bluuebunny/crossref_metadata_2025 huggingface dataset:
Bilateral spontaneous Descemet membrane detachment after uneventful immediate sequential bilateral cataract surgery
Authors: Erikitola Ore-oluwa Catherine , Sekaran Anisha , Zhang Vera , Diaper Charles , Anijeet Deepa
Published: June 2024

Introduction:

Immediate sequential bilateral cataract surgery (ISBCS) is a practice on the rise. To the authors' knowledge, this is the first reported case of bilateral Descemet membrane detachment (DMD) after uneventful same-day ISBCS, with emphasis on diagnosis and management.

Patient and Clinical Findings:

The case of a 66-year-old diabetic woman with chronic obstructive pulmonary disease and obstructive sleep apnea on home oxygen who developed spontaneous bilateral DMD after uneventful ISBCS for visually significant cataracts is presented. Although spontaneous DMD after uneventful phacoemulsification has been reported before, it has not been reported after same-day ISBCS to the authors' knowledge. The success rates with air pneumatic descemetopexy are excellent, with ranges between 90% and 95%. In this case, surgical intervention with gas injection in the anterior chamber and surgical peripheral iridotomies resulted in excellent visual acuity restoration in the patient.

Diagnosis, Intervention, and Outcomes:

Patient underwent same-day ISBCS under local anesthesia by different surgeons in either eye. Standard phacoemulsification techniques were used, and no intraoperative complications were noted. The patient returned with bilateral counting fingers vision 4 weeks postoperatively and reported her vision never improved after her cataract extraction. Anterior segment optical coherence tomography (AS-OCT) confirmed the presence of bilateral DMDs. Because of the patient's severely impaired vision, bilateral air descemetopexies were performed with clinical resolution of the DMD and excellent restoration of vision in both eyes.

Conclusions:

Sufficient evidence supports that performing ISBCS using internationally agreed protocols minimizes the risk of experiencing bilateral complications to a negligible level when compared with staged surgery. However, with ISBCS being on the rise, spontaneous bilateral DMDs may also be seen increasingly in those eyes with no underlying commonly recognized risk factors for spontaneous DMD. With unilateral DMD, watch and wait is a viable option. However, in bilateral DMD cases, earlier air or gas descemetopexy may be preferable to increase the likelihood of success and reduce the patient's period of decreased vision.
Optimizing the Team Approach: Designing a Clinical Care Pathway for Functional Neurological Disorder
Authors: Brown Laurey , Norwood Meredith , Thompson Laurie G.
Published: June 2024

Functional neurological disorder (FND) sits at the intersection of neurology and psychology and has a variety of presentations, severity, and symptomatology. It affects a considerable number of pediatric patients and overwhelmingly influences healthcare spending. Diagnosis, treatment, and outcomes are varied, challenging, and lack standardization, often leading to frustration from patients, caregivers, and providers. Multidisciplinary care is essential though communication is often complex and disjunct. Using quality improvement tools and experiences from one institution, a team was established to ameliorate these concerns. A clinical care pathway was designed for the diagnosis and treatment of FND in the pediatric inpatient setting. This pathway was the result of the multidisciplinary team effort and an outcome, highlighting the need for early and intentional diagnosis with diagnosing provider specified, provider education and consistent language, patient and caregiver education, and clear and thorough discharge planning. Through the implementation of this pathway, it is anticipated that patient and provider satisfaction will improve as will the outcomes and care given to affected individuals. This work can be applied to the global treatment of FND and raise awareness to effectively managed care as well as the opportunity for clinicians to drive institutional change.
Management of Idiopathic Intracranial Hypertension: A Case Report
Authors: Huang Xiang-Ling , Tseng Pao-Hui , Wang Wan-Hsiang , Tsai Sheng-Tzung
Published: June 2024

