Table Of Contents Page, PNAS Volume 123, Number 11
This Week in PNAS
Opinion
Retrospective
A. James (Jim) Hudspeth, who devoted five decades to studying how hair cells—the mechanoreceptor
cells of the inner ear—mediate the senses of hearing and balance, passed away on August
16, 2025, at his home in New York City. He was 79. Among his many ...
Commentaries
Perspectives
The Epstein–Barr virus (EBV) infects greater than 95% of humans and is associated
with initiating and perpetuating multiple sclerosis (MS). Antibody to Epstein–Barr
Nuclear Antigen-1 (EBNA1) is present in nearly 100% of patients with MS before the
...
Room-temperature superconductivity is arguably the greatest challenge in condensed
matter physics, with significant practical and commercial implications if it can be
solved. There are no physical laws preventing this from occurring; indeed, ...
Letters
View the original article:
The proofreading mechanism of the human leading-strand DNA polymerase ε holoenzyme
This article has a reply:Brief Report
Tuberculosis (TB) is a major public health concern and the leading infectious cause
of mortality globally. The disease exhibits strong prevalence patterns by age and
sex, but the implications of these patterns for likely TB exposure and transmission
have ...
Physical Sciences
Applied Mathematics
Astrocyte endfeet form a near-continuous sheath around the brain’s vasculature, defining
the perivascular spaces (PVS) that are crucial for brain fluid flow and solute transport.
Yet, their precise physiological role remains poorly understood. Using 3D ...
Applied Physical Sciences
Achieving accurate monitoring of electrophysiological activity from the brain cortex
is critical for preventing postoperative neurological deficits during craniotomy.
However, current technologies face profound challenges in enabling consistent high-...
Phase control is fundamental to acoustic wave manipulation. The propagation and resonant
phases have been widely used to modulate acoustic waves. However, the real-space geometric
phase, also known as the Pancharatnam–Berry (PB) phase, has remained ...
The extent to which two brains align during information processing is thought to be
central to collaborative memory encoding; however, the neural mechanisms that support
such interpersonal alignment remain elusive. Traditional interbrain synchrony models
...
Biophysics and Computational Biology
Heterotrophic bacteria play a central role in attenuating the sequestration of carbon
to the deep ocean by degrading sinking marine particles. The role of certain copiotrophic
adaptations such as surface attachment and motility in particle degradation has ...
The molecular mechanisms governing internal fluctuations in intrinsically disordered
protein (IDP) assemblies are crucial to the stability and dynamics of both regulated
and aberrant toxic cellular aggregates, but remain poorly understood. By ...
Mechanisms of wet adhesion have evolved in several aquatic organisms over millions
of years. Yet, the repertoire of synthetic biocompatible wet adhesive materials is
still limited. The byssus is a well-studied proteinaceous bioadhesive structure utilized
...
Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function
in Alzheimer’s disease and are strongly associated with cognitive decline. Early events
in tau aggregation are increasingly linked to the formation of biomolecular ...
To reach targets outside the bloodstream, immune cells can extravasate and migrate
through connective tissue. During tissue infiltration, immune cells migrate in an
amoeboid fashion, characterized by weak matrix adhesions and low traction forces,
that ...
Collective bacterial condensation is fundamentally constrained by the emergence of active turbulence
Collective bacterial condensation arises from positive feedback between the ability
of bacteria to generate chemical gradients in their environment and their chemotactic
ability to follow those gradients. This feedback drives the spontaneous formation
of ...
Chemistry
The orange carotenoid protein (OCP) is a key photoreceptor in the photoprotection
of cyanobacterial antenna complexes. Its peculiar activity is governed by a bound
keto-carotenoid that functions both as a light sensor and an energy quencher. Upon
blue ...
Viral mimicry may be an underappreciated contributor to chemotherapeutic potency in
animal models and patients. This hypothesis is based on studies of a bis-Au(I)-NHC
complex that was found to generate a strong anti-tumor immune response in vivo in two ...
Microbial natural products are a foundational source of therapeutic agents, yet a
vast majority remain inaccessible due to the limited expression of their biosynthetic
gene clusters under standard laboratory conditions. To address this challenge, we
...
