bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Techniques for Extracellular Particle Separation and Single-Particle Multiparametric Characterization to Track Cancer Biomarkers from Tissue to Biofluids
Authors: Nguyen Kim Truc , Xia Jiangping , Chang Chaoran , Hade Mangesh Dattu , Rima Xilal Y. , An Ji Yeong , Min Byung Hoon , Nagaraj Chiranth K. , Wang Lin , Huang Tony Jun , Li Feng , Kim Yong , Wong David T.W. , Reategui Eduardo
Published: January 2025

Gastric cancer (GC) remains a formidable global health challenge, with late-stage diagnosis and high recurrence rates resulting in poor patient outcomes. This study explores the potential of advanced technologies, namely Bessel Beam Excitation Separation Technology (BEST) and multiparametric biochip assay (MBA), to track single extracellular vesicle and particle (EVP) cargo from organs of pathology into biofluids such as plasma and saliva. Using GC as a study model, we conducted high throughput, multiparametric analyses of EVPs derived from plasma, saliva, and tissue samples. Our findings demonstrate the feasibility of these techniques in isolating and characterizing EVPs, revealing consistent EVP morphology and size across biofluids. Furthermore, differential expression patterns of the developed and validated salivary GC biomarkers, miR-140-5p and miR-301a-3p, were observed in GC patient biofluids, supporting the diagnostic relevance of EVP cargo. Notably, saliva emerged as the most promising biofluid for GC diagnosis, achieving superior Receiver Operating Characteristic (ROC) curve values compared to plasma and tissue. This study highlights the role of BEST and MBA in advancing single-EVP analysis and elucidating EVP trafficking, paving the way for future diagnostic applications of EVP cargo.
easyEWAS: a flexible and user-friendly R package for Epigenome-Wide Association Study
Authors: Wang Yuting , Jiang Meijie , Niu Siyuan , Gao Xu
Published: January 2025

Motivation

Rapid advancements in high-throughput sequencing technologies especially the Illumina DNA methylation Beadchip greatly fueled the surge in epigenome-wide association study (EWAS), providing crucial insights into intrinsic DNA methylation modifications associated with environmental exposure, diseases, and health traits. However, current tools are complex and less user-friendly to accommodate appropriate EWAS designs and make downstream analyses and result interpretations complicated, especially for clinicians and public health professionals with limited bioinformatic skills.

Results

We integrated the current state-of-the-art EWAS analysis methods and tools to develop a flexible and user-friendly R packageeasyEWASfor conducting DNA methylation-based research using Illumina DNA methylation Beadchips. WitheasyEWAS, we provide a battery of statistical methods to support differential methylation position analysis across various scenarios, as well as differential methylation region analysis based on the DMRcate method. To facilitate result interpretation, we provide comprehensive functional annotation and result visualization functionalities. Additionally, a bootstrap-based internal validation was incorporated intoeasyEWASto ensure the robustness of EWAS results. Evaluation in asthma patients as the example demonstrated thateasyEWAScould simplify and streamline the conduction of EWAS and corresponding downstream analyses, thus effectively advancing DNA methylation research in public health and clinical settings.

Availability and implementation

easyEWASis implemented as an R package and is available athttps://github.com/ytwangZero/easyEWAS.

Contact

xu.gao@pku.edu.cn,ytwang@pku.edu.cn
Database Permeating through Time, Space, and Medicine: A sequence, structure, and clinical compilation and comparison of transmembrane amino acids in VGL ion channels
Authors: Yeh Frank , Patel Arya , Mun Matthew , Oh Youjin , Aldrich Richard W.
Published: January 2025

Ion channels of the VGL superfamily are extremely diverse in their physiological roles – critical in all excitable cells. Mutations in these channels can cause clinical deficits and symptomologies. With recent advances in sequencing and structural data in the past 30 years, there is a plethora of bioinformatic information that experimentalists can utilize to draw hypotheses about structure and function. However, there is no cohesive database that has compiled this data and presents it in an easily accessible and avoids the confounds of close evolutionary lineages. Here, we seek to fill this gap in resources by compiling and comparing groups of sequences and structures across many channels of the VGL superfamily. Additionally, we corroborate the well-conserved amino acid positions with previous experimental work as well as put forth some understudied but well-conserved amino acid positions that might be fundamental to the certain generalizable mechanisms present in the VGL superfamily channels. To further lend evidence to understudied positions being critical to certain generalizable mechanisms, we also compiled clinical mutation data at these positions across many channels to show the likely functional relevance of these positions. Finally, we will make all of the alignments and resources we generated publicly available athttps://github.com/Frank-Yeh-95/VGLDatabaseCompilationfor ease of hypothesis generation.
Dynamic Face-related Eye Movement Representations in the Human Ventral Pathway
Authors: Su Zhongbin , Zhou Xiaolin , Pollmann Stefan , Wang Lihui
Published: January 2025

