abi Seasonal timing adaptation across the geographic range of Arabidopsis thaliana [Evolution] By www.pnas.org Published On :: 2020-05-05T10:31:24-07:00 The most fundamental genetic program of an annual plant defines when to grow and reproduce and when to remain dormant in the soil as a seed. With the right timing, plants can even live in hostile regions with only a few months of growth-favorable abundant rains and mild temperatures. To... Full Article
abi Habituation of the cardiovascular response to restraint stress is inhibited by exposure to other stressor stimuli and exercise training [RESEARCH ARTICLE] By jeb.biologists.org Published On :: 2020-04-23T22:21:31-07:00 Ricardo Benini, Leandro A. Oliveira, Lucas Gomes-de-Souza, Bruno Rodrigues, and Carlos C. Crestani This study evaluated the effect of exposure to either a chronic variable stress (CVS) protocol or social isolation, as well as treadmill exercise training, in the habituation of the cardiovascular response upon repeated exposure to restraint stress in rats. The habituation of the corticosterone response to repeated restraint stress was also evaluated. For this, animals were subjected to either acute or 10 daily sessions of 60 min of restraint stress. CVS and social isolation protocols lasted for 10 consecutive days, whereas treadmill training was performed for 1 h per day, 5 days per week for 8 weeks. We observed that the increase in serum corticosterone was reduced during both the stress and the recovery period of the 10th session of restraint. Habituation of the cardiovascular response was identified in terms of a faster return of heart rate to baseline values during the recovery period of the 10th session of restraint. The increase in blood pressure and the decrease in tail skin temperature were similar at the 1st and 10th session of restraint. Exposure to CVS, social isolation or treadmill exercise training inhibited the habituation of the restraint-evoked tachycardia. Additionally, CVS increased the blood pressure response at the 10th session of restraint, whereas social isolation enhanced both the tachycardia during the first session and the drop in skin temperature at the 10th session of restraint. Taken together, these findings provide new evidence that pathologies evoked by stress might be related to impairment in the habituation process to homotypic stressors. Full Article
abi Body temperature stability observed in the whale sharks, the world's largest fish [RESEARCH ARTICLE] By jeb.biologists.org Published On :: 2020-05-04T02:24:22-07:00 Itsumi Nakamura, Rui Matsumoto, and Katsufumi SatoIt is generally assumed that the body temperature of large animals is less likely to change due to their large body size, resulting in a high thermal inertia and a smaller surface area to volume ratio. The goal of this study was to investigate the stability of body temperature in large fish using data from field experiments. We measured the muscle temperatures of free-ranging whale sharks (Rhincodon typus), the largest extant fish globally, and investigated their ectothermic physiology and the stability of their body temperatures. The measured muscle temperature of the whale sharks changed substantially more slowly than the water temperature fluctuations associated with vertical movements, and the whole-body heat-transfer coefficients (HTC) of whale sharks estimated using heat-budget models were lower than those of any other fish species measured to date. The heat-budget models also showed that internal heat production does not contribute to changes in muscle temperature. A comparative analysis showed that the HTC at cooling in various fish species including both ectothermic and endothermic species ranging from 10–4 to 103 kg was proportional to body mass–0.63. This allometry was present regardless of whether the fish were ectothermic or endothermic, and was an extension of the relationship observed in previous studies on small fish. Thus, large fish have the advantage of body temperature stability while moving in environments with large temperature variations. Our results suggest that the large body size of whale sharks aids in preventing a decrease in body temperature during deep excursions to more than 1000 m depths without high metabolic costs of producing heat. Full Article
abi Fish embryo vulnerability to combined acidification and warming coincides with low capacity for homeostatic regulation [RESEARCH ARTICLE] By jeb.biologists.org Published On :: 2020-05-05T05:22:41-07:00 Flemming Dahlke, Magnus Lucassen, Ulf Bickmeyer, Sylke Wohlrab, Velmurugu Puvanendran, Atle Mortensen, Melissa Chierici, Hans-Otto Pörtner, and Daniela StorchThe vulnerability of fish embryos and larvae to environmental factors is often attributed to a lack of adult-like organ systems (gills) and thus insufficient homeostatic capacity. However, experimental data supporting this hypothesis are scarce. Here, by using Atlantic cod (Gadus morhua) as a model, the relationship between embryo vulnerability (to projected ocean acidification and warming) and homeostatic capacity was explored through parallel analyses of stage-specific mortality and in vitro activity and expression of major ion pumps (ATP-Synthase, Na+/K+-ATPase, H+-ATPase) and co-transporters (NBC1, NKCC1). Immunolocalization of these transporters was used to study ionocyte morphology in newly-hatched larvae. Treatment-related embryo mortality until hatch (+20% due to acidification and warming) occurred primarily during an early period (gastrulation) characterized by extremely low ion transport capacities. Thereafter, embryo mortality decreased in parallel with an exponential increase in activity and expression of all investigated ion transporters. Significant changes in transporter activity and expression in response to acidification (+15% activity) and warming (-30% expression) indicate some potential for short-term acclimatization, although likely associated with energetic trade-offs. Interestingly, whole-larvae enzyme capacities (supported by abundant epidermal ionocytes) reached levels similar to those previously measured in gill tissue of adult cod, suggesting that early-life stages without functional gills are better equipped in terms of ion homeostasis than previously thought. This study implies that the gastrulation period represents a critical transition from inherited (maternal) defenses to active homeostatic regulation, which facilitates enhanced resilience of later stages to environmental factors. Full Article
