bluuebunny/crossref_metadata_2025_split huggingface dataset:
Maximum Likelihood Estimation for Unrooted 3-Leaf Trees: An Analytic Solution for the CFN Model
Authors: Hill Max , Roch Sebastien , Rodriguez Jose Israel 
Published: February 2024

AbstractMaximum likelihood estimation is among the most widely-used methods for inferring phylogenetic trees from sequence data. This paper solves the problem of computing solutions to the maximum likelihood problem for 3-leaf trees under the 2-state symmetric mutation model (CFN model). Our main result is a closed-form solution to the maximum likelihood problem for unrooted 3-leaf trees, given generic data; this result characterizes all of the ways that a maximum likelihood estimate can fail to exist for generic data and provides theoretical validation for predictions made in [28]. Our proof makes use of both classical tools for studying group-based phylogenetic models such as Hadamard conjugation and reparameterization in terms of Fourier coordinates, as well as more recent results concerning the semi-algebraic constraints of the CFN model. To be able to put these into practice, we also give a complete characterization to test genericity.
Increased Frequency of Clonal Hematopoiesis of Indeterminate Potential in Bloom Syndrome Probands and Carriers
Authors: Lin Isabella , Wei Angela , Gebo Tsumugi A , Boutros PC , Flanagan Maeve , Kucine Nicole , Cunniff C , Arboleda VA , Chang VY 
Published: February 2024

ABSTRACTBackgroundBloom Syndrome (BSyn) is an autosomal recessive disorder caused by biallelic germline variants inBLM,which functions to maintain genomic stability. BSyn patients have poor growth, immune defects, insulin resistance, and a significantly increased risk of malignancies, most commonly hematologic. The malignancy risk in carriers of pathogenic variants inBLM(BLMvariant carriers) remains understudied. Clonal hematopoiesis of indeterminate potential (CHIP) is defined by presence of somatic mutations in leukemia-related genes in blood of individuals without leukemia and is associated with increased risk of leukemia. We hypothesize that somatic mutations driving clonal expansion may be an underlying mechanism leading to increased cancer risk in BSyn patients andBLMvariant carriers.MethodsTo determine whetherde novoor somatic variation is increased in BSyn patients or carriers, we performed and analyzed exome sequencing on BSyn and control trios.ResultsWe discovered that both BSyn patients and carriers had increased numbers of low-frequency, putative somatic variants in CHIP genes compared to controls. Furthermore, BLM variant carriers had increased numbers of somatic variants in DNA methylation genes compared to controls. There was no statistical difference in the numbers ofde novovariants in BSyn probands compared to control probands.ConclusionOur findings of increased CHIP in BSyn probands and carriers suggest that one or two germline pathogenic variants inBLMcould be sufficient to increase the risk of clonal hematopoiesis. These findings warrant further studies in larger cohorts to determine the significance of CHIP as a potential biomarker of aging, cancer, cardiovascular disease, morbidity and mortality.
Capture and Release of Minke Whales Offers New Research Opportunities Including Measurements of Mysticete Hearing
Authors: Kleivane Lars , Kvadsheim Petter H , Vinje Anna Victoria Pyne , Mulsow Jason , Ølberg Rolf Arne , Teilmann Jonas , Harms Craig , Houser Dorian 
Published: February 2024

AbstractKnowledge about species-specific hearing is vital to assessing how anthropogenic noise impacts marine mammals. Unfortunately, no empirical audiogram exists for any mysticete whale. We therefore developed a catch-and-release method to assess hearing in a small mysticete, the minke whale (Balaenoptera acutorostrata). Stationary lead nets were placed to intercept migratory routes and direct animals into an ocean basin enclosed by nets and islets, while another net was pulled across the entrance once a whale entered the basin. The whales were then slowly corralled into a modified aquaculture pen using a net suspended between two boats. Subsequently, the water volume available to the whales was gradually reduced by raising the pen net by hand until the whales were secured in a “hammock” between the floating pen ring and a raft. From the raft, researchers could access the whales to monitor their health, apply instruments for hearing tests, or other research objectives, and attach tags to monitor the movements and diving behavior of the whale post-release. The method is a slow and controlled procedure, allowing continuous monitoring, and quick release of the whales, if needed. In the first three field seasons employing the method, three animals were caught for research procedures. Initial hearing measurements using auditory evoked potentials were successfully completed. After release the animals resumed migration and dive behavior were considered normal. Our observations demonstrate that minke whales can be safely guided via moored net barriers, corralled into an aquaculture pen, and safely handled for research purposes, before being released back into the wild.
Decoding the Impact of Neighboring Amino Acid on ESI-MS Intensity Output through Deep Learning
Authors: Abdul-Khalek Naim , Wimmer Reinhard , Overgaard Michael Toft , Echers Simon Gregersen 
Published: February 2024