Multiple brain areas along the ventral pathway have been known to represent face images. Here, in a magnetoencephalography (MEG) experiment, we show dynamic representations of face-related eye movements in the ventral pathway in the absence of image perception. Participants followed a dot presented on a uniform background, the movement of which represented gaze tracks acquired previously during their free-viewing of face and house pictures. We found a dominant role of the ventral stream in representing face-related gaze tracks, starting from the orbitofrontal cortex (OFC) and anterior temporal lobe (ATL), and extending to the medial temporal and ventral occipitotemporal cortex. Our findings show that the ventral pathway represents the gaze tracks used to explore faces, by which top-down prediction of face category in OFC and ATL may guide, via the medial temporal cortex or directly, face perception in the ventral occipitotemporal cortex.
The Mutated p.H222P A-type Lamins Drive Loxl2-Mediated Extracellular Matrix Remodeling in Both Patient-Derived Cardiomyocytes and Mouse Models of Dilated Cardiomyopathy
Authors: Kervella Marie , Peccate Cecile , Guesmia Zoheir , Grandi Fiorella , Mougenot Nathalie , Forand Anne , Charrabi Azzouz , Brochier Guy , Andriantsitohaina Ramaroson , Meli Albano C. , Muchir Antoine
Published: January 2025

LMNAcardiomyopathy, caused by mutations in theLMNAgene, is a severe form of dilated cardiomyopathy characterized by arrhythmias, contractile dysfunction, and increased myocardial fibrosis, which impairs left ventricular function and predisposes to heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis impeded the development of therapies. We here used patient-derivedLMNAp.H222P cardiomyocytes (hiPSC-CMs) and their isogenic controls and aLmnaH222P/H222Pmouse model to dissect abnormal cardiac mechanisms leading to the development of the disease. We showed thatLMNAp.H222P hiPSC-CMs exhibit elevated diastolic calcium levels and hypocontractility. They displayed nuclear shape abnormalities, a hallmark ofLMNAcardiomyopathy, associated with altered chromosome spatial organization and gene expression profiles. Using transcriptomic analysis, we further revealed that genes related to cardiac extracellular matrix (ECM) remodeling, deposition, and components are dysregulated in bothLMNAp.H222P hiPSC-CMs and mutated mice, suggesting a conserved pathogenic mechanism across species. Conversely, molecular inhibition of Loxl2, a key component of the ECM establishment, preserved the cardiac functionin vivo. Taken together, our findings suggest that targeting Loxl2 could be a promising therapeutic strategy to maintain cardiac function inLMNAcardiomyopathy.
Ancestral and recent bursts of transposition shaped the massive genomes of plant pathogenic rust fungi
Authors: Corre Emma , Morin Emmanuelle , Duplessis Sebastien , Lorrain Cecile
Published: January 2025

Background

Transposable elements (TEs) play a crucial role in genome evolution, influencing gene regulation, diversity, and genome architecture. Rust fungi of the order Pucciniales (Subphylum Pucciniomycotina) are the largest group of obligate biotrophic plant pathogens and harbor some of the largest and most TE-rich genomes - up to 1.2Gb - compared to other fungi. This global genomic expansion contrasts with the smaller genomes and minimal mobilome found in other Pucciniomycotina species. Despite the availability of high-quality genome assemblies, our understanding of TE dynamics in Pucciniales remains limited due to inconsistent and incomplete TE annotations.

Results

We analyzed the mobilomes of 13 Pucciniomycotina species, producing a manually curated TE library for each genome. In Pucciniales, TEs occupy 47–92% of the genome, whereas 2- 36% of TEs are detected in other Pucciniomycotina genomes. The comparison of gene and TE repertoires indicates that TEs, particularly LTR-retrotransposons and TIR-DNA transposons, are the primary contributors to the genome expansion of the Pucciniales. We reconstructed the proliferation histories of TEs in the Pucciniales, combining sequence similarity, clustering, and molecular clock approaches. We highlight recent and ancient TE invasions with some LTR-Gypsy elements predating the divergence of Pucciniomycotina (∼176 Mya), while most TE accumulation in Pucciniales occurred within the last 50 Mya. However, the TE invasions in the Pucciniales genomes do not seem to result from specific deficiencies in known TE-control mechanisms.

Conclusion

Our findings uncover extensive TE proliferation in Pucciniales, predominantly driven by recent LTR-Gypsy expansions. The retention of ancestral TEs and the consistently TE-rich genomes observed in Pucciniales highlight TE proliferation as an ancestral genomic feature in rust fungi.
Myofibroblasts reduce angiogenesis and vasculogenesis in a vascularized microphysiological model of lung fibrosis
Authors: Cambria Elena , Blazeski Adriana , Ko Eunkyung Clare , Thai Tran , Dantes Shania , Barbie David A. , Shelton Sarah E. , Kamm Roger D.
Published: January 2025

Lung fibrosis, characterized by chronic and progressive scarring, has no cure. Hallmarks are the accumulation of myofibroblasts and extracellular matrix, as well as vascular remodeling. The crosstalk between myofibroblasts and vasculature is poorly understood, with conflicting reports on whether angiogenesis and vessel density are increased or decreased in lung fibrosis. We developed a microphysiological system that recapitulates the pathophysiology of lung fibrosis and disentangles myofibroblast-vascular interactions. Lung myofibroblasts maintained their phenotype in 3D without exogenous TGF-β and displayed anti-angiogenic and anti-vasculogenic activities when cultured with endothelial cells in a microfluidic device. These effects, including decreased endothelial sprouting, altered vascular morphology, and increased vascular permeability, were mediated by increased TGF-β1 and reduced VEGF secretion. Pharmacological interventions targeting these cytokines restored vascular morphology and permeability, demonstrating the potential of this model to screen anti-fibrotic drugs. This system provides insights into myofibroblast-vascular crosstalk in lung fibrosis and offers a platform for therapeutic development.
A low-complexity linker as a driver of intra- and intermolecular interactions in DNAJB chaperones
Authors: Hobbs Billy , Limmer Noor , Ossa Felipe , Knüpling Ella , Lenton Samuel , Foderà Vito , Kalverda Arnout P. , Karamanos Theodoros K.
Published: January 2025

