bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cross-species analysis reveals unique and shared roles of Sox9 and Sox10 (SOXE family) transcription factors in melanoma
Authors: Kramer Eva T. , Godoy Paula M. , Kaufman Charles K. 
Published: December 2022

ABSTRACTSOX9 and SOX10 are two highly similar transcription factors with nearly 100% identity at their DNA binding domains. Both transcription factors play key but distinct roles in neural crest cell fate specification and melanoma formation. High expression of SOX9 and SOX10 appear to be mutually exclusive, with high SOX10 characteristic of proliferative melanoma and high SOX9 characteristic of metastatic melanoma. To further elucidate the role of SOX9 in melanoma, we over-express SOX9 in a zebrafish melanoma model and a human melanoma cell line. Analysis of tumor onset, binding dynamics, and transcriptional identities supports the notion of SOX9 driving a more mesenchymal signature, which is important for metastasis. Additionally, we identified a potential mechanism of SOX9 down-regulation via analysis of a functional and recurrent non-coding variant in human melanoma. Altogether, our results present a dosage-dependent role of SOX9 and, likely, SOX10 in the melanoma lifespan.
Unexpected finding ofFusobacterium variumabundance in cattle rumen: implications for liver abscess interventions
Authors: Schwarz Cory , Mathieu Jacques , Gomez Jenny Laverde , Miller Megan R. , Tikhonova Marina , Nagaraja T.G. , Alvarez Pedro J.J. 
Published: December 2022

ABSTRACTFusobacterium variumhas been generally overlooked in cattle rumen microbiome studies relative to the presumably more abundant, liver abscess-causingFusobacterium necrophorum. Here, we revisit that conventional wisdom and report greater relative abundance ofF. variumthanF. necrophorumin both raw rumen samples and in lactate-supplemented enrichments tailored forF. necrophorumgrowth, despite its consistent inadvertence in past ruminal surveys and putative inability to metabolize lactate. Our observation thatF. variumgrows under restrictive conditions used to enumerateF. necrophorumsuggests that previous estimations were inaccurate andF. variumis an underestimated player within the ruminal community. Exposure to tylosin, the current gold standard among prophylactic liver abscess prevention strategies in cattle, consistently reduced growth of allF. necrophorumstrains screened by greater than 67% relative to unexposed controls. In contrast,F. variumstrains were completely or highly resistant (0 - 11% reduction in maximum yield). Monensin, an ionophore fed to cattle to improve feed efficiency also had stronger inhibitory activity againstF. necrophorumthan againstF. varium. Finally, preliminary genomic analysis of twoF. variumbovine isolates revealed the presence of virulence genes related to those of pathogenicF. variumhuman isolates associated with active invasion of mammalian cells.ImportanceJudicious antibiotic use is essential to mitigate the spread of antimicrobial resistance. Dogmatic prophylactic use of in-feed tylosin to control cattle liver abscesses hinges on the assumption thatF. necrophorumin the rumen is the main etiologic agent. However, our unexpected finding of abundance ofF. variumin the rumen and its resistance to antibiotics, in hand with the potential pathogenicity of this species, calls for increased attention toF. varium. Further investigation intoF. variumis necessary to better understand bovine liver abscess development and devise higher-precision alternatives to antibiotic treatment.
Lack of effectiveness of Bebtelovimab Monoclonal Antibody Among High-Risk Patients with SARS-Cov-2 Omicron During BA.2, BA.2.12.1 and BA.5 Subvariants Dominated Era
Authors: Sridhara Srilekha , Gungor Ahmet B. , Erol Halil K. , Al-Obaidi Mohanad , Zangeneh Tirdad T. , Bedrick Edward J. , Ariyamuthu Venkatesh K. , Shetty Aneesha , Qannus Abd A. , Mendoza Katherine , Murugapandian Sangeetha , Gupta Gaurav , Tanriover Bekir 
Published: December 2022

ABSTRACTSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N=1,091) compared to propensity score (PS) matched control (N=1,091). The primary outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p=0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or ≥65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026-0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.
Preferences of health care workers using tongue swabs for tuberculosis diagnosis during COVID-19
Authors: Codsi Renée , Errett Nicole A. , Luabeya Angelique K. , Hatherill Mark , Shapiro Adrienne E. , Lochner Katherine A. , Vingino Alexandria R. , Kohn Marlena J. , Cangelosi Gerard A. 
Published: December 2022

ABSTRACTHealthcare workers (HCW) who come into contact with tuberculosis (TB) patients are at elevated risk of TB infection and disease. The collection and handling of sputum samples for TB diagnosis poses exposure risks to HCW, particularly in settings where aerosol containment is limited. An alternative sample collection method, tongue swabbing, was designed to help mitigate this risk, and is under evaluation in multiple settings. This study assessed risk perceptions among South African HCW who used tongue swabbing in TB diagnostic research during the COVID-19 pandemic. We characterized their context-specific preferences as well as the facilitators and barriers of tongue swab use in clinical and community settings. Participants (n=18) were HCW with experience using experimental tongue swabbing methods at the South African Tuberculosis Vaccine Initiative (SATVI). We used key informant semi-structured interviews to assess attitudes toward two tongue swab strategies: Provider-collected swabbing (PS) and supervised self-swabbing (SSS). Responses from these interviews were analyzed by rapid qualitative analysis and thematic analysis methods. Facilitators included aversion to sputum (PS and SSS), perceived safety of the method (SSS), and educational resources to train patients (SSS). Barriers included cultural stigmas, as well as personal security and control of their work environment when collecting swabs in community settings. COVID-19 risk perception was a significant barrier to the PS method. Motivators for HCW use of tongue swabbing differed substantially by use case, and whether the HCW has the authority and agency to implement safety precautions in specific settings. These findings point to a need for contextually specific educational resources to enhance safety of and adherence to the SSS collection method.
A high-resolution single-particle cryo-EM hydrated structure ofStreptococcus pyogenesenolase offers insights into its function as a plasminogen receptor
Authors: Tjia-Fleck Sheiny , Readnour Bradley M. , Ayinuola Yetunde A. , Castellino Francis J. 
Published: December 2022

ABSTRACTCellular plasminogen (Pg) receptors (PgR) are utilized to recruit Pg, stimulate its activation to the serine protease, plasmin (Pm), and sterically protect the generated Pm from inactivation by natural host inhibitors. The net result is that cells contain a stable proteolytic surface used for biological mechanisms involved in cell migration. One such PgR is the moonlighting enzyme, enolase, some of which leaves the cytoplasm and resides at the cell surface to potentially function as a PgR. Since microbes employ conscription of host Pg by PgRs as one virulence mechanism, we explored the structural basis of the ability ofStreptococcus pyogenesenolase (Sen) to function in this regard. Employing single-particle cryo-electron microscopy (cryo-EM), recombinant Sen fromS. pyogeneswas modeled at 2.6 Å as a stable symmetrical homooctamer displaying point group 422 (D4) symmetry, with a monomeric subunit molecular weight of ~49 kDa. Subunit-subunit interactions showed four major and four minor interfaces in the octamer. Binding sites for hPg were previously proposed to include the COOH-terminal K434,435residues of Sen, but in native Sen these residues are buried within the minor interfaces of the octamer and do not function as a Pg binding epitope. Whereas Sen and hPg do not interact in solution, when Sen is bound to a surface, hPg interacts with Sen independently of K434,434. We propose that the octameric structure of Sen is important to its ability to interact with hPg, but disruption of its overall octameric conformation without dissociation of the octamer exposes neoepitopes for hPg binding.
Mega-scale experimental analysis of protein folding stability in biology and protein design
Authors: Tsuboyama Kotaro , Dauparas Justas , Chen Jonathan , Laine Elodie , Mohseni Behbahani Yasser , Weinstein Jonathan J. , Mangan Niall M. , Ovchinnikov Sergey , Rocklin Gabriel J. 
Published: December 2022