AbstractPeptide-level quantification using mass spectrometry (MS) is no trivial task as the physicochemical properties affect both response and detectability. The specific amino acid (AA) sequence affects these properties, however the link from sequence to intensity output remains poorly understood. In this work, we explore combinations of amino acid pairs (i.e., dimer motifs) to determine a potential relationship between the local amino acid environment and MS1 intensity. For this purpose, a deep learning (DL) model, consisting of an encoder-decoder with an attention mechanism, was built. The attention mechanism allowed to identify the most relevant motifs. Specific patterns were consistently observed where a bulky/aromatic and hydrophobic AA followed by a cationic AA as well as consecutive bulky/aromatic and hydrophobic AAs were found important for the MS1 intensity. Correlating attention weights to mean MS1 intensities revealed that some important motifs, particularly containing Trp, His, and Cys, were linked with low responding peptides whereas motifs containing Lys and most bulky hydrophobic AAs were often associated with high responding peptides. Moreover, Asn–Gly was associated with low MS1 response. The model could predict MS1 response with a mean average percentage error of ∼11% and a Pearson correlation coefficient of ∼0.68.
Metagenomic estimation of dietary intake from human stool
Authors: Diener Christian , Gibbons Sean M. 
Published: February 2024

AbstractDietary intake is tightly coupled to gut microbiota composition, human metabolism, and to the incidence of virtually all major chronic diseases. Dietary and nutrient intake are usually quantified using dietary questionnaires, which tend to focus on broad food categories, suffer from self-reporting biases, and require strong compliance from study participants. Here, we present MEDI (Metagenomic Estimation of Dietary Intake): a method for quantifying dietary intake using food-derived DNA in stool metagenomes. We show that food items can be accurately detected in metagenomic shotgun sequencing data, even when present at low abundances (>10 reads). Furthermore, we show how dietary intake, in terms of DNA abundance from specific organisms, can be converted into a detailed metabolic representation of nutrient intake. MEDI could identify the onset of solid food consumption in infants and it accurately predicted food questionnaire responses in an adult population. Additionally, we were able to identify specific dietary features associated with metabolic syndrome in a large clinical cohort, providing a proof-of-concept for detailed quantification of individual-specific dietary patterns without the need for questionnaires.
BMI1 regulates human erythroid self-renewal through both gene repression and gene activation
Authors: McGrath Kathleen E. , Koniski Anne D. , Murphy Kristin , Getman Michael , An Hyun Hyung , Schulz Vincent P. , Kim Ah Ram , Zhang Bin , Schofield Taylor L. , Papoin Julien , Blanc Lionel , Kingsley Paul D. , Westhoff Connie M. , Gallagher Patrick G. , Chou Stella T. , Steiner Laurie A. , Palis James 
Published: February 2024

AbstractThe limited proliferative capacity of erythroid precursors is a major obstacle to generate sufficient numbers of in vitro-derived red blood cells (RBC) for clinical purposes. We and others have determined that BMI1, a member of the polycomb repressive complex 1 (PRC1), is both necessary and sufficient to drive extensive proliferation of self-renewing erythroblasts (SREs). However, the mechanisms of BMI1 action remain poorly understood. BMI1 overexpression led to 10 billion-fold increase BMI1-induced (i)SRE self-renewal. Despite prolonged culture and BMI1 overexpression, human iSREs can terminally mature and agglutinate with typing reagent monoclonal antibodies against conventional RBC antigens. BMI1 and RING1B occupancy, along with repressive histone marks, were identified at known BMI1 target genes, including the INK-ARF locus, consistent with an altered cell cycle following BMI1 inhibition. We also identified upregulated BMI1 target genes with low repressive histone modifications, including key regulator of cholesterol homeostasis. Functional studies suggest that both cholesterol import and synthesis are essential for BMI1-associated self-renewal. These findings support the hypothesis that BMI1 regulates erythroid self-renewal not only through gene repression but also through gene activation and offer a strategy to expand the pool of immature erythroid precursors for eventual clinical uses.
Pre-existing cancer cells and induced fibroblasts are key cells for early chemoresistance in ovarian cancer
Authors: Gu Langyu , He Shasha , Wu Linxiang , Zeng Yu , Zhang Yang , Zheng Chenqing , Wu Chuling , Xu Huishan , Zhang Xiaoyan , Shen Hongwei , Yao Shuzhong , Ren Yufeng , Yang Guofen 
Published: February 2024

