tbuckley/cabot-search huggingface dataset:
Read Length Dominates Phylogenetic Placement Accuracy of Ancient DNA Reads
Authors: Ben Bettisworth, Nikolaos Psonis, Nikos Poulakakis, Pavlos Pavlidis, Alexandros Stamatakis
Journal: Molecular Biology and Evolution (2025)

Abstract A common problem when analyzing ancient DNA (aDNA) data is to identify the species which corresponds to the recovered aDNA sequence(s). The standard approach is to deploy sequence similarity based tools, such as BLAST. However, as aDNA reads may frequently stem from unsampled taxa due to extinction, it is likely that there is no exact match in any database. As a consequence, these tools may not be able to accurately place such reads in a phylogenetic context. Phylogenetic placement is a technique where a read is placed onto a specific branch of a phylogenetic reference tree, which allows for a substantially finer resolution when identifying reads. Prior applications of phylogenetic placement has deployed only on data from extant sources. Therefore, it is unclear how the aDNA damage affects phylogenetic placement's applicability to aDNA data. To investigate how aDNA damage affects placement accuracy, we re-implemented a statistical model of aDNA damage. We deploy this model, along with a modified version of the existing assessment pipeline PEWO, to seven empirical datasets with four leading tools: APPLES, EPA-NG, pplacer, and RAPPAS. We explore the aDNA damage parameter space via a grid search in order to identify the aDNA damage factors that exhibit the largest impact on placement accuracy. We find that the frequency of DNA backbone nicks (and consequently read length) has the, by far, largest impact on aDNA read placement accuracy, and that other factors, such as misincorporations, have a negligible effect on overall placement accuracy.
Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells
Authors: Chu-An Wang, Ya-Chin Hou, Yi-Kai Hong, Yu-Jing Tai, Chieh Shen, Pei-Chi Hou, Jhao-Lin Fu, Cheng-Lin Wu, Siao Muk Cheng, Daw-Yang Hwang, Yung-Yeh Su, Yan-Shen Shan, Shaw-Jenq Tsai
Journal: Molecular Cancer (2025)

Oncogenic KRAS mutations are present in approximately 90% of pancreatic ductal adenocarcinoma (PDAC). However, Kras mutation alone is insufficient to transform precancerous cells into metastatic PDAC. This study investigates how KRAS-mutated epithelial cells acquire the capacity to escape senescence or even immune clearance, thereby progressing to advanced PDAC. Single-cell RNA sequencing and analysis of primary PDAC tumors were conducted. Genetically engineered pancreas-specific Kras-mutated, dual specificity phosphatase-2 (Dusp2) knockout mouse models were established. Human and mouse primary pancreatic cancer cell lines were used for in vitro assessment of cancer characteristics. Tumor progression was studied via pancreas orthotopic and portal vein injection in the immune-competent mice. Clinical relevance was validated by digital spatial transcriptomic analysis of PDAC tumors. Kras mutation induces the formation of pancreatic intraepithelial neoplasia (PanIN), these lesions also exhibit significant apoptotic signals. Single-cell RNA sequencing identified a subset of ERKactiveDUSP2low cells continuing to expand from early to advanced stage PDAC. In vitro and in vivo studies reveal that early infiltrating macrophage-derived tissue inhibitor of metallopeptidase 1 (TIMP-1) is the key factor in maintaining the ERKactiveDUSP2low cell population in a CD63-dependent manner. The ERKactiveDUSP2low cancer cells further exacerbate macrophage-mediated cancer malignancy, including loss of epithelial trait, increased lymphangiogenesis, and immune escape. Digital spatial profiling analysis of PDAC samples demonstrates the colocalization of TIMP-1high macrophages and CD63high cancer cells. The presence of TIMP-1high macrophages and CD63high epithelial cells correlates with poor prognosis in PDAC. Our study reveals the vicious cycle between early infiltrating macrophages and pancreatic cancer cells, providing a mechanistic insight into the dynamic regulation directing pancreatic cancer progression.
Most m5C modifications in mammalian mRNAs are nonadaptive
Authors: Zheng Li, Kai Mi, Chuan Xu
Journal: Molecular Biology and Evolution (2025)

