bluuebunny/crossref_metadata_2025 huggingface dataset:
The lifelong orgasm gap: exploring age’s impact on orgasm rates
Authors: Gesselman Amanda N , Bennett-Brown Margaret , Dubé Simon , Kaufman Ellen M , Campbell Jessica T , Garcia Justin R
Published: July 2024

Background

Research demonstrates significant gender- and sexual orientation–based differences in orgasm rates from sexual intercourse; however, this “orgasm gap” has not been studied with respect to age.

Aim

The study sought to examine age-related disparities in orgasm rates from sexual intercourse by gender and sexual orientation.

Methods

A survey sample of 24 752 adults from the United States, ranging in age from 18 to 100 years. Data were collected across 8 cross-sectional surveys between 2015 and 2023.

Outcomes

Participants reported their average rate of orgasm during sexual intercourse, from 0% to 100%.

Results

Orgasm rate was associated with age but with minimal effect size. In all age groups, men reported higher rates of orgasm than did women. Men’s orgasm rates ranged from 70% to 85%, while women’s ranged from 46% to 58%. Men reported orgasm rates between 22% and 30% higher than women’s rates. Sexual orientation impacted orgasm rates by gender but not uniformly across age groups.

Clinical Translation

The persistence of the orgasm gap across ages necessitates a tailored approach in clinical practice and education, focusing on inclusive sexual health discussions, addressing the unique challenges of sexual minorities and aging, and emphasizing mutual satisfaction to promote sexual well-being for all.

Strengths and Limitations

This study is the first to examine the orgasm gap with respect to age, and does so in a large, diverse sample. Findings are limited by methodology, including single-item assessments of orgasm and a sample of single adults.

Conclusion

This study revealed enduring disparities in orgasm rates from sexual intercourse, likely resulting from many factors, including sociocultural norms and inadequate sex education.
Novel biomarkers derived from the Maintenance of Wakefulness Test as predictors of sleepiness and response to treatment
Authors: Tracey Brian , Culp Mark , Fabregas Stephan , Mignot Emmanuel , Buhl Derek L , Volfson Dmitri
Published: July 2024

The Maintenance of Wakefulness Test (MWT) is a widely accepted objective test used to evaluate daytime somnolence and is commonly used in clinical studies evaluating novel therapeutics for excessive daytime sleepiness. In the latter, sleep onset latency (SOL) is typically the sole MWT endpoint. Here, we explored microsleeps, sleep probability measures derived from automated sleep scoring, and quantitative electroencephalography (qEEG) features as additional MWT biomarkers of daytime sleepiness, using data from a phase 1B trial of the selective orexin receptor 2 agonist danavorexton (TAK-925) in people with narcolepsy type 1 (NT1) or type 2 (NT2). Danavorexton treatment reduced the rate and duration of microsleeps during the MWT in NT1 (days 1 and 7; p ≤ .005) and microsleep rate in NT2 (days 1 and 7; p < .0001). The use of an EEG-sleep-staging − derived measure to determine the probability of wakefulness for each minute revealed a novel metric to track changes in daytime sleepiness, which were consistent with the θ/α ratio, a known biomarker of drowsiness. The slopes of line-fits to both the log-transformed sleepiness score or log-transformed θ/α ratio correlated well to (inverse) MWT SOL for NT1 (R = 0.93 and R = 0.83, respectively) and NT2 (R = 0.97 and R = 0.84, respectively), suggesting that individuals with narcolepsy have increased sleepiness immediately after lights-off. These analyses demonstrate that novel EEG-based biomarkers can augment SOL as predictors of sleepiness and its response to treatment and provide a novel framework for the analysis of wake EEG in hypersomnia disorders.
Should I stay for local hormone therapy or should I go for radiofrequency to treat vulvovaginal atrophy? A patient preference trial
Authors: Dell'Utri Chiara MF , Manzoni Elisabetta , Bonfanti Irene , Marrocco Francesca , Barbara Giussy , Pifarotti Paola , Chiaffarino Francesca
Published: July 2024

Objective

To compare patient satisfaction rate in postmenopausal women who chose dynamic quadripolar radiofrequency or topical estrogens as their preferred treatment for genitourinary syndrome of menopause.

Methods

Patients were divided into two groups according to their preference: one was treated with estrogen therapy (ET) and the other with dynamic quadripolar radiofrequency treatment (RF). All patients included fulfilled a series of validated questionnaires, at baseline and at the 6-mo follow-up, in order to evaluate the discomfort degree associated with the presence of vulvovaginal atrophy and the impact of the reported symptoms on QoL and sexuality.

Results

After propensity score matching, the proportion of women considering themselves satisfied with their genital health conditions was extremely small at study entry (5.2% of the RF group and 6.9% of the ET group), while at a 6-mo follow-up, it increased to 46.7% and 46.6%, respectively. No statistically significant between-group differences were found regarding mean numerical rating scale scores for dryness and dyspareunia at follow-up (5.6 ± 2.6 vs 5.3 ± 2.3, P = 0.5; and 2.9 ± 2.5 vs 3.0 ± 2.7, P = 0.46). At 6-mo follow-up, we observed no statistically significant differences between the two groups regarding the other items evaluated. RF treatment was overall well tolerated.