abi Interaction between Epithelial Sodium Channel {gamma}-Subunit and Claudin-8 Modulates Paracellular Sodium Permeability in Renal Collecting Duct By jasn.asnjournals.org Published On :: 2020-04-30T10:00:30-07:00 Background Water and solute transport across epithelia can occur via the transcellular or paracellular pathways. Tight junctions play a key role in mediating paracellular ion reabsorption in the kidney. In the renal collecting duct, which is a typical absorptive tight epithelium, coordination between transcellular sodium reabsorption and paracellular permeability may prevent the backflow of reabsorbed sodium to the tubular lumen along a steep electrochemical gradient. Methods To investigate whether transcellular sodium transport controls tight-junction composition and paracellular permeability via modulating expression of the transmembrane protein claudin-8, we used cultured mouse cortical collecting duct cells to see how overexpression or silencing of epithelial sodium channel (ENaC) subunits and claudin-8 affect paracellular permeability. We also used conditional kidney tubule–specific knockout mice lacking ENaC subunits to assess the ENaC’s effect on claudin-8 expression. Results Overexpression or silencing of the ENaC -subunit was associated with parallel and specific changes in claudin-8 abundance. Increased claudin-8 abundance was associated with a reduction in paracellular permeability to sodium, whereas decreased claudin-8 abundance was associated with the opposite effect. Claudin-8 overexpression and silencing reproduced these functional effects on paracellular ion permeability. Conditional kidney tubule–specific ENaC -subunit knockout mice displayed decreased claudin-8 expression, confirming the cell culture experiments' findings. Importantly, ENaC β-subunit or α-subunit silencing or kidney tubule–specific β-ENaC or α-ENaC knockout mice did not alter claudin-8 abundance. Conclusions Our data reveal the specific coupling between ENaC -subunit and claudin-8 expression. This coupling may play an important role in preventing the backflow of reabsorbed solutes and water to the tubular lumen, as well as in coupling paracellular and transcellular sodium permeability. Full Article
abi An Interrater Reliability Study of Pulmonary Function Assessment With a Portable Spirometer By rc.rcjournal.com Published On :: 2020-04-28T00:42:49-07:00 BACKGROUND:In this study, we aimed to validate the agreement between pulmonary function measurements obtained with a portable spirometer and measurements obtained with conventional spirometry in Chinese pediatric and adult populations.METHODS:Pulmonary function testing was performed to evaluate subjects enrolled at Shanghai Zhongshan Hospital (n = 104) and Shanghai Children's Medical Center (n = 103). The portable spirometers and conventional devices were applied to each subject with a 20-min quiescent period between each measurement. Pulmonary function parameters of FVC, FEV1, peak expiratory flow, maximum expiratory flow at 25%, 50%, and 75% of FVC (MEF25, MEF50, and MEF75, respectively), and FEV1/FVC% were compared with intraclass correlation and Bland-Altman methods.RESULTS:A satisfactory concordance of pulmonary function was observed between spirometry measurements obtained with portable versus conventional spirometers. Intraclass correlation indicated excellent reliability (>0.75) for all pulmonary function indicators in pediatric and adult subjects. Significant positive correlations of all variables measured with different spirometers were observed (all P < .001). No significant bias was observed in either group, although limits of agreement varied. Funnel effects were observed for peak expiratory flow in pediatric subjects and for FVC, FEV1, MEF50, and MEF25 in adult subjects.CONCLUSIONS:The portable spirometer is an alternative to the conventional device for the measurement of pulmonary function. Compared with the conventional device, the portable spirometer is expected to provide convenient, operational, and financial advantages. Full Article
abi SUMOylation of the transcription factor ZFHX3 at Lys-2806 requires SAE1, UBC9, and PIAS2 and enhances its stability and function in cell proliferation [Protein Synthesis and Degradation] By www.jbc.org Published On :: 2020-05-08T03:41:14-07:00 SUMOylation is a posttranslational modification (PTM) at a lysine residue and is crucial for the proper functions of many proteins, particularly of transcription factors, in various biological processes. Zinc finger homeobox 3 (ZFHX3), also known as AT motif-binding factor 1 (ATBF1), is a large transcription factor that is active in multiple pathological processes, including atrial fibrillation and carcinogenesis, and in circadian regulation and development. We have previously demonstrated that ZFHX3 is SUMOylated at three or more lysine residues. Here, we investigated which enzymes regulate ZFHX3 SUMOylation and whether SUMOylation modulates ZFHX3 stability and function. We found that SUMO1, SUMO2, and SUMO3 each are conjugated to ZFHX3. Multiple lysine residues in ZFHX3 were SUMOylated, but Lys-2806 was the major SUMOylation site, and we also found that it is highly conserved among ZFHX3 orthologs from different animal species. Using molecular analyses, we identified the enzymes that mediate ZFHX3 SUMOylation; these included SUMO1-activating enzyme subunit 1 (SAE1), an E1-activating enzyme; SUMO-conjugating enzyme UBC9 (UBC9), an E2-conjugating enzyme; and protein inhibitor of activated STAT2 (PIAS2), an E3 ligase. Multiple analyses established that both SUMO-specific peptidase 1 (SENP1) and SENP2 deSUMOylate ZFHX3. SUMOylation at Lys-2806 enhanced ZFHX3 stability by interfering with its ubiquitination and proteasomal degradation. Functionally, Lys-2806 SUMOylation enabled ZFHX3-mediated cell proliferation and xenograft tumor growth of the MDA-MB-231 breast cancer cell line. These findings reveal the enzymes involved in, and the functional consequences of, ZFHX3 SUMOylation, insights that may help shed light on ZFHX3's roles in various cellular and pathophysiological processes. Full Article
abi Void ratio-permeability relations for clays By qjegh.lyellcollection.org Published On :: 2020-05-01T00:46:18-07:00 In spite of the Kozeny–Carman formula having been applied effectively to sands, there is at present no generally accepted explanation for why it is inadequate for clays. The impermeable adsorbed water layer surrounding the soil particles throws further light on the issue. By introducing the pervious void ratio, which accounts for the effective voids that a fluid flows through, a modified Kozeny–Carman formula is presented. The results presented here show that the modified Kozeny–Carman formula predicts fairly well the hydraulic conductivity of clays, especially for fine-grained soils. Full Article
