bluuebunny/crossref_metadata_2025 huggingface dataset:
Closing the Gap in Direct Admissions: A Quality Improvement Project
Authors: McKenna Amanda L. , Carter Laurel E. , Kase Adam M. , McCain Josiah D. , Fitzgerald Patrick J. , Kesler Alex M. , Varma Suneel , Cowdell J. Colt
Published: June 2023

Background and Objectives:

Direct admissions (DAs) are nonemergent admissions to the inpatient unit that bypass the emergency department. Our institution lacked a standardized DA process, which resulted in postponement of prompt patient care. The purpose of the present study was to review and modify the existing DA process and to decrease the time between patient arrival for DA and placement of initial clinician orders.

Methods:

A team was assembled and tasked with using quality improvement tools (eg, Define-Measure-Analyze-Improve-Control, fishbone diagrams, process mapping) to streamline the DA process to decrease average time between patient arrival for DA and initial clinician orders, from 84.4 minutes in July 2018 to 60 minutes or less by June 2019, without negatively affecting patient admission loyalty questionnaire scores.

Results:

In a standardized and streamlined DA process, average time between patient arrival and provider order placement decreased to less than 60 minutes. This reduction was achieved without substantially affecting patient loyalty questionnaire scores.

Conclusion:

By using a quality improvement methodology, we developed a standardized DA process that resulted in prompt care for patients without decreasing admission loyalty scores.
Improving Waste Segregation in the Operating Room to Decrease Overhead Cost
Authors: Plezia Daniel , Sabol Valerie K. , Nelson Christoffer , Simmons Virginia C.
Published: June 2023

Background and Objectives:

Operating rooms (ORs) disproportionally contribute 20% to 33% of hospital waste nationwide and therefore have a major impact on hospital waste management. Seventy percent of general OR waste is incorrectly eliminated as clinical waste, which compounds unnecessary financial burden and produces negative environmental impact. The primary purpose of this quality improvement (QI) project was to evaluate the effectiveness of waste segregation education for OR anesthesia staff on improving waste segregation compliance in the OR.

Methods:

A waste segregation QI project was implemented at a 19-OR hospital. Sharps bins in each OR were monitored for weight in pounds and 6 ORs were monitored for percent compliance both pre- and post-institution of a waste segregation education. In addition, a waste segregation knowledge assessment, waste segregation barriers assessment, and a demographic survey were administered to anesthesia staff. Twenty-two certified registered nurse anesthetists (CRNAs), 13 anesthesiologists, and 4 anesthesia technicians responded to the initial surveys and assessments while 30 of these original 39 participants (77%) responded following the educational intervention. A cost analysis was calculated pre- and post-implementation by multiplying total weight of the sharps bins by the price per pound of sharps.

Results:

Twenty-three percent of participants reported having formal waste segregation training. Survey responses revealed that the greatest barrier to waste segregation involved bin location (56.4%), followed by lack of time to segregate (25.6%), lack of knowledge of what content goes in the bin (25.6%), and lack of incentive (25.6%). A waste segregation knowledge assessment showed improvement from pre- (M = 9.18, SD = 1.66) to post-implementation (M = 9.90, SD = 1.64). Pre-implementation sharps bin compliance was 50.70% while post-implementation bin compliance improved to 58.44%. A 27.64% decrease in sharps disposal cost occurred following implementation, which is estimated to produce a $2964 cost savings per year.

Conclusions:

Waste segregation education for anesthesia staff increased their waste management knowledge, improved sharps waste bin compliance, and produced an overall cost savings.
Myocardial Scar Detection Using High-Resolution Free-Breathing 3D Dark-Blood and Standard Breath-Holding 2D Bright-Blood Late Gadolinium Enhancement MRI: A Comparison of Observer Confidence
Authors: Nies Hedwig M.J.M. , Martens Bibi , Gommers Suzanne , Bijvoet Geertruida P. , Wildberger Joachim E. , ter Bekke Rachel M.A. , Holtackers Robert J. , Mihl Casper
Published: June 2023

Objective:

To compare observer confidence for myocardial scar detection using 3 different late gadolinium enhancement (LGE) data sets by 2 observers with different levels of experience.

Materials and Methods:

Forty-one consecutive patients, who were referred for 3D dark-blood LGE MRI before implantable cardioverter-defibrillator implantation or ablation therapy and who underwent 2D bright-blood LGE MRI within a time frame of 3 months, were prospectively included. From all 3D dark-blood LGE data sets, a stack of 2D short-axis slices was reconstructed. All acquired LGE data sets were anonymized and randomized and evaluated by 2 independent observers with different levels of experience in cardiovascular imaging (beginner and expert). Confidence in detection of ischemic scar, nonischemic scar, papillary muscle scar, and right ventricular scar for each LGE data set was scored using a using a 3-point Likert scale (1 = low, 2 = medium, or 3 = high). Observer confidence scores were compared using the Friedman omnibus test and Wilcoxon signed-rank post hoc test.

