Human ClpP protease contributes to mitochondrial protein quality control by degrading misfolded proteins. ClpP is overexpressed in cancers such as acute myeloid leukemia (AML), where its inhibition leads to the accumulation of damaged respiratory chain subunits and cell death. Conversely, hyperactivating ClpP with small-molecule activators, such as the recently discovered ONC201, disrupts mitochondrial

H5Nx viruses continue to wreak havoc in avian and mammalian species worldwide. The virus distinguishes itself by the ability to replicate to high titers and transmit efficiently in a wide variety of hosts in diverse climatic environments. Fortunately, transmission to and between humans is scarce. Yet, if such an event were to occur, it could spark a pandemic as humans are immunologically naïve to H5

Trait regression and loss have occurred repeatedly in numerous lineages in response to environmental changes. In parasitoid wasps, a megadiverse group of hymenopteran insects, yolk protein reduction or loss has been observed in many species, likely linked to the transition from ectoparasitism to endoparasitism. However, the genetic basis of this trait and the impact of its loss on genome evolution

Theory predicts that well-adapted populations may evolve mechanisms to counteract the inevitable influx of deleterious mutations. While mutational robustness can be directly selected in the laboratory, evidence for its spontaneous evolution during general adaptation is mixed. Moreover, whether robustness evolves to include pleiotropic effects remains largely unexplored. Here, we studied the effects

The concept that proteins are selected to fold into a well-defined native state has been effectively addressed within the framework of energy landscapes, underpinning the recent successes of structure prediction tools like AlphaFold. The amyloid fold, however, does not represent a unique minimum for a given single sequence. While the cross- β hydrogen-bonding pattern is common to all amyloids, other

CD20 is a four-transmembrane protein expressed at the surface of B cells from late pro-B cells to memory B cells, with the exception of plasma cells. Its expression pattern makes it an attractive therapeutic target for different B cell malignancies and autoimmune diseases. Despite the clinical success of CD20-targeting antibodies, the biology of the CD20 protein is still not well understood. We investigated

Translational research suggests that the basolateral part of the amygdala (BLA) computes some of the core processes underlying social preferences, but its precise role in prosocial choice remains unclear. We hypothesize that the human BLA is not necessary for prosocial behavior per se, but fine-tunes the degree of prosociality as a function of the social distance between actor and recipient of a prosocial

Enchondromas are common bone tumors composed of chondrocytes originating from growth plate cells which can progress to malignant chondrosarcoma. Mutations in the genes encoding isocitrate dehydrogenase (IDH1 and IDH2) are identified in a large proportion of these tumors. IDH enzymes convert isocitrate to alpha-ketoglutarate (α-KG), an essential component of the citric acid cycle. While mutant IDH enzymes

As in many diploid organisms with genetic sex determination, haploid-dominant organisms have also evolved sex chromosomes or extensive genomic regions that lack genetic recombination. An understanding of sex chromosome evolution should explain the causes and consequences of such regions in both diploids and haploids. However, haploids have been little studied, even though differences from sex chromosomes

Definitions of sustainability commonly stress both systemic continuity and equality over time. However, the degree to which these two sides of sustainability might be related has not been systematically investigated. Recent theoretical and methodological insights have provided archaeologists with new tools for investigating sustainability in premodern societies. Here, we use Gini coefficients on residence

Indoor residual spraying (IRS) is one of the core vector control interventions available to malaria control programs. Normative and scientific guidance has long held that very high IRS coverage (at least 80 to 85% houses sprayed) is necessary to provide community protection, but there is little evidence backing these recommendations, in large part due to the operational and ethical concerns that conducting

The urethra is considered a passive conduit for urine. Here, we reveal a surprising multicellular signaling pathway guiding the urethra’s dynamic response to an invading pathogen. Using a genetic approach in female mice, we deposited uropathogenic Escherichia coli into the distal urethra to establish a model of ascending urinary tract infection that progresses to the bladder within 4 h. We show that

Here, we assess the extent to which land use relating to food acquisition (farming, herding, foraging) and associated value regimes shaped past economic inequality. We consider the hypothesis that land-use systems in which production was limited by heritable material wealth (such as land) sustained higher levels of inequality than those limited by (free) human labor. We address this hypothesis using

