bluuebunny/crossref_metadata_2025 huggingface dataset:
Deep Ensemble Model for Quantitative Optical Property and Chromophore Concentration Images of Biological Tissues
Authors: Yan Bingbao , Song Bowen , Ge Chang , Yin Xinman , Jia Wenchao , Mu Gen , Zhao Yanyu
Published: December 2024

The ability to quantify widefield tissue optical properties (OPs, i.e., absorption and scattering) has major implications on the characterization of various physiological and disease processes. However, conventional image processing methods for tissue optical properties are either limited to qualitative analysis, or have tradeoffs in speed and accuracy. The key to quantification of optical properties is the extraction of amplitude maps from reflectance images under sinusoidal illumination of different spatial frequencies. Conventional three-phase demodulation (TPD) method has been demonstrated for the mapping of OPs, but it requires as many as 14 measurement images for accurate OP extraction, which leads to limited throughput and hinders practical translation. Although single-phase demodulation (SPD) method has been proposed to map OPs with a single measurement image, it is typically subject to image artifacts and decreased measurement accuracy. To tackle those challenges, here we develop a deep ensemble model (DEM) that can map tissue optical properties with high accuracy in a single snapshot, increasing the measurement speed by 14× compared to conventional TPD method. The proposed method was validated with measurements on an array of optical phantoms,ex vivotissues, andin vivotissues. The errors for OP extraction were 0.83 ± 5.0% for absorption and 0.40 ± 1.9% for reduced scattering, dramatically lower than that of the state-of-the-art SPD method (2.5 ± 15% for absorption and -1.2 ± 11% for reduced scattering). It was further demonstrated that while trained with data from a single wavelength, the DEM can be directly applied to other wavelengths and effectively obtain optical property and chromophore concentration images of biological tissues. Together, these results highlight the potential of DEM to enable new capabilities for quantitative monitoring of tissue physiological and disease processes.
MerQuaCo: a computational tool for quality control in image-based spatial transcriptomics
Authors: Martin Naomi , Olsen Paul , Quon Jacob , Campos Jazmin , Cuevas Nasmil Valera , Nagra Josh , VanNess Marshall , Maltzer Zoe , Gelfand Emily C , Oyama Alana , Gary Amanda , Wang Yimin , Alaya Angela , Ruiz Augustin , Reynoldson Cade , Bielstein Cameron , Pom Christina Alice , Huang Cindy , Slaughterbeck Cliff , Liang Elizabeth , Alexander Jason , Ariza Jeanelle , Malone Jocelin , Melchor Jose , Colbert Kaity , Brouner Krissy , Shulga Lyudmila , Reding Melissa , Latimer Patrick , Sanchez Raymond , Barta Stuard , Egdorf Tom , Madigan Zachary , Pagan Chelsea M , Close Jennie L , Long Brian , Kunst Michael , Lein Ed S , Zeng Hongkui , McMillen Delissa , Waters Jack
Published: December 2024

Image-based spatial transcriptomics platforms are powerful tools often used to identify cell populations and describe gene expression in intact tissue. Spatial experiments return large, high-dimension datasets and several open-source software packages are available to facilitate analysis and visualization. Spatial results are typically imperfect. For example, local variations in transcript detection probability are common. Software tools to characterize imperfections and their impact on downstream analyses are lacking so the data quality is assessed manually, a laborious and often a subjective process. Here we describe imperfections in a dataset of 641 fresh-frozen adult mouse brain sections collected using the Vizgen MERSCOPE. Common imperfections included the local loss of tissue from the section, tissue outside the imaging volume due to detachment from the coverslip, transcripts missing due to dropped images, varying detection probability through space, and differences in transcript detection probability between experiments. We describe the incidence of each imperfection and the likely impact on the accuracy of cell type labels. We develop MerQuaCo, open-source code that detects and quantifies imperfections without user input, facilitating the selection of sections for further analysis with existing packages. Together, our results and MerQuaCo facilitate rigorous, objective assessment of the quality of spatial transcriptomics results.
Whole mitochondrial genome analysis ofAedes aegyptireveal association withWolbachiainfection
Authors: Gupta Bhavna , Sumitha Melveettil Kishor , Pandiyan G Navaneetha , Kalimuthu Mariapillai , Paramasivan Rajaiah , Rahi Manju
Published: December 2024

The mitochondrial genomes (mitogenomes) of nineAedes aegyptisamples from India were analysed along with 34 mitogenomes from global samples retrieved from GenBank. The mitogenome size of Indian samples ranged from 15,730 bp to 16,374 bp. A total of 199 genetic variants were identified among Indian samples, with the majority (90%) occurring in protein-coding genes, followed by rRNA and tRNA genes. Phylogenetic analysis of the 43 genomes revealed two major clades. The similar clustering pattern was observed in the traditional mitochondrial markers for which extensive global data is available, indicating that individual mitochondrial markers ofAe. aegyptishare the common genealogy as reflected by the complete mitogenome. In addition to exploring genetic diversity, we investigated the relationship of these two mitochondrial clades withWolbachiainfection. Our analysis revealed thatWolbachia-infected samples were predominantly located within one of the mitochondrial clades, suggesting a potential association between specific mitochondrial lineage andWolbachiainfection. This analysis demonstrates the extent of genetic diversity inAe. aegyptimitogenome and highlights how this diversity is associated withWolbachiainfection, a maternally inherited endosymbiont. These findings have implications for the effectiveness ofWolbachia-based mosquito control strategies.
Protein2Text: Providing Rich Descriptions for Protein Sequences
Authors: Dotan Edo , Lyubman Iris , Bacharach Eran , Pupko Tal , Belinkov Yonatan
Published: December 2024