J-domain proteins (JDPs) act as major regulators of the proteostasis network by driving the specificity of the Hsp70 machine. Their important functions are mediated by a low-complexity glycine-/phenylalanine-rich region (GF-linker) that links the folded J-domain with the substrate binding domain. Recently, we and others have shown that in an autoinhibited JDP state, an α-helix formed within GF blocks the Hsp70 binding site on the J-domain. However, the role of the disordered GF-linker in autoinhibition and how the latter is released, are still not understood. Here, using autoinhibited DNAJB1 and DNAJB6 constructs, we show that in combination with the J-domain, the GF-linker creates a hydrophobic, partially collapsed cluster that shows a remarkable degree of allosteric communication, disruption of which can lead to destabilisation of autoinhibition. Apart from this crucial intramolecular role, we reveal that the GF-linker can also be recognised by the substrate-binding domain of Hsc70 and dictate the lifetime of the entire JDP–Hsc70 complex. Importantly, both the intra- and intermolecular GF-linker functions are DNAJB-class member-specific.
Highly potent novel multi-armoured IL13Rα2 CAR-T subverts the immunosuppressive microenvironment of Glioblastoma
Authors: Mangolini Maurizio , Srivastava Saket , Souster Emily , Yang Yajing , Wang Huimin , Karattil Rajesh , Schultz Liam , Ma Biao , Pombal Diana , Greenig Matthew , Ramon Aubin , Sormanni Pietro , Cordoba Shaun , Onuoha Shimobi
Published: January 2025

Glioblastoma (GBM) remains one of the most challenging and lethal brain cancers, with limited treatment options. While CAR-T cells have shown promise in some patients, sustaining T-cell activity and overcoming the immunosuppressive tumour microenvironment (TME) remain significant hurdles. Here, we present an armoured CAR-T cell design to address these challenges and enhance persistence in GBM tumours. We developed a highly specific humanised single-domain antibody (VHH) targeting IL13Rα2 and included it alongside four additional modular elements in a single retroviral vector for CAR-T generation. Our results demonstrate that this single-cassette CAR-T cell design possesses high resilience against TGF-β-mediated immunosuppression, enhanced tumour-killing capacity through IL-12 secretion while maintaining a favourable safety profile, extended persistence in the host, and an additional layer of safety control through the incorporation of a suicide switch. Importantly, despite its complexity, the construct can still be manufactured efficiently. These advancements represent a significant step forward in addressing key challenges associated with CAR-T cell therapy in solid tumours.
Localized delivery of corticosteroids via insitumodification of gut commensals using a synthetic stem peptide prodrug
Authors: Baryakova Tsvetelina H. , Yu Marina H. , Segatori Laura , McHugh Kevin J.
Published: January 2025

Oral colonic drug delivery systems (CDDSs) are oftentimes associated with a short duration of action and poor tissue specificity. To address these challenges, we engineered an oral prodrug that leverages the engraftment and semi-permanence of gut commensals to create a long-acting colonic drug depot. We show that two synthetic stem peptide probes can be stereoselectively incorporated onto the surface of gut bacteria in C57BL/6 mice following oral administration. We then show that a prodrug consisting of budesonide, a corticosteroid with otherwise limiting side effects used to treat ulcerative colitis (UC), conjugated to one of these probes via a hydrolyzable ester is significantly less bioactive and is cleaved over a period of days to weeks in simulated physiological fluids. This prodrug can be integrated into the bacterial peptidoglycanin vitroand be cleaved into free budesonide over time, thereby improving drug localization and potentially rendering it safer for longer-term use.

GRAPHICAL ABSTRACT

SIGNIFICANCE

Corticosteroids are highly effective anti-inflammatory drugs used in the treatment of a variety of conditions. Unfortunately, long-term corticosteroid ingestion can lead to a host of dangerous and undesirable side effects including osteoporosis, glaucoma, and a higher risk of infection, among others. Topical corticosteroids delivered via inhalation (chiefly, budesonide and fluticasone) are the primary long-term treatment modality for chronic asthma symptoms. In contrast to oral corticosteroids, they are considered safer for long-term use when given in moderation because they are directly applied to the airways and exhibit low systemic bioavailability. We sought to apply this successful paradigm to another autoimmune-related disease, ulcerative colitis (UC). We developed a drug delivery system that combines the weakly targeting method of ingestion with a highly specific parameter, microbe prevalence along the gastrointestinal tract, to help improve the specificity and colonic retention of the corticosteroid budesonide, which is currently limited to being used as a short-term treatment for moderate-to-severe UC. Our approach utilizes a largely inert prodrug that can be incorporated into the peptidoglycan of commensal bacteria found at high densities in the colon. After tethering to the bacterial surface via a synthetic stem peptide, the prodrug passively hydrolyzes (cleaves) to release the active, unadulterated form of the drug into the local area, whereas prodrug that traffics elsewhere has a higher chance of being cleared from the body before cleavage. In this manner, we can achieve targeted immunosuppression and sustained release, rendering corticosteroids, and potentially other small molecules, safer for longer term use in treating patients with UC.
Exploring the Role of Kv1.3 and MAPK14 in Mediating Microglial Oxidative Stress and Neuroinflammation Following Organic Dust Exposure
Authors: Massey Nyzil , Bhat Sanjana Mahadev , Shrestha Denusha , Malovic Emir , Karriker Locke A. , Choudhary Shivani , Robertson Alan P. , Nguyen Hai Minh , Wulff Heike , Kanthasamy Anumantha G. , Charavaryamath Chandrashekhar
Published: January 2025