Results:

For the beginner observer, a significant difference in confidence regarding ischemic scar detection was observed in favor of reconstructed 2D dark-blood LGE compared with standard 2D bright-blood LGE (p = 0.030) while for the expert observer, no significant difference was found (p = 0.166). Similarly, for right ventricular scar detection, a significant difference in confidence was observed in favor of reconstructed 2D dark-blood LGE compared with standard 2D bright-blood LGE (p = 0.006) while for the expert observer, no significant difference was found (p = 0.662). Although not significantly different for other areas of interest, 3D dark-blood LGE and its derived 2D dark-blood LGE data set showed a tendency to score higher for all areas of interest at both experience levels.

Conclusions:

The combination of dark-blood LGE contrast and high isotropic voxels may contribute to increased observer confidence in myocardial scar detection, independent of observer's experience level but in particular for beginner observers.
Insulin resistance in thyroid disorders: association between anti-TPO and HOMA-IR
Authors: Krishnamurthy Hari , Siriwardhane Thushani , Krishna Karthik , Song Qi , Jayaraman Vasanth , Wang Tianhao , Bei Kang , Rajasekaran John J.
Published: June 2023

The association of thyroid disease and diabetes has been classically described. However, the comorbidity of thyroid disparities and insulin resistance is not frequently assessed, especially the sequence of the occurrence of these markers. We performed a retrospective analysis to evaluate the association between thyroid disease and diabetes markers. We further investigated the sequence of occurrence of thyroid and diabetes markers to identify any predictive capabilities of these markers. We evaluated 32787 subjects who were classified based on their serum thyroid hormones and autoantibody levels. Our general prevalence results showed that HOMA-IR was elevated in overt hypothyroid subjects (43.7%) and overt hyperthyroid subjects (42.2%). HbA1C was elevated in subclinical hypothyroid subjects (19.2%), overt hypothyroid subjects (22.3%) and overt hyperthyroid subjects (21.2%). Glucose was significantly elevated in subclinical hypothyroid subjects (24.2%) and overt hyperthyroid subjects (31.0%). Insulin was only significantly elevated in overt hypothyroid subjects (15.1%). Interestingly, we found that 70.3% of subjects who had their HOMA-IR score escalated from negative (HOMA-IR<2.7) to positive (HOMA-IR>2.7) during their multiple visits had anti-TPO 369 (±242) days prior to the onset of this change. Our comprehensive study provided evidence that the presence of anti-TPO may suggest a predictive role in developing insulin resistance later in life.

Strengths and limitations of the study

The strength of our study is the large population size including a larger set of markers from both thyroid disease and diabetes.

The limitation in our study is the distorted male and female ratio.
Chronic oxytocin administration stimulates the endogenous oxytocin system: an RCT in autistic children
Authors: Moerkerke Matthijs , Daniels Nicky , Tibermont Laura , Tang Tiffany , Evenepoel Margaux , Van der Donck Stephanie , Debbaut Edward , Prinsen Jellina , Chubar Viktoria , Claes Stephan , Vanaudenaerde Bart , Willems Lynn , Steyaert Jean , Boets Bart , Alaerts Kaat
Published: June 2023

Background

Clinical efficacy of chronic intranasal administration of oxytocin is increasingly explored in autism spectrum disorder (ASD), but to date, little is known regarding its biological effects and in particular how chronic administration regimes impact endogenous oxytocinergic function.

Methods

To fill this gap, this double-blind, randomized, placebo-controlled study explored chronic oxytocin administration effects on endogenous salivary oxytocin levels and oxytocin receptor gene (OXTR) epigenetics (DNA methylation) in 8-to-12-year-old children with ASD (n = 79, 16 females). Biological sampling was performed at baseline (pre-treatment), immediately (24 hours) after the four-week oxytocin administration period (12 IU, twice daily) and at a follow-up session, four weeks after the last nasal spray administration.

Results

Compared to placebo, children receiving the oxytocin nasal spray displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at the four-week follow up session. Regarding epigenetics, oxytocin-induced reductions inOXTRmethylation were observed, reflecting a facilitation of oxytocin receptor expression in the oxytocin, compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reducedOXTRDNA methylation and improved feelings of secure attachment.

Conclusion

Four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with ASD, as evidenced by increased salivary oxytocin levels and reducedOXTRDNA methylation (indicating increased receptor expression).
Factors related to the performance of the periodontal specialty in secondary oral health in Brazil
Authors: Simião Vinícius de Moraes , Gonzalez Estéfany Figueiredo , Probst Livia Fernandes , Pinto Rafaela da Silveira , De-Carli Alessandro Diogo
Published: June 2023

Objective

The aim of this study was to investigate, at a national level, which individual factors of the work process/infrastructure are associated with the achievement of goals in the periodontics specialty in Brazilian Dental Specialty Centers (CEO).

Methods

This was a quantitative, analytical, cross-sectional study. Secondary data from DATASUS and the external evaluation of the second cycle of the CEO Access and Quality Improvement Program were used. Variable description was carried out in the first stage, and then the bivariate Poisson regression was performed to verify possible associations between the variables and the outcome (achievement of goals in Periodontics in the CEO). In this analysis, the covariates that were associated with the outcome at the p <0.20 significance level were included in the next step of the analysis. Multivariate Poisson regression with a robust estimator was then performed with those that met the above criterion. The variables that showed a p value < 0.05 were considered in the final model.