AbstractChemoresistance has long been a significant but unresolved issue in the treatment of various cancers, including the most deadly gynecological cancer, the high-grade serous ovary cancer (HGSOC). In this study, single nuclei transcriptome analyses were utilized to identify key cells and core networks for chemoresistance in HGSOC patients with different early responses to platinum-based chemotherapy at the single-cell level. Biomarkers for chemoresistance were also screened using bulk transcriptome data from independent cohorts with larger sample sizes. A total of 62,482 single cells from six samples were analyzed, revealing that chemoresistant cancer cells (Epithelial cells_0) pre-existed within individual patient before treatment. Two network modules formed with hub genes such as hormone-related genes (ESR1 and AR), insulin-related genes (INSR and IGF1R), and CTNNB1, were significantly overexpressed in these cells in the chemoresistant patient. BMP1 and TPM2 could be promise biomarkers in identifying chemoresistant patients before chemotherapy using bulk transcriptome data. Additionally, chemotherapy-induced fibroblasts (Fibroblasts_01_after) emerged as key stromal cells for chemoresistance. One network module containing one subnetwork formed by cholesterol biosynthesis-related genes and one subnetwork formed by cancer-related genes such as STAT3 and MYC, was significantly overexpressed in these cells in the chemoresistant patient. Notably, the NAMPT-INSR was the most prioritized ligand-receptor pair for cells interacting with Fibroblasts_01_after cells and Epithelial cells_0 cells to drive the up-regulation of their core genes, including IL1R1, MYC and INSR itself. Our findings deepen the understandings about mechanisms of early chemoresistance in HGSOC patients.
PRESCOTT: a population aware, epistatic and structural model accurately predicts missense effect
Authors: Tekpinar Mustafa , David Laurent , Henry Thomas , Carbone Alessandra 
Published: February 2024

AbstractPredicting the functional impact of point mutations is a complex yet vital task in genomics. PRESCOTT stands at the forefront of this challenge and reconstructs complete mutational landscapes of proteins, enables the identification of protein regions most vulnerable to mutations and assigns scores to individual mutations, assisting pathologists in evaluating the pathogenic potential of missense variants. PRESCOTT categorizes these variants into three distinct classes: Benign, Pathogenic, or Variants of Uncertain Significance (VUS). The model leverages protein sequences across millions of species, advanced protein structural models, and extensive genomic and exomic data from diverse human populations. By using only sequence and structural information, it significantly improves on current standards for predicting mutations in human proteins and matches AlphaMissense performance, which incorporates allele frequency data in its analysis. By including population-specific allele frequencies, PRESCOTT excels in genome-scale score separation of ClinVar benign and pathogenic variants and surpasses AlphaMissense in analyzing the ACMG reference human dataset and the over 1800 proteins from the Human Protein Dataset. Its efficacy is particularly notable in autoinflammatory diseases, accurately predicting pathogenic gain-of-function missense mutations, a task known for its difficulty. Efficiency and accessibility are key aspects of PRESCOTT. The user-friendly PRESCOTT webserver facilitates mutation effect calculations on any protein and protein variants. The server hosts a Comprehensive Human Protein Database for over 19,000 human proteins, based on sequences and structures, ready for a customized allele population analysis. Additionally, the tool provides open access to all intermediate scores, ensuring interpretability and transparency in variant analysis. PRESCOTT is a significant stride forward in the field of genomic medicine, offering unparalleled insights into protein mutational impacts.
In vivoaffinity maturation of the HIV-1 Env-binding domain of CD4
Authors: Pan Andi , Bailey Charles C. , Ou Tianling , Xu Jinge , Liu Xin , Hu Baodan , Crynen Gogce , Skamangas Nickolas , Bronkema Naomi , Tran Mai , Mu Huihui , Zhang Xia , Yin Yiming , Alpert Michael D. , He Wenhui , Farzan Michael 
Published: February 2024

