The claustrum, with its extensive reciprocal connections to nearly all cortical regions, has long been hypothesized as a key hub for integrating diverse cognitive, sensory and motor information. However, despite its anatomical connectivity, whether and how it functionally integrates different inputs to generate coherent representations has remained unclear. Here, we developed a recurrent neural network (RNN) trained via supervised learning on behavioral metrics of delayed escape—a behavioral paradigm that requires integration of temporally separated task-relevant signals. A subset of RNN neurons exhibited dynamics similar to those of anterior claustral neurons during this behavior. These neurons formed a recurrent cluster, a structure supported by in vitro stimulation experiments in claustral brain slices. We analyzed the computational properties of this claustrum-like cluster via dimensionality reduction of population activity. The network showed nonlinear integration of temporally distributed inputs and increased synergistic information. Rather than settling into attractors, integrated information was dynamically encoded along continuously evolving neural trajectories. Notably, similar trajectory patterns associated with dynamic integration were observed in claustral recordings, suggesting the model’s biological plausibility. We propose that the anterior claustrum dynamically integrates task-relevant input signals over time and broadcasts the evolving representation to downstream brain regions capable of reading and interpreting it in a context-dependent manner.
Science Journals
Natural killer (NK) cells contribute to early immunity against <i>Plasmodium falciparum</i> by recognizing and eliminating infected red blood cells (iRBCs), a process mediated in part by the integrin LFA-1. However, the cognate parasite ligand for LFA-1 has remained unknown. Here, we identify glycophorin binding protein-130 (<i>Pf</i>GBP-130) as a surface-expressed ligand on iRBCs that binds the I-domain of LFA-1 (LFA-1 αI). Using an LFA-1 αI-Fc fusion protein, we demonstrate stage-specific binding to iRBCs, and LC-MS/MS analysis of immunoprecipitates of αI-Fc bound to iRBC revealed <i>Pf</i>GBP-130 as a high-confidence interactor. Recombinant <i>Pf</i>GBP-130 binds NK and THP-1 cells in an LFA-1-dependent manner. Co-culture assays show that <i>Pf</i>GBP-130 promotes NK cell activation and degranulation and facilitates contact-dependent killing of iRBCs. Neutralizing antibodies against <i>Pf</i>GBP-130 significantly impair these responses. Our findings establish <i>Pf</i>GBP-130 as the LFA-1 ligand on iRBCs, providing new insight into NK cell-mediated immunity in malaria and identifying a potential target for host-directed interventions.
<p>by Jennifer L. Garrison</p>
Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective makes the case that ovarian aging is a primary determinant of healthspan and belongs at the center of geroscience.
Classifying ovaries solely as reproductive organs has obscured their role as systemic regulators of female physiology. This Perspective discusses that ovarian aging is a primary determinant of healthspan and belongs at the center of geroscience.
Calcium-sensitive fluorescent indicators enable monitoring of spiking activity in large neuronal populations in animal models. Despite the plethora of algorithms developed over the past decades, accurate spike-time inference methods for spike rates exceeding 20 Hz are lacking. More importantly, little attention has been devoted to the quantification of statistical uncertainties in spike time estimation, which is essential for assigning confidence levels to inferred spike patterns. To address these challenges, we introduce (1) a statistical model that accounts for bursting neuronal activity and baseline fluorescence modulation and (2) apply a Monte Carlo strategy (particle Gibbs with ancestor sampling) to estimate the joint posterior distribution of spike times and model parameters. Our method is competitive with state-of-the-art supervised and unsupervised algorithms, as evaluated on the CASCADE benchmark datasets. Analysis of fluorescence transients recorded with the ultrafast genetically encoded calcium indicator GCaMP8f demonstrates that our method can resolve interspike intervals as short as 5 ms. Overall, our study describes a Bayesian inference method for detecting neuronal spiking patterns and quantifying their uncertainty. The use of particle Gibbs samplers enables unbiased estimates of spike times and all model parameters, providing a flexible statistical framework for testing more specific models of calcium indicators.