Conclusion

The use of quadripolar radiofrequency devices seems effective, but it is not associated with better clinical outcomes compared with topical hormone treatment, which is a substantially cheaper and more convenient treatment for genitourinary syndrome of menopause. Therefore, we suggest limiting the use of dynamic quadripolar radiofrequency selectively when topical estrogens are not effective, not tolerated, or contraindicated.
Revenue Cycle Management: The Art and the Science
Authors: Chandawarkar Rajiv , Nadkarni Prakash , Barmash Elizabeth , Thomas Stephany , Capek Allison , Casey Kathleen , Carradero Freddy
Published: July 2024

Simply working hard is not enough to maintain a profitable clinical practice. Prompt and complete payment for services is just as critical. Revenue cycle management (RCM) tracks the payment process from patient scheduling through treatment, coding, billing, and reimbursement. Even though reimbursement rates for service codes are preset, and the service is documented, this apparently straightforward process is complicated by insurance payors, negotiated contracts, coding requirements, compliance regulators, and an ever-changing reimbursement environment. Not typically trained in RCM, physicians struggle with its demands of timeliness, accuracy, paperwork, and the constant scrutiny for underpayment or unfulfilled reimbursements. Consequently, they often relent to the pressures and simply accept the decreased reimbursements as “cost of doing business” or else relegate RCM to others on the team. In either case, they leave significant amounts of money on the table. Using published work in health care and other allied sectors, we present a systematic method to understand and improve RCM processes. It also creates a strong partnership between clinicians and their administrative counterparts. Optimizing RCM improves patient experience, reduces the time between submission of claims and payment, eliminates fraud at both the coding and patient levels, and increases cash flow, all of which create a financially stable clinical practice.
A Study on Symptoms of Pelvic Floor Dysfunction in Assigned Female at Birth Patients Diagnosed with Gender Dysphoria Undergoing Vaginectomy
Authors: Kjölhede Anders , Huss Fredrik , Kratz Gunnar
Published: July 2024

Background:

A person diagnosed with gender dysphoria who was assigned female at birth (AFAB) may request a vaginectomy as part of gender-affirming treatment. The aim of this study was to investigate the impact of vaginectomy on symptoms of pelvic floor dysfunction (PFD).

Methods:

This is a cohort study on patient-reported symptoms of PFD in patients who were AFAB, diagnosed with gender dysphoria, and undergoing vaginectomy in a single surgical center. Patients responded to a questionnaire preoperatively and 1 year postoperatively. The questionnaire consisted of 33 questions, including a modified short-form version of the Pelvic Floor Distress Inventory (PFDI-20).

Results:

Twenty-three consecutive patients were included in the study and 20 patients (87%) completed the 1-year follow-up. The preoperative median PFDI-20 score was 24 (0–114) compared with 32 (0–168) at the 1-year follow-up (P = 0.07). Patients who had previously undergone neophallus construction with a metoidioplasty (n = 15) had no significant change between the preoperative and the 1-year postoperative PFDI-20 score [median 17.5 (0–114) and 27.5 (0–145) (P = 0.65), respectively]; whereas those with a groin flap phalloplasty (n = 5) had a significant increase in reported symptoms [median 37 (10–95) and 124 (45–168), respectively (P = 0.04)].

Conclusions:

Overall, vaginectomy could be performed without any major impact on symptoms of PFD. However, this seemed to be true mainly for patients with previous metoidioplasty, whereas patients with previous groin flap phalloplasty reported worsening of symptoms.
Web Site Accessibility Among Doctor of Physical Therapy Programs in the United States
Authors: Ness Brandon M. , Pathare Neeti , Wilhelm Mark P. , Wonsetler-Jones Elizabeth C. , Parent-Nichols Jennifer
Published: July 2024

Introduction.

Given the impetus to improve accessibility for diverse learners seeking physical therapist education, it is critical that all entry points to access information have minimal barriers. This study identified Web site accessibility barriers among Doctor of Physical Therapy (DPT) programs in the United States.

Review of Literature.

Web site accessibility has been evaluated among many institutions of higher education, but none focused on DPT education. Individuals with disabilities may be adversely affected by Web site accessibility barriers.

Subjects.

This cross-sectional study included 262 DPT programs in the United States. Doctor of Physical Therapy program characteristics collected were geographic region, institutional control type (public/private), medical school affiliation, accreditation status, total institutional enrollment, and DPT class size.

Methods.

The Web Accessibility Evaluation (WAVE) Tool assessed data related to accessibility barriers among DPT program homepage Uniform Resource Locators. Three primary outcomes from the WAVE Tool included WAVE Total Errors, Error Density, and Total Alerts.

Results.

Web site homepage accessibility barriers varied among programs for WAVE Total Errors (range 0–150), Error Density (range 0–14.6%), and Total Alerts (range 1–331). Median Total Errors were greater among private (9.0) versus public (5.0) institution Web sites (P < .001). Median Total Errors were greater among those institutions not affiliated with a medical school (9.0) compared with those that had an affiliated medical school (7.0) (P = .04). No differences in accessibility barriers were identified according to geographic region or accreditation status (P > .05). Median Total Errors were significantly different between institutional enrollment quartiles (H[3] = 17.9, P < .001), with no differences noted between DPT class size quartiles for any outcome (P > .05). Generally, weak–fair inverse correlations were observed between student enrollment for the institution and Web site accessibility barrier outcomes.

