bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuronal expression of E2F4DN restores adult neurogenesis in homozygous 5xFAD mice via TrkB signaling
Authors: Lozano-Ureña Anna , Llabrés-Mas Aina Maria , Ramón-Landreau Morgan , Fraj-Cebrián Alberto , Sánchez-Puelles Cristina , Garrido-García Alberto , Cano-Daganzo Vanesa , Valdés-Lora Lorena , Frade José María
Published: January 2025

The etiology of Alzheimer’s disease (AD) has been associated with impaired neurogenesis in the adult subventricular zone (SVZ), but the molecular mechanism leading to this impairment remains poorly understood. Neuronal dysfunction in the AD-affected brain might lead to reduced production of neuron-derived paracrine factors acting through receptors necessary for adult SVZ neurogenesis (ASN). To test this hypothesis, we focused on the TrkB receptor, which can transduce signals from the neurotrophins BDNF and NT4/5, since TrkB is known to regulate the ASN process and its function becomes altered in AD. Here we show that ASN is impaired in the SVZ of homozygous 5xFAD (h5xFAD) mice. This impairment is prevented by administering an AAV.PHP.eB vector that expresses in neurons the transcription factor E2F4 carrying the Thr249Ala/Th251Ala mutation (E2F4DN), a gene therapeutic approach previously demonstrated to exert multifactorial effects in this mouse model of AD. The use of culture media conditioned by primary cortical neurons expressing E2F4DN was able to recover the proliferative and differentiative capacity of neural stem cells (NSCs) isolated from h5xFAD mice. This effect was blocked by inhibiting the TrkB receptor. Accordingly, TrkB activation mimicked the effect of the E2F4DN-conditioned medium on the proliferative and differentiative capacity of h5xFAD NSCs, a finding consistent with the upregulation of NT4/5 expression in the E2F4DN-transduced neurons. We conclude that the activation of TrkB by neurotrophins released by E2F4DN-expressing neurons can recover the ASN phenotype in 5xFAD mice. Therefore, the multifactorial therapeutic capacity of E2F4DN includes the recovery of impaired ASN through the upregulation of TrkB signaling in NSCs.
Integrating multi-system environmental factors to predict brain and behavior in adolescents
Authors: Ramduny Jivesh , Paskewitz Samuel , Brazil Inti A. , Baskin-Sommers Arielle
Published: January 2025

Objective

Environmental factors have long been shown to influence brain structure and adolescent psychopathology. However, almost no research has included environmental factors spanning micro-to-macro-systems, brain structure, and psychopathology in an integrated framework. Here, we assessed the ways and degree to which multi-system environmental factors during late childhood predict subcortical volume and psychopathology during early adolescence.

Method

We used the baseline and 2-year follow-up data from the Adolescent Brain Cognitive DevelopmentSMStudy (N= 2,766). A Bayesian latent profile analysis was applied to obtain distinct multi-system environmental profiles during late childhood. The profiles were used in a path analysis to predict their direct and indirect effects on subcortical volume and psychopathology during early adolescence.

Results

Bayesian latent profile analysis revealed nine environmental profiles. Two distinct profiles predicted greater externalizing problems in adolescents: (i) adversity across, family, school, and neighborhood systems and (ii) family conflict and low school involvement. In contrast, a profile of family and neighborhood affluence predicted fewer externalizing difficulties. Further, family and neighborhood affluence predicted higher subcortical volume, which in turn, predicted fewer externalizing problems; whereas, family economic and neighborhood adversity predicted lower subcortical volume, which in turn, predicted greater externalizing difficulties.

Conclusion

We captured direct and indirect influences of environmental factors across multiple systems on externalizing psychopathology. Specifying the equifinal pathways to externalizing psychopathology serves to provide an evidence base for establishing different types of interventions based on the needs and risk profiles of youth.

Diversity and Inclusion Statement

The current study is part of the ongoing Adolescent Brain Cognitive DevelopmentSMStudy (ABCD Study®) for which youth are recruited from elementary schools in the United States that are informed by gender, race, ethnicity, socioeconomic status, and urbanicity. The ABCD Study® aims to recruit youth longitudinally by sampling the sociodemographic makeup of the US population. Two of the authors self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. One of the authors identifies as a part of an underrepresented gender group in science. The authors also are representative of the communities for which data was collected and contributed to design, analysis, and/or interpretation of the work. Finally, every effort was made to cite the work of authors from underrepresented and minoritized groups in academic research.
Psychedelic enhancement of flexible learning weeks after a single dose
Authors: Brouns Elizabeth J , Ekins Tyler G , Ahmed Omar J
Published: January 2025