Hsp70s are essential molecular chaperones that are increasingly recognized to be regulated by post-translational modifications. Here, we show that phosphorylation of a conserved threonine (T495), previously shown to be exploited by a <i>Legionella pneumophila</i> kinase to inhibit Hsp70, occurs endogenously in human cells in response to DNA damage, particularly when base excision repair is overburdened. This modification is cell cycle dependent, and in yeast, phosphomimetic or phosphonull Hsp70 variants disrupt G1/S progression under normal and DNA-damaging conditions. Biochemically, the phosphomimetic T495E mutation locks Hsp70 in an open-like conformation without blocking substrate engagement. Together, our results reveal a conserved mechanism by which dynamic Hsp70 phosphorylation regulates the G1/S transition and delays cell cycle progression during DNA damage, highlighting how pathogen-derived insights can uncover fundamental cell biology principles.
<p>by The PLOS Biology Staff </p>
<p>by Sara Alam, Linda Partridge, Nazif Alic</p>
Globally, the growing proportion of older individuals is imposing personal and societal costs. However, interventions that slow aging are possible; for example, dampened nutrient signaling pathway activity in animal models promotes better health later in life. Recent findings indicate that such interventions have long-term effects even when applied transiently in early adulthood, forming a “physiological memory.” Similar memory has been extensively documented in human epidemiology, where the health of older people is shaped by their earlier environmental exposures, such as diet composition. This Essay argues that the study of the biology of aging should encompass determinants of healthspan across the entire life course.
<p>by Priscila Chiavellini, Vittorio Sebastiano</p>
Aging is typically framed as a one-way, irreversible accumulation of molecular damage in cells and tissues, leading to progressive functional decline. Yet mammalian reproduction, and particularly female reproduction, reveals a striking exception to this rule. Despite residing within an aging organism and within a fast-aging ovarian tissue environment, oocytes give rise to embryos that begin life with restored developmental potential and youthful molecular organization. By reframing ovarian biology as a model for rejuvenation rather than solely as a site of reproductive decline, this Essay proposes that the ovary offers a powerful blueprint for advancing the biology of aging and longevity.
<p>by The PLOS Biology Editors </p>
Visual motion information is essential to guiding the movements of many animals. The establishment of direction-selective signals, a hallmark of motion detection, is considered a core neural computation and has been characterized extensively in primates, mice, and fruit flies. In flies, the circuits that produce direction-selective signals rely on feedforward visual pathways that connect peripheral visual inputs to the dendrites of the ON and OFF-direction-selective cells. Here, we describe a novel role for feedback inhibition in motion computation. Two GABAergic neurons, C2 and C3, connect to neurons upstream of the direction-selective T4 and T5 cells, and blocking C2 and C3 affects direction selectivity in T4/T5. In the ON pathway, this is likely achieved by C2-mediated suppression of responses in the major T4 input neuron Mi1. Together, C2 and C3 suppress responses to non-preferred stimuli in both T4 and T5. At the behavioral level, feedback inhibition temporally sharpens responses to ON-moving stimuli, enhancing the fly’s ability to discriminate visual stimuli that occur in quick succession. GABAergic inhibitory feedback neurons thus constitute an essential component within the circuitry that computes visual motion.
Metabolic dysfunction-associated steatotic liver disease (MASLD) progression is characterized by hepatic inflammation and cell death, yet the mechanisms underlying Kupffer cell (KC) loss remain poorly understood. Here, we sought to elucidate the metabolic basis of KC death during MASLD. Using metabolomics, immunostaining, and flow cytometry, we evaluated metabolic alterations and KC death throughout early MASLD progression. We found that KC death is an early hallmark of MASLD, exhibiting greater susceptibility and a spatial distribution consistent with KC zonation. Moreoever, KCs undergo progressive metabolic reprogramming toward enhanced glucose utilization during MASLD development, which is correlated with KC death. In combination with biochemical agonist, isotope tracing, and primary KC culture, we further demonstrated that augmented glycolytic metabolism directly drives KC death in vitro. Consistently, using <i>Chi3l1</i>-deficient mice, we further demonstrated that increased glucose utilization accelerates KC death in vivo. Together, these findings establish a causal link between glycolytic activation and KC loss during MASLD progression, highlighting glucose metabolic pathways as potential therapeutic targets to preserve KC homeostasis and mitigate MASLD.