Artificial N2 reduction offers a sustainable approach to green NH3 synthesis, but the practical implementation is challenged by N2 activation and competing hydrogen evolution. Photoelectrochemical nitrate and nitrite
(NOx–, x = 2 and 3) reduction with ...
Understanding solvent/solute-borne coordination structures and their impact on electrode
intercalation chemistry is crucial for the rational design of high-performance electrolytes.
Nevertheless, the anion coordination mechanisms governing solvation ...
The HIV-1 capsid is a fullerene cone composed of hexameric and pentameric capsid proteins
(CA) that packages the viral genome and mediates nuclear entry. Lenacapavir (LEN),
a potent molecular long-acting inhibitor developed by Gilead, disrupts capsid ...
Proteolysis-targeting chimeras (PROTACs) have emerged as a promising molecular approach
for degrading undruggable proteins and for overcoming drug resistance in cancer therapy.
However, their clinical translation remains limited by challenges such as poor ...
Chemical defenses are fundamental in organismal biology and widely used in medicine
and agriculture. Plant defense chemistry evolves in response to various selective
pressures, particularly herbivory, and theory has emphasized predicting toxin abundance
...
Earth, Atmospheric, and Planetary Sciences
Evidence for the shallow cycling of calcium carbonate in the global ocean is mounting,
but the mechanisms driving the dissolution of thermodynamically stable polymorphs,
like aragonite and calcite, in the surface ocean remain unconstrained. Here, we ...
The inception of the Antarctic ice sheet (AIS) marked a major global climatic reorganization
of the Cenozoic, but the response of the subtropical marine biosphere remains poorly
constrained. A new sediment archive from the subtropical South Atlantic (IODP ...
Stratocumulus-topped boundary layers play a crucial role in influencing daily weather
and earth energy balance. Entrainment at the stratocumulus cloud top affects the cloud’s
lifetime, precipitation, and radiative properties, but our understanding remains ...
Engineering
Online supervised learning of temporal patterns in biological neural networks under feedback control
In vitro biological neural networks (BNNs) provide well-defined model systems for
constructively investigating how living cells interact with their environments to
shape high-dimensional dynamics that can be used to generate coherent temporal outputs,
...
Clathrate hydrates are fascinating materials that offer many attractive benefits for
carbon sequestration, water desalination, intermittent natural gas storage, chemical
separations, and other applications. However, their slow growth kinetics prevents
the ...
In situ monitoring of sweat glucose during exercise can provide a real-time and continuous
assessment of blood glucose dynamics. However, the relatively poor correlation between
sweat and blood glucose concentrations during exercise makes it challenging ...
Active filaments are a workhorse for propulsion and actuation across biology, soft
robotics, and mechanical metamaterials. However, artificial active rods suffer from
limited robustness and adaptivity because they rely on external control, or are tethered
...
Physics
of topologically nontrivial matter across electronic, mechanical, cold-atom, and photonic
platforms is advancing rapidly, yet understanding the breakdown of topological protection
remains a major challenge. In this work, we use magnetic imaging combined ...
We investigate a twisted bilayer of 1T-TaSe2 (twist angle
Superconductivity has been a vigorously researched topic since its discovery in 1911.
Raising the superconducting transition temperature (Tc) has been the main driving force behind such long-sustained efforts due to its potential
for impacting humanity ...
We introduce twisted anisotropic homobilayers as a distinct class of moiré systems,
characterized by a distinctive “magic angle,”
Electrostatically driven pattern formation in mixed charged–neutral multicomponent elastic membranes
Multicomponent crystalline and amorphous elastic shells exhibit heterogeneous surface
patterns that provide distinctive functionalities in cellular environments. Such patterning
typically arises from the competition between short-range attractive and long-...
In density functional theory, the SCAN (Strongly Constrained and Appropriately Normed)
and r2SCAN (regularized–restored SCAN) functionals significantly improve over GGA (Generalized
Gradient Approximation) functionals such as PBE (Perdew–Burke–Ernzerhof) ...
Large Language Models (LLMs) show great promise as a powerful tool for scientific
literature exploration. However, their effectiveness in providing scientifically accurate
and comprehensive answers to complex questions within specialized domains remains
...
