participating in protein-protein interactions.IMPORTANCESevere acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) assembles a double-membrane vesicle (DMV) by the viral non-structural proteins for viral replication. Understanding the mechanisms of the DMV assembly is of paramount importance for antiviral development. Nsp6, a multiple-spanning transmembrane protein, plays an important role in the DMV biogenesis. Herein, we predicted the nsp6 structure of SARS-CoV-2 and other human coronaviruses using AlphaFold2 and identified a putative membrane-associated element (MAE) in the highly conserved C-terminal regions of nsp6. Experimentally, we verified a functionally conserved minimal MAE composed of two α-helices, the H1, and the amphipathic helix-like H2. Mutagenesis studies confirmed the requirement of H2 for MAE-mediated membrane association and viral replication and demonstrated a dual role of the MAE in viral replication, by mediating membrane association and participating in residue-specific interactions. This functionally conserved MAE may serve as a novel anti-viral target.
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  • Article
    Zschocke J, Bayatti N, Clement AM, Witan H, Figiel M, Engele J, Behl C.
    J Biol Chem. 2005 Oct 14;280(41):34924-32.
    Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked by the specific GLT-1 inhibitor dihydrokainate. The promoting effect of dexamethasone on GLT-1 gene expression and function was abolished by the GR antagonist mifepristone. A predominant role of the GR was further supported by the observation that corticosterone could elevate GLT-1 expression in a dose-dependent manner, whereas aldosterone, the physiological ligand of the mineralocorticoid receptor, exerted only weak effects even when applied at high concentrations. Moreover, we monitored brain region-specific differences, since all corticosteroids used in this study failed to alter the expression of GLT-1 in midbrain and cerebellar glia, although expression levels of both corticosteroid receptor subtypes were similar in all brain regions analyzed. Dexamethasone, however, modestly enhanced GLT-1 expression in cerebellar glia in combination with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine, suggesting that suppression of GLT-1 expression in cerebellar cultures may at least in part be epigenetically mediated by a DNA methylation-dependent process. Taken together, our data highlight a potential role for glucocorticoids in regulating GLT-1 gene expression during central nervous system development or pathophysiological processes including stress.
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  • Article
    Davoodi M, Davar F, Rezayat MR, Jafari MT, Bazarganipour M, Shalan AE.
    RSC Adv. 2021 Oct 25;11(55):34924.
    [This corrects the article DOI: 10.1039/D1RA01056E.].
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  • Article
    Kawar ZS, Van Die I, Cummings RD.
    J Biol Chem. 2002 Sep 20;277(38):34924-32.
    A common terminal structure in glycans from animal glycoproteins and glycolipids is the lactosamine sequence Gal(beta)4GlcNAc-R (LacNAc or LN). An alternative sequence that occurs in vertebrate as well as in invertebrate glycoconjugates is GalNAc(beta)4GlcNAc-R (LacdiNAc or LDN). Whereas genes encoding beta4GalTs responsible for LN synthesis have been reported, the beta4GalNAcT(s) responsible for LDN synthesis has not been identified. Here we report the identification of a gene from Caenorhabditis elegans encoding a UDP-GalNAc:GlcNAc(beta)-R beta1,4-N-acetylgalactosaminyltransferase (Ce(beta)4GalNAcT) that synthesizes the LDN structure. Ce(beta)4GalNAcT is a member of the beta4GalT family, and its cDNA is predicted to encode a 383-amino acid type 2 membrane glycoprotein. A soluble, epitope-tagged recombinant form of Ce(beta)4GalNAcT expressed in CHO-Lec8 cells was active using UDP-GalNAc, but not UDP-Gal, as a donor toward a variety of acceptor substrates containing terminal beta-linked GlcNAc in both N- and O-glycan type structures. The LDN structure of the product was verified by co-chromatography with authentic standards and (1)H NMR spectroscopy. Moreover, Chinese hamster ovary CHO-Lec8 and CHO-Lec2 cells expressing Ce(beta)4GalNAcT acquired LDN determinants on endogenous glycoprotein N-glycans, demonstrating that the enzyme is active in mammalian cells as an authentic beta4GalNAcT. The identification and availability of this novel enzyme should enhance our understanding of the structure and function of LDN-containing glycoconjugates.