BACKGROUND: Idiopathic intracranial hypertension (IIH) is a neurological disorder characterized by elevated intracranial pressure, affecting predominantly obese women of childbearing age. Early recognition and comprehensive management are vital for preventing severe complications, particularly vision loss. METHODS: This study reports a case of a 27-year-old woman who presented with chronic headaches and blurred vision. Notable findings included headaches that were intensified upon waking and exacerbated by activities that elevated intracranial pressure. The patient also reported nausea, vomiting, transient visual obscurations, and pulsatile tinnitus. After a clinical examination, she was given a diagnosis of IIH. RESULTS: The patient underwent a lumbar-peritoneal shunt procedure to alleviate her symptoms in conjunction with medication treatment. This case study highlights the importance of a multidisciplinary approach in diagnosing and treating IIH. In particular, weight management emerged as a crucial preventive measure against IIH recurrence. CONCLUSION: A multidisciplinary team strategy can enhance outcomes and quality of life, accentuating the need for continued research into IIH recurrence, treatments, and wider implications.
Assessing the ripple effects of natural disasters on healthcare systems: a narrative review
Authors: Dagnino Filippo , Qian Zhiyu , Beatrici Edoardo
Published: June 2024

Purpose of review

Natural disasters are on the rise, driven by shifts in climatic patterns largely attributed to human-induced climate change. This relentless march of climate change intensifies the frequency and severity of these disasters, heightening the vulnerability of communities and causing significant harm to both lives and socio-economic systems. Healthcare services are particularly strained during extreme weather events, with impacts felt not only on infrastructure but also on patient care.

Recent findings

This narrative review explored the overarching impact of natural disasters on healthcare infrastructure. We delved into how these disasters impact diverse health conditions, the healthcare systems of low and middle-income countries (LMICs), the psychological toll on both clinicians and survivors, and the ramifications for end-of-life care.

Natural disasters significantly impact healthcare, especially in LMICs due to their limited resources. Patients with cancer or chronic diseases struggle to access care following a natural disaster. Those in need for palliative care experience delay due to shortages in medical resources. Psychological consequences like posttraumatic stress disorder on disaster survivors and healthcare providers highlight the need for mental health support. Addressing challenges requires proactive disaster preparedness policies and urgent public policy initiatives are needed for optimal disaster response.
Effects of combining a high-intensity interval training programme with a standard programme on mobility and function in lower limb amputees
Authors: Bevacqua Nicolás , Dell Elce Gabriela , Intelangelo Leonardo
Published: June 2024

High-energy expenditure during walking is one of the most important limiting factors for lower limb amputees. Although several physical training methods have been proposed to reduce energy expenditure, little is known about the effects of high-intensity interval training in lower limb amputees. This study aimed to test the effects of a 6-week high-intensity interval training protocol in subjects with lower limb amputation on walking distance, physiological cost of walking, and functional mobility. A quasi-experimental pre and post-study included 13 subjects with lower limb amputation. They performed 12 sessions of a high-intensity interval training protocol with a frequency of 2 days/week for 6 weeks. Walking distance, physiological cost of walking, and functional mobility before and after the training protocol were assessed. Walking distance increased from 204.48 to 229.09 m (P = 0.003), physiological cost of walking decreased from 0.66 to 0.31 beats/m (P = 0.001), and functional mobility improved from 30.38 to 33.61 points (P = 0.001). High-intensity interval training improved walking distance, physiological cost of walking, and functional mobility in subjects with lower limb amputation.
Examination of the Relationship Between Clinical Hours and NCLEX Success
Authors: Moran Vicki , Bultas Margaret , Evans Cathleen , Wenner Teresa A. , Israel Heidi , Fuller Kelli
Published: June 2024

Background: Clinical education provides important learning opportunities for students. Finding clinical sites and faculty can be a challenge. Exploring the relationship between the number of clinical practice hours and NCLEX-RN success may be helpful for curriculum development and revision.

Purpose: The purpose of this study was to provide descriptive information about clinical education in RN programs and determine if a relationship existed between the number of clinical hours and NCLEX-RN pass rate.

Method: A descriptive research design using a survey was sent to over 1000 accredited nursing programs in the United States.