Cognitive abilities are central to how animals navigate complex environments. Beyond individual cognition, group living can also enhance navigation by pooling individually acquired information. One way this may be achieved is by following experienced leaders, which requires recognizing expertise within group members. Alternatively, accurate decisions could also emerge without expert opinions, through simpler mechanisms like the ‘wisdom of crowds’ principle that average out individual biases. Consequently, collective navigation strategies range from cognitively complex to simple, and yet, the prevalence or interplay of different collective strategies in nature remains unexplored. In this study, we asked: what is the navigation mechanism, requiring minimal cognitive demands, that is necessary and sufficient to quantitatively replicate the experimental results of a 2017 study on homing pigeons (<i>Columba livia</i>), which showed that sequential chains of bird pairs flying home—similar to a game of telephone—led to shorter homing routes compared to control birds flying individually or in fixed pairs. Our results show that the experimental data aligns closely with the simplest strategy—route averaging. Surprisingly, the complex mechanism of selectively propagating the best flight through social learning offered no additional advantage. We further observed that mixed strategies, although not supported by the experimental data, in theory combined advantages from both averaging and active selection of better routes, resulting in even greater performance. Hence, our results highlight the potential for future research to investigate selective pressures shaping the evolution of cultural learning and trade-offs among different decision mechanisms theoretically available to social animals in nature.
Homologous recombination repair (HRR) deficiency is associated with improved immunotherapy responses in non-small cell lung cancer (NSCLC) patients. The HRR genes <i>BRCA1</i>/<i>2</i> are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Using single-cell sequencing and multi-omics data, we characterized <i>BRCA1/2</i> mutation-associated transcriptional programs, immune cell composition, and functional alterations in T cells, investigating the molecular and immune architecture of BRCA-mutant LUAD patients. <i>BRCA1</i>/<i>2</i> mutations were associated with increased genomic instability and poor prognosis in LUAD patients, but predicted better clinical outcomes following immune checkpoint blockade (ICB) treatment. <i>BRCA1</i> mutations correlated with an upregulated type I IFN/IFN-γ signature and CD8<sup>+</sup> T cell activation. <i>BRCA2</i> mutations were associated with alveolar/stress/inflammatory responses and enhanced MHC-II antigen presentation, linked to CD4<sup>+</sup> T cell differentiation. Both alterations coincided with reduced CD28 co-stimulation and CTL activity, hinting at immune evasion. We identified two tissue-resident memory T cell (Trm) subsets as predictors of clinical outcomes and ICB response. <i>BRCA1</i> mutations were associated with CD8<sup>+</sup> Trm expansion, whereas <i>BRCA2</i> mutations were linked to tumor CD4<sup>+</sup> Trm expansion and peripheral T/NK cell cytotoxicity. Furthermore, a cancer-promoting program activated by <i>BRCA1</i> mutation was vulnerable to histone deacetylase inhibitors, which inhibited LUAD tumor growth. This study provides a preliminary characterization of the BRCA-mutant TME in LUAD patients, revealing distinct transcriptional and immune patterns that highlight differences in <i>BRCA1/2</i>-associated molecular architecture and offer a framework for improving therapy efficacy in LUAD.
This randomized clinical trial evaluates whether embolization of the middle meningeal artery as an adjunct to surgical drainage reduces recurrence and poor outcomes in patients with symptomatic chronic subdural hematoma compared with surgical drainage alone.
To the Editor Age-adjusted thresholds are used to improve the diagnostic yield of D-dimer testing in suspected pulmonary embolism, but prospective management data in suspected deep vein thrombosis (DVT) have been limited. In a recent study reported by Dr Le Gal and colleagues, the primary outcome focused on patients with D-dimer values between the conventional cutoff and their age-adjusted cutoff. Use of the age-adjusted cutoff increased the proportion of negative D-dimer results from 24.5% to 31.9% by identifying 161 additional patients with D-dimer values between 500 µg/L and their age-adjusted threshold.