5-methylation (m5C) on mRNA molecules is a prevalent internal posttranscriptional modification in eukaryotes. Although m5C modification has been reported to regulate some biological processes, it is unknown whether most mRNA m5C modifications are functional. To address this question, we analyzed the genome-wide evolutionary characteristics of m5C modifications in protein-coding genes of humans and mice. Our analysis of RNA sequencing data from 13 tissues of both species revealed that (1) the occurrence of m5C modification is exceedingly low, (2) the fraction of m5Cs decreases with the amount of Cs across genes or tissues, (3) m5C modifications are mostly unshared between species, (4) m5C sites and motifs do not exhibit greater evolutionary conservation. Additionally, we estimate that a large fraction of the observed mRNA m5C modifications may be deleterious. Together, these observations suggest that most m5C modifications in mammalian mRNAs are nonadaptive, which has important implications for understanding the biological significance of m5C and other posttranscriptional modifications.
Roll out and prospects of the malaria vaccine R21/Matrix-M
Authors: Lorenz von Seidlein
Journal: PLoS Medicine (2025)

More than a century passed between the discovery of Plasmodium, the pathogen causing malaria, and the invention of the first robust malaria vaccine, RTS,S, in the 1980s.RTS,S consists of the circumsporozoite protein (CSP) of the sporozoite stage of Plasmodium falciparum antigen on a Hepatitis B virus surface antigen (HbsAg) backbone and is given as a course of 3 monthly doses with a booster 12 months after the third dose.It took another 30 years until RTS,S, with the adjuvant AS01, was licensed and prequalified by the World Health Organization (WHO).RTS,S/AS01 is currently owned and produced by the multinational pharmaceutical company Glaxo Smith Kline (GSK).The second malaria vaccine, R21/Matrix-M, was first described in 2017 and was licensed and WHO-prequalified within 6 years [1].The regulatory pathway opened by RTS,S/AS01 helped hasten the time to approval.R21 was conceived as an advancement on RTS,S by increasing the ratio of the antigen CSP to the backbone HbsAg.R21 is adjuvanted by Matrix-M, which is owned by Novavax, Inc. R21/Matrix-M is also given as a 4-dose regimen.It is produced by Serum Institute of India PVT LTD (SIIPL).Both vaccines are based on the circumsporozoite protein (CSP) of the sporozoite stage of Plasmodium falciparum and protect exclusively against the sporozoite life stage.Both vaccines afford no cross-protection against the blood or sexual stages of P. falciparum, or against other Plasmodium species such as P. vivax.With 2 safe and well-tolerated malaria vaccines licensed, the question comes up which vaccine is "better."In a multicountry Phase 3 study, the protection conferred by RTS,S/ AS01 against uncomplicated malaria was 55.8% (97.5% confidence interval, 50.6 to 60.4) in the per-protocol population of children 5 to 17 months of age during the 14 months of follow-up after the first dose [2].When subclinical infections were cleared by coadministration of seasonal malaria chemoprevention (SMC), the protective efficacy of the combination was 62.8% (95% CI, 58.4 to 66.8) against clinical malaria, 70.5% (95% CI, 41.9 to 85.0) against severe malaria, and 72.9% (95% CI, 2.9 to 92.4) against death from malaria [3].The 12-month vaccine efficacy of R21/Matrix-M against uncomplicated malaria was 78% (95% CI, 73 to 82) in children 5 to 17 months old from a multicountry Phase 3 study [4].However, a direct comparison of the reported vaccine efficacies of 56% for RTS,S/AS01 and 78% for R21/Matrix-M may not be appropriate since the 2 trial methodologies were not identical and conducted more than a decade apart.For example, there were differences in the timing of the vaccinations in relation to the peak of the malaria season, which could impact the measured vaccine efficacy due to waning vaccine-induced immunity.The objective way to compare the 2 vaccines would be a head-to-head trial.Such a trial would depend on cooperation from GSK and SIIPL.
An expanding universe of mutational signatures and its rapid evolution in single-stranded RNA viruses
Authors: Yue Yang, Xinyi Zhang, Tingting Chen, Fengyuan Wu, Yu S Huang, Yanhua Qu, Miao Xu, Liang Ma, Mo Liu, Weiwei Zhai
Journal: Molecular Biology and Evolution (2025)

