bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional genomics reveals the mechanism of hypoxic adaptation in nontuberculous mycobacteria
Authors: Tateishi Yoshitaka , Ozeki Yuriko , Nishiyama Akihito , Morishige Yuta , Minato Yusuke , Baughn Anthony D. , Matsumoto Sohkichi 
Published: May 2024

AbstractMycobacterium intracellulareis a major etiological agent of the recently expandingMycobacterium avium–intracellularecomplex pulmonary disease (MAC-PD). Therapeutic regimens that include a combination of macrolides and antituberculous drugs have been implemented with limited success. To identify novel targets for drug development that accommodate the genomic diversity ofM. avium–intracellulare, we subjected eight clinical MAC-PD isolates and the type strain ATCC13950 to genome-wide profiling to comprehensively identify universally essential functions. Among these strains, we identified 131 shared essential or growth-defect-associated genes. Unlike the type strain, the clinical strains showed an increased requirement for genes involved in gluconeogenesis and the type VII secretion system under standard growth conditions, the same genes required for hypoxic pellicle-type biofilm formation in ATCC13950. Consistent with the central role of hypoxia in the evolution ofM. intracellulare, the clinical MAC-PD strains showed more rapid adaptation to hypoxic growth than the type strain. Importantly, the increased essentiality of hypoxic fitness genes was confirmed in a mouse lung infection model. These findings confirm the concordant gene essentiality under hypoxic conditionsin vitroand hypoxia-related conditionsin vivo, and highlight the importance of using clinical strains and host-relevant growth conditions to identify high-value targets for drug development.
Artificial Intelligence Uncertainty Quantification in Radiotherapy Applications - A Scoping Review
Authors: Wahid Kareem A. , Kaffey Zaphanlene Y. , Farris David P. , Humbert-Vidan Laia , Moreno Amy C. , Rasmussen Mathis , Ren Jintao , Naser Mohamed A. , Netherton Tucker J. , Korreman Stine , Balakrishnan Guha , Fuller Clifton D. , Fuentes David , Dohopolski Michael J. 
Published: May 2024

AbstractBackground/purposeThe use of artificial intelligence (AI) in radiotherapy (RT) is expanding rapidly. However, there exists a notable lack of clinician trust in AI models, underscoring the need for effective uncertainty quantification (UQ) methods. The purpose of this study was to scope existing literature related to UQ in RT, identify areas of improvement, and determine future directions.MethodsWe followed the PRISMA-ScR scoping review reporting guidelines. We utilized the population (human cancer patients), concept (utilization of AI UQ), context (radiotherapy applications) framework to structure our search and screening process. We conducted a systematic search spanning seven databases, supplemented by manual curation, up to January 2024. Our search yielded a total of 8980 articles for initial review. Manuscript screening and data extraction was performed in Covidence. Data extraction categories included general study characteristics, RT characteristics, AI characteristics, and UQ characteristics.ResultsWe identified 56 articles published from 2015-2024. 10 domains of RT applications were represented; most studies evaluated auto-contouring (50%), followed by image-synthesis (13%), and multiple applications simultaneously (11%). 12 disease sites were represented, with head and neck cancer being the most common disease site independent of application space (32%). Imaging data was used in 91% of studies, while only 13% incorporated RT dose information. Most studies focused on failure detection as the main application of UQ (60%), with Monte Carlo dropout being the most commonly implemented UQ method (32%) followed by ensembling (16%). 55% of studies did not share code or datasets.ConclusionOur review revealed a lack of diversity in UQ for RT applications beyond auto-contouring. Moreover, there was a clear need to study additional UQ methods, such as conformal prediction. Our results may incentivize the development of guidelines for reporting and implementation of UQ in RT.
The Effects of Intermittent Vibrational Stimulation on Lower Limb Kinematics Two Months After Anterior Cruciate Ligament Reconstruction: A Randomized Controlled Trial
Authors: Yona Tomer , Peskin Bezalel , Fischer Arielle 
Published: May 2024