Background

Agricultural contaminants, including inhaled organic dust (OD) and gases, are known to cause inflammation in the lungs and the brain. We investigated the role of the potassium channel Kv1.3 in organic dust (OD)-induced neuroinflammation models. Kv1.3 channels play a multifaceted role in microglial immune modulation, cancer, neurodegenerative diseases, and constitute a potential therapeutic target.

Methods

We usedin vivo(C57BL/6 mice),in vitro(microglial cell line, primary microglia), andex vivo(brain slice culture) models of OD-induced neuroinflammation. A sterile OD extract (ODE) was prepared, and mice were exposed to either normal saline or ODE intra-nasally for 5 weeks (5 days/week) to simulate an occupational exposure scenario. Primary microglia were isolated from neonatal mice for total RNA sequencing (RNA-seq). The ODE-induced expression of Kv1.3 was quantified usingin vitroandex vivomodels with and without PAP-1 treatments. Exposure-induced changes in cytokines and reactive species markers were measured. Using western blot, we quantified phosphorylated p38 MAPK14 (p-p38 MAPK) and NOX2. We measured the currents through Kv1.3 channels using a microglial patch-clamp assay.

Results

Exposure to ODE increased the expression of Kv1.3 and p-p38 MAPK in mouse microglia without affecting the Kv1.3 currents at the cell surface. Exposure increased the levels of inflammatory cytokines and NOX2. Kv1.3 inhibition with PAP-1 decreased inflammatory markers (TNF-α and IL-6), levels of Kv1.3, p-p38 MAPK, NOX2, and nitrites.

Conclusion

Our study revealed that pharmacological inhibition of Kv1.3 potassium channels reduces ODE-induced neuroinflammation by decreasing inflammatory and oxidative stress markers.
Broad PFAS binding with fatty acid binding protein 4 is enabled by variable binding modes
Authors: Birchfield Aaron S. , Musayev Faik N. , Castillo Abdul J. , Zorn George , Fuglestad Brian
Published: January 2025

Per- and polyfluoroalkyl substances (PFAS) are ubiquitous pollutants that bioaccumulate in wildlife and humans, yet the molecular basis of their protein interactions remains poorly understood. Here, we show that human adipocyte fatty acid-binding protein (FABP4) can bind a diverse array of PFAS, including next-generation replacements for legacy chemicals and longer-chain perfluorocarboxylic acids. Shorter-chain PFAS, although weaker binders, still displayed measurable affinities—surpassing those of their nonfluorinated analogs. We determined crystal structures of FABP4 bound to perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), and perfluorohexadecanoic acid (PFHxDA), revealing three distinct binding modes. Notably, PFOA binds in two separate sites, and two distinct conformations define single-ligand binding of PFDA and PFHxDA. These arrangements enhance hydrophobic interactions within the binding cavity and likely explain the low micromolar dissociation constants observed in fluorescence competition assays. Our findings underscore the critical roles of chain length, headgroup functionality, and protein conformation in PFAS–FABP4 interactions. Given the emerging implications of the role of FABP4 in endocrine function, even subtle PFAS-induced perturbations could affect metabolic regulation and disease risk. Overall, this work highlights the value of direct structural and biochemical insights into PFAS–FABP4 interactions and paves the way for future research on PFAS transport and toxicological outcomes.
Noncoding elements withinMYCNmRNA are autonomous drivers of oncogenesis in neuroblastoma
Authors: Patel Vishwa , Benhamou Lorraine-Rana E. , Powers John T.
Published: January 2025

