The ongoing Coronavirus Disease 2019 (COVID-19) pandemic caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) threatens global public health and economy unprecedentedly, requiring accelerating development of prophylactic and therapeutic interventions. Molecular understanding of neutralizing antibodies (NAbs) would greatly help advance the development of monoclonal antibody (mAb) therapy, as well as the design of next generation recombinant vaccines. Here, we applied H2L2 transgenic mice encoding the human immunoglobulin variable regions, together with a state-of-the-art antibody discovery platform to immunize and isolate NAbs. From a large panel of isolated antibodies, 25 antibodies showed potent neutralizing activities at sub-nanomolar levels by engaging the spike receptor-binding domain (RBD). Importantly, one human NAb, termed PR1077, from the H2L2 platform and 2 humanized NAb, including PR953 and PR961, were further characterized and subjected for subsequent structural analysis. High-resolution X-ray crystallography structures unveiled novel epitopes on the receptor-binding motif (RBM) for PR1077 and PR953, which directly compete with human angiotensin-converting enzyme 2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961. Moreover, we further tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. A single injection provided potent protection against SARS-CoV-2 infection in either prophylactic or treatment groups. Taken together, these results shed light on the development of mAb-related therapeutic interventions for COVID-19.

Update of medRxiv. 2021 Mar 12;:

Understanding brain operation demands linking basic behavioral traits to cell-type specific dynamics of different brain-wide subcircuits. This requires a system to classify the basic operational modes of neurons and circuits. Single-cell phenotyping of firing behavior during ongoing oscillations in vivo has provided a large body of evidence on entorhinal-hippocampal function, but data are dispersed and diverse. Here, we mined literature to search for information regarding the phase-timing dynamics of over 100 hippocampal/entorhinal neuron types defined in Hippocampome.org. We identified missing and unresolved pieces of knowledge (e.g., the preferred theta phase for a specific neuron type) and complemented the dataset with our own new data. By confronting the effect of brain state and recording methods, we highlight the equivalences and differences across conditions and offer a number of novel observations. We show how a heuristic approach based on oscillatory features of morphologically identified neurons can aid in classifying extracellular recordings of single cells and discuss future opportunities and challenges towards integrating single-cell phenotypes with circuit function.

The study of unconscious processing requires a measure of conscious awareness. Awareness measures can be either subjective (based on participant's report) or objective (based on perceptual performance). The preferred awareness measure depends on the theoretical position about consciousness and may influence conclusions about the extent of unconscious processing and about the neural correlates of consciousness. We obtained functional magnetic resonance imaging (fMRI) measurements from 43 subjects while they viewed masked faces and houses that were either subjectively or objectively invisible. Even for objectively invisible (perceptually indiscriminable) stimuli, we found significant category information in both early, lower-level visual areas and in higher-level visual cortex, although representations in anterior, category-selective ventrotemporal areas were less robust. For subjectively invisible stimuli, similar to visible stimuli, there was a clear posterior-to-anterior gradient in visual cortex, with stronger category information in ventrotemporal cortex than in early visual cortex. For objectively invisible stimuli, however, category information remained virtually unchanged from early visual cortex to object- and category-selective visual areas. These results demonstrate that although both objectively and subjectively invisible stimuli are represented in visual cortex, the extent of unconscious information processing is influenced by the measurement approach. Furthermore, our data show that subjective and objective approaches are associated with different neural correlates of consciousness and thus have implications for neural theories of consciousness.

In an effort to better utilize published evidence obtained from animal experiments, systematic reviews of preclinical studies are increasingly more common-along with the methods and tools to appraise them (e.g., SYstematic Review Center for Laboratory animal Experimentation [SYRCLE's] risk of bias tool). We performed a cross-sectional study of a sample of recent preclinical systematic reviews (2015-2018) and examined a range of epidemiological characteristics and used a 46-item checklist to assess reporting details. We identified 442 reviews published across 43 countries in 23 different disease domains that used 26 animal species. Reporting of key details to ensure transparency and reproducibility was inconsistent across reviews and within article sections. Items were most completely reported in the title, introduction, and results sections of the reviews, while least reported in the methods and discussion sections. Less than half of reviews reported that a risk of bias assessment for internal and external validity was undertaken, and none reported methods for evaluating construct validity. Our results demonstrate that a considerable number of preclinical systematic reviews investigating diverse topics have been conducted; however, their quality of reporting is inconsistent. Our study provides the justification and evidence to inform the development of guidelines for conducting and reporting preclinical systematic reviews.

Obesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet (HFD) rodent models, but their precise role remains unclear. Here, we establish a HFD model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell type-specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A HFD drives nephrocyte lipid uptake via the multiligand receptor Cubilin (Cubn), leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with endoplasmic reticulum (ER) and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL), and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria, and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue HFD-induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a HFD via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.

Single-cell RNA sequencing (scRNA-seq) provides an unprecedented view of cellular diversity of biological systems. However, across the thousands of publications and datasets generated using this technology, we estimate that only a minority (<25%) of studies provide cell-level metadata information containing identified cell types and related findings of the published dataset. Metadata omission hinders reproduction, exploration, validation, and knowledge transfer and is a common problem across journals, data repositories, and publication dates. We encourage investigators, reviewers, journals, and data repositories to improve their standards and ensure proper documentation of these valuable datasets.

Comment in Eur J Neurosci. 2022 Jan;55(1):201-204.

Premature termination codons (PTC) cause over 10% of genetic disease cases. Some aminoglycosides that bind to the ribosome decoding center can induce PTC readthrough and restore low levels of full-length functional proteins. However, concomitant inhibition of protein synthesis limits the extent of PTC readthrough that can be achieved by aminoglycosides like G418. Using a cell-based screen, we identified a small molecule, the phenylpyrazoleanilide Y-320, that potently enhances TP53, DMD, and COL17A1 PTC readthrough by G418. Unexpectedly, Y-320 increased cellular protein levels and protein synthesis, measured by SYPRO Ruby protein staining and puromycin labeling, as well as ribosome biogenesis measured using antibodies to rRNA and ribosomal protein S6. Y-320 did not increase the rate of translation elongation and it exerted its effects independently of mTOR signaling. At the single cell level, exposure to Y-320 and G418 increased ribosome content and protein synthesis which correlated strongly with PTC readthrough. As a single agent, Y-320 did not affect translation fidelity measured using a luciferase reporter gene but it enhanced misincorporation by G418. RNA-seq data showed that Y-320 up-regulated the expression of CXC chemokines CXCL10, CXCL8, CXCL2, CXCL11, CXCL3, CXCL1, and CXCL16. Several of these chemokines exert their cellular effects through the receptor CXCR2 and the CXCR2 antagonist SB225002 reduced cellular protein levels and PTC readthrough in cells exposed to Y-320 and G418. These data show that the self-limiting nature of PTC readthrough by G418 can be compensated by Y-320, a potent enhancer of PTC readthrough that increases ribosome biogenesis and protein synthesis. They also support a model whereby increased PTC readthrough is enabled by increased protein synthesis mediated by an autocrine chemokine signaling pathway. The findings also raise the possibility that inflammatory processes affect cellular propensity to readthrough agents and that immunomodulatory drugs like Y-320 might find application in PTC readthrough therapy.

New technologies make it possible to measure activity from many neurons simultaneously. One approach is to analyze simultaneously recorded neurons individually, then group together neurons which increase their activity during similar behaviors into an "ensemble." However, this notion of an ensemble ignores the ability of neurons to act collectively and encode and transmit information in ways that are not reflected by their individual activity levels. We used microendoscopic GCaMP imaging to measure prefrontal activity while mice were either alone or engaged in social interaction. We developed an approach that combines a neural network classifier and surrogate (shuffled) datasets to characterize how neurons synergistically transmit information about social behavior. Notably, unlike optimal linear classifiers, a neural network classifier with a single linear hidden layer can discriminate network states which differ solely in patterns of coactivity, and not in the activity levels of individual neurons. Using this approach, we found that surrogate datasets which preserve behaviorally specific patterns of coactivity (correlations) outperform those which preserve behaviorally driven changes in activity levels but not correlated activity. Thus, social behavior elicits increases in correlated activity that are not explained simply by the activity levels of the underlying neurons, and prefrontal neurons act collectively to transmit information about socialization via these correlations. Notably, this ability of correlated activity to enhance the information transmitted by neuronal ensembles is diminished in mice lacking the autism-associated gene Shank3. These results show that synergy is an important concept for the coding of social behavior which can be disrupted in disease states, reveal a specific mechanism underlying this synergy (social behavior increases correlated activity within specific ensembles), and outline methods for studying how neurons within an ensemble can work together to encode information.

Genomic research led the way in open science, a tradition continued by genome-wide association studies (GWAS)-through the sharing of materials, results, and data. Coordinated quality control procedures also contributed to robust findings. However, recent years have seen declines in GWAS transparency. Here, we assess some shifts away from open science practices with the aim of stimulating a discussion of these issues.

