Using exome sequencing, we identified a p.R191Q amino acid change in the
valosin-containing protein (
VCP) gene in an Italian family with autosomal dominantly inherited amyotrophic lateral sclerosis ...(ALS). Mutations in
VCP have previously been identified in families with Inclusion Body Myopathy, Paget disease, and Frontotemporal Dementia (IBMPFD). Screening of
VCP in a cohort of 210 familial ALS cases and 78 autopsy-proven ALS cases identified four additional mutations including a p.R155H mutation in a pathologically proven case of ALS. VCP protein is essential for maturation of ubiquitin-containing autophagosomes, and mutant VCP toxicity is partially mediated through its effect on TDP-43 protein, a major constituent of ubiquitin inclusions that neuropathologically characterize ALS. Our data broaden the phenotype of IBMPFD to include motor neuron degeneration, suggest that
VCP mutations may account for ∼1%–2% of familial ALS, and provide evidence directly implicating defects in the ubiquitination/protein degradation pathway in motor neuron degeneration.
► Exome sequencing was used to identify a mutation in VCP in a family with ALS ► Mutational screening indicates that VCP mutations account for ∼1%–2% of familial ALS ► Our data extend the clinical spectrum associated with IBMPFD syndrome to include ALS ► Identified defect in protein degradation pathway in motor neuron degeneration
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Cells must duplicate their mass in order to proliferate. Glucose and glutamine are the major nutrients consumed by proliferating mammalian cells, but the extent to which these and other nutrients ...contribute to cell mass is unknown. We quantified the fraction of cell mass derived from different nutrients and found that the majority of carbon mass in cells is derived from other amino acids, which are consumed at much lower rates than glucose and glutamine. While glucose carbon has diverse fates, glutamine contributes most to protein, suggesting that glutamine's ability to replenish tricarboxylic acid cycle intermediates (anaplerosis) is primarily used for amino acid biosynthesis. These findings demonstrate that rates of nutrient consumption are indirectly associated with mass accumulation and suggest that high rates of glucose and glutamine consumption support rapid cell proliferation beyond providing carbon for biosynthesis.
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•Glucose and glutamine are not the sources of the majority of mammalian cell mass•Non-glutamine amino acids provide abundant carbon and nitrogen to proliferating cells•Non-proliferating mammalian cells exhibit variable degrees of cell mass turnover•Nutrient fates are determined, showing that glutamine contributes primarily to protein
Hosios et al. analyze nutrient contributors to cell mass and find that although glucose and glutamine have the highest consumption rates, the majority of proliferative cell mass actually derives from non-glutamine amino acids. This quantitative analysis provides a framework for understanding proliferative metabolism of mammalian cells and cancer metabolism.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and ...epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.
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•T cells utilize GLS to support glutaminolysis that integrates with glycolysis•GLS promotes differentiation and function of Th17 cells yet restrains Th1 cells•GLS alters chromatin and gene expression to enhance IL2 and mTORC1 signaling•Targeting GLS protects from Th17 and enhances Th1 cells but can lead to exhaustion
Glutamine metabolism, and its effects on chromatin, promotes Th17 but constrains Th1 and CTL effector cell differentiation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Elastin, arterial mechanics, and cardiovascular disease Cocciolone, Austin J; Hawes, Jie Z; Staiculescu, Marius C ...
American journal of physiology. Heart and circulatory physiology,
08/2018, Volume:
315, Issue:
2
Journal Article
Peer reviewed
Open access
Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible ...elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies.
Studies suggest a high prevalence of burnout among nurses. The aim of this study was to evaluate the relationship between burnout among nurses and absenteeism and work performance.
A national sample ...of U.S. nurses was sent an anonymous, cross-sectional survey in 2016. The survey included items about demographics, fatigue, and validated instruments to measure burnout, absenteeism, and poor work performance in the last month.
Of the 3098 nurses who received the survey, 812 (26.2%) responded. The mean age was 52.3 years (SD 12.5), nearly all were women (94.5%) and most were married (61.9%) and had a child (75.2%). Participating nurses had a mean of 25.7 (SD 13.9) years of experience working as nurse and most held a baccalaureate (38.2%) or masters of science (37.1%) degree in nursing. A quarter worked in the inpatient setting (25.5%) and the average hours worked per week was 41.3 (SD 14.1). Overall, 35.3% had symptoms of burnout, 30.7% had symptoms of depression, 8.3% had been absent 1 or more days in the last month due to personal health, and 43.8% had poor work performance in the last month. Nurses who had burnout were more likely to have been absent 1 or more days in the last month (OR 1.85, 95% CI 1.25-2.72) and have poor work performance (referent: high performer; medium performer, OR 2.68,95% CI 1.82-3.99; poor performer, OR 5.01, 95% CI 3.09-8.14). After adjusting for age, sex, relationship and parental status, highest academic degree, practice setting, burnout, depression, and satisfaction with work-life integration, nurses who were more fatigued (for each point worsening, OR 1.22, 95% CI 1.10-1.37) were more likely to have had absenteeism while those who worked more hours (for each additional hour OR 0.98, 95% CI 0.96-1.00) were less likely to have had absenteeism. Factors independently associated with poor work performance included burnout (OR 2.15, 95% CI 1.43-3.24) and fatigue (for each point of worsening, OR 1.22, 95% CI 1.12-1.33).
