Update of bioRxiv. 2022 Nov 23;:

Using measures of research productivity to assess academic performance puts women at a disadvantage because gender roles and unconscious biases, operating both at home and in academia, can affect research productivity. The impact of the COVID-19 pandemic on research productivity has been the subject of a number of studies, including studies based on surveys and studies based on numbers of articles submitted to and/or published in journals. Here, we combine the results of 55 studies that compared the impact of the pandemic on the research productivity of men and women; 17 of the studies were based on surveys, 38 were based on article counts, and the total number of effect sizes was 130. We find that the gender gap in research productivity increased during the COVID-19 pandemic, with the largest changes occurring in the social sciences and medicine, and the changes in the biological sciences and TEMCP (technology, engineering, mathematics, chemistry and physics) being much smaller.

Brazil would benefit from a long-term strategy for science and innovation that improves the standing of both science and scientists in the country.

Update of bioRxiv. 2023 Apr 24;:

Impaired spermatogenesis and male infertility are common manifestations of mitochondrial diseases, but the underlying mechanisms are unclear. Here we show that mice deficient for the mitochondrial intra-membrane rhomboid protease PARL, a recently reported model of Leigh syndrome, develop early testicular atrophy caused by a complete arrest of spermatogenesis at meiotic prophase I, followed by germ cell death independently of neurodegeneration. Genetic modifications of PINK1, PGAM5, and TTC19, three major substrates of PARL with important roles in mitochondrial homeostasis, do not reproduce or modify this severe phenotype. PARL deficiency in spermatocytes leads to severe abnormalities in mitochondrial structure associated with prominent electron transfer chain defects, alterations in Coenzyme Q (CoQ) biosynthesis, and metabolic rewiring. These mitochondrial defects are associated with a germ-cell specific decrease in GPX4 expression committing arrested spermatocytes to ferroptosis, a regulated cell death modality characterized by uncontrolled lipid peroxidation. Thus, mitochondrial defects, such as those induced by depletion of PARL, spontaneously initiate ferroptosis in primary spermatocytes in vivo by simultaneous effects on GPX4 and CoQ, the two major ferroptosis-inhibitors. Ferroptosis warrants to be further scrutinized in the pathogenesis of mitochondrial diseases and male infertility.

Despite ground-breaking genetic studies that have identified thousands of risk variants for developmental diseases, how these variants lead to molecular and cellular phenotypes remains a gap in knowledge. Many of these variants are non-coding and occur at enhancers, which orchestrate key regulatory programs during development. The prevailing paradigm is that non-coding variants alter the activity of enhancers, impacting gene expression programs, and ultimately contributing to disease risk. A key obstacle to progress is the systematic functional characterization of non-coding variants at scale, especially since enhancer activity is highly specific to cell type and developmental stage. Here, we review the foundational studies of enhancers in developmental disease and current genomic approaches to functionally characterize developmental enhancers and their variants at scale. In the coming decade, we anticipate systematic enhancer perturbation studies to link non-coding variants to molecular mechanisms, changes in cell state, and disease phenotypes.

The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O2-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.

Ultrasonic vocalizations (USVs) fulfill an important role in communication and navigation in many species. Because of their social and affective significance, rodent USVs are increasingly used as a behavioral measure in neurodevelopmental and neurolinguistic research. Reliably attributing USVs to their emitter during close interactions has emerged as a difficult, key challenge. If addressed, all subsequent analyses gain substantial confidence. We present a hybrid ultrasonic tracking system, HyVL, that synergistically integrates a high-resolution acoustic camera with high-quality ultrasonic microphones. HyVL is the first to achieve millimeter precision (~3.4-4.8mm, 91% assigned) in localizing USVs, ~3x better than other systems, approaching the physical limits (mouse snout ~ 10mm). We analyze mouse courtship interactions and demonstrate that males and females vocalize in starkly different relative spatial positions, and that the fraction of female vocalizations has likely been overestimated previously due to imprecise localization. Further, we find that when two male mice interact with one female, one of the males takes a dominant role in the interaction both in terms of the vocalization rate and the location relative to the female. HyVL substantially improves the precision with which social communication between rodents can be studied. It is also affordable, open-source, easy to set up, can be integrated with existing setups, and reduces the required number of experiments and animals.

Phosphorylation of proteins is a ubiquitous mechanism of regulating their function, localization, or activity. Protein kinases, enzymes that use ATP to phosphorylate protein substrates are, therefore, powerful signal transducers in eukaryotic cells. The mechanism of phosphoryl-transfer is universally conserved among protein kinases, which necessitates the tight regulation of kinase activity for the orchestration of cellular processes with high spatial and temporal fidelity. In response to a stimulus, many kinases enhance their own activity by autophosphorylating a conserved amino acid in their activation loop, but precisely how this reaction is performed is controversial. Classically, kinases that autophosphorylate their activation loop are thought to perform the reaction in trans, mediated by transient dimerization of their kinase domains. However, motivated by the recently discovered regulation mechanism of activation loop cis-autophosphorylation by a kinase that is autoinhibited in trans, we here review the various mechanisms of autoregulation that have been proposed. We provide a framework for critically evaluating biochemical, kinetic, and structural evidence for protein kinase dimerization and autophosphorylation, and share some thoughts on the implications of these mechanisms within physiological signaling networks.

The BBSome is an octameric protein complex that regulates ciliary transport and signaling. Mutations in BBSome subunits are closely associated with ciliary defects and lead to ciliopathies, notably Bardet-Biedl syndrome. Over the past few years, there has been significant progress in elucidating the molecular organization and functions of the BBSome complex. An improved understanding of BBSome-mediated biological events and molecular mechanisms is expected to help advance the development of diagnostic and therapeutic approaches for BBSome-related diseases. Here, we review the current literature on the structural assembly, transport regulation, and molecular functions of the BBSome, emphasizing its roles in cilium-related processes. We also provide perspectives on the pathological role of the BBSome in ciliopathies as well as how these can be exploited for therapeutic benefit.

Update of doi: 10.1101/2022.11.21.517392.

Actin dynamics in cell motility, division, and phagocytosis is regulated by complex factors with multiple feedback loops, often leading to emergent dynamic patterns in the form of propagating waves of actin polymerization activity that are poorly understood. Many in the actin wave community have attempted to discern the underlying mechanisms using experiments and/or mathematical models and theory. Here, we survey methods and hypotheses for actin waves based on signaling networks, mechano-chemical effects, and transport characteristics, with examples drawn from Dictyostelium discoideum, human neutrophils, Caenorhabditis elegans, and Xenopus laevis oocytes. While experimentalists focus on the details of molecular components, theorists pose a central question of universality: Are there generic, model-independent, underlying principles, or just boundless cell-specific details? We argue that mathematical methods are equally important for understanding the emergence, evolution, and persistence of actin waves and conclude with a few challenges for future studies.