bluuebunny/crossref_metadata_2025_split huggingface dataset:
A simple demonstration of a privacy-preserving de-centralised genotype imputation workflow
Authors: Letaillandier Alban , Picard-Druet David , Ludwig Thomas E. , Marenne Gaëlle , Herzig Anthony F. 
Published: January 2025

AbstractRecently, a number of studies have looked at the problem of privacy and data-sharing restrictions in the context of missing genotype imputation servers. This relates to the most typical imputation pipelines which involve a whole-genome sequenced haplotype reference panel being compared to genotyped study individuals (who have missing data to be imputed). Hence, involving two datasets from separate sources coming together in one informatic environment, where relatively complicated statistical models are applied; specifically, hidden Markov modelling. We give a short review of the current literature in this domain, observing three prevalent strategies: complicated data encryption, technical solutions to secure computation environments, and rearrangements of haplotype data in an effort to provide anonymisation. We embarked on a thought experiment to provide a potential fourth type of solution involving federating the different internal tasks within the statistical methods used for imputation. This idea is relevant considering there is currently motivation for federated analyses platforms in Europe for making combined inference across multiple genomic data resources. This allows for very simple manipulations to protect sensitive individual level data, which enable imputation algorithms to complete on simple plain-text files. We provide here an illustration of how such a federated imputation server could be put in place, along with associated code, including a simple implementation of the Li-Stephens haplotype mosaic model to achieve the imputation of missing genotypes. We name our general framework ANONYMP for anonymised imputation. A demonstration of the concept is given involving simulated data generated with msprime. We show that dividing different parts of the required calculations for statistical imputation between several sites is a valuable new avenue in the field of privacy-preserving imputation server development.
A novel tool for designing targeted gene amplicons and an optimised set of primers for high-throughput sequencing in tuberculosis genomic studies
Authors: Wang Linfeng , Thawong Naphatcha , Thorpe Joseph , Higgins Matthew , Kia Ik Mark Tan , Sawaengdee Waritta , Mahasirimongkol Surakameth , Perdigao Joao , Campino Susana , Clark Taane G. , Phelan Jody E. 
Published: January 2025

ABSTRACTAmplicon sequencing (Amp-Seq) ofMycobacterium tuberculosisgenes associated with drug resistance and strain typing offers a cost-effective approach for profiling infections and tailoring the clinical management of tuberculosis. However, Amp-Seq assays require continual updates to incorporate new loci and mutations linked to drug resistance. We introduce TOAST (Tuberculosis Optimised Amplicon Sequencing Tool), a customisable software tool that optimises amplicon design across any loci and sequencing platforms (e.g., Illumina, Oxford Nanopore Technology (ONT)), informed by an integrated and expanding database of mutations from >50KM. tuberculosisisolates. TOAST software allows users to define parameters such as melting temperature, amplicon length, and GC content, while accounting for potential primer interactions like homodimer formation and non-specific binding. To demonstrate its robustness, we designed 33 amplicons in a single multiplex group, prioritising coverage of resistance-associated mutations in the form of insertions, deletions and single nucleotide polymorphisms (SNPs) for 13 different drugs. An efficient experimental protocol was established, resulting in a minimum depth coverage exceeding 50-fold for each amplicon region as validated by ONT sequencing of two clinical samples with multi-drug resistance. TOAST software enables the development of Amp-Seq assays for the rapid detection of drug-resistant TB, enhancing treatment strategies, improving outcomes, and curbing resistant infections. The cost-effectiveness and adaptability of Amp-Seq approaches make it crucial for managing TB in resource-limited settings, advancing global control efforts.
ARDUINO-BASED ORGAN PERFUSION SYSTEM
Authors: Domenico Stefano Di 
Published: January 2025