Discussion and Conclusion.

Homepage accessibility barriers varied greatly among DPT programs in the United States. Factors, including being a private institution, no medical school affiliation, and lower institutional enrollment, were related to increased accessibility barriers.
Usefulness of the Kansas University Standing Balance Scale in inpatient rehabilitation: a retrospective validation study
Authors: Kim Asall , Kim Younji , Ji Myungki , Lim Jae-Young
Published: July 2024

Adequate balance assessment is essential for designing rehabilitation programs and preventing falls. This study aimed to report the cross-cultural adaptation of the Korean version of the Kansas University Standing Balance Scale (KUSBS), investigate its concurrent and predictive validities, and examine aging-related differences. The adaptation was performed using a standard protocol. In this retrospective study, 1179 patients were included and classified into adult, young-old, old-old, and oldest-old groups. Furthermore, we compared the concurrent, discriminant, and predictive validities of the KUSBS and Berg Balance Scale (BBS). Nonparametric analysis was also conducted. The Spearman rho test revealed strong correlation coefficients between the KUSBS and BBS (rs > 0.7; P < 0.001). At admission, the relationship was strong in the adult, young-old, and old-old groups (rs = 0.931, 0.913, and 0.914, respectively; P < 0.001) but not the oldest-old group (rs = 0.790; P < 0.001). At discharge, the correlation coefficients were above 0.9 in all groups. Additionally, the relationship between the changes in both scales was moderate-to-strong (rs > 0.68; P < 0.001). The predictive validity for independent walking of the KUSBS was strong (rs = 0.791; P < 0.001) and significantly lower than that of the BBS (rs = 0.833; P < 0.001; Z = −3.001; P = 0.003). Furthermore, the cutoff value of the KUSBS at admission to predict independent ambulatory walkers at discharge was 3.5 in ordinal ranking in all age groups. The KUSBS is a reliable and effective tool for measuring balance in patients in inpatient rehabilitation.
Improving Diversity in a Rural Academic Obstetrics and Gynecology Training Program
Authors: DeAngelis Christina , Espinosa Sofia , Wright Tonya
Published: July 2024

Both the Accreditation Council for Graduate Medical Education and the American College of Obstetricians and Gynecologists advocate for greater diversity within our workforce, which starts with recruiting and retaining a diverse residency pool. Historically, applicants who are underrepresented in medicine have been more likely to apply to residency programs located in urban locations, as opposed to a rural training environment. In this commentary, we discuss a novel strategy used to attract underrepresented in medicine applicants to a rural academic obstetrics and gynecology training program. The strategy encompassed a virtual weeklong elective with the goals of bolstering their residency applications and showcasing our faculty and residency training.
Temporal Trends and Outcomes of Gender-Affirming Gynecologic Surgery
Authors: Chen Ling , Houghton Lauren C. , Bergstein Adrianna , Suzuki Yukio , Ferris Jennifer S. , Matsuo Koji , Xu Xiao , Hershman Dawn L. , Wright Jason D.
Published: July 2024

We performed a population-based analysis to examine the trends in utilization and outcomes of gynecologic surgical procedures performed for gender-affirming care using the National Inpatient and Ambulatory Surgery Samples. Overall, 3,344,186 (95% CI, 3,281,163–3,407,209) unique individuals who underwent gynecologic surgery were identified. Transgender and gender-diverse (TGD) individuals accounted for 19.7% (345/1,748) of the labiaplasty–clitoroplasty procedures, 15.0% (3,355/22,433) of vaginoplasties, 2.0% (212/10,679) of vaginectomies, 0.2% (5,369/2,346,748) of hysterectomies, and 0.1% (515/962,578) of oophorectomies. The percentage of cases performed in TGD individuals increased substantially from 2016 to 2020 for vaginoplasty (6.2–24.1%) and clitoroplasty–labiaplasty (8.0–35.1%). Among patients who underwent vaginoplasty, the complication rate was significantly higher among TGD individuals (16.5% vs 11.1%) (adjusted odds ratio 1.85, 95% CI, 1.22–2.81). For the other procedures, the complication rate was not higher.
David Henry Cushing. 14 March 1920—14 March 2008
Authors: Shepherd FRS John , Horwood Joe
Published: July 2024

David Cushing was Britain's foremost twentieth-century marine fisheries ecologist, who did more than anyone else to develop the subject into a distinctive science over a career of more than 50 years. He was born and raised in Northumberland, and took both his first degree and a DPhil at Oxford, separated by war service in the Royal Artillery. He married Diana Antona-Traversi in 1943, and they had one daughter, Camilla. He worked for the whole of his career at the Fisheries Laboratory, Lowestoft, where he started in 1946 as a scientific officer, studying plankton off the northeast coast of England, and eventually becoming deputy director and head of the Fish Population Dynamics Divi­sion until his retirement in 1980. He published around 200 papers and reports, and wrote 11 books on marine ecology and fisheries, with four principal areas of interest: fisheries acoustics; planktonic biological production in the sea; the causes of the collapse of the North Sea herring; and the factors controlling recruitment of young fish, notably the influences of stock size and of climate. He famously proposed the match/mismatch hypothesis to explain how the great variability of fish recruitment arises from minor variations in climate from year to year.

