Table Of Contents Page, PNAS Volume 123, Number 6
This Week in PNAS
Editorial
Retrospective
Stephen Long pioneered a multidisciplinary approach to advance our knowledge of photosynthesis,
by integrating research at the molecular, cellular, organismal, and ecological levels
along with a pragmatic understanding of the implications for agriculture. ...
Commentaries
Perspective
Vigorous debate has erupted over the trustworthiness of scientific research findings
in a number of domains. The question “what makes research findings trustworthy?” elicits
different answers depending on whether the emphasis is on research integrity and ...
Letters
View the original article:
Divergent evolutionary dynamics of benign and malignant tumors
This article has a reply:Reply to Compton et al.: Another paradoxical misunderstanding
View the original article:
Apparent learning biases emerge from optimal inference: Insights from master equation analysis
This article has a reply:Reply to Cecchi and Palminteri: On the need to model temporal variation in learning rates
Brief Reports
Behavioral research has been criticized for relying on demographically narrow WEIRD
samples-Western, Educated, Industrialized, Rich, and Democratic. While recent work
has expanded to explore cross-country behavioral differences, the study of within-...
Sociality has evolved several times and is a key strategy for overcoming environmental
challenges and promoting ecological success. Yet, it remains unclear how environmental
conditions shape global variation in social traits of animals. With their diverse
...
Lead (Pb) is well known to be toxic to humans. We use archived hair from individuals
living along the Wasatch Front in Utah to evaluate changes in exposure to lead over
the last 100 y. Current concentrations of lead in hair from this population average
...
Physical Sciences
Applied Physical Sciences
Evaporation from a multicomponent aqueous mixture not only establishes a hydration
gradient but may also lead to composition gradients in the other components. Here,
we show that such a gradient induces a strong segregation between two phospholipids
that ...
The control of particle trajectories in structured microfluidic environments has significantly
advanced sorting technologies, most notably through deterministic lateral displacement
(DLD). While previous works have largely targeted rigid, near-spherical ...
Active matter refers to a broad class of nonequilibrium systems where energy is continuously
injected at the level of individual “particles.” These systems exhibit emergent collective
behaviors that have no direct thermal-equilibrium counterpart. Their ...
Biophysics and Computational Biology
Symbiotic nutrient exchange between arbuscular mycorrhizal (AM) fungi and their host
plants varies widely depending on their physical, chemical, and biological environment.
Yet dissecting this context dependency remains challenging because we lack methods
...
Hierarchical friction memory leads to subdiffusive configurational dynamics of fast-folding proteins
Proteins often exhibit subdiffusive configurational dynamics, the origins of which
are still unresolved. We investigate the impact of non-Markovian friction and the
free-energy landscape on the dynamics of fast-folding proteins in terms of the mean
...
Epithelial cell polarization is essential for many physiological processes, including
tissue morphogenesis, nutrient absorption, barrier integrity, and directional secretion.
A defining feature of such polarization is the separation of plasma membrane (PM)...
Flamboyant sexual ornaments serve as conspicuous visual signals optimized to the visual
receptors and perception of potential mates. While numerous studies have explored
the mechanisms and functions of body coloration as a sexual signal, the role of ...
Chemistry
Obtaining the free energies of condensed phase chemical reactions remains computationally
prohibitive for high-level quantum mechanical methods. We introduce a hierarchical
machine learning framework that bridges this gap by distilling knowledge from a ...
The organizational complexity of biominerals has long fascinated scientists seeking
to understand biological programming and implement new developments in biomimetic
materials chemistry. Nonclassical crystallization pathways have been observed and
...
Many important solid-phase synthesis reactions proceed slowly and inefficiently, for
example, the coupling of an activated ester to a sterically hindered, bead-displayed
amine, a critical step in the synthesis of many peptides. Forcing conditions are ...
Poly(N-isopropylacrylamide) (PNIPAM), a thermoresponsive homopolymer, is a well-established
model for investigating coil-to-globule transitions. Here, we combine long molecular
dynamics (MD) simulations, data sonification, and graph-theory analysis to ...