Psychedelic drugs have shown therapeutic potential for the treatment of multiple neuropsychiatric disorders chiefly by promoting long-lasting plasticity in the prefrontal cortex (PFC). A critical function of the PFC is the ability to apply previously learned rules to novel scenarios, a skill known as cognitive flexibility. Here, we show that a single dose of 25CN-NBOH, a serotonin 2A receptor-preferring psychedelic, improves performance on a relatively complex flexible reversal learning task in mice, measured 2-3 weeks after the dose. This effect was seen in both male and female mice. This behavioral finding complements previous cellular results showing that a single psychedelic dose induces long-term structural changes in the PFC and uniquely demonstrates sustained improvements in cognitive flexibility in a novel behavioral paradigm weeks after the initial psychedelic dose in mice. This high throughput task also provides a rapid, automated way to assess other candidate psychedelics for their impact on cognitive flexibility in mice.
A Diagnostic Blind Spot: Deep intronic SVA_E Insertion identified as the most Common Pathogenic Variant Associated with Canavan Disease
Authors: Dominguez Gonzalez Carlos A. , Bell Katrina M. , Rajagopalan Ramakrishnan , de Silva Michelle G. , Lemes Aída , Zabala Cristina , Pérez Florencia , Cerisola Alfredo , Vossough Arastoo , Whitehead Matthew T. , Cunningham Chloe , Brown Natasha J. , Quin Rebecca , Simons Cas , Conway Thomas , Uebergang Eloise , Rius Rocio , Kumaheri Meutia A. , Kotes Emma , Vohra Ananya , Zalusky Miranda PG , Anderson Zachary B. , Storz Sophie HR , Ward Sydney A. , Goffena Joy , Gustafson Jonas A. , White Susan M. , Vanderver Adeline , Miller Danny E.
Published: January 2025

Canavan disease (CD) is a neurodegenerative disorder caused by biallelic disease-causing variants in theASPAgene. Here, we utilized long-read sequencing (LRS) to investigate eight individuals clinically diagnosed with Canavan disease but without definitive genetic diagnoses. Our analyses identified a recurring previously unreported intronic SVA_E retrotransposon insertion withinASPAin all eight individuals. Surprisingly, the frequency of this variant in population databases suggests it is the most common pathogenic variant inASPAand should be evaluated in diagnostic testing and carrier screening for CD. Additionally, this finding has implications for the broader rare disease community, as it highlights a substantial blind spot in standard short-read diagnostic pipelines, which historically have missed or overlooked these types of insertions. This discovery highlights the power of emerging technologies, such as LRS and RNA-sequencing (RNA-seq), to bring new classes of variants into diagnostic utility for genetic disorders like CD.
Measurement of perceived healthcare discrimination and its implications on population health research: A systematic review protocol
Authors: Green Michael D. , Harlow Ashleigh B. , Janek Sarah E. , Weinfert Kevin P. , Skalla Lesley , O’Brien Emily C. , Brookhart M. Alan , Navar Ann Marie , Muhigaba Perusi , Bentley-Edwards Keisha L. , Dupre Matthew E. , Thorpe Roland J.
Published: January 2025

Purpose

Discrimination in healthcare settings significantly impacts population health, affecting individuals of racial and ethnic minoritized identities, sexual and gender minoritized identities, and individuals with disabilities. Most measures of discrimination are derived from instruments assessing everyday discrimination experiences and do not adequately capture the specific nuances of healthcare-related discrimination. This systematic review protocol outlines a planned study that will evaluate and synthesize tools designed to measure discrimination in healthcare settings in the United States (U.S.). By providing a detailed overview of these measurement tools and their psychometric properties, this review will enhance understanding of healthcare discrimination and guide policy and practice towards improving health equity.

Methods

A comprehensive search will be conducted across four databases (PubMed, Embase, PsycINFO, and Web of Science) and supplemented by citation tracking of reviewed articles. The review will focus on studies involving measurements of perceived discrimination within healthcare settings in the United States. The primary outcomes include the reliability, validity, and specificity of discrimination measurement instruments. Quality assessment will use the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) Risk of Bias tool. Our systematic review will be present findings based on the Preferred Reporting Items for Systematic Review and Meta-Analyses COnsensus-based Standards for the selection of Health Measurment INstruments of outcome measurements 2024 (PRISMA-COSMIN for OMIs 2024) reporting standard. The protocol is registered with PROSPERO (Registration number: CRD42024592267.

Discussion

This review will synthesize existing literature and offer a comprehensive evaluation of discrimination measurement tools to guide future health equity research. This review aims to contribute to the mitigation of healthcare inequities and the promotion of health equity by offering actionable insights into the measurement of discrimination in healthcare settings.
Physical activity and favourable adiposity genetic liability reduce the risk of hypertension among high body mass individuals
Authors: Hezekiah Chukwueloka , Pazoki Raha
Published: January 2025

Background and Purpose

Hypertension is a global health issue, and the risk factors include genetics, physical inactivity, and excess body fat (adiposity). Genetic predisposition to adiposity generally increases risk of hypertension. Several genetic variants have been identified to increase adiposity but unexpectedly reduce hypertension (favourable adiposity genes). Here, we tested the effect of these genetic variants on risk of hypertension in European ancestry participants under various scenarios of physical activity and body mass index.

Methods

Favourable adiposity genetic liability was estimated using previously identified genetic variants and their effect sizes. The study analysed data from 230,027 unrelated participants in the UK Biobank. Logistic regression was used to examine the association between this genetic liability and hypertension (defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg, or the use of anti-hypertensive medications). The analyses were conducted separately based on physical activity status (physically active and inactive) within low and high body mass groups.

Results

Individuals with high body mass, could reduce their risk of hypertension by up to 16% depending on the favourable adiposity genetic liability and physical activity status (Padjusted= 1.32 x10-8). In high body mass individuals, physical activity alone contributes to 6-9% reduction in risk of hypertension.