To the Editor In the Spinal Manipulation and Patient Self-Management for Preventing Acute to Chronic Back Pain (PACBACK) randomized clinical trial, Dr Bronfort and colleagues reported that clinician-supported biopsychosocial self-management, alone or combined with spinal manipulation, led to statistically significant but small reductions in low back pain–related disability over 12 months vs guideline-based medical care, without differences in pain intensity. The time-averaged, adjusted between-group differences in the Roland-Morris Disability Questionnaire (RMDQ; range, 0-24) scores were −1.2 points for supported self-management and −1.1 points for supported self-management with spinal manipulation. A 2- to 3-point change on the RMDQ has been proposed as a minimally important difference, although such thresholds can vary by population and estimation approach. Even when a modest mean difference coexists with large improvements for some individuals, it remains uncertain whether the observed disability signal reflects gains in physical capacity, improved coping with symptoms, or changes in appraisal of activity limitation.
And what if the whole thing works—the small white pill dissolving in the acid of his stomach, finding the blood, crossing into the brain where the receptor opens, the synapse strengthens, and what happened is not all he is— what if tonight he sleeps without the dream and tomorrow he sits across from his daughter, his hands flat on the table, just hands, and the plate he passes her is only a plate, not a thing that could become a thing, and she learns this in her body the way we learn without language, without knowing we’re learning, until one day she’s a woman who doesn’t flinch when a man walks into a room—just a man, just a room, just a house—I hand him the cup and he looks at me and I think: what if this is the beginning of something I’ll never see the end of, what if it’s already traveling out of my hands toward a future where a girl I’ll never meet lives without the alphabet of danger, and I move to the next window, the next cup, the next invisible repair, not knowing what I’ve done, if I’ve done anything at all.
Perhaps surprising in the emerging world of personalized, precision medicine, the physiologic targets of many pharmacologic agents, especially psychiatric medicines, remain poorly understood, even as they continue to be widely prescribed. Similarly, exactly how poetry and other art forms have their profound effects on us also remains mysterious, even as research into possible underlying neural pathway activation proceeds (albeit less intensively). In the poem “Mechanism of Action,” the clinician’s faith in treatments prescribed without fully knowing how they work is intriguingly compared with how we may also just as hopefully rely on art for its therapeutic effects. The speaker of the poem wonders at the possible potency of a drug, “the small white pill” he administers to a patient, and whether it might not only modulate minute neural structures, as “the receptor opens” and “the synapse strengthens,” but also change the course of entire lives. Just as the medicine crosses the blood-brain barrier, so then poetry crosses into the realm of dreams and imagination, perhaps influencing the same neural circuitry and reshaping our thinking “the way we learn without language,/without knowing we’re learning,/until one day she’s a woman who doesn’t flinch/when a man walks into a room.” The medication, and the speaker’s belief in its healing effects, diffuses through the pharmacology of poetry into us as readers, as we too feel intoxicated by the twin power and uncertainty of “the next invisible repair, not knowing/what I’ve done, if I’ve done anything at all.”
To the Editor The recently published PACBACK trial reported no significant differences in low back pain scores between groups randomized to undergo spinal manipulations, medical management, and self-management. This study included exclusively chiropractic and physical therapist–administered spinal manipulations and did not evaluate manipulative treatments performed by US-trained osteopathic physicians. Although it is valuable to examine different modalities of treatment for such a common and debilitating condition, the exclusion of osteopathic physician–performed manipulations raises concerns about this study’s conclusion that manipulations do not affect back pain scores.
This descriptive analysis study examines trends in manufacturer-sponsored coupon use, coupon amounts, and patient out-of-pocket spending among patients with commercial insurance.
This randomized clinical trial examines the effectiveness of a whole health team intervention in veterans with chronic pain compared with cognitive behavioral therapy and usual care in reducing long-term pain interference.
To the Editor The PACBACK randomized clinical trial by Dr Bronfort and colleagues evaluated spinal manipulation combined with clinician-supported biopsychosocial self-management for acute low back pain. Although the study addresses an important clinical question, we have some concerns.
The US Centers for Disease Control and Prevention (CDC) reported that most health care workers were vaccinated against influenza whereas less than half were vaccinated against COVID-19 during the 2024-2025 respiratory virus season.
Diverticulitis, a digestive condition characterized by inflammation within the large intestine, may peak in warmer months, according to research published in JAMA Surgery.
In this narrative medicine essay, as a pediatric critical care physician prepares to move to a new hospital building, he reflects on the memories that the old building held, including the death of his infant grandson.