Field observations of turbidity currents remain scarce, and thus there is continued debate about their internal structure and how they modify underlying bedforms. Here, I present the results of a new ...imaging method that examines multiple surge-like turbidity currents within a delta front channel, as they pass over crescent-shaped bedforms. Seven discrete flows over a 2-h period vary in speed from 0.5 to 3.0 ms(-1). Only flows that exhibit a distinct acoustically attenuating layer at the base, appear to cause bedform migration. That layer thickens abruptly downstream of the bottom of the lee slope of the bedform, and the upper surface of the layer fluctuates rapidly at that point. The basal layer is inferred to reflect a strong near-bed gradient in density and the thickening is interpreted as a hydraulic jump. These results represent field-scale flow observations in support of a cyclic step origin of crescent-shaped bedforms.
Using a national longitudinal survey data set from the Higher Education Research Institute, this study tested whether students who identified as a sexual minority (for example, lesbian, gay, ...bisexual, or queer) were more or less likely to persist after 4 years in science, technology, engineering, and mathematics (STEM) fields, as opposed to switching to a non-STEM program, compared to their heterosexual peers. A multilevel regression model controlling for various experiences and characteristics previously determined to predict retention in STEM demonstrated that, net of these variables, sexual minority students were 8% less likely to be retained in STEM compared to switching into a non-STEM program. Despite this finding, sexual minority STEM students were more likely to report participating in undergraduate research programs, and the gender disparity in STEM retention appears to be reversed for sexual minority STEM students.
Mitochondria and lysosomes are functionally linked, and their interdependent decline is a hallmark of aging and disease. Despite the long-standing connection between these organelles, the function(s) ...of lysosomes required to sustain mitochondrial health remains unclear. Here, working in yeast, we show that the lysosome-like vacuole maintains mitochondrial respiration by spatially compartmentalizing amino acids. Defects in vacuole function result in a breakdown in intracellular amino acid homeostasis, which drives age-related mitochondrial decline. Among amino acids, we find that cysteine is most toxic for mitochondria and show that elevated non-vacuolar cysteine impairs mitochondrial respiration by limiting intracellular iron availability through an oxidant-based mechanism. Cysteine depletion or iron supplementation restores mitochondrial health in vacuole-impaired cells and prevents mitochondrial decline during aging. These results demonstrate that cysteine toxicity is a major driver of age-related mitochondrial deterioration and identify vacuolar amino acid compartmentation as a cellular strategy to minimize amino acid toxicity.
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•Elevated cysteine disrupts mitochondrial respiration in vacuole-impaired cells•Cysteine inhibits mitochondrial function by limiting iron bioavailability•Vacuoles sequester cysteine to promote efficient mitochondrial respiration•Cysteine restriction or iron supplementation sustains mitochondrial health in aging
Breakdown of the spatial compartmentalization of amino acids by vacuoles is a key driver of age-related mitochondrial deterioration through ROS-dependent perturbation of iron homeostasis.
Alpine plant radiations are compared across the world's major mountain ranges and shown to be overwhelmingly young and fast, largely confined to the Pliocene and Pleistocene, and some of them ...apparently in the early explosive phase of radiation. Accelerated diversification triggered by island-like ecological opportunities following the final phases of mountain uplift, and in many cases enabled by the key adaptation of perennial habit, provides a general model for alpine plant radiations. Accelerated growth form evolution facilitated by perenniality provides compelling evidence of ecological release and suggests striking parallels between island-like alpine, and especially tropicalpine radiations, and island radiations more generally. These parallels suggest that the world's mountains offer an excellent comparative system for explaining evolutionary radiation.
To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all ...protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional "rush hours" preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spiiceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.
The goal of this work is to determine how GCaMP6m's fluorescence is altered in response to Ca2+-binding. Our detailed spectroscopic study reveals the simplest explanation for how GCaMP6m changes ...fluorescence in response to Ca2+ is with a four-state model, in which a Ca2+-dependent change of the chromophore protonation state, due to a shift in pKa, is the predominant factor. The pKa shift is quantitatively explained by a change in electrostatic potential around the chromophore due to the conformational changes that occur in the protein when calmodulin binds Ca2+ and interacts with the M13 peptide. The absolute pKa values for the Ca2+-free and Ca2+-saturated states of GCaMP6m are critical to its high signal-to-noise ratio. This mechanism has important implications for further improvements to GCaMP6m and potentially for other similarly designed biosensors.
Many advances in the treatment of cancer have been driven by the development of targeted therapies that inhibit oncogenic signaling pathways and tumor-associated angiogenesis, as well as by the ...recent development of therapies that activate a patient's immune system to unleash antitumor immunity. Some targeted therapies can have effects on host immune responses, in addition to their effects on tumor biology. These immune-modulating effects, such as increasing tumor antigenicity or promoting intratumoral T cell infiltration, provide a rationale for combining these targeted therapies with immunotherapies. Here, we discuss the immune-modulating effects of targeted therapies against the MAPK and VEGF signaling pathways, and how they may synergize with immunomodulatory antibodies that target PD1/PDL1 and CTLA4. We critically examine the rationale in support of these combinations in light of the current understanding of the underlying mechanisms of action of these therapies. We also discuss the available preclinical and clinical data for these combination approaches and their implications regarding mechanisms of action. Insights from these studies provide a framework for considering additional combinations of targeted therapies and immunotherapies for the treatment of cancer.
Globally, there are now over 160 million confirmed cases of COVID-19 and more than 3 million deaths. While the majority of infected individuals recover, a significant proportion continue to ...experience symptoms and complications after their acute illness. Patients with ‘long COVID’ experience a wide range of physical and mental/psychological symptoms. Pooled prevalence data showed the 10 most prevalent reported symptoms were fatigue, shortness of breath, muscle pain, joint pain, headache, cough, chest pain, altered smell, altered taste and diarrhoea. Other common symptoms were cognitive impairment, memory loss, anxiety and sleep disorders. Beyond symptoms and complications, people with long COVID often reported impaired quality of life, mental health and employment issues. These individuals may require multidisciplinary care involving the long-term monitoring of symptoms, to identify potential complications, physical rehabilitation, mental health and social services support. Resilient healthcare systems are needed to ensure efficient and effective responses to future health challenges.
Bicyclic hydrocarbons, and bicyclo1.1.1pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage ...of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from 1.1.1propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from 2.1.1 to 3.2.1 scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons.
Detecting periodicity in large scale data remains a challenge. While efforts have been made to identify best of breed algorithms, relatively little research has gone into integrating these methods in ...a generalizable method. Here, we present MetaCycle, an R package that incorporates ARSER, JTK_CYCLE and Lomb-Scargle to conveniently evaluate periodicity in time-series data. MetaCycle has two functions, meta2d and meta3d, designed to analyze two-dimensional and three-dimensional time-series datasets, respectively. Meta2d implements N-version programming concepts using a suite of algorithms and integrating their results.
MetaCycle package is available on the CRAN repository (https://cran.r-project.org/web/packages/MetaCycle/index.html) and GitHub (https://github.com/gangwug/MetaCycle).
hogenesch@gmail.comSupplementary information: Supplementary data are available at Bioinformatics online.
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