He died on 14 March 2008, on his eighty-eighth birthday.
Lacticaseibacillus parahuelsenbergensis sp. nov., Lacticaseibacillus styriensis sp. nov. and Lacticaseibacillus zeae subsp. silagei subsp. nov., isolated from different grass and corn silage
Authors: Grabner F. Monika , Grabner H. Monika , Schein Hermine , Schrank Andrea , Töglhofer Manuela , Weidenholzer Elisabeth , Rückert-Reed Christian , Busche Tobias , Buchebner-Jance Marlene
Published: July 2024

Four rod-shaped, non-motile, non-spore-forming, facultative anaerobic, Gram-stain-positive lactic acid bacteria, designated as EB0058T, SCR0080, LD0937T and SCR0063T, were isolated from different corn and grass silage samples. The isolated strains were characterized using a polyphasic approach and EB0058T and SCR0080 were identified as Lacticaseibacillus zeae by 16S rRNA gene sequence analysis. Based on whole-genome sequence-based characterization, EB0058T and SCR0080 were separated into a distinct clade from Lacticaseibacillus zeae DSM 20178T, together with CECT9104 and UD2202, whose genomic sequences are available from NCBI GenBank. The average nucleotide identity (ANI) values within the new subgroup are 99.9 % and the digital DNA–DNA hybridization (dDDH) values are 99.3–99.9 %, respectively. In contrast, comparison of the new subgroup with publicly available genomic sequences of L. zeae strains, including the type strain DSM 20178T, revealed dDDH values of 70.2–72.5 % and ANI values of 96.2–96.6 %. Based on their chemotaxonomic, phenotypic and phylogenetic characteristics, EB0058T and SCR0080 represent a new subspecies of L. zeae. The name Lacticaseibacillus zeae subsp. silagei subsp. nov. is proposed with the type strain EB0058T (=DSM 116376T=NCIMB 15474T). According to the results of 16S rRNA gene sequencing, LD0937T and SCR0063T are members of the Lacticaseibacillus group. The dDDH value between the isolates LD0937T and SCR0063T was 67.6 %, which is below the species threshold of 70 %, clearly showing that these two isolates belong to different species. For both strains, whole genome-sequencing revealed that the closest relatives within the Lacticaseibacillus group were Lacticaseibacillus huelsenbergensis DSM 115425 (dDDH 66.5 and 65.9 %) and Lacticaseibacillus casei DSM 20011T (dDDH 64.1 and 64.9 %). Based on the genomic, chemotaxonomic and morphological data obtained in this study, two novel species, Lacticaseibacillus parahuelsenbergensis sp. nov. and Lacticaseibacillus styriensis sp. nov. are proposed and the type strains are LD0937T (=DSM 116105T=NCIMB 15471T) and SCR0063T (=DSM 116297T=NCIMB 15473T), respectively.
Activity-dependent lateral inhibition enables the synchronization of olfactory bulb projection neurons
Authors: Dalal Tal , Haddad Rafi
Published: July 2024

Information in the brain is represented by the activity of neuronal ensembles. These ensembles are adaptive and dynamic, formed and truncated based on the animal’s experience. One mechanism by which spatially distributed neurons form an ensemble is by synchronizing their spike times in response to a sensory event. In the olfactory bulb, odor stimulation evokes rhythmic gamma activity in spatially distributed mitral and tufted cells (MTCs). This rhythmic activity is thought to enhance the relay of odor information to the downstream olfactory targets. However, how specifically the odor-activated MTCs are synchronized is unknown. Here, we demonstrate that optogenetic activation of one set of MTCs can gamma-entrain the spiking activity of another set. This lateral synchronization was particularly effective when the recorded MTC fired at the gamma rhythm, facilitating the synchronization of only the substantially active MTCs. Furthermore, we show that lateral synchronization did not depend on the distance between the MTCs and is mediated by granule-cell layer neurons. In contrast, lateral inhibition between MTCs that reduced their firing rates was spatially restricted to adjacent MTCs and was not mediated by granule-cell layer neurons. This dissociation between these two interaction types suggests that they are mediated by different neural circuits. Our findings propose a simple yet robust mechanism by which spatially distributed neurons entrain each other spiking activity to form an ensemble.

Highlights

MTC activation entrains the spike timing of other MTCs in an activity-dependent and distance-independent manner.

MTC to MTC suppression is activity- and distance-dependent

Spatially distributed Granule cell layer neurons control MTC’s spike timing, yet do not substantially affect their odor-evoked firing rate.
Pathogenic variants inTMEM184Bcause a neurodevelopmental syndrome via alteration of metabolic signaling
Authors: Chapman Kimberly A , Ullah Farid , Yahiku Zachary A , Kodiparthi Sri Varsha , Kellaris Georgios , Correia Sandrina P , Stödberg Tommy , Sofokleous Christalena , Marinakis Nikolaos M , Fryssira Helena , Tsoutsou Eirini , Traeger-Synodinos Jan , Accogli Andrea , Salpietro Vincenzo , Striano Pasquale , Berger Seth I , Pond Kelvin W , Sirimulla Suman , Davis Erica E , Bhattacharya Martha RC
Published: July 2024