Understanding the functionality of proteins has been a focal point of biological research due to their critical roles in various biological processes. Unraveling protein functions is essential for advancements in medicine, agriculture, and biotechnology, enabling the development of targeted therapies, engineered crops, and novel biomaterials. However, this endeavor is challenging due to the complex nature of proteins, requiring sophisticated experimental designs and extended timelines to uncover their specific functions. Public large language models (LLMs), though proficient in natural language processing, struggle with biological sequences due to the unique and intricate nature of biochemical data. These models often fail to accurately interpret and predict the functional and structural properties of proteins, limiting their utility in bioinformatics. To address this gap, we introduce BetaDescribe, a collection of models designed to generate detailed and rich textual descriptions of proteins, encompassing properties such as function, catalytic activity, involvement in specific metabolic pathways, subcellular localizations, and the presence of particular domains. The trained BetaDescribe model receives protein sequences as input and outputs a textual description of these properties. BetaDescribe’s starting point was the LLAMA2 model, which was trained on trillions of tokens. Next, we trained our model on datasets containing both biological and English text, allowing biological knowledge to be incorporated. We demonstrate the utility of BetaDescribe by providing descriptions for proteins that share little to no sequence similarity to proteins with functional descriptions in public datasets. We also show that BetaDescribe can be harnessed to conductin-silicomutagenesis procedures to identify regions important for protein functionality without needing homologous sequences for the inference. Altogether, BetaDescribe offers a powerful tool to explore protein functionality, augmenting existing approaches such as annotation transfer based on sequence or structure similarity.
A feline model of human LDLR-related atherosclerosis
Authors: Hytonen Marjo K , Karkamo Veera , Hundi Sruthi , Airas Niina , Kaukonen Maria , Sukura Antti , Lyons Leslie A , Anderson Heidi A , Kareinen Ilona , Lohi Hannes
Published: December 2024

Background: Atherosclerosis, a chronic inflammatory vascular disease driven by the accumulation of LDL-derived cholesterol on arterial walls, is the leading cause of mortality worldwide but is rare in animals. We recently identified spontaneous atherosclerosis in the Korat cat breed, characterized by severe hypercholesterolemia and clinical signs of congestive heart failure, ultimately leading to death. Histopathological examination revealed lesions similar to those observed in human atherosclerosis. Given the close genetic relationship among affected cats, we hypothesized a genetic basis for the condition. Methods: We expanded our sample recruitment and employed whole genome sequencing to identify genetic variants associated with the condition. Results: We identified a homozygous XM_003981898.6:c.2406G>A variant specific to the cases in the LDLR gene. This variant is predicted to result in a premature stop codon, XP_003981947.3:p.Trp758*, leading to a truncated LDLR protein that lacks the last 108 amino acids, including the transmembrane and intracellular C-terminal domains. Genotyping this LDLR variant in an additional cohort of 309 Korat cats confirmed its segregation and revealed new affected cats for clinical follow-up. In silico analyses demonstrated that the identified variant appears optimal for gene-editing-based therapeutics. Conclusions: This is the first report of a spontaneous atherosclerosis animal model with an LDLR variant, the most common gene associated with familial hypercholesterolemia in humans. Given that PCSK9, another known hypercholesterolemia gene, has been lost in many mammalian genomes, including cats, our study provides an exciting double knockout model for human atherosclerosis. The affected Korats may also serve as a valuable model for DNA base editing therapeutics.
Zymoseptoria triticistealth infection is facilitated by stage-specific down-regulation of a β-glucanase
Authors: Rebaque Diego , Carrasco-López Cristian , Krishnan Parvathy , López Gemma , López-Cobos Sergio , de Salas Felipe , Meile Lukas , Lorrain Cécile , Largo-Gosens Asier , McDonald Bruce A. , Vilaplana Francisco , Martinez Maria Jesus , Mélida Hugo , Molina Antonio , Sánchez-Vallet Andrea
Published: December 2024

Plant cell walls constitute a major defence barrier against pathogens, although it is unclear how specific cell wall components impact pathogen colonisation. Pathogens secrete cell wall degrading enzymes (CWDEs) to facilitate plant colonisation, but damaged, infected cells are often a source of cell wall-derived oligosaccharides that trigger host immunity. The mechanisms by which pathogens minimize the release of cell wall-derived oligosaccharides while colonizing the host remain to be elucidated. We combined biochemical, molecular genetics and transcriptomic analyses to functionally characterize a glycoside hydrolase (ZtGH45) from the wheat pathogenZymoseptoria tritici.ZtGH45gene is expressed during the necrotrophic phase of the fungus, coinciding with an accumulation of wheat β-1,3/1,4-mixed-linked glucan (MLG)-derived oligosaccharides. We show that overexpression ofZtGH45enhances β-1,3/1,4-glucan hydrolysis and the derived oligosaccharides trigger an immune response in wheat, which hindersZ. triticivirulence. The results demonstrate that tight regulation ofZtGH45is critical for the infection process to prevent early accumulation of MLG oligosaccharides that would prematurely induce host immunity counterbalancing fungal virulence. We suggest that the balance between plant cell wall degradation by fungal CWDE and the release of immunogenic wall-derived oligosaccharides governs the outcome of host invasion by pathogens.
ERGA-BGE Reference Genome of the Striped Field Mouse (Apodemus agrarius), a Widespread and Abundant Species in Central and Eastern Europe
Authors: Janžekovič Franc , Buzan Elena , Bončina Aja , Escudero Nuria , Fernández Rosa , Böhne Astrid , Monteiro Rita , Aguilera Laura , Gut Marta , Ferreira Francisco Câmara , Cruz Fernando , Gómez-Garrido Jèssica , Alioto Tyler S. , Haggerty Leanne , Martin Fergal , De Panis Diego
Published: December 2024