abi Stability analyses of large waste dumps via 3D numerical modelling considering cracks and earthquake loading: a case study of Zhujiabaobao waste dump By qjegh.lyellcollection.org Published On :: 2020-05-01T00:46:18-07:00 This paper uses a 3D model for stability assessment of Zhujiabaobao waste dump with ground cracks. The study data were gathered via reconnaissance, geomorphological analysis and laboratory experiment. A 3D finite extended element method model that can consider cracks was then used to calculate the factor of safety (FOS) of the waste dump via the strength reduction technique. The simulation shows the dump to have an FOS of 1.22 and both the position and depth of penetration of cracks in the waste dump have a crucial impact on the stability of the slope. Because the study area is located in a seismically active area, simulation and analysis of the dynamic response of the waste dump under different magnitudes of seismic waves (peak acceleration is 0.05, 0.15, 0.25 and 0.45g) were performed via an explicit dynamic model. The simulation shows that high steps in the slope are particularly responsive to earthquakes. The approach used here for analysing stability under static and dynamic loads is useful for hazard prevention and mitigation. Full Article
abi Arabidopsis retrotransposon virus-like particles and their regulation by epigenetically activated small RNA [RESEARCH] By genome.cshlp.org Published On :: 2020-04-27T12:09:24-07:00 In Arabidopsis, LTR retrotransposons are activated by mutations in the chromatin gene DECREASE in DNA METHYLATION 1 (DDM1), giving rise to 21- to 22-nt epigenetically activated siRNA (easiRNA) that depend on RNA DEPENDENT RNA POLYMERASE 6 (RDR6). We purified virus-like particles (VLPs) from ddm1 and ddm1rdr6 mutants in which genomic RNA is reverse transcribed into complementary DNA. High-throughput short-read and long-read sequencing of VLP DNA (VLP DNA-seq) revealed a comprehensive catalog of active LTR retrotransposons without the need for mapping transposition, as well as independent of genomic copy number. Linear replication intermediates of the functionally intact COPIA element EVADE revealed multiple central polypurine tracts (cPPTs), a feature shared with HIV in which cPPTs promote nuclear localization. For one member of the ATCOPIA52 subfamily (SISYPHUS), cPPT intermediates were not observed, but abundant circular DNA indicated transposon "suicide" by auto-integration within the VLP. easiRNA targeted EVADE genomic RNA, polysome association of GYPSY (ATHILA) subgenomic RNA, and transcription via histone H3 lysine-9 dimethylation. VLP DNA-seq provides a comprehensive landscape of LTR retrotransposons and their control at transcriptional, post-transcriptional, and reverse transcriptional levels. Full Article
abi Leveraging mouse chromatin data for heritability enrichment informs common disease architecture and reveals cortical layer contributions to schizophrenia [RESEARCH] By genome.cshlp.org Published On :: 2020-04-27T12:09:23-07:00 Genome-wide association studies have implicated thousands of noncoding variants across common human phenotypes. However, they cannot directly inform the cellular context in which disease-associated variants act. Here, we use open chromatin profiles from discrete mouse cell populations to address this challenge. We applied stratified linkage disequilibrium score regression and evaluated heritability enrichment in 64 genome-wide association studies, emphasizing schizophrenia. We provide evidence that mouse-derived human open chromatin profiles can serve as powerful proxies for difficult to obtain human cell populations, facilitating the illumination of common disease heritability enrichment across an array of human phenotypes. We demonstrate that signatures from discrete subpopulations of cortical excitatory and inhibitory neurons are significantly enriched for schizophrenia heritability with maximal enrichment in cortical layer V excitatory neurons. We also show that differences between schizophrenia and bipolar disorder are concentrated in excitatory neurons in cortical layers II-III, IV, and V, as well as the dentate gyrus. Finally, we leverage these data to fine-map variants in 177 schizophrenia loci nominating variants in 104/177. We integrate these data with transcription factor binding site, chromatin interaction, and validated enhancer data, placing variants in the cellular context where they may modulate risk. Full Article
abi The Endocannabinoid System Alleviates Pain in a Murine Model of Cancer-Induced Bone Pain [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 Metastatic breast cancer is prevalent worldwide, and one of the most common sites of metastasis is long bones. Of patients with disease, the major symptom is pain, yet current medications fail to adequately result in analgesic efficacy and present major undesirable adverse effects. In our study, we investigate the potential of a novel monoacylglycerol lipase (MAGL) inhibitor, MJN110, in a murine model of cancer-induced bone pain. Literature has previously demonstrated that MAGL inhibitors function to increase the endogenous concentrations of 2-arachydonylglycerol, which then activates CB1 and CB2 receptors to inhibit inflammation and pain. We demonstrate that administration of MJN110 significantly and dose dependently alleviates spontaneous pain behavior during acute administration compared with vehicle control. In addition, MJN110 maintains its efficacy in a chronic-dosing paradigm over the course of 7 days without signs of receptor sensitization. In vitro analysis of MJN110 demonstrated a dose-dependent and significant decrease in cell viability and proliferation of 66.1 breast adenocarcinoma cells to a greater extent than KML29, an alternate MAGL inhibitor, or the CB2 agonist JWH015. Chronic administration of the compound did not appear to affect tumor burden, as evidenced by radiograph or histologic analysis. Together, these data support the application for MJN110 as a novel therapeutic for cancer-induced bone pain. SIGNIFICANCE STATEMENT Current standard of care for metastatic breast cancer pain is opioid-based therapies with adjunctive chemotherapy, which have highly addictive and other deleterious side effects. The need for effective, non–opioid-based therapies is essential, and harnessing the endogenous cannabinoid system is proving to be a new target to treat various types of pain conditions. We present a novel drug targeting the endogenous cannabinoid system that is effective at reducing pain in a mouse model of metastatic breast cancer to bone. Full Article