Results: One hundred and fourteen surveys were completed. When comparing 2021 NCLEX-RN pass rates with clinical hours, there was a statistically significant difference at the 500 clinical hour interval.

Conclusion: Nursing programs can ensure fiduciary responsibility while supporting clinical judgment development and licensure success by reviewing their curriculum and reconsidering the number of clinical hours in their programs.
Response Rates by Condom Use Measurement Type Among Sexually Active Young Black Men Who Have Sex With Women
Authors: Ratnayake Aneeka , Kissinger Patricia
Published: June 2024

Background

Measuring condom use accurately is important to understanding sexual behaviors; however, there is still no consensus on the criterion standard of condom use measurement. In this study, authors aimed to investigate if nonresponse rates were higher when absolute or relative frequency condom use questions were used.

Methods

This study used Check It study data of Black men who have sex with women aged 15 to 26 years in New Orleans, LA. All men underwent a survey of sexual behavior, which included questions on condom use. From January 2017 to August 2019, participants were asked for the number of sex acts during which they had used a condom (absolute frequency question), and after August 2019 until March 2020, this was changed to response options of “never,” “sometimes,” or “always” (relative frequency question). Participants could refuse to answer the question; the rate of refusal was tabulated by question type to determine if nonresponse rates differed.

Results

There were 1907 participants included in the study, with data on 2957 partnerships. Of those asked the relative frequency question, 92.7% responded compared with 86.1% who were asked the absolute frequency. In generalized estimating equation modeling, those asked the relative frequency question had 2.42 (95% confidence interval, 1.42–4.13; P < 0.001) greater odds of response than those asked the absolute frequency question.

Conclusions

Relative frequency questions may be more likely to elicit a response, in research among this population.

Key Message

There is no current criterion standard for measuring condom use in surveys. This study demonstrated that asking participants about their condom use qualitatively (i.e., whether they use condoms “never,” “sometimes,” or “always”), as opposed to asking them to provide the number of sex acts during which they used a condom, was associated with lower rates of nonresponse. Investigators should consider using qualitative condom use questions to maximize response rates.
Sexually Transmitted Infection Prevention Services for Women Experiencing Homelessness: A Safety-Net Health System Quality Improvement Initiative
Authors: Diener Anelise K. , Saverine Andrew J. , Akpan Idara N. , Brilleslyper Emma , Griner Stacey B. , Thompson Erika L.
Published: June 2024

Background

Consistent use of sexually transmitted infection (STI) prevention methods is proven to decrease transmission of STIs. However, rates continue to rise within the United States, particularly among high-risk populations. Women experiencing homelessness may face barriers to access reproductive health care. This quality improvement initiative sought to examine perceived barriers to STI prevention and opportunities for expanding STI prevention services and education for women experiencing homelessness.

Methods

Surveys were administered during a 1-day health event in August 2023 at a clinic that predominately serves persons experiencing homelessness in North Texas. Respondents included adult, nonpregnant, English-speaking individuals assigned female at birth with a history of homelessness. Demographic characteristics, sexual history, participants' knowledge of STIs, and perceived barriers to obtaining sexual health care were gathered. Participants had the opportunity to suggest methods for improving access to STI care.

Results

Among participants (n = 36), more than half (59%) were tested for STIs within the past year. Most preferred condoms for STI prevention. The average knowledge score among questions about STI transmission and methods of prevention was 65%, with the lowest scores observed among trichomoniasis (39% correct), preexposure prophylaxis (31%), and dental dams (25%). Common barriers included cost (33%) and side effects (33%). One-third (36%) of participants reported no barriers to the use of prevention products.