The reference genome ofApodemus agrariusprovides a valuable resource for phylogenetic studies of rodents, particularly mice, and for understanding factors that influence the geographical distribution of the species across East Asia and East Europe. A total of 25 contiguous chromosomal pseudomolecules were assembled from the genome sequence (23 autosomes and 2 sex chromosomes). This chromosome-level assembly encompasses 2.6 Gb, composed of 242 contigs and 60 scaffolds, with contig and scaffold N50 values of 35 Mb and 119 Mb, respectively.
Epigenetic remodeling and 3D chromatin reorganization governed by NKX2-1 drive neuroendocrine prostate cancer
Authors: Lu Xiaodong , Keo Viriya , Cheng Irina , Xie Wanqing , Gritsina Galina , Wang Juan , Jin Qiushi , Jin Peng , Yue Feng , Sanda Martin G. , Corces Victor , Altemose Nicolas , Zhao Jonathan C. , Yu Jindan
Published: December 2024

A significant number of castration-resistant prostate cancer (CRPC) evolve into a neuroendocrine (NE) subtype termed NEPC, leading to resistance to androgen receptor (AR) pathway inhibitors and poor clinical outcomes. Through Hi-C analyses of a panel of patient-derived xenograft tumors, here we report drastically different 3D chromatin architectures between NEPC and CRPC samples. Such chromatin re-organization was faithfully recapitulated in vitro on isogenic cells undergoing NE transformation (NET). Mechanistically, neural transcription factor (TF) NKX2-1 is selectively and highly expressed in NEPC tumors and is indispensable for NET across various models. NKX2-1 preferentially binds to gene promoters, but it interacts with chromatin-pioneering factors such as FOXA2 at enhancer elements through chromatin looping, further strengthening FOXA2 binding at NE enhancers. Conversely, FOXA2 mediates regional DNA demethylation, attributing to NE enhancer priming and inducing NKX2-1 expression, forming a feed-forward loop. Single-cell multiome analyses of isogenic cells over time-course NET cells identify individual cells amid luminal-to-NE transformation, exhibiting intermediate epigenetic and transcriptome states. Lastly, NKX2-1/FOXA2 interacts with, and recruits CBP/p300 proteins to activate NE enhancers, and pharmacological inhibitors of CBP/p300 effectively blunted NE gene expression and abolished NEPC tumor growth. Thus, our study reports a hierarchical network of TFs governed by NKX2-1 in regulating the 2D and 3D chromatin re-organization during NET and uncovers a promising therapeutic approach to eradicate NEPC.
Environmentally induced variation in sperm sRNAs is linked to gene expression and transposable elements in zebrafish offspring
Authors: Godden Alice May , Silva Willian , Kiehl Berrit , Jolly Cecile , Folkes Leighton , Alavioon Ghazal , Immler Simone
Published: December 2024

Environmental factors affect not only paternal condition but may translate into the following generations where sperm-mediated small RNAs (sRNAs) can contribute to the transmission of paternal effects. SRNAs play a key role in the male germ line in genome maintenance and repair, and particularly in response to environmental stress and the resulting increase in transposable element (TE) activity. Here, we investigated how the social environment (high competition, low competition) of male zebrafish Danio rerio affects small RNAs in sperm and how these are linked to gene expression and TE activity in their offspring. In a first experiment, we collected sperm samples after exposing males to each social environment for two weeks to test for differentially expressed sperm micro- (miRNA) and piwi-interacting RNAs (piRNA). In a separate experiment, we performed in vitro fertilisations after one two-week period using a split-clutch design to control for maternal effects and collected embryos at 24 hours to test for differentially expressed genes and transposable elements. We developed new computational prediction tools to link sperm sRNAs with differentially expressed TEs and genes in the embryos. Our results support the idea that the molecular stress response in the male germ line has significant down-stream effects on the molecular pathways, and we provide a direct link between sRNAs, TEs and gene expression.
Bayesian Perspective for Orientation Estimation in Cryo-EM and Cryo-ET
Authors: Xu Sheng , Balanov Amnon , Bendory Tamir
Published: December 2024