Removal of apoptotic cells is essential for maintenance of tissue homeostasis. Chemotactic cues termed "find-me" signals attract phagocytes toward apoptotic cells, which selectively expose the anionic phospholipid phosphatidylserine (PS) and other "eat-me" signals to distinguish healthy from apoptotic cells for phagocytosis. Blebs released by apoptotic cells can deliver find-me signals; however, the mechanism is poorly understood. Here, we demonstrate that apoptotic blebs generated in vivo from mouse thymus attract phagocytes using endogenous chemokines bound to the bleb surface. We show that chemokine binding to apoptotic cells is mediated by PS and that high affinity binding of PS and other anionic phospholipids is a general property of many but not all chemokines. Chemokines are positively charged proteins that also bind to anionic glycosaminoglycans (GAGs) on cell surfaces for presentation to leukocyte G protein-coupled receptors (GPCRs). We found that apoptotic cells down-regulate GAGs as they up-regulate PS on the cell surface and that PS-bound chemokines, unlike GAG-bound chemokines, are able to directly activate chemokine receptors. Thus, we conclude that PS-bound chemokines may serve as find-me signals on apoptotic vesicles acting at cognate chemokine receptors on leukocytes.

Hyperactivation of the mammalian target of rapamycin (mTOR) pathway can cause malformation of cortical development (MCD) with associated epilepsy and intellectual disability (ID) through a yet unknown mechanism. Here, we made use of the recently identified dominant-active mutation in Ras Homolog Enriched in Brain 1 (RHEB), RHEBp.P37L, to gain insight in the mechanism underlying the epilepsy caused by hyperactivation of the mTOR pathway. Focal expression of RHEBp.P37L in mouse somatosensory cortex (SScx) results in an MCD-like phenotype, with increased mTOR signaling, ectopic localization of neurons, and reliable generalized seizures. We show that in this model, the mTOR-dependent seizures are caused by enhanced axonal connectivity, causing hyperexcitability of distally connected neurons. Indeed, blocking axonal vesicle release from the RHEBp.P37L neurons alone completely stopped the seizures and normalized the hyperexcitability of the distally connected neurons. These results provide new evidence of the extent of anatomical and physiological abnormalities caused by mTOR hyperactivity, beyond local malformations, which can lead to generalized epilepsy.

Normal cellular processes give rise to toxic metabolites that cells must mitigate. Formaldehyde is a universal stressor and potent metabolic toxin that is generated in organisms from bacteria to humans. Methylotrophic bacteria such as Methylorubrum extorquens face an acute challenge due to their production of formaldehyde as an obligate central intermediate of single-carbon metabolism. Mechanisms to sense and respond to formaldehyde were speculated to exist in methylotrophs for decades but had never been discovered. Here, we identify a member of the DUF336 domain family, named efgA for enhanced formaldehyde growth, that plays an important role in endogenous formaldehyde stress response in M. extorquens PA1 and is found almost exclusively in methylotrophic taxa. Our experimental analyses reveal that EfgA is a formaldehyde sensor that rapidly arrests growth in response to elevated levels of formaldehyde. Heterologous expression of EfgA in Escherichia coli increases formaldehyde resistance, indicating that its interaction partners are widespread and conserved. EfgA represents the first example of a formaldehyde stress response system that does not involve enzymatic detoxification. Thus, EfgA comprises a unique stress response mechanism in bacteria, whereby a single protein directly senses elevated levels of a toxic intracellular metabolite and safeguards cells from potential damage.

For junior investigators starting their independent careers, the challenges of the Coronavirus Disease 2019 (COVID-19) pandemic extend beyond lost time and are career threatening. Without intervention, academic science could lose a generation of talent.

We here conducted an image-based chemical screen to evaluate how medically approved drugs, as well as drugs that are currently under development, influence overall translation levels. None of the compounds up-regulated translation, which could be due to the screen being performed in cancer cells grown in full media where translation is already present at very high levels. Regarding translation down-regulators, and consistent with current knowledge, inhibitors of the mechanistic target of rapamycin (mTOR) signaling pathway were the most represented class. In addition, we identified that inhibitors of sphingosine kinases (SPHKs) also reduce mRNA translation levels independently of mTOR. Mechanistically, this is explained by an effect of the compounds on the membranes of the endoplasmic reticulum (ER), which activates the integrated stress response (ISR) and contributes to the toxicity of SPHK inhibitors. Surprisingly, the toxicity and activation of the ISR triggered by 2 independent SPHK inhibitors, SKI-II and ABC294640, the latter in clinical trials, are also observed in cells lacking SPHK1 and SPHK2. In summary, our study provides a useful resource on the effects of medically used drugs on translation, identified compounds capable of reducing translation independently of mTOR and has revealed that the cytotoxic properties of SPHK inhibitors being developed as anticancer agents are independent of SPHKs.