Abstract The study of mutational processes in somatic genomes has gained recent momentum, uncovering a wide array of endogenous and exogenous factors associated with somatic changes. However, the overall landscape of mutational processes in germline mutations across the tree of life and associated evolutionary driving forces are rather unclear. In this study, we analyzed mutational processes in single-stranded RNA (ssRNA) viruses which are known to jump between different hosts with divergent exogenous environments. We found that mutational spectra in different ssRNA viruses differ significantly and are mainly associated with their genetic divergence. Surprisingly, host environments contribute much less significantly to the mutational spectrum, challenging the prevailing view that exogenous cellular environment is a major determinant of the mutational spectrum in viruses. To dissect the evolutionary forces shaping viral spectra, we selected two important scenarios, namely the inter-host evolution between different viral strains as well as the intra-host evolution. In both scenarios, we found mutational spectra change significantly through space and time, strongly correlating with levels of natural selection. Combining the mutations across all ssRNA viruses, we identified a suite of mutational signatures with varying degrees of similarity to somatic signatures in humans, indicating universal and divergent mutational processes across the tree of life. Taken together, we unraveled an unprecedented dynamic landscape of mutational processes in ssRNA viruses, pinpointing important evolutionary forces shaping fast evolution of mutational spectra in different species.
Diagnosing the undiagnosed—what happened to PIMS?
Authors: Adriel Chen, Devi Sridhar
Journal: BMJ (2025)

In mid-March 2020 and into April 2020, paediatric wards in England-usually full with children needing medical care due to respiratory diseases and other illnesses-were empty.The UK, and other countries in the world, were in a covid-19 lockdown.Schools were closing and children were staying at home and not mingling.The usual infectious disease mix that would result in children needing hospital care had a break.Paediatricians expected a quiet few months while NHS resources were directed towards the mounting wave of covid-19 hospital admissions, which were expected to be largely in the older and middle-aged population.And then incredibly unwell children started showing up in hospital. 1First one, then another one, and then several more.The children all had symptoms similar to the rare Kawasaki disease, an autoimmune disease, which can cause cardiac arrest and result in children being admitted to intensive care (ICU).Within the span of 10 days in April 2020, eight children were admitted to hospital in England, and one died. 1 This sounded alarms.The children were previously fit and well, with no underlying illnesses.
Efficacy and safety of finerenone in patients with chronic kidney disease and type 2 diabetes by diuretic use: A <scp>FIDELITY</scp> analysis
Authors: Robert J. Mentz, Stefan D. Anker, Bertram Pitt, Peter Rossing, Luis M. Ruilope, Martin Gebel, Peter Kolkhof, Robert Lawatscheck, Katja Rohwedder, George L. Bakris
Journal: European Journal of Heart Failure (2025)
Fibroblast Growth Factor Receptor 2 Variants in Schimmelpenning–Feuerstein–Mims Syndrome
Authors: Yixin Wang, Lingyun Zhao, Yuling Chen, Lingyu Pan, Runke Zhou, Li Li
Journal: British Journal of Dermatology (2025)

We report a patient diagnosed for SFM with a variant in the FEFR2 gene. The clinical presentation of skin fold changes was different from that of other gene variants causing the disease, showing specific skin fold changes. In SFM patients with skin folds, evaluation for FGFR2 gene variants should be considered.
Rapid radiation of a plant lineage sheds light on the assembly of dry valley biomes
Authors: Ya-Ping Chen, Purayidathkandy Sunojkumar, Robert A Spicer, Richard G J Hodel, Douglas E Soltis, Pamela S Soltis, Alan J Paton, Miao Sun, Bryan T Drew, Chun-Lei Xiang
Journal: Molecular Biology and Evolution (2025)

Abstract Southwest China is characterized by high plateaus, large mountain systems, and deeply incised dry valleys formed by major rivers and their tributaries. Despite the considerable attention given to alpine plant radiations in this region, the timing and mode of diversification of the numerous dry valley plant lineages remain unknown. To address this knowledge gap, we investigated the macroevolution of Isodon (Lamiaceae), a lineage commonly distributed in the dry valleys in southwest China and wetter areas of Asia and Africa. We reconstructed a robust phylogeny encompassing nearly 90% of the approximately 140 extant Isodon species using transcriptome and genome-resequencing data. Our results suggest a rapid radiation of Isodon during the Pliocene that coincided with a habit shift from herbs to shrubs and a habitat shift from humid areas to dry valleys. The shrubby growth form likely acted as a preadaptation allowing for the movement of Isodon species into these dry valleys. Ecological analyses highlight drought-related factors as key drivers influencing the niche preferences of different growth forms and species richness of Isodon. The interplay between topography and the development of the East Asian monsoon since the middle Miocene likely contributed to the formation of the dry valley biome in southwest China. This study enhances our understanding of evolutionary dynamics and ecological drivers shaping the distinctive flora of southwest China and reveals the strategies employed by montane plants in response to climate change and dryland expansion, thus facilitating conservation efforts globally.
Derivation and Validation of D-RISK: An Electronic Health Record–Driven Risk Score to Detect Undiagnosed Dysglycemia in Clinical Practice
Authors: Michael E. Bowen, Ildiko Lingvay, Luigi Meneghini, Brett Moran, Noel O. Santini, Song Zhang, Ethan A. Halm
Journal: Diabetes Care (2025)

