bluuebunny/crossref_metadata_2025_split huggingface dataset:
Revisiting the activity of two poly(vinyl chloride)- and polyethylene-degrading enzymes
Authors: Stepnov Anton A. , Lopez-Tavera Esteban , Klauer Ross , Lincoln Clarissa L. , Chowreddy Ravindra R. , Beckham Gregg T. , Eijsink Vincent G. H. , Solomon Kevin , Blenner Mark , Vaaje-Kolstad Gustav 
Published: March 2024

AbstractBiocatalytic degradation of non-hydrolyzable plastics is a rapidly growing field of research, driven by the global accumulation of waste. Enzymes capable of cleaving the carbon-carbon bonds in synthetic polymers are highly sought-after as they may provide tools for environmentally friendly plastic recycling. Despite some reports of oxidative enzymes acting on non-hydrolyzable plastics, including polyethylene or poly(vinyl chloride), the notion that these materials are susceptible to efficient enzymatic degradation remains controversial, partly driven by a general lack of studies independently reproducing previous observations. We attempted to replicate two recent studies reporting that deconstruction of polyethylene and poly(vinyl chloride) can be achieved using an insect hexamerin fromGalleria mellonella(so-called “Ceres”) or a bacterial catalase-peroxidase fromKlebsiella sp., respectively. Reproducing previously described experiments with the recombinant proteins, we did not observe any activity on plastics using multiple reaction conditions and multiple substrate types. Digging deeper into the discrepancies between the previous data and our observations, we show how and why the original experimental results may have been misinterpreted, leading to the erroneous claim that enzymatic deconstruction of polyethylene and poly(vinyl chloride) had occurred. Our results should lead to caution when interpreting the growing amount of literature claiming enzymatic degradation of non-hydrolyzable plastics.
Imputation of ancient canid genomes reveals inbreeding history over the past 10,000 years
Authors: Bougiouri Katia , Aninta Sabhrina Gita , Charlton Sophy , Harris Alex , Carmagnini Alberto , Piličiauskienė Giedrė , Feuerborn Tatiana R. , Scarsbrook Lachie , Tabadda Kristina , Blaževičius Povilas , Parker Heidi G. , Gopalakrishnan Shyam , Larson Greger , Ostrander Elaine A. , Irving-Pease Evan K. , Frantz Laurent A.F. , Racimo Fernando 
Published: March 2024

AbstractThe multi-millenia long history between dogs and humans has placed them at the forefront of archeological and genomic research. Despite ongoing efforts including the analysis of ancient dog and wolf genomes, many questions remain regarding their geographic and temporal origins, and the microevolutionary processes that led to the diversity of breeds today. Although ancient genomes provide valuable information, their use is hindered by low depth of coverage and post-mortem damage, which inhibits confident genotype calling. In the present study, we assess how genotype imputation of ancient dog and wolf genomes, utilising a large reference panel, can improve the resolution provided by ancient datasets. Imputation accuracy was evaluated by down-sampling high coverage dog and wolf genomes to 0.05-2x coverage and comparing concordance between imputed and high coverage genotypes. We measured the impact of imputation on principal component analyses and runs of homozygosity. Our findings show high (R2>0.9) imputation accuracy for dogs with coverage as low as 0.5x and for wolves as low as 1.0x. We then imputed a dataset of 90 ancient dog and wolf genomes, to assess changes in inbreeding during the last 10,000 years of dog evolution. Ancient dog and wolf populations generally exhibited lower inbreeding levels than present-day individuals. Interestingly, regions with low ROH density maintained across ancient and present-day samples were significantly associated with genes related to olfaction and immune response. Our study indicates that imputing ancient canine genomes is a viable strategy that allows for the use of analytical methods previously limited to high-quality genetic data.
Population structure and genetic diversity of the Critically Endangered bowmouth guitarfish (Rhina ancylostomus) in the Northwest Indian Ocean
Authors: Kipperman Marja J. , Jabado Rima W. , Haque Alifa Banthe , Fernando Daniel , Anjani P.A.D.L , Spaet Julia L.Y. , Humble Emily 
Published: March 2024