Transmembrane protein 184B (TMEM184B) is an endosomal 7-pass transmembrane protein with evolutionarily conserved roles in synaptic structure and axon degeneration. We report six pediatric patients who havede novoheterozygous variants inTMEM184B. All individuals harbor rare missense or mRNA splicing changes and have neurodevelopmental deficits including intellectual disability, corpus callosum hypoplasia, seizures, and/or microcephaly. TMEM184B is predicted to contain a pore domain, wherein many human disease-associated variants cluster. Structural modeling suggests that all missense variants alter TMEM184B protein stability. To understand the contribution of TMEM184B to neural developmentin vivo, we suppressed the TMEM184B ortholog in zebrafish and observed microcephaly and reduced anterior commissural neurons, aligning with patient symptoms. EctopicTMEM184Bexpression resulted in dominant effects for K184E and G162R. However,in vivocomplementation studies demonstrate that all other variants tested result in diminished protein function and indicate a haploinsufficiency basis for disease. Expression of K184E and other variants increased apoptosis in cell lines and altered nuclear localization of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, suggesting disrupted nutrient signaling pathways. Together, our data indicate that TMEM184B variants cause cellular metabolic disruption likely through divergent molecular effects that all result in abnormal neural development.
Towards a More Objective and High-throughput Spheroid Invasion Assay Quantification Method
Authors: Mungai Rozanne W. , Hartman Roger J. , Jolin Grace E. , Piskorowski Kevin W. , Billiar Kristen L.
Published: July 2024

Multicellular spheroids embedded in 3D hydrogels are prominentin vitromodels for 3D cell invasion. Yet, quantification methods for spheroid cell invasion that are high□throughput, objective and accessible are still lacking. Variations in spheroid sizes and the shapes of the cells within render it difficult to objectively assess invasion extent. The goal of this work is to develop a high-throughput quantification method of cell invasion into 3D matrices that minimizes sensitivity to initial spheroid size and cell spreading and provides precise integrative directionally-dependent metrics of invasion. By analyzing images of fluorescent cell nuclei, invasion metrics are automatically calculated at the pixel level. The initial spheroid boundary is segmented and automated calculations of the nuclear pixel distances from the initial boundary are used to compute common invasion metrics (i.e., the change in invasion area, mean distance) for the same spheroid at a later timepoint. We also introduce the area moment of inertia as an integrative metric of cell invasion that considers the invasion area as well as the pixel distances from the initial spheroid boundary. Further, we show that principal component analysis can be used to quantify the directional influence of a stimuli to invasion (e.g., due to a chemotactic gradient or contact guidance). To demonstrate the power of the analysis for cell types with different invasive potentials and the utility of this method for a variety of biological applications, the method is used to analyze the invasiveness of five different cell types. In all, implementation of this high□throughput quantification method results in consistent and objective analysis of 3D multicellular spheroid invasion. We provide the analysis code in both MATLAB and Python languages as well as a GUI for ease of use for researchers with a range of computer programming skills and for applications in a variety of biological research areas such as wound healing and cancer metastasis.
PRDM16-DT: A Brain and Astrocyte-Specific lncRNA Implicated in Alzheimer’s Disease
Authors: Schröder Sophie , Fuchs Ulrike , Gisa Verena , Pena Tonatiuh , Krüger Dennis M , Hempel Nina , Burkhardt Susanne , Salinas Gabriela , Schütz Anna-Lena , Delalle Ivana , Sananbenesi Farahnaz , Fischer Andre
Published: July 2024

Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimer’s disease (AD), highlighting the growing interest in targeting astrocyte function to address early phases of AD pathogenesis. While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNAPRDM16-DTas highly enriched in the human brain, where it is almost exclusively expressed in astrocytes.PRDM16-DTand its murine homolog,Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown ofPRDM16-DTandPrdm16osrevealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression ofPrdm16osmitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance ofPRDM16-DTin astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction
SCREEN: a graph-based contrastive learning tool to infer catalytic residues and assess mutation tolerance in enzymes
Authors: Pan Tong , Bi Yue , Wang Xiaoyu , Zhang Ying , Webb Geoffrey I. , Gasser Robin B. , Kurgan Lukasz , Song Jiangning
Published: July 2024

The accurate identification of catalytic residues contributes to our understanding of enzyme functions in biological processes and pathways. The increasing number of protein sequences necessitates computational tools for the automated prediction of catalytic residues in enzymes. Here, we introduce SCREEN, a graph neural network for the high-throughput prediction of catalytic residues via the integration of enzyme functional and structural information. SCREEN constructs residue representations based on spatial arrangements and incorporates enzyme function priors into such representations through contrastive learning. We demonstrate that SCREEN (i) consistently outperforms currently-available predictors; (ii) provides accurate results when applied to inferred enzyme structures; and (iii) generalizes well to enzymes dissimilar from those in the training set. We also show that the putative catalytic residues predicted by SCREEN mimic key structural and biophysical characteristics of native catalytic residues. Moreover, using experimental data sets, we show that SCREEN’s predictions can be used to distinguish residues with a high mutation tolerance from those likely to cause functional loss when mutated, indicating that this tool might be used to infer disease-associated mutations.
Mechanical evolution of metastatic cancer cells in three-dimensional microenvironment
Authors: Hilai Karlin , Grubich Daniil , Akrawi Marcus , Zhu Hui , Zaghloul Razanne , Shi Chenjun , Do Man , Zhu Dongxiao , Zhang Jitao
Published: July 2024