AbstractAdvances in DNA sequencing and machine learning are illuminating protein sequences and structures on an enormous scale. However, the energetics driving folding are invisible in these structures and remain largely unknown. The hidden thermodynamics of folding can drive disease, shape protein evolution, and guide protein engineering, and new approaches are needed to reveal these thermodynamics for every sequence and structure. We present cDNA display proteolysis, a new method for measuring thermodynamic folding stability for up to 900,000 protein domains in a one-week experiment. From 1.8 million measurements in total, we curated a set of ~850,000 high-quality folding stabilities covering all single amino acid variants and selected double mutants of 354 natural and 188 de novo designed protein domains 40-72 amino acids in length. Using this immense dataset, we quantified (1) environmental factors influencing amino acid fitness, (2) thermodynamic couplings (including unexpected interactions) between protein sites, and (3) the global divergence between evolutionary amino acid usage and protein folding stability. We also examined how our approach could identify stability determinants in designed proteins and evaluate design methods. The cDNA display proteolysis method is fast, accurate, and uniquely scalable, and promises to reveal the quantitative rules for how amino acid sequences encode folding stability.One-Sentence SummaryMassively parallel measurement of protein folding stability by cDNA display proteolysis
Astrocytic engagement of the corticostriatal synaptic cleft is disrupted in a mouse model of Huntington disease
Authors: Villanueva Carlos Benitez , Stephensen Hans J. T. , Mokso Rajmund , Benraiss Abdellatif , Sporring Jon , Goldman Steven A. 
Published: December 2022

AbstractAstroglial dysfunction contributes to the pathogenesis of Huntington’s disease (HD), and glial replacement can ameliorate disease course. To establish the topographic relationship of diseased astrocytes to medium spiny neuron (MSN) synapses in HD, we used 2-photon imaging to map the relationship of tRFP-tagged striatal astrocytes and rabies-traced, EGFP-tagged coupled neuronal pairs, in R6/2 HD and wild-type (WT) mice. The tagged, prospectively-identified corticostriatal synapses were then studied by correlated light electron microscopy followed by serial block-face scanning EM, allowing nm scale assessment of synaptic structure in 3D. By this means, we compared the astrocytic engagement of single striatal synapses in HD and WT brains. R6/2 HD astrocytes exhibited constricted domains, with significantly less coverage of mature dendritic spines than WT astrocytes, despite enhanced engagement of immature, thin spines. These data suggest that disease-dependent changes in astroglial engagement and sequestration of MSN synapses enable the high synaptic and extrasynaptic levels of glutamate and K+that underlie the striatal hyperexcitability of HD. As such, these data suggest that astrocytic structural pathology may causally contribute to the synaptic dysfunction and disease phenotype of those neurodegenerative disorders characterized by network overexcitation.Significance StatementAstrocytic physiological dysfunction contributes to development of the neurodegenerative phenotype in Huntington’s disease (HD), but the structural correlates to this dysfunction are unclear. Here, we used a combination of viral tracing, phenotype-specific tagging, and ultrastructural modalities to reconstruct and study HD synapses at nm scale, in the neostriata of HD mice. We discovered significant impairment in the glial engagement of mature striatal synapses. In light of the known deficiencies in glutamate and potassium uptake by HD astrocytes, these findings suggest the potential for leakage of excitatory synaptic contents during neurotransmission, and hance a structural basis for neuronal hyperexcitability in HD. More broadly, our data suggest that astrocytic structural pathology may causally contribute to those neurodegenerative disorders associated with central hyperexcitability.
Fractions strategy differences in those born extremely preterm
Authors: Carr Sarah , Babinchak W. Michael , Istrate Ana , Martyn-Dow Blaine , Wang George , Chen Weicong , Fondran Jeremy , Zhang Jing , Wien Michael , Yoon Seo Yeon , Birnbaum Anne , Roth Elizabeth , Gross Carol , Minich Nori , Thompson Lee , Kim Won Hwa , Stern Yaakov , Nosarti Chiara , Taylor H. Gerry , Tatsuoka Curtis 
Published: December 2022