Inflammation is implicated in the onset and progression of various diseases, including cerebral pathologies. Here, we report that DJ-1, which plays a role within cells as an antioxidant protein, functions as a damage-associated molecular pattern (DAMP) and triggers inflammation if released from dead cells into the extracellular space. We first found that recombinant DJ-1 protein induces the production of various inflammatory cytokines in bone marrow-derived macrophages (BMMs) and dendritic cells (BMDCs). We further identified a unique peptide sequence in the αG and αH helices of DJ-1 that activates Toll-like receptor 2 (TLR2) and TLR4. In the ischemic brain, DJ-1 is released into the extracellular space from necrotic neurons within 24 h after stroke onset and makes direct contact with TLR2 and TLR4 in infiltrating myeloid cells. Although DJ-1 deficiency in a murine model of middle cerebral artery occlusion did not attenuate neuronal injury, the inflammatory cytokine expression in infiltrating immune cells was significantly decreased. Next, we found that the administration of an antibody to neutralize extracellular DJ-1 suppressed cerebral post-ischemic inflammation and attenuated ischemic neuronal damage. Our results demonstrate a previously unknown function of DJ-1 as a DAMP and suggest that extracellular DJ-1 could be a therapeutic target to prevent inflammation in tissue injuries and neurodegenerative diseases.

As a part of growing up, immature orangutans must acquire vast repertoires of skills and knowledge, a process that takes several years of observational social learning and subsequent practice. Adult female and male orangutans show behavioral differences including sex-specific foraging patterns and male-biased dispersal. We investigated how these differing life trajectories affect social interest and emerging ecological knowledge in immatures. We analyzed 15 years of detailed observational data on social learning, associations, and diet repertoires of 50 immatures (16 females and 34 males), from 2 orangutan populations. Specific to the feeding context, we found sex differences in the development of social interest: Throughout the dependency period, immature females direct most of their social attention at their mothers, whereas immature males show an increasing attentional preference for individuals other than their mothers. When attending to non-mother individuals, males show a significant bias toward immigrant individuals and a trend for a bias toward adult males. In contrast, females preferentially attend to neighboring residents. Accordingly, by the end of the dependency period, immature females show a larger dietary overlap with their mothers than do immature males. These results suggest that immature orangutans show attentional biases through which they learn from individuals with the most relevant ecological knowledge. Diversifying their skills and knowledge likely helps males when they move to a new area. In sum, our findings underline the importance of fine-grained social inputs for the acquisition of ecological knowledge and skills in orangutans and likely in other apes as well.

Protected areas are the flagship management tools to secure biodiversity from anthropogenic impacts. However, the extent to which adjacent areas with distinct protection levels host different species numbers and compositions remains uncertain. Here, using reef fishes, European alpine plants, and North American birds, we show that the composition of species in adjacent Strictly Protected, Restricted, and Non-Protected areas is highly dissimilar, whereas the number of species is similar, after controlling for environmental conditions, sample size, and rarity. We find that between 12% and 15% of species are only recorded in Non-Protected areas, suggesting that a non-negligible part of regional biodiversity occurs where human activities are less regulated. For imperiled species, the proportion only recorded in Strictly Protected areas reaches 58% for fishes, 11% for birds, and 7% for plants, highlighting the fundamental and unique role of protected areas and their environmental conditions in biodiversity conservation.

Comment on PLoS Biol. 2021 Apr 26;19(4):e3001199.

The replicability of research results has been a cause of increasing concern to the scientific community. The long-held belief that experimental standardization begets replicability has also been recently challenged, with the observation that the reduction of variability within studies can lead to idiosyncratic, lab-specific results that cannot be replicated. An alternative approach is to, instead, deliberately introduce heterogeneity, known as "heterogenization" of experimental design. Here, we explore a novel perspective in the heterogenization program in a meta-analysis of variability in observed phenotypic outcomes in both control and experimental animal models of ischemic stroke. First, by quantifying interindividual variability across control groups, we illustrate that the amount of heterogeneity in disease state (infarct volume) differs according to methodological approach, for example, in disease induction methods and disease models. We argue that such methods may improve replicability by creating diverse and representative distribution of baseline disease state in the reference group, against which treatment efficacy is assessed. Second, we illustrate how meta-analysis can be used to simultaneously assess efficacy and stability (i.e., mean effect and among-individual variability). We identify treatments that have efficacy and are generalizable to the population level (i.e., low interindividual variability), as well as those where there is high interindividual variability in response; for these, latter treatments translation to a clinical setting may require nuance. We argue that by embracing rather than seeking to minimize variability in phenotypic outcomes, we can motivate the shift toward heterogenization and improve both the replicability and generalizability of preclinical research.