Conclusions

Findings highlight the need for educational opportunities among this population to increase knowledge of STI transmission and prevention. Patients may benefit from clinicians emphasizing education and increasing the visibility of services.
Multifocal tuberculosis revealed by a sternal swelling in an immunocompetent child
Authors: CHEHRASTANE GHIZLANE , Benaissa Elmostafa , Radi Abdelilah , EL Hassani Amal , Elouennass Mostafa
Published: June 2024

Tuberculosis (TB) is one of the most common pathogens of bacterial lung infections, especially in underdeveloped nations like Morocco, where the incidence of TB was 97 cases per 100,000 persons in 2019. Thanks to its national TB prevention and control plan, Morocco was able to achieve remarkable progress in the management of TB with an 80% reduction in the total number of patients diagnosed with TB between 1980 and 2018. The national plan also allowed us to reach and maintain a therapeutic rate above 86% since 2002. Sternal TB is a rare clinical condition accounting for 1% of all musculoskeletal TB cases. Due to its rarity and the lack of awareness of clinical presentations, the diagnosis of sternal TB can be quite complex.  We describe the case of a 14-year-old Moroccan patient consulting in the Military Hospital Mohammed V-Rabat with central chest pain for four months which was not associated with breathing, physical exercise, or eating. The patient also had a history of asthenia, fever, and weight loss. A Computed Tomography (CT) scan of the chest showed a destructive lesion of the sternum. Afterward, a chirurgical biopsy was performed and enabled to confirm the microbiological diagnosis of TB with the realization of the real-time Polymerase Chain Reaction (PCR). The antitubercular therapy was given to the patient who had complete resolution of symptoms. This condition should be included in the differential diagnosis of chronic chest pain that mimics costochondritis particularly in patients from endemic areas.
Ubiquitous microbial contaminants associated with scientific ocean drilling
Authors: Labonte Jessica , Campbell Kathryn L. , Walker Jordan R. , Rodriguez-Pilco Milena A.
Published: June 2024

Deep-sea subsurface samples typically have low microbial biomass, making them more susceptible to contamination. Potential contaminants can be introduced during any step of the scientific process, including drilling (contamination from the drilling fluid and lubricants, seawater), sample preparation (contamination from air and human handling), and DNA extraction, amplification, and sequencing (contamination from reagents). International Ocean Discovery Program (IODP) samples that are dedicated for microbiological analyses (known as MBIO samples) are routinely tested for contamination by drilling fluids by injecting known concentrations of fluorescent microspheres or tracers directly into the drilling fluids. These tracers are a great tool to determine the level of drilling fluid contamination on board, but they are not consistently used and contamination of the samples could occur during other steps of sample processing and analysis. Moreover, there is an increased risk of contamination dominating the results of microbial surveys using PCR-based methods. Here, we built a database of common contaminants through the screening of contamination controls from available 16S rRNA gene amplicon datasets from past IODP expeditions. These controls included various lubricants used on board, drilling fluids, seawater, DNA extraction blanks, and PCR blanks. The order Burkholderiales dominated most of the very low biomass samples, including negative controls, indicating the order’s ubiquity and its potential to be overamplified with common 16S rRNA amplification protocols. We amplified the 16S rRNA gene from preserved IODP legacy microbiological core samples and tested their level of contamination using the database. We also looked at published studies that did not sequence negative controls. Our results demonstrate that the type of drilling, amount of manipulation of the sample prior to preservation, and sample depth, often associated with biomass, can influence the level of contamination within subsurface samples. This work provides an analysis framework for microbial taxonomic survey studies from low biomass subsurface samples for future scientific ocean drilling expeditions.
Rapid functional remodeling of the targeted contralesional hemisphere induced by one week of noninvasive closed-loop neurofeedback guides motor recovery in post-stroke patients with chronic motor impairment: a phase I trial
Authors: Takasaki Kenichi , Iwama Seitaro , Liu Fumio , Ogura-Hiramoto Miho , Okuyama Kohei , Kawakami Michiyuki , Mizuno Katsuhiro , Kasuga Shoko , Noda Tomoyuki , Morimoto Jun , Liu Meigen , Ushiba Junichi
Published: June 2024