Neuroblastoma (NB) is a highly metastatic pediatric cancer arising from the neural crest lineage. Genetic amplification of theMYCNproto-oncogene is a defining feature of NB, present in about 20% of all cases. Thelet-7tumor suppressor microRNA targets the 3’ UTR ofMYCNmRNA. We previously demonstrated that the 3’ UTR ofMYCNmRNA acquires the ability to sequesterlet-7inMYCN-amplified (MA) disease, thus inhibiting its function. This work established that a noncoding element within an oncogenic mRNA can contribute independently to disease pathology and genetic patterning. To further investigate the roles of noncoding RNA elements within theMYCNmRNA, we engineered cells expressing eitherMYCN-ORF(MYCN open reading frame only),MYCN-GL(full-length MYCN mRNA from the intact genetic locus), andNull-GL(full-lengthMYCNmRNA variant where EGFP replaces MYCN protein). We observe that all constructs enhance growth compared to controlsin vitroandin vivo. MYCN-GL-expressing cells displayed the most robust growthin vitrodespite containing multiple regulatory RNA elements. Remarkably, theNull-GLconstruct induces cells to grow as fast or faster thanMYCN-ORF-expressing cells. Animal studies further confirmed these observations, where theNull-GL-driven tumors had the highest incidence and lowest latency, followed byMYCN-GLand thenMYCN-ORF. Further, through NGS analysis,let-7, miR-101, andmiR-34atargets are enriched in bothMYCN-GLandNull-GLexpressing cells. Thus, the 3’UTR ofMYCN, which is also targeted by these microRNAs, may interact with them inMYCN-GLandNull-GLcells to deliver a protective effect for the mRNA targets of these microRNAs. We also observed more dynamic differential gene expression in the -GL constructs than in ORF and GFP-expressing cells. In addition,MYCN-GLandNull-GLexpressing cells are similarly enriched in gene ontology pathways for cancer, RNA metabolism, and microRNA processing pathways as compared toORFandGFP. Whole genome sequencing also revealed more similarities in copy number variation inMYCN-GLandNull-GLthan inORFandGFP, suggesting that these constructs may provide selective pressure to favor specific CNV patterns. These observations show that full-lengthMYCNmRNA containing noncoding regulatory elements are more robust drivers of cell growth and oncogenicity than MYCN protein alone and provide insights into the mechanisms of oncogenic contribution. These results open an exciting door for our understanding of NB pathology and genetic patterning and have broad implications for other oncogene-driven cancers.
Wildfire ash impacts to photosynthesis and growth of marine phytoplankton cultures
Authors: Van Houtan Kyle S. , Lambert John , Provatas Anthony A. , Van Houtan Dillon J. , Smith Celia M.
Published: January 2025

Climate change includes increasing surface temperatures as well as extreme events—heatwaves, storms, floods, and droughts. In 2020, these factors produced a record 10,000 wildfires that burned 18,000 km2in California USA. Air pollution, including airborne ash, from these fires was a widespread human health hazard. While the ecological effects of wildfires have been extensively documented in terrestrial and freshwater systems, impacts on ocean and coastal ecosystems are largely unexplored. Here, we describe the physical and chemical properties of ash from the CZU Lightning Complex fire and experimentally test its effects on the photosynthesis and growth of four unicellular marine phytoplankton. Sieved air-fall ash was primarily composed of particles 250-500 μm and contained ∼1 ‰ of Fe, Mn, and Ba. Diagnostic indices of polycyclic aromatic hydrocarbons indicated the air-fall ash originated from combusted wood, and the total concentration of the EPA 16 high-priority PAHs exceeded 2.7 ppm. Pulse Amplitude Modulation fluorometry documented various declines in the photosynthetic efficiency of Isochrysis and Dunaliella cultures dosed with ash, and the bulk cellular growth of these cultures was inhibited. While our study demonstrated the impacts of wildfire ash on marine producers, the precise mechanisms are unclear. We provide recommendations for how future studies may further resolve the impacts of ash on phytoplankton productivity, community diversity, and trophic transfer of toxins and describe the long-term impacts of wildfires on coastal marine ecosystems.
The Population Genetics of Biological Noise
Authors: Weinreich Daniel M. , Sgouros Tom , Raynes Yevgeniy , Burtsev Hlib , Chang Edison , Rajakumar Sanyu , Bravo Ignacio G. , Petak Csenge
Published: January 2025

Noise is intrinsic to information transmission, and information transmission is intrinsic to life. Critically, while biological noise is random, its amount is in part genetically determined. Here, we explore the population genetics of alleles that heritably influence the amount of noise in any biological mechanism. We argue that biological noise is a doubleedged sword: almost always inducing deleterious phenotypes but also occasionally yielding high fitness outcomes. We further suggest that this implies the existence of an equilibrium amount of noise, at which the advantage of producing additional, rare beneficial phenotypes is balanced by the cost of producing the vastly more common deleterious phenotypes. The location of this equilibrium will reflect the rate at which its environment is changing, the persistence of association between noise-modifying alleles and the phenotypic perturbations they induce, the mode of selection, and the population size. The population genetics of alleles that heritable change mean trait values have been established for nearly a century, but to our knowledge, this is the first general treatment of the evolution of heritable changes in the statistical distribution around that mean. Our framework generalizes modifier theory in the sense used by Altenberg, Feldman and others, and resolves teleological criticisms of the hypothesis that evolvability can evolve via natural selection. We conclude with an outline of open theoretical and empirical questions posed by our framework.
The structure of mitochondrial genomes is associated with geography inArabidopsis thaliana
Authors: Xian Wenfei , Bao Zhigui , Vorbrugg Sebastian , Tao Yueqi , Movilli Andrea , Bezrukov Ilja , Weigel Detlef
Published: January 2025

Chloroplasts and mitochondria are the primary sites for photosynthesis and respiration, each harboring its own unique genome. Although the organellar genomes are considerably smaller compared to the nuclear genome, they are nonetheless essential for survival of the organism. A common feature of many chloroplast and mitochondrial genomes is the presence of large repeated sequences longer than 1 kb. These can be either in inverted or direct orientation, and recombination between them leads to structural heteroplasmy. To understand the intraspecific evolution of organellar genomes, we assembled chloroplast and mitochondrial genomes of 143A. thalianaaccessions from PacBio HiFi sequencing data. We find large repeats to be associated with heteroplasmy and structural variation. Our extensive genome annotation identifies novel open reading frames (ORFs) in those accessions that lost large repeats, potentially introduced via horizontal gene transfer, illuminating additional paths for diversification of plant organelles. The loss of large repeats correlates with geography and phenotypes, pointing to their adaptive importance. The assembled and annotated organellar genomes constitute a rich source for future functional studies of the interaction between the three genomes of a plant.
Prospective Blinded evaluation of Thermalytix, an artificial intelligence-enhanced breast thermal imaging software, correlated with radiologist-interpreted mammograms: Results of an exploratory study in Zambia
Authors: Mwale Maurice , Nteeni Mutinta S. , Mwaba Peter , Chipamp Mercy N.
Published: January 2025