DNA methylation, chromatin accessibility, and gene expression represent different levels information in biological process, but a comprehensive multiomics analysis of the mammalian heart is lacking. Here, we applied nucleosome occupancy and methylome sequencing, which detected DNA methylation and chromatin accessibility simultaneously, as well as RNA-seq, for multiomics analysis of the 4 chambers of adult and fetal human hearts, and adult mouse hearts. Our results showed conserved region-specific patterns in the mammalian heart at transcriptome and DNA methylation level. Adult and fetal human hearts showed distinct features in DNA methylome, chromatin accessibility, and transcriptome. Novel long noncoding RNAs were identified in the human heart, and the gene expression profiles of major cardiovascular diseases associated genes were displayed. Furthermore, cross-species comparisons revealed human-specific and mouse-specific differentially expressed genes between the atria and ventricles. We also reported the relationship among multiomics and found there was a bell-shaped relationship between gene-body methylation and expression in the human heart. In general, our study provided comprehensive spatiotemporal and evolutionary insights into the regulation of gene expression in the heart.

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.

The repeated evolution of multicellularity led to a wide diversity of organisms, many of which are sessile, including land plants, many fungi, and colonial animals. Sessile organisms adhere to a surface for most of their lives, where they grow and compete for space. Despite the prevalence of surface-associated multicellularity, little is known about its evolutionary origin. Here, we introduce a novel theoretical approach, based on spatial lineage tracking of cells, to study this origin. We show that multicellularity can rapidly evolve from two widespread cellular properties: cell adhesion and the regulatory control of adhesion. By evolving adhesion, cells attach to a surface, where they spontaneously give rise to primitive cell collectives that differ in size, life span, and mode of propagation. Selection in favor of large collectives increases the fraction of adhesive cells until a surface becomes fully occupied. Through kin recognition, collectives then evolve a central-peripheral polarity in cell adhesion that supports a division of labor between cells and profoundly impacts growth. Despite this spatial organization, nascent collectives remain cryptic, lack well-defined boundaries, and would require experimental lineage tracking technologies for their identification. Our results suggest that cryptic multicellularity could readily evolve and originate well before multicellular individuals become morphologically evident.

The mitochondrial ATP synthase emerges as key hub of cellular functions controlling the production of ATP, cellular signaling, and fate. It is regulated by the ATPase inhibitory factor 1 (IF1), which is highly abundant in neurons. Herein, we ablated or overexpressed IF1 in mouse neurons to show that IF1 dose defines the fraction of active/inactive enzyme in vivo, thereby controlling mitochondrial function and the production of mitochondrial reactive oxygen species (mtROS). Transcriptomic, proteomic, and metabolomic analyses indicate that IF1 dose regulates mitochondrial metabolism, synaptic function, and cognition. Ablation of IF1 impairs memory, whereas synaptic transmission and learning are enhanced by IF1 overexpression. Mechanistically, quenching the IF1-mediated increase in mtROS production in mice overexpressing IF1 reduces the increased synaptic transmission and obliterates the learning advantage afforded by the higher IF1 content. Overall, IF1 plays a key role in neuronal function by regulating the fraction of ATP synthase responsible for mitohormetic mtROS signaling.