Social Sciences
Anthropology
Humans occupy a geographic and ecological range wider than that of any other extant
vertebrates, having rapidly expanded into nearly every habitat on the planet. This
expansion was driven not only by biological adaptations but, crucially, by cultural
...
Demography
US life expectancy remained essentially flat in the 2010s. This trend has occurred
in the presence of advancing innovations in medical care, especially for chronic disease,
and a growing economy. While research has identified selected contributing factors,...
Psychological and Cognitive Sciences
Major depressive disorder (MDD) is associated with widespread alterations in functional
brain networks across the lifespan. However, heterogeneity in atypical brain development
among patients with MDD remains largely uncharacterized. Using a multisite ...
Given the same input, understanding of that input can differ depending on context.
How does the brain represent the latent mental frameworks that support different interpretations
of the same sensory information? In this study, participants listened to ...
Social Sciences
Fatal police violence is a public health problem in the United States, with large
racial and spatial inequities that remain understudied. Indigenous people, for example,
experience some of the highest rates of fatal police violence of any racial/ethnic
...
Biological Sciences
Agricultural Sciences
Cattle have a synepitheliochorial type of placenta characterized by placental cotyledons
and maternal endometrial caruncles forming placentomes that are essential for fetal
development to term. As the elongated conceptus begins implantation, binucleated ...
Anthropology
Humans occupy a geographic and ecological range wider than that of any other extant
vertebrates, having rapidly expanded into nearly every habitat on the planet. This
expansion was driven not only by biological adaptations but, crucially, by cultural
...
Reconstructing past lifeways and diets is essential to understanding the emergence
of urban societies. However, in what are now arid environments like southern Mesopotamia,
poor collagen preservation has long hampered direct isotopic analysis of trophic ...
Prior to the formation of the present-day North Sea during the mid-Holocene, North-Western
Europe was connected through the Doggerland landmass. While it has been known for
the past century that Doggerland was forested, it has not been clear when the ...
Applied Biological Sciences
Marine animals that build shells, such as oysters, carefully regulate the chemistry
of their internal calcifying fluids, but the molecular mechanisms behind this control,
as well as whether microbes play a role in calcification, are poorly understood. To
...
Biochemistry
Mechanisms of wet adhesion have evolved in several aquatic organisms over millions
of years. Yet, the repertoire of synthetic biocompatible wet adhesive materials is
still limited. The byssus is a well-studied proteinaceous bioadhesive structure utilized
...
The distinctive aroma of banana fruit (Musa spp.) results from the upregulation of a pathway that is, paradoxically, understood
to be feedback limited. The primary character impact compounds in banana are branched-chain
esters with 3-methylbutyl moieties. ...
Cytochrome bd is a terminal oxidase expressed under low oxygen conditions and central for the survival
of many pathogens. Here, we characterize the cyt bd-II from Mycobacterium smegmatis, a member of a hitherto uncharacterized evolutionary group (qOR-2) ...
Biophysics and Computational Biology
Astrocyte endfeet form a near-continuous sheath around the brain’s vasculature, defining
the perivascular spaces (PVS) that are crucial for brain fluid flow and solute transport.
Yet, their precise physiological role remains poorly understood. Using 3D ...
Heterotrophic bacteria play a central role in attenuating the sequestration of carbon
to the deep ocean by degrading sinking marine particles. The role of certain copiotrophic
adaptations such as surface attachment and motility in particle degradation has ...
The orange carotenoid protein (OCP) is a key photoreceptor in the photoprotection
of cyanobacterial antenna complexes. Its peculiar activity is governed by a bound
keto-carotenoid that functions both as a light sensor and an energy quencher. Upon
blue ...
Neurofibrillary tangles (NFTs) formed from the protein tau disrupt neuronal function
in Alzheimer’s disease and are strongly associated with cognitive decline. Early events
in tau aggregation are increasingly linked to the formation of biomolecular ...
PER2 is a central transcriptional regulator in the mammalian circadian clock that
closes the negative transcription–translation feedback loop by repressing its own
transcription. The balance between the synthesis of PER2 and its degradation is a
key ...
Biochemical mechanisms of macrophage-driven tumor promotion are well documented, but
the contribution of physical forces to early tumor development remains poorly understood.
Here, we combine experimental analyses with physical modeling to investigate ...