ABSTRACTMany human proteins have been repurposed as biologics for clinical use. These proteins have been engineered within vitrotechniques that improve affinity for their ligands. However, these approaches do not select against properties that impair efficacy such as protease sensitivity or self-reactivity. Here we engineer the B-cell receptor of primary murine B cells to express a human protein biologic without disrupting their ability to affinity mature. Specifically, CD4 domains 1 and 2 (D1D2) of a half-life enhanced-HIV-1 entry inhibitor CD4-Ig (CD4-Ig-v0) were introduced into the heavy-chain loci of murine B cells, which were then adoptively transferred to wild-type mice. After immunization, transferred B cells proliferated, class switched, affinity matured, and efficiently produced D1D2-presenting antibodies. Somatic hypermutations found in the D1D2-encoding region of engrafted B cells improved binding affinity of CD4-Ig-v0 for the HIV-1 envelope glycoprotein (Env) and the neutralization potency of CD4-Ig-v0 by more than ten-fold across a global panel of HIV-1 isolates, without impairing its pharmacokinetic properties. Thus, affinity maturation of non-antibody protein biologicsin vivocan guide development of more effective therapeutics.
Genomic insights into photosymbiotic evolution inTridacna squamosa
Authors: Zhang Yang , Mao Fan , Li Yuanning , Wong Nai-Kei , Bao Yongbo , Dai He , Sun Jin , Yi Wenjie , Xiao Shu , Xiang Zhiming , Li Jun , Zhang Yuehuan , Xia Xiaomin , Zhang Lvping , Zhou Huawei , Yu Ziniu 
Published: February 2024

AbstractPhotosymbiosis is fundamental driving force for ecological success of benthic coral reef ecosystems, and contributing to their biodiversity and resilience. As a benchmark organism indicative of reef health, the fluted giant clam (Tridacna squamosa) forms an exemplary photosymbiotic relationship with the symbiont Symbiodiniaceae dinoflagellates, whose initiation and maturation require finely coordinated interactions. However, much of the origin and dynamics of this reciprocal interplay remains unclarified. Here, we report the first complete whole genome ofT. squamosa, in conjunction with integrated multi-omics data, to illuminate the key evolutionary innovations and molecular events supporting the establishment and maintenance of photosymbiotic lifestyle in the giant clam. Programmed regulation of symbiont recognition, host immune system and GPCRs signaling activation co-contributed to dinoflagellates acquisition inT. squamosalarvae. Adaptive metabolic remodeling in the host siphonal mantle, a photosymbiotic niche, is critical to maintain the robustness of phtosymbiosis.T. squamosahas expanded light sensing gene family and evolved sophisticated signaling pathways to protect against UV photo-damage. Evidence also supports significant contribution of positive selection to host DNA-repair. Overall, our study here offers fresh mechanistic insights into the parallel evolution and molecular machinery of photosymbiosis in the giant clam-dinoflagellates duet, with implications for devising solutions to sustainable conservation.
Before and after delisting: population dynamics of North Atlantic humpback whales over two decades in the Gulf of Maine
Authors: Robbins Jooke , Bérubé Martine , Clapham Phillip J. , Mattila David K. , Palsbøll Per J. , Asmutis-Silvia Regina , Hill Alex , Howes Laura J. , Landry Scott , Lonergan Shelley , Schulte Dianna , Tackaberry Jennifer E. , Weinrich Mason T. , Pace Richard M. 
Published: February 2024

AbstractWhales are long-lived, slow-reproducing species that were decimated by commercial whaling. Although some populations seem close to recovery, others are challenging to assess. We studied humpback whales (Megaptera novaeangliae) in the Gulf of Maine, an area of the North Atlantic (NA) with well-documented threats. Long-term studies and mark-recapture data were used to estimate humpback whale apparent survival, abundance and population growth from 2000 through 2019. Estimates were derived from a hierarchical, Bayesian state-space model with sex, age, and random time effects on survival while accounting for individual capture probability. Abundance increased from 744 (95% CI: 726-762) in 2000 to 1,706 (95% CI: 1,639-1,771) in 2019, with 4.6% mean annual growth. However, adult males exhibited higher survival and outnumbered adult females by the end of the study. Over time, fewer calves were observed, calf survival varied and the juvenile class declined. These are rare insights into the dynamics underlying whale abundance trends and they revealed similarities to an endangered species that is declining due to environmental and human impacts. The results inform a listing change under the U.S. Endangered Species Act, a mortality event of unprecedented magnitude off the U.S and humpback whale recovery from historical whaling in the NA.
TMEM16 and OSCA/TMEM63 proteins share a conserved potential to permeate ions and phospholipids
Authors: Lowry Augustus J. , Liang Pengfei , Song Mo , Wan Y.C. Serena , Pei Zhen-Ming , Yang Huanghe , Zhang Yang 
Published: February 2024