ABSTRACTLaboratory equipment could be expensive and their cost can be unsustainable for scientists with limited financial resources. In order to overcome these impediments and to improve our experimental studies on liver resection in rats, a multipurpose organ perfusion system was projected and realized using low-cost components.The device is based on Arduino boards, an easy-to-use and open-source microcontroller, that receives digital and analog inputs, can produce digital outputs and it is programmable in C++. Our perfusion system is composed of: 1) the main control unit that receives pressure data from two independent pressure transducers commonly used in the OR, it receives input from two potentiometers, seven switches, and a push-button; it can display data with an LCD and it can control the speed and the direction of two independent peristaltic-pump, 2) a motor unit composed by peristaltic pumps controlled by two stepper motors, 3) a thermostatic unit that received data from temperature probe and can control up to three heating units.The pulsating flow generated by the peristaltic pump can be flattened by a dampener unit to simulate the portal flow, and the interposition of a hollow-fiber micro-oxygenator can increase the pO2 of the perfusion fluid in the arterial line.This cheap system is designed to measure the compliance of regenerating rat liver at increasing and decreasing portal and arterial flow during normothermic ex-vivo perfusion. However the system can be easily rearranged to perform different kinds of organ perfusion: subnormothermic o hypothermic ex-vivo preservation tests can be done by adding a Peltier-based cooling module. Indeed the main control unit can be programmed to control the flow rate based on pressure data to realize peritoneal perfusion or isolated limb perfusion.
Resorbable alginate embolic microsphere for Musculoskeletal embolization applications
Authors: Agarwal Sankalp , Pandey Masum , Duggan Ronan , O’ Brien Con , Lewis Andrew. L. , Duffy Brendan , McCabe Joan , Farrissey Liam 
Published: January 2025

AbstractResorbable embolic agents can be used for musculoskeletal (MSK) pain relief applications using a Transarterial Embolisation (TAE) technique. However, inconsistent particle size and shape, degradation rates, and unpredictable resorption and excretion of the breakdown products, limit their widespread clinical adoption. The present study reports self-degradable, rehydratable, freeze-dried, resorbable Ca²⁺-crosslinked alginate microspheres as a novel vascular embolic agent. The alginate lyase enzyme was incorporated into the alginate microspheres to achieve a controlled degradation rate under physiological conditions. Whilst the feasibility of alginate microspheres as embolic agents has been demonstrated, this is the first study where the controlled release is achieved in physiological conditions. To incorporate the alginate lyase enzyme in the alginate matrix, its activity was reversibly inhibited by preparing an alginate lyase-alginate-excipient mixture in a pH 3.6–3.9 buffered solution. An electrostatic encapsulator enabled the scalable preparation of microspheres of size 210 ± 8 µm at room temperature. The results showed that freeze-dried microspheres regained their shape and size within two minutes after reconstitution with saline, along with active alginate lyase. The reperfusion time of alginate microspheres was evaluated using digital subtraction angiography (DSA) and compared with imipenem and celestine (IMP-CS)in a porcine renal arterial embolisation model. It was observed that most of the blood vessels reperfused within 130–210 minutes, and complete vascular blush was recovered within 24 hours. Embolization with resorbable alginate microspheres induced recoverable ischemic necrosis in the targeted renal arteries. This unique feature of resorbable alginate microspheres in inducing ischemic necrosis, potentially in pain-propagating neovessels, makes it an ideal candidate embolic agent for treating MSK-associated pain using the TAE technique.
Paclitaxel causesde novoinduction of invasive breast cancer cells by repolarizing tumor-associated macrophages
Authors: Friedman-DeLuca Madeline , Karagiannis George S. , Duran Camille L. , Shukla Suryansh , Li Jiufeng , Condeelis John S. , Oktay Maja H. , Entenberg David 
Published: January 2025