AbstractIntroductionTo investigate the effects of different strategies and cognitive load we explored brain hemodynamic responses associated with the use of different strategies to solve subtraction of fractions. We focused on those born extremely preterm (EPT; <28 weeks’ gestation) as they are known to have cognitive challenges and struggle with mathematics. We also included a group of full-term (FT) peers for comparison.MethodsFunctional MRI was acquired while the participants mentally solved fraction equations using either a strategy based on improper or mixed fractions. Different fraction item types were given, which affected respective required cognitive loads per strategy. Diffusion and T1-weighted structural images were also acquired.ResultsThe EPT and FT groups differed in terms of task-related hemodynamic responses. Functional group differences were greatest when strategies were applied to item types that result in high cognitive load. Other findings showed reduced white and grey matter volume and reduced white matter connectivity in widespread areas in the EPT group compared to the FT group.ConclusionThe understanding of function and structure presented here may help inform pedagogical practices by allowing for tailoring of mathematical education through identifying suitable strategy adoption that depends on item type, to circumvent weaknesses in cognitive skills.
Substrate profiling of the metalloproteinase ovastacin – Implications for its physiological function in mammalian fertilization
Authors: Felten Matthias , Distler Ute , Wiegen Nele v. , Łącki Mateusz , Behl Christian , Tenzer Stefan , Stöcker Walter , Körschgen Hagen 
Published: December 2022

AbstractThe metalloproteinase ovastacin is released by the mammalian egg upon fertilization and cleaves a distinct peptide bond in zona pellucida protein 2, a component of the enveloping extracellular matrix. This limited proteolysis causes zona pellucida hardening, abolishes sperm binding and thereby regulates fertility. Accordingly, this process is tightly controlled by the plasma protein fetuin-B, an endogenous competitive inhibitor. At present, little is known about how the cleavage characteristics of ovastacin differ from closely related proteases. Physiological implications of ovastacin beyond ZP2 cleavage are still obscure. In this study, we employed N-terminal amine isotopic labeling of substrates (N-TAILS) contained in the secretome of mouse embryonic fibroblasts to elucidate the substrate specificity and the precise cleavage site specificity. Furthermore, we were able to unravel the physicochemical properties governing enzyme-substrate interactions. Eventually, we identified several potential physiological substrates with significance for mammalian fertilization. These data suggest that ovastacin might regulate sperm-oocyte interaction and fertility beyond zona pellucida hardening.Graphical Abstract
Interactions betweenMycoplasma mycoidessubsp.mycoidesand bovine macrophages under physiological conditions
Authors: Totté Philippe , Bonnefois Tiffany , Manso-Silván Lucia 
Published: December 2022

AbstractWe investigated the interactions of unopsonized and opsonizedMycoplasma mycoidessubsp.mycoides(Mmm) with bovine macrophagesin vitro. Mmmsurvived and proliferated extracellularly on bovine macrophage cell layers in the absence ofMmm-specific antisera. Bovine complement used at non-bactericidal concentrations did neither have opsonizing effect nor promoted intracellular survival, whereasMmm-specific antisera substantially increased phagocytosis andMmmkilling. A phagocytosis-independent uptake ofMmmby macrophages occurred at a high multiplicity of infection, also found to induce the production of TNF, and both responses were unaffected by non-bactericidal doses of bovine complement. Bovine complement used at higher doses killedMmmin cell-free cultures and completely abrogated TNF responses by macrophages. These results provide a framework to identifyMmmantigens involved in interactions with macrophages and targeted by potentially protective antibodies and point towards a pivotal role of complement in the control of inflammatory responses in contagious bovine pleuropneumonia.
EEG correlates of olfactory processing during an instructed-delay task
Authors: Ninenko Ivan , Kleeva Daria F. , Bukreev Nikita , Lebedev Mikhail A. 
Published: December 2022