From Rousseau onward, scholars have identified the transition to sedentary agriculture as crucial to the history of wealth inequality. Here, using the GINI project’s global database on disparities in residential size, we examine the effects of important innovations in plant cultivation, animal husbandry, and traction on wealth inequality. Over a series of regional case studies, we find no evidence

Defining wealth broadly to include wealth in people, relational connections, and material possessions, we examine the prehistory of wealth inequality at the level of the residential units using the consistent proxy of Gini coefficients calculated across areas of contemporaneous residential units. In a sample of >1,100 sites and > 47,000 residential units spanning >10,000 y, persistent wealth inequality

The Gini coefficient is a statistical measure commonly used to characterize distributions of socioeconomic quantities. Archaeologists and social scientists have recently adopted this method to analyze ancient inequality by targeting specific proxy variables (e.g., residential unit size, burial data, etc.). Variations in the Gini are then examined in relation to key factors such as time, geography,

Scholars are divided over the long-term effects that war has had on inequality. Some have argued that conflict grows the gap between rich and poor. Others counter that violence levels out wealth differences. The GINI Project Database is a large global sample of archaeological data on house sizes created to investigate what factors influenced economic inequality over long periods of time, including

Renal ischemia–reperfusion injury (IRI) is a common complication in several clinical scenarios including kidney transplantation. Mannan-binding lectin-associated serine proteinase (MASP)-2 is essential for activation of the complement lectin pathway, which has been implicated in the pathogenesis of renal IRI and therefore represents a potential therapeutic target. We developed a new, affinity-enhanced

The structure of the environment includes more horizontal and vertical (i.e. cardinal) orientations than oblique orientations, meaning that edges tend to be aligned with or perpendicular to the direction of gravity. This bias in the visual scene is associated with a bias in visual sensitivity in adults. Although infants must learn to function in this biased environment, their immature motor control

Marine heatwaves are extreme climatic events consisting of persistent periods of warm ocean waters that have profound impacts on marine life. These episodes are becoming more intense, longer, and more frequent in response to anthropogenic global warming. Here, we provide a comprehensive and quantitative assessment on the role of global warming on marine heatwaves. To do so, we construct a counterfactual

Specialized metabolism plays a central role in how plants cope with both biotic and abiotic stresses in order to survive and reproduce within dynamic and challenging environments. One recently described class of plant-specific, ribosomally synthesized, and posttranslationally modified peptides are the burpitides, which are characterized by the installation of distinct sidechain macrocycles by enzymes

Humans often live in neighborhoods, nested socio-spatial clusters within settlements of varying size and population density. In today’s cities, neighborhoods are often characterized as relatively homogenous and may exhibit segregation along various socioeconomic dimensions. However, even within neighborhoods of similar social or economic status, there is often residential disparity, which in turn impacts

We address three basic issues regarding the long-term dynamics of inequality in society. First, we consider the interpretation of residence sizes in socioeconomic terms by comparing statistical patterns extracted from the Global Dynamics of Inequality (GINI) Project database with those from the 21st-century United States. Second, we examine the degree to which the size and productivity of human networks

Understanding the relationship between inequality and economic growth is a critical science problem that hinders sustainable development. In 1955, Simon Kuznets hypothesized that rising economic growth raises inequality, which levels off as that growth continues. Kuznets’ “curve,” which is a cornerstone of development economics, was based on data from a small sample of rich capitalist economies. Here

Long-entrenched grand narratives have tied inequality in large human aggregations to generally linear trends, a direct outcome of domestication, then fostered by population growth and/or stepped scalar transitions in the hierarchical complexity of human institutions. This general pattern has been argued to short-circuit or reverse only in the context of cataclysmic disasters or societal breakdowns

CLAVATA3/EMBRYO SURROUNDING REGION-related (CLE) peptides have emerged as key regulators of plant–microbe interactions, including arbuscular mycorrhizal (AM) symbiosis. Here, we identify Medicago truncatula CLE16 as a positive regulator of AM symbiosis. MtCLE16 is expressed in root cells colonized by AM fungi (AMF) and its overexpression within colonized tissues increases arbuscule abundance by finetuning

