Atf6alpha impacts cell number by influencing survival, death and proliferation

BACKGROUND: A growing body of literature suggests the cell-intrinsic activity of Atf6alpha during ER stress responses has implications for tissue cell number during growth and development, as well as in adult biology and tumorigenesis [1]. This concept is important, linking the cellular processes of secretory protein synthesis and endoplasmic reticulum stress response with functional tissue capacity and organ size. However, the field contains conflicting observations, especially notable in secretory cell types like the pancreatic beta cell. SCOPE OF REVIEW: Here we summarize current knowledge of the basic biology of Atf6alpha, along with the pleiotropic roles Atf6alpha plays in cell life and death decisions and possible explanations for conflicting observations. We include studies investigating the roles of Atf6alpha in cell survival, death and proliferation using well-controlled methodology and specific validated outcome measures, with a focus on endocrine and metabolic tissues when information was available. MAJOR CONCLUSIONS: The net outcome of Atf6alpha on cell survival and cell death depends on cell type and growth conditions, the presence and degree of ER stress, and the duration and intensity of Atf6alpha activation. It is unquestioned that Atf6alpha activity influences the cell fate decision between survival and death, although opposite directions of this outcome are reported in different contexts. Atf6alpha can also trigger cell cycle activity to expand tissue cell number through proliferation. Much work remains to be done to clarify the many gaps in understanding in this important emerging field

Endoplasmic Reticulum Stress Induced Proliferation Remains Intact in Aging Mouse beta-Cells

Aging is associated with loss of proliferation of the insulin-secreting beta-cell, a possible contributing factor to the increased prevalence of type 2 diabetes in the elderly. Our group previously discovered that moderate endoplasmic reticulum (ER) stress occurring during glucose exposure increases the adaptive beta-cell proliferation response. Specifically, the ATF6alpha arm of the tripartite Unfolded Protein Response (UPR) promotes beta-cell replication in glucose excess conditions. We hypothesized that beta-cells from older mice have reduced proliferation due to aberrant UPR signaling or an impaired proliferative response to ER stress or ATF6alpha activation. To investigate, young and old mouse islet cells were exposed to high glucose with low-dose thapsigargin or activation of overexpressed ATF6alpha, and beta-cell proliferation was quantified by BrdU incorporation. UPR pathway activation was compared by qPCR of target genes and semi-quantitative Xbp1 splicing assay. Intriguingly, although old beta-cells had reduced proliferation in high glucose compared to young beta-cells, UPR activation and induction of proliferation in response to low-dose thapsigargin or ATF6alpha activation in high glucose were largely similar between young and old. These results suggest that loss of UPR-led adaptive proliferation does not explain the reduced cell cycle entry in old beta-cells, and raise the exciting possibility that future therapies that engage adaptive UPR could increase beta-cell number through proliferation even in older individuals

Possible glass-like random singlet magnetic state in 1T-TaS2

Two-dimensional layered transition-metal-dichalcogenide compound 1T-TaS2 shows the rare coexistence of charge density wave (CDW) and electron correlation driven Mott transition. In addition, atomic-cluster spins on the triangular lattice of the CDW state of 1T-TaS2 give rise to the possibility of the exotic spin-singlet state in which quantum fluctuations of spins are strong enough to prevent any long range magnetic ordering down to absolute zero ( 0 K). We present here the evidences of a glass-like random singlet magnetic state in 1T-TaS2 at low temperatures through a study of temperature and time dependence of magnetization. Comparing the experimental results with a representative canonical spin-glass system Au(1.8%Mn), we show that this glass-like state is distinctly different from the well established canonical spin-glass state.Comment: 11 pages, 6 figure

Ergocalciferol in New-onset Type 1 diabetes: A Randomized Controlled Trial

Background: The impact of the anti-inflammatory and immunomodulatory actions of Vitamin D on the duration of partial clinical remission (PR) in youth with type 1 diabetes (T1D) is unclear. Objective: To determine the effect of adjunctive ergocalciferol on residual β-cell function (RBCF) and PR in youth with newly-diagnosed T1D who were maintained on a standardized insulin treatment protocol. Hypothesis: Ergocalciferol supplementation increases RBCF and prolongs PR. Methods: A 12-month randomized, double-blind, placebo-controlled trial of 50,000 IU of ergocalciferol per week for 2 months, and then once every 2 weeks for 10 months, versus placebo in 36 subjects of ages 10-21years(y), with T1D ofmonths, and a stimulated C-peptide (SCP) level of ≥0.2nmol/L (≥0.6ng/mL). The ergocalciferol group had 18 randomized subjects (10m/ 8f), mean age 13.3±2.8y; while the control group had 18 subjects (14m/4f), age 14.3±2.9y. Results: The ergocalciferol treatment group had significantly higher serum 25-hydroxyvitamin D at 6 months (p=0.01) and 9 months (p=0.02) than the placebo group. At 12 months, the ergocalciferol group had a significantly lower serum TNF-α concentration (p=0.03). There were no significant differences between the groups at each timepoint from baseline to 12 months for SCP concentration (p=0.08), HbA1c (p=0.09), insulin-dose-adjusted A1c (IDAA1c), or total daily dose of insulin. Temporal trends for rising HbA1c (p=0.044) and IDAA1c (p=0.015) were significantly blunted in the ergocalciferol group. Conclusions: Ergocalciferol significantly reduced serum TNF-α concentration and the rates of increase in both A1c and IDAA1c suggesting a protection of RBCF and PR in youth with newly-diagnosed T1D