Conclusion

The study provides evidence that the protective effect of favourable adiposity on hypertension risk varies according to body mass composition and physical activity status.
Top-down inputs are controlled by somatostatin-expressing interneurons during associative learning
Authors: Studer Florian , Zeppillo Tommaso , Barkat Tania Rinaldi
Published: January 2025

Associative learning links sensory signals to their behavioral meaning by combining bottom-up inputs with top-down contextual information, enabling decision-making based on expected outcomes. It triggers plastic changes of neuronal responses in both excitatory and inhibitory cell populations. However, the role of inhibition in shaping this plasticity remains debated. Here we used chronic extracellular electrophysiology and optogenetic manipulation of inhibitory neurons and top-down inputs in mice learning an auditory discrimination task. We found that learning enhances stimulus selectivity in a subset of neurons in the primary auditory cortex. Interestingly, somatostatin-expressing (SST) interneurons decrease their response to the rewarded cue and bidirectionally regulate associative learning. More specifically, an increased activity of SST neurons impairs learning by altering bottom-up signaling, whereas the reduction of their activity facilitates learning by gating top-down inputs from the orbitofrontal cortex. These findings demonstrate that inhibition plays a critical role in gating top-down inputs to primary sensory cortices involved in associative learning.
Design and Validation of a Wearable Imaging System for Automated Wound Monitoring in Porcine Model
Authors: Hee Wan Shen , Tebyani Maryam , Baniya Prabhat , Franco Celeste , Keller Gordon , Lu Fan , Li Houpu , Asefifeyzabadi Narges , Yang Hsin-ya , Villa-Martinez Guillermo , Schorger Kaelan , Devarajan Koushik , Barbee Alexie , Hernandez Cristian , Nguyen Tiffany , Gomez Marcella , Isseroff Roslyn Rivkah , Rolandi Marco , Teodorescu Mircea
Published: January 2025

Effective wound monitoring has the potential to guide treatment regiments and improve healing outcomes, yet current clinical assessment methods remain largely subjective and labor-intensive. To address this challenge, we present a high-resolution wearable imaging system designed for continuous wound monitoring. The system integrates a 64 MP camera with a plano-convex lens housed in an enclosure measuring 73 mm in diameter and 36.1 mm in height, and features a custom printed circuit board (PCB) for programmable LED illumination. The 3D-printed device enclosure is designed to accommodate a silicone bioelectronic device and can be securely attached using a commercially available ostomy skin barrier. In porcine model validation studies, the system successfully captured daily wound progression over periods up to 7 days. The captured images were wirelessly transmitted to a processing unit where DeepMapper, a machine learning algorithm, processed z-stacked images and performed multi-level feature extraction to predict wound healing stages and indicate potential complications such as infection. This imaging system enables automated analysis of wound progression and supports the development of smart wound care platforms for personalized treatment strategies. The integrated design approach demonstrates the feasibility of creating compact, high-resolution imaging systems suitable for clinical wound monitoring applications.
Defective DcpS Decapping Manifests in Creatine Deficiency Syndrome and Neurological impairment
Authors: Yang Jun , Palsule Geeta , Jiao Xinfu , Hart Ronald P. , Kiledjian Megerditch
Published: January 2025

Biallelic mutations in theDCPSgene disrupting the decapping activity of the scavenger decapping protein DcpS, leads to neurodevelopmental deficiencies and intellectual disability. However, the molecular basis for the neurogenesis defects in these individuals remains unknown. Here we show that cells derived from individuals with aDCPSmutation harbor a creatine deficiency and a corresponding elevation of the creatine precursor, guanidinoacetate (GAA). The altered metabolite levels are a consequence of a reduction in both the mRNA and protein levels for the enzyme that converts GAA into creatine, guanidinoacetate methyltransferase. Importantly, the compromised neurogenesis and neurite outgrowth phenotypes observed during the differentiation of DcpS mutant patient derived induced pluripotent stem cell differentiation into neurons was reversed upon supplementation of creatine monohydrate. These findings suggest creatine deficiency as the major underlying factor for the neurogenetic defect detected in DcpS mutant cells and a potential driver of the neurological deficiencies in affected individuals.
PRLX-93936 and BMS-214662 are cytotoxic molecular glues that leverage TRIM21 to degrade nucleoporins
Authors: Scemama de Gialluly Marc A , Allen Anthony R , Hayes Elijah H , Zhuang Patrick , Goldfarb Ralston B , Farrar Amanda N , Fedorov Yuriy , Adams Drew James
Published: January 2025

Although molecular glues have emerged as innovative tools within the field of chemically induced proximity, approaches for their discovery remain limited. Here we report a phenotypic screening approach in which small molecules whose cytotoxic mechanisms require ubiquitination show gain of viability following pharmacological inhibition of the E1 enzyme UAE. This approach revealed two previously clinically-evaluated cytotoxins of unknown mechanism, PRLX-93936 and BMS-214662, as molecular glues that directly target the E3 ubiquitin ligase TRIM21. These molecules induce TRIM21-mediated proteasomal degradation of multiple nucleoporin proteins, leading to inhibition of nuclear export and ultimately cell death. Loss of nucleoporins and nuclear export accounts for past observations in which BMS-214662 led to disrupted subcellular protein localization. Furthermore, the cytotoxicity of these agents correlates strongly with TRIM21 expression, suggesting clinical re-evaluation of these agents in patients with TRIM21-high cancers. Additionally, relative to recently-reported TRIM21-targeting glues, these two scaffolds display high cellular potency, creating new opportunities for targeted protein degradation via the design of additional glues and "TRIMTACs".
Unique spatiotemporal synchronization solutions of heterogeneous local Ca2+dynamics underlie the formation of each impulse that emerges from the cardiac sinoatrial node
Authors: Tagirova Syevda , Maltsev Alexander V. , Baca Georgiana L. , Bychkov Rostislav , Maltsev Victor A. , Lakatta Edward G.
Published: January 2025