Computer Sciences
Continual learning (CL) enables animals to learn new tasks without erasing prior knowledge.
CL in artificial neural networks (NNs) is challenging due to catastrophic forgetting,
where new learning degrades performance on older tasks. While various ...
Brainstem white matter (WM) bundles are essential conduits for neural signals that
modulate homeostasis and consciousness. Their architecture forms the anatomic basis
for brainstem connectomics, subcortical circuit models, and deep brain navigation
tools. ...
Earth, Atmospheric, and Planetary Sciences
Stress is not uniform in the Earth. Therefore, we must use natural experiments to
measure the distribution of stresses and related quantities, rather than single values.
For instance, dynamic triggering shows that faults are uniformly distributed over
...
Extending the N2O lifetime derived from Microwave Limb Sounder satellite observations, we find a mean
value of 117 y and a likely decrease of –1.4 ± 0.9% per decade over the period 2004
to 2024. This trend is consistent with the previously published 2004 ...
As well known, almost 80% of the total oceanic kinetic energy is contained within
the mesoscale eddies, but the cross-scale energy transfers linking eddy generation
and dissipation remain an open question. The Earth rotation controls the generation
of ...
The Pliocene is the most recent epoch in which the Earth warmed under atmospheric
CO2 levels similar to today (>400 ppm). The Pliocene then transitioned to the colder
Pleistocene epoch, with the initiation of large-scale Northern Hemisphere glaciations.
...
It is widely accepted that meltwater from northern ice sheets drove changes in the
Atlantic Meridional Overturning Circulation, impacting global climate. In contrast,
data are lacking on the Antarctic Ice Sheet’s (AIS) effect on Southern Ocean overturning,...
Cities are often warmer than rural surroundings due to a phenomenon known as the urban
heat island, which can be influenced by various factors, such as regional climate
and land surface types. Under climate change, cities face not only the challenge of
...
Engineering
Actuators drive robotic motion, and their energy conversion efficiency is a key performance
metric that informs power consumption. Soft electrostatic actuators promise new opportunities
for bioinspired and wearable robotics, being driven by electrical ...
Rolling contact joints (RCJs) guide motion in robotic linkages, including manipulators,
surgical devices, prosthetics, and more. In this work, we present a generalized optimization
method to tailor the kinematic properties of RCJs by simultaneously ...
Agile and efficient modern flyers like birds and insects rely on complex aerodynamics
to increase performance such as leading edge vortices, tip vortices, rapid pitch rotations
as well as wing–wake and wing–wing interactions. However, their evolutionary ...
Environmental Sciences
Remotely sensed Earth science information (ESI) has become increasingly central to
addressing global challenges, yet its societal value, i.e., the difference ESI makes
in real-world decisions and outcomes, is rarely quantified. In this study, we ...
Physics
Biomolecular condensates form on timescales of seconds in cells upon environmental
or compositional changes. Condensate formation is thus argued to act as a mechanism
for sensing such changes and quickly initiating downstream processes, such as forming
...
Quantum-chaotic systems exhibit several universal properties, ranging from level repulsion
in the energy spectrum to wavefunction delocalization. On the other hand, if wavefunctions
are localized, the energy levels exhibit no level repulsion and their ...
Statistics
Current single-cell profiling technologies enable the capture of multiple cellular
modalities, providing valuable insights into complex biological systems. While a substantial
amount of single-cell multimodal data has been generated and accumulated, most ...
Sustainability Science
Solar energy–driven hydrogen peroxide (H2O2) synthesis from atmospheric oxygen and water represents a sustainable and highly
promising avenue for the production of this essential chemical. Covalent organic frameworks
(COFs) offer a molecular platform for ...
Social Sciences
Anthropology
The Middle Pleistocene (MP; ca. 774 to 129 ka) marks a critical period of human evolution,
characterized by increasing behavioral complexity and the first unambiguous evidence
of plant-based technologies. Despite this, direct evidence for early wooden ...