AbstractThe bowmouth guitarfish (Rhina ancylostomus) is a unique and relatively understudied species of wedgefish with a distribution spanning the Indo-Pacific Oceans. Due to targeted and bycatch fisheries, this species is experiencing serious declines across its range. It is now considered among the most threatened species of elasmobranch. Despite this, species-specific management is limited, particularly around primary fishing hotspots. This is in part due to knowing very little about fundamental population processes. Here, we combine mitochondrial and single nucleotide polymorphism (SNP) data to carry out the first genetic assessment ofR. ancylostomusacross the Northwest Indian Ocean. We find evidence for population structure across the species’ northwest range that is best explained by dispersal constraints and therefore emphasises the importance of habitat connectivity. We also uncover a cline in genetic variation from east to west of the sampling distribution and identify regions in potential need of heightened protection. In doing so, our study provides baseline information to support conservation management ofR. ancylostomusand highlights the value of genomic data in elasmobranch conservation.
Welding PROxAb Shuttles: A modular approach for generating bispecific antibodies via site-specific protein-protein conjugation
Authors: Lehmann Tanja , Schneider Hendrik , Tonillo Jason , Schanz Jennifer , Schwarz Daniel , Schröter Christian , Kolmar Harald , Hecht Stefan , Anderl Jan , Rasche Nicolas , Rieker Marcel , Dickgiesser Stephan 
Published: March 2024

AbstractTargeted protein degradation is an innovative therapeutic strategy to selectively eliminate disease-causing proteins. Exemplified by proteolysis-targeting chimeras (PROTACs), it has shown promise in overcoming drug resistance and targeting previously undruggable proteins. However, PROTACs face challenges such as low oral bioavailability and limited selectivity. The recently published PROxAb Shuttle technology offers a solution enabling targeted delivery of PROTACs using antibodies fused with PROTAC-binding domains derived from camelid single-domain antibodies (VHHs). Here, a modular approach to quickly generate PROxAb Shuttles by enzymatically coupling PROTAC-binding VHHs to off- the-shelf antibodies was developed. The resulting conjugates retained their target binding and internalization properties and incubation with BRD4-targeting PROTACs resulted in formation of defined PROxAb-PROTAC complexes. These complexes selectively induced degradation of the BRD4 protein, resulting in cytotoxicity specifically in cells expressing the antibody’s target. The chemoenzymatic approach described here provides a versatile and efficient solution for generating antibody-VHH conjugates for targeted protein degradation applications but could also be used to combine antibody and VHH binders to generate bispecific antibodies for further applications.
A numbers game: Mosquito-based arbovirus surveillance in two distinct geographic regions of Latin America
Authors: Mojica Jacqueline , Arévalo Valentina , Juarez Jose G. , Galarza Ximena , Gonzalez Karla , Carrazco Andrés , Suazo Harold , Harris Eva , Coloma Josefina , Ponce Patricio , Balmaseda Angel , Cevallos Varsovia 
Published: March 2024

AbstractAedesmosquitoes, as vectors of medically important arthropod-borne viruses (arboviruses), constitute a major public health threat that requires entomological and epidemiological surveillance to guide vector control programs to prevent and reduce disease transmission. In this study, we present the collaborative effort of one year of mosquito-based arbovirus surveillance in two geographically distinct regions of Latin America (Nicaragua and Ecuador). Adult female mosquitoes were collected using backpack aspirators in over 2,800 randomly selected households (Nicaragua, Ecuador) and 100 key sites (Nicaragua) from eight distinct communities (Nicaragua: 2, Ecuador: 6). A total of 1,358 mosquito female pools were processed for RNA extraction and viral RNA detection using real-time RT-PCR. Ten positive dengue virus (DENV) pools were detected (3 in Nicaragua and 7 in Ecuador), all of which were found during the rainy season and matched the serotypes found in humans (Nicaragua: DENV-1 and DENV-4; Ecuador: DENV-2). Infection rates ranged from 1.13 to 23.13, with the Nicaraguan communities having the lowest infection rates. Our results demonstrate the feasibility of detecting DENV-infectedAedesmosquitoes in low-resource settings and underscore the need for targeted mosquito arbovirus sampling and testing, providing valuable insights for future surveillance programs in the Latin American region.
Dysregulation of cell state dynamics during early stages of serous endometrial carcinogenesis
Authors: Flesken-Nikitin Andrea , Pirtz Matalin G. , Ashe Christopher S. , Ellenson Lora H. , Cosgrove Benjamin D. , Nikitin Alexander Yu. 
Published: March 2024