Spontaneous, stochastic, local Ca2+oscillations (LCOs) that are heterogeneous in phase, frequency, and amplitude incessantly occur throughout the neuronal-like cytoarchitecture of the heart’s pacemaker, the sinoatrial node (SAN). How information encoded within ensembles of these heterogeneous LCOs is linked to the incessant emergence of the formation of rhythmic SAN impulses, however, is an unsolved problem. We applied a wide range of analytical techniques adapted from dynamical systems and neuroscience to map fine details of spatiotemporal distributions of local Ca2+dynamics in time-series of high-speed acquisition panoramic images of mouse SANsex vivo.Phase analysis delineated a network of functional pacemaker cell clusters, in which Ca2+dynamic amplitudes, kinetics, and phases were similar, but still differed from each other, and differed from those of other clusters. Local Ca2+dynamics within the network of clusters formed rhythmic global Ca2+impulses, with a mean rate identical to that recorded by the reference sharp electrode in the right atria. Initial conditions of each impulse initiation differed from each other, due mostly to stochastic nature of Ca2+dynamics within a small cluster located near the crista terminalis, having the highest intrinsic power, earliest rotor-like energy transfer, most frequent point-to-point instability, earliest acrophase, and greatest impulse-to-impulse variability within the network of functional clusters. A spontaneous, slowly increasing ensemble Ca2+signal within this cluster forms a foot of each CaT. Following this foot, the amplitude of the global CaT increased rapidly, due to rapid increases in the kinetics and amplitudes of Ca2+dynamics in some adjacent clusters. In other clusters near to the inter-atrial septum, a delayed, but rapid increase in the Ca2+dynamic occurred when the relaxation phase of the CaT had already begun.

Orbit plots and Lyapunov exponent analyses detected both deterministic and stochastic features within the SAN Ca2+ dynamics. Correlation analyses detected cross-talk among the Ca2+dynamics withindifferent clustersthat varied, not only throughout an impulse, but also from one impulse to the next, forming unique dynamic small-world networks, assessed as ratios of the highest correlation coefficientsand shortest path lengths, ultimately creatinga uniquespatiotemporal Ca2+dynamic synchronization solution for each CaT. Thus, the emergence of each CaT from individual LCOs during each cycle is unique underlies cycle length variability in SAN, recapitulating the emergence of spontaneous CaTs in isolated, single, SAN pacemaker cells.
Autoimmune mechanisms elucidated through muscle acetylcholine receptor structures
Authors: Li Huanhuan , Pham Minh C , Teng Jinfeng , O'Connor Kevin C , Noviello Colleen M , Hibbs Ryan E
Published: January 2025

Skeletal muscle contraction is mediated by acetylcholine (ACh) binding to its ionotropic receptors (AChRs) at neuromuscular junctions. In myasthenia gravis (MG), autoantibodies target AChRs, disrupting neurotransmission and causing muscle weakness. Despite available treatments, patient responses vary, suggesting pathogenic heterogeneity. Current information on molecular mechanisms of autoantibodies is limited due to the absence of structures of an intact human muscle AChR. Here, we overcome challenges in receptor purification and present high-resolution cryo-EM structures of the human adult AChR in different functional states. Using a panel of six MG patient-derived monoclonal antibodies, we mapped distinct epitopes involved in diverse pathogenic mechanisms, including receptor blockade, internalization, and complement activation. Electrophysiological and binding assays further defined how these autoantibodies impair AChR function. These findings provide critical insights into MG immunopathology, revealing previously unrecognized antibody epitope diversity and mechanisms of receptor inhibition, offering a foundation for personalized therapies targeting antibody-mediated autoimmune disorders.
Left-right cortical interactions drive intracellular pattern formation in the ciliateTetrahymena
Authors: Lee Chinkyu , Joachimiak Ewa , Maier Wolfgang , Jiang Yu-Yang , Lechtreck Karl F. , Cole Eric S. , Gaertig Jacek
Published: January 2025

In ciliates, cortical organelles are positioned at precise locations along two polarity axes: anterior-posterior and circumferential (lateral). We explored the poorly understood mechanism of circumferential patterning, which generates left-right asymmetry. The model ciliateTetrahymenahas a single anteriorly-located oral apparatus. During cell division, a single new oral apparatus forms near the equator of the parental cell and along the longitude of the parental organelle. Cells homozygous forhypoangular 1(hpo1) alleles, assemble multiple oral apparatuses positioned either to the left or right flanking the normal oral longitude. We identifiedHPO1as a gene encoding an ARMC9-like protein. Hpo1 colocalizes with ciliary basal bodies, forming a bilateral concentration gradient with the high point on the cell’s right side and a sharp drop-off that marks the longitude at which oral development initiates on the ventral side. Hpo1 acts to exclude oral development from the cell’s right side. Hpo1 interacts with the Beige-Beach domain protein Bcd1, a cell’s left side-enriched factor, whose loss also confers formation of multiple oral apparatuses. A loss of both Hpo1 and Bcd1 is lethal and profoundly disrupts both positioning and organization of the forming oral apparatus (including its internal left-right polarity). We conclude that in ciliates, the circumferential/chiral patterning involves gradient-forming factors that are concentrated on either the cell’s right or left side and that the two sides of the cortex interact to create boundary effects that induce, position and shape developing cortical organelles.
Probabilistic Annotations of Protein Sequences for Intrinsically Disordered Features
Authors: Malhis Nawar
Published: January 2025