Post-stroke hemiplegia of the upper extremities continues to pose a significant therapeutic hurdle. Contralesional uncrossed corticospinal pathways (CST) are involved in the recovery processes. Here, we test the feasibility, safety, and preliminary efficacy of targeted upregulation of uncrossed CST excitability using self-modulation training of cortical activities. In this phase I trial, eight individuals with persistent (1-8 years) severe post-stroke motor disability, who did not respond to conventional rehabilitation, voluntarily actuated their affected shoulder using a closed-loop, noninvasive digital connection, bridging the contralesional motor cortex (M1) and an exoskeleton robot. While patients attempted to elevate the affected arm, scalp electroencephalogram signals over the contralesional M1 were processed online to provide them with feedback on induced excitability change. Extensive neurophysiological examinations were conducted to evaluate the intervention effect using whole-head EEG and magnetic stimulations. The digital connection reconstructed neural pathways, allowing arm elevation contingent on voluntary upregulation of contralesional M1 excitability without any adverse effects. As evidenced by clinical score increases and neurophysiological examinations, seven days of consecutive system use resulted in rapid, sustained, and clinically significant improvement in motor function when removed from the system and promoted contralesional M1 functional remodeling. This closed-loop system is safe, feasible, and a promising intervention that recruits intact neural resources to allow patients to recover upper-extremity motor abilities. Larger clinical trials are needed to confirm these results.
Head-to-head comparison of leading blood tests for Alzheimer's disease pathology
Authors: Schindler Suzanne E. , Petersen Kellen K. , Saef Benjamin , Tosun Duygu , Shaw Leslie M. , Zetterberg Henrik , Dage Jeffrey L. , Ferber Kyle , Triana-Baltzer Gallen , Du-Cuny Lei , Li Yan , Coomaraswamy Janaky , Baratta Michael , Mordashova Yulia , Saad Ziad S. , Raunig David L. , Ashton Nicholas J. , Meyers Emily A. , Rubel Carrie E. , Rosenbaugh Erin G. , Bannon Anthony W. , Potter William Z.
Published: June 2024

Introduction: Blood tests have the potential to improve the accuracy of Alzheimer disease (AD) clinical diagnosis, which will enable greater access to AD-specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD-related outcomes. Methods: Plasma samples from the Alzheimers Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. Results: Measures of plasma p-tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. Discussion: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD-related outcomes.
Novel type 2 diabetes prediction score based on traditional risk factors and circulating metabolites: Model derivation and validation in two large cohort studies
Authors: Xie Ruijie , Herder Christian , Sha Sha , Peng Lei , Brenner Hermann , Schöttker Ben
Published: June 2024

Importance

The predictive value of metabolomics quantified by nuclear magnetic resonance (NMR) for type 2 diabetes risk has not been assessed before. In addition, previous studies with other metabolomics quantification methods did not have an external validation cohort, which leaves doubts about the robustness of the derived models in other settings.

Objective

This project aimed to evaluate the incremental predictive value of metabolomic biomarkers for assessing the 10-year risk of type 2 diabetes when added to the clinical Cambridge Diabetes Risk Score (CDRS), which includes HbA1c.

Design, Setting, and Participants

We utilized 60,362 participants of the UK Biobank (UKB) for model derivation, 25,870 participants of the UKB for internal validation and 4,383 participants from the German ESTHER cohort for external validation.

Exposures

A total of 249 NMR-derived metabolites were quantified using nuclear magnetic resonance (NMR) spectroscopy.

Main Outcomes and Measures

The main outcome was 10-year type 2 diabetes incidence.

Results

Eleven metabolomic biomarkers, including glycolysis-related metabolites, ketone bodies, amino acids, and lipids, were selected with LASSO regression. In internal validation within the UKB, adding these metabolites Harrel’s C-index of the clinical CDRS from 0.815 to 0.834 (P<0.001) and the continuous net reclassification index (NRI) was 39.8% (P<0.001). External validation in the ESTHER cohort showed a comparable C-index increase from 0.770 to 0.798 (P<0.001) and a continuous NRI of 33.8% (P<0.001).

Conclusions and Relevance

Adding 11 biomarkers, mainly from glucose and lipid metabolism, to the clinical CDRS led to a novel type 2 diabetes prediction model, the “UK