The 9-valent human papillomavirus (HPV) vaccine was associated with a lower risk of HPV-related cancers in adolescents and younger males, research published in JAMA Oncology found.
Science Journals
The objective of this study was to assess whether embolization of the middle meningeal artery (EMMA) after surgical drainage reduces the recurrence of chronic subdural hematoma compared with surgery alone.
This Viewpoint argues that artificial intelligence can be used to unburden physicians from administrative work that pulls them away from patient care.
Listen to the JAMA Editor’s Summary for an overview and discussion of the important articles appearing in JAMA.
In Reply We thank the Letter authors for raising several practical considerations relevant to interpretation and implementation of our study.
This Viewpoint discusses how programs from the COVID-19 pandemic, including Acute Hospital Care at Home, have created the infrastructure to widely deliver hospital at home care, which could transform US health care delivery in the future.
<p>by Susmit Mhatre, Darcie L. Moore</p>
The field of human adult neurogenesis has been controversial despite mounting evidence. The authors propose moving beyond debating the existence of adult neurogenesis and towards discovering strategies to harness endogenous stem cell potential for resilience against cognitive aging.
The field of human adult neurogenesis has been controversial despite mounting evidence. This Perspective proposes moving beyond debating the existence of adult neurogenesis, and towards discovering strategies to harness endogenous stem cell potential for resilience against cognitive aging.
Motion vision underpins a wide range of adaptive behaviours essential for individual and species survival. In hoverflies, some visual behaviours are sexually dimorphic, including for example male high-speed pursuit of conspecifics matched by improved optics and faster photoreceptors. Other visual behaviours are sexually monomorphic, with for example similar foraging flight speeds in male and female hoverflies. However, whether the descending neurons responsible for sensorimotor transformation of optic flow are sexually dimorphic is unknown. To address this, we combined morphological analysis with electrophysiology of optic flow sensitive descending neurons and compared neural responses to the behavioural output in tethered hoverflies. We found that while optomotor flight behaviour is largely sexually monomorphic, the underlying neural responses are sexually dimorphic, especially at higher optic flow velocities. Additionally, behavioural responses were noticeably slower than neural responses. Together, our findings uncover a nuanced, sex- and stimulus-dependent sensorimotor transformation, shaped by both neural architecture and behavioural demands.
We have a remarkable ability to seamlessly and rapidly coordinate actions with others, from double Dutch to dancing. Humans use high-level partner representations to jointly control voluntary actions, while other work shows lower-level involuntary feedback responses to sudden visual perturbations. Yet, it is unknown if a high-level partner representation can be rapidly expressed through lower-level involuntary sensorimotor circuitry. Here, we test the idea that a partner representation influences involuntary visuomotor feedback responses during a cooperative sensorimotor task. Using two experiments and dynamic game theory predictions, we show that involuntary visuomotor feedback responses reflect a partner representation and consideration of a partner’s movement cost (i.e., accuracy and energy). Collectively, our results suggest there is top-down modulation from high-level partner representations to lower-level sensorimotor circuits, enabling fast and flexible feedback responses during jointly coordinated actions.
Small extracellular vesicles (sEVs) are heterogeneous biological vesicles released by cells under both physiological and pathological conditions. Due to their potential as valuable diagnostic and prognostic biomarkers in human blood, there is a pressing need to develop effective methods for isolating high-purity sEVs from the complex milieu of blood plasma, which contains abundant plasma proteins and lipoproteins. Size exclusion chromatography (SEC) and density gradient ultracentrifugation (DGUC) are two commonly employed isolation techniques that have shown promise in addressing this challenge. In this study, we aimed to determine the optimal combination and sequence of SEC and DGUC for isolating sEVs from small plasma volumes, in order to enhance both the efficiency and purity of the resulting isolates. To achieve this, we compared sEV isolation using two combinations: SEC-DGUC and DGUC-SEC, from unit volumes of 500 μL plasma. Both protocols successfully isolated high-purity sEVs; however, the SEC-DGUC combination yielded higher sEV protein and RNA content. We further characterized the isolated sEVs obtained from the SEC-DGUC protocol using flow cytometry and mass spectrometry to assess their quality and purity. In conclusion, the optimized SEC-DGUC protocol is efficient, highly reproducible, and well suited for isolating high-purity sEVs from small blood volumes.