Results

The outcome was achieved in more than seven months of the year (mean 7.03 months, SD 4.20). Most CEO monitored the established goals (93.2%), had referral as the only way of access (61.7%), had only municipal coverage (68.4%), carried out planning and periodic evaluation of actions (89.2%). A minority has quotas of procedures by Oral Health teams (OHTs) in Primary Health Care (PHC) (18.8%). The presence of a specialist in periodontics was (on average) 1.16 per CEO and the sum of the workload of dentists working in this specialty was 31.1 hours (SD = 23.9).

Conclusion

It was concluded that the individual factors of the work process/infrastructure associated with the achievement of goals in periodontics in Brazilian CEO are: monitoring of established goals, CEO scope and number of professionals working in the specialty.
What contraceptive side effects are women told about during counseling? Evidence from PMA Ethiopia 2019 cross-sectional survey
Authors: Zimmerman Linnea A. , Sarria Isabella , Kassa Munir , Karp Celia , Seme Assefa , Shiferaw Solomon
Published: June 2023

Background

Despite widespread concerns about contraceptive side effects, few studies explore the specific side effects women are told about during contraceptive counseling. This study explored patterns of counseling on specific side effects by user characteristics in Ethiopia.

Methods

Data were collected from a nationally representative sample of women between October and December 2019. Analyses were restricted to 2,039 current users of hormonal contraception or the non-hormonal IUD. Descriptive analyses identified the types and number of side effects, across all methods and by the injectable, implant, and pill. Multinomial regression identified factors associated with receipt of counseling on bleeding changes only, non-bleeding changes only, or both, relative to no counseling on side effects, adjusting for method type, source, and socio-economic characteristics.

Results

Less than 10% of users were told of at least one bleeding and non-bleeding side effect. Relative to implant users, injectable and other method users were less likely to be told about bleeding changes only (aRRR: 0.65, 95% CI: 0.46-0.93 and aRRR: 0.31, 95% CI: 0.16-0.61, respectively) and users of other methods were less likely to be told about both a bleeding and non-bleeding change (aRRR: 0.43, 95% CI: 0.19-0.93). Users who received their method from a non-public source were less likely to receive counseling on any kind of side effect and nulliparous women were less likely to be told about both kinds of side effects.

Conclusion

There is need to improve counseling in the private sector. Research to understand provider barriers to counseling on side effects is needed.
Multiomic Analysis Identifies a High-Risk Metabolic and TME Depleted Signature that Predicts Early Clinical Failure in DLBCL
Authors: Wenzl Kerstin , Stokes Matt , Novak Joseph P. , Bock Allison M. , Khan Sana , Hopper Melissa A. , Krull Jordan E. , Dropik Abigail R. , Walker Janek S. , Sarangi Vivekananda , Mwangi Raphael , Ortiz Maria , Stong Nicholas , Huang C. Chris , Maurer Matthew J. , Rimsza Lisa , Link Brian K. , Slager Susan L. , Asmann Yan , Mondello Patrizia , Morin Ryan , Ansell Stephen M , Habermann Thomas M. , Feldman Andrew L. , King Rebecca L. , Nowakowski Grzegorz , Cerhan James R. , Gandhi Anita K. , Novak Anne J.
Published: June 2023

PURPOSE

60-70% of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients avoid events within 24 months of diagnosis (EFS24) and the remainder have poor outcomes. Recent genetic and molecular classification of DLBCL has advanced our knowledge of disease biology, yet were not designed to predict early events and guide anticipatory selection of novel therapies. To address this unmet need, we used an integrative multiomic approach to identify a signature at diagnosis that will identify DLBCL at high risk of early clinical failure.

PATIENTS AND METHODS

Tumor biopsies from 444 newly diagnosed DLBCL were analyzed by WES and RNAseq. A combination of weighted gene correlation network analysis and differential gene expression analysis followed by integration with clinical and genomic data was used to identify a multiomic signature associated with high risk of early clinical failure.

RESULTS

Current DLBCL classifiers are unable to discriminate cases who fail EFS24. We identified a high risk RNA signature that had a hazard ratio (HR, 18.46 [95% CI 6.51-52.31]P< .001) in a univariate model, which did not attenuate after adjustment for age, IPI and COO (HR, 20.8 [95% CI, 7.14-61.09]P< .001). Further analysis revealed the signature was associated with metabolic reprogramming and a depleted immune microenvironment. Finally, WES data was integrated into the signature and we found that inclusion ofARID1Amutations resulted in identification of 45% of cases with an early clinical failure which was validated in external DLBCL cohorts.

CONCLUSION

This novel and integrative approach is the first to identify a signature at diagnosis that will identify DLBCL at high risk for early clinical failure and may have significant implications for design of therapeutic options.
Clinical course of COVID-19 patients admitted to the Intensive Care Unit of a tertiary care hospital in Central India
Authors: Modi Asati Alka , Patel Rakesh , Singhal Kritika , Jain Chakresh
Published: June 2023

Background

COVID-19 pandemic also known as Corona virus pandemic, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2). In India, the first case of COVID-19 was reported on 30 January 2020 while in Madhya Pradesh on 20 March 2020 and in Rewa on 27 April 2020. Nearly 95 % of people recovered from COVID-19, and nearly three to five percent of cases needed Intensive Care Unit care and most of them needed mechanical ventilation.