Decreased dendritic spine density in the cortex is a key pathological feature of neuropsychiatric diseases including depression, addiction, and schizophrenia (SCZ). Psychedelics possess a remarkable ability to promote cortical neuron growth and increase spine density; however, these compounds are contraindicated for patients with SCZ or a family history of psychosis. Here, we report the molecular design

Antibody–drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable efficacy in breast cancer. Despite the promising efficacy of anti-HER2 ADCs, many patients are still experiencing disease progression under treatment. Here, by analyzing the transcriptome data from patient-derived organoid models, I-SPY2 trial, and resistant cell lines, we identified

Montane ecosystems are crucial for maintaining global biodiversity and function that sustain life on our planet. Yet, these ecosystems are highly vulnerable to changing temperatures and may undergo critical transitions under ongoing climate change. What we do not know is to what extent montane biodiversity and ecosystem services will respond to local temperature variations in a gradual versus abrupt

Major depressive disorder (MDD) is a leading cause of disability worldwide. Risk for MDD is heritable, and the genetic structure of founder populations enables investigation of rare susceptibility alleles with large effect. In an extended Old Order Mennonite family cohort, we identified a rare missense variant in GPR156 (c.1599G>T, p.Glu533Asp) associated with a two-fold increase in the relative risk

Insights into the molecular processes that drive early development of the human placenta is crucial for our understanding of pregnancy complications such as preeclampsia and fetal growth restriction, since defects in maturation of its epithelial cell, the trophoblast, have been detected in the severe forms of these diseases. However, key regulators specifying the differentiated trophoblast subtypes

The view that words are arbitrary is a foundational assumption about language, used to set human languages apart from nonhuman communication. We present here a study of the alignment between the semantic and phonological structure (systematicity) of American Sign Language (ASL), and for comparison, two spoken languages—English and Spanish. Across all three languages, words that are semantically related

The pure mapping class group of an oriented surface acts on the character variety of the surface. We investigate the closure of its orbits under either Zariski or analytic topologies. We show that a generic infinite orbit is dense in an open subset of the corresponding modified relative character variety. Moreover, we specify that being generic can be captured as a combination of passing to a Zariski-open

Social institutions are systems of shared norms and rules that regulate people’s behaviors, often emerging without external enforcement. They provide criteria to distinguish cooperation from defection and establish rules to sustain cooperation, shaped through long-term trial and error. While principles for successful institutions have been proposed, the mechanisms underlying their emergence remain

When soft matter is driven out of equilibrium its constituents interact via effective interactions that escape Newton’s action–reaction principle. Prominent examples include the hydrodynamic interactions between colloidal particles driven in viscous fluids, phoretic interactions between chemically active colloids, and quorum-sensing interactions in bacterial colonies. Despite a recent surge of interest

Metastasis is an inefficient process requiring cancer cells to adapt metabolically for survival and colonization in new environments. The contributions of tumor metabolic reprogramming to lymph node (LN) metastasis and its underlying mechanisms remain elusive. Through single-cell RNA sequencing, we identified rare metastasis-initiating cells (MICs) with stem-like properties that drive early LN metastasis

Differentially private gradient descent (DP-GD) is a popular algorithm to train deep learning models with provable guarantees on the privacy of the training data. In the last decade, the problem of understanding its performance cost with respect to standard GD has received remarkable attention from the research community, which has led to upper bounds on the excess population risk R P in different

Ecosystems are experiencing changing global patterns of mean annual precipitation (MAP) and enrichment with multiple nutrients that potentially colimit plant biomass production. In grasslands, mean aboveground plant biomass is closely related to MAP, but how this relationship changes after enrichment with multiple nutrients remains unclear. We hypothesized the global biomass–MAP relationship becomes

Natural transformation (NT) represents one of the major modes of horizontal gene transfer in bacterial species. During NT, cells can take up free DNA from the environment and integrate it into their genome by homologous recombination. While NT has been studied for >90 y, the molecular details underlying this recombination remain poorly understood. Recent work has demonstrated that ComM is an NT-specific

