Strategies for 21st-century environmental management and conservation under global change require a strong understanding of the biological mechanisms that mediate responses to climate- and ...human-driven change to successfully mitigate range contractions, extinctions, and the degradation of ecosystem services. Biodiversity responses to past rapid warming events can be followed in situ and over extended periods, using cross-disciplinary approaches that provide cost-effective and scalable information for species' conservation and the maintenance of resilient ecosystems in many bioregions. Beyond the intrinsic knowledge gain such integrative research will increasingly provide the context, tools, and relevant case studies to assist in mitigating climate-driven biodiversity losses in the 21st century and beyond.
Ambient-noise-based seismic monitoring of the near surface often has limited spatiotemporal resolutions because dense seismic arrays are rarely sufficiently affordable for such applications. In ...recent years, however, distributed acoustic sensing (DAS) techniques have emerged to transform telecommunication fiber-optic cables into dense seismic arrays that are cost effective. With DAS enabling both high sensor counts ("large N") and long-term operations ("large T"), time-lapse imaging of shear-wave velocity (V
) structures is now possible by combining ambient noise interferometry and multichannel analysis of surface waves (MASW). Here we report the first end-to-end study of time-lapse V
imaging that uses traffic noise continuously recorded on linear DAS arrays over a three-week period. Our results illustrate that for the top 20 meters the V
models that is well constrained by the data, we obtain time-lapse repeatability of about 2% in the model domain-a threshold that is low enough for observing subtle near-surface changes such as water content variations and permafrost alteration. This study demonstrates the efficacy of near-surface seismic monitoring using DAS-recorded ambient noise.
Abstract
Aims
Pulmonary hypertension (PH) and pulmonary vascular disease (PVD) are common and associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). Little is ...known about the impact of PVD on the pathophysiology of exercise intolerance.
Methods and results
Heart failure with preserved ejection fraction patients (n = 161) with elevated pulmonary capillary wedge pressure (≥15 mmHg) at rest were classified into three groups: non-PH-HFpEF (n = 21); PH but no PVD (isolated post-capillary PH, IpcPH; n = 95); and PH with PVD (combined post- and pre-capillary PH, CpcPH; n = 45). At rest, CpcPH-HFpEF patients had more right ventricular (RV) dysfunction and lower pulmonary arterial (PA) compliance compared to all other groups. While right atrial pressure (RAP) and left ventricular transmural pressure (LVTMP) were similar in HFpEF with and without PH or PVD at rest, CpcPH-HFpEF patients demonstrated greater increase in RAP, enhanced ventricular interdependence, and paradoxical reduction in LVTMP during exercise, differing from all other groups (P < 0.05). Lower PA compliance was correlated with greater increase in RAP with exercise. During exercise, CpcPH-HFpEF patients displayed an inability to enhance cardiac output, reduction in forward stroke volume, and blunted augmentation in RV systolic performance, changes that were coupled with marked limitation in aerobic capacity.
Conclusion
Heart failure with preserved ejection fraction patients with PVD demonstrate unique haemodynamic limitations during exercise that constrain aerobic capacity, including impaired recruitment of LV preload due to excessive right heart congestion and blunted RV systolic reserve. Interventions targeted to this distinct pathophysiology require testing in patients with HFpEF and PVD.
This Letter describes the chemistry and structure–activity trends for a series of cyanoanthranilic diamides that exhibit their insecticidal action by release of intracellular Ca2+ stores mediated by ...the ryanodine receptor. From this work, cyantraniliprole was selected for commercial development.
Anthranilic diamides are an exceptionally active class of insect control chemistry that selectively activates insect ryanodine receptors causing mortality from uncontrolled release of calcium ion stores in muscle cells. Work in this area led to the successful commercialization of chlorantraniliprole for control of Lepidoptera and other insect pests at very low application rates. In search of lower logP analogs with improved plant systemic properties, exploration of cyano-substituted anthranilic diamides culminated in the discovery of a second product candidate, cyantraniliprole, having excellent activity against a wide range of pests from multiple insect orders. Here we report on the chemistry, biology and structure–activity trends for a series of cyanoanthranilic diamides from which cyantraniliprole was selected for commercial development.
We used the 10x Genomics Visium platform to define the spatial topography of gene expression in the six-layered human dorsolateral prefrontal cortex. We identified extensive layer-enriched expression ...signatures and refined associations to previous laminar markers. We overlaid our laminar expression signatures on large-scale single nucleus RNA-sequencing data, enhancing spatial annotation of expression-driven clusters. By integrating neuropsychiatric disorder gene sets, we showed differential layer-enriched expression of genes associated with schizophrenia and autism spectrum disorder, highlighting the clinical relevance of spatially defined expression. We then developed a data-driven framework to define unsupervised clusters in spatial transcriptomics data, which can be applied to other tissues or brain regions in which morphological architecture is not as well defined as cortical laminae. Last, we created a web application for the scientific community to explore these raw and summarized data to augment ongoing neuroscience and spatial transcriptomics research ( http://research.libd.org/spatialLIBD ).
Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) strategies with proven in vivo efficacy rely on antiretroviral drugs, creating the potential for drug resistance and complicated ...treatment options in individuals who become infected. Moreover, on-demand products are currently missing from the PrEP development portfolio. Griffithsin (GRFT) is a non-antiretroviral HIV entry inhibitor derived from red algae with an excellent safety profile and potent activity in vitro. When combined with carrageenan (CG), GRFT has strong activity against herpes simplex virus-2 (HSV-2) and human papillomavirus (HPV) in vitro and in vivo. Here, we report that GRFT/CG in a freeze-dried fast dissolving insert (FDI) formulation for on-demand use protects rhesus macaques from a high dose vaginal SHIV SF162P3 challenge 4 h after FDI insertion. Furthermore, the GRFT/CG FDI also protects mice vaginally against HSV-2 and HPV pseudovirus. As a safe, potent, broad-spectrum, on-demand non-antiretroviral product, the GRFT/CG FDI warrants clinical development.
Whole-exome sequencing (WES), which analyzes the coding sequence of most annotated genes in the human genome, is an ideal approach to studying fully penetrant autosomal-recessive diseases, and it has ...been very powerful in identifying disease-causing mutations even when enrollment of affected individuals is limited by reduced survival. In this study, we combined WES with homozygosity analysis of consanguineous pedigrees, which are informative even when a single affected individual is available, to identify genetic mutations responsible for Walker-Warburg syndrome (WWS), a genetically heterogeneous autosomal-recessive disorder that severely affects the development of the brain, eyes, and muscle. Mutations in seven genes are known to cause WWS and explain 50%–60% of cases, but multiple additional genes are expected to be mutated because unexplained cases show suggestive linkage to diverse loci. Using WES in consanguineous WWS-affected families, we found multiple deleterious mutations in GTDC2 (also known as AGO61). GTDC2’s predicted role as an uncharacterized glycosyltransferase is consistent with the function of other genes that are known to be mutated in WWS and that are involved in the glycosylation of the transmembrane receptor dystroglycan. Therefore, to explore the role of GTDC2 loss of function during development, we used morpholino-mediated knockdown of its zebrafish ortholog, gtdc2. We found that gtdc2 knockdown in zebrafish replicates all WWS features (hydrocephalus, ocular defects, and muscular dystrophy), strongly suggesting that GTDC2 mutations cause WWS.
To demonstrate the potential for geologic storage of CO2 in saline aquifers, the Frio-I Brine Pilot was conducted, during which 1600tons of CO2 were injected into a high-permeability sandstone and ...the resulting subsurface plume of CO2 was monitored using a variety of hydrogeological, geophysical, and geochemical techniques. Fluid samples were obtained before CO2 injection for baseline geochemical characterization, during the CO2 injection to track its breakthrough at a nearby observation well, and after injection to investigate changes in fluid composition and potential leakage into an overlying zone. Following CO2 breakthrough at the observation well, brine samples showed sharp drops in pH, pronounced increases in HCO3 a and aqueous Fe, and significant shifts in the isotopic compositions of H2O and dissolved inorganic carbon. Based on a calibrated 1-D radial flow model, reactive transport modeling was performed for the Frio-I Brine Pilot. A simple kinetic model of Fe release from the solid to aqueous phase was developed, which can reproduce the observed increases in aqueous Fe concentration. Brine samples collected after half a year had lower Fe concentrations due to carbonate precipitation, and this trend can be also captured by our modeling. The paper provides a method for estimating potential mobile Fe inventory, and its bounding concentration in the storage formation from limited observation data. Long-term simulations show that the CO2 plume gradually spreads outward due to capillary forces, and the gas saturation gradually decreases due to its dissolution and precipitation of carbonates. The gas phase is predicted to disappear after 500years. Elevated aqueous CO2 concentrations remain for a longer time, but eventually decrease due to carbonate precipitation. For the Frio-I Brine Pilot, all injected CO2 could ultimately be sequestered as carbonate minerals.
Accumulating evidence suggests that selective M4 muscarinic acetylcholine receptor (mAChR) activators may offer a novel strategy for the treatment of psychosis. However, previous efforts to develop ...selective M4 activators were unsuccessful because of the lack of M4 mAChR subtype specificity and off-target muscarinic adverse effects. We recently developed VU0152100, a highly selective M4 positive allosteric modulator (PAM) that exerts central effects after systemic administration. We now report that VU0152100 dose-dependently reverses amphetamine-induced hyperlocomotion in rats and wild-type mice, but not in M4 KO mice. VU0152100 also blocks amphetamine-induced disruption of the acquisition of contextual fear conditioning and prepulse inhibition of the acoustic startle reflex. These effects were observed at doses that do not produce catalepsy or peripheral adverse effects associated with non-selective mAChR agonists. To further understand the effects of selective potentiation of M4 on region-specific brain activation, VU0152100 alone and in combination with amphetamine were evaluated using pharmacologic magnetic resonance imaging (phMRI). Key neural substrates of M4-mediated modulation of the amphetamine response included the nucleus accumbens (NAS), caudate-putamen (CP), hippocampus, and medial thalamus. Functional connectivity analysis of phMRI data, specifically assessing correlations in activation between regions, revealed several brain networks involved in the M4 modulation of amphetamine-induced brain activation, including the NAS and retrosplenial cortex with motor cortex, hippocampus, and medial thalamus. Using in vivo microdialysis, we found that VU0152100 reversed amphetamine-induced increases in extracellular dopamine levels in NAS and CP. The present data are consistent with an antipsychotic drug-like profile of activity for VU0152100. Taken together, these data support the development of selective M4 PAMs as a new approach to the treatment of psychosis and cognitive impairments associated with psychiatric disorders such as schizophrenia.
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