Targeted protein degradation is a promising strategy for drug discovery, but designing
effective PROTACs remains challenging, especially for proteins without well-defined
binding sites. Current methods rely on modifying linkers between fixed ligands, ...
We sought to identify universal organizing principles behind phenotypic variation
within cell types. Pareto optimality describes how trade-offs between optimal solutions
account for variation, predicting that the boundary points of a data distribution
...
Cell Biology
To reach targets outside the bloodstream, immune cells can extravasate and migrate
through connective tissue. During tissue infiltration, immune cells migrate in an
amoeboid fashion, characterized by weak matrix adhesions and low traction forces,
that ...
Gut microbiome–produced bile acid metabolite lengthens the circadian period in host intestinal cells
Host circadian signaling, feeding, and the gut microbiome are tightly interconnected.
Changes in the gut microbial community can affect the expression of core clock genes,
but the specific metabolites and molecular mechanisms that mediate this ...
Extrachromosomal circular DNA (ecDNA) is frequently generated within the nucleus,
contributing to genome dynamics and heterogeneity, thereby promoting cancer cell evolution
and adaptation. However, the mechanisms underlying ecDNA biogenesis remain poorly
...
Luminal breast cancer is characterized by a persistent risk of recurrence and dysregulated
lipid metabolism. However, the role of phase separation, a novel mechanism for the
spatial compartmentalization of proteins, in lipid remodeling within the context ...
The transcription factor c-Myc is a master oncoprotein that regulates over 15% of
all genes. Protein phosphatase 2A (PP2A), a crucial tumor suppressor, destabilizes
c-Myc protein. Classically, PP2A-mediated dephosphorylation of Ser62 followed by Thr58
...
Environmental Sciences
Evidence for the shallow cycling of calcium carbonate in the global ocean is mounting,
but the mechanisms driving the dissolution of thermodynamically stable polymorphs,
like aragonite and calcite, in the surface ocean remain unconstrained. Here, we ...
Evolution
The evolution and maintenance of public goods cooperation, despite cheating, remains
a key interest in social biology. Identifying how ecological factors determine the
direct and indirect benefits that maintain cooperation has proven challenging, as
these ...
Phenotypic variation is the raw material for evolutionary diversification and adaptation.
However, a critical gap remains in evolutionary theory between developmental and statistical
representations of phenotypic variation, limiting our ability to ...
Mutation spectra vary across genetic and environmental contexts, leading to differences
between and within species. Most research on mutation spectrum has focused on trinucleotide
(3-mer) mutation types in mammals, limiting the breadth and depth of ...
How species time reproduction and adapt to environmental conditions are key topics
in ecology and evolutionary biology. Here, we conducted a high-resolution population
genetic analysis of Baltic herring, a subspecies of Atlantic herring (Clupea harengus). ...
Genetics
Histone modifications represent an untapped resource for biological age prediction
that overcomes limitations of traditional DNA methylation-based epigenetic clocks.
Here, we developed and validated histone modification-based epigenetic clocks by ...
Phenotypic heterogeneity is prevalent during aging, yet its underlying molecular drivers
remain poorly understood. In budding yeast, two distinct aging trajectories, characterized
by either ribosomal DNA (rDNA) instability or mitochondrial decline, have ...
Immunology and Inflammation
Viral mimicry may be an underappreciated contributor to chemotherapeutic potency in
animal models and patients. This hypothesis is based on studies of a bis-Au(I)-NHC
complex that was found to generate a strong anti-tumor immune response in vivo in two ...
Linear ubiquitination and deubiquitination represent critical regulatory mechanisms
in inflammation and cell death, yet their roles in RIG-I-like receptor (RLR)-dependent
signaling remain unclear. Here, we identified OTU deubiquitinase with linear linkage
...
Meningeal inflammation, as a clinical feature of multiple sclerosis (MS), is associated
with worse clinical disease outcomes. In both relapsing and secondary progressive
MS and the experimental autoimmune encephalomyelitis (EAE) MS model, the meninges
...
Activation of retinoic acid-inducible gene-I-like receptors (RLRs) is important for
type I interferon (IFN-I) production and antiviral innate immunity initiation. However,
the epigenetic mechanisms that regulate RLR signaling remain poorly understood and
...