abi A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition [Drug Discovery and Translational Medicine] By jpet.aspetjournals.org Published On :: 2020-04-13T13:53:50-07:00 Abicipar pegol (abicipar) is a novel DARPin therapeutic and highly potent vascular endothelial growth factor (VEGF) inhibitor intended for the treatment of neovascular age-related macular degeneration (nAMD). Here we develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for abicipar to guide dosing regimens in the clinic. The model incorporated abicipar-VEGF binding kinetics, VEGF expression levels, and VEGF turnover rates to describe the ocular and systemic PK data collected from the vitreous, aqueous humor (AH), choroid, retina, and serum of rabbits after a 1-mg abicipar intravitreal (IVT) dose. The model was translated to humans using human-specific mechanistic parameters and refitted to human serum and AH concentrations from patients with diabetic macular edema and nAMD. The model was then used to simulate 8-, 12- (quarterly), and 16-week dosing intervals in the clinic. Simulations of 2 mg abicipar IVT at 8-week or quarterly dosing in humans indicates minimum steady-state vitreal concentrations are maintained above both in vitro IC50 and in vivo human IC50 values. The model predicted virtually complete VEGF inhibition for the 8-week and quarterly dosing schedule during the 52-week treatment period. In the 16-week schedule, clinically significant VEGF inhibition was maintained during the 52-week period. The model quantitatively described abicipar-VEGF target engagement leading to rapid reduction of VEGF and a long duration of VEGF inhibition demonstrating the clinical feasibility of up to a 16-week dosing interval. Abicipar is predicted to reduce IVT dosing compared with other anti-VEGF therapies with the potential to lessen patient treatment burden. SIGNIFICANCE STATEMENT Current anti-VEGF treatments for neovascular age-related macular degeneration require frequent (monthly) intravitreal injections and monitoring, which increases patient burden. We developed a mechanistic pharmakinetic/pharmadynamic model to describe the interaction between abicipar (a novel VEGF inhibitor) and VEGF to evaluate the duration of action. The model demonstrates extended abicipar-VEGF target engagement leading to clinical feasibility of up to a 16-week dosing interval. Our model predicted that abicipar 8-week and quarterly dosing schedules maintain virtually complete VEGF inhibition during the 52-week period. Full Article
abi Survival benefit of lung transplantation compared with medical management and pulmonary rehabilitation for patients with end-stage COPD By openres.ersjournals.com Published On :: 2020-04-27T00:30:10-07:00 Background COPD patients account for a large proportion of lung transplants; lung transplantation survival benefit for COPD patients is not well established. Methods We identified 4521 COPD patients in the United Network for Organ Sharing (UNOS) dataset transplanted from May 2005 to August 2016, and 604 patients assigned to receive pulmonary rehabilitation and medical management in the National Emphysema Treatment Trial (NETT). After trimming the populations for NETT eligibility criteria and data completeness, 1337 UNOS and 596 NETT patients remained. Kaplan–Meier estimates of transplant-free survival from transplantation for UNOS, and NETT randomisation, were compared between propensity score-matched UNOS (n=401) and NETT (n=262) patients. Results In propensity-matched analyses, transplanted patients had better survival compared to medically managed patients in NETT (p=0.003). Stratifying on 6 min walk distance (6 MWD) and FEV1, UNOS patients with 6 MWD <1000 ft (~300 m) or FEV1 <20% of predicted had better survival than NETT counterparts (median survival 5.0 years UNOS versus 3.4 years NETT; log-rank p<0.0001), while UNOS patients with 6 MWD ≥1000 ft (~300 m) and FEV1 ≥20% had similar survival to NETT counterparts (median survival, 5.4 years UNOS versus 4.9 years NETT; log-rank p=0.73), interaction p=0.01. Conclusions Overall survival is better for matched lung transplant patients compared with medical management alone. Patients who derive maximum benefit are those with 6 MWD <1000 ft (~300 m) or FEV1 <20% of predicted, compared with pulmonary rehabilitation and medical management. Full Article
abi Medical Cannabinoid Products in Children and Adolescents By pedsinreview.aappublications.org Published On :: 2020-05-01T01:00:19-07:00 Full Article
abi Advancing Biologics Development Programs with Legacy Cell Lines: Advantages and Limitations of Genetic Testing for Addressing Clonality Concerns Prior to Availability of Late Stage Process and Product Consistency Data By journal.pda.org Published On :: 2020-04-09T09:40:03-07:00 The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins, it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line "clonal origin" an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years, and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal derivation. However, older production cell lines developed before the implementation of these methods, herein referred to as "legacy cell lines," may not meet current regulatory expectations for demonstration of clonal derivation. In this article, the members of the IQ Consortium Working Group on Clonality present our position that the demonstration of process consistency and product comparability of critical quality attributes throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal derivation standards. With this commentary, we discuss advantages and limitations of genetic testing methods to support clonal derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to Investigational New Drug (IND) application and before demonstration of product and process consistency at Biologics License Applications (BLA) submission. Full Article
abi Bioavailability Based on the Gut Microbiota: a New Perspective [Review] By mmbr.asm.org Published On :: 2020-04-29T05:30:12-07:00 The substantial discrepancy between the strong effects of functional foods and various drugs, especially traditional Chinese medicines (TCMs), and the poor bioavailability of these substances remains a perplexing problem. Understanding the gut microbiota, which acts as an effective bioreactor in the human intestinal tract, provides an opportunity for the redefinition of bioavailability. Here, we discuss four different pathways associated with the role of the gut microbiota in the transformation of parent compounds to beneficial or detrimental small molecules, which can enter the body’s circulatory system and be available to target cells, tissues, and organs. We further describe and propose effective strategies for improving bioavailability and alleviating side effects with the help of the gut microbiota. This review also broadens our perspectives for the discovery of new medicinal components. Full Article