Accurate orientation estimation is a crucial component of 3D molecular structure reconstruction, both in single-particle cryo-electron microscopy (cryo-EM) and in the increasingly popular field of cryo-electron tomography (cryo-ET). The dominant method, which involves searching for an orientation with maximum cross-correlation relative to given templates, falls short, particularly in low signal-to-noise environments. In this work, we propose a Bayesian framework to develop a more accurate and flexible orientation estimation approach, with the minimum mean square error (MMSE) estimator as a key example. This method effectively accommodates varying structural conformations and arbitrary rotational distributions. Through simulations, we demonstrate that our estimator consistently outperforms the cross-correlation-based method, especially in challenging conditions with low signal-to-noise ratios, and offer a theoretical framework to support these improvements. We further show that integrating our estimator into the iterative refinement in the 3D reconstruction pipeline markedly enhances overall accuracy, revealing substantial benefits across the algorithmic workflow. Finally, we show empirically that the proposed Bayesian approach enhances robustness against the “Einstein from Noise” phenomenon, reducing model bias and improving reconstruction reliability. These findings indicate that the proposed Bayesian framework could substantially advance cryo-EM and cryo-ET by enhancing the accuracy, robustness, and reliability of 3D molecular structure reconstruction, thereby facilitating deeper insights into complex biological systems.
Role of Dynamin 2 in mitochondrial fission and cell cycle regulation:Dysregulation of a miR-124-3p-STAT3-DNM2-Drp1-RGCC pathway connects fission and cell proliferation in pulmonary arterial hypertension
Authors: Dasgupta Asish , Chen Kuang-Hueih , Wu Danchen , Yerramilli V. Siddartha , Lima Patricia D.A. , Martin Ashley Y. , Ott Benjamin P. , Mewburn Jeffrey D. , Tian Lian , Al-Qazazi Ruaa , Emon Isaac M. , Colpman Pierce , Jefferson Lindsay , Noordhof Curtis , Jones Oliver , Hindmarch Charles C.T. , Archer Stephen L.
Published: December 2024

Introduction

Dynamin-related protein 1 (Drp1) activation increases mitochondrial fission and cell cycle progression in hyperproliferative cells, termedmitotic fission. However, the diameter of a fission apparatus comprised solely of Drp1 and its binding partners appears insufficient to complete fission. Moreover, the mechanism linking fission to cell cycle progression is unknown, suggesting an additional mediator in the terminal steps of mitotic fission.

Hypothesis

The large GTPase, dynamin 2 (DNM2), interacts with Drp1 to complete mitochondrial fission and regulate cell cycle progression.

Corollary

DNM2 is epigenetically upregulated in pulmonary arterial smooth muscle cells in pulmonary arterial hypertension (PAH PASMC).

Methods

Mitochondrial morphology, protein colocalization and mitochondrial fission sites were assessed using super-resolution microscopy. Protein-protein interaction was confirmed using immunoprecipitation. The role of DNM2’s GTPase domain in mitochondrial targeting was studied by heterologous expression of truncated constructs. Transcriptomic changes from silencing DNM2 in PAH PASMC were measured by RNA-seq. DNM2 expression was quantified in normal and PAH PASMC and lungs from PAH patients and rats with monocrotaline (MCT) and SU5416/hypoxia (Su/Hx)-induced PAH. The effects of manipulating DNM2 on cell proliferation, cell cycle progression and apoptosis were assessed by flow cytometry. siRNA targeting DNM2 was nebulized to rats with MCT-PAH.

Results

DNM2 is increased in PAH PASMC in humans and rodents and interacts with Drp1 via its GTPase domain, permitting mitochondrial translocation. Silencing DNM2 in PAH PASMC inhibits fission and slows cell proliferation by causing G1/G0 phase blockade. Augmenting DNM2 in normal PASMC induces fission and accelerates proliferation. siDNM2 downregulates the positive cell cycle regulator, Regulator of Cell Cycle (RGCC), in PAH PASMC. Moreover, siRGCC causes G1/G0 cell cycle arrest. miR-124-3p negatively regulates DNM2 and is decreased in PAH PASMC. Augmenting miR-124-3p in PAH PASMC decreases DNM2, inhibits proliferation and induces apoptosis. STAT3 is also negatively regulated by miR-124-3p and siSTAT3 reduces DNM2 and mitochondrial fission in PAH PASMC. Nebulized siDNM2 regresses PAH in MCT-PAH.

Conclusion

DNM2’s GTPase domain binds Drp1, mediating mitochondrial translocation and tighter mitochondrial fission. DNM2 is upregulated in PAH by miR-124a-3p deficiency and STAT3 activation. The miR-124a-3p-STAT3-DNM2-Drp1-RGCC pathway underlies accelerated mitotic fission in PAH and offers novel therapeutic targets.
A Study of Patient-Reported Dry Eye Disease in Diabetes Mellitus in Indonesia
Authors: Mokoagow Md Ikhsan , Noor Nina Asrini , Rahayu Tri , Andalia Damara , Ramandari Niluh Archi Sri , Epriliawati Marina
Published: December 2024

Background

Diabetes mellitus (DM), one of the most common metabolic diseases in the world, is a chronic metabolic disorder characterized by persistent hyperglycemia. In diabetic patients, ocular symptoms can develop. One commonly found ocular disease is dry eye disease (DED). DED is a multifactorial disease characterized by instability of the tear layer that causes various symptoms and/or visual impairment, usually accompanied by damage to the ocular surface.

Objective

This study aims to determine the prevalence of dry eye disease (DED) in type 2 DM patients and to assess the correlation between DED and various type 2 DM-related conditions in Indonesia.

Methodology

This study is a cross-sectional observational study. The study population includes all consecutive patients diagnosed with type 2 DM between Feb 5 and Mar 26, 2024, at three hospitals and two clinics in Jakarta. The DED assessment was conducted using the DEQ-5 questionnaire, translated and validated in Bahasa, Indonesia. The Kolmogorov-Smirnov normality test and Spearman correlation test were performed on all data sets to determine the correlation between DEQ-5 outcome and the patient’s age, disease duration, fasting blood glucose (FBG) levels, and HbA1c levels.

