IgH class switch recombination (CSR) replaces Cμ constant region (CH) exons with one of six downstream CHs by joining transcription-targeted double-strand breaks (DSBs) in the Cμ switch (S) region to DSBs in a downstream S region. Chromatin loop extrusion underlies fundamental CSR mechanisms including 3′IgH regulatory region (3′IgHRR)-mediated S region transcription, CSR center formation, and deletional

Humans express seven heparan sulfate (HS) 3-O-sulfotransferases that differ in substrate specificity and tissue expression. Although genetic studies have indicated that 3-O-sulfated HS modulates many biological processes, ligand requirements for proteins engaging with HS modified by 3-O-sulfate (3-OS) have been difficult to determine. In particular, the context in which the 3-OS group needs to be presented

Flaviviruses, including dengue and Zika, are widespread human pathogens; however, no broadly active therapeutics exist to fight infection. Recently, remodeling of endoplasmic reticulum (ER) proteostasis by pharmacologic regulators, such as compound 147, was shown to correct pathologic ER imbalances associated with protein misfolding diseases. Here, we establish an additional activity of compound 147

When physician Babar Khan started studying delirium seven years ago, he set out to find a drug that could sooth the agitation, inattention, and hallucinations that characterize the disorder. Delirium is common in the intensive care units (ICUs) where Khan works, most recently as an ICU physician at Indiana University School of Medicine and a researcher at Regenstrief Institute, both in Indianapolis

Antibiotic resistance is a growing health concern. Efforts to control resistance would benefit from an improved ability to forecast when and how it will evolve. Epistatic interactions between mutations can promote divergent evolutionary trajectories, which complicates our ability to predict evolution. We recently showed that differences between genetic backgrounds can lead to idiosyncratic responses

From 25 to 29 April 2020, the state of Indiana undertook testing of 3,658 randomly chosen state residents for the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, the agent causing COVID-19 disease. This was the first statewide randomized study of COVID-19 testing in the United States. Both PCR and serological tests were administered to all study participants. This paper describes

NEUROSCIENCE Exogenous R-spondin promotes taste cell generation in the absence of innervation. Signaling protein regenerates taste cells, maintains taste tissue homeostasis in mice Like all cells, the 50 to 100 taste cells in the human taste bud age and lose their integrity over time. First shown more than a century...

Using travel time to cities of different sizes, we map populations across an urban–rural continuum to improve on the standard dichotomous representations of urban–rural interactions. We extend existing approaches by 1) building on central place theory to capture the urban hierarchy in access to services and employment opportunities provided by urban centers of different sizes, 2) defining urban–rural

A number of recent studies have documented long-term declines in abundances of important arthropod groups, primarily in Europe and North America. These declines are generally attributed to habitat loss, but a recent study [B.C. Lister, A. Garcia, Proc. Natl. Acad. Sci. USA 115, E10397–E10406 (2018)] from the Luquillo Experimental Forest (LEF) in Puerto Rico attributed declines to global warming. We

Insects constitute the vast majority of known animal species and are ubiquitous across terrestrial ecosystems, playing key ecological roles. As prey, they are critical to the survival of countless other species, including the majority of bats, birds, and freshwater fishes (1). As herbivores, predators, and parasites, they are major determinants of the distribution and abundance of innumerable plants

Nature is under siege. In the last 10,000 y the human population has grown from 1 million to 7.8 billion. Much of Earth’s arable lands are already in agriculture (1), millions of acres of tropical forest are cleared each year (2, 3), atmospheric CO2 levels are at their highest concentrations in more than 3 million y (4), and climates are erratically and steadily changing from pole to pole, triggering

Time series data on arthropod populations are critical for understanding the magnitude, direction, and drivers of change. However, most arthropod monitoring programs are short-lived and restricted in taxonomic resolution. Monitoring data from the Arctic are especially underrepresented, yet critical to uncovering and understanding some of the earliest biological responses to rapid environmental change

Reports of declines in biomass of flying insects have alarmed the world in recent years. However, how biomass declines reflect biodiversity loss is still an open question. Here, we analyze the abundance (19,604 individuals) of 162 hoverfly species (Diptera: Syrphidae), at six locations in German nature reserves in 1989 and 2014, and generalize the results with a model varying decline rates of common

Recent dramatic and deadly increases in global wildfire activity have increased attention on the causes of wildfires, their consequences, and how risk from wildfire might be mitigated. Here we bring together data on the changing risk and societal burden of wildfire in the United States. We estimate that nearly 50 million homes are currently in the wildland–urban interface in the United States, a number