abi Exceptionally well-preserved Permocalculus cf. tenellus (Pia) (Gymnocodiaceae) from Upper Permian Khuff Formation limestones, Saudi Arabia By jm.lyellcollection.org Published On :: 2017-08-10T08:29:35-07:00 An exceptionally well-preserved specimen of the articulated rhodophyte Permocalculus, compared with P. tenellus sensu Elliott, 1955, is described from fine-grained Upper Permian limestones of the Khuff Formation of Saudi Arabia. Longitudinal medullary and sheaf-like cortical filaments extend through the uniserial series of elongate-globular, concave- and convex-terminating, interlocking segments for which they are interpreted to have functioned in articulation. The filaments tend to splay and branch laterally into the cortex where they terminate at the pores. At the terminal aperture, the filaments extend as bifurcating and possibly trifurcating branches and may serve as the origin of a new segment. Numerous elongate-globular chambers, up to five in each row and intimately involved with the filaments, are developed in the outer medulla and are considered to represent reproductive sporangia. The specimen is considered to have occupied predominantly low-energy, normal to slightly elevated salinity, shallow conditions within the subtidal regime of a lagoon. Full Article
abi Both Prediabetes and Type 2 Diabetes Are Associated With Lower Heart Rate Variability: The Maastricht Study By care.diabetesjournals.org Published On :: 2020-04-20T12:00:33-07:00 OBJECTIVE Low heart rate variability (HRV), a marker for cardiac autonomic dysfunction, is a known feature of type 2 diabetes, but it remains incompletely understood whether this also applies to prediabetes or across the whole glycemic spectrum. Therefore, we investigated the association among prediabetes, type 2 diabetes, and measures of glycemia and HRV. RESEARCH DESIGN AND METHODS In the population-based Maastricht Study (n = 2,107; mean ± SD age 59 ± 8 years; 52% men; normal glucose metabolism [n = 1,226], prediabetes [n = 331], and type 2 diabetes [n = 550, oversampled]), we determined 24-h electrocardiogram-derived HRV in time and frequency domains (individual z-scores, based upon seven and six variables, respectively). We used linear regression with adjustments for age, sex, and major cardiovascular risk factors. RESULTS After adjustments, both time and frequency domain HRV were lower in prediabetes and type 2 diabetes as compared with normal glucose metabolism (standardized β [95% CI] for time domain: –0.15 [–0.27; –0.03] and –0.34 [–0.46; –0.22], respectively, P for trend <0.001; for frequency domain: –0.14 [–0.26; –0.02] and –0.31 [–0.43; –0.19], respectively, P for trend <0.001). In addition, 1-SD higher glycated hemoglobin, fasting plasma glucose, and 2-h postload glucose were associated with lower HRV in both domains (time domain: –0.16 [–0.21; –0.12], –0.16 [–0.21; –0.12], and –0.15 [–0.20; –0.10], respectively; frequency domain: –0.14 [–0.19; –0.10], –0.14 [–0.18; –0.09], and –0.13 [–0.18; –0.08], respectively). CONCLUSIONS Both prediabetes and type 2 diabetes were independently associated with lower HRV. This is further substantiated by independent continuous associations between measures of hyperglycemia and lower HRV. These data strongly suggest that cardiac autonomic dysfunction is already present in prediabetes. Full Article
abi Global Disability Burdens of Diabetes-Related Lower-Extremity Complications in 1990 and 2016 By care.diabetesjournals.org Published On :: 2020-04-20T12:00:32-07:00 OBJECTIVE No study has reported global disability burden estimates for individual diabetes-related lower-extremity complications (DRLECs). The Global Burden of Disease (GBD) study presents a robust opportunity to address this gap. RESEARCH DESIGN AND METHODS GBD 2016 data, including prevalence and years lived with disability (YLDs), for the DRLECs of diabetic neuropathy, foot ulcer, and amputation with and without prosthesis were used. The GBD estimated prevalence using data from systematic reviews and DisMod-MR 2.1, a Bayesian meta-regression tool. YLDs were estimated as the product of prevalence estimates and disability weights for each DRLEC. We reported global and sex-, age-, region-, and country-specific estimates for each DRLEC for 1990 and 2016. RESULTS In 2016, an estimated 131 million people (1.8% of the global population) had DRLECs. An estimated 16.8 million YLDs (2.1% global YLDs) were caused by DRLECs, including 12.9 million (95% uncertainty interval 8.30–18.8) from neuropathy only, 2.5 million (1.7–3.6) from foot ulcers, 1.1 million (0.7–1.4) from amputation without prosthesis, and 0.4 million (0.3–0.5) from amputation with prosthesis. Age-standardized YLD rates of all DRLECs increased by between 14.6% and 31.0% from 1990 estimates. Male-to-female YLD ratios ranged from 0.96 for neuropathy only to 1.93 for foot ulcers. The 50- to 69-year-old age-group accounted for 47.8% of all YLDs from DRLECs. CONCLUSIONS These first-ever global estimates suggest that DRLECs are a large and growing contributor to the disability burden worldwide and disproportionately affect males and middle- to older-aged populations. These findings should facilitate policy makers worldwide to target strategies at populations disproportionately affected by DRLECs. Full Article
abi It could happen to anyone: vulnerability and boundaries By bjgp.org Published On :: 2020-04-30T16:04:41-07:00 Full Article
abi Managing patients with COVID-19 infections: a first-hand experience from the Wuhan Mobile Cabin Hospital By bjgp.org Published On :: 2020-04-30T16:04:41-07:00 Full Article
abi Diazotrophs Show Signs of Restoration in Amazon Rain Forest Soils with Ecosystem Rehabilitation [Microbial Ecology] By aem.asm.org Published On :: 2020-05-05T08:00:35-07:00 Biological nitrogen fixation can be an important source of nitrogen in tropical forests that serve as a major CO2 sink. Extensive deforestation of the Amazon is known to influence microbial communities and the biogeochemical cycles they mediate. However, it is unknown how diazotrophs (nitrogen-fixing microorganisms) respond to deforestation and subsequent ecosystem conversion to agriculture, as well as whether they can recover in secondary forests that are established after agriculture is abandoned. To address these knowledge gaps, we combined a spatially explicit sampling approach with high-throughput sequencing of nifH genes. The main objectives were to assess the functional distance decay relationship of the diazotrophic bacterial community in a tropical forest ecosystem and to quantify the roles of various factors that drive the observed changes in the diazotrophic community structure. We observed an increase in local diazotrophic diversity (α-diversity) with a decrease in community turnover (β-diversity), associated with a shift in diazotrophic community structure as a