Demography
Preventing premature death is a global policy objective reflected in the SDGs. While
numerous studies have found socioeconomic factors to be significantly associated with
premature death everywhere in the world, the debate on the relative effect of such
...
Psychological and Cognitive Sciences
Depression is shaped by both genetic and environmental factors, but genome-wide interaction
studies (GWIS) often lack power to detect complex gene–environment (G × E) interactions.
We applied a forest-based machine learning approach to 38,018 UK Biobank (...
“More than 1 in 8 LGBTQ people live in states where doctors can refuse to treat them.”
This headline describes a flurry of laws passed in 2025 allowing doctors to refuse
treatment of LGBTQ patients based on personal beliefs. This and other laws like it
...
When outgroups are present, adults may endorse ingroup choices that are at odds with
their personal preferences, in an outward show of ingroup loyalty. Here, we examined
whether 2-y-old toddlers (N = 108) might already understand such shows of loyalty. In ...
Deciphering the structure of variable sensory input is key to building an accurate
model of one’s environment. Humans can accumulate evidence from sequences of stimuli
to estimate their sensory statistics, predict the timing of upcoming stimuli, but
also ...
Sustainability Science
Remotely sensed Earth science information (ESI) has become increasingly central to
addressing global challenges, yet its societal value, i.e., the difference ESI makes
in real-world decisions and outcomes, is rarely quantified. In this study, we ...
Biological Sciences
Agricultural Sciences
Proteins secreted from a mouth stylet of sedentary plant-parasitic root-knot nematodes
self-polymerize to form a unique feeding tube structure within host cells modified
into giant feeding cells by the nematode. Feeding tubes have essential functions as
...
Applied Biological Sciences
Current methodologies for detecting the sequence of double-stranded DNA (dsDNA) require
amplifying and denaturing the target into single-stranded DNA (ssDNA) to enable sequence
detection through Watson–Crick base pairing. However, these approaches are ...
Mitochondrial transfer in the HSC–HCC–macrophage network shapes hepatocellular carcinoma progression
Mitochondrial crosstalk between tumor cells and components of the tumor microenvironment
(TME) is a critical yet underexplored mechanism driving hepatocellular carcinoma (HCC)
progression. Here, we demonstrate that in HCC, mitochondria can be transferred ...
Biochemistry
Amyloid β (Aβ) accumulation is a hallmark of Alzheimer’s disease (AD). Emerging evidence
suggests that impaired microglial Aβ phagocytosis is a key feature in AD, highlighting
the therapeutic potential of enhancing this innate immune function. Here, we ...
Tyrosine nitration alters the structure, function, and cellular localization of proteins
and is implicated in the pathology of multiple diseases [G. Ferrer-Sueta et al., Chem. Rev. 118, 1338–1408 (2018), H. Ischiropoulos, Arch. Biochem. Biophys. 356, 1–11 ...
The heart can adapt its performance in response to changing metabolic demands of the
rest of the body. A central mechanism intrinsic to the heart is to modulate the function
of the cardiac contractile proteins via posttranslational modifications. Although
...
Cell fates regulated by ERK respond to different thresholds of signaling strength.
In mammalian cells, conditions that activate ERK to submaximal levels are sufficient
to sustain proliferation, survival, and transformation, while stimuli that activate
ERK ...
Rhodopsin, the most intensively studied G protein–coupled receptor (GPCR), is activated
by light-induced isomerization of its chromophore 11-cis-retinal. This study employed cryogenic electron microscopy (cryo-EM) to investigate
rhodopsin structure using ...
Polycomb Repressive Complex 2 (PRC2) facilitates the formation of facultative heterochromatin,
instrumental to tissue specific gene expression. PRC2 catalyzes trimethylation of
lysine 27 of histone H3 (H3K27me3), which is targeted for chromatin compaction ...
GABAA receptors (GABAARs) mediate fast inhibitory neurotransmission in the brain and are assembled from
19 subunit isoforms into multiple pentameric assemblies. Although α1-containing GABAARs are broadly expressed and are pharmacologically important, the ...