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  • Article
    Johannesen E, Høines ÅS, Dolgov AV, Fossheim M.
    PLoS One. 2012;7(4):e34924.
    Direct and indirect effects of global warming are expected to be pronounced and fast in the Arctic, impacting terrestrial, freshwater and marine ecosystems. The Barents Sea is a high latitude shelf Sea and a boundary area between arctic and boreal faunas. These faunas are likely to respond differently to changes in climate. In addition, the Barents Sea is highly impacted by fisheries and other human activities. This strong human presence places great demands on scientific investigation and advisory capacity. In order to identify basic community structures against which future climate related or other human induced changes could be evaluated, we analyzed species composition and diversity of demersal fish in the Barents Sea. We found six main assemblages that were separated along depth and temperature gradients. There are indications that climate driven changes have already taken place, since boreal species were found in large parts of the Barents Sea shelf, including also the northern Arctic area. When modelling diversity as a function of depth and temperature, we found that two of the assemblages in the eastern Barents Sea showed lower diversity than expected from their depth and temperature. This is probably caused by low habitat complexity and the distance to the pool of boreal species in the western Barents Sea. In contrast coastal assemblages in south western Barents Sea and along Novaya Zemlya archipelago in the Eastern Barents Sea can be described as diversity "hotspots"; the South-western area had high density of species, abundance and biomass, and here some species have their northern distribution limit, whereas the Novaya Zemlya area has unique fauna of Arctic, coastal demersal fish. (see Information S1 for abstract in Russian).
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  • Article
    Kim AL, Raffo AJ, Brandt-Rauf PW, Pincus MR, Monaco R, Abarzua P, Fine RL.
    J Biol Chem. 1999 Dec 03;274(49):34924-31.
    A p53-derived C-terminal peptide induced rapid apoptosis in breast cancer cell lines carrying endogenous p53 mutations or overexpressed wild-type (wt) p53 but was not toxic to nonmalignant human cell lines containing wt p53. Apoptosis occurred through a Fas/APO-1 signaling pathway involving increased extracellular levels of Fas/FasL in the absence of protein synthesis, as well as activation of a Fas/APO-1-specific protease, FLICE. The peptide activity was p53-dependent, and it had no effect in three tumor cell lines with null p53. Furthermore, the C-terminal peptide bound to p53 protein in cell extracts. Thus, p53-dependent, Fas/APO-1 mediated apoptosis can be induced in breast cancer cells with mutant p53 similar to the recently described Fas/APO-1 induced apoptosis by wt p53. However, mutant p53 without p53 peptide does not induce a Fas/APO-1 activation or apoptosis. Docking of the computed low energy conformations for the C-terminal peptide with those for a recently defined proline-rich regulatory region from the N-terminal domain of p53 suggests a unique low energy complex between the two peptide domains. The selective and rapid induction of apoptosis in cancer cells carrying p53 abnormalities may lead to a novel therapeutic modality.
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  • Article
    Wang M.
    Environ Sci Pollut Res Int. 2021 Jul;28(26):34924-34936.
    The inefficient enforcement of environmental policies cannot address global environmental challenges. As a result, China's government has implemented the Central Environmental Protection Inspection (CEPI) to overcome the policy-implementation gap between higher and lower levels of government. The existing literature has examined the positive effects of CEPI on environmental pollution, but has not explained the mechanisms for its success. To examine these mechanisms, this article uses a series of regression analyses on an empirical data set of 282 prefecture-level cities from 2010 to 2018. The results identify the mechanism for the effective implementation of CEPI, from the perspective of the campaign-style governance of local officials at local levels. This study also shows the heterogeneity of the campaign-style governance behavior of local officials, including position types and professional and cultural backgrounds. And finally, this study demonstrates that the campaign-style governance behavior of local officials has a moderating effect on the relationship between environmental pollution and local officials' promotion. Ultimately the article proposes that higher government levels should adopt the effective incentives policy to address gaps between environmental policy and implementation.
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  • Article
    Morgan AM, Ibrahim MA, Hussien AM.
    Environ Sci Pollut Res Int. 2019 Dec;26(34):34924-34930.
