In a well-publicized case that stoked public outrage, Providence, a nonprofit health system headquartered in the state of Washington, implemented a program in 2018 called Rev Up to increase revenue collection from patients. Following enforcement action by the state’s attorney general, Providence was ultimately forced to refund or forgive nearly $160 million worth of payments and outstanding debt, but not before throwing the management consultants behind the program squarely under the bus. “The intent of Rev Up, a program developed with the consulting firm McKinsey & Company, was not to target or pressure those in financial distress…We recognize the tone of the training materials developed by McKinsey was not consistent with our values.”
Science Journals
This JAMA Medical News story discusses multicancer early detection (MCED) tests, a handful of which are already on the US market despite a lack of evidence about their utility.
This phase 3 randomized superiority trial conducted in China assesses the adverse events and efficacy of tenecteplase prior to endovascular treatment (EVT), vs EVT alone, in patients 4.5 to 24 hours after onset of ischemic stroke due to proximal middle cerebral artery occlusion.
In patients with acute ischemic stroke undergoing endovascular thrombectomy, guidelines recommend achieving near-complete or complete reperfusion (defined as an expanded Thrombolysis in Cerebral Infarction score of 2c or 3) whenever safely achievable. Yet even after successful recanalization of the target vessel, many patients do not have excellent functional outcomes, raising the question whether macrovascular patency fully reflects the adequacy of tissue-level reperfusion.
This study uses Canadian administrative data to evaluate 1-year mortality among opioid overdose survivors in Ontario, Canada, and characterize postoverdose mortality risk after the widespread availability of fentanyl.
This Perspective discusses the merits of whole-body magnetic resonance imaging (MRI) screening in the general population.
This study examines maternal and obstetric risks of birth after uterus transplant and neonatal outcomes.
To the Editor Dr Patel and colleagues reported impressive results regarding a lay health worker–led symptom intervention that reduced emergency department use and hospitalizations among older adults with cancer. While the reported reduction in hospitalizations is remarkably higher than many previous electronic patient-reported outcome trials, the mechanism driving this magnitude of effect warrants further scrutiny before broad implementation.
In this narrative medicine essay, a psychiatrist and residency program director discusses how her lung cancer diagnosis caused her to shift her priorities regarding work and home life.
Trained immunity involves the reprogramming of innate immune cells after an initial exposure, resulting in heightened inflammatory responses to subsequent stimuli and enhanced bactericidal capacity during infection. However, this pro-inflammatory state could also exacerbate chronic conditions like inflammatory bowel disease (IBD), which is characterized by persistent inflammation and microbial imbalance. It remains unclear how trained immunity influences IBD pathogenesis and whether it can be harnessed therapeutically. In our study, pretreatment with β-glucan reprogrammed bone marrow hematopoietic progenitors and peripheral monocytes, inducing a profound shift in monocyte plasticity and significantly reducing the severity of dextran sulfate sodium (DSS)-induced colitis. Adoptive transfer of bone marrow or peripheral monocytes from β-glucan-trained mice into naive mice conferred robust protection against colitis, demonstrating that this protective effect is transferable. Trained mice also displayed improved clearance of intestinal bacterial infections. Single-cell RNA sequencing revealed an expansion of reparative Cx3cr1<sup>+</sup> macrophages derived from Ly6C<sup>hi</sup> monocytes, correlating with accelerated colonic epithelial regeneration. Collectively, these findings reveal how β-glucan-induced trained immunity modulates monocyte differentiation to ameliorate experimental colitis, highlighting the potential of harnessing trained immunity as a therapeutic strategy to recalibrate innate immune responses and restore gut homeostasis in IBD, shedding light for future clinical applications.