OBJECTIVE We derive and validate D-RISK, an electronic health record (EHR)-driven risk score to optimize and facilitate screening for undiagnosed dysglycemia (prediabetes + diabetes) in clinical practice. RESEARCH DESIGN AND METHODS We used retrospective EHR data (derivation sample) and a prospective diabetes screening study (validation sample) to develop D-RISK. Logistic regression with backward selection was used to predict dysglycemia (HbA1c ≥5.7%) using diabetes risk factors consistently captured in structured EHR data. Model coefficients were converted to a points-based risk score. We report discrimination, sensitivity, and specificity and compare D-RISK to the American Diabetes Association (ADA) risk test and the ADA and United States Preventive Services Task Force (USPSTF) screening guidelines. RESULTS The derivation cohort included 11,387 patients (mean age 48 years; 65% female; 42% Hispanic; 32% non-Hispanic Black; mean BMI 32; 29% with hypertension). D-RISK included age, race, BMI, hypertension, and random glucose. The area under curve (AUC) for the risk score was 0.75 (95% CI 0.74–0.76). In the validation screening study (n = 519), the AUC was 0.71 (95% CI 0.66–0.75) which was better than the ADA and USPSTF diabetes screening guidelines (AUC = 0.52 and AUC = 0.58, respectively; P &amp;lt; 0.001 for both). Discrimination was similar to the ADA risk test (AUC = 0.67) using patient-reported data to supplement EHR data, although D-RISK was more sensitive (75% vs. 61%) at the recommended screening thresholds. CONCLUSIONS Designed for use in EHR, D-RISK performs better than commonly used screening guidelines and risk scores and may help detect undiagnosed cases of dysglycemia in clinical practice.
Incidence and predictors of weaning failure from veno‐arterial extracorporeal membrane oxygenation therapy in patients with cardiogenic shock
Authors: Angela Dettling, Caroline Kellner, Jonas Sundermeyer, Benedikt N. Beer, Lisa Besch, Letizia Fausta Bertoldi, Stefan Blankenberg, Jeroen Dauw, Dennis Eckner, Ingo Eitel, Tobias Graf, Patrick Horn, Joanna Jozwiak‐Nozdrzykowska, Paulus Kirchhof, Stefan Kluge, Jannis Krais, Dirk von Lewinski, Axel Linke, Peter Luedike, Enzo Lüsebrink, Peter Nordbeck, Federico Pappalardo, Matthias Pauschinger, Alastair Proudfoot, Tienush Rassaf, Hermann Reichenspurner, Can Martin Sag, Clemens Scherer, P. Christian Schulze, Robert H.G. Schwinger, Carsten Skurk, Marek Sramko, Guido Tavazzi, Holger Thiele, Nuccia Morici, Ephraim B. Winzer, Dirk Westermann, Benedikt Schrage, Norman Mangner
Journal: European Journal of Heart Failure (2025)

This study aimed to investigate incidence and predictors of weaning failure and in-hospital death after successful weaning from veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with cardiogenic shock (CS). Overall, 685 patients with CS treated with VA-ECMO from 23 tertiary care centres in 7 countries were analysed (median age 57 [interquartile range 49-66] years, 542 [79.1%] male, median lactate 7.6 [interquartile range 4.1-12.7] mmol/L). The cause of CS was acute myocardial infarction in 438 (63.9%) patients, and 431 (62.9%) patients presented with cardiac arrest. A total of 410 patients (59.9%) were successfully weaned from VA-ECMO, whereas in 275 patients (40.1%) weaning failed (i.e. patients died on or within 48 h after VA-ECMO support). Of the successfully weaned patients, 150 (36.6%) died before hospital discharge. On multivariable logistic regression, predictors for both patient groups varied: age (per 10 years, odds ratio [OR] 1.49, 95% confidence interval [CI] 1.25-1.76; p < 0.001) and cardiac arrest before VA-ECMO implantation (OR 1.64, 95% CI 1.01-2.64; p = 0.04) were associated with weaning failure, whereas lactate clearance within 24 h after VA-ECMO initiation was associated with successful weaning (OR 0.21, 95% CI 0.1-0.44; p < 0.001). In-hospital death after successful weaning was more likely with higher age (per 10 years, OR 1.56, 95% CI 1.24-1.97; p < 0.001), renal replacement therapy (OR 2.56, 95% CI 1.4-4.68; p = 0.002) and bleeding events (OR 2.93, 95% CI 1.4-6.14; p = 0.004). Weaning from VA-ECMO fails in 40% of patients treated with VA-ECMO for CS. When successful, survival after VA-ECMO weaning mostly depends on age and the incidence of device- and shock-related complications.
Psychometric validation of the Copenhagen Hip and Groin Outcome Score (HAGOS) and Oxford Hip Score (OHS) in patients with hip-abductor tendon pathology
Authors: Karl Bang Christensen, Kristian Thorborg, Signe Kierkegaard-Brøchner, Mathias Høgsholt, Jeppe Lange, Marie Bager Bohn
Journal: British Journal of Sports Medicine (2025)