Materials and Methods

This was a hospital based cross-sectional study, done among 75 clinical or RT-PCR confirmed cases of COVID-19 infection admitted to the ICU of tertiary care unit.

Results

In the present study, 63% were male and maximum (35%) belonged to 41-60 years of age. The most common symptom was fever at the time of admission to the hospital. Co-morbidity was reported in 21(28%) of patients. Out of these, majority of patients recorded combination of hypertension and diabetes as the most common comorbidity.

Conclusion

Delayed medical intervention, advanced age, and the presence of underlying health conditions, such as cardiovascular disease, diabetes, etc., are known risk factors for severe illness and can contribute to worse outcomes and increased mortality in COVID-19 patients.
Aberrant landscapes of maternal meiotic crossovers contribute to aneuploidies in human embryos
Authors: Ariad Daniel , Madjunkova Svetlana , Madjunkov Mitko , Chen Siwei , Abramov Rina , Librach Clifford , McCoy Rajiv C.
Published: June 2023

Meiotic recombination is crucial for human genetic diversity and chromosome segregation accuracy. Understanding its variation across individuals and the processes by which it goes awry are long-standing goals in human genetics. Current approaches for inferring recombination landscapes either rely on population genetic patterns of linkage disequilibrium (LD)—capturing a time-averaged view—or direct detection of crossovers in gametes or multi-generation pedigrees, which limits dataset scale and availability. Here, we introduce an approach for inferring sex-specific recombination landscapes using data from preimplantation genetic testing for aneuploidy (PGT-A). This method relies on low-coverage (<0.05×) whole-genome sequencing ofin vitrofertilized (IVF) embryo biopsies. To overcome the data sparsity, our method exploits its inherent relatedness structure, knowledge of haplotypes from external population reference panels, as well as the frequent occurrence of monosomies in embryos, whereby the remaining chromosome is phased by default. Extensive simulations demonstrate our method’s high accuracy, even at coverages as low as 0.02×. Applying this method to PGT-A data from 18,967 embryos, we mapped 70,660 recombination events with∼150 kbp resolution, replicating established sex-specific recombination patterns. We observed a reduced total length of the female genetic map in trisomies compared to disomies, as well as chromosome-specific alterations in crossover distributions. Based on haplotype configurations in pericentromeric regions, our data indicate chromosome-specific propensities for different mechanisms of meiotic error. Our results provide a comprehensive view of the role of aberrant meiotic recombination in the origins of human aneuploidies and offer a versatile tool for mapping crossovers in low-coverage sequencing data from multiple siblings.
emObject: domain specific data abstraction for spatial omics
Authors: Baker Ethan A. G. , Huang Meng-Yao , Lam Amy , Rahim Maha K. , Bieniosek Matthew F. , Wang Bobby , Zhang Nancy R. , Mayer Aaron T. , Trevino Alexandro E.
Published: June 2023

Recent advances in high-parameter spatial biology have yielded a rapidly growing new class of biological data, allowing researchers to more comprehensively characterize cellular state and morphology in native tissue context. However, spatial biology lacks a cohesive data abstraction on which to build novel computational tools and algorithms, making it difficult to fully leverage these emergent data. Here, we present emObject, a domain-specific data abstraction for spatial biology data and experiments. We demonstrate the simplicity, flexibility, and extensibility of emObject for a range of spatial omics data types, including the analysis of Visium, MIBI, and CODEX data, as well as for integrated spatial multiomic experiments. The development of emObject is an essential step towards building a unified data science ecosystem for spatial biology and accelerating the pace of scientific discovery.
Restoration of metabolic functional metrics from label-free, two-photon cervical tissue images using multiscale deep-learning-based denoising algorithms
Authors: Vora Nilay , Polleys Christopher M. , Sakellariou Filippos , Georgalis Georgios , Thieu Hong-Thao , Genega Elizabeth M. , Jahanseir Narges , Patra Abani , Miller Eric , Georgakoudi Irene
Published: June 2023

Label-free, two-photon imaging captures morphological and functional metabolic tissue changes and enables enhanced understanding of numerous diseases. However, this modality suffers from low signal arising from limitations imposed by the maximum permissible dose of illumination and the need for rapid image acquisition to avoid motion artifacts. Recently, deep learning methods have been developed to facilitate the extraction of quantitative information from such images. Here, we employ deep neural architectures in the synthesis of a multiscale denoising algorithm optimized for restoring metrics of metabolic activity from low-SNR, two-photon images. Two-photon excited fluorescence (TPEF) images of reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) and flavoproteins (FAD) from freshly excised human cervical tissues are used. We assess the impact of the specific denoising model, loss function, data transformation, and training dataset on established metrics of image restoration when comparing denoised single frame images with corresponding six frame averages, considered as the ground truth. We further assess the restoration accuracy of six metrics of metabolic function from the denoised images relative to ground truth images. Using a novel algorithm based on deep denoising in the wavelet transform domain, we demonstrate optimal recovery of metabolic function metrics. Our results highlight the promise of denoising algorithms to recover diagnostically useful information from low SNR label-free two-photon images and their potential importance in the clinical translation of such imaging.
Sexual Dimorphism of Skeletal Muscle in a Mouse Model of Breast Cancer: A Functional and Molecular Analysis
Authors: Rentz Lauren E. , Whetsell Marcella , Clayton Stuart A. , Mizener Alan D. , Holásková Ida , Chapa Matthew G. , Hoblitzell E. Hannah , Eubank Timothy D. , Pistilli Emidio E.
Published: June 2023

1.