Psoriasis is a chronic inflammatory skin disease affecting millions of people worldwide.
Although growing evidence links chronic inflammation with increased cancer risk, the
association between psoriasis and cutaneous squamous cell carcinoma (cSCC) is ...
Functional gastrointestinal (GI) tract disorders affect a substantial proportion of
the global population and are often preceded by intestinal infections that cause injury
to enteric neurons and glia through unrestrained immune responses. However, the ...
The immunological synapse (IS) integrates antigen recognition and adhesion to control
T cell activation and effector functions. Reductionist systems have been instrumental
in dissecting IS organization, but conventional systems constrain all ligands to be
...
Medical Sciences
Inhibiting stimulator of interferon genes (STING) is critical for treating rheumatoid
arthritis (RA), yet achieving precise suppression with high tissue specificity across
protein variants remains challenging. Here, we engineer a multilevel, intelligent
...
Widely used phthalates, especially di-(2-ethylhexyl) phthalate (DEHP), increase breast
cancer risk in experimental animals and humans, but long-term follow-up evidence of
its human breast carcinogenicity remains inconclusive. This nested case–control ...
Microbiology
Microbial natural products are a foundational source of therapeutic agents, yet a
vast majority remain inaccessible due to the limited expression of their biosynthetic
gene clusters under standard laboratory conditions. To address this challenge, we
...
Collective bacterial condensation is fundamentally constrained by the emergence of active turbulence
Collective bacterial condensation arises from positive feedback between the ability
of bacteria to generate chemical gradients in their environment and their chemotactic
ability to follow those gradients. This feedback drives the spontaneous formation
of ...
Mechanisms by which macrophages deploy antibacterial zinc toxicity are poorly understood.
To gain insight into this antimicrobial pathway, we developed bacterial reporter–paired
single-cell RNA sequencing of human monocyte-derived macrophages (HMDM) ...
The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed
as a mechanism for cancer immune evasion. Nevertheless, the mechanism is poorly understood.
We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), ...
Exopolysaccharides are carbohydrate polymers secreted by bacteria to perform various
roles including adhesion to surfaces, protection from environmental stressors, and
as key components in the production of biofilms. The human pathogen Vibrio cholerae ...
Mycobacterium abscessus infections represent a growing global health concern due to their severe pathology
and difficulty of treatment, largely driven by their intrinsic antimicrobial resistance.
While phage therapy has emerged as a promising alternative ...
Rhabdoviruses exhibit a broad host range, yet the cellular receptors underlying their
cross-species tropism remain poorly defined. Here, we identified tetraspanin CD9 as
a conserved functional entry receptor for diverse rhabdoviruses across genera, ...
The genomic RNA of negative-strand RNA viruses is encapsidated by nucleocapsid proteins
and associates with RNA polymerase to form a ribonucleoprotein (RNP) complex. Lacking
both a 5’ cap and a 3’ poly (A) tail, viral RNAs are highly unstable and prone to
...
The anaerobic conversion of organic matter to methane and carbon dioxide typically
relies on obligate syntrophic interactions between bacteria and methanogenic archaea,
where interspecies electron transfer enables thermodynamically constrained reactions
...
Bacterial outer membrane vesicles (OMVs) and the cargo they carry are increasingly
recognized as a means of communication between microbial symbionts and the cells of
their host. However, few studies have focused on the biochemical and molecular ...
Neuroscience
Online supervised learning of temporal patterns in biological neural networks under feedback control
In vitro biological neural networks (BNNs) provide well-defined model systems for
constructively investigating how living cells interact with their environments to
shape high-dimensional dynamics that can be used to generate coherent temporal outputs,
...
Major depressive disorder (MDD) is associated with widespread alterations in functional
brain networks across the lifespan. However, heterogeneity in atypical brain development
among patients with MDD remains largely uncharacterized. Using a multisite ...
The µ-opioid receptor (MOP) is a critical pharmaceutical target that mediates both
the therapeutic benefits and adverse effects of opioid drugs. However, the large-scale
neural circuit dynamics underlying key opioid effects, such as analgesia and ...
Microglia use a highly complex and dynamic network of branched processes to sense
and respond to their surroundings. Despite emerging evidence that microglial motility
plays important roles in brain development, neurodegeneration, and neuropsychiatric
...