AbstractObjectiveTo investigate the immediate effects of intermittent vibrational stimulation on gait and stair ambulation among patients two months post anterior cruciate ligament reconstruction.DesignRandomized, parallel, 2-group-randomized controlled trial.SettingHospital setting.ParticipantsThere were 27 male and female participants aged 18-45, two months post-ACLR, and a convenience sample of 24 healthy controls.InterventionsThe participants were randomly assigned to two groups. One group received a device designed to apply intermittent vibrational stimulation above and below the knee; the other received a sham device.Main Outcome Measure(s)The main outcomes were the knee sagittal kinematics during gait at three speeds and stair ascent and descent. The assessment was performed with and without one of the study devices.ResultsCompared to the sham device, intermittent vibrational stimulation significantly increased the minimum knee flexion angles while walking at normal, slow, and fast paces and stair ascent.ConcblusionIntermittent vibrational stimulation affects the lower limb kinematics during rehabilitation for individuals post-ACLR. However, further research is necessary to confirm long-term benefits and establish optimal application parameters.
Mutation frequency and copy number alterations determine prognosis and metastatic tropism in 60,000 clinical cancer samples
Authors: Calonaci Nicola , Krasniqi Eriseld , Scalera Stefano , Gandolfi Giorgia , Milite Salvatore , Ricciuti Biagio , Maugeri-Saccà Marcello , Caravagna Giulio 
Published: May 2024

AbstractThe intricate interplay between somatic mutations and copy number alterations critically influences tumour evolution and patient prognosis. Traditional genomic studies often overlook this interplay by analysing these two biomarker types in isolation. Leveraging an innovative computational model capable of detecting allele-specific copy number alterations from clinical targeted panels without matched normal, we conducted a comprehensive analysis of over 500,000 mutations across 60,000 clinical samples spanning 39 cancer types. Our findings uncovered 11 genes and 6 hotspots exhibiting recurrent tumour-specific patterns of co-existing mutations and copy-number alterations across 17 tumours. By stratifying more than 24,000 patients based on these composite genotypes across multiple oncogenes and tumour suppressor genes, we identified 66 groups with distinct prognostic significance, 25% more than using a standard mutation-centric stratification. Notably, 7 groups displayed a heightened propensity for metastasis, while 16 were associated with site-specific patterns of metastatic dissemination. This augmented insight into genomic drivers enhances our understanding of cancer progression and metastasis, holding the potential to significantly foster biomarker discovery.Statement of significanceBy leveraging large datasets and new computational modelling, this study demonstrates the critical interplay between somatic mutations and copy number alterations in driving patient prognosis, tumour progression and metastatic tropism. This work implies a shift towards a more integrative and comprehensive approach in clinical sequencing, with significant implications for biomarker discovery and target identification.
Deep Learning for Contrast Enhanced Mammography - a Systematic Review
Authors: Sorin Vera , Sklair-Levy Miri , Glicksberg Benjamin S. , Konen Eli , Nadkarni Girish N. , Klang Eyal 
Published: May 2024

AbstractBackground/Aim:Contrast-enhanced mammography (CEM) is a relatively novel imaging technique that enables both anatomical and functional breast imaging, with improved diagnostic performance compared to standard 2D mammography. The aim of this study is to systematically review the literature on deep learning (DL) applications for CEM, exploring how these models can further enhance CEM diagnostic potential.MethodsThis systematic review was reported according to the PRISMA guidelines. We searched for studies published up to April 2024. MEDLINE, Scopus and Google Scholar were used as search databases. Two reviewers independently implemented the search strategy.ResultsSixteen relevant studies published between 2018 and 2024 were identified. All studies but one used convolutional neural network models. All studies evaluated DL algorithms for classification of lesions at CEM, while six studies also assessed lesion detection or segmentation. In three studies segmentation was performed manually, two studies evaluated both manual and automatic segmentation, and ten studies automatically segmented the lesions.ConclusionWhile still at an early research stage, DL can improve CEM diagnostic precision. However, there is a relatively small number of studies evaluating different DL algorithms, and most studies are retrospective. Further prospective testing to assess performance of applications at actual clinical setting is warranted.Graphic Abstract
Proteasomal control of anti-CRISPRs for the regulation of CRISPR/Cas9 activity using Cas9-ACROBAT
Authors: Martin Timothy D. , Watson Emma V. , Choi Mei Yuk , Nabet Behnam , Gray Nathanael S. , Xu Qikai , Elledge Stephen J. 
Published: May 2024

ABSTRACTSmall molecule-mediated proteasomal degradation of proteins is a powerful tool for synthetic regulation of biological activity. To control Cas9 activity in cells, we engineered an anti-CRISPR protein, AcrIIA4, fused to a degradation (dTAG) or small molecule assisted shutoff (SMASh) tag. Co-expression of the tagged AcrIIA4 along with Cas9 and riboswitch-regulated sgRNAs enables precise tunable control of CRISPR activity by small molecule addition.
Bacterial microcompartment utilisation in the human commensalEscherichia coliNissle 1917
Authors: Clare Chania , Rutter Jack W. , Fedorec Alex J.H. , Frank Stefanie , Barnes Chris P. 
Published: May 2024