These findings suggest burnout is prevalent among nurses and likely impacts work performance.
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IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UL, UM, UPUK, VSZLJ
Summary
Clearing senescent cells extends healthspan in mice. Using a hypothesis‐driven bioinformatics‐based approach, we recently identified pro‐survival pathways in human senescent cells that ...contribute to their resistance to apoptosis. This led to identification of dasatinib (D) and quercetin (Q) as senolytics, agents that target some of these pathways and induce apoptosis preferentially in senescent cells. Among other pro‐survival regulators identified was Bcl‐xl. Here, we tested whether the Bcl‐2 family inhibitors, navitoclax (N) and TW‐37 (T), are senolytic. Like D and Q, N is senolytic in some, but not all types of senescent cells: N reduced viability of senescent human umbilical vein epithelial cells (HUVECs), IMR90 human lung fibroblasts, and murine embryonic fibroblasts (MEFs), but not human primary preadipocytes, consistent with our previous finding that Bcl‐xl siRNA is senolytic in HUVECs, but not preadipocytes. In contrast, T had little senolytic activity. N targets Bcl‐2, Bcl‐xl, and Bcl‐w, while T targets Bcl‐2, Bcl‐xl, and Mcl‐1. The combination of Bcl‐2, Bcl‐xl, and Bcl‐w siRNAs was senolytic in HUVECs and IMR90 cells, while combination of Bcl‐2, Bcl‐xl, and Mcl‐1 siRNAs was not. Susceptibility to N correlated with patterns of Bcl‐2 family member proteins in different types of human senescent cells, as has been found in predicting response of cancers to N. Thus, N is senolytic and acts in a potentially predictable cell type‐restricted manner. The hypothesis‐driven, bioinformatics‐based approach we used to discover that dasatinib (D) and quercetin (Q) are senolytic can be extended to increase the repertoire of senolytic drugs, including additional cell type‐specific senolytic agents.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and ...extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
This paper examines how tactical-grade Inertial Navigation Systems (INS), aided by Global Navigation Satellite System (GNSS) modules, vary from a survey-grade system in the bathymetric mapping in ...depths less than 20 m. The motivation stems from the advancements in sensor developments, measurement processing algorithms, and the proliferation of autonomous and uncrewed surface vehicles often seeking to use tactical-grade systems for high-quality bathymetric products. While the performance of survey-grade GNSS + INS is well-known to the hydrographic and marine science community, the performance and limitations of the tactical-grade micro-electro-mechanical system (MEMS) and tactical-grade fiber-optic-gyro (FOG) INS aided with GNSS require some study to answer the following questions: (1) How close or far is the tactical-grade GNSS + INS performance from the survey-grade systems? (2) For what survey order (IHO S-44 6th ed.) can a user deploy them? (3) Can we use them for navigation chart production? We attempt to answer these questions by deploying two tactical-grade GNSS + INS units (MEMS and FOG) and a survey-grade GNSS + INS on a survey boat. All systems collected data while operating a multibeam system with the lever-arm offsets accurately determined using a total station. The tactical-grade GNSS + INSs shared one pair of antennas for heading, while the survey-grade system used an independent antenna pair. We analyze the GNSS + INS results in sequence, examine the patch-test results, and the sensor-specific SBET-integrated bathymetric surfaces as metrics for determining the tactical-grade GNSS + INSs' reliability. In addition, we evaluate the multibeam's sounding uncertainties at different beam angles. The bathymetric surfaces using the tactical-grade navigation solutions are within 15 cm of the surface generated with the survey-grade solutions.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
A complete set of experimental data on novel Electrodialysis Metathesis (EDM) desalination was analyzed using factorial design. EDM consists of repeating quads of four ion-exchange membranes and ...solution compartments to allow double decomposition reaction between the cations and anions of a feed and a substitution solution when current is applied between the electrodes. The effect of factors affecting the EDM desalination efficiency, such as voltage, flow rate, membrane type, and feed water source was studied using a full 24 factorial experimental design. The General Linear Model was used to evaluate the combined effect of the discrete and continuous factor variables introduced in the design. It was found that voltage, water source and membrane type were the most influential factors on the EDM process. Interaction terms were found to be insignificant. The effect of main factors on EDM desalination follow the order voltage>water source>type of membrane. EDM desalinate well saline waters with TDS concentrations higher that the TDS of surface water by applying 15V and using Neosepta membranes. The responses obtained with the GLM were in agreement with the experimental data, thus confirming the ability of the model to predict desalination results. Complete desalination of high salinity water was achieved without formation of precipitates in the stack due to the ability of EDM to convert sparingly soluble salts into highly soluble salts.
•Electrodialysis metathesis (EDM) is a novel desalination process based on the use of metathesis reactions.•EDM desalinates well TDS concentrations higher that the TDS of surface water at 15V and with Neosepta membranes.•The effect of main factors on EDM desalination follows the order voltage>water source>type of membrane.•The general linear model (GLM) takes continuous factors as covariates for the discrete factors in the EDM process.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
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