AbstractBackgroundMetastasis is the leading cause of breast cancer (BC) death, and tumor cells must migrate and invade to metastasize. BC cells that express the pro-metastatic actin regulatory protein MenaINV have an enhanced ability to migrate and intravasate within the primary tumor and extravasate at secondary sites. Though chemotherapy improves patient survival, treatment with paclitaxel leads to upregulation of MenaINV and an increase in metastasis in mice. MenaINV expression can be induced in BC cells through cooperative NF-κB/ Notch1 signaling with macrophages, which are often increased in tumors in response to chemotherapy. MenaINV-expressing cells are also resistant to paclitaxel, begging the question of whether paclitaxel increases MenaINV byde novoinduction or by selectively killing non-MenaINV-expressing cells. We hypothesized that paclitaxel causesde novoMenaINV induction by increasing macrophage-tumor cell NF-κB/ Notch1 signaling. Understanding this pro-metastatic effect of chemotherapy is crucial to refining treatment strategies.FindingsPaclitaxel-treated tumors expressed significantly more MenaINV than vehicle-treated tumors. This effect was dependent upon both macrophages and NF-κB/ Notch signaling. This indicates that chemotherapy increases MenaINV expression by induction. Mechanistically, paclitaxel causes macrophages to take on a pro-inflammatory phenotype and increase NF-κB/ Notch1 signaling with tumor cells.ConclusionPaclitaxel causesde novoMenaINV induction. Mechanistically, paclitaxel repolarizes tumor-associated macrophages towards a pro-inflammatory phenotype. These pro-inflammatory macrophages then participate in enhanced NF-κB/ Notch1 signaling with tumor cells, which leads to MenaINV induction in the tumor cells. These results lay the groundwork for novel microenvironment-based therapies to alleviate the pro-metastatic effects of chemotherapy in BC.
Exploring the impact of mitonuclear discordance on disease in Latin American admixed populations
Authors: Ruiz Mauricio , Böhme Daniela , Repetto Gabriela M. , Rebolledo-Jaramillo Boris 
Published: January 2025

AbstractThe coevolution of nuclear and mitochondrial genomes has guaranteed mitochondrial function for millions of years. The introduction of European (EUR) and African (AFR) genomes into the Ameridian continent during the Columbus exchange in Latin America created an opportunity to naturally test different combinations of nuclear and mitochondrial genomes. However, the impact of potential “mitonuclear discordance” (MND, differences in ancestries) has not been evaluated in Latin American admixed individuals (AMR) affected with developmental disorders, even though MND alters mitochondrial function and reduces viability in other organisms. To characterize MND in healthy and affected AMR individuals, we used AMR genotype data from the 1000 Genomes Project (n=385), two cohorts of 22q.11 deletion syndrome patients 22qDS-ARG (n=26) and 22qDS-CHL (n=58), and a cohort of patients with multiple congenital anomalies and/or neurodevelopmental disorders (DECIPHERD, n=172). Based on their importance to mitochondrial function, genes were divided into all mitonuclear genes (n=1035), high-mt (n=167), low-mt (n=793), or OXPHOS (n=169). We calculated local ancestry using FLARE, and estimated MND as the fraction of nuclear mitochondrial genes ancestry not matching the mtDNA ancestry, and ΔMND as (MNDoffspring- MNDmother)/MNDmother. Generally, MND showed population and haplogroup distinctive distributions (ANOVA p<0.05), with haplogroup D showing the lowest MND 0.49±0.17 (mean ± s.d.). MND was significantly lower in 22qDS-ARG patients 0.43±0.24 and DECIPHERD patients 0.56±0.12 compared to healthy individuals 0.60±0.09 (ANOVA p<0.05). OXPHOS and high-mt showed the same trend, but with greater differences between healthy and affected individuals. MND seems to inform population history, and constraint among affected individuals, especially for OXPHOS and high-mt genes.Author summaryWe investigated the role of mitonuclear discordance (MND) in disease among Latin American admixed populations, describing how mismatches between nuclear and mitochondrial ancestries could impact mitochondrial function and disease phenotypes. Utilizing datasets from the 1000 Genomes Project and cohorts with rare genetic disorders, we demonstrated population- and haplogroup-specific patterns of MND, with haplogroup A showing the highest MND values. Affected individuals exhibited significantly lower MND than healthy controls, particularly in genes related to oxidative phosphorylation, suggesting potential links between MND and disease. Intergenerational analyses also revealed constraints on MND, pointing to selective pressures in disease contexts. These findings underscore the importance of mitonuclear interactions in shaping disease phenotypes and highlight the need for further research into their functional and clinical implications, particularly in underrepresented populations.
Wnt/β-catenin signaling promotes posterior axial regeneration in non-regenerative tissue of the annelidCapitella teleta
Authors: Kunselman Lauren F. , Seaver Elaine C. 
Published: January 2025