AbstractBacterial microcompartments (BMCs) are self-assembled protein structures often utilised by bacteria as a modular metabolic unit, enabling the catalysis and utilisation of less common carbon and nitrogen sources within a self-contained compartment. Theethanolamine (EA) utilisation (eut)BMC has been widely demonstrated in enteropathogens, such asSalmonella enterica, and current research is exploring its activity in the commensal species that populate the human gut.Escherichia coliNissle 1917 (EcN) is a strong coloniser and probiotic in gut microbial communities, and has been used extensively for microbiome engineering. In this study, the utilisation of ethanolamine as a sole carbon source and the formation of theeutBMC in EcN were demonstrated through growth assays and visualisation with transmission electron microscopy. Subsequently, flux balance analysis was used to further investigate the metabolic activity of this pathway. It was found that not only is the utilisation of theeutBMC for the degradation of EA as a carbon source in EcN comparable to that ofSalmonella enterica, but also that ammonium is released into solution as a byproduct in EcN but not inS. enterica. Control of EA-dependent growth was demonstrated using different concentrations of the operon inducer, vitamin-B12. We show that vitamin B12-dependent EA utilisation as the sole carbon source enables growth in EcN, and demonstrate the concurrent formation of the BMC shell and inducible control of theeutoperon.
Risk-free polio vaccine: Recombinant expression systems for production of stabilised virus-like particles
Authors: Sherry Lee , Bahar Mohammad W , Porta Claudine , Fox Helen , Grehan Keith , Nasta Veronica , Duyvesteyn Helen M E , de Colibus Luigi , Marsian Johanna , Murdoch Inga , Ponndorf Daniel , Kim Seong-Ryong , Shah Sachin , Carlyle Sarah , Swanson Jessica J , Matthews Sue , Nicol Clare , Lomonossoff George P , Macadam Andrew J , Fry Elizabeth E , Stuart David I , Stonehouse Nicola J , Rowlands David J 
Published: May 2024

AbstractPolioviruses have caused crippling disease in humans for centuries, prior to the successful development of vaccines in the mid-1900’s, which dramatically reduced disease prevalence. Continued use of these vaccines, however, threatens ultimate disease eradication and achievement of a polio-free world. Virus-like particles (VLPs) that lack a viral genome represent a safer potential vaccine, although they require particle stabilization. Using our previously established genetic techniques to stabilize the structural capsid proteins, we demonstrate production of poliovirus VLPs of all three serotypes, from four different recombinant expression systems. We compare the antigenicity, thermostability and immunogenicity of these stabilized VLPs against the current inactivated polio vaccine, demonstrating equivalent or superior immunogenicity. Structural analyses of these recombinant VLPs provide a rational understanding of the stabilizing mutations and the role of potential excipients. Collectively, we have established these poliovirus stabilized VLPs as viable next-generation vaccine candidates for the future.
Neandertal ancestry through time: Insights from genomes of ancient and present-day humans
Authors: Iasi Leonardo N. M. , Chintalapati Manjusha , Skov Laurits , Mesa Alba Bossoms , Hajdinjak Mateja , Peter Benjamin M. , Moorjani Priya 
Published: May 2024

AbstractGene flow from Neandertals has shaped the landscape of genetic and phenotypic variation in modern humans. We identify the location and size of introgressed Neandertal ancestry segments in more than 300 genomes spanning the last 50,000 years. We study how Neandertal ancestry is shared among individuals to infer the time and duration of the Neandertal gene flow. We find the correlation of Neandertal segment locations across individuals and their divergence to sequenced Neandertals, both support a model of single major Neandertal gene flow. Our catalog of introgressed segments through time confirms that most natural selection–positive and negative–on Neandertal ancestry variants occurred immediately after the gene flow, and provides new insights into how the contact with Neandertals shaped human origins and adaptation.
WUSCHEL-dependent chromatin regulation in maize inflorescence development at single-cell resolution
Authors: Bang Sohyun , Zhang Xuan , Gregory Jason , Chen Zongliang , Galli Mary , Gallavotti Andrea , Schmitz Robert J. 
Published: May 2024