AbstractSerous endometrial carcinoma (SEC) constitutes about 10% of endometrial carcinomas and is one of the most aggressive and lethal types of uterine cancer. Due to the rapid progression of SEC, early detection of this disease is of utmost importance. However, molecular and cellular dynamics during the pre-dysplastic stage of this disease remain largely unknown. Here, we provide a comprehensive census of cell types and their states for normal, pre-dysplastic, and dysplastic endometrium in a mouse model of SEC. This model is associated with inactivation of tumor suppressor genesTrp53andRb1, whose pathways are altered frequently in SEC. We report that pre-dysplastic changes are characterized by an expanded and increasingly diverse immature luminal epithelial cell populations. Consistent with transcriptome changes, cells expressing the luminal epithelial marker TROP2 begin to substitute FOXA2+ cells in the glandular epithelium. These changes are associated with a reduction in number and strength of predicted interactions between epithelial and stromal endometrial cells. By using a multi-level approach combining single-cell and spatial transcriptomics paired with screening for clinically relevant genes in human endometrial carcinoma, we identified a panel of 44 genes suitable for further testing of their validity as early diagnostic and prognostic markers. Among these genes are known markers of human SEC, such as CDKN2A,and novel markers, such asOAS2 and OASL,members of 2-5A synthetase family that is essential for the innate immune response. In summary, our results suggest an important role of the luminal epithelium in SEC pathogenesis, highlight aberrant cell-cell interactions in pre-dysplastic stages, and provide a new platform for comparative identification and characterization of novel, clinically relevant prognostic and diagnostic markers and potential therapeutic modalities.
Machine learning methods to track dynamic facial function in facial palsy
Authors: Rao Akshita A. , Greene Jacqueline J. , Coleman Todd P. 
Published: March 2024

AbstractFor patients with facial paralysis, the wait for return of facial function and resulting vision risk from poor eye closure, difficulty speaking and eating from flaccid oral sphincter muscles, as well as psychological morbidity from the inability to smile or express emotions through facial movement can be devastating. There are limited methods to assess ongoing facial nerve regeneration: clinicians rely on subjective descriptions, imprecise scales, and static photographs to evaluate facial functional recovery, and thus facial nerve regeneration remains poorly understood. We propose a more precise evaluation of dynamic facial function through video-based machine learning analysis to facilitate a better understanding of the sometimes subtle onset of facial nerve recovery and improve guidance for facial reanimation surgery.MethodsWe here present machine learning methods employing likelihood ratio tests, optimal transport theory, and Mahalanobis distances to: 1) assess the use of defined facial landmarks for binary classification of different facial palsy types; identify regions of asymmetry and potential paralysis during specific facial cues; and 3) quantify palsy severity and map it directly to widely used clinical scores, offering clinicians an objective way to assess facial nerve function.ResultsOur work presents promising results of utilizing videos, rather than static photographs, to provide robust quantitative analyses of dynamic properties for various facial movements without requiring manual assessment.SignificanceThe long-term potential of this project is to enable clinicians to have more accurate and timely information to make decisions for facial reanimation surgery which will have drastic consequences on the quality of life for affected patients.
sSocial Determinants of Health and Cumulative Incidence of Mortality among U.S. Adults without Major Chronic Diseases
Authors: Claudel Sophie E. , Verma Ashish 
Published: March 2024

AbstractBackgroundSocial determinants of health (SDOH) are widely known to contribute to poor health outcomes and premature mortality among individuals with prevalent diseases. Understanding the impact of SDOH on mortality among adults without major chronic diseases may inform public policy in the United States (U.S.).MethodsWe conducted a prospective observational study using the National Health and Nutrition Examination Survey data (1999-2018) among 11,413 adults without hypertension, diabetes, hyperlipidemia, severe obesity, chronic kidney disease, cardiovascular disease, chronic respiratory disease, cancer, liver disease, arthritis, hepatitis B or C, human immunodeficiency virus, or pregnancy. We calculated 15-year adjusted cumulative incidences of all-cause mortality by baseline SDOH and described the trends in the prevalence of adverse SDOH.ResultsThe mean ±SD age was 34.9±11.2 years. Over a median follow-up of 10.3 years, 275 participants died. The prevalence of low educational attainment decreased over the study period from 19.8% to 12.1%, while the prevalence of food insecurity increased from 11.5% to 23.1%. The 15-year adjusted cumulative incidences of all-cause mortality were 5.6% (95% CI, 2.8-8.5), 5.2% (95%CI, 3.2-7.3), 4.9% (95%CI, 2.7-7.2), 4.0% (95%CI, 2.8-5.2) for participants who had < 100 % of the federal poverty level, below high school education, food insecurity, and were born in the U.S., respectively. In the final adjusted model, a 1-point increase in cumulative SDOH score was associated with 33% increased risk of all-cause mortality.ConclusionsIn this study of community-dwelling U.S. adults without major chronic diseases, we demonstrate a pronounced increase in all-cause mortality associated with adverse SDOH.
Aging-dependent Change in Th17 and Cytokine Response in Multiple Sclerosis
Authors: Zhu Wen , Revu Shankar , Chen Chenyi , Dahl Megan , Ramkumar Archana , Kelly Conor , McGeachy Mandy J , Xia Zongqi 
Published: March 2024