AbstractTo rescue regeneration, the mechanisms underlying regeneration failure must be identified and overcome. In the annelidCapitella teleta, a transverse cut triggers asymmetric responses across the amputation plane: head fragments regenerate the tail, but tail fragments do not regenerate. We compare regeneration of head fragments (successful regeneration) to that of tail fragments (unsuccessful regeneration) using cell proliferation assays, immunolabeling, andin situhybridization. Surprisingly, following amputation, a dynamic response of the nervous system occurs in the non-regenerating tail fragments ofC. teletathat has not previously been described in annelids. Wnt/β-catenin signaling plays a conserved role in patterning the primary axis of some bilaterians during regeneration, but this role has never been demonstrated in annelids. Wnt/β-catenin pathway components are expressed in the blastema of head fragments but not at the cut site of tail fragments inC. teleta. Experimental activation of Wnt/β-catenin signaling following amputation of tail fragments (24 – 72 hr post amputation) induces expression of stem cell markers, increases cell division at the wound site, and produces differentiated muscle and hindgut. Furthermore, activation of Wnt/β-catenin signaling induces ectopic posterior identity at the amputation site, as it does in other bilaterians. Inhibition of Wnt/β-catenin signaling does not rescue head regeneration. Our results indicate thatC. teletatail fragments have latent regenerative potential that is activated by Wnt/β-catenin signaling. However, the incomplete regenerative response suggests that additional cell signaling pathways are required for this complex process. Comparing tissues with different regenerative abilities elucidates the mechanisms underlying regeneration regulation, thereby enabling the prospect of rescuing or increasing regeneration ability in regeneration-deficient tissues.
Zonal endothelial cell heterogeneity underlies murine renal vascular development
Authors: Luo Peter M , Ahuja Neha , Chaney Christopher , Pi Danielle , Cwiek Aleksandra , Markowska Zaneta , Hiremath Chitkale , Marciano Denise , Hirschi Karen K , Iruela-Arispe M Luisa , Carroll Thomas J , Cleaver Ondine 
Published: January 2025

ABSTRACTThe renal vasculature consists of highly specialized blood vessels that carry out distinct physiological functions. Defining their transcriptional signatures and tracing their developmental ontogeny has thus far been challenging due to a lack of regionally specific endothelial biomarkers. Here, we performed single nuclear RNA sequencing (snucRNA-Seq) to interrogate embryonic renal endothelial cells. We identified nine different endothelial cell types, and validated expression of novel candidates using multiplex RNAScope. We interrogate biological characteristics, including cell cycle stage, of developmental blood vessels with a variety ofinvivo tools. Using genetic tools based on expression of tip cell markerEsm1, we performed detailed lineage tracing, demonstrating multi-clonal and multi-directional endothelial contribution to glomerular vasculature. Together, this study provides the first validated, tool-focused developmental atlas of the murine renal vasculature and elucidates several novel cellular mechanisms of nephron vascularization.
Reappraisal of the Dilution and Amplification Effect Framework: A Case Study in Lyme Disease
Authors: Chen Shirley , McFarlane S. Eryn 
Published: January 2025

AbstractThe role of biodiversity in regulating zoonotic disease in ecological communities has been broadly referred to as the biodiversity-disease relationship in disease ecology. Whether biodiversity decreases or increases disease risk, known as a dilution or amplification effect respectively, remains unclear. The literature has focused on the strength, generality, nature, and context dependencies that could explain contradictory evidence. We suggest that a continued focus on this approach to resolving the biodiversity-disease debate detracts from a more foundational problem with testing these dilution and amplification hypotheses, in that these hypotheses are not falsifiable as proposed. When tested and interpreted as net effects in a system, these hypotheses do not possess a true null outcome and they are vulnerable toad hocexplanations. To remedy this problem, we propose that biodiversity and disease risk can be modelled as latent variables in multivariate causal models to test specific mechanistic pathways. We present a case study on Lyme disease through a systematic review and meta-analysis, concluding that there is little evidence for a net dilution or amplification effect. We demonstrate how testing these net effect hypotheses falls short of providing robust evidence for its underlying mechanisms. While these hypotheses have previously been helpful in conceptualizing this idea of biodiversity as a potentially protective factor for human health, they need further specificity and clarity to move forwards with greater unity.
Community, Belonging, and Peer-Engagement: Participant Experiences Reflect Consistency of Facilitation Practices in Inclusive STEM Teaching Learning Communities
Authors: Codding Diane , Yen Alexandria H. , Lewis Haley , Johnson-Ojeda Vanessa , Hokanson Sarah Chobot , Goldberg Bennett B. 
Published: January 2025