AbstractEEG correlates of olfaction are of fundamental and practical interest for many reasons. In the field of neural technologies, olfactory-based brain-computer interfaces (BCIs) represent an approach that could be useful for neurorehabilitation of anosmia, dysosmia and hyposmia. While the idea of a BCI that decodes neural responses to different odors and/or enables odor-based neurofeedback is appealing, the results of previous EEG investigations into the olfactory domain are rather inconsistent, particularly when non-primary processing of olfactory signals is concerned. Here we report the results from an EEG study where an olfaction-based instructed-delay task was implemented. We utilized an olfactory display and a sensor of respiration to present odors in a strictly controlled fashion. Spatio-spectral EEG properties were analyzed to assess the olfactory-related components. Under these experimental conditions, EEG components representing processing of olfactory information were found around channel C4, where changes were detected for the 12-Hz spectral component. Additionally, significant differences in EEG patterns were observed when responses to odors were compared to the responses to odorless stimuli. We conclude EEG recordings are suitable for detecting active processing of odors. As such they could be integrated in a BCI that strives to rehabilitate olfactory disabilities or uses odors for hedonistic purposes.
COMBINe: Automated Detection and Classification of Neurons and Astrocytes in Tissue Cleared Mouse Brains
Authors: Cai Yuheng , Zhang Xuying , Li Chen , Ghashghaei H. Troy , Greenbaum Alon 
Published: December 2022

SummaryTissue clearing renders entire organs transparent to enable combination with light sheet fluorescence microscopy and accelerate whole tissue imaging. Yet, challenges remain in analyzing the large resulting 3D datasets that consist of terabytes of images and information on millions of labeled cells. Previous work has established pipelines for automated analysis of tissue cleared mouse brains. However, they have focused on single color channels and/or detection of nuclear localized signals, in relatively low-resolution images. To address this gap, we present an automated workflow to map labeled neurons and astrocytes in the genetically distinct Mosaic Analysis with Double Markers (MADM) mouse forebrains. We named the workflow COMBINe (Cell detectiOn in Mouse BraIN) as it combines modules from multiple pipelines. With RetinaNet in its core, we quantitatively analyzed the regional and subregional effects of MADM-based deletion of the Epidermal growth factor receptor on neuronal and astrocyte populations in the mouse forebrain.
Sex-dependent noradrenergic modulation of premotor cortex during decision making
Authors: Rodberg Ellen M. , den Hartog Carolina R. , Dauster Emma S. , Vazey Elena M. 
Published: December 2022

ABSTRACTRodent premotor cortex (M2) integrates information from sensory and cognitive networks for action selection and planning during goal-directed decision making. M2 function is regulated by cortical inputs and ascending neuromodulators, including norepinephrine (NE) released from the locus coeruleus (LC). LC-NE has been shown to modulate the signal to noise ratio of neural representations in target regions prior to decision execution, to increase the salience of relevant stimuli. Using rats performing a two-alternative forced choice task after administration of a β adrenergic antagonist (propranolol), we show that action planning in M2 is mediated by β adrenergic signaling. Loss of β adrenergic signaling results in failure to suppress irrelevant action plans in M2 that disrupts decoding of cue related information, delays decision times, and increases trial omissions, particularly in females. Furthermore, we identify a potential mechanism for the sex bias in behavioral and neural changes after propranolol administration via differential expression of β2 receptors across sexes, particularly on local inhibitory neurons. Overall, we show a critical role for β adrenergic signaling in M2 during decision making by suppressing irrelevant information to enable efficient action planning and decision execution.