Accurate projections of temperate tree growing seasons under climate change require representing developmental constraints that determine tree resource allocation. A phenological ‘switch point’ after the summer solstice (21 June) has been proposed, with pre-solstice warming advancing autumn phenology and post-solstice warming delaying it. We propose that this switch is flexible and occurs at the compensatory point between early-season development and late-season temperature effects. We performed trans-solstice climate manipulation experiments on potted European beech (<i>Fagus sylvatica</i>) saplings to test (i) how spring leaf-out timing and June-August temperatures influence end-of-season timing (bud set and leaf senescence) and (ii) whether daytime and nighttime temperatures before and after the solstice have distinct effects. Bud set and senescence were tightly coupled (<i>R<sup>2</sup></i>=0.49), with stronger bud responses. Each day of delayed leaf-out postponed bud set by 0.24±0.06 days and senescence by 0.22±0.08 days. July full-day cooling delayed autumn phenology in late-leafing individuals (bud set +4.9±2.6 days; senescence +3.1± 2.8 days) but had a negligible impact on early-leafing trees. August full-day cooling advanced both stages. Pre-solstice daytime cooling had no effect, while post-soltice daytime cooling advanced autumn phenology. Nighttime cooling consistently delayed bud set. These findings support the Solstice-as-Phenology-Switch model and highlight the central role of developmental progression in constraining growing seasons. Faster early-season development – especially under nighttime warming – moves trees past the switch earlier, increasing sensitivity to late-season cooling and thereby triggering earlier autumn phenology. Phenology models should incorporate these developmentally-mediated and diel-specific temperature responses.
Whole-mount 3D imaging at the cellular scale is a powerful tool for exploring complex processes during morphogenesis. In organoids, it allows examining tissue architecture, cell types, and morphology simultaneously in 3D models. However, cell packing in multilayered organoid tissues hinders both deep imaging and quantification of cell-scale processes. To address these challenges, we developed an experimental and computational pipeline to extract properties at scales ranging from cell to tissue. The experimental module is based on two-photon imaging of immunostained organoids. The computational module corrects for optical artifacts, performs accurate 3D nuclei segmentation and reliably quantifies gene expression. We provide the computational module as a user-friendly Python package called Tapenade, along with napari plugins which enable joint data processing and exploration across scales. We demonstrate the pipeline by quantifying 3D spatial patterns of gene expression and nuclear morphology in gastruloids, revealing how local cell deformations and gene co-expression relate to tissue-scale organization. This quantitative pipeline improves our understanding of gastruloid development, and lays the groundwork for a wide range of multi-layered organoids and tumoroids systems
The establishment of tissue axes is fundamental during embryonic development. In the <i>Drosophila</i> wing, the anterior/posterior (AP) and the dorsal/ventral (DV) compartment boundaries provide the basic coordinates around which the tissue develops. These boundaries arise as a result of two lineage decisions, the acquisition of posterior fate by the selector gene <i>engrailed</i> (<i>en</i>) and dorsal fate by the selector gene <i>apterous</i> (<i>ap</i>). While the <i>en</i> expression domain is set up during embryogenesis, <i>ap</i> expression begins only during early wing development. Thus, the correct establishment of the <i>ap</i> expression pattern relative to <i>en</i> must be tightly controlled. Here, we functionally investigate the transcriptional inputs integrated by the early <i>ap</i> enhancer (apE) and their requirement for correct boundary formation. Detailed mutational analyses using CRISPR/Cas revealed a role for apE in positioning the DV boundary relative to the AP boundary, with apE mutants often displaying mirror-image anterior wing duplications. We then designed and applied methods to accomplish tissue-specific enhancer disruption via dCas9 expression. This approach allowed us to dissect the spatiotemporal requirement for apE function, clarifying the mechanism by which apE misregulation leads to AP defects. Base-pair-resolution analyses of apE uncovered a single HOX-binding site essential for wing development that, when mutated, led to wingless flies. We demonstrated that the transcription factors Pointed (Pnt), Homothorax (Hth), and Grain (Grn) are required for apE function, and the HOX gene Antennapedia (Antp) contributes to early wing development. Together, our results provide a comprehensive molecular basis of early <i>ap</i> activation and the developmental consequences of its misregulation, shedding light on how compartmental boundaries are set up during development.