Biophysics and Computational Biology
Missense mutations play a critical role in human disease, contributing to both inherited
disorders and cancer. However, accurately predicting their functional impact—particularly
for cancer driver mutations—remains a major challenge due to limited ...
Cell Biology
Epithelial cell polarization is essential for many physiological processes, including
tissue morphogenesis, nutrient absorption, barrier integrity, and directional secretion.
A defining feature of such polarization is the separation of plasma membrane (PM)...
Stomata, specialized structures of plant epidermis, are crucial for gas (e.g., CO2, O2, and H2O) exchange between plants and the environment. Stomatal density and pattern are governed
by ERECTA family (ERf) receptor-like kinases-controlled signaling. ...
Herpes simplex virus type 1 (HSV-1) infection remodels the host nucleus, marginalizing
chromatin and forming viral replication compartments (VRCs). Nuclear speckles, nuclear
bodies enriched in RNA-processing factors, reposition around VRCs and undergo ...
The SEL1L–HRD1 complex is the most conserved branch of endoplasmic reticulum–associated
degradation (ERAD), yet whether SEL1L is strictly required for HRD1 function in mammals
has remained unclear. Here, we show, using complementary in vivo and in vitro ...
Developmental Biology
Juvenile hormone (JH) is essential for maintaining juvenile status and promoting reproduction
in insects, yet the transcriptional regulation of JH biosynthesis remains poorly understood.
Previous transcriptomic studies of the Drosophila ring gland—which ...
Ecology
Symbiotic nutrient exchange between arbuscular mycorrhizal (AM) fungi and their host
plants varies widely depending on their physical, chemical, and biological environment.
Yet dissecting this context dependency remains challenging because we lack methods
...
Flamboyant sexual ornaments serve as conspicuous visual signals optimized to the visual
receptors and perception of potential mates. While numerous studies have explored
the mechanisms and functions of body coloration as a sexual signal, the role of ...
Genetic diversity, the fundamental substrate for evolutionary potential, is declining
globally at unprecedented rates. Yet the mechanisms governing its distribution across
species remain poorly understood, with competing hypotheses emphasizing either ...
After widespread extirpation, conservation efforts have restored large carnivores
to portions of their former range. Substantial research has since focused on their
ability to alter ecological communities through effects on herbivores and mesocarnivores,
...
Eusocial hymenoptera recognize nestmates based on colony-specific profiles of cuticular
hydrocarbons (CHCs). While these profiles contain a variety of alkanes, the less abundant
alkenes are crucial for nestmate recognition [F. R. Dani et al., Chem. Senses ...
The removal of livestock grazers from historically grazed grasslands is widely proposed
as a key strategy for the enhancement of soil organic carbon (SOC) for climate mitigation.
Yet, accurate assessments of how grazer exclusion impacts SOC pools of ...
The search for predictors of plant diversity has challenged scientists for decades.
Here we identify intense photosynthetically active radiation (PAR) as a major factor
constraining plant species richness in global grasslands. We show that the strength
of ...
Environmental Sciences
The viral shunt is a fundamental ecosystem process which diverts the flux of organic
carbon fixed through photosynthesis during algal bloom events from heterotrophic grazers
to bacteria. Through the extracellular release of metabolites, lytic viral ...
Evolution
Agile and efficient modern flyers like birds and insects rely on complex aerodynamics
to increase performance such as leading edge vortices, tip vortices, rapid pitch rotations
as well as wing–wake and wing–wing interactions. However, their evolutionary ...
Energy is required for the expression and maintenance of complex traits. In many habitats,
however, free energy available to support biosynthesis is in vanishingly short supply.
As a result, many taxa have evolved persistence strategies that support ...
The Qinghai–Tibet Plateau (QTP) region is the greatest hotspot of social bumblebee
diversity worldwide. However, how the high diversity of bumblebees in the QTP evolved
and contributed to their diversification in adjacent and far-reaching regions remains
...
Lions and tigers, as dominant apex predators, likely became competitors when lions
expanded from Africa into Eurasia approximately one million years ago (Ma), forming
a lion–tiger transition belt from the Middle East through Central Asia to the Russian
...