Background

While mammography is commonly used for breast cancer detection, its widespread implementation in resource-constrained nations is challenging. Artificial intelligence-based Thermalytix is a low-cost, portable, radiation-free, automated test for breast cancer detection in women of all ages. Although used in India, the efficacy of Thermalytix has not been tested in an African population.

Objectives

To assess the agreement and correlation coefficient of Thermalytix output with radiologist-reported mammography, in a Zambian tertiary care population.

Methodology

In October 2023, 169 women were evaluated with both Thermalytix and standard mammography at Maina Soko Military Hospital at Lusaka. Thermalytix uses advanced machine learning algorithms to interpret breast thermal scans and generates a quantitative score indicating the likelihood of malignancy. All women underwent both tests, with results blinded both ways. Subsequently the Spearman correlation coefficient and level of agreement between Thermalytix output and BIRADs scoring from radiologist-interpreted mammography was calculated.

Results

144 women with complete data were analysed in this report, with median age of 50 years (53.5% postmenopausal, 65.3% asymptomatic). Six women were assessed as mammography test positive and 138 as mammography negative; in these, the correlation between Thermalytix and mammography using Spearman test of rank correlation was 0.9 [very strong], and using the US FDA recommended test of agreement, positive agreement was obtained in 83.3%.

Conclusion

Demonstrating a very strong correlation and level of agreement with mammography, along with its good sensitivity, specificity and negative predictive value in previous clinical trials, Thermalytix has the potential to be an additional tool in the early detection of breast cancer in Zambia.
Efficacy of Preemptive Intravenous Ibuprofen and Dexketoprofen on Postoperative Opioid Consumption in Laparoscopic Cholecystectomy: Randomized Controlled Study
Authors: Soyalp Celaleddin , Yayik Ahmet Murat , Öksüz Ersoy , Yüzkat Nurettin
Published: January 2025

Background

To compare the effects of preemptive single-dose intravenous (IV) ibuprofen and dexketoprofen on postoperative pain and opioid consumption in patients undergoing laparoscopic cholecystectomy (LCC).

Methods

The study included 90 patients aged 18-65 years with an ASA score of I or II who underwent LCC. Patients were equally divided into three groups: Control Group (Group P), 100 cc 0.9% NaCl was infused intravenously over 30 min, Dexketoprofen Group (Group D), 50 mg dexketoprofen in 100 cc 0.9% NaCl was infused intravenously over 30 min, and Ibuprofen Group (Group I), 800 mg ibuprofen in 100 cc 0.9% NaCl was administered intravenously over 30 min. Visual Analog Scale (VAS) scores and opioid requirement were recorded at 1, 2, 4, 6, 12 and 24 hours postoperatively.

Results

There was no significant difference between the Dexketoprofen and Ibuprofen groups with regard to VAS scores, whereas VAS scores were higher in the control group than in other groups. In addition, fentanyl consumption was higher in the control group at 0-6 hours and at 24 hours compared to the other two groups.

Conclusion

Preemptive ibuprofen and dexketoprofen administration showed no significant difference with regard to postoperative pain and opioid consumption, particularly within the first 6 hours after LCC.
Overturning circulation structures the microbial functional landscape of the South Pacific
Authors: Kolody Bethany Cristine , Sachdeva Rohan , Zheng Hong , Fussy Zoltan , Tsang Eunice , Sonnerup Rolf E , Purkey Sarah G , Allen Eric E , Banfield Jill F , Allen Andrew E.
Published: January 2025

Global overturning circulation partitions the deep ocean into regions with unique physicochemical characteristics, but the extent to which these water masses represent distinct ecosystems remains unknown. Here, we integrate extensive genomic information with hydrography and water mass age to delineate microbial taxonomic and functional boundaries across the South Pacific. Prokaryotic richness steeply increases with depth in the surface ocean, forming a "phylocline", below which richness is consistently high, dipping slightly in highly aged water. Reconstructed genomes self-organize into six spatially-distinct taxonomic cohorts and ten functionally-distinct biomes that are primarily structured by wind-driven circulation at the surface and density-driven circulation at depth. Overall, water physicochemistry, modulated at depth by water age, drives microbial diversity and functional potential in the pelagic ocean.
Distinct CD8+T-cell types Associated with COVID-19 Severity in Unvaccinated HLA-A2+Patients
Authors: Masuda Kazuya , Iketani Sho , Liu Lihong , Huang Jing , Qiao Yujie , Shah Jayesh , McNairy Meredith L. , Groso Christine , Ricupero Christopher , Loffredo Lucas F. , Wang Qian , Purpura Lawrence , Coelho-dos-Reis Jordana Grazziela Alves , Sheng Zizhang , Yin Michael T , Tsuji Moriya
Published: January 2025