Personal experiences are encoded and stored in memory engram cells and are crucial
for social preference dynamics in future social contexts, yet the neural circuit mechanisms
involved are still poorly understood. Here, we develop a mouse model that ...
Binge eating disorder (BED) is the most common type of eating disorder; however, the
neural circuit mechanisms underlying BED remain elusive. Here, we report that tachykinin-expressing
neurons in the lateral hypothalamic area (LHTac1 neurons) are ...
Infraslow (<0.1 Hz) global brain activity, quantified by the global mean blood-oxygenation-level-dependent
(gBOLD) signal in resting-state functional magnetic resonance imaging (fMRI), is elevated
during sleep and coupled to cerebrospinal fluid (CSF) ...
A high risk of relapse triggered by craving during abstinence remains a main challenge
in opioid addiction treatment. Multiple brain regions have been implicated in opioid
craving, but the brain-wide neural mechanisms underlying this process remain poorly
...
Aggregation and deposition of TAR DNA-binding protein 43 (TDP-43) is a salient pathological
signature of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration-TDP
(FTLD-TDP). TDP-43 proteostasis and aggregation are controlled by ...
Stress undermines extinction learning and hinders exposure-based clinical therapies
for a variety of neuropsychiatric disorders. In both animals and humans, dysfunction
in the ventromedial prefrontal cortex (vmPFC) contributes to stress-impaired ...
Physiology
Early-onset obesity, especially in girls, is frequently associated with advanced puberty;
a phenomenon bound to increased risk of long-term complications. Hypothalamic endoplasmic
reticulum (ER) stress has been implicated in the pathophysiology of obesity ...
Intrinsic neuronal excitability, defined by the balance between input and output signals,
is crucial to neural function, and its disruption underlies various neurological diseases.
Kv3.1 channels, encoded by KCNC1, are essential for high-frequency action ...
Plant Biology
Chemical defenses are fundamental in organismal biology and widely used in medicine
and agriculture. Plant defense chemistry evolves in response to various selective
pressures, particularly herbivory, and theory has emphasized predicting toxin abundance
...
Enhancements to crop morphology, such as the semidwarfing that helped drive the green
revolution, are often driven by changes in gene expression. These are challenging
to translate across species, which slows the rate of crop improvement. Synthetic ...
Plants face hypoxic conditions either chronically, as particular tissues are characterized
by fluctuating or stable low oxygen levels, or acutely, when flooded. In vascular
plants, transcriptional adaptive responses to hypoxia are rapidly mounted by ...
Population Biology
Pandemics often involve complex transmission dynamics in which epidemiological surveillance
is essential but not sufficient for containment, as resurgence may be driven by emerging
or imported variants. Rapidly evolving pathogens produce complex disease ...
Psychological and Cognitive Sciences
The extent to which two brains align during information processing is thought to be
central to collaborative memory encoding; however, the neural mechanisms that support
such interpersonal alignment remain elusive. Traditional interbrain synchrony models
...
Given the same input, understanding of that input can differ depending on context.
How does the brain represent the latent mental frameworks that support different interpretations
of the same sensory information? In this study, participants listened to ...
Intrusive traumatic memories are a hallmark symptom of posttraumatic stress disorder
(PTSD). Conventional therapies typically require explicit and emotionally distressing
reexposure to trauma cues, often leading to high dropout rates among severely ...
Corrections
Cover image:Pictured is a chain of robotic units excavating a granular pile of beads. Sami Al-Izzi, Yao Du et al. designed flexible mechatronic beams that autonomously crawl, dig, and walk. The beams amplify vibrations unidirectionally by breaking the reciprocal symmetry typically seen in elastic buckling, enabling stable nonlinear oscillations and programmable movement. The design could be developed for soft robots and active materials that operate without centralized control. See the article by Al-Izzi, Du et al. e2531723123. Image Credit: Yao Du.
Sign up for PNAS alerts.
Get alerts for new articles, or get an alert when an article is cited.
Learn MoreAdvertisement
Recent Issues
Submit to PNAS
Submit to the Proceedings of the National Academy of Sciences (PNAS) and have your research discovered by millions of researchers in the biological, physical, and social sciences.
Submit your manuscript