<p>by Paul Knabl, June F. Ordoñez, Juan Daniel Montenegro Cabrera, Daniel Abed-Navandi, Roland Halbauer, Oliver Link, Tim Wollesen, Grigory Genikhovich</p>
In Bilateria with centralized nervous systems (e.g., in vertebrates or arthropods), the minimum of the BMP signaling activity gradient defines the position of the central nervous system. BMP-dependent patterning of the secondary body axis is ancestral for Bilateria and possibly also for the bilaterian sister clade Cnidaria. However, the variety of levels of centralization of the nervous systems in Bilateria—from diffuse to fully centralized—as well as the lack of centralization of the nervous system in Cnidaria, suggest that BMP signaling cannot be perceived as a universally “anti-neural” signal. Here we use transgenic reporter lines in the anthozoan cnidarian <i>Nematostella</i> to show that BMP signaling is active in distinct neuronal populations. Moreover, attenuation of BMP signaling followed by RNA-Seq shows that BMP signaling is a positive regulator of many neuronal genes, including the top-tier neural progenitor marker <i>soxB(2)</i>. Furthermore, we analyze BMP signaling activity in the cubozoan jellyfish <i>Tripedalia</i> and the scyphozoan jellyfish <i>Stomolophus</i> and prove that BMP signaling in parts of the diffuse nervous system is not an anthozoan but an ancestral cnidarian feature, shared by anthozoans and medusozoans. Finally, we show that the highly centralized ventral nervous system of the nonmodel spiralian, the chaetognath <i>Spadella</i>, forms out of paired BMP signaling-positive domains on the lateral sides of the embryo. Together, our data suggest that one of the ancestral roles of BMP signaling may have been in promoting neurogenesis. We propose that the “anti-neural” function of BMP signaling in vertebrates and arthropods is a consequence of its global role in the dorsoventral patterning of the ectoderm.
<p>by Garrison W. Bullard, Lauren B. Buckley, Joel G. Kingsolver</p>
Predicting survival of ectotherms in stressful and variable thermal environments is an essential challenge in this era of heat waves and climate change. Recent thermal death time (TDT) models, based on an exponential relationship between average time to death (or failure) <i>t</i><sub>f</sub> and temperature, enable accounting for average survival responses to both the magnitude and duration of stressful temperatures. However, extending these deterministic and probabilistic models to predict patterns of survival in fluctuating temperatures currently requires additional assumptions: e.g., that injury accumulation due to heat stress is additive across temperatures, and that the shape of the cumulative survival curve does not change with temperature. We evaluate these assumptions and their consequences by using a parametric survival model and available data on failure (knockdown) times of adult <i>Drosophila.</i> We find that the variance in log(<i>t</i><sub>f</sub>) increases with increasing constant temperatures in most <i>Drosophila</i> species, resulting in changes in the shape of the failure density and survival curves across temperatures. We compare predictions of three deterministic and probabilistic models that differ in their TDT assumptions using <i>D. melanogaster</i> data in fluctuating (but stressful) temperatures. All three models consistently underestimate observed median failure times except at extremely high temperatures, suggesting non-additivity of heat injury accumulation. Our parametric model, incorporating temperature-dependent variance, provides more accurate predictions of cumulative survival curves in fluctuating temperatures. Our findings highlight the importance of understanding both mean and variation in failure times, and how these change across temperatures, for modeling survival in fluctuating thermal environments.
<p>by Yan Xu, Wenbo Zeng, Guodian Xiong, Zhenhua Zheng, Jingwen Wang</p>
Ticks transmit numerous viruses that pose significant threats to human and animal health, however, the molecular interactions between ticks and viruses remain poorly understood. Using Langat virus (LGTV)—a surrogate for tick-borne encephalitis virus (TBEV), we show that the JAK/STAT pathway promotes viral infection in <i>Haemaphysalis longicornis</i>. Rather than directly interacting with viral proteins, this proviral effect is mediated by a low-density lipoprotein receptor-related protein (LRP), whose expression is regulated by STAT. Silencing <i>LRP</i> in <i>H. longicornis</i> reduced LGTV infection, while ectopic expression of <i>LRP</i> enhanced it. Unlike its mammalian counterparts, <i>H. longicornis</i> LRP lacks a transmembrane domain and localizes intracellularly. Functionally, LRP promotes lipophagy, leading to lipid droplets breakdown and providing energy to support viral replication. Together, these findings reveal a non-canonical mechanism by which the JAK/STAT pathway facilitates LGTV replication through STAT-dependent regulation of an atypical, intracellular LRP that drives lipophagy.