This paper introduces a novel platform for IDR Probabilistic Annotation (IPA). The IPA platform now encompasses tools for predicting ‘Linker’ regions and ‘nucleic’, ‘protein’, and ‘all’ (protein or nucleic) IDR binding sites within protein amino acid sequences. Despite its simplicity and computational efficiency, results demonstrate that IPA performs competitively with leading tools in predicting ‘protein’ and ‘all’ IDR binding sites while considerably outperforming all tools in identifying Linker regions and nucleic binding sites. An important contribution of this work is the introduction of a new output paradigm for computational feature predictions. Traditional tools typically express predictions as scores, with higher values indicating greater probabilities. However, these scores lack true probabilistic meaning and interpretability, even derived from logistic regression models. This limitation arises primarily because training data priors differ from broader populations’ unknown priors. This paper proposes applying a reverse Bayes Rule to logistic regression outputs, effectively normalizing for the priors in the training data. This adjustment produces scores representing actual probabilities, assuming 50% priors in the general population. Such scores are interpretable in isolation and enable comparability and integration across different tools, marking a significant step toward standardization in feature prediction methodologies.

Availability

orca.msl.ubc.ca/nmshare/ipa.tar.gz
The use of iconPCR for 16S library preparation improves data quality and workflow
Authors: Jouvenot Yann , Obert Caroline , Hale Brett , Metcalfe Kyle , Kaur Gagneet , Boddicker Andrew , Krivet Marielle , Zhao Junhua , Ben-Yehezkel Tuval , Patel Pranav
Published: January 2025

Polymerase Chain Reaction (PCR) is a cornerstone of contemporary biological research, enabling the amplification of specific DNA sequences for various applications. However, suboptimal cycling conditions often undermine its efficacy, which can generate chimeric products, exacerbate PCR duplication rates, and skew species representation in metabarcoding experiments due to the preferential amplification of dominant populations.

To address these limitations, we present iconPCR—Individually Controlled PCR—a novel technology that allows each reaction in a 96-well plate to be cycled independently and programmatically. By setting a predefined fluorescence threshold, iconPCR ensures that all Next Generation Sequencing (NGS) libraries are amplified to equivalent levels, thereby eliminating the risks of over- or under-amplification through a process known as “Auto-Normalization.”

In this study, we applied iconPCR to generate V3, V4, and full-length 16S rRNA gene libraries using Avidite sequencing. The V1-V9 variable region libraries were also evaluated with HiFi sequencing, which significantly demonstrated its potential to improve microbial community analysis accuracy and reliability.
Burden and Economic Impact of Respiratory Viral Infections in Adults Aged 60 and Older: A Focus on RSV
Authors: Peláez A. , Jimeno S. , Villarreal M. , Gil M. , Gutiérrez I. , Sanz M. , Natalini S.
Published: January 2025

Background/Objectives

Respiratory syncytial virus (RSV) represents a significant cause of acute respiratory infections (ARI) in adults aged 60 years and older, often leading to severe clinical out-comes and high healthcare costs. This study aimed to evaluate the clinical and economic burden of RSV compared to other ARI, focusing on specific age groups, comorbidities, and demographic factors.

Methods

A retrospective observational study was conducted using electronic medical records of adults aged ≥60 years hospitalized for ARI, including RSV, in Spain. Direct costs related to hospitalizations, intensive care unit (ICU) admissions, and treatments were analyzed. The study also assessed demographic, clinical, and comorbidity-related factors influencing the economic burden.

Results

RSV infections resulted in significantly higher direct costs compared to other ARI, particularly in patients aged 70–80 years. Comorbidities such as asthma and smoking history were associated with increased costs in RSV cases. Although ICU costs were comparable between groups, hospitalizations for RSV required longer stays and more intensive treatments, amplifying the overall economic burden. Differences in costs by age and sex highlighted the need for tailored clinical management strategies.

Conclusions

RSV poses a substantial economic and clinical burden on adults aged 60 years and older, particularly in those with comorbidities. Preventive measures, such as vaccination, could reduce healthcare costs and improve outcomes in this vulnerable population. These findings support the inclusion of RSV vaccines in immunization programs, especially in aging populations like Spain, to alleviate healthcare pressures during peak respiratory disease seasons.
Prognostic value of compact myocardial thinning in patients with left ventricular non-compaction
Authors: Gegenava Tea , Tukker Martijn , Caliskan Kadir , Hirsch Alexander , Manohar Ashish , Lee Seung-Pyo , Owens Anjali , Kwon Deborah H. , Ramchand Jay , Wheeler Matthew T. , Tang W. H. Wilson , Nieman Koen
Published: January 2025

Introduction

Left ventricular non-compaction (LVNC) can be associated with a wide spectrum of clinical presentations, ranging from asymptomatic to ventricular tachyarrhythmia (VT), heart failure (HF), and cerebrovascular accidents (CVA). In this multicenter study, we explored the associations between clinical and imaging characteristics and outcomes of patients with LVNC, and externally validated the predictive value of myocardial thinning identified on cardiac magnetic resonance imaging (CMR) as previously described.