Result

A total of 309 patients were recruited in this study. The patients’ age varies from 23 to 84 years old, and the majority of them have had type 2 DM for five years or less. From 309 patients, 264 FBG and 72 HbA1c test results were recorded. Through the DEQ-5 questionnaire, 64 (20.71%) scored higher than 6, indicating they are experiencing DED. Among the factors considered, including age, gender, duration of disease, FBG level, and HbA1c level, only the FBG level correlated with DED (rs= .186, n = 263, p < .002).

Conclusion

There’s a positive correlation between the FBG level and DED. Elevating FBG levels are associated with an increased likelihood of developing DED.
Exploring current and potential roles of informal healthcare providers in tuberculosis care in West Bengal, India: a qualitative content analysis
Authors: Thapa Poshan , Narasimhan Padmanesan , Hall John J. , Jayasuriya Rohan , Mukherjee Partha Sarathi , Das Dipesh Kr , Beek Kristen
Published: December 2024

India accounts for 27 percent of global Tuberculosis (TB) cases, the highest among the 30 high-burden countries. Despite growing evidence highlighting the significance and potential of Informal Healthcare Providers (IPs) in TB care, their role remains ambiguous in India’s TB policies and guidelines, in contrast to the well-defined roles of the formal private sector. Considering such gaps, this study explores the perspectives of IPs and Formal Providers (FPs) regarding IPs’ current and potential roles in TB care. The study was conducted in West Bengal, India. We adopted a qualitative approach and conducted in-depth interviews with 23 IPs and 11 FPs. The study data was analysed using a content analysis approach. The study’s findings identified four current roles of IPs in TB care, two of which were corroborated by FPs: 1) Passive case finding and referral and 2) Treatment supporter. As for potential roles, an alignment was observed between the two groups of providers for the majority of the roles (5/7 roles). However, both IPs and FPs expressed reservations about assigning IPs the roles of 1) Clinical evaluation of TB cases and 2) Initiation of treatment for confirmed TB patients. The findings highlight the active involvement of IPs in various TB care roles, acknowledged by FPs, and also demonstrate significant potential for their expanded engagement under the National TB Elimination Program (NTEP) of India.
EXaCT-2: An augmented and customizable oncology-focused whole exome sequencing platform
Authors: Waltman Peter , Chandra Pooja , Eng Ken W , Wilkes David C , Park Hyeon , Pabon Carlos , Delpe Princesca , Bhinder Bhavneet , Manohar Jyothi , Kane Troy , Fernandez Evan , Gorski Kathryn , Greco Noah , Simi Manuele , Tang Jeffrey M , Zisimopoulos Pantelis , King Abigail , Assaad Majd Al , Teneyck Theresa , Roberts Douglas , Monge Jorge , Demichelis Francesca , Tam Wayne , Ouseph Madhu M , Sigaras Alexandros , Beltran Himisha , Rennert Hannah , Lindeman Neal , Song Wei , Solomon James , Mosquera Juan Miguel , Kim Rob , Catalano Jeffrey , Hassane Duane C , Sigouros Michael , Elemento Olivier , Alonso Alicia , Sboner Andrea
Published: December 2024

With the rapid advances in cancer research, the list of variants and genes that drive human diseases is constantly expanding. Moreover, the FDA has approved more cancer therapies that incorporate a broader set of genomic features than simple gene variants such as Tumor Mutation Burden (TMB), microsatellite instability status (MSI), and fusion events in gene families such as the NTRK receptors. These features currently require multiple testing methods (IHC/FISH/etc.). With the cost of NGS testing dropping, it is now possible to envision an NGS assay capable of reliably detecting these features without the need for additional testing. The EIPM multidisciplinary team has developed EXaCT-2: a whole exome sequencing (WES) assay that gives the coverage of a targeted assay on cancer genes and the breadth to detect copy number events, cancer-related fusions, and viruses, which can facilitate diagnostic and therapeutic decisions for cancer patients.

We evaluated EXaCT-2 on 250 matched tumor/normal pairs and compared its performance with orthogonally validated results. We show the assay achieves the expected coverage of critical cancer genes, provides a better characterization of somatic copy number alterations, detects common cancer rearrangements and viruses, and enables the accurate estimation of global molecular metrics, such as tumor mutational burden and microsatellite instability.
Uncovering Phenotypic Expansion in AXIN2-Related Disorders through Precision Animal Modeling
Authors: Aceves-Ewing Nathalie M. , Lanza Denise G. , Marcogliese Paul C. , Lu Di , Hsu Chih-Wei , Gonzalez Matthew , Christiansen Audrey E. , Rasmussen Tara L. , Ho Alex J. , Gaspero Angelina , Seavitt John , Dickinson Mary E. , Yuan Bo , Shayota Brian J. , Pachter Stephanie , Hu Xiaolin , Day-Salvatore Debra Lynn , Mackay Laura , Kanca Oguz , Wangler Michael F. , Potocki Lorraine , Rosenfeld Jill A. , Lewis Richard Alan , Chao Hsiao-Tuan , Lee Brendan , Lee Sukyeong ,   Undiagnosed Diseases Network,   Baylor College of Medicine Center for Precision Medicine Models, Yamamoto Shinya , Bellen Hugo J. , Burrage Lindsay C. , Heaney Jason D.
Published: December 2024

