Known as elite suppressors, some individuals infected with HIV show no symptoms and barely detectable virus levels years after initial infection, despite never having received treatment. Joel N. Blankson has spent much of his career studying elite suppressors, who represent less than 1% of people with HIV, with the hope that they may serve as models for developing new treatments. Blankson is a professor

Decades of preclinical studies indicate that dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain modulate animal behavior and cognition (1). The role of dopaminergic VTA neurons in wakefulness, and hence consciousness, emerged more recently from VTA stimulation experiments utilizing pharmacologic (2, 3), electrophysiologic (4), optogenetic (5, 6), and chemogenetic (7) methods,

John Speakman’s interest in science was spurred by his early interest in birds. “I was a very keen birdwatcher, and I used to spend lots of time watching birds in my youth,” he says. At age 16, he would go to the same site every day to count small wading birds and try to work out the factors influencing their numbers.

Breastfeeding is the best way to feed an infant. Not only does it supply the proper nutrition, but it also supports the development of the immune system, provides healthy microbiome, reduces risk of diseases, and brings down overall mortality (1). There are also benefits resulting from the ability of breastfeeding to suppress maternal ovarian function and to delay the next pregnancy. Birth spacing

Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics

Many species of plants, animals, and microorganisms exchange genes well after the point of evolutionary divergence at which taxonomists recognize them as species. Genomes contain signatures of past gene exchange and, in some cases, they reveal a legacy of lineages that no longer exist. But genomic data are not available for many organisms, and particularly problematic for reconstructing and interpreting

Biofilms are aggregates of bacterial cells surrounded by an extracellular matrix. Much progress has been made in studying biofilm growth on solid substrates; however, little is known about the biophysical mechanisms underlying biofilm development in three-dimensional confined environments in which the biofilm-dwelling cells must push against and even damage the surrounding environment to proliferate

Electromagnetic radiation (EMR) in the environment has increased sharply in recent decades. The effect of environmental EMR on living organisms remains poorly characterized. Here, we report the impact of wireless-range EMR on the sleep architecture of mouse. Prolonged exposure to 2.4-GHz EMR modulated by 100-Hz square pulses at a nonthermal output level results in markedly increased time of wakefulness

Therapies that boost the antitumor immune response have shown a great deal of success. Although most of these therapies have focused on enhancing T cell functions, there is a growing interest in developing therapies that can target other immune cell subsets. Like T cells, natural killer (NK) cells are cytotoxic effector cells that play a key role in the antitumor response. To advance the development

Outer-membrane beta barrels (OMBBs) are found in the outer membrane of gram-negative bacteria and eukaryotic organelles. OMBBs fold as antiparallel β-sheets that close onto themselves, forming pores that traverse the membrane. Currently known structures include only one barrel, of 8 to 36 strands, per chain. The lack of multi-OMBB chains is surprising, as most OMBBs form oligomers, and some function

UDP-glucose pyrophosphorylase 2 (UGP2), the enzyme that synthesizes uridine diphosphate (UDP)-glucose, rests at the convergence of multiple metabolic pathways, however, the role of UGP2 in tumor maintenance and cancer metabolism remains unclear. Here, we identify an important role for UGP2 in the maintenance of pancreatic ductal adenocarcinoma (PDAC) growth in both in vitro and in vivo tumor models

Salmonella spp. express Salmonella pathogenicity island 1 Type III Secretion System 1 (T3SS-1) genes to mediate the initial phase of interaction with their host. Prior studies indicate short-chain fatty acids, microbial metabolites at high concentrations in the gastrointestinal tract, limit population-level T3SS-1 gene expression. However, only a subset of Salmonella cells in a population express these

Secondary small interfering RNA (siRNA) production, triggered by primary small RNA targeting, is critical for proper development and antiviral defense in many organisms. RNA-dependent RNA polymerase (RDR) is a key factor in this pathway. However, how RDR specifically converts the targets of primary small RNAs into double-stranded RNA (dsRNA) intermediates remains unclear. Here, we develop an in vitro

The evolutionary context of why caloric restriction (CR) activates physiological mechanisms that slow the process of aging remains unclear. The main goal of this analysis was to identify, using metabolomics, the common pathways that are modulated across multiple tissues (brown adipose tissue, liver, plasma, and brain) to evaluate two alternative evolutionary models: the “disposable soma” and “clean

When aged below the glass transition temperature, Tg, the density of a glass cannot exceed that of the metastable supercooled liquid (SCL) state, unless crystals are nucleated. The only exception is when another polyamorphic SCL state exists, with a density higher than that of the ordinary SCL. Experimentally, such polyamorphic states and their corresponding liquid–liquid phase transitions have only