result of the forest-to-pasture conversion. Both diazotrophic community turnover and structure showed signs of recovery in secondary forests. Changes in the diazotrophic community were primarily driven by the change in land use rather than differences in geochemical characteristics or geographic distances. The diazotroph communities in secondary forests resembled those in primary forests, suggesting that at least partial recovery of diazotrophs is possible following agricultural abandonment. IMPORTANCE The Amazon region is a major tropical forest region that is being deforested at an alarming rate to create space for cattle ranching and agriculture. Diazotrophs (nitrogen-fixing microorganisms) play an important role in supplying soil N for plant growth in tropical forests. It is unknown how diazotrophs respond to deforestation and whether they can recover in secondary forests that establish after agriculture is abandoned. Using high-throughput sequencing of nifH genes, we characterized the response of diazotrophs’ β-diversity and identified major drivers of changes in diazotrophs from forest-to-pasture and pasture-to-secondary-forest conversions. Studying the impact of land use change on diazotrophs is important for a better understanding of the impact of deforestation on tropical forest ecosystem functioning, and our results on the potential recovery of diazotrophs in secondary forests imply the possible restoration of ecosystem functions in secondary forests. Full Article
abi Temperature and Nutrient Levels Correspond with Lineage-Specific Microdiversification in the Ubiquitous and Abundant Freshwater Genus Limnohabitans [Environmental Microbiology] By aem.asm.org Published On :: 2020-05-05T08:00:35-07:00 Most freshwater bacterial communities are characterized by a few dominant taxa that are often ubiquitous across freshwater biomes worldwide. Our understanding of the genomic diversity within these taxonomic groups is limited to a subset of taxa. Here, we investigated the genomic diversity that enables Limnohabitans, a freshwater genus key in funneling carbon from primary producers to higher trophic levels, to achieve abundance and ubiquity. We reconstructed eight putative Limnohabitans metagenome-assembled genomes (MAGs) from stations located along broad environmental gradients existing in Lake Michigan, part of Earth’s largest surface freshwater system. De novo strain inference analysis resolved a total of 23 strains from these MAGs, which strongly partitioned into two habitat-specific clusters with cooccurring strains from different lineages. The largest number of strains belonged to the abundant LimB lineage, for which robust in situ strain delineation had not previously been achieved. Our data show that temperature and nutrient levels may be important environmental parameters associated with microdiversification within the Limnohabitans genus. In addition, strains predominant in low- and high-phosphorus conditions had larger genomic divergence than strains abundant under different temperatures. Comparative genomics and gene expression analysis yielded evidence for the ability of LimB populations to exhibit cellular motility and chemotaxis, a phenotype not yet associated with available Limnohabitans isolates. Our findings broaden historical marker gene-based surveys of Limnohabitans microdiversification and provide in situ evidence of genome diversity and its functional implications across freshwater gradients. IMPORTANCE Limnohabitans is an important bacterial taxonomic group for cycling carbon in freshwater ecosystems worldwide. Here, we examined the genomic diversity of different Limnohabitans lineages. We focused on the LimB lineage of this genus, which is globally distributed and often abundant, and its abundance has shown to be largely invariant to environmental change. Our data show that the LimB lineage is actually comprised of multiple cooccurring populations for which the composition and genomic characteristics are associated with variations in temperature and nutrient levels. The gene expression profiles of this lineage suggest the importance of chemotaxis and motility, traits that had not yet been associated with the Limnohabitans genus, in adapting to environmental conditions. Full Article
abi In Vitro Activity of Beauvericin against All Developmental Stages of Sarcoptes scabiei [Susceptibility] By aac.asm.org Published On :: 2020-04-21T08:01:09-07:00 Scabies is a frequent cutaneous infection caused by the mite Sarcoptes scabiei in a large number of mammals, including humans. As the resistance of S. scabiei against several chemical acaricides has been previously documented, the establishment of alternative and effective control molecules is required. In this study, the potential acaricidal activity of beauvericin was assessed against different life stages of S. scabiei var. suis and in comparison with dimpylate and ivermectin, two commercially available molecules used for the treatment of S. scabiei infection in animals and/or humans. The toxicity of beauvericin against cultured human fibroblast skin cells was evaluated using an MTT proliferation assay. In our in vitro model, developmental stages of S. scabiei were placed in petri dishes filled with Columbia agar supplemented with pig serum and different concentrations of the drugs. Cell sensitivity assays demonstrated low toxicity of beauvericin against primary human fibroblast skin cells. At 0.5 and 5 mM, beauvericin showed higher activity against adults and eggs of S. scabiei compared to dimpylate and ivermectin. These results revealed that the use of beauvericin is promising and might be considered for the treatment of S. scabiei infection. Full Article
abi Protein Instability Is Targetable in Mismatch Repair-Deficient Tumors [Research Watch] By cancerdiscovery.aacrjournals.org Published On :: 2020-05-01T00:05:26-07:00 Mismatch repair (MMR)–deficient tumors exhibit proteome-wide protein instability and aggregation. Full Article