Heterozygous pathogenic variants inAXIN2are associated with oligodontia-colorectal cancer syndrome (ODCRCS), a disorder characterized by oligodontia, colorectal cancer, and in some cases, sparse hair and eyebrows. We have identified four individuals with one of twode novo, heterozygous variants (NM_004655.4:c.196G>A, p.(Glu66Lys) and c.199G>T, p.(Gly67Arg)) inAXIN2whose presentations expand the phenotype of AXIN2-related disorders. In addition to ODCRCS features, these individuals have global developmental delay, microcephaly, and limb, ophthalmologic, and renal abnormalities. Structural modeling of these variants suggests that they disrupt AXIN2 binding to tankyrase, which regulates AXIN2 levels through PARsylation and subsequent proteasomal degradation. To test whether these variants produce a phenotypein vivo, we utilized an innovative prime editing N1 screen to phenotype heterozygous (p.E66K) mouse embryos, which were perinatal lethal with short palate and skeletal abnormalities, contrary to published viableAxin2null mouse models. Modeling of the p.E66K variant in theDrosophilawing revealed gain-of-function activity compared to reference AXIN2. However, the variant showed loss-of-function activity in the fly eye compared to reference AXIN2, suggesting that the mechanism by which p.E66K affects AXIN2 function is cell context-dependent. Together, our studies in humans, mice, and flies demonstrate that specific variants in the tankyrase-binding domain of AXIN2 are pathogenic, leading to phenotypic expansion with context-dependent effects on AXIN2 function and WNT signaling. Moreover, the modeling strategies used to demonstrate variant pathogenicity may be beneficial for the resolution of otherde novoheterozygous variants of uncertain significance associated with congenital anomalies in humans.
Emergence and transmission dynamics of the FY.4 Omicron variant in Kenya
Authors: Musundi Sebastian , Mwanga Mike J. , Lambisia Arnold W. , Morobe John Mwita , Murunga Nickson , Moraa Edidah , Ndwiga Leonard , Cheruyoit Robinson , Musyoki Jennifer , Mutunga Martin , Guzman-Rincon Laura M , Sande Charles , Mwangangi Joseph , Bejon Philip , Ochola-Oyier Lynette Isabella , Nokes D James , Agoti Charles N. , Nyiro Joyce , Githinji George
Published: December 2024

The recombinant FY.4 SARS-CoV-2 variant was first reported in Kenya in March 2023 and was the dominant circulating variant between April and July 2023. The variant was characterised by two important mutations: Y451H in the receptor binding domain of the spike protein and P42L in open reading frame 3a. Using phylogenetics and phylodynamic approaches, we investigated the emergence and spread of the FY.4 in Kenya and the rest of the world. Our findings suggest FY.4 circulated early in Kenya before export to North America and Europe. Early circulation of FY.4 in Kenya was predominantly observed in the coastal part of the country and the estimated time to the most recent common ancestor suggests FY.4 circulated as early as December 2022. The collected genomic and epidemiological data show that the FY.4 variant led to a large local outbreak in Kenya and resulted in localised outbreaks in Europe, North America and Asia-pacific. These findings underscore the importance of sustained genomic surveillance especially in under sampled regions in deepening our understanding of the evolution and spread of SARS-CoV-2 variants.
Inflammatory Bowel Disease Drivers Revealed in Human Organ Chips
Authors: Özkan Alican , Merry Gwenn , Chou David B. , Posey Ryan R. , Stejskalova Anna , Calderon Karina , Sperry Megan , Horvath Viktor , Ferri Lorenzo E. , Carlotti Emanuela , McDonald Stuart A. C. , Winton Douglas J. , Riccardi Rocco , Bordeianou Lilianna , Hall Sean , Goyal Girija , Ingber Donald E.
Published: December 2024

Abstract

Inflammatory bowel disease (IBD) patients exhibit compromised intestinal barrier function and decreased mucus accumulation, as well as increased inflammation, fibrosis, and cancer risk, with symptoms often being exacerbated in women during pregnancy. Here, we show that these IBD hallmarks can be replicated using human Organ Chips lined by IBD patient-derived colon epithelial cells interfaced with matched fibroblasts cultured under flow. Use of heterotypic tissue recombinants revealed that IBD fibroblasts are the primary drivers of multiple IBD symptoms. Inflammation and fibrosis are accentuated by peristalsis-like motions in IBD Chips and when exposed to pregnancy-associated hormones in female IBD Chips. Carcinogen exposure also increases inflammation, gene mutations, and chromosome duplication in IBD Chips, but not in Healthy Chips. These data enabled by human Organ Chip technology suggest that the intestinal stroma and peristalsis-associated mechanical deformations play a key role in driving inflammation and disease progression in male and female IBD patients.
Vaccination exemptions among Kindergartners by state-level 2024 Presidential election result
Authors: Faust Jeremy Samuel , Renton Benjamin K.
Published: December 2024

Importance

Pediatric vaccine exemptions have increased in recent years. How political environments influence these trends is unknown.

Objective

To analyze state-level kindergarten vaccination exemption rates from 2009-2024, stratified by 2024 Presidential election results, to assess changes over time.

Design, Setting, and Participants

This cross-sectional study used publicly available CDC data on kindergarten vaccination exemptions across all U.S. states and Washington, DC. States were categorized as Donald Trump or Kamala Harris states based on 2024 election results. Previous elections were also assessed.

Main Outcomes and Measures

Incident rates (IRs) of vaccination exemptions (all, medical, and non-medical) were calculated yearly. Incident rate ratios (IRRs) comparing vaccination exemption rates in Harris versus Trump win states were calculated. and Spearman correlations assessed associations between exemption rates and Republican vote share in the four most recent Presidential elections.

Results

Analysis included 53,997,748 person-years of kindergarten data. By 2023-2024, non-medical exemptions were permitted in 90.2% of states. Exemption rates increased in Trump states but decreased in Harris states during the study period. Most exemptions were non-medical.