Although emerging data have revealed the critical role of memory CD8+T cells in preventing and controlling SARS-CoV-2 infection, virus-specific CD8+T-cell responses against SARS-CoV-2 and its memory and innate-like subsets in unvaccinated COVID-19 patients with various disease manifestations in an HLA-restricted fashion remain to be understood. Here, we show the strong association of protective cellular immunity with mild COVID-19 and unique cell types against SARS-CoV-2 virus in an HLA-A2 restricted manner. ELISpot assays reveal that SARS-CoV-2-specific CD8+T-cell responses in mild COVID-19 patients are significantly higher than in severe patients, whereas neutralizing antibody responses against SARS-CoV-2 virus significantly correlate with disease severity. Single-cell analyses of HLA-A2-restricted CD8+T cells, which recognize highly conserved immunodominant SARS-CoV-2-specific epitopes, demonstrate divergent profiles in unvaccinated patients with mild versus severe disease. CD8+T-cell types including cytotoxicKLRB1+CD8αα cells with innate-like T-cell signatures,IFNGhiID3himemory cells andIL7R+proliferative stem cell-like memory cells are preferentially observed in mild COVID-19, whereas distinct terminally-differentiated T-cell subsets are predominantly detected in severe COVID-19: highly activatedFASLhiT-cell subsets and early-terminated or dysfunctionalIL4R+GATA3+stem cell-like memory T-cell subset. In conclusion, our findings suggest that unique and contrasting SARS-CoV-2-specific CD8+T-cell profiles may dictate COVID-19 severity.

Abstract Figure

Graphical abstract.

SARS-CoV-2 epitope-specific CD8+T-cell subtypes associated with mild or severe COVID-19 patients.

Potent memory CD8+T-cell subtypes with gene signature in mild COVID-19 patients (upper) and dysfunctional CD8+T-cell subtypes with gene signature in severe COVID-19 patients (lower).
Lower slow wave sleep and rapid eye-movement sleep are associated with brain atrophy of AD-vulnerable regions
Authors: Cho Gawon , Mecca Adam P. , Buxton Orfeu M. , Liu Xiao , Miner Brienne
Published: January 2025

Study objectives

Sleep deficiency is associated with Alzheimer’s disease (AD) pathogenesis. We examined the association of sleep architecture with anatomical features observed in AD: (1) atrophy of hippocampus, entorhinal, inferior parietal, parahippocampal, precuneus, and cuneus regions (“AD-vulnerable regions”) and (2) cerebral microbleeds.

Methods

In 271 participants of the Atherosclerosis Risk in the Communities Study, we examined the association of baseline sleep architecture with anatomical features identified on brain MRI 13∼17 years later. Sleep architecture was quantified as the proportion of slow wave sleep (SWS), proportion of rapid eye-movement sleep (REM), and arousals index using polysomnography. Outcomes included (1) volumetric measurements of each AD-vulnerable region and (2) the presence of any cerebral microbleeds (CMBs) and that of lobar CMBs, which are more specifically associated with AD. We analyzed the association of each sleep predictor with each MRI outcome, adjusting for covariates.

Results

Having less SWS was associated with smaller inferior parietal region (β=−44.19 mm3[95%CI=−76.63,−11.76]) and cuneus (β=−11.99 mm3[−20.93,−3.04]) after covariate adjustment. Having less REM was associated with smaller inferior parietal region (β=−75.52 mm3[−129.34, −21.70]) and precuneus (β=−31.93 mm3[−63.79,−0.07]). After FDR adjustments, lower SWS and REM, respectively, were associated with smaller inferior parietal region. Arousal index was not associated with the volumes of AD-vulnerable regions. None of the sleep architecture variables were associated with CMBs or lobar CMBs.

Conclusions

Sleep deficiency is associated with the atrophy of the inferior parietal region, which is observed in early AD. Sleep architecture may be a modifiable risk factor for AD.

Brief summary

a.

Current Knowledge/Study Rationale: two sentences summarizing why the study was done

While impaired sleep architecture has been associated with Alzheimer’s disease [AD] diagnosis and cognitive decline. To better understand the impact of sleep on AD pathogenesis, this study examined the association of sleep architecture with anatomical features observed in AD, including the atrophy of AD-vulnerable regions and CMBs.

b.

Study Impact: two sentences summarizing how the study impacts the field

Our study shows that lower slow wave sleep and rapid eye movement sleep may be precipitating factors of inferior parietal region atrophy, which is associated with AD risk. Importantly, the current study’s findings can help characterize underlying mechanisms of how sleep deficiency, a prevalent disturbance among middle-aged and older adults, may facilitate AD pathogenesis and cognitive impairment.
Hormone gene expression changes in the zebrafish caudal neurosecretory system under acute environmental challenges
Authors: Bichon Bérénice , Alfama Gladys , Gaillard Anne-Laure , Tostivint Hervé , Pézeron Guillaume
Published: January 2025