Naive B cells exit quiescence and enter a proliferative state upon activation, ultimately differentiating into antibody-secreting or memory B cells. Toll-like receptor (TLR) ligands, such as lipopolysaccharide (LPS), can serve as physiological stimuli to initiate this transition. Using quantitative proteomics, we show that TLR4 engagement induces metabolic reprogramming in murine B cells, increasing the expression of amino acid transporters and cholesterol biosynthetic enzymes. The amino acid transporter SLC7A5 is markedly upregulated following LPS stimulation, and conditional deletion of <i>Slc7a5</i> impairs B cell proliferation, underscoring its essential role in B cell activation. LPS also elevates intracellular cholesterol levels, and inhibition of the rate-limiting enzyme HMG-CoA reductase blocks proliferation. This effect was mediated by a dual requirement for cholesterol metabolism and protein prenylation downstream of HMG-CoA reductase. Notably, this was not unique to TLR4 signalling but is also observed in B cells activated via TLR7, TLR9, CD40, or the B cell receptor. Together, these findings reveal that metabolic rewiring, including amino acid uptake and cholesterol metabolism, is an essential feature of B cell activation and proliferation.
A form of short-term memory called serial dependence can predict how effectively perceptual learning transfers to novel visual locations.
The medial nucleus accumbens shell (medNAcSh) is a key regulator of hedonic feeding, controlling reward consumption through its projections to downstream structures. Recent studies showed that the primary cellular mediators of these effects are dopamine 1 receptor-positive striatal projection neurons (D1-SPNs). Specifically, D1-SPN activity gets inhibited during reward consumption, and such inhibition is necessary and sufficient to authorize consumption, independent of metabolic need. Anatomically, the medNAcSh spans 1–1.5 mm along the rostro-caudal axis in mice, and previous studies have reported functional gradients along this axis. For instance, pharmacological studies have suggested that rostral rather than caudal medNAcSh regulates appetitive behavior. However, the mechanisms underlying this topographical gradient remain unknown. Here, we hypothesized that D1-SPNs contribute to this gradient by regulating hedonic feeding via a specific hotspot in the rostral medNAcSh. Using calcium monitoring with fiber photometry in mice, we show that rostral medNAcSh D1-SPNs demonstrate inhibitory responses during reward consumption, while caudal D1-SPNs do not. Consistently, optogenetic stimulation of rostral D1-SPNs inhibits consumption, while stimulation of caudal D1-SPNs had minimal effects, confirming the existence of a functional rostro-caudal gradient. Importantly, we observed no differences between rostral and caudal D1-SPNs in their responses to aversive stimuli, suggesting that the D1-SPN gradient is specific to appetitive contexts. To investigate potential molecular correlates of this functional gradient, we leveraged open-source anatomy datasets and performed fluorescent in situ hybridization, identifying <i>Stard5</i> and <i>Peg10</i> as markers enriched in the rostral and caudal medNAcSh, respectively. Finally, we developed a novel Stard5-Flp driver line to selectively target the rostral hotspot and demonstrated that Stard5+ neurons recapitulate rostral D1-SP…
During vertebrate embryogenesis, axial tendons develop from the paraxial mesoderm and differentiate through specific developmental stages to reach the syndetome stage. While the main roles of signaling pathways in the earlier stages of differentiation have been well established, pathway nuances in syndetome specification from the sclerotome stage have yet to be explored. Here, stepwise differentiation of human induced pluripotent stem cells to the syndetome stage is shown, using chemically defined media and small molecules that were modified based on single-cell RNA-sequencing and pathway analysis. A significant population of branching off-target cells differentiating toward a neural phenotype overexpressing Wnt was identified. Further transcriptomics post-addition of a WNT inhibitor at the somite stage and onwards revealed not only total removal of the neural off-target cells, but also increased syndetome induction efficiency. Fine-tuning tendon differentiation in vitro is essential to address the current challenges in developing a successful cell-based tendon therapy.