ABSTRACTThe calcium-activated TMEM16 proteins and the mechanosensitive/osmolarity-activated OSCA/TMEM63 proteins belong to the Transmembrane Channel/Scramblase (TCS) superfamily. Within the superfamily, OSCA/TMEM63 proteins, as well as TMEM16A and TMEM16B, are thought to function solely as ion channels. However, most TMEM16 members, including TMEM16F, maintain an additional function as scramblases, rapidly exchanging phospholipids between leaflets of the membrane. Although recent studies have advanced our understanding of TCS structure-function relationships, the molecular determinants of TCS ion and lipid permeation remain unclear. Here we show that single mutations along the transmembrane helix (TM) 4/6 interface allow non-scrambling TCS members to permeate phospholipids. In particular, this study highlights the key role of TM 4 in controlling TCS ion and lipid permeation and offers novel insights into the evolution of the TCS superfamily, suggesting that, like TMEM16s, the OSCA/TMEM63 family maintains a conserved potential to permeate ions and phospholipids.
Enhanced Antibody Response to the Conformational Non-RBD RegionviaDNA Prime-Protein Boost Elicits Broad Cross-Neutralization Against SARS-CoV-2 Variants
Authors: Ma Yun-Fei , Chen Kun , Xie Bowen , Zhu Jiayi , He Xuan , Chen Chunying , Yang Yuhe Renee , Liu Ye 
Published: February 2024

AbstractPreventing immune escape of SARS-CoV-2 variants is crucial in vaccine development to ensure broad protection against the virus. Conformational epitopes beyond the RBD region are vital components of the spike protein but have received limited attention in the development of broadly protective SARS-CoV-2 vaccines. In this study, we used a DNA prime-protein boost regimen to evaluate the broad cross-neutralization potential of immune response targeting conformational non-RBD region against SARS-CoV-2 viruses in mice. Mice with enhanced antibody responses targeting conformational non-RBD region show better performance in cross-neutralization against the Wuhan-01, Delta, and Omicron subvariants.Viaanalyzing the distribution of conformational epitopes, and quantifying epitope-specific binding antibodies, we verified a positive correlation between the proportion of binding antibodies against the N-terminal domain (NTD) supersite (a conformational non-RBD epitope) and SARS-CoV-2 neutralization potency. The current work highlights the importance of high ratio of conformational non-RBD-specific binding antibodies in mediating viral cross-neutralization and provides new insight into overcoming the immune escape of SARS-CoV-2 variants.
Evaluating a Motor Progression Connectivity Model Across Parkinson’s Disease Stages
Authors: Hacker Mallory L. , Isaacs David A. , Rajamani Nanditha , Pazira Kian , Abdou Eli , Sharp Sheffield , Davis Thomas L. , Hedera Peter , Phibbs Fenna T. , Charles David , Horn Andreas 
Published: February 2024

ABSTRACTBackgroundStimulation of a specific site in the dorsolateral subthalamic nucleus (STN) was recently associated with slower motor progression in Parkinson’s Disease (PD), based on the deep brain stimulation (DBS) in early-stage PD pilot trial.ObjectiveTo test whether stimulation of this site is associated with improvements of long-term motor outcomes in advanced-stage PD.MethodsActive contacts of the early DBS cohort (N=14) were analyzed. Sweet spot and connectivity models derived from this cohort were then used to estimate long-term motor outcomes in an independent DBS cohort of advanced-stage PD patients (N=29).ResultsIn early-stage PD, proximity of stimulation to the dorsolateral STN associated with slower motor progression. In advanced-stage PD, stimulation proximity to the same site associated with better long-term motor outcomes (R=0.60, P<0.001).ConclusionsResults suggest stimulation of a specific site in the dorsolateral STN associates with both slower motor progression and long-term motor improvements in PD.