Breast cancer incidence in men is statistically rare; however, given the lack of screening in males, more advanced stages at initial diagnosis results in lower 5-year survival rates for men with breast cancer compared to women. A sexual dimorphism, with respect to the effect of tumor growth on cachexia incidence and severity, has also been reported across cancer types. The purpose of this study was to examine the sexual dimorphism of breast cancer as it pertains to skeletal muscle function and molecular composition. Using female and male transgenic PyMT mice, we tested the hypothesis that isometric contractile properties and molecular composition of skeletal muscle would be differentially affected by breast tumors. PyMT tumor-bearing mice of each sex, corresponding to maximal tumor burden, were compared to their respective controls. RNA-sequencing of skeletal muscle revealed different pathway alterations that were exclusive to each sex. Further, differentially expressed genes and pathways were substantially more abundant in female tumor mice, with only minimal dysregulation in male tumor mice, each compared to their respective controls. These differences in the transcriptome were mirrored in isometric contractile properties, with greater tumor-induced dysfunction in females than male mice, as well as muscle wasting. Collectively, these data support the concept of sexually dimorphic responses to cancer in skeletal muscle and suggest these responses may be associated with the clinical differences in breast cancer between the sexes. The identified sex-dependent pathways within muscle of male and female mice provide a framework to evaluate therapeutic strategies targeting tumor-associated skeletal muscle alterations.

Statement of significance

The PyMT mouse model of breast cancer, which recapitulates clinical characteristics, exhibits differences in molecular and functional responses of skeletal muscle that are sex-dependent.
Combination fedratinib and venetoclax has activity against human B-ALL with high FLT3 expression
Authors: Rinella Sean P , Bell Haley C , Hess Nicholas J , Hoang Nguyet-Minh , Nguyen Thao Trang , Turicek David P , Shi Lei , Rui Lixin , LaBelle James L , Capitini Christian M
Published: June 2023

Treatment of relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL) remains a challenge, particularly in patients who do not respond to traditional chemotherapy or immunotherapy. The objective of this study was to assess the efficacy of fedratinib, a semi selective JAK2 inhibitor and venetoclax, a selective BCL-2 inhibitor, on human B-ALL using both single-agent and combinatorial treatments. The combination treatment of fedratinib and venetoclax improved killing of the human B-ALL cell lines RS4;11 and SUPB-15 in vitro over single-agent treatments. This combinatorial effect was not detected in the human B-ALL cell line NALM-6, which was less responsive to fedratinib due to the absence of Flt3 expression. The combination treatment induces a unique gene expression profile relative to single-agent treatment and with an enrichment in apoptotic pathways. Finally, the combination treatment was superior to single agent treatment in an in vivo xenograft model of human B-ALL, with a two-week treatment regimen significantly improving overall survival while inducing CD19 expression. Overall, our data demonstrates the efficacy of a combinatorial treatment strategy of fedratinib and venetoclax against human B-ALL expressing high levels of Flt3.

Statement of Implication

The combination treatment of fedratinib and venetoclax has activity against human B-ALL with high FLT3 expression and has the potential to be a salvage therapy for patients with relapsed/refractory B-ALL.
Hidden protein-altering variants influence diverse human phenotypes
Authors: Hujoel Margaux L.A. , Handsaker Robert E. , Sherman Maxwell A. , Kamitaki Nolan , Barton Alison R. , Mukamel Ronen E. , Terao Chikashi , McCarroll Steven A. , Loh Po-Ru
Published: June 2023

Structural variants (SVs) comprise the largest genetic variants, altering from 50 base pairs to megabases of DNA. However, SVs have not been effectively ascertained in most genetic association studies, leaving a key gap in our understanding of human complex trait genetics. We ascertained protein-altering SVs from UK Biobank whole-exome sequencing data (n=468,570) using haplotype-informed methods capable of detecting sub-exonic SVs and variation within segmental duplications. Incorporating SVs into analyses of rare variants predicted to cause gene loss-of-function (pLoF) identified 100 associations of pLoF variants with 41 quantitative traits. A low-frequency partial deletion ofRGL3exon 6 appeared to confer one of the strongest protective effects of gene LoF on hypertension risk (OR = 0.86 [0.82–0.90]). Protein-coding variation in rapidly-evolving gene families within segmental duplications—previously invisible to most analysis methods—appeared to generate some of the human genome’s largest contributions to variation in type 2 diabetes risk, chronotype, and blood cell traits. These results illustrate the potential for new genetic insights from genomic variation that has escaped large-scale analysis to date.
Organization of an Ascending Circuit that Conveys Flight Motor State
Authors: Cheong Han S. J. , Boone Kaitlyn N. , Bennett Marryn M. , Salman Farzaan , Ralston Jacob D. , Hatch Kaleb , Allen Raven F. , Phelps Alec M. , Cook Andrew P. , Phelps Jasper S. , Erginkaya Mert , Lee Wei-Chung A. , Card Gwyneth M. , Daly Kevin C. , Dacks Andrew M.
Published: June 2023