There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2’s activity depends upon its phosphorylation state. While an

We present APAC-Net, an alternating population and agent control neural network for solving stochastic mean-field games (MFGs). Our algorithm is geared toward high-dimensional instances of MFGs that are not approachable with existing solution methods. We achieve this in two steps. First, we take advantage of the underlying variational primal-dual structure that MFGs exhibit and phrase it as a convex–concave

Polyguanine tracts (PolyGs) are short guanine homopolymer repeats that are prone to accumulating mutations when cells divide. This feature makes them especially suitable for cell lineage tracing, which has been exploited to detect and characterize precancerous and cancerous somatic evolution. PolyG genotyping, however, is challenging because of the inherent biochemical difficulties in amplifying and

A network of molecular factors drives the development, differentiation, and maintenance of endothelial cells. Friend leukemia integration 1 transcription factor (FLI1) is a bona fide marker of endothelial cells during early development. In zebrafish Tg(fli1:EGFP)y1, we identified two endothelial cell populations, high-fli1+ and low-fli1+, by the intensity of green fluorescent protein signal. By comparing

When I signed on as Editor-in-Chief of PNAS, I had no idea that killing zombies would be part of the job. These zombies aren't the spirits of Haitian mythology doomed to roam the earth in thrall to sorcerers and shamans or the brain-eating undead of contemporary movie and television fame. Rather, in scientific publishing, the phrase “zombie literature” refers to papers, deemed invalid for any number

The heart pumps blood against the mechanical afterload from arterial resistance, and increased afterload may alter cardiac electrophysiology and contribute to life-threatening arrhythmias. However, the cellular and molecular mechanisms underlying mechanoelectric coupling in cardiomyocytes remain unclear. We developed an innovative patch-clamp-in-gel technology to embed cardiomyocytes in a three-dimensional

Conjugative plasmids are mobile elements that spread horizontally between bacterial hosts and often confer adaptive phenotypes, including antimicrobial resistance (AMR). Theory suggests that opportunities for horizontal transmission favor plasmids with higher transfer rates, whereas selection for plasmid carriage favors less-mobile plasmids. However, little is known about the mechanisms leading to

Gram-negative bacterial pathogens have an outer membrane that restricts entry of molecules into the cell. Water-filled protein channels in the outer membrane, so-called porins, facilitate nutrient uptake and are thought to enable antibiotic entry. Here, we determined the role of porins in a major pathogen, Pseudomonas aeruginosa, by constructing a strain lacking all 40 identifiable porins and 15 strains

Stress is often associated with pathophysiologic responses, like blood pressure (BP) reactivity, which when experienced repeatedly may be one pathway through which stress leads to poor physical health. Previous laboratory and field studies linking stress to physiological measures are limited by small samples, narrow demographics, and artificial stress manipulations, whereas large-scale studies often

Estimated millions of tons of plastic are dumped annually into oceans. Plastic has been produced only for 70 y, but the exponential rise of mass production leads to its widespread proliferation in all environments. As a consequence of their large abundance globally, microplastics are also found in many living organisms including humans. While the health impact of digested microplastics on living organisms

Bulk crystalline ices with ultralow densities have been demonstrated to be thermodynamically metastable at negative pressures. However, the direct formation of these bulk porous ices from liquid water at negative pressures is extremely challenging. Inspired by approaches toward porous media based on host–guest chemistry, such as metal–organic frameworks and covalent...

Molecular, polymeric, colloidal, and other classes of liquids can exhibit very large, spatially heterogeneous alterations of their dynamics and glass transition temperature when confined to nanoscale domains. Considerable progress has been made in understanding the related problem of near-interface relaxation and diffusion in thick films. However, the origin of “nanoconfinement effects” on the glassy

Streptomyces genomes harbor numerous, biosynthetic gene clusters (BGCs) encoding for drug-like compounds. While some of these BGCs readily yield expected products, many do not. Biosynthetic crypticity represents a significant hurdle to drug discovery, and the biological mechanisms that underpin it remain poorly understood. Polycyclic tetramate macrolactam (PTM) antibiotic production is widespread within

Loss-of-function mutations in acid beta-glucosidase 1 (GBA1) are among the strongest genetic risk factors for Lewy body disorders such as Parkinson’s disease (PD) and Lewy body dementia (DLB). Altered lipid metabolism in PD patient–derived neurons, carrying either GBA1 or PD αS mutations, can shift the physiological α-synuclein (αS) tetramer–monomer (T:M) equilibrium toward aggregation-prone monomers