Cohesin is a DNA tethering complex essential for chromosome structure and function. In fission yeast, defects in the cohesin loader Mis4 result in chromosome segregation defects and dysregulated expression of genes near chromosome ends. A genetic screen for suppressors of the thermosensitive growth defect of <i>mis4-G1487D</i> identified several hypomorphic mutants of the Target of Rapamycin Complex 1 (TORC1), a conserved kinase that integrates cellular signals to regulate growth and metabolism through substrate-specific phosphorylation. Here, we demonstrate that the TORC1 pathway modulates cohesin functions in chromosome segregation and gene expression. In the context of compromised cohesin loading, the incidence of chromosome segregation defects was modulated by the growth medium in a TORC1-dependent manner. Pharmacological or genetic downregulation of TORC1 activity restored cohesin binding to its chromosomal sites and improved mitotic chromosome segregation. Notably, reduced TORC1 activity also increased cohesin binding and chromosome transmission fidelity in wild-type cells. These results suggest that environmental cues influence chromosome stability via TORC1. Biochemically, TORC1 co-purified with cohesin and reduced TORC1 activity correlated with decreased phosphorylation of specific residues on Mis4 and cohesin. Mutations in cohesin that mimic the non-phosphorylated state mirrored the effects of TORC1 downregulation, showing that TORC1 is part of the network that controls cohesin phosphorylation to modulate its functions. Finally, we show that the functional interaction between TORC1 and Mis4 extends to the regulation of stress-responsive genes. Our findings reveal a TORC1–cohesin link that may facilitate cellular adaptation to environmental changes. Given that TORC1 inhibitors and calorie restriction extend lifespan in diverse species, this connection raises the intriguing possibility that cohesin-mediated changes in chromosome structure contribute to th…
The blood–brain barrier (BBB) protects the brain from circulating metabolites and plays central roles in neurological diseases. Endothelial cells (ECs) of the BBB are enwrapped by mural cells including pericytes and vascular smooth muscle cells (vSMCs) that regulate angiogenesis, vessel stability and barrier function. To explore mural cell control of the BBB, we investigated neurovascular phenotypes in zebrafish <i>pdgfrb</i> mutants that lack brain pericytes and vSMCs. As expected, mutants showed an altered cerebrovascular network with mispatterned capillaries. Unexpectedly, mutants displayed no BBB leakage at larval stages of development. This suggests that pericytes and vSMCs are not essential for normal BBB function in developing zebrafish. Instead, we observed juvenile and adult BBB disruption occurring at ‘hotspot’ focal hemorrhages at large vessel aneurysms. ECs at leakage hotspots showed induction of caveolae on abluminal surfaces and structural defects including basement membrane thickening and disruption. Our work suggests that capillary pericytes primarily regulate cerebrovascular patterning in development and vSMCs of major arteries protect from hemorrhage and BBB breakdown in older zebrafish. The fact that young zebrafish have a functional BBB in the absence of mural cells calls for renewed interrogation of mural cell control of the BBB throughout vertebrate evolution.
Neural circuits evolved to produce variable cognitive processes through adaptive mechanisms operating within a background of developmental and functional constraints. Understanding how this conflict is resolved requires a comparative framework encapsulating clear behavioural variation. We leverage Heliconiini butterflies to examine how selection shaped the evolution of the central complex and mushroom bodies, two insect integration centres involved in navigation. The evolution of systematic spatial foraging in <i>Heliconius</i> has led to changes in brain morphology and learning and memory profiles over a short evolutionary timescale. Here, we show that in contrast to massively expanded mushroom bodies, the central complex is strongly conserved in size and general architecture. However, we identify divergences in the expression of a neuropeptide, Allatostatin A, in the noduli, and in the numbers of GABA-ergic ring neurons and their branching in the fan-shaped body, which are essential members of the anterior compass pathway. These differences are rare examples of divergence inside the central complex network matching expectations of where evolutionary adaptability might occur. We conclude that due to the contrasting volumetric conservation of the central complex, and the massive differences in the mushroom bodies, their circuit logics must determine distinct responses to selection associated with divergent foraging behaviours.
<p>by Jiasong Li, Lingwei Tang, Xinhang Wei, Yumin Chen, Haibing Xu</p>
Flexible goal‑directed navigation requires integrating changing goal information with a stable spatial map, yet how cortico-hippocampal circuits accomplish this remains unclear. We simultaneously recorded medial orbitofrontal cortex (mOFC) and dorsal CA1 (dCA1) while rats learned daily changing goal locations on a cheeseboard maze. Rats rapidly learned new goal locations and retained memory for them in the post‑probe session. Both regions contained goal‑related neuronal representations, but their profiles differed: dCA1 showed stronger spatial specificity, whereas mOFC showed more prominent learning‑related updating of goal‑related activity. Combining dCA1 and mOFC activity improved decoding of behavioral stage and learning block relative to either region alone, consistent with complementary contributions to ongoing behavior and learning state. Across learning, these population‑level differences were accompanied by stronger theta‑range synchronization and theta–gamma coupling during navigation than during goal periods. A recurrent network model with dynamic synaptic efficacy captured qualitative features of efficient acquisition and flexible goal updating, providing a candidate computational framework for how learning‑related temporal coordination could contribute to adaptive navigation.