Cellular biomechanics plays critical roles in cancer metastasis and tumor progression. Existing studies on cancer cell biomechanics are mostly conducted in flat 2D conditions, where cells’ behavior can differ considerably from those in 3D physiological environments. Despite great advances in developing 3Din vitromodels, probing cellular elasticity in 3D conditions remains a major challenge for existing technologies. In this work, we utilize optical Brillouin microscopy to longitudinally acquire mechanical images of growing cancerous spheroids over the period of eight days. The dense mechanical mapping from Brillouin microscopy enables us to extract spatially resolved and temporally evolving mechanical features that were previously inaccessible. Using an established machine learning algorithm, we demonstrate that incorporating these extracted mechanical features significantly improves the classification accuracy of cancer cells, from 74% to 95%. Building on this finding, we have developed a deep learning pipeline capable of accurately differentiating cancerous spheroids from normal ones solely using Brillouin images, suggesting the mechanical features of cancer cells could potentially serve as a new biomarker in cancer classification and detection.
Scalable Hypothalamic Arcuate Neuron Differentiation from Human Pluripotent Stem Cells Suitable for Modeling Metabolic and Reproductive Disorders
Authors: Jovanovic Vukasin M. , Narisu Narisu , Bonnycastle Lori L. , Tharakan Ravi , Mesch Kendall T. , Glover Hannah J. , Yan Tingfen , Sinha Neelam , Sen Chaitali , Castellano David , Yang Shu , Blivis Dvir , Ryu Seungmi , Bennett Daniel F. , Rosales-Soto Giovanni , Inman Jason , Ormanoglu Pinar , LeClair Christopher A. , Xia Menghang , Schneider Martin , Hernandez-Ochoa Erick O. , Erdos Michael R. , Simeonov Anton , Chen Shuibing , Collins Francis S. , Doege Claudia A. , Tristan Carlos A.
Published: July 2024

The hypothalamus, composed of several nuclei, is essential for maintaining our body’s homeostasis. The arcuate nucleus (ARC), located in the mediobasal hypothalamus, contains neuronal populations with eminent roles in energy and glucose homeostasis as well as reproduction. These neuronal populations are of great interest for translational research. To fulfill this promise, we used a robotic cell culture platform to provide a scalable and chemically defined approach for differentiating human pluripotent stem cells (hPSCs) into pro-opiomelanocortin (POMC), somatostatin (SST), tyrosine hydroxylase (TH) and gonadotropin-releasing hormone (GnRH) neuronal subpopulations with an ARC-like signature. This robust approach is reproducible across several distinct hPSC lines and exhibits a stepwise induction of key ventral diencephalon and ARC markers in transcriptomic profiling experiments. This is further corroborated by direct comparison to human fetal hypothalamus, and the enriched expression of genes implicated in obesity and type 2 diabetes (T2D). Genome-wide chromatin accessibility profiling by ATAC-seq identified accessible regulatory regions that can be utilized to predict candidate enhancers related to metabolic disorders and hypothalamic development. In depth molecular, cellular, and functional experiments unveiled the responsiveness of the hPSC-derived hypothalamic neurons to hormonal stimuli, such as insulin, neuropeptides including kisspeptin, and incretin mimetic drugs such as Exendin-4, highlighting their potential utility as physiologically relevant cellular models for disease studies. In addition, differential glucose and insulin treatments uncovered adaptability within the generated ARC neurons in the dynamic regulation of POMC and insulin receptors. In summary, the establishment of this model represents a novel, chemically defined, and scalable platform for manufacturing large numbers of hypothalamic arcuate neurons and serves as a valuable resource for modeling metabolic and reproductive disorders.
CD28 Shapes T Cell Receptor Signaling by Regulating ZAP70 Activation and Lck Dynamics
Authors: Raychaudhuri Kumarkrishna , Rangu Rohita , Ma Alison , Alvinez Neriah , Tran Andy D. , Pallikkuth Sandeep , McIntire Katherine M. , Garvey Joseph A. , Yi Jason , Samelson Lawrence E.
Published: July 2024

T cell activation requires T cell receptor (TCR) engagement, which initiates a series of proximal events including tyrosine phosphorylation of the CD3 and TCRζ chains, recruitment, and activation of the protein tyrosine kinases Lck and ZAP70, followed by recruitment of adapter and signaling proteins. CD28 co-stimulation is also required to generate a functional immune response. Currently we lack a full understanding of the molecular mechanism of CD28 activation. TCR microclusters (MC) are submicron-sized molecular condensates and basic signaling units that form immediately after TCR ligation. Our results show that CD28 co-stimulation specifically accelerated recruitment of ZAP70 to the TCRζ chain in MCs and increased ZAP70 activation. This CD28-mediated acceleration of ZAP70 recruitment was driven by enhanced Lck recruitment to the MCs. A greater spatial separation between active and inactive species of Lck was also observed in the MCs as a consequence of CD28 co-stimulation. These results suggest that CD28 co-stimulation may lower the TCR activation threshold by enhancing the activated form of Lck in the TCR MCs.
Deep Learning-Based Classification of CRISPR Loci Using Repeat Sequences
Authors: Liao Xingyu , Li Yanyan , Wu Yingfu , Li Xingyi , Shang Xuequn
Published: July 2024