Conclusions and Relevance

Kindergarten vaccination exemptions now diverge by political environment, increasing over time in states won by Trump in 2024 and decreasing in states won by Harris. The findings suggest growing politicization of vaccination practices, warranting targeted public health interventions.
Global analysis of protein and small-molecule substrates of ubiquitin-like proteins (UBLs)
Authors: Shao Guang-Can , Chen Zhen-Lin , Lu Shan , Wu Qing-Cui , Sheng Yao , Wang Jing , Ma Yan , Sui Jian-Hua , Chi Hao , Qi Xiang-Bing , He Si-Min , Du Li-Lin , Dong Meng-Qiu
Published: December 2024

Ubiquitin-like proteins (UBLs) constitute a family of evolutionarily conserved proteins that share similarities with ubiquitin in 3D structures and modification mechanisms. For most UBLs including Small-Ubiquitin-like Modifiers (SUMO), their modification sites on substrate proteins cannot be identified using the mass spectrometry-based method that has been successful for identifying ubiquitination sites, unless a UBL protein is mutated accordingly. To identify UBL modification sites without having to mutate UBL, we have developed a dedicated search engine pLink-UBL on the basis of pLink, a software tool for identification of cross-linked peptide pairs. pLink-UBL exhibited superior precision, sensitivity, and speed than “make-do” search engines such as MaxQuant, pFind, and pLink. For example, compared to MaxQuant, pLink-UBL increased the number of identified SUMOylation sites by 50 ∼ 300% from the same datasets. Additionally, we present a method for identifying small-molecule modifications of UBLs. This method involves antibody enrichment of a UBL C-terminal peptide following enrichment of a UBL protein, followed by LC-MS/MS analysis and a pFind 3 blind search to identify unexpected modifications. Using this method, we have discovered non-protein substrates of SUMO, of which spermidine is the major one for fission yeast SUMO Pmt3. Spermidine can be conjugated to the C-terminal carboxylate group of Pmt3 through its N1or also likely, N8amino group in the presence of SUMO E1, E2, and ATP. Pmt3-spermidine conjugation does not require E3 and can be reversed by SUMO isopeptidase Ulp1. SUMO-spermidine conjugation is present in mice and humans. Also, spermidine can be conjugated to ubiquitinin vitroby E1 and E2 in the presence of ATP. The above observations suggest that spermidine may be a common small molecule substrate of SUMO and possibly ubiquitin across eukaryotic species.

Highlights

A specialized software pLink-UBL enables precise identification of UBL modification sites on protein substrates.

pFind 3 blind search enables identification of unexpected small-molecule substrates of a UBL protein.

Spermidine is a small molecule substrate of fission yeast SUMO Pmt3 as well as mammalian SUMO proteins.

The C-terminal carboxyl group of Pmt3 can be attached to the N1or likely also the N8amino group of spermidine in the presence of E1, E2, and ATP, and can be detached by SUMO isopeptidase.
First Detection of Oropouche Virus inCulicoides insignisin the Ucayali Region, Peru: Evidence of a Possible New Vector
Authors: Requena-Zúñiga Edwin , Palomino-Salcedo Miriam , García-Mendoza María P. , Figueroa-Romero Maribel D. , Merino-Sarmiento Nancy S. , Escalante-Maldonado Oscar , Cornelio-Santos Ana L. , Cárdenas-Garcia Patricia , Jiménez Carlos Augusto , Cabezas-Sanchez César
Published: December 2024

This report details the first detection of the Oropouche virus (OROV) inCulicoides insignisin the Ucayali region (Peruvian Amazon) during an outbreak study in 2024. Captures conducted in peri-urban and rural areas showed thatC. insignisaccounted for 96.7% of the collectedCulicoidesspecimens. RT-qPCR testing confirmed the presence of the virus in twoC. insignispools, establishing this species as a potential OROV vector in the study area, thereby contributing to the understanding of the virus’s epidemiology in the Amazon region.
Quality Improvement (QI) Project: Enhancing Surgical Safety Checklist Utilization at a Rural Primary Hospital
Authors: Gemechu Melaku Teshale , Adinew Anteneh Cheru , Ledamo Elias Ermias
Published: December 2024

Background

Despite evidence demonstrating various benefits of the World Health Organization (WHO) Surgical Safety Checklist (SSC), its utilization is less frequent in low and middle income countries. This quality improvement project was conducted at a Primary Hospital, a rural facility in Ethiopia, to address suboptimal utilization of the SSC. At baseline, an average SSC utilization rate was 50% and a completion rate was 80% over the prior 6 months.

Methods

A single cycle Plan-Do-Study-Act (PDSA) approach was employed to enhance adherence. Key interventions included translating the SSC into Amharic, conducting a two-day training session, introducing pre- and post-operative briefings, and requiring surgeons to remain in the operating room until checklist completion. Bi-weekly audits and regular supervision were conducted to monitor progress. Key performance indicators were SSC utilization and completion rates, while secondary indicators included rate of prophylactic antibiotic administration and surgical site infection. Trend analysis using run charts and Interrupted Time Series (ITS) analysis evaluated changes over time, while staff interviews provided insights into behavioral and attitudinal shifts.

Results

The quality improvement project demonstrated a significant and sustained improvement in the utilization and completion rates of the WHO Surgical Safety Checklist (SSC). Baseline measurements in October 2023 showed a utilization rate of 53% and a completion rate of 65%. Following targeted interventions, both metrics steadily improved, reaching 100% by June 2024 and maintaining this level through September 2024.