Although widespread declines in insect biomass and diversity are increasing concerns within the scientific community, it remains unclear whether attention to pollinator declines has also increased within information sources serving the general public. Examining patterns of journalistic attention to the pollinator population crisis can also inform efforts to raise awareness about the importance of declines

We review changes in the status of butterflies in Europe, focusing on long-running population data available for the United Kingdom, the Netherlands, and Belgium, based on standardized monitoring transects. In the United Kingdom, 8% of resident species have become extinct, and since 1976 overall numbers declined by around 50%. In the Netherlands, 20% of species have become extinct, and since 1990 overall

Moths are the most taxonomically and ecologically diverse insect taxon for which there exist considerable time-series abundance data. There is an alarming record of decreases in moth abundance and diversity from across Europe, with rates varying markedly among and within regions. Recent reports from Costa Rica reveal steep cross-lineage declines of caterpillars, while other sites (Ecuador and Arizona

Major declines in insect biomass and diversity, reviewed here, have become obvious and well documented since the end of World War II. Here, we conclude that the spread and intensification of agriculture during the past half century is directly related to these losses. In addition, many areas, including tropical mountains, are suffering serious losses because of climate change as well. Crops currently

We have been field observers of tropical insects on four continents and, since 1978, intense observers of caterpillars, their parasites, and their associates in the 1,260 km2 of dry, cloud, and rain forests of Área de Conservación Guanacaste (ACG) in northwestern Costa Rica. ACG’s natural ecosystem restoration began with its national park designation in 1971. As human biomonitors, or “insectometers

Most animal species on Earth are insects, and recent reports suggest that their abundance is in drastic decline. Although these reports come from a wide range of insect taxa and regions, the evidence to assess the extent of the phenomenon is sparse. Insect populations are challenging to study, and most monitoring methods are labor intensive and inefficient. Advances in computer vision and deep learning

Insects have diversified through more than 450 million y of Earth’s changeable climate, yet rapidly shifting patterns of temperature and precipitation now pose novel challenges as they combine with decades of other anthropogenic stressors including the conversion and degradation of land. Here, we consider how insects are responding to recent climate change while summarizing the literature on long-term

X-ray diffraction is routinely used for structure determination of stationary molecular samples. Modern X-ray photon sources, e.g., from free-electron lasers, enable us to add temporal resolution to these scattering events, thereby providing a movie of atomic motions. We simulate and decipher the various contributions to the X-ray diffraction pattern for the femtosecond isomerization of azobenzene

Biominerals such as seashells, coral skeletons, bone, and tooth enamel are optically anisotropic crystalline materials with unique nanoscale and microscale organization that translates into exceptional macroscopic mechanical properties, providing inspiration for engineering new and superior biomimetic structures. Using Seriatopora aculeata coral skeleton as a model, here, we experimentally demonstrate

Rev-Erbβ is a nuclear receptor that couples circadian rhythm, metabolism, and inflammation. Heme binding to the protein modulates its function as a repressor, its stability, its ability to bind other proteins, and its activity in gas sensing. Rev-Erbβ binds Fe3+-heme more tightly than Fe2+-heme, suggesting its activities may be regulated by the heme redox state. Yet, this critical role of heme redox

Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk

Topological superconductivity has been sought in a variety of heterostructure systems, the interest being that a material displaying such a phenomenon could prove to be the ideal platform to support Majorana fermions, which in turn could be the basis for advanced qubit technologies. Recently, the high-Tc family of superconductors, FeTe1−xSex, have been shown to exhibit the property of topological superconductivity

When talking about his career as a developmental and evolutionary biologist, Stanford University’s David M. Kingsley likes to say that “genetics works.” He means that genetics can solve biological problems that have long been mysterious. He has repeatedly put that theory to the test throughout his research career, initially using genetics to study a cellular process called receptor-mediated endocytosis

Dolph Schluter explores the origin of species on Earth, an avenue of research he has pursued with persistence, creativity, and methodical precision for more than 40 years. Schluter has taken what for Darwin was mainly a thought experiment and applied modern experimental methods to provide scientific evidence of the process of natural selection on species’ origins and the evolution of differences between

MICROBIOLOGY Correction for “Repurposing a peptide toxin from wasp venom into antiinfectives with dual antimicrobial and immunomodulatory properties,” by Osmar N. Silva, Marcelo D. T. Torres, Jicong Cao, Elaine S. F. …