Natural behaviors are a coordinated symphony of motor acts which drive self-induced or reafferent sensory activation. Single sensors only signal presence and magnitude of a sensory cue; they cannot disambiguate exafferent (externally-induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to make appropriate decisions and initiate adaptive behavioral outcomes. This is mediated by predictive motor signaling mechanisms, which emanate from motor control pathways to sensory processing pathways, but how predictive motor signaling circuits function at the cellular and synaptic level is poorly understood. We use a variety of techniques, including connectomics from both male and female electron microscopy volumes, transcriptomics, neuroanatomical, physiological and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs), which putatively provide predictive motor signals to several sensory and motor neuropil. Both AHN pairs receive input primarily from an overlapping population of descending neurons, many of which drive wing motor output. The two AHN pairs target almost exclusively non-overlapping downstream neural networks including those that process visual, auditory and mechanosensory information as well as networks coordinating wing, haltere, and leg motor output. These results support the conclusion that the AHN pairs multi-task, integrating a large amount of common input, then tile their output in the brain, providing predictive motor signals to non-overlapping sensory networks affecting motor control both directly and indirectly.
Protein-Protein Interaction Prediction is Achievable with Large Language Models
Authors: Hallee Logan , Gleghorn Jason P.
Published: June 2023

Predicting protein-protein interactions (PPIs) is vital for elucidating fundamental biology, designing peptide therapeutics, and for high-throughput protein annotation. This is particularly relevant in the current biotechnology landscape characterized by the proliferation of protein generative models, which necessitate a high-throughput and generalized PPI predictor for proteins regardless of conventional motifs or known biological functions. Our work addresses this need and provides strong evidence of the utility and reliability of protein language models (pLMs) in learning the PPI objective. We demonstrated that with the use of a sizable balanced dataset, pLMs achieve state-of-the-art performance metrics in PPI prediction on diverse proteins. To generate a dataset that allows for the approximation of these conditions, we implemented a novel synthetic data generation scheme to augment BIOGRID and Negatome datasets. The enhancement of these datasets was then used to fine-tune ProtBERT for PPI prediction to develop a model that we call SYNTERACT (SYNThetic data-driven protein-protein intERACtion Transformer). Our results are compelling, demonstrating 92% accuracy on validated positive and negative interacting pairs derived from 50 different organisms, all of which were excluded from the training phase. In addition to the high metrics, secondary analysis revealed that our synthetic negative data was able to successfully mimic actual negative samples, further reinforcing the integrity of synthetic data additions to PPI datasets. Another notable discovery was the ease in which previously existing PPI datasets could be predicted with simplistic features, calling into question if they can actually inform PPI prediction. We find that the subcellular compartment bias inherent to the compilation of these datasets is learnable with deep learning methods and demonstrate that our approach is not burdened by this disadvantage.
Fundamental role for the creatine kinase pathway in protection from murine colitis
Authors: Hall Caroline HT , Lanis Jordi M , Dowdell Alexander S , Murphy Emily M , Colgan Sean P
Published: June 2023

Inflammatory diseases of the digestive tract, including inflammatory bowel disease (IBD), cause metabolic stress within mucosal tissue. Creatine is a key energetic regulator. We previously reported a loss of creatine kinases (CKs) and the creatine transporter expression in IBD patient intestinal biopsy samples and that creatine supplementation was protective in a dextran sulfate sodium (DSS) colitis mouse model. In the present studies, we evaluated the role of CK loss in active inflammation using the DSS colitis model. Mice lacking expression of CKB/CKMit (CKdKO) showed increased susceptibility to DSS colitis (weight loss, disease activity, permeability, colon length and histology). In a broad cytokine profiling, CKdKO mice expressed near absent IFN-γ levels. We identified losses in IFN-γ production from CD4+and CD8+T cells isolated from CKdKO mice. Addback of IFN-γ during DSS treatment resulted in partial protection for CKdKO mice. We identified basal stabilization of the transcription factor hypoxia-inducible factor (HIF) in CKdKO splenocytes and pharmacological stabilization of HIF resulted in reduced IFN-γ production by control splenocytes. Thus, the loss of IFN-γ production by CD4+and CD8+T cells in CKdKO mice resulted in increased colitis susceptibility and indicates that CK is protective in active mucosal inflammation.
The genomic landscape of wildSaccharomyces cerevisiaeis shaped by complex patterns of admixture, aneuploidy and recombination
Authors: Ward Chris M. , Onetto Cristobal A. , Van Den Heuvel Steven , Cuijvers Kathleen M. , Hale Laura J. , Borneman Anthony R.
Published: June 2023