Methods

214 adult patients (54% male, mean age 41±16 years) meeting the imaging criteria for LVNC were identified. Baseline clinical data, echocardiographic findings, and CMR characteristics were analyzed. Long-axis balanced steady-state free precession CMR sequences were used to assess myocardial thickness. Myocardial thinning was defined as a 50% or greater diameter reduction of the compacted myocardium compared to a contiguous segment. The primary endpoint was a composite of all-cause mortality, HF hospitalization, need of left ventricular assist device (LVAD) or heart transplant, cardiac resynchronization therapy (CRT), CVA/transient ischemic attacks (TIA), and VT and appropriate implantable cardioverter defibrillator (ICD) therapy.

Results

Focal myocardial thinning was observed in 42 patients (20%). Over a median follow-up period of 7 years (IQR, 4–10 years), 54 patients (24%) experienced a primary outcome (including all-cause mortality n=15 (7%), HF hospitalization/CRT n=33 (15%), CVA/TIA n=10 (5%), VT and appropriate ICD therapy n=14 (7%), LVAD/heart transplant n=3 (1.4%). Patients with myocardial thinning had more cumulative adverse events compared to those without myocardial thinning (chi-square = 29.516, log-rank < 0.001), even after matching for medical risk score. In a multivariate Cox regression model, myocardial thinning remained associated with outcomes: HR 3.052(95% CI: 1.569-5.937, p=0.001). When evaluating the incremental prognostic value of myocardial thinning over clinical and imaging characteristics, we observed that adding myocardial thinning added value to prediction models that included clinical and imaging features.

Conclusions

The presence of myocardial thinning is associated with adverse cardiovascular events in adult LVNC patients. Along with the medical risk score and other imaging variables, this feature enhances the risk stratification of individuals with LVNC. Incorporating myocardial thinning into medical risk assessments can improve the prediction and management of adverse outcomes in these patients.
Intussusceptive angiogenesis-on-a-chip: Evidence for transluminal vascular bridging by endothelial delamination
Authors: Staples Sabrina C.R. , Yin Hao , Sutherland Frances S.K. , Prescott Emma , Tinney Dylan , Hamilton Douglas W. , Goldman Daniel , Poepping Tamie L. , Ellis Christopher G. , Pickering J. Geoffrey
Published: January 2025

Intussusceptive angiogenesis is an increasingly recognized vessel duplication process that generates and reshapes microvascular beds. However, the mechanism by which a vessel splits into two is poorly understood. Particularly vexing is formation of the hallmark transluminal endothelial cell bridge. How an endothelial cell comes to cross a flowing lumen rather than line it is enigmatic. To elucidate this, we used a microvessel-on-a-chip strategy, creating a micro-conduit coherently lined with flow-sensitive endothelial cells but in which transluminal bridges also formed. Bridge morphologies ranged from filamentous strand to multicellular columns with a central core. These bridge architectures were found to recapitulate those in microvessels in embryos, tumours, diseased organs, and the dermis of patients with limb-threatening ischemia. Time-lapse, multi-plane, 3D microscopy of the micro-physiologic conduit revealed that bridges arose from endothelial cells oriented orthogonal to flow that partially released from the wall while retaining attachments at the ends. This delamination process was blocked by hyperactivation of Rho and augmented by interventions that weaken cell-substrate interactions, including inhibiting non-muscle myosin II and blocking α5ß1 integrin but, interestingly, not αvß3 integrin. Thus, endothelial cells can leave their monolayer and transect a flowing lumen through controlled delamination. This previously unrecognized lumen entry program could explain the launch of intussusceptive angiogenesis and opens a framework for intervening.

Significance Statement

Rapid generation of small blood vessels is vital for embryonic development and many diseases. An efficient means of creating a new microvessel is for an existing vessel to split into two, a process recognized for over 35 years. However, the cellular events underlying vessel splitting remain largely a mystery. The challenge is how to look inside a microvessel and capture transient events. We address this challenge using a microvessel-on-a-chip strategy. We discovered that select endothelial cells lining the wall can partially lift to transect the lumen. This resolves the paradox of an adhesion-dependent cell reaching across a pressurized lumen. It also reframes microvascular therapy considerations, including for diabetics with leg ulcers, a condition we show has hallmarks of microvessel splitting.
Heritable Immunization Establishes a New Model for Pathogen Control
Authors: Buchthal Joanna , Chory Emma J. , Hill Zachary , Zhou Yu , Bondage Devanand , DeAmelio Summer , Freeman Julien , Jaenisch Rudolf , Markoulaki Styliani , Marasco Wayne A. , Telford Sam R. , Esvelt Kevin M.
Published: January 2025