Proinflammatory activation of macrophages in metabolic tissues is critically important in the induction of obesity-induced metaflammation. Here, we demonstrate that the soluble mannose receptor (sMR) plays a direct functional role in both macrophage activation and metaflammation. We show that sMR binds CD45 on macrophages and inhibits its phosphatase activity, leading to an Src/Akt/NF-κB–mediated cellular

Elastography is an imaging technique to reconstruct elasticity distributions of heterogeneous objects. Since cancerous tissues are stiffer than healthy ones, for decades, elastography has been applied to medical imaging for noninvasive cancer diagnosis. Although the conventional strain-based elastography has been deployed on ultrasound diagnostic-imaging devices, the results are prone to inaccuracies

The lymphatic system is involved in various biological processes, including fluid transport from the interstitium into the venous circulation, lipid absorption, and immune cell trafficking. Despite its critical role in homeostasis, lymphangiogenesis (lymphatic vessel formation) is less widely studied than its counterpart, angiogenesis (blood vessel formation). Although the incorporation of lymphatic

A delicate balance of noncovalent interactions directs the hierarchical self-assembly of molecular amphiphiles into spherical micelles that pack into three-dimensional periodic arrays, which mimic intermetallic crystals. Herein, we report the discovery that adding water to a mixture of an ionic surfactant and n-decane induces aperiodic ordering of oil-swollen spherical micelles into previously unrecognized

The motor protein dynein undergoes coordinated conformational changes of its domains during motility along microtubules. Previous single-molecule studies analyzed the motion of the AAA rings of the dynein homodimer, but not the distal microtubule-binding domains (MTBDs) that step along the track. Here, we simultaneously tracked with nanometer precision two MTBDs and one AAA ring of a single dynein

The current model of replication-dependent (RD) histone biosynthesis posits that RD histone gene expression is coupled to DNA replication, occurring only in S phase of the cell cycle once DNA synthesis has begun. However, several key factors in the RD histone biosynthesis pathway are up-regulated by E2F or phosphorylated by CDK2, suggesting these processes may instead begin much earlier, at the point

The inheritance of predisposition to nonsyndromic familial nonmedullary thyroid cancer (FNMTC) remains unclear. Here, we report six individuals with papillary thyroid cancer (PTC) in two unrelated nonsyndromic FNMTC families. Whole-exome sequencing revealed two germ-line loss-of-function variants occurring within a 28-bp fragment of WDR77, which encodes a core member of a transmethylase complex formed

Genetic variance is not equal for all multivariate combinations of traits. This inequality, in which some combinations of traits have abundant genetic variation while others have very little, biases the rate and direction of multivariate phenotypic evolution. However, we still understand little about what causes genetic variance to differ among trait combinations. Here, we investigate the relative

The p53 pathway is a universal tumor suppressor mechanism that limits tumor progression by triggering apoptosis or permanent cell cycle arrest, called senescence. In recent years, efforts to reactivate p53 function in cancer have proven to be a successful therapeutic strategy in murine models and have gained traction with the development of a range of small molecules targeting mutant p53. However,

G protein–coupled receptors (GPCRs) are important pharmaceutical targets for the treatment of a broad spectrum of diseases. Although there are structures of GPCRs in their active conformation with bound ligands and G proteins, the detailed molecular interplay between the receptors and their signaling partners remains challenging to decipher. To address this, we developed a high-sensitivity, high-throughput

We extract the folding free energy landscape and the time-dependent friction function, the two ingredients of the generalized Langevin equation (GLE), from explicit-water molecular dynamics (MD) simulations of the α-helix forming polypeptide alanine9 for a one-dimensional reaction coordinate based on the sum of the native H-bond distances. Folding and unfolding times from numerical integration of the

The observational absence of giant convection cells near the Sun’s outer surface is a long-standing conundrum for solar modelers. We herein propose an explanation. Rotation strongly influences the internal dynamics, leading to suppressed convective velocities, enhanced thermal-transport efficiency, and (most significantly) relatively smaller dominant length scales. We specifically predict a characteristic

Creating invariant representations from an everchanging speech signal is a major challenge for the human brain. Such an ability is particularly crucial for preverbal infants who must discover the phonological, lexical, and syntactic regularities of an extremely inconsistent signal in order to acquire language. Within the visual domain, an efficient neural solution to overcome variability consists in

To mimic the mechanical response of passive biological cilia in complex fluids, we study the bending dynamics of an anchored elastic fiber submitted to a dilute granular suspension under shear. We show that the bending fluctuations of the fiber accurately encode minute variations of the granular suspension concentration. Indeed, besides the stationary bending induced by the continuous phase flow, the