Monoclonal antibody IE-3 prevents mouse fertilization by binding ZP2, a major component of the oocyte-specific zona pellucida (ZP). We show that an IE-3-derived single-chain variable fragment (scFV) is sufficient for blocking fertilization in vitro and determine the structural basis of IE-3/ZP2 recognition. The high affinity of this interaction depends on induced fit of the epitope, offering insights

Unraveling the relationship between structural information and the dynamic properties of supercooled liquids is one of the great challenges of physics. Dynamic heterogeneity, characterized by the propensity of particles, is often used as a proxy for dynamic slowing. Over the years, significant efforts have been made to capture the structural variations linked to dynamic heterogeneity in supercooled

Researchers are key contributors to innovation. Their migration results in talent circulation and recombination of ideas. Due to data shortage, little is known about subnational mobility of scientists and the interrelationships between their internal and international migration patterns. We used data on 30+ million Scopus publications of 19+ million authors to infer migration from changes in affiliations

In Drosophila ovaries, germ cells differentiate through several stages of cyst development before entering meiosis. This early differentiation program depends on both the stepwise deployment of specific regulatory mechanisms and on maintenance of germline sexual identity. The study of female sterile mutations that result in formation of germ cell tumors has been invaluable in identifying the mechanisms

The evolutionary adaptation of an organism to a stressful environment often comes at the cost of reduced fitness. For example, resistance to antimicrobial drugs frequently reduces growth rate in the drug-free environment. This cost can be compensated without loss in resistance by mutations at secondary sites when the organism evolves again in the stress-free environment. Here, we analytically and numerically

In supersymmetric Yang–Mills theories tension-degenerate domain walls are typical. Adding matter fields in fundamental representation, we arrive at supersymmetric quantum chromodynamics (SQCD) supporting similar walls. We demonstrate that the degenerate domain walls can belong to one of two classes: i) locally distinguishable, i.e. those which differ from each other locally (which could be detected

Wound healing after spinal cord injury involves highly coordinated interactions among multiple cell types, which are poorly understood. Astrocytes play a central role in creating a border against the non-neural lesion core. To do so, astrocytes undergo dramatic morphological changes by first thickening and elongating their processes and then overlapping them to form a physical barrier. We show here

Neural stem cells (NSCs) can self-renew and undergo differentiation via asymmetric division. Dysregulation in the balance between self-renewal and differentiation can lead to tumor formation or neurodevelopmental disorders. However, the regulation of phosphatidylinositol transfer protein (PITP)-dependent PI(4)P pools and myosin localization during asymmetric division in dividing cells is not well established

Runx2 is a master regulator of bone formation, and its dysfunction causes cleidocranial dysplasia (CCD) in humans. When iPS cells were generated from patients with CCD and Runx2-deficient iPS cells were generated using gene-editing techniques, abnormal laminopathy-like nuclei were observed. Runx2-deficient cells showed reduced Lamin A/C expression, but not protein levels. However, in Runx2-deficient

The hepatocyte Ashwell–Morell receptor (AMR) is the prototypical mammalian lectin and the first cell receptor isolated. This recycling endocytic receptor of the plasma membrane determines the concentrations of hundreds of circulating glycoproteins in the blood and plays important roles in host responses to and outcomes of infection. The compositional and topological determinants of a physiological

The microenvironment around catalytic sites plays crucial roles in enzymatic catalysis while its precise control in heterogeneous catalysts remains challenging. Herein, the coordinatively unsaturated metal nodes of Hf-based metal-organic framework nanosheets are simultaneously codecorated with catalytically active Co(salen) units and adjacent pyridyl-substituted alkyl carboxylic acids via a post modification

Advanced Placement (AP) provides college-level courses to over 1 million US secondary students annually. Black, Hispanic, and female students have historically been underrepresented in AP Computer Science (CS). A new, broadly focused course—AP CS Principles—launched nationally in 2016–17 with the goal of increasing student participation and diversity. We examine its effects on AP CS participation.

Pregnancy loss is a major problem in clinical medicine with devastating consequences for families. Next generation sequencing has improved our ability to identify underlying molecular causes, though over half of all cases lack a clear etiology. Here, we began with clinical evaluation combined with exome sequencing across independent families to identify bi-allelic candidate genetic variants in the