Conclusion

The QI project demonstrated that achieving 100% utilization and completion of the WHO Surgical Safety Checklist (SSC) is feasible even in rural hospitals of low- and middle-income countries (LMICs). Formal training proved crucial for improving adherence, addressing gaps seen with informal approaches, and fostering better team communication and culture. This underscores the value of structured, localized interventions for improving surgical safety practices and encourages broader adoption in similar contexts. To sustain the results, ongoing supportive trainings, monthly supervision, and staff recognition initiatives were initiated.
Lumbar Spine Degenerative Classification Using YOLO v8 and DeepScoreNet
Authors: Mousavi Amir
Published: December 2024

Degenerative conditions of the lumbar spine, such as neural foraminal narrowing, subarticular stenosis, and spinal canal stenosis, are common and can lead to chronic pain and disability. Detecting and assessing the severity of these conditions is a key task in radiology, often requiring considerable expertise. In this work, we aim to develop automated models that aid radiologists in diagnosing these conditions using lumbar spine MR images. We utilize state-of-the-art deep learning methods for both detection and classification tasks, focusing on severity classification across five intervertebral disc levels and three different imaging modalities. The dataset and methodology used in this study are part of the RSNA 2024 Lumbar Spine Degenerative Classification competition. Our approach involves a two-step process, combining object detection with YOLO v8 and severity classification using a DeepScoreNet architecture. Through careful cross-validation and model evaluation, we demonstrate the potential of these models to improve diagnostic accuracy and efficiency. The DeepScoreNet model, introduced in this article, comprises 2,787,651 parameters and achieved accuracies of 81% for score(severity) prediction in cases of Neural Foraminal Narrowing, 89% for Spinal Canal Stenosis, and 74% for Subarticular Stenosis.

The code for this approach is available in the GitHub repository.(https://github.com/liamirpy/Lumbar-Spine-Degenerative-Classification)
Cigarette Smoking Across Life from 1946 to 2018: Harmonisation of Four British Birth Cohort Studies
Authors: Wright Liam , Kock Loren , Tattan-Birch Harry , Bann David
Published: December 2024

Background and Aims

Tobacco smoking has declined dramatically in the many high-income countries over the past seventy years. Studies that have mapped this trend have relied on repeat cross-sectional or retrospectively measured smoking data which has limitations regarding accurate measurement, inclusion of early smokers, and capturing of within-person change over time. Here, we (1) introduce a new resource detailing harmonisable smoking data in four British birth cohort studies spanning 1946-2018 and (2) use this data to document age and cohort changes in smoking.

Methods

We used prospectively and longitudinally measured smoking data in four British Birth Cohort Studies, born 1946, 1958, 1970 and 2000/02, respectively, to examine changes in the prevalence of daily smoking and cigarettes smoked per day between cohorts and within cohorts over the life course in males and females combined and stratified by sex.

Results

The prevalence of smoking and the average number of cigarettes smoked by daily smokers declined between each successive cohort. Males smoked more and with greater intensity than females, on average, though sex differences were smaller in latter cohorts. Within a cohort, the prevalence and intensity of smoking peaked in early adulthood (< age 30y) and declined thereafter; participants who continued to smoke daily, smoked fewer cigarettes as they grew older.

Conclusion

Smoking prevalence and cigarette consumption declined substantially between cohorts born across the latter half of the twentieth and early twenty-first centuries. The British Birth Cohorts represent a unique and largely underutilized resource for investigating trends in smoking across life (prenatal to old age) and by year of birth (1946-2001), including changes in the determinants, correlates, and consequences of smoking. We provide syntax and information on items on smoking in these cohorts to catalyse future research, also available at:osf.io/54w6q.
Lung cancer and Risk of Cardiovascular Mortality
Authors: Wang Chengshi , Wang Zhu , Yang Jing , Zhang Songbo , Zhang Purong , Yang Ye
Published: December 2024

Purpose

To investigate the cardiovascular mortality risk among lung cancer patients compared to the general population.

Methods

Using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results program, we conducted a population-based cohort study including 278,418 lung cancer patients over 30 years old between January 1, 1990, and December 31, 2020 as well as the general population. Poisson regression was employed to calculate incidence rate ratios (IRRs) for cardiovascular mortality.

Results

Patients exhibited a significantly higher incidence rate ratio (IRR) of cardiovascular mortality risk compared to the general population [IRR 1.74, 95% confidence interval (CI) 1.71-1.77]. The risk was most pronounced in patients aged 30-79 years (IRR 2.61, 95% CI 2.55-2.66), peaking at ages 30-34 (IRR 48.93, 95% CI 21.98-108.92). Elevated cardiovascular mortality risks were observed across all subgroups, including diseases of the heart (IRR 1.79, 95% CI 1.75-1.82), cerebrovascular diseases (IRR 1.52, 95% CI 1.45-1.59), and other cardiovascular diseases (IRR 1.78, 95% CI 1.67-1.90). The first month post-diagnosis presented the highest risk for ages 30-79 (IRR 12.08, 95% CI 11.49-12.70) and ≥80 years (IRR 4.03, 95% CI 3.70-4.39). Clinical characteristics significantly modified cardiovascular mortality.

Conclusions

Integrating cardiovascular disease monitoring and proactive management into lung cancer treatment protocols is essential to the improvement of overall survival and quality of life for lung cancer patients, particularly those who were young or with advanced tumor stage.