Melanin, a black-brown pigment found throughout all kingdoms of life, has diverse biological functions including UV protection, thermoregulation, oxidant scavenging, arthropod immunity, and microbial virulence. Given melanin's broad roles in the biosphere, particularly in insect immune defenses, it is important to understand how exposure to ubiquitous environmental contaminants affects melanization. Glyphosate-the most widely used herbicide globally-inhibits melanin production, which could have wide-ranging implications in the health of many organisms, including insects. Here, we demonstrate that glyphosate has deleterious effects on insect health in 2 evolutionary distant species, Galleria mellonella (Lepidoptera: Pyralidae) and Anopheles gambiae (Diptera: Culicidae), suggesting a broad effect in insects. Glyphosate reduced survival of G. mellonella caterpillars following infection with the fungus Cryptococcus neoformans and decreased the size of melanized nodules formed in hemolymph, which normally help eliminate infection. Glyphosate also increased the burden of the malaria-causing parasite Plasmodium falciparum in A. gambiae mosquitoes, altered uninfected mosquito survival, and perturbed the microbial composition of adult mosquito midguts. Our results show that glyphosate's mechanism of melanin inhibition involves antioxidant synergy and disruption of the reaction oxidation-reduction balance. Overall, these findings suggest that glyphosate's environmental accumulation could render insects more susceptible to microbial pathogens due to melanin inhibition, immune impairment, and perturbations in microbiota composition, potentially contributing to declines in insect populations.

Although visceral adipocytes located within the body's central core are maintained at approximately 37°C, adipocytes within bone marrow, subcutaneous, and dermal depots are found primarily within the peripheral shell and generally exist at cooler temperatures. Responses of brown and beige/brite adipocytes to cold stress are well studied; however, comparatively little is known about mechanisms by which white adipocytes adapt to temperatures below 37°C. Here, we report that adaptation of cultured adipocytes to 31°C, the temperature at which distal marrow adipose tissues and subcutaneous adipose tissues often reside, increases anabolic and catabolic lipid metabolism, and elevates oxygen consumption. Cool adipocytes rely less on glucose and more on pyruvate, glutamine, and, especially, fatty acids as energy sources. Exposure of cultured adipocytes and gluteal white adipose tissue (WAT) to cool temperatures activates a shared program of gene expression. Cool temperatures induce stearoyl-CoA desaturase-1 (SCD1) expression and monounsaturated lipid levels in cultured adipocytes and distal bone marrow adipose tissues (BMATs), and SCD1 activity is required for acquisition of maximal oxygen consumption at 31°C.

Comment in PLoS Biol. 2021 Jun 8;19(6):e3001293.

Exaggerated sexually selected traits, often carried by males, are characterized by the evolution of hyperallometry, resulting in their disproportionate growth relative to the rest of the body among individuals of the same population. While the evolution of allometry has attracted much attention for centuries, our understanding of the developmental genetic mechanisms underlying its emergence remains fragmented. Here we conduct comparative transcriptomics of the legs followed by an RNA interference (RNAi) screen to identify genes that play a role in the hyperallometric growth of the third legs in the males of the water strider Microvelia longipes. We demonstrate that a broadly expressed growth factor, Bone Morphogenetic Protein 11 (BMP11, also known as Growth Differentiation Factor 11), regulates leg allometries through increasing the allometric slope and mean body size in males. In contrast, BMP11 RNAi reduced mean body size but did not affect slope either in the females of M. longipes or in the males and females of other closely related Microvelia species. Furthermore, our data show that a tissue-specific factor, Ultrabithorax (Ubx), increases intercept without affecting mean body size. This indicates a genetic correlation between mean body size and variation in allometric slope, but not intercept. Strikingly, males treated with BMP11 RNAi exhibited a severe reduction in fighting frequency compared to both controls and Ubx RNAi-treated males. Therefore, male body size, the exaggerated weapon, and the intense fighting behavior associated with it are genetically correlated in M. longipes. Our results support a possible role of pleiotropy in the evolution of allometric slope.

Sex/gender differences in the human brain attract attention far beyond the neuroscience community. Given the interest of nonspecialists, it is important that researchers studying human female-male brain difference assume greater responsibility for the accurate communication of their findings.

The biogenic amine octopamine (OA) and its precursor tyramine (TA) are involved in controlling a plethora of different physiological and behavioral processes. The tyramine-β-hydroxylase (tβh) gene encodes the enzyme catalyzing the last synthesis step from TA to OA. Here, we report differential dominance (from recessive to overdominant) of the putative null tβhnM18 allele in 2 behavioral measures in Buridan's paradigm (walking speed and stripe deviation) and in proboscis extension (sugar sensitivity) in the fruit fly Drosophila melanogaster. The behavioral analysis of transgenic tβh expression experiments in mutant and wild-type flies as well as of OA and TA receptor mutants revealed a complex interaction of both aminergic systems. Our analysis suggests that the different neuronal networks responsible for the 3 phenotypes show differential sensitivity to tβh gene expression levels. The evidence suggests that this sensitivity is brought about by a TA/OA opponent system modulating the involved neuronal circuits. This conclusion has important implications for standard transgenic techniques commonly used in functional genetics.