GPR15 is a G protein-coupled receptor (GPCR) proposed to play a role in mucosal immunity that also serves as a major entry cofactor for HIV-2 and simian immunodeficiency virus (SIV). To discover novel endogenous GPR15 ligands, we screened a hemofiltrate (HF)-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of cystatin C (CysC95-146)

Neurotransmitter release occurs by regulated exocytosis from synaptic vesicles (SVs). Evolutionarily conserved proteins mediate the essential aspects of this process, including the membrane fusion step and priming steps that make SVs release-competent. Unlike the proteins constituting the core fusion machinery, the SV protein Mover does not occur in all species and all synapses. Its restricted expression

The ability of cortical networks to integrate information from different sources is essential for cognitive processes. On one hand, sensory areas exhibit fast dynamics often phase-locked to stimulation; on the other hand, frontal lobe areas with slow response latencies to stimuli must integrate and maintain information for longer periods. Thus, cortical areas may require different timescales depending

Plasmacytoid dendritic cells (pDCs) specialize in the production of type I IFN (IFN-I). pDCs can be depleted in vivo by injecting diphtheria toxin (DT) in a mouse in which pDCs express a diphtheria toxin receptor (DTR) transgene driven by the human CLEC4C promoter. This promoter is enriched for binding sites for TCF4, a transcription factor that promotes pDC differentiation and expression of pDC markers

A cardinal, intractable symptom of neuropathic pain is mechanical allodynia, pain caused by innocuous stimuli via low-threshold mechanoreceptors such as Aβ fibers. However, the mechanism by which Aβ fiber-derived signals are converted to pain remains incompletely understood. Here we identify a subset of inhibitory interneurons in the spinal dorsal horn (SDH) operated by adeno-associated viral vectors

T cell receptors (TCRs) are generated by somatic recombination of V/D/J segments to produce up to 1015 unique sequences. Highly sensitive and specific techniques are required to isolate and identify the rare TCR sequences that respond to antigens of interest. Here, we describe the use of mRNA sequencing via cross-linker regulated intracellular phenotype (CLInt-Seq) for efficient recovery of antigen-specific

There is considerable evidence for hippocampal time cells that briefly activate in succession to represent the temporal structure of memories. Previous studies have shown that time cells can be disrupted while leaving place cells intact, indicating that spatial and temporal information can be coded in parallel. However, the circuits in which spatial and temporal information are coded have not been

The COVID-19 pandemic is a shocking reminder of how our world would look in the absence of vaccination. Fortunately, new technologies, the pace of understanding new and existing pathogens, and the increased knowledge of the immune system allow us today to develop vaccines at an unprecedented speed. Some of the vaccine technologies that are fast-tracked by the urgency of COVID-19 may also be the answer

Exposure to lead (Pb) during early life has persistent adverse health effects. During childhood, ingestion of bioavailable Pb in contaminated soils can be a major route of Pb absorption. Remediation to alter physiochemical properties of soil-borne Pb can reduce Pb bioavailability. Our laboratory-based approach for soil Pb remediation uses addition of iron (Fe) sulfate and application of heat to promote

The C-terminal domain (CTD) kinase I (CTDK-1) complex is the primary RNA Polymerase II (Pol II) CTD Ser2 kinase in budding yeast. CTDK-1 consists of a cyclin-dependent kinase (CDK) Ctk1, a cyclin Ctk2, and a unique subunit Ctk3 required for CTDK-1 activity. Here, we present a crystal structure of CTDK-1 at 1.85-Å resolution. The structure reveals that, compared to the canonical two-component CDK-cyclin

Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters

We show that the Zeeman field can induce a topological transition in two-dimensional spin–orbit-coupled metals and, concomitantly, a first-order phase transition in the superconducting state involving a discontinuous change of Cooper pair momentum. Depending on the spin–orbit coupling strength, we find different phase diagrams of two-dimensional (2D) superconductors under in-plane magnetic field.