abi Advanced ADC Histogram, Perfusion, and Permeability Metrics Show an Association with Survival and Pseudoprogression in Newly Diagnosed Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium [FUNCTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Diffuse intrinsic pontine glioma is a lethal childhood brain cancer with dismal prognosis and MR imaging is the primary methodology used for diagnosis and monitoring. Our aim was to determine whether advanced diffusion, perfusion, and permeability MR imaging metrics predict survival and pseudoprogression in children with newly diagnosed diffuse intrinsic pontine glioma. MATERIALS AND METHODS: A clinical trial using the poly (adenosine diphosphate ribose) polymerase (PARP) inhibitor veliparib concurrently with radiation therapy, followed by maintenance therapy with veliparib + temozolomide, in children with diffuse intrinsic pontine glioma was conducted by the Pediatric Brain Tumor Consortium. Standard MR imaging, DWI, dynamic contrast-enhanced perfusion, and DSC perfusion were performed at baseline and approximately every 2 months throughout treatment. ADC histogram metrics of T2-weighted FLAIR and enhancing tumor volume, dynamic contrast-enhanced permeability metrics for enhancing tumors, and tumor relative CBV from DSC perfusion MR imaging were calculated. Baseline values, post-radiation therapy changes, and longitudinal trends for all metrics were evaluated for associations with survival and pseudoprogression. RESULTS: Fifty children were evaluable for survival analyses. Higher baseline relative CBV was associated with shorter progression-free survival (P = .02, Q = 0.089) and overall survival (P = .006, Q = 0.055). Associations of higher baseline mean transfer constant from the blood plasma into the extravascular extracellular space with shorter progression-free survival (P = .03, Q = 0.105) and overall survival (P = .03, Q = 0.102) trended toward significance. An increase in relative CBV with time was associated with shorter progression-free survival (P < .001, Q < 0.001) and overall survival (P = .004, Q = 0.043). Associations of longitudinal mean extravascular extracellular volume fraction with progression-free survival (P = .03, Q = 0.104) and overall survival (P = .03, Q = 0.105) and maximum transfer constant from the blood plasma into the extravascular extracellular space with progression-free survival (P = .03, Q = 0.102) trended toward significance. Greater increases with time were associated with worse outcomes. True radiologic progression showed greater post-radiation therapy decreases in mode_ADC_FLAIR compared with pseudoprogression (means, –268.15 versus –26.11, P = .01.) CONCLUSIONS: ADC histogram, perfusion, and permeability MR imaging metrics in diffuse intrinsic pontine glioma are useful in predicting survival and pseudoprogression. Full Article
abi Reliability of CT Angiography in Cerebral Vasospasm: A Systematic Review of the Literature and an Inter- and Intraobserver Study [INTERVENTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Computed tomography angiography offers a non-invasive alternative to DSA for the assessment of cerebral vasospasm following subarachnoid hemorrhage but there is limited evidence regarding its reliability. Our aim was to perform a systematic review (Part I) and to assess (Part II) the inter- and intraobserver reliability of CTA in the diagnosis of cerebral vasospasm. MATERIALS AND METHODS: In Part I, articles reporting the reliability of CTA up to May 2018 were systematically searched and evaluated. In Part II, 11 raters independently graded 17 arterial segments in each of 50 patients with SAH for the presence of vasospasm using a 4-category scale. Raters were additionally asked to judge the presence of any moderate/severe vasospasm (≥ 50% narrowing) and whether findings would justify augmentation of medical treatment or conventional angiography ± balloon angioplasty. Four raters took part in the intraobserver reliability study. RESULTS: In Part I, the systematic review revealed few studies with heterogeneous vasospasm definitions. In Part II, we found interrater reliability to be moderate at best ( ≤ 0.6), even when results were stratified according to specialty and experience. Intrarater reliability was substantial ( > 0.6) in 3/4 readers. In the per arterial segment analysis, substantial agreement was reached only for the middle cerebral arteries, and only when senior raters’ judgments were dichotomized (presence or absence of ≥50% narrowing). Agreement on the medical or angiographic management of vasospasm based on CTA alone was less than substantial ( ≤ 0.6). CONCLUSIONS: The diagnosis of vasospasm using CTA alone was not sufficiently repeatable among observers to support its general use to guide decisions in the clinical management of patients with SAH. Full Article
abi Anoxic Brain Injury Detection with the Normalized Diffusion to ASL Perfusion Ratio: Implications for Blood-Brain Barrier Injury and Permeability [FUNCTIONAL] By www.ajnr.org Published On :: 2020-04-09T06:30:48-07:00 BACKGROUND AND PURPOSE: Anoxic brain injury is a result of prolonged hypoxia. We sought to describe the nonquantitative arterial spin-labeling perfusion imaging patterns of anoxic brain injury, characterize the relationship of arterial spin-labeling and DWI, and evaluate the normalized diffusion-to-perfusion ratio to differentiate patients with anoxic brain injury from healthy controls. MATERIALS AND METHODS: We identified all patients diagnosed with anoxic brain injuries from 2002 to 2019. Twelve ROIs were drawn on arterial spin-labeling with coordinate-matched ROIs identified on DWI. Linear regression analysis was performed to examine the relationship between arterial spin-labeling perfusion and diffusion signal. Normalized diffusion-to-perfusion maps were generated using a custom-built algorithm. RESULTS: Thirty-five patients with anoxic brain injuries and 34 healthy controls were identified. Linear regression analysis demonstrated a significant positive correlation between arterial spin-labeling and DWI signal. By means of a combinatory cutoff of slope of >0 and R2 of > 0.78, linear regression using arterial spin-labeling and DWI showed a sensitivity of 0.86 (95% CI, 0.71–0.94) and specificity of 0.82 (95% CI, 0.66–0.92) for anoxic brain injuries. A normalized diffusion-to-perfusion color map demonstrated heterogeneous ratios throughout the brain in healthy controls and homogeneous ratios in patients with anoxic brain injuries. CONCLUSIONS: In anoxic brain injuries, a homogeneously positive correlation between qualitative perfusion and DWI signal was identified so that areas of increased diffusion signal showed increased ASL signal. By exploiting this relationship, the normalized diffusion-to-perfusion ratio color map may be a valuable imaging biomarker for diagnosing anoxic brain injury and potentially assessing BBB integrity. Full Article
abi Mini apartment with an area of 30m2, 1.2 billion price, 5 star facilities, riverside habitat-Jamona By batdongsan.com.vn Published On :: Thu, 07 May 2020 16:44:00 GMT Smart 1-to-2 investment opportunity with TTC Land's Smartel Jamona Heights.Just working at the office of the company - just staying.Diverse area of 30m2 - 79m2.OCB bank borrows 50%.Payment in 18 months.There are 650 million still can invest in real estate in the center.50 year sa... Full Article