Heritable immunization represents a promising approach for controlling infectious diseases by embedding immunity directly into the genomes of wild species that spread human pathogens. Here, we report the genetic engineering ofMus musculusto produce a neutralizing, protective single-chain antibody againstBorrelia burgdorferi, the causative agent of Lyme disease. Engineered mice stably produced a LA-2 scFv-albumin fusion protein across multiple generations, demonstrating robust heritability and stability of gene expression. Following sequential challenges with infected and uninfected ticks, heterozygous mice exhibited strong resistance to infection, effectively interrupting theBorrelia burgdorferidisease transmission cycle. Having recently established novel protocols to genetically engineer the white-footed mouse,Peromyscus leucopus, a key reservoir of Lyme disease, these findings demonstrate the feasibility of heritable immunization as a potential strategy for mitigating Lyme disease transmission in the environment. More broadly, engineered reservoir immunity may offer a generalizable approach to controlling vector-borne and zoonotic disease with profound potential to improve human health.
Thermodynamic Stability Modulates Chaperone-Mediated Disaggregation of α-Synuclein Fibrils
Authors: Fricke Celia , Kunka Antonin , Norrild Rasmus K. , Wang Shuang-Yan , Dang Thi Lieu , Wentink Anne S. , Bukau Bernd , Buell Alexander K.
Published: January 2025

The aggregation of the intrinsically disordered protein alpha-synuclein into amyloid fibrils and their subsequent intracellular accumulation are characteristic features of several neurodegenerative disorders, such as Parkinson’s disease. Currently, there are no curative treatment options available. In this study, we demonstrate that the thermodynamic stability of alpha-synuclein fibrils is a crucial factor influencing the efficiency with which they are disaggregated by the human chaperone system comprising HSP70, DNAJB1, and Apg2. We quantify the increasing stability of alpha-synuclein fibrils formed under four different solution conditions over a three-month incubation period. The chaperone system effectively disaggregates three out of the four fibril types, with varying efficiencies that correlate with their thermodynamic stability. The fibrils exhibit differential sensitivities to chaperone-mediated depolymerization, suggesting that both structural features and thermodynamic stability contribute to the susceptibility of alpha-synuclein fibrils to chaperone disaggregation. Our findings thus reveal a connection between the thermodynamic stability of fibrils and their susceptibility to chaperone-mediated disaggregation.
Endocrine modulation of cortical and retinal blood flow across the menstrual cycle
Authors: Wright Melissa E. , Crofts Andrew , Davies Saajan , Chandler Hannah L. , Driver Ian , Germuska Michael , Giarratano Ylenia , Rashid Darwin , Bernabeu Miguel O. , Terry Louise , Steventon Jessica J. , Murphy Kevin
Published: January 2025

The ovarian hormones, oestrogen and progesterone, have vaso- and neuroprotective effects, likely due to interactions with the cerebrovascular system. This study investigates their neuroendocrine influence on a range of cerebral and retinal vascular functions across a healthy menstrual cycle.

Twenty-six healthy, menstruating females completed imaging sessions and assessment of circulating hormone levels during their early follicular, late follicular, and mid-luteal phase (1-4, 10-12 and 20-22 days after menses onset). Cerebral blood flow (CBF), arterial arrival time (AAT), global oxygen extraction fraction (OEF), cerebrovascular metabolic rate of oxygen (CMRO2), carotid artery radius and carotid pulsatility index (PI) were measured using 3T MRI. Retinal vessel density and blood flow resistance were assessed with optical coherence tomography angiography (OCT-A).

Assessed with linear models, increased oestradiol was related to increased global CBF (χ2(1)=35.05; p=3.2×10-9) and increased AAT (χ2(1)=5.87; p=0.015). Increased progesterone was associated with increased global CBF (χ2(1)=13.00; p=0.0003). In the retina, a relationship was found between oestradiol and decreased retinal blood flow resistance (χ2(1)=5.28; p=0.0215), which was primarily driven by centrally localised vessels.

This study finds that circulating oestrogen increases blood flow in the eye and brain, while progesterone significantly impacts the brain alone. These effects suggest a potential pathway for neuroprotective mechanisms.
Voice identity invariance by anterior temporal lobe neurons
Authors: Giamundo M. , Trapeau R. , Thoret E. , Renaud L. , Brochier T. G. , Belin P.
Published: January 2025

The ability to recognize speakers by their voice despite acoustical variation plays a significant role in primate social interactions. While neurons in the macaque anterior temporal lobe (ATL) show invariance to face viewpoint, whether they also encode abstract representations of caller identity is not known. Here we show that neurons in the voice-selective ATL of two macaques show invariance to voice identity via dynamic representations that minimize within-caller neuronal distances while maintaining distinct neural trajectories for different individuals. A small proportion of highly identity-selective neurons plays a central role although less selective neurons are also informative. Our findings provide a neural basis for voice identity recognition in primates and highlight the ATL as a key hub for integrating perceptual voice features into higher-level identity representations.
EngineeringSaccharomyces cerevisiaefor growth on xylose using an oxidative pathway
Authors: Tanaka Kenya , Yukawa Takahiro , Bamba Takahiro , Wakiya Miho , Kumokita Ryota , Jin Yong-Su , Kondo Akihiko , Hasunuma Tomohisa
Published: January 2025