AbstractBackgroundMultiple sclerosis (MS) is a chronic autoimmune disease damaging the central nervous system. Diminished inflammatory disease activity (DA) as people with MS (pwMS) age motivated randomized clinical trials assessing disease-modifying therapy (DMT) discontinuation in older pwMS given the concern for risks outweighing benefits. This study aims to examine whether peripheral production of Myelin Basic Protein (MBP)-driven cytokine responses mediate the aging-associated decline in MS inflammatory DA.MethodsWe included the clinical data of 669 adult pwMS between 2017 and 2022 who enrolled in a clinic-based prospective cohort. From a subset of 80 participants, we isolated fresh peripheral blood mononuclear cells (PBMCs) and cultured with 50μg/ml of MBP (or heat-killed Candida) for 24 hours. We assayed cell culture supernatants for interleukin 17 (IL-17) and interferon gamma (IFN-γ) using Enzyme-Linked Immunosorbent Assay and a subset of the supernatant samples using a commercial human cytokine/chemokine array. We examined the associations between age and annualized relapse rate (ARR) as well as between age and MBP-stimulated cytokine production (by cultured PBMC) using covariate-adjusted linear regressions. We performed mediation analyses to determine the extent to which MBP-driven cytokine response drives the association between age and ARR.ResultsAmong 669 pwMS (mean age 51.7±12.7 years, 80.7% women, 89.4% non-Hispanic White), ARR declined with age (β=-0.003, p<0.001). Among the subgroup of 80 pwMS whose cultured PBMCs underwent ex vivo MBP stimulation, IL-17 production declined with age in women (β=-0.27, p=0.04) but not men (β=-0.1, p=0.73). MBP-driven IL-17 response partially mediated the association between older age and lower ARR (24.7% in women, 15.3% in men). In exploratory analyses, older pwMS (≥50 years) had marginally lower (IL-4, MCP-2, MCP-3, PDGF-AA, PDGF-AB/BB) and higher (Fractalkine, MDC) concentrations of several cytokines than younger pwMS (<50 years), while certain cytokines (MCP-2, MDC) mediated whereas others negated the effect of age on ARR.ConclusionDiminished peripheral IL-17 response as a potential biological mechanism underlying the aging-dependent decline in MS inflammatory DA warrants further investigation.
Exploring plasma cell motility and extracellular matrix protein biomarkers for primary progressive multiple sclerosis: A pilot study
Authors: Lackey Elijah , Reinke Stephanie , Luo Sheng , Laskowitz Daniel , Eckstein Christopher , Gregory Simon G 
Published: March 2024

AbstractPrimary progressive multiple sclerosis is associated with neurodegeneration and chronic inflammation, and results in the accumulation of gradual disability. This pilot study investigated 92 plasma proteins using proximal extension assay to identify MS subtype-specific biomarkers with a focus on predicting primary progressive MS. We analyzed samples from 66 MS patients (22 relapsing-remitting, 22 secondary progressive, and 22 primary progressive) and 22 controls. ANOVA identified five proteins (ACAN, TMSB10, BST1, CLEC11A, MYOC) with p < 0.05 for differentiating phenotypes of MS, four of which have been previously implicated in MS pathophysiology. However, after correcting for multiple comparisons no individual proteins remained statistically significant. Logistic regression and support vector models using these 5 proteins for predicting primary progressive, in one-vs all-models, against other MS phenotypes and controls were of low accuracy (0.69 and 0.68, respectively). While not immediately translatable, these results lay the groundwork for future studies into MS progression biomarkers.
Tumor and pan-tumor diversity and heterogeneity of cancer tissue microbiomes: a medical ecology analysis across 32 cancer types
Authors: Ma Zhanshan (Sam) 
Published: March 2024