Validated patient-reported outcome measures for patients with hip-abductor tendon pathology are lacking. Recent studies indicate that the Copenhagen Hip and Groin Outcome Score (HAGOS), in the original or the revised scoring format, and the Oxford Hip Score (OHS) may be relevant for use in patients with hip-abductor tendon pathology. The objective of this study was to assess the validity of the Danish version of the HAGOS, the revised HAGOS, and the OHS psychometrically in patients with hip-abductor tendon pathology. This involved the six subscales in the original and the revised version of HAGOS, the standard one-factor scoring of the OHS and the two-factor scoring of the OHS. We included individual responses to HAGOS and OHS from 210 patients with hip-abductor tendon pathology (17 men; 193 women; median age 56 years, range 18-91, IQR 48-65). Overall fit, model fit, individual item fit and measurement invariance were examined using confirmatory factor analysis (CFA) and item response theory. CFA rejected psychometric validity of three original HAGOS subscales (symptoms, pain, physical function in sport and recreation) (p<0.0001) and the OHS (p<0.0001), whereas the revised scoring format for HAGOS subscales fit adequately. Results indicate a notable discrepancy between observed and expected scores on OHS item 10 in the patient group. The original HAGOS and OHS are not psychometrically valid, but the revised HAGOS scoring format is an appropriate PROM for patients with hip-abductor tendon pathology. The OHS would need slight adjustment before being used in patients with hip-abductor tendon pathology.
Multinational retrospective analysis of bridging therapy prior to chimeric antigen receptor t cells for relapsed/refractory acute lymphoblastic leukemia in children and young adults
Authors: Maike Breidenbach, Peter Bader, Andishe Attarbaschi, Claudia Rossig, Roland Meisel, Markus Metzler, Marion Subklewe, Fabian Mueller, Paul-Gerhardt Schlegel, Irene Teichert von Lüttichau, Jean-Pierre Bourquin, Gabriele Escherich, Gunnar Cario, Peter Lang, Ramona Coffey, Arend von Stackelberg, Semjon Willier, Brigitte Strahm, Christina Peters, Tobias Feuchtinger
Journal: Journal of Hematology & Oncology (2025)

Anti-CD19 chimeric antigen receptor T cells (CAR) are a well-established treatment option for children and young adults suffering from relapsed/refractory B-lineage acute lymphoblastic leukemia. Bridging therapy is used to control disease prior to start of lymphodepletion before CAR infusion and thereby improve efficacy of CAR therapy. However, the effect of different bridging strategies on outcome, side effects and response to CAR therapy is still poorly understood. In this retrospective, multinational study, real-world data were collected from 14 different sites in Germany, Austria and Switzerland on 88 patients receiving 93 2nd-generation CAR therapies. Bridging therapy was classified into the categories 1) no systemic therapy (15/93 treatments), 2) low-intensity therapy (38/93 treatments) and 3) high-intensity therapy (39/93 treatments). We analyzed the impact of bridging regimens on clinical outcome. Patients receiving a high-intensity bridging therapy had a significantly higher tumor burden at time of eligibility compared to patients treated with a low-intensity or no systemic bridging therapy. They suffered significantly more from bacterial adverse events and mucositis. Overall survival was significantly better for patients who did not receive any bridging therapy in comparison to patients who had been treated with a low- or high-intensity bridging regimen. In conclusion, in this retrospective cohort, high-intensity bridging therapy has not improved the outcome in terms of overall and progression-free survival in comparison to a low-intensity therapy. Yet, high-intensity bridging therapy was associated with more adverse events. Our study suggests that a low-intensity bridging regimen may be preferred whenever tumor burden and disease kinetics allow this treatment strategy.