With the widespread application of the CRISPR-Cas system in gene editing and related fields, the demand for detecting and classifying CRISPR-Cas systems in metagenomic data has continuously increased. The traditional classification of the CRISPR-Cas system mainly relies on identifying neighboring cas genes of repeats. However, in some cases where there is a lack of information about cas genes, such as in metagenomes and fragmented genome assemblies, traditional classification methods may become ineffective. Here, we introduce a deep learning-based method called CRISPRclassify-CNN-Att, which classifies CRISPR-Cas systems solely based on repeat sequences. CRISPRclassify-CNN-Att utilizes convolutional neural networks (CNNs) and self-attention mechanisms to extract features from repeat sequences. It employs a stacking strategy to handle sample imbalances across different subtypes and improves classification accuracy for subtypes with fewer samples through transfer learning. CRISPRclassify-CNN-Att demonstrates excellent performance in classifying multiple subtypes, particularly in subtypes with a larger number of samples. Although CRISPR loci classification primarily relies on cas genes, CRISPRclassify-CNN-Att offers a new approach as a significant complement to current methods. It can identify unclassified loci missed by traditional cas-based methods, breaking the limitations of traditional approaches, and simplifying the classification process. The proposed tool is freely accessible viahttps://github.com/Xingyu-Liao/CRISPRclassify-CNN-Att.
Exploring the genetic and epigenetic underpinnings of early-onset cancers: Variant prioritization for long read whole genome sequencing from family cancer pedigrees
Authors: Kramer Melissa , Goodwin Sara , Wappel Robert , Borio Matilde , Offit Kenneth , Feldman Darren R. , Stadler Zsofia K. , McCombie W. Richard
Published: July 2024

Despite significant advances in our understanding of genetic cancer susceptibility, known inherited cancer predisposition syndromes explain at most 20% of early-onset cancers. As early-onset cancer prevalence continues to increase, the need to assess previously inaccessible areas of the human genome, harnessing a trio or quad family-based architecture for variant filtration, may reveal further insights into cancer susceptibility. To assess a broader spectrum of variation than can be ascertained by multi-gene panel sequencing, or even whole genome sequencing with short reads, we employed long read whole genome sequencing using an Oxford Nanopore Technology (ONT) PromethION of 3 families containing an early-onset cancer proband using a trio or quad family architecture. Analysis included 2 early-onset colorectal cancer family trios and one quad consisting of two siblings with testicular cancer, all with unaffected parents. Structural variants (SVs), epigenetic profiles and single nucleotide variants (SNVs) were determined for each individual, and a filtering strategy was employed to refine and prioritize candidate variants based on the family architecture. The family architecture enabled us to focus on inapposite variants while filtering variants shared with the unaffected parents, significantly decreasing background variation that can hamper identification of potentially disease causing differences. Candidatedenovoand compound heterozygous variants were identified in this way. Gene expression, in matched neoplastic and pre-neoplastic lesions, was assessed for one trio. Our study demonstrates the feasibility of a streamlined analysis of genomic variants from long read ONT whole genome sequencing and a way to prioritize key variants for further evaluation of pathogenicity, while revealing what may be missing from panel based analyses.
GeneBag: training a cell foundation model for broad-spectrum cancer diagnosis and prognosis with bulk RNA-seq data
Authors: Liang Yuhu , Li Dan , Xu Aguix Guohua , Shao Yan , Tang Kun
Published: July 2024

Numerous Pre-trained cell foundation models (CFM) have been crafted to encapsulate the comprehensive gene-gene interaction network within cells, leveraging extensive single-cell sequencing data. These models have shown promise in various cell biology applications, including cell type annotation, perturbation inference, and cell state embedding, etc. However, their clinical utility, particularly in cancer diagnosis and prognosis, remains an open question. We introduce the GeneBag model, a novel CFM that represents a cell as “a bag of unordered genes” with continuous expression values and a full-length gene list. Pre-trained on single-cell data and fine-tuned on bulk RNA-seq datasets, GeneBag achieves superior performance across cancer diagnosis and prognosis scenarios. In a zero-shot learning setting, GeneBag can classify cancer and non-cancer tissues with approximately 96.2% accuracy. With fine-tuning, it can annotate 40 different types of cancers and corresponding normal biopsies with an overall accuracy of ∼97.2%. It notably excels in classifying challenging cancers such as bladder (93%) and stomach (90%). Furthermore, GeneBag is capable of cancer staging with 68.5% accuracy and 5-year survival prediction with an AUC of ∼80.4%. This study marks the first to demonstrate the potential of CFMs in RNA-based cancer diagnostics and prognostics, indicating a promising avenue for AI-assisted molecular diagnosis.
Distributing Safer Smoking Pipes Increases Engagement with Harm Reduction Services in the United States: Findings from the National Survey of Syringe Services Programs
Authors: Chung Esther O. , Patel Sheila V. , Wenger Lynn D. , Humphrey Jamie L. , Bluthenthal Ricky N. , Tookes Hansel E. , Des Jarlais Don C. , Glick Sara N. , LaKosky Paul A. , Prohaska Stephanie , Guzman Laura , Kral Alex H. , Lambdin Barrot H. ,   National Survey of Syringe Services Programs Group
Published: July 2024

Background

In response to the recent and growing shift from injecting opioids to smoking fentanyl, an increasing number of syringe services programs (SSPs) in the USA are distributing safer smoking supplies. A recent federal ban prevents SSPs from using federal funding to procure safer smoking supplies. There is a lack of research on safer smoking supply distribution and harm reduction outcomes. Therefore, we assessed the relationship between distribution of safer smoking supplies by SSPs and levels of participant engagement and naloxone distribution.