<p>by William B. Mair, Ines Alvarez-Garcia</p>
Aging affects us all, but we still do not know how the process evolves or if we can modulate its pace. This issue of PLOS Biology presents a Collection of articles that explores different aspects of aging, discussing what challenges still need to be overcome.
Aging affects us all, but we still do not know how the process evolves or if we can modulate its pace. This Editorial presents a Collection of articles that explores different aspects of aging, discussing what challenges still need to be overcome.
<p>by Frans Nordén, Irene Zanettin, Mikael Lundqvist, Artin Arshamian, Johan N. Lundström</p>
Perceived stimulus intensity is a core feature of sensory experience, yet how it emerges in the human olfactory system remains unknown. Here, we demonstrate that oscillatory dynamics in the human olfactory bulb (OB) and piriform cortex (PC) primarily encode subjective perceived intensity rather than physical concentration. Using noninvasive electrobulbogram recordings, we show that early gamma-band activity in the OB reflects bottom-up transmission of perceived intensity to the PC, which in turn sends top-down beta-band feedback that modulates OB activity via phase–amplitude coupling and transient beta bursts. This bidirectional communication supports a dynamic updating mechanism that maintains perceptual constancy across varying environmental odor concentrations. Our findings reveal a previously uncharacterized oscillatory framework for intensity coding in the human olfactory system, highlighting the primacy of perception over stimulus properties and offering a mechanistic basis for predictive processing in early sensory circuits.
<p>by Chengchao Ding, Xinyi Ashley Liu, Fushun Zhang, Saori Uematsu, Shu-Bing Qian, Yan Xiang</p>
Schlafens proteins (SLFNs) are interferon-inducible regulators of RNA metabolism that influence antiviral defense and cell fate. Human SLFN14 is a ribosome-associated endoribonuclease whose pathogenic variants cause autosomal dominant inherited thrombocytopenia (IT), but the molecular basis of this disorder remains unclear. Here, using HEK293T cells expressing human SLFN14 variants, we show that SLFN14 represses global protein synthesis through selective cleavage of type II tRNAs. IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage. This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death. These findings reveal how altered RNA targeting by SLFN14 can drive disease and highlight selective tRNA targeting as a mechanism than regulates translation and cell fate.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection poses a major threat to public health, and understanding the mechanism of viral replication and virion release would help identify therapeutic targets and effective drugs for combating the virus. Herein, we identified E3 ubiquitin protein ligase Itchy homolog (ITCH) as a central regulator of SARS-CoV-2 at multiple steps and processes. ITCH enhances the ubiquitination of viral envelope and membrane proteins and mutual interactions of structural proteins, thereby aiding in virion assembly. ITCH-mediated ubiquitination also enhances the interaction of viral proteins to the autophagosome receptor p62, promoting their autophagosome-dependent secretion. Additionally, ITCH disrupts the trafficking of the protease furin and the maturation of cathepsin L, thereby suppressing their activities in cleaving and destabilizing the viral spike protein. Furthermore, ITCH exhibits robust activation during the SARS-CoV-2 replication stage, and SARS-CoV-2 replication is significantly decreased by genetic or pharmacological inhibition of ITCH. These findings provide new insights into the mechanisms of the SARS-CoV-2 life cycle and identify a potential target for developing treatments for the virus-related diseases.
Alternative splicing (AS) of pre-mRNA plays a crucial role in tissue-specific gene regulation, with disease implications due to splicing defects. Predicting and manipulating AS can therefore uncover new regulatory mechanisms and aid in therapeutic design. We introduce TrASPr+BOS, a generative AI model with Bayesian Optimization for predicting and designing RNA for tissue-specific splicing outcomes. Transformer for Alternative Splicing Prediction (TrASPr) is a multi-transformer model that can handle different types of AS events and generalize to unseen cellular conditions. It then serves as an oracle, generating labeled data to train a Bayesian Optimization for Splicing (BOS) algorithm to design RNA for condition-specific splicing outcomes. We show TrASPr+BOS outperforms existing methods, enhancing tissue-specific AUPRC by up to 1.8-fold and capturing tissue-specific regulatory elements. We validate hundreds of predicted novel tissue-specific splicing variations and confirm new regulatory elements using dCas13. We envision TrASPr+BOS as a light yet accurate method researchers can probe or adopt for specific tasks.