Genetics
Depression is shaped by both genetic and environmental factors, but genome-wide interaction
studies (GWIS) often lack power to detect complex gene–environment (G × E) interactions.
We applied a forest-based machine learning approach to 38,018 UK Biobank (...
Why mutation rates (μ) and genome sizes (GS) vary among species remains a central question in evolutionary
genetics. Two influential models, the drift-barrier hypothesis (DBH) and the mutational-hazard
hypothesis, propose that effective population size (N...
The ATR/CHK1 pathway governs a crucial intra-S-phase checkpoint that safeguards genome
stability under replication stress by stabilizing stalled replication forks and ensuring
high-fidelity DNA replication. Traditionally, activation of this pathway is ...
Spatial transcriptomics reveals tumor microenvironment–driven subtypes of invasive lobular carcinoma
Invasive lobular carcinoma (ILC) is the second most common histological subtype of
breast cancer and displays distinct clinical and biological behavior compared to breast
cancer of no special type. However, current molecular classifications largely ...
Proper crossover (CO) formation in meiosis serves dual roles in ensuring accurate
chromosome segregation and generating genetic diversity. However, the molecular mechanisms
underlying CO number and distribution remain incompletely understood. Previous ...
Double-strand break (DSB) repair is highly mutagenic compared to normal replication.
In budding yeast, repair of an HO (homothallism) endonuclease-induced DSB at the mating-type
α locus (MATα) can be repaired by using an ectopic heterochromatic HMR::Kl-...
A daily cycle of White Collar Complex dephosphorylation sustains circadian rhythmicity in Neurospora
The transcription factor complex White Collar Complex (WCC) functions both as a photoreceptor
and as the circadian positive element. In response to light, WCC acutely activates
~5% of all genes, whereas in the dark it influences expression of about 40% of ...
Immunology and Inflammation
Myocarditis is a potentially fatal disease that can progress to inflammatory dilated
cardiomyopathy (DCMi), a condition that is a leading cause of noncongenital heart
failure in young adults. However, the mechanisms driving the transition from acute
...
We compared duodenal biopsies showing active celiac disease (CeD) to normal controls
using single-cell RNA sequencing, cyclic immunofluorescence, RNAScope, and proximity
ligation assays. There is increased infiltration of villous but not crypt epithelium
...
Medical Sciences
Delta-like ligand 3 (DLL3) is a tumor-selective cell surface protein upregulated in
high-grade neuroendocrine tumors, including small-cell lung cancer (SCLC) and neuroendocrine
prostate cancer (NEPC). Here, we report on the development of anti-DLL3 ...
Estrogen receptor (ER) positive breast cancer is the most prevalent subtype, commonly
responsive to endocrine therapies. Immune checkpoint inhibitors (ICIs) have limited
efficacy in ER-positive disease, highlighting the need for the development of ...
Microbiology
Antigenic variation in Trypanosoma brucei (T. brucei) requires monoallelic expression of one variant surface glycoprotein (VSG) from one
of the subtelomeric bloodstream form (BSF) expression sites (BESs). This transcription
is unusually mediated by RNA ...
The continuous spread of mpox disease caused by mpox virus (MPXV) has posed great
threat to global public health. The postattachment membrane fusion process of MPXV
is mediated by a multimeric protein machinery, termed as entry-fusion complex (EFC).
Among ...
Nipah virus is a highly pathogenic virus in the family Paramyxoviridae that utilizes two distinct surface glycoproteins to infect cells. The receptor-binding
protein (RBP) binds host receptors whereas the fusion protein (F) merges viral and
host ...
Neuroscience
Continual learning (CL) enables animals to learn new tasks without erasing prior knowledge.
CL in artificial neural networks (NNs) is challenging due to catastrophic forgetting,
where new learning degrades performance on older tasks. While various ...
Deciphering the structure of variable sensory input is key to building an accurate
model of one’s environment. Humans can accumulate evidence from sequences of stimuli
to estimate their sensory statistics, predict the timing of upcoming stimuli, but
also ...