Cultural exchange of fermentation techniques has driven the spread ofSaccharomyces cerevisiaeacross the globe, establishing wild populations in many countries. Despite this, most modern commercial fermentations are inoculated using monocultures, rather than relying on natural populations, potentially impacting wild population diversity. Here we investigate the genomic landscape of 411 wildS. cerevisiaeisolated from spontaneous grape fermentations in Australia across multiple locations, years, and grape cultivars. Spontaneous fermentations contained highly recombined mosaic strains that commonly exhibited aneuploidy of chromosomes 1, 3, 6 and 9. Assigning wild genomic windows to putative ancestral origin revealed that few closely related commercial lineages have come to dominate the genetic landscape, contributing most of the genetic variation. Fine-scale phylogenetic analysis of loci not observed in strains of commercial wine origin identified widespread admixture with the Beer2 clade along with three independent admixture events from potentially endemic Oceanic lineages that last shared an ancestor with modern East AsianS. cerevisiaepopulations. Our results illustrate how commercial use of microbes can affect local microorganism genetic diversity and demonstrates the presence of non-domesticated, non-European derived lineages ofS. cerevisiaein Australian ecological niches that are actively admixing.
Sex specific role of RNA-binding protein, AUF1, on prolonged hypersensitivity after repetitive ischemia with reperfusion injury
Authors: Quijas Meranda M. , Queme Luis F. , Weyler Alex A. , Butterfield Ally , Joshi Diya P. , Mitxelena-Balerdi Irati , Jankowski Michael P.
Published: June 2023

Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. I/R injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity due to I/R may be due to sex specific gene expression in the DRGs and distinct upregulation of growth factors and cytokines in the affected muscles. In order to determine how these unique gene expression programs may be established in a sex dependent manner in a model that more closely mimics clinical scenarios, we utilized a newly developed prolonged ischemic myalgia model in mice whereby animals experience repeated I/R injuries to the forelimb and compared behavioral results to unbiased and targeted screening strategies in male and female DRGs. Several distinct proteins were found to be differentially expressed in male and female DRGs, including AU-rich element RNA binding protein (AUF1), which is known to regulate gene expression. Nerve specific siRNA-mediated knockdown of AUF1 inhibited prolonged hypersensitivity in females only, while overexpression of AUF1 in male DRG neurons increased some pain-like responses. Further, AUF1 knockdown was able to specifically inhibit repeated I/R induced gene expression in females but not males. Data suggests that RNA binding proteins like AUF1 may underlie the sex specific effects on DRG gene expression that modulate behavioral hypersensitivity after repeated I/R injury. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.
Brain network dynamics in transitions of consciousness reorganize according to task engagement
Authors: Kumar Samika S. , Arzi Anat , Bareham Corinne , Gonzalez-Castillo Javier , Fernandez Isabel , Tagliazucchi Enzo , Mediano Pedro A.M. , Bandettini Peter A. , Bekinschtein Tristan A.
Published: June 2023

Substantial changes in behavior, physiology, and brain function occur when alertness decreases1– 5. These changes in brain function involve increased synchronization between cortical areas6,7as well as alterations in sensory processing pathways and networks connecting the thalamus and cortex5,8–11. Cognitive tasks engage overlapping functional networks with sensory pathways facilitating information processing12,13, and thalamocortical and corticocortical networks supporting task performance14,15. Frontoparietal circuits play a crucial role in cognitive tasks16and states of decreased consciousness17. To develop an integrated framework of consciousness and cognition, it is important to understand how fluctuations in alertness and cognitive processing interact in these shared circuits18. Our hypothesis is that during periods of low alertness, individuals who actively maintain task engagement would recruit additional frontoparietal and sensory processing networks, while thalamocortical dynamics that typically change during sleep onset would remain unaffected. Our findings demonstrated that as alertness decreased, passively listening to auditory tones led to increased synchronization in the parietal lobe, whereas actively performing an auditory task resulted in increased long-range frontoparietal synchronization. During decreasing alertness, passive listening (but not active task engagement) was associated with widespread increased synchronization between the thalamus and cortex. In contrast, active task engagement (but not passive listening) led to increased synchronization between the auditory cortex and the rest of the brain. These results reveal the functional mechanisms of the brain’s flexible reorganization during transitions of consciousness when individuals are actively engaged in cognitive processes.
Genome analysis ofLegionella pneumophilaST901 an Italian endemic strain
Authors: Ricci Maria Luisa , Fillo Silvia , Giordani Francesco , Ciammaruconi Andrea , Girolamo Antonietta , Anselmo Anna , Monte Anella , Cusimano Valerio , Caporali Maria Grazia , Rota Maria Cristina , Petzol Markus , Afshar Baharak , Lista Florigio , Luck Christian , Scaturro Maria
Published: June 2023

Legionella pneumophilatyping, based on SBT analysis, has been allowing to identify sequence types (ST) responsible for many Legionnaires’ disease cases. ST901 has so far been identified only in a town of the northern Italy, where it caused numerous travel-associated Legionnaires’ disease cases over a 32-year period. In this study, ST901 were analyzed by whole genome sequencing in looking for both differences and similarities inside this ST and with other unrelatedLegionellastrains. To this aim core genome multi locus sequence type, single nucleotide polymorphisms and pangenome analyses were performed. ST901 resulted highly similar each other, characterized by I-C CRISPR-cas system, located on the chromosome and by a putative plasmid, highly similar to that found in Lp strain Lens, which contains I-F CRISPR-cas system. Accessory genomic islands, either already described or specifically found in ST901, were also shown.