Methods

We used data from the 2023 National Survey of Syringe Services Programs (NSSSP) (N=429), which measured services delivered in 2022. SSPs reported whether they distributed safer smoking pipes (yes/no). We examined the relationship between safer smoking pipe distribution and two outcomes: the number of participant encounters and naloxone doses distributed.

Results

There were 187 SSPs (43.6%) that distributed pipes for smoking to participants. Compared to SSPs that did not distribute pipes, those that distributed pipes reported more participant encounters (aRR=1.49, 95% CI: 1.09-2.02) and naloxone dose distribution (aRR=1.21, 95% CI: 0.89-1.65), though this latter finding was not statistically significant.

Conclusions

Findings showed SSPs distributing safer smoking pipes had more participant engagement and naloxone distribution. To maximize their full individual and population-level health benefits, SSPs should be supported technically, legally, and financially to implement safer smoking supply distribution for their participants.

Highlights

In 2022, 44% of syringe services programs (SSPs) distributed safer smoking pipes.

More community-based organizations distributed pipes than public health or health care programs.

Distribution of safer smoking pipes was associated with more participant encounters.
APV9WR: An Integrated Web Resource of Alpha papillomavirus 9 for Genomics, Proteomics, Phylogenetic and Therapeutic Analysis
Authors: Kulshreshtha Akanksha , Goel Vasu , Verma Akriti , Goel Sparsh , Dinesh Susha , Sharma Sameer , Bhowmik Ratul , Aspatwar Ashok
Published: July 2024

Purpose

Alphapapillomavirus 9 is a virus belonging to the Papillomaviridae family. It has a close genetic relationship with high-risk HPV-16 and other HPV strains such as HPV-31, HPV-52, HPV-35, HPV-58, HPV-67, and HPV-35. This virus is responsible for causing warts and malignant tumors and is responsible for about 75% of cervical malignancies and pre-cancerous lesions worldwide. As a result, it requires specialized research and attention. Our goal is to create a comprehensive resource that can assist researchers and scientific groups in their work.

Material and Methodology

A total of 1230 full genome sequences and 9140 protein sequences were obtained from GenBank and NCBI Virus, respectively. Further Phylogenetic Analysis, Codon usage and context analysis, CpG islands analysis, Glycosylation sites, Diagnostic Primers, B cell Epitopes and MHC I and MHC II binders were identified and analyzed using relevant Bioinformatics tools and Python program

Results

APV9WR is a web resource that was developed after analysis. Our data indicate that HPV 35 and HPV 38 have the most genomic diversity. From codon usage analysis, it was observed that AAA, AUU, UAU, UGU, and UUU are the most used codons, while ACG, CCG, CGA, CGG, CGU, GCG, and UCG are some of the unusual codons in APV9 nucleotide sequence with accession id -LC626346.1. We found 4714 CpG island locations in 1230 complete nucleotide sequences of APV9, and only 663 CpG island locations were unique. Further N-linked glycosylation, O-linked glycosylation, diagnostic primers, Potential B-cell epitopes and MHC I and MHC II binders were also analyzed and tabulated.

Conclusion

We have consolidated basic information about the virus, such as entire genomic sequences and proteins. It primarily comprises a wide range of studies and outcomes, including genome alignment, phylogenetic inferences, codon context and usage bias, and important CpG island statistics. Furthermore, primers for molecular diagnostics were identified, and glycosylation sites were located and investigated. Most significantly, potential therapeutic elements such as vaccine epitopes and obtaining potential information about them were investigated. Our collective effort on this tool is meant to serve the greater good of the research community for therapeutic intervention for Alphapapillomavirus 9. Using this linkhttps://apv9nsut.web.appwill take you to the web app.
ADM: Adaptive Graph Diffusion for Meta-Dimension Reduction
Authors: Feng Junning , Liang Yong , Yu Tianwei
Published: July 2024

Dimension reduction is ubiquitous in high dimensional data analysis. Divergent data characteristics have driven the development of various techniques in this field. Although individual techniques can capture specific aspects of data, they often struggle to grasp all the intricate and complex patterns and structures. To address this limitation, we introduceADM (Adaptive graph Diffusion for Metadimension reduction), a novel meta-dimension reduction method grounded in graph diffusion theory. ADM integrates results from diverse dimension reduction techniques to leverage the unique strength of each individual technique. By employing dynamic Markov processes, ADM simulates information propagation for each dimension reduction result, thereby transforming traditional spatial measurements into dynamic diffusion distances. Importantly, ADM incorporates an adaptive mechanism to tailor the time scale of information diffusion according to sample-specific attributes. This improvement facilitates a more thorough exploration of the dataset’s overall structure and allows the heterogeneity among samples.