    Atrazine (ATR) is a common herbicide used worldwide. It is a potent endocrine disruptor that causes hormonal imbalance. We investigated the modulatory role predisposed by glycyrrhizic acid (GA) against the hazardous effects caused by the ATR in the rabbit spleen. Sixty rabbits were assigned into 4 groups. The first group is the negative control; the ATR group received 1/10 of the oral LD 50 ATR; the GA group received 50 mg/kg body weight daily intraproteinally; and group 4 received both ATR and GA concurrently. ATR and GA administrations were done for 60 days. ATR-induced humoral immunotoxicity was illustrated by decreased serum total protein, albumin, and globulin levels and rabbit hemorrhagic disease virus antibody titer, 4 weeks after vaccination. Moreover, upregulation of spleen Fas and caspase-III genes was recorded in ATR-exposed rabbits. Clear splenocyte apoptosis was observed in the immunohistochemical examination by the caspase-III technique. GA diminished the ATR-induced splenocyte apoptosis through downregulation of Fas and caspase-III expressions. In conclusion, our findings bounced a new perspective into the mechanism by which ATR induces immunotoxicity and assumed the potential modulatory role of GA.
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  • Article
    Hasany M, Thakur A, Taebnia N, Kadumudi FB, Shahbazi MA, Pierchala MK, Mohanty S, Orive G, Andresen TL, Foldager CB, Yaghmaei S, Arpanaei A, Gaharwar AK, Mehrali M, Dolatshahi-Pirouz A.
    ACS Appl Mater Interfaces. 2018 Oct 17;10(41):34924-34941.
    Despite the promise of hydrogel-based stem cell therapies in orthopedics, a significant need still exists for the development of injectable microenvironments capable of utilizing the  regenerative potential of donor cells. Indeed, the quest for biomaterials that can direct stem cells into bone without the need of external factors has been the "Holy Grail" in orthopedic stem cell therapy for decades. To address this challenge, we have utilized a combinatorial approach to screen over 63 nanoengineered hydrogels made from alginate, hyaluronic acid, and two-dimensional nanoclays. Out of these combinations, we have identified a biomaterial that can promote osteogenesis in the absence of well-established differentiation factors such as bone morphogenetic protein 2 (BMP2) or dexamethasone. Notably, in our "hit" formulations we observed a 36-fold increase in alkaline phosphate (ALP) activity and a 11-fold increase in the formation of mineralized matrix, compared to the control hydrogel. This induced osteogenesis was further supported by X-ray diffraction, scanning electron microscopy, Fourier transform infrared spectroscopy, and energy-dispersive X-ray spectroscopy. Additionally, the Montmorillonite-reinforced hydrogels exhibited high osteointegration as evident from the relatively stronger adhesion to the bone explants as compared to the control. Overall, our results demonstrate the capability of combinatorial and nanoengineered biomaterials to induce bone regeneration through osteoinduction of stem cells in a natural and differentiation-factor-free environment.
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  • Article
    Chen B, Chen P, Xu H, Jin F, Guo Z, Lan D, Wan S, Gao G, Chen F, Wu W.
    ACS Appl Mater Interfaces. 2016 Dec 21;8(50):34924-34932.
    Controlling functionalities in oxide heterostructures remains challenging for the rather complex interfacial interactions. Here, by modifying the interface properties with chemical doping, we achieve a nontrivial control over the ferromagnetism in ultrathin La0.67Ca0.33MnO3 (LCMO) layer sandwiched between CaRu1-xTixO3 [CRTO(x)] epilayers. The Ti doping suppresses the interfacial electron transfer from CRTO(x) to LCMO side; as a result, a steadily decreased Curie temperature with increasing x, from 262 K at x = 0 to 186 K at x = 0.8, is observed for the structures with LCMO fixed at 3.2 nm. Moreover, for more insulating CRTO(x ≥ 0.5), the electron confinement induces an interfacial Mn-eg(x2-y2) orbital order in LCMO which further attenuates the ferromagnetism. Also, in order to characterize the heterointerfaces, for the first time the doping- and thickness-dependent metal-insulator transitions in CRTO(x) films are examined. Our results demonstrate that the LCMO/CRTO(x) heterostructure could be a model system for investigating the interfacial multiple interactions in correlated oxides.
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  • Article
    DE Oliveira VM, Magalhães WF, Lana PDC.