In conclusion ST901 has been quite preserved over the time. The co-occurrence of two phage resistance systems and genomic islands of virulence could have made the ST901 enough virulent to cause such a high number of cases.

Summary blurb

ST901 appears as endemic of the Northern Italy, with virulence traits similar to those in Alcoy and Corby, and with two CRISPR-cas systems which probably preserved them in their environmental niche.
Tonic Meningeal Interleukin-10 Upregulates Delta Opioid Receptor to Prevent Relapse to Pain
Authors: Inyang Kufreobong E. , Sim Jaewon , Clark Kimberly B. , Matan Geron , Monahan Karli , Evans Christine , Beng Po , Ma Jiacheng “Vicky” , Heijnen Cobi J. , Dantzer Robert , Scherrer Gregory , Kavelaars Annemieke , Bernard Matthew , Aldhamen Yasser , Folger Joseph K. , Laumet Geoffroy
Published: June 2023

Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain. IL-10 upregulated expression and analgesic activity of δ-opioid receptor (δOR) in the dorsal root ganglion. Genetic or pharmacological inhibition of IL-10 signaling or δOR triggered relapse to pain in both sexes. These data challenge the widespread assumption that remission of pain is simply a return to the naïve state before pain was induced. Instead, our findings strongly suggest a novel concept that: remission is a state of lasting pain vulnerability that results from a long-lasting neuroimmune interactions in the nociceptive system.
Co-evolutionary dynamics of mammalian brain and body size
Authors: Venditti Chris , Baker Joanna , Barton Robert A.
Published: June 2023

Despite decades of comparative studies, fundamental questions remain about how brain and body size co-evolved. Divergent explanations exist concurrently in the literature for phenomena such as variation in brain relative to body size, variability in the scaling relationship across taxonomic levels and between taxonomic groups, and purported evolutionary trends. Here we resolve these issues using a comprehensive dataset of brain and body masses across the mammal radiation, and a method enabling us to study brain relative to body mass evolution while estimating their evolutionary rates along the branches of a phylogeny. Contrary to the rarely questioned assumption of a log-linear relationship, we find that a curvilinear model best describes the evolutionary relationship between log brain mass and log body mass. This model greatly simplifies our understanding of mammalian brain-body co-evolution: it can simultaneously explain both the much-discussed taxon-level effect and variation in slopes and intercepts previously attributed to complex scaling patterns. We also document substantial variation in rates of relative brain mass evolution, with bursts of change scattered through the tree. General trends for increasing relative brain size over time are found in only three mammalian orders, with the most extreme case being primates, setting the stage for the uniquely rapid directional increase that ultimately produced the computational powers of the human brain.
Brain Representations of Affective Valence and Intensity in Sustained Pleasure and Pain
Authors: Lee Soo Ahn , Lee Jae-Joong , Han Jisoo , Choi Myunghwan , Wager Tor D. , Woo Choong-Wan
Published: June 2023

Pleasure and pain are two opposites that compete and influence each other, implying the existence of brain systems that integrate them to generate modality-general affective experiences. Here, we examined the brain’s general affective codes (i.e., affective valence and intensity) across sustained pleasure and pain through an fMRI experiment (n= 58). We found that the distinct sub-populations of voxels within the ventromedial and lateral prefrontal cortices, the orbitofrontal cortex, the anterior insula, and the amygdala were involved in decoding affective valence versus intensity, which was replicated in an independent test dataset (n= 62). The affective valence and intensity models were connected to distinct large-scale brain networks—the intensity model to the ventral attention network and the valence model to the limbic and default mode networks. Overall, this study identified the brain representations of affective valence and intensity across pleasure and pain, promoting the systems-level understanding of human affective experiences.
Not everything, not everywhere, not all at once: a study of brain-wide encoding of movement
Authors: Wang Ziyue Aiden , Chen Susu , Liu Yi , Liu Dave , Svoboda Karel , Li Nuo , Druckmann Shaul
Published: June 2023

Activity related to movement is found throughout sensory and motor regions of the brain. However, it remains unclear how movement-related activity is distributed across the brain and whether systematic differences exist between brain areas. Here, we analyzed movement related activity in brain-wide recordings containing more than 50,000 neurons in mice performing a decision-making task. Using multiple techniques, from markers to deep neural networks, we find that movement-related signals were pervasive across the brain, but systematically differed across areas. Movement-related activity was stronger in areas closer to the motor or sensory periphery. Delineating activity in terms of sensory- and motor-related components revealed finer scale structures of their encodings within brain areas. We further identified activity modulation that correlates with decision-making and uninstructed movement. Our work charts out a largescale map of movement encoding and provides a roadmap for dissecting different forms of movement and decision-making related encoding across multi-regional neural circuits.