The caudal neurosecretory system (CNSS) is a neuroendocrine complex, found only in fishes, suggested to be involved in osmoregulation and thermo-adaptation. Although being discovered 70 years ago, the CNSS has been understudied and its physiological significance remains poorly understood. The zebrafish (Danio rerio) is a well-established model organism for functional studies, yet, so far, the role of the CNSS has not really been investigated in this species. In the present study, we attempted to identify environmental factors whose variations induce changes in CNSS activity. Juvenile zebrafish were submitted to acute (2 h, 8 h, and 24 h) pH, salinity, and temperature challenges, and CNSS activity was quantified by measuring the expression levels of peptide hormone-encoding genes using quantitative PCR. Our findings revealed that temperature challenge affected the expression of the largest number of gene, followed by salinity and pH challenges. This suggested that, in the zebrafish, the CNSS is involved in thermo-adaptation and osmoregulation, which is consistent with what has been reported in other species, and showed that the zebrafish is a relevant model to study the function of the CNSS.
Detection of resistance inPhytophthora infestansto the carboxylic acid amide (CAA) fungicides using digital droplet PCR
Authors: Kaur Amanpreet , Mullins Ewen , Kildea Steven
Published: January 2025

Background

Potato late blight caused byPhytophthora infestansremains the greatest biotic threat to potato production globally. In northern Europe to prevent the disease and associated yield losses fungicides are heavily relied upon, with multiple applications required during the potato growing season. Unfortunately, such intensive fungicide usage has the potential to compromise control efficacy as it puts in place immense selective pressure for the emergence and spread of fungicide resistant strains ofP. infestans. In recent years this scenario has been realised, with the emergence of strains resistant to the carboxylic acid amide (CAA) fungicides. As resistance to the CAA fungicides inP. infestanshas been confirmed to result from changes in the pathogen’s cellulose synthase A3 gene (CesA3), specifically at amino acid position 1105, it opens the possibility to develop molecular tools to rapidly monitor populations of the pathogen for the resistance allele.

Results

Using the Stilla nacia 3-colour system a droplet digital PCR (ddPCR) was successfully developed to simultaneously detect theP. infestans CesA3gene irrespective of its CAA sensitivity status, and either the CAA wild-type sequence for position 1105 or that conferring the resistant allele G1105S. Using a ‘drop-off’ in ratio of positive droplets for either the wild-type or G1105S alleles relative to those positive for the generalP. infestansCesA3 it was also possible to demonstrate that using the assay other potential alterations known to confer resistance that may occur at this position (e.g. G1105V) can be detected. The assay was validated using multiple sources ofP. infestansDNA, including FTA cards.

Conclusions

The assay developed will allow for the accurate and sensitive detection of CAA resistance conferred by alterations at amino acid position 1105 in the CesA3 gene inP. infestans. The capacity to use the assay with multiple DNA sources and potential to adapt the ‘drop-off’ approach to different ddPCR platforms will ensure its applicability to the widerP. infestanscommunity in monitoring the continued use of CAA-based fungicides forP. infestansmanagement.
Structures of vesicular stomatitis virus glycoprotein G alone and in complex with a neutralizing antibody
Authors: Minoves Marie , Ouldali Malika , Belot Laura , Roche Stéphane , Zakardas Lefteris , Schoehn Guy , Gaudin Yves , Albertini Aurélie
Published: January 2025

VSV G mediates viral entryviaendocytosis. In the endosome, G undergoes a pH-dependent conformational change from pre- to post-fusion state, catalyzing membrane fusion. So far, no complete structure of G has been reported. We report cryo-EM structures of G, isolated from virions using detergent, alone and in complex with neutralizing antibody FAb that binds G in all conformations. The post-fusion structure reveals novel details about the organization of the C-terminal part of the ectodomain, showing that it undergoes conformational rearrangement and stabilizes the post-fusion trimer by nesting into a groove between adjacent fusion domains. The fusion loops are visible inside the micelle, which is not the case of the transmembrane domains, suggesting that they are rather mobile. Structures of G-FAb complex show that the epitope belongs to a conserved antigenic site. This work has potential implications for vaccine development and oncolytic virotherapy.
EEG-Informed fMRI Analysis Reveals Neurovascular Coupling in Motor Execution and Imagery
Authors: Bondi Elena , Ding Yidan , Zhang Yisha , Maggioni Eleonora , He Bin
Published: January 2025

The complementary strengths of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have driven extensive research into integrating these two noninvasive modalities to better understand the neural mechanisms underlying cognitive, sensory, and motor functions. However, the precise neural patterns associated with motor functions, especially imagined movements, remain unclear. Specifically, the correlations between electrophysiological responses and hemodynamic activations during executed and imagined movements have not been fully elucidated at a whole-brain level. In this study, we employed an EEG-informed fMRI approach on concurrent EEG-fMRI data to map hemodynamic changes associated with dynamic EEG temporal features during motor-related brain activities. We localized and differentiated the hemodynamic activations corresponding to continuous EEG temporal dynamics across multiple motor execution and imagery tasks. Validation against conventional block fMRI analysis demonstrated high precision in identifying regions specific to motor activities, underscoring the accuracy of the EEG-driven model. Beyond the expected sensorimotor activations, the integrated analysis revealed supplementary coactivated regions showing significant negative covariation between blood oxygenation level-dependent (BOLD) activities and sensorimotor EEG alpha power, including the cerebellum and insular cortex. These findings confirmed both the colocalization of EEG and fMRI activities in sensorimotor regions and a negative covariation between EEG alpha band power and BOLD changes. Moreover, the results provide novel insights into neurovascular coupling during motor execution and imagery on a brain-wide scale, advancing our understanding of the neural dynamics underlying motor functions.