AbstractDiversity and heterogeneity are hallmarks of any ecosystems including cancer ecosystems. Tumor heterogeneities have been a hot spot in cancer research because of their critical roles in promoting clonal evolution and metastasis of cancer cells and in influencing cancer progression and therapy efficacy. Cancer tissue microbiome as part of tumor microenvironment can influence tumor heterogeneities both directly and indirectly through their “intimate” intracellular and intercellular interactions with human cells including tumor, immune and normal cells. From an ecological perspective, the relationship between tumor microenvironment and tumor heterogeneity is not unlike that between habitat heterogeneity and community heterogeneity. That is, their heterogeneities should be interwoven with each other, and then the net effects of the microbiomes on cancer development, malignant progression, and therapy responses can be either promotive or suppressive depending on the so-termed immune-oncology-microbiome axis or trio. The objective of this study is to assess and interpret the heterogeneity and often conflated diversity of tumor microbiomes. Our findings, from reanalyzing a big microbiome dataset originally distilled from the TCGA (The Cancer Genome Atlas) database by Pooreet al. (2020, Nature) including 16555 tumor microbiome samples from the primary tumor (PT), solid tissue normal (SN) and blood derived normal (B) of 32 cancer types, include: (i) The tumor microbiome heterogeneity (diversity) cancer relationship HCR (DCR),i.e.,the heterogeneity (diversity) differences between PTvs.SN (B) are only significantly in approximately 10%-40% depending on the cancer types. (ii) The pan-tumor HCR (DCR),i.e.,microbiome heterogeneity/diversity differences of same tissue type (e.g., PT) across cancer types (e.g., lung vs. breast cancers) are approximately twice the range of previous tumor-HCR (DCR) (i.e., 30%-80% for pan-tumorvs. 10%-40% of tumor scale). In both tumor and pan-tumor scales, the heterogeneity differences ranges are wider than the diversity ranges. (iii) The NSR values range between 0.4 and 0.8 and in 75% cases NSR>0.5, suggesting that tumor selection plays a dominant role than stochastic drifts in shaping microbiome diversity/heterogeneity patterns. Furthermore, the NSR values are significantly different between PT and NT (B) in 50%-100% (mostly 70%-80%) cases across 32 cancer types, further confirming that it should be the tumor growth that is largely responsible for the dominance of selection forces. Finally, we postulate that the HCR (DCR) should be dynamic with tumor types, progression, microbial taxa, host genomics and physiology, therapy and diets.
Pathways and barriers to becoming physician-scientists for first-generation individuals
Authors: Christophers Briana , Macedo Briana , Weng Jessica , Granovetter Michael C. , Kumar Rachit , Smith Chynna , Andersen Olaf S. , Boothroyd Catharine 
Published: March 2024

AbstractIntroductionPhysician-scientists are uniquely positioned to contribute translational research that will impact patient care and our understanding of disease. Having a diverse cadre of physician-scientists is critical to ensuring that the biomedical research enterprise explores the breadth of problems affecting the nation’s health. The National Institutes of Health has identified diversity, including educational background, to be important for the biomedical workforce. In 2020, less than ten percent of MD-PhD program matriculants were the first in their families to pursue higher education (first-generation) despite the majority of the US population having less than a Bachelor’s degree. Little is known about the specific challenges that first-generation students face, which makes it challenging to address this gap in matriculation.MethodsThis qualitative study used a phenomenological approach to examine the experiences of first-generation individuals, from the applicant stage to the early-career stage. We conducted semi-structured interviews with 41 participants and analyzed responses in accordance with a networked ecological systems theory.ResultsThe interviews revealed that first-generation individuals put together a patchwork of support. Whereas many MD-PhD trainees struggle at some point in their training, first-generation individuals tend to lack a support system that may provide proactive advice and prepare them for milestones. Interviews shared a common sentiment of isolation due to both a lack of social capital within medicine and academia, as well as a growing disconnect from their families and community.DiscussionKey interventions that would support first-generation students include greater access to high-quality information about the pathway, tailored mentorship throughout training, and more financial resources at the application stage. Trainees and early career physician-scientists seek more flexibility, opportunities for finding community, financial guidance and options, and mentorship around building their careers.