Controlling the Transverse Proton Relaxivity of Magnetic Graphene Oxide

The engineering of materials with controlled magnetic properties by means other than a magnetic feld is of great interest in nanotechnology. In this study, we report engineered magnetic graphene oxide (MGO) in the nanocomposite form of iron oxide nanoparticles (IO)-graphene oxide (GO) with tunable core magnetism and magnetic resonance transverse relaxivity (r2). These tunable properties are obtained by varying the IO content on GO. The MGO series exhibits r2 values analogous to those observed in conventional single core and cluster forms of IO in diferent size regimes—motional averaging regime (MAR), static dephasing regime (SDR), and echo-limiting regime (ELR) or slow motion regime (SMR). The maximum r2 of 162±5.703mM−1s−1 is attained for MGO with 28 weight percent (wt%) content of IO on GO and hydrodynamic diameter of 414 nm, which is associated with the SDR.These fndings demonstrate the clear potential of magnetic graphene oxide for magnetic resonance imaging (MRI) applications

PLAS-5k: Dataset of Protein-Ligand Affinities from Molecular Dynamics for Machine Learning Applications

Computational methods and recently modern machine learning methods have played a key role in structure-based drug design. Though several benchmarking datasets are available for machine learning applications in virtual screening, accurate prediction of binding affinity for a protein-ligand complex remains a major challenge. New datasets that allow for the development of models for predicting binding affinities better than the state-of-the-art scoring functions are important. For the first time, we have developed a dataset, PLAS-5k comprised of 5000 protein-ligand complexes chosen from PDB database. The dataset consists of binding affinities along with energy components like electrostatic, van der Waals, polar and non-polar solvation energy calculated from molecular dynamics simulations using MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) method. The calculated binding affinities outperformed docking scores and showed a good correlation with the available experimental values. The availability of energy components may enable optimization of desired components during machine learning-based drug design. Further, OnionNet model has been retrained on PLAS-5k dataset and is provided as a baseline for the prediction of binding affinities

Dynamically mapping tasks with priorities and multiple deadlines in a heterogeneous environment

Includes bibliographical references (pages 166-167).In a distributed heterogeneous computing system, the resources have different capabilities and tasks have different requirements. To maximize the performance of the system, it is essential to assign the resources to tasks (match) and order the execution of tasks on each resource (schedule) to exploit the heterogeneity of the resources and tasks. Dynamic mapping (defined as matching and scheduling) is performed when the arrival of tasks is not known a priori. In the heterogeneous environment considered in this study, tasks arrive randomly, tasks are independent (i.e., no inter-task communication), and tasks have priorities and multiple soft deadlines. The value of a task is calculated based on the priority of the task and the completion time of the task with respect to its deadlines. The goal of a dynamic mapping heuristic in this research is to maximize the value accrued of completed tasks in a given interval of time. This research proposes, evaluates, and compares eight dynamic mapping heuristics. Two static mapping schemes (all arrival information of tasks are known) are designed also for comparison. The performance of the best heuristics is 84% of a calculated upper bound for the scenarios considered

Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia

Previous studies revealed a paradox whereby mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) acted as a negative regulator of insulin sensitivity in chronically obese mice, yet systemic deletion of Map4k4 did not improve glucose tolerance. Here, we report markedly reduced glucose-responsive plasma insulin and C-peptide levels in whole body Map4k4-depleted mice (M4K4 iKO) as well as an impaired first phase of insulin secretion from islets derived from M4K4 iKO mice ex vivo After long-term high fat diet (HFD), M4K4 iKO mice pancreata also displayed reduced beta cell mass, fewer proliferating beta cells and reduced islet-specific gene mRNA expression compared with controls, although insulin content was normal. Interestingly, the reduced plasma insulin in M4K4 iKO mice exposed to chronic (16 weeks) HFD was not observed in response to acute HFD challenge or short term treatment with the insulin receptor antagonist S961. Furthermore, the improved insulin sensitivity in obese M4K4 iKO mice was abrogated by high exogenous insulin over the course of a euglycemic clamp study, indicating that hypoinsulinemia promotes insulin sensitivity in chronically obese M4K4 iKO mice. These results demonstrate that protein kinase Map4k4 drives obesity-induced hyperinsulinemia and insulin resistance in part by promoting insulin secretion from beta cells in mice

Asthma in the elderly: what we know and what we have yet to know

In the past, asthma was considered mainly as a childhood disease. However, asthma is an important cause of morbidity and mortality in the elderly nowadays. In addition, the burden of asthma is more significant in the elderly than in their younger counterparts, particularly with regard to mortality, hospitalization, medical costs or health-related quality of life. Nevertheless, asthma in the elderly is still been underdiagnosed and undertreated. Therefore, it is an imperative task to recognize our current challenges and to set future directions. This project aims to review the current literature and identify unmet needs in the fields of research and practice for asthma in the elderly. This will enable us to find new research directions, propose new therapeutic strategies, and ultimately improve outcomes for elderly people with asthma. There are data to suggest that asthma in older adults is phenotypically different from young patients, with potential impact on the diagnosis, assessment and management in this population. The diagnosis of AIE in older populations relies on the same clinical findings and diagnostic tests used in younger populations, but the interpretation of the clinical data is more difficult. The challenge today is to encourage new research in AIE but to use the existing knowledge we have to make the diagnosis of AIE, educate the patient, develop a therapeutic approach to control the disease, and ultimately provide a better quality of life to our elderly patients