Classically, the dorsal and ventral hippocampus are thought to play distinct roles
in fear conditioning, with the dorsal hippocampus primarily handling information about
environmental cues and contexts, and the ventral hippocampus more involved in ...
N-methyl-D-aspartate-type glutamate receptors (NMDARs) initiate the synaptic plasticity
underlying learning and memory. In forebrain excitatory neurons, NMDARs are heteromeric
tetramers composed of two GluN1 subunits and two glutamate ionotropic receptor ...
Precise and adaptable movements are achieved by well-regulated muscle contractions,
which are mainly governed by the excitability of motor neurons. Several neuromodulatory
systems originating in the motor cortex, brainstem, and spinal cord regulate motor
...
Animals remain awake in unfamiliar environments to assess potential safety threats,
a process involving changes in neuronal activity within sleep–wake regulatory brain
regions. However, the specific circuits and neurotransmitters involved remain poorly
...
Adolescence is a crucial period for the refinement of neural circuits and cognitive
skills. During this time, executive functions mature alongside pronounced structural
changes in the brain, including reductions in synapse density. Computational models
...
Fast-spiking parvalbumin-positive (PV) neurons provide precisely timed, context-dependent
inhibition within cortical circuits. PV neuron firing properties are specialized among
cortical neurons, suggesting that they express a unique complement of ion ...
Physiology
Essential metals accumulate in the basal ganglia at elevated levels and induce incurable
motor disease. But, unlike other motor diseases, the neuronal targets of essential
metals are unknown, and this fundamental knowledge gap has limited therapeutic ...
Plant Biology
Stomata, specialized structures of plant epidermis, are crucial for gas (e.g., CO2, O2, and H2O) exchange between plants and the environment. Stomatal density and pattern are governed
by ERECTA family (ERf) receptor-like kinases-controlled signaling. ...
The liverwort Marchantia polymorpha has emerged as a model for studying plant immunity in bryophytes, providing unique
insights into conserved defense mechanisms across land plants. By contrast, Marchantia-specific
immune mechanisms remained largely ...
Cells must continuously adjust metabolic output to maintain homeostasis under changing
environmental conditions, yet the mechanisms that enable rapid and reversible control
of pathway activity remain largely unknown. The methylerythritol phosphate (MEP) ...
Microalgae induce a CO2-concentrating mechanism (CCM) to maintain photosynthesis when CO2 is limited. Because this system consumes a substantial portion of photosynthetically
generated ATP, its suppression when CO2 levels rise is critical for energy ...
Injury-induced disruption of cellular homeostasis leads to accumulation of stress
at sites adjacent to a wound. How do these cells mitigate wound-induced stress and
restore cellular homeostasis to promote regeneration? To address this question, we
...
Psychological and Cognitive Sciences
Anxiety disorders are the most common mental disorders, resulting in substantial social
and economic costs stemming from reduced productivity. Pharmacotherapy is the most
widely used treatment for these disorders, and effective improvement requires a ...
Deficits in dopamine function cause alterations in episodic memory. Converging evidence
implicates dopamine in postencoding hippocampal mechanisms inferred to support long-term
memory, though there is a lack of direct evidence in humans. We address this ...
Systems Biology
The theoretical possibility for leukemia stem cells (LSCs) to produce both leukemia
blasts and dysfunctional immune cells remains underexplored. Here, we investigate
three major fusion transcription factor (fTF)-driven acute myeloid leukemia (AML)
...
Corrections
Cover image: Pictured is a regenerating root from an Arabidopsis thaliana leaf. Akansha Ganguly et al. detached plant leaves to study the mechanisms of stress mitigation associated with wound repair. The authors found that plant-specific PLETHORA transcription factors activate the ATG8 gene, which initiates recycling of damaged cell components to decrease intracellular stress and allow stem cells to differentiate. ATG8 is not activated if the plant is simply forming a callus, rather than regenerating roots. The results reveal how plant-specific autophagy regulators interact with intracellular stress signaling to aid in wound repair. See the article by Ganguly et al., e2513954123. Image credit: Akansha Ganguly.
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