    Zootaxa. 2021 Feb 03;4924(1):zootaxa.4924.1.1.
    Herein we provide a taxonomic revision of Phyllodoce species from Brazil, describing 10 new species in addition to two new records, Phyllodoce longipes Kinberg, 1866 and Phyllodoce cf. madeirensis Langerhans, 1880. Phyllodoce sp. A. and Phyllodoce sp. B. are probably new but the number and condition of available specimens do not provide adequate and reliable diagnostic features for a formal description. These species have been collected in diverse marine and estuarine environments from shallow estuarine bottoms to continental shelf and slope sediments and submarine canyons from off southern and southeastern Brazil. A key to the fourteen species of Phyllodoce occurring in Brazil is also given.
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  • Book
    [edited by] Bernard Rousseau, Ryan C. Branski.
    Summary: Anatomy and Physiology of Speech and Hearing Anatomy and Physiology of Speech and Hearing by Bernard Rousseau and Ryan C. Branski fulfills a growing need for a contemporary resource for students in speech and hearing science training programs. Extending well beyond traditional speech science and human anatomy, this publication encompasses the latest advances in the understanding of human physiology, basic cell functions, biological control systems, and coordinated body functions. Anatomy and Physiology of Speech and Hearing includes award-winning anatomic artwork from Thieme's Atlas of Anatomy.

    Contents:
    Framework for anatomy and physiology / Samuel R. Atcherson, Melanie Lowry, Bonnie K. Slavych
    Composition of the body : cells, tissues, organs / Elizabeth Erickson-DiRenzo, Daniel DiRenzo
    Genetics / Barbara Lewis, Sudha Iyengar, Catherine Stein
    Embryology and development of the speech and hearing mechanism / Steven L. Goudy, Christen Lennon
    Neuroanatomy / Torrey Loucks, Li-Hsin Ning
    Neurophysiology / Michelle R. Ciucci, Erwin B. Montgomery, Lyn S. Turkstra
    Central motor control / Erwin B. Montgomery, Michelle R. Ciucci, Lyn S. Turkstra
    Peripheral motor control / Mary J. Sandage, David D. Pascoe
    Sensory systems / Richard Andreatta, Nicole Etter
    Respiration / Bari Hoffman-Ruddy, Erin P. Silverman
    Phonation / Christopher R. Watts
    Articulation and resonance / Jessica E. Huber, Kate Bunton
    Hearing / Jason T. Sanchez, Tina M. Grieco-Calub
    Swallowing / Michelle Troche, Alexandria E. Brandimore
    Balance / Elizabeth Adams.
    Digital Access Thieme MedOne ComSci [2018]
  • Article
    LaFevre-Bernt MA, Ellerby LM.
    J Biol Chem. 2003 Sep 12;278(37):34918-24.
    X-linked spinal and bulbar muscular atrophy is a degenerative disease affecting motor neurons that is caused by polyglutamine (polyQ) expansion within the androgen receptor (AR). The polyQ-expanded form of AR is cytotoxic to cells, and proteolytic cleavage enhances cell death. The intracellular signaling pathways activated and/or required for cell death induced by the expanded form of AR (AR112) are unknown. We found that AR regulates mitogen-activated protein kinase (MAP kinase) pathways and, therefore, hypothesized that these pathway(s) may be required for AR112-induced cell death. The polyQ expansion in AR activates three MAP kinase pathways, causing increasing levels of phosphorylation of p44/42, p38, and SAPK/JNK MAP kinase. Inhibitors of either the JNK or p38 pathways had no effect on AR112-induced cell death, suggesting they are not required for polyQ-induced cell death. Strikingly, the MEK1/2 inhibitor, U0126, which selectively inhibits the p44/42 MAP kinase pathway, reduces AR112-stimulated cell death. The inhibition of the MEK1/2 pathway correlates directly with a change in phosphorylation state of the androgen receptor. Mutation of the MAP kinase consensus phosphorylation site in AR at serine 514 blocked AR-induced cell death and the generation of caspase-3-derived cleavage products. We propose a mechanism by which phosphorylation at serine 514 of AR enhances the ability of caspase-3 to cleave AR and generate cytotoxic polyQ fragments.
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