Mud nests built by swallows (Hirundinidae) and phoebes (Sayornis) are stable granular piles attached to cliffs, walls, or ceilings. Although these birds have been observed to mix saliva with incohesive mud granules, how such biopolymer solutions provide the nest with sufficient strength to support the weight of the residents as well as its own remains elusive. Here, we elucidate the mechanism of strong

The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been

Plastic deformation of crystalline materials with isotropic particle attractions proceeds by the creation and migration of dislocations under the influence of external forces. If dislocations are produced and migrated under the action of local forces, then material shape change can occur without the application of surface forces. We investigate how particles with variable diameters can be embedded

Rock recycling within the forearcs of subduction zones involves subduction of sediments and hydrated lithosphere into the upper mantle, exhumation of rocks to the surface, and erosion to form new sediment. The compositions of, and inclusions within detrital minerals revealed by electron microprobe analysis and Raman spectroscopy preserve petrogenetic clues that can be related to transit through the

Disordered hyperuniformity (DHU) is a recently discovered novel state of many-body systems that possesses vanishing normalized infinite-wavelength density fluctuations similar to a perfect crystal and an amorphous structure like a liquid or glass. Here, we discover a hyperuniformity-preserving topological transformation in two-dimensional (2D) network structures that involves continuous introduction

The mechanical properties of engineering structures continuously weaken during service life because of material fatigue or degradation. By contrast, living organisms are able to strengthen their mechanical properties by regenerating parts of their structures. For example, plants strengthen their cell structures by transforming photosynthesis-produced glucose into stiff polysaccharides. In this work

While forced labor in the world’s fishing fleet has been widely documented, its extent remains unknown. No methods previously existed for remotely identifying individual fishing vessels potentially engaged in these abuses on a global scale. By combining expertise from human rights practitioners and satellite vessel monitoring data, we show that vessels reported to use forced labor behave in systematically

Nuclear factor κB (NF-κB)–mediated signaling pathway plays a crucial role in the regulation of inflammatory process, innate and adaptive immune responses. The hyperactivation of inflammatory response causes host cell death, tissue damage, and autoinflammatory disorders, such as sepsis and inflammatory bowel disease. However, how these processes are precisely controlled is still poorly understood. In

Hepatitis C virus (HCV) is a major worldwide health burden, and a preventive vaccine is needed for global control or eradication of this virus. A substantial hurdle to an effective HCV vaccine is the high variability of the virus, leading to immune escape. The E1E2 glycoprotein complex contains conserved epitopes and elicits neutralizing antibody responses, making it a primary target for HCV vaccine

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens

Antimicrobial activity is being increasingly linked to amyloid fibril formation, suggesting physiological roles for some human amyloids, which have historically been viewed as strictly pathological agents. This work reports on formation of functional cross-α amyloid fibrils of the amphibian antimicrobial peptide uperin 3.5 at atomic resolution, an architecture initially discovered in the bacterial

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2

Deep neural networks currently provide the best quantitative models of the response patterns of neurons throughout the primate ventral visual stream. However, such networks have remained implausible as a model of the development of the ventral stream, in part because they are trained with supervised methods requiring many more labels than are accessible to infants during development. Here, we report

The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson’s disease (PD) where functional up-regulation of postsynaptic D2 receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the

To cope with environmental challenges, plants produce a wide diversity of phytochemicals, which are also the source of numerous medicines. Despite decades of research in chemical ecology, we still lack an understanding of the organization of plant chemical diversity across species and ecosystems. To address this challenge, we hypothesized that molecular diversity is not only related to species diversity

One of the most conserved traits in the evolution of biomineralizing organisms is the taxon-specific selection of skeletal minerals. All modern scleractinian corals are thought to produce skeletons exclusively of the calcium-carbonate polymorph aragonite. Despite strong fluctuations in ocean chemistry (notably the Mg/Ca ratio), this feature is believed to be conserved throughout the coral fossil record

The selection of a single molecular handedness, or homochirality across all living matter, is a mystery in the origin of life. Frank’s seminal model showed in the ’50s how chiral symmetry breaking can occur in nonequilibrium chemical networks. However, an important shortcoming in this classic model is that it considers a small number of species, while there is no reason for the prebiotic system, in

Inflammatory pathologies caused by phagocytes lead to numerous debilitating conditions, including chronic pain and blindness due to age-related macular degeneration. Many members of the sialic acid-binding immunoglobulin-like lectin (Siglec) family are immunoinhibitory receptors whose agonism is an attractive approach for antiinflammatory therapy. Here, we show that synthetic lipid-conjugated glycopolypeptides

Homologous recombination (HR) is an important DNA double-strand break (DSB) repair pathway that copies sequence information lost at the break site from an undamaged homologous template. This involves the formation of a recombination structure that is processed to restore the original sequence but also harbors the potential for crossover (CO) formation between the participating molecules. Synthesis-dependent