The ability of newborns to distinguish between different voices helps them to establish verbal memories from a very early age.
RAB5-GTP activation of the multiprotein VPS34 complex II (VPS34-CII) is critical for endosomal sorting and maturation, phagocytosis, and receptor downregulation. RAB5-GTP activates VPS34-CII by binding to a helical insertion in the C2 domain of VPS34 on the BECLIN1/UVRAG-containing adaptor arm of the complex. The autophagy complex, VPS34 complex I (VPS34-CI), features a unique ATG14L subunit in place of the VPS34-CII UVRAG subunit, and we found that this distorts the adaptor arm to alter the VPS34 RAB-GTPase binding pocket so that it preferentially binds RAB1-GTP. Surprisingly, our higher-resolution single-particle cryo-EM structure of VPS34-CII showed a second RAB5-GTP binding site on the VPS15 solenoid region. This site (VPS15-RAB5-site) appears to be the primordial RAB5-binding region. A mutant in the helical insertion of the C2 domain of human VPS34 that mimics the <i>Saccharomyces cerevisiae</i> sequence abolishes RAB5 binding to VPS34. Mutation of the VPS15-RAB5-site ortholog in <i>S. cerevisiae</i> VPS15 resulted in defective CPY sorting, loss of colocalisation with the RAB5 ortholog Vps21, and loss of binding to Vps21 in vitro. Evolutionary expansion from one to two RAB5-orthologue binding sites may have increased membrane binding and VPS34-CII activity to adapt to more complex endocytic systems.
Multiplexed assays of variant effects (MAVEs) make it possible to measure the functional impact of all possible single amino acid residue substitutions in a protein in a single experiment. Combination of variant effect data from several such experiments provides the opportunity to conduct large-scale analyses of variant effect scores measured across proteins, but can be complicated by variations in the phenotypes that are probed across experiments. Thus, using variant effect datasets obtained with similar MAVE techniques can help reveal general rules governing the effects of amino acid variation for a single molecular phenotype. In this work, we accordingly combined data from six individual variant abundance by massively parallel sequencing (VAMP-seq) experiments and analysed a total of 31,614 variant effect scores reporting solely on the impact of single amino acid residue substitutions on the cellular abundance of proteins. Using our combined variant effect dataset, we derived and analysed a collection of amino acid substitution matrices describing the average impact on cellular abundance of all residue substitution types in different structural environments. We found that the substitution matrices predict the cellular abundance of protein variants with surprisingly high accuracy when given structural information only in the form of whether a residue is buried or exposed. We thus propose our substitution matrix-based predictions as strong baselines for future abundance model development.
Coleoid cephalopods, a subclass of mollusks that includes octopuses, cuttlefish, and squid, exhibit sophisticated biological features, such as dynamic and neurally driven camouflage behavior, inter-individual communication, single-lens camera-like eyes, the largest brains among invertebrates, and a distinctive embryonic development. The common cuttlefish <i>Sepia officinalis</i> has served as a model organism in various research fields, spanning biophysics, neurobiology, behavior, evolution, ecology, and biomechanics. More recently, it has become a model to investigate the neural mechanisms underlying cephalopod camouflage, using quantitative behavioral approaches alongside molecular techniques to characterize the identity, evolution, and development of neuronal cell types. Despite significant interest in this animal, a high-quality, annotated genome of this species is still lacking. To address this, we sequenced and assembled a chromosome-scale genome for <i>S. officinalis</i>. Our assembly spans 5.68 billion base pairs and comprises 1n=47 repeat-rich chromosome scaffolds. This was unexpected because the haploid karyotypes of other decapods indicate 46 chromosomes. Detailed comparisons of our data to those from published decapod genome assemblies and to another recent genome assembly of <i>S. officinalis</i> (itself suggesting 1n=49 chromosomes) in fact revealed clear homologies between 46 scaffolds across all the datasets. In-depth comparison of datasets reveals highly repetitive regions at discordant scaffold boundaries and suggests that the true karyotype of <i>S. officinalis</i> is probably 1n=46 chromosomes, a likely ancestral and if true, conserved decapod karyotype. Our results include a comprehensive gene annotation and full-length transcript prediction, which we used to characterize orthologous gene families across mollusks. We identified several large-scale expansions specific to cephalopods, with many genes specific to neural or non-neural tissues of …