abi A NASA telescope has found its first habitable Earth-sized planet By www.newscientist.com Published On :: Tue, 07 Jan 2020 18:08:32 +0000 The TESS space telescope has found its first Earth-sized planet with conditions that might be right for life, orbiting a small star 100 light years away Full Article
abi Let’s Build Robots That Are as Smart as Babies By feedproxy.google.com Published On :: Thu, 24 Oct 2019 19:00:00 GMT Self-driving cars and medical robots need an infant’s understanding of physics to succeed Full Article robotics robotics/artificial-intelligence
abi 'Terrible twos' not inevitable: With engaged parenting, happy babies can become happy toddlers By www.sciencedaily.com Published On :: Wed, 06 May 2020 10:44:23 EDT Parents should not feel pressured to make their young children undertake structured learning or achieve specific tasks, particularly during lockdown. A new study of children under the age of two has found that parents who take a more flexible approach to their child's learning can - for children who were easy babies - minimize behavioral problems during toddlerhood. Full Article
abi Survey: Half of Americans concerned about new moms, babies being in public amid COVID-19 By www.sciencedaily.com Published On :: Thu, 07 May 2020 10:24:28 EDT A new national U.S. survey finds that nearly 80 percent of respondents would be concerned about themselves or an expectant mother in their life in the midst of the current COVID-19 outbreak, with almost half expressing fear of going to a scheduled prenatal appointment. Full Article
abi Skin-to-skin 'kangaroo care' shows important benefits for premature babies By www.sciencedaily.com Published On :: Thu, 07 May 2020 10:24:34 EDT A world-first study has demonstrated significant benefits to a premature baby's heart and brain function when held by the parent in skin-to-skin contact. Parent-infant skin-to-skin care (SSC) or kangaroo care, started in the late 1970s in Columbia when incubators to keep babies warm were not available. It is now widely recognized as a beneficial component of holistic care provided for pre-term infants. Full Article
abi Rights group says Saudi Arabia is holding a senior prince incommunicado since March By news.yahoo.com Published On :: Sat, 09 May 2020 04:32:33 -0400 Full Article
abi 'Bois Locker Room': Experts Say Youngsters Need Rehabilitative Measures, Not Just Punitive Action By in.news.yahoo.com Published On :: Fri, 08 May 2020 23:01:08 -0500 A dialogue on sex, consent, ownership over bodies must be introduced from a young age so that it becomes part of a dominant narrative, say experts. Full Article
abi The bacteria in a mother’s gut may protect babies from food allergies By www.newscientist.com Published On :: Tue, 24 Mar 2020 16:00:40 +0000 The presence of bacteria that break down fibre in a mother’s gut is linked to a reduced risk of food allergies in her child’s first year of life Full Article
abi Eating too much salt seems to impair body's ability to fight bacteria By www.newscientist.com Published On :: Wed, 25 Mar 2020 18:00:45 +0000 High salt intake seems to impair the immune cells in humans that fight bacteria because of a side effect of the hormones that help get rid of salt Full Article
abi Breastfed babies have fewer viruses in their guts that affect humans By www.newscientist.com Published On :: Wed, 15 Apr 2020 16:00:14 +0000 Early in life, babies gain billions of viruses that target gut bacteria – but breastfed babies are less likely to pick up viruses that infect human cells Full Article
abi Some babies who were born prematurely have weaker hearts as adults By www.newscientist.com Published On :: Wed, 22 Apr 2020 06:30:14 +0000 People born prematurely may have weaker hearts that recover less well after exercise, potentially explaining their increased risk of heart disease Full Article
abi People put on ventilators for covid-19 may need lengthy rehabilitation By www.newscientist.com Published On :: Thu, 30 Apr 2020 18:29:27 +0000 Healthcare systems need to prepare for the extensive physiotherapy and mental rehabilitation that people put on ventilators for covid-19 will need as they recover Full Article
abi Global push seeks to unlock genetic key of coronavirus' vulnerability By www.foxnews.com Published On :: Thu, 07 May 2020 22:20:28 GMT One of the mysteries of the coronavirus pandemic that scientists are trying to solve is why some people are barely affected while others who seem to be young and healthy become very sick. Full Article 7c9588aa-bc9b-5cf9-bc26-ac60361adbe1 fox-news/health/infectious-disease/coronavirus fox-news/science fnc fnc/science article Fox News Christopher Carbone
abi All the power, no accountability. That's Trump's COVID success. By www.nbcnews.com Published On :: Thu, 07 May 2020 20:16:00 GMT Analysis: As the president declares victory over the coronavirus amid a rising death toll, his clear focus on extricating himself from responsibility becomes clearer. Full Article
abi House Republicans demand Postmaster General turn over plan for financial stability By www.washingtontimes.com Published On :: Fri, 08 May 2020 12:26:54 -0400 Republicans on the House Oversight Committee said Friday repeated efforts to learn how the cash-strapped U.S. Postal Service intends to become financially stable have been stymied by U.S. Postmaster General Megan Brennan. The lawmakers say they've requested a financial plan from Ms. Brennan three different times, but it hasn't been ... Full Article
abi Coronavirus hospital admissions in London 'stabilising', health chief says By www.standard.co.uk Published On :: 2020-04-12T16:19:38Z Follow our live updates HERE Full Article
abi Coronavirus UK LIVE: Number of people in London hospitals 'stabilising' as death toll soars past 10,000 By www.standard.co.uk Published On :: 2020-04-12T20:05:00Z It comes Matt Hancock has described Easter Sunday as a "sombre day" for the nation, as the the UK death toll among Covid-19 hospital patients soared past the grim 10,000 milestone. Full Article
abi Rishi Sunak 'to warn Cabinet of tipping point between coronavirus concerns and economy' as UK lockdown to be reviewed By www.standard.co.uk Published On :: 2020-04-13T08:09:00Z Follow our live coronavirus updates HERE Coronavirus: the symptoms Full Article
abi Boris Johnson 'raring to go' as he hosts coronavirus 'war cabinet' amid questions over Government's strategy By www.standard.co.uk Published On :: 2020-04-27T06:28:00Z Boris Johnson is back in Downing Street to chair the regular Covid-19 "war cabinet" meeting as he retakes charge of the Government's response to the pandemic. Full Article
abi Iceye's small radar satellites achieve big capability By news.yahoo.com Published On :: Wed, 06 May 2020 11:37:05 -0400 One of the hardest tasks in Earth observation is tracking tiny changes in the shape of the ground. Full Article