The fermentative production of valuable chemicals from lignocellulosic feedstocks has attracted considerable attention. AlthoughSaccharomyces cerevisiaeis a promising microbial host, it lacks the ability to efficiently metabolize xylose, a major component of lignocellulosic feedstocks. The xylose oxidative pathway offers advantages such as simplified metabolic regulation and fewer enzymatic steps. Specifically, the pathway involves the conversion of xylose into 2-keto-3-deoxy-xylonate, which can be channeled into two distinct pathways, the Dahms pathway and the Weimberg pathway. However, the growth of yeast on xylose as the sole carbon source through the xylose oxidative pathway has not been achieved, limiting its utilization. We successfully engineeredS. cerevisiaeto metabolize xylose as its sole carbon source via the xylose oxidative pathways, achieved by enhancing enzyme activities through iron metabolism engineering and rational enzyme selection. We found that increasing the supply of the iron-sulfur cluster to activate the bottleneck enzyme XylD byBOL2disruption andtTYW1overexpression facilitated the growth on xylose and the production of ethylene glycol at 1.5 g/L via the Dahms pathway. Furthermore, phylogenetic analysis of xylonate dehydratases led to the identification of a highly active homologous enzyme. A strain possessing the Dahms pathway with this highly active enzyme exhibited reduced xylonate accumulation. Furthermore, the introduction of enzymes based on phylogenetic tree analysis allowed for the utilization of xylose as the sole carbon source through the Weimberg pathway. This study highlights the potential of iron metabolism engineering and phylogenetic enzyme selection for the development of non-native metabolic pathways in yeast.

Key points

1.5 g/L ethylene glycol was produced via Dahms pathway inS. cerevisiae.

Enzyme activation enabled growth on xylose via both the Dahms and Weimberg pathways.

Tested enzymes in this study may expand application of xylose oxidative pathway.
Multispecies relations shape bird-feeding practices
Authors: Aivelo Tuomas , Aulio Mikko , Enström Johanna , Deshpande Purabi , Haukka Anna , Lähdesmäki Heta , Rönkä Katja , Santangeli Andrea , Väkkärä Virpi , Lehikoinen Aleksi , Thorogood Rose , Kervinen Anttoni
Published: January 2025

While humans often feed birds in their backyards, there is growing awareness that this has positive and negative effects on local biodiversity. Whether the observed species assemblage shapes human activities has, however, rarely been investigated. We analyzed 15,088 open-ended answers from 9,473 Finnish respondents about why they have increased or reduced feeding birds. They mentioned 58 avian and non-avian species linked to changed practices. The main reasons for change were 1) respondent’s relation to non-human species, 2) respondent’s relation to other humans and 3) relations between non-human species. Most taxa and reasons could lead to both increase or decrease in feeding, although the direction was context-dependent. We suggest that bird-feeding is an interactive process where the species community strongly affects feeding practices, which in turn can affect community composition. Recognising this process is crucial for understanding the effects of bird-feeding on both humans and nature and providing more nuanced guidance.
Cryo-EM Structure of the relaxosome, a complex essential for bacterial mating and the spread of antibiotic resistance genes
Authors: Williams Sunanda M. , Raffl Sandra , Kienesberger Sabine , Ilangovan Aravindan , Zechner Ellen L. , Waksman Gabriel
Published: January 2025

Bacterial mating, or conjugation was discovered nearly 80 years ago as a process transferring genes from one bacterial cell (the donor) to another (the recipient). It requires three key multiprotein complexes in the donor cell: a DNA-processing machinery called the relaxosome, a double-membrane spanning type 4 secretion system (T4SS), and an extracellular appendage termed pilus. While the near-atomic resolution structures of the T4SS and pilus are known, that of the relaxosome is not1–3. Here, we describe the cryo-EM structure of the fully assembled relaxosome encoded by the paradigm F plasmid in two different states corresponding to distinct functional steps along the DNA processing reaction. By varying the structures of model DNAs we delineate conformational changes required to initiate conjugation. Mutational studies of the various protein-protein and protein-DNA interaction hubs suggest a complex highly sensitive to trigger signals, that could arise from cell-to-cell contacts with recipient cells.
StreptoCAD: An open-source software toolbox automating genome engineering workflows in streptomycetes
Authors: Levassor Lucas , Whitford Christopher M. , Petersen Søren D. , Blin Kai , Weber Tilmann , Frandsen Rasmus J. N.
Published: January 2025

Streptomycetes hold immense potential for discovering novel bioactive molecules for applications in medicine or sustainable agriculture. However, high-throughput exploration is hampered by the currentStreptomycesgenetic engineering methods that involve the manual design of complex experimental molecular biological engineering strategies for each targeted gene. Here, we introduceStreptoCAD, an open-source software toolbox that automates and streamlines the design of genome engineering strategies inStreptomyces,supporting various CRISPR-based and gene overexpression methods. Once initiated, StreptoCAD designs all necessary DNA primers and CRISPR guide sequences, simulates plasmid assemblies (cloning) and the resulting modification of the genomic target(s), and further summarizes the information needed for laboratory implementation and documentation. StreptoCAD currently offers six design workflows, including the construction of overexpression libraries, base-editing, including multiplexed CRISPR-BEST plasmid generation, and genome engineering using CRISPR-Cas9, CRISPR-Cas3, and CRISPRi systems. In addition to automating the design process, StreptoCAD further secures compliance with the FAIR principles, ensuring reproducibility and ease of data management via standardized output files. To experimentally demonstrate the design process and output of StreptoCAD, we designed and constructed a series of gene overexpression strains inStreptomyces Gö40/10, underscoring the tool’s efficiency and user-friendliness. This tool simplifies complex genetic engineering tasks and promotes collaboration through standardized workflows and design parameters. StreptoCAD is set to transform genome engineering inStreptomyces, making sophisticated genetic manipulations accessible for all and accelerating natural product discovery.

Graphical abstract