AbstractA primary reason for the persistent underrepresentation of minoritized people in STEM careers are their marginalizing experiences in STEM courses, which has spurred efforts to prepare STEM faculty to implement inclusive teaching practices. The Inclusive STEM Teaching Project (ISTP) addresses this nationwide challenge by providing STEM faculty a free, online course and associated learning communities (LCs) led by project-trained facilitators. ISTP centers identity, power, privilege and positionality and has successfully shifted educators’ mindsets and abilities. A central question is whether local LCs across contexts maintain equity-minded core practices and achieve inclusive, reflective practitioner outcomes. Our mixed methods analysis of LC participant (n= 165) and facilitator (n= 83) matching survey data spanning five course offerings over two years directly explores the relationship between the learning environments created by facilitators and their participant experiences. Findings demonstrate high fidelity of implementation to training by facilitators that resulted in consistent LC experiences of participants, especially around building a community, sense of belonging and positive peer engagement. Participants overall speak to the importance of facilitated LCs as an inclusive space where they can critically engage with one another as they reflect on, discuss, and ultimately improve their inclusive teaching practices.
Combinatorial phenotypic landscape enables bacterial resistance to phage infection
Authors: Gupta Anika , Morella Norma , Sutormin Dmitry , Li Naisi , Gaisser Karl , Robertson Alexander , Ispolatov Yaroslav , Seelig Georg , Dey Neelendu , Kuchina Anna 
Published: January 2025

AbstractSuccess of phage therapies is limited by bacterial defenses against phages. While a large variety of anti- phage defense mechanisms has been characterized, how expression of these systems is distributed across individual cells and how their combined activities translate into protection from phages has not been studied. Using bacterial single-cell RNA sequencing, we profiled the transcriptomes of ∼50,000 cells from cultures of a human pathobiont,Bacteroides fragilis,infected with a lytic bacteriophage. We quantified the asynchronous progression of phage infection in single bacterial cells and reconstructed the infection timeline, characterizing both host and phage transcriptomic changes as infection unfolded. We discovered a subpopulation of bacteria that remained uninfected and determined the heterogeneously expressed host factors associated with protection. Each cell’s vulnerability to phage infection was defined by combinatorial phase-variable expression of multiple genetic loci, including capsular polysaccharide (CPS) biosynthesis pathways, restriction-modification systems (RM), and a previously uncharacterized operon likely encoding fimbrial genes. By acting together, these heterogeneously expressed phase-variable systems and anti-phage defense mechanisms create a phenotypic landscape where distinct protective combinations enable the survival and re-growth of bacteria expressing these phenotypes without acquiring additional mutations. The emerging model of complementary action of multiple protective mechanisms heterogeneously expressed across an isogenic bacterial population showcases the potent role of phase variation and stochasticity in bacterial anti-phage defenses.One Sentence SummaryCombinatorial phenotypic states with differential vulnerability to phage infection across aBacteroides fragilispopulation enable a small number of super-resistant bacterial cells to evade the phage without the need for acquiring mutations.
Exploring FDA-Approved Antiviral Drugs for Human Metapneumovirus Treatment: Integrative Computational Insights
Authors: Dubey Amit , Kumar Manish , Tufail Aisha , Dwivedi Vivek Dhar 
Published: January 2025

AbstractThis study leverages advanced computational methodologies to identify potential antiviral therapies targeting human metapneumovirus (HMPV), focusing on FDA-approved antiviral drugs and control compounds. A comprehensive computational framework, encompassing virtual screening, molecular docking, molecular dynamics (MD) simulations, density functional theory (DFT) analysis, and ADMET profiling, was employed. Key findings highlight Remdesivir and Peramivir as the most promising candidates, with superior binding energies (−9.5 kcal/mol and - 9.2 kcal/mol, respectively), stable interaction profiles, and robust pharmacological properties. Molecular dynamics revealed exceptional stability for Remdesivir, with the lowest RMSD (0.20 nm), and pharmacophore analysis emphasized its strong hydrogen bonding and hydrophobic interactions. ADMET profiling confirmed their high bioavailability (85% ± 3 for Remdesivir) and low toxicity, positioning these drugs for repurposing against HMPV. This integrative study underscores the potential of computational tools in streamlining drug discovery and advancing therapeutic interventions.