Despite the remarkable variability music displays across cultures, certain recurrent musical features motivate the hypothesis that fundamental cognitive principles constrain the way music is produced. One such feature concerns the structure of musical scales. The vast majority of musical cultures use scales that are not uniformly symmetric—that is, scales that contain notes spread unevenly across the

Vaccine uptake is critical for mitigating the impact of COVID-19 in the United States, but structural inequities pose a serious threat to progress. Racial disparities in vaccination persist despite the increased availability of vaccines. We ask what factors are associated with such disparities. We combine data from state, federal, and other sources to estimate the relationship between social determinants

Constraints on CO2 emissions are confronting society with multiple massive challenges: creating new sources of clean energy beyond solar and wind; electrifying our transportation systems and using lighter weight materials; decarbonizing the industrial sector; and dealing with the economic fallout associated with shrinking the fossil hydrocarbon industry, which accounts for about 7% of the world economy

In early 2020, the trajectory of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on the African continent was much discussed. Slow growth in mortality even prompted speculation that the continent might be “spared” as a result of an overall younger population, effective government responses (1), or perhaps even protection via cross-immunity from other coronaviruses. In 2021

Many bacteria, including the major human pathogen Pseudomonas aeruginosa, are naturally found in multicellular, antibiotic-tolerant biofilm communities, in which cells are embedded in an extracellular matrix of polymeric molecules. Cell–cell interactions within P. aeruginosa biofilms are mediated by CdrA, a large, membrane-associated adhesin present in the extracellular matrix of biofilms, regulated

To advance the mission of in silico cell biology, modeling the interactions of large and complex biological systems becomes increasingly relevant. The combination of molecular dynamics (MD) simulations and Markov state models (MSMs) has enabled the construction of simplified models of molecular kinetics on long timescales. Despite its success, this approach is inherently limited by the size of the

Single-particle tracking (SPT) is a key tool for quantitative analysis of dynamic biological processes and has provided unprecedented insights into a wide range of systems such as receptor localization, enzyme propulsion, bacteria motility, and drug nanocarrier delivery. The inherently complex diffusion in such biological systems can vary drastically both in time and across systems, consequently imposing

Vertebrates have repeatedly modified skeletal structures to adapt to their environments. The threespine stickleback is an excellent system for studying skeletal modifications, as different wild populations have either increased or decreased the lengths of their prominent dorsal and pelvic spines in different freshwater environments. Here we identify a regulatory locus that has a major morphological

Optical cavities confine light on a small region in space, which can result in a strong coupling of light with materials inside the cavity. This gives rise to new states where quantum fluctuations of light and matter can alter the properties of the material altogether. Here we demonstrate, based on first-principles calculations, that such light-matter coupling induces a change of the collective phase

It is commonly assumed that cities are detrimental to mental health. However, the evidence remains inconsistent and at most, makes the case for differences between rural and urban environments as a whole. Here, we propose a model of depression driven by an individual's accumulated experience mediated by social networks. The connection between observed systematic variations in socioeconomic networks

In 1881 the first significant work on earthworm behavior and ecology was published (1). It was Charles Darwin´s last scientific book and is still a fascinating and rewarding read. In PNAS, Geier et al. (2) use an earthworm taken directly from nature to present a method that allows in situ...

In our everyday life, we are often exposed to addictive agents like pain killers, tobacco, alcohol, even food, sex, or video games. Although the majority of people will not develop an addiction upon contact with those agents, a part of the population will. What determines whether a person is going...

Optical cavities confine light on a small region in space, which can result in a strong coupling of light with materials inside the cavity. This gives rise to new states where quantum fluctuations of light and matter can alter the properties of the material altogether. Here we demonstrate, based on...

It is commonly assumed that cities are detrimental to mental health. However, the evidence remains inconsistent and at most, makes the case for differences between rural and urban environments as a whole. Here, we propose a model of depression driven by an individual’s accumulated experience mediated by social networks. The...

The rapid development of COVID-19 vaccines is a tremendous scientific response to the current global pandemic. However, vaccines per se do not save lives and restart economies. Their success depends on the number of people getting vaccinated. We used a survey experiment to examine the impact on vaccine intentions of...

ECOLOGY Upside-down jellyfish from the Florida Keys. How upside-down jellyfish engineer mangrove ecosystems Winds and tides roil the still waters of shallow coastal ecosystems, aiding nutrient transport, gas exchange, and predator–prey encounters. In contrast, sheltered habitats, such as mangroves, where such physical forces are rare, rely on biotic agents for...