<p>by Katlyn Todd, Olivia Schneider, Joshua M. Lawrence, Josefina L. Aronoff, Bartosz Witek, Valerie Velázquez-Colón, Verónica Santana-Ufret, Nicole L. Anderson, Krista Gunter, Moraima Noda, Ryan F. Relich, Lifan Zeng, Dominique H. Limoli, Christopher Whidbey, Jay Vornhagen</p>
<i>Pseudomonas aeruginosa</i> and <i>Klebsiella pneumoniae</i> are gram-negative opportunistic pathogens that frequently colonize the human body and are major causes of infection. These bacteria are often co-isolated in polymicrobial urinary tract and lung infections, the latter of which is associated with increased disease severity and worse clinical outcomes. Despite their overlapping niches and clinical relevance, little is known about how these two pathogens interact and how those interactions influence human health. Given the growing recognition that microbial interactions are key drivers of disease, we investigated how <i>P. aeruginosa</i> and <i>K. pneumoniae</i> influence one another. We discovered an antagonistic interaction in which <i>P. aeruginosa</i> restricts the growth of <i>K. pneumoniae</i>. This inhibition is driven by phenazine production in <i>P. aeruginosa</i>, specifically the secondary metabolites pyocyanin and pyorubin, which are both necessary and sufficient to suppress <i>K. pneumoniae</i> growth. Using a diverse set of clinical isolates, we found that this antagonism is strain-dependent. Both the susceptibility of <i>K. pneumoniae</i> to phenazines and the ability of <i>P. aeruginosa</i> to restrict <i>K. pneumoniae</i> growth varies between strains. Moreover, the necessity of phenazine production is specific to the site of infection. Together, these findings demonstrate that strain background and environmental context are critical determinants of pathogen interactions. These findings reveal that both strain background and environmental redox conditions govern the ecological rules of pathogen interaction, providing a framework for predicting outcomes.
<p>by Hangyu Liao, Jun Yang, Lei Cai, Luhao Chi, Chunming Wang, Yuyan Xu, Juncheng Xie, Kunling Chen, Jingyuan Pei, Zesheng Jiang, Mingxin Pan, Liang Zhao</p>
Crosstalk between hepatocellular carcinoma (HCC) and the tumor microenvironment (TME) is pivotal for the initiation and management of HCC. The infiltration and function of natural killer (NK) cells in the TME are frequently hindered. However, it is unclear whether a crucial regulatory factor originating from HCC cells directly modulates NK cell activity to evade immune surveillance. In this study, we found that mannose-binding lectin 2 (MBL2) expression was markedly decreased in HCC and positively correlated with HCC prognosis. MBL2 inhibited the proliferation and migration of HCC cells intracellularly. Human and murine co-culture systems of HCC and NK cells were established to demonstrate that secreted MBL2 recruited and activated NK cells in the TME, particularly upregulating the infiltration of NKp46<sup>+</sup> NK cells. Furthermore, secreted MBL2 promoted the production of IL-13 and IL-25 by NK cells, resulting in a decrease in exhausted cytotoxic T lymphocytes. Mechanistically, MBL2 interacts with the integrin β1 receptor, activating the FAK/AKT pathway and increasing PD-L1 expression on NK cells. Our discovery identifies MBL2 as an NK cell–activating cytokine, initiating the integrin β1/FAK/AKT pathway in NK cells and reshaping an immune-activated microenvironment of HCC. Strategies to up-regulate MBL2 may enhance the anti-PD-L1 immunotherapy efficacy and serve as a potential therapeutic approach for HCC.
<p>by Alejandro Vasquez-Rifo, Denis Susorov, Emily H. Sholi, Gabriel Demo, Yasaman Jami, Jihui Sha, James A. Wohlschlegel, Andrei Korostelev, Victor Ambros</p>
<i>Pseudomonas aeruginosa</i> employs host translation inhibition as a virulence-enhancing strategy. We previously showed that the bacterium induces cleavage of <i>Caenorhabditis elegans</i> large ribosomal RNA at helix 69 (H69), part of a central intersubunit bridge and the ribosomal decoding center. In this study, we demonstrate that a previously uncharacterized ribonuclease, Ribocin, is necessary and sufficient for H69 cleavage. Recombinant Ribocin cuts H69 in worm and mammalian ribosomes, indicating that H69 cleavage by <i>P. aeruginosa</i> is phylogenetically conserved. In worms, mammalian cells, and rabbit reticulocyte lysates, H69 cleavage results in translation inhibition. Furthermore, Ribocin contributes to bacterial virulence toward <i>C. elegans</i>, triggers a major host response to translation inhibition, and operates in parallel with Exotoxin A-mediated translation inhibition. These findings unveil the first known nuclease that cleaves eukaryotic ribosomes at H69 and expand the understanding of host translation-inhibition by establishing targeted rRNA cleavage as a mechanism of host attack.