SUMMARYWUSCHEL (WUS) is transcription factor vital for stem cell proliferation in plant meristems. In maize,ZmWUS1is expressed in the inflorescence meristem, including the central zone, the reservoir of stem cells.ZmWUS1overexpression in theBarren inflorescence3mutant leads to defects in inflorescence development. Here, single-cell ATAC-seq analysis shows thatZmWUS1overexpression alters chromatin accessibility throughout the central zone. The CAATAATGC motif, a known homeodomain recognition site, is predominantly observed in the regions with increased chromatin accessibility suggesting ZmWUS1 is an activator in the central zone. Regions with decreased chromatin accessibility feature various motifs and are adjacent toAUXIN RESPONSE FACTORgenes, revealing negative regulation of auxin signaling in the central zone. DAP-seq of ZmWUS1 identified the TGAATGAA motif, abundant in epidermal accessible chromatin compared to the central zone. These findings highlight ZmWUS1’s context-dependent mechanisms for stem cell maintenance in the inflorescence meristem.
Differential roles of putative arginine fingers of AAA+ATPases Rvb1 and Rvb2
Authors: Warnock Jennifer L. , Ball Jacob A. , Najmi Saman M. , Henes Mina , Vazquez Amanda , Koshnevis Sohail , Wieden Hans-Joachim , Conn Graeme L. , Ghalei Homa 
Published: May 2024

AbstractThe evolutionarily conserved AAA+ATPases Rvb1 and Rvb2 proteins form a heteromeric complex (Rvb1/2) required for assembly or remodeling of macromolecular complexes in essential cellular processes ranging from chromatin remodeling to ribosome biogenesis. Rvb1 and Rvb2 have a high degree of sequence and structural similarity, and both contain the classical features of ATPases of their clade, including an N-terminal AAA+subdomain with the Walker A motif, an insertion domain that typically interacts with various binding partners, and a C-terminal AAA+subdomain containing a Walker B motif, the Sensor I and II motifs, and an arginine finger. In this study, we find that despite the high degree of structural similarity, Rvb1 and Rvb2 have distinct active sites that impact their activities and regulation within the Rvb1/2 complex. Using a combination of biochemical and genetic approaches, we show that replacing the homologous arginine fingers of Rvb1 and Rvb2 with different amino acids not only has distinct effects on the catalytic activity of the complex, but also impacts cell growth, and the Rvb1/2 interactions with binding partners. Using molecular dynamics simulations, we find that changes near the active site of Rvb1 and Rvb2 cause long-range effects on the protein dynamics in the insertion domain, suggesting a molecular basis for how enzymatic activity within the catalytic site of ATP hydrolysis can be relayed to other domains of the Rvb1/2 complex to modulate its function. Further, we show the impact that the arginine finger variants have on snoRNP biogenesis and validate the findings from molecular dynamics simulations using a targeted genetic screen. Together, our results reveal new aspects of the regulation of the Rvb1/2 complex by identifying a relay of long-range molecular communication from the ATPase active site of the complex to the binding site of cofactors. Most importantly, our findings suggest that despite high similarity and cooperation within the same protein complex, the two proteins have evolved with unique properties critical for the regulation and function of the Rvb1/2 complex.SignificanceAAA ATPases constitute a large family of proteins involved in various essential cellular functions in living organisms in all kingdoms of life. Members of this family typically form homo or hetero multimers that convert the energy from ATP hydrolysis to mechanical work. How the conserved features of AAA ATPases relay the energy from ATP hydrolysis to other functional domains of the complex remains largely unknown. Here, using arginine finger variants of Rvb1 and Rvb2, two evolutionarily conserved closely related AAA+ATPases that form a heterohexameric complex, we reveal how individual protomers in a heteromeric complex can uniquely contribute to the overall function of the complex and how changes in the ATP binding site can be relayed to distal functional domains.
Complex structural variation and behavioral interactions underpin a balanced sexual mimicry polymorphism
Authors: Dodge Tristram O. , Kim Bernard Y. , Baczenas John J. , Banerjee Shreya M. , Gunn Theresa R. , Donny Alex E. , Given Lyle A. , Rice Andreas R. , Haase Cox Sophia K. , Weinstein M. Luke , Cross Ryan , Moran Benjamin M. , Haber Kate , Haghani Nadia B. , Machin Kairuz Jose Angel , Gellert Hannah R. , Du Kang , Aguillon Stepfanie M. , Tudor M. Scarlett , Gutierrez-Rodríguez Carla , Rios-Cardenas Oscar , Morris Molly R. , Schartl Manfred , Powell Daniel L. , Schumer Molly 
Published: May 2024

SummaryHow phenotypic diversity originates and persists within populations are classic puzzles in evolutionary biology. While polymorphisms hypothesized to be under balancing selection segregate within many species, it remains rare for the genetic basis and the selective forces to both be known for the same trait, leading to an incomplete understanding of many classes of polymorphisms. Here, we uncover the genetic architecture of a balanced sexual mimicry polymorphism and identify behavioral mechanisms that may be involved in its maintenance in the swordtail fishXiphophorus birchmanni. We find that ∼40% ofX. birchmannimales develop a “false gravid spot”, a melanic pigmentation pattern that mimics the “pregnancy spot” associated with sexual maturity in female live-bearing fish. Using genome-wide association mapping, we detect a single intergenic region associated with variation in the false gravid spot, which is upstream ofkitlga, a gene involved in melanophore patterning. By performing long-read sequencing within and across populations, we identify complex structural rearrangements between alternate alleles at this locus. The false gravid spot haplotype drives increased allele-specific expression ofkitlga, which provides a mechanistic explanation for the increased melanophore abundance that causes the spot. By studying social interactions in the laboratory and in nature, we find that males with the false gravid spot experience less aggression; however, they also receive increased attention from other males and are disdained by females. These behavioral interactions may play a role in maintaining this phenotypic polymorphism in natural populations. We speculate that structural variants affecting gene regulation may be an underappreciated driver of balanced polymorphisms across diverse species.
A large pocket structure surrounding the catalytic center in the BCG protein fromMycobacterium tuberculosis
Authors: Takeshita Kohei , Sakai Naoki , Ueno Go , Horie Midori , Tsujino Hirofumi , Arisawa Mitsuhiro , Yamamoto Masaki , Arai Masayoshi , Yamashita Taku 
Published: May 2024

AbstractThe widespread prevalence of tuberculosis and the need for extensive chemotherapy in its treatment are caused by the ability of tuberculosis (TB) bacteria to enter a dormant state. Therefore, it is crucial to develop effective compounds that can inhibit the growth of TB bacteria in both the active and dormant states. Previous research has identified agelasine D (marine sponge-derived diterpene alkaloid) capable of resisting dormant mycobacteria. Additionally, BCG3185c has been designated as a target mycobacterial protein. In this study, the crystal structure of BCG3185c was determined at a resolution of 1.86 Å. Analysis of this crystal structure revealed a large pocket toward the catalytic center of BCG3185c, which is potentially adequate for agelasine D binding. Based on the results of the interaction analysis between agelasine D andBacillusCalmette-Guérin (BCG) proteins, it was inferred that the binding of agelasine D to this large pocket is crucial for suppressing the growth ofMycobacterium tuberculosis.
miR-29a-3p, a new myokine orchestrating resistance exercise via coordinated metabolic responses
Authors: Pinto-Hernandez Paola , Fernandez-Sanjurjo Manuel , Paget Daan , Caravia Xurde M , Roiz-Valle David , Castilla-Silgado Juan , Diez-Robles Sergio , Coto-Vilcapoma Almudena , Gama Pau , Garcia-Roves Pablo M , Lopez-Otin Carlos , Zierath Juleen , Krook Anna , Fernandez-Garcia Benjamin , Tomas-Zapico Cristina , Iglesias-Gutierrez Eduardo 
Published: May 2024

SUMMARYIt remains unclear whether the adaptive response to different exercise models is mediated by EV miRNAs released from skeletal muscle and their functional metabolic role. We sequenced miRNA-loaded plasma EVs obtained from resting mice after 4-weeks endurance or resistance training. Resistance exercise increased the expression of a 11-miRNA profile grouped into two functional clusters. Using both genetically modified animal models and in vitro approaches, we have identified miR-29a-3p as a novel myokine secreted into the bloodstream as EV cargo by contracting skeletal muscle. It is a cornerstone in the adaptation to resistance training by mediating the coordinated expression and secretion of other miRNAs and affecting muscle mass development and energy metabolism in muscle and liver. Taken together, our study suggests a coordinating and determinant role of miR-29a-3p in the response and adaptation to resistance training, possibly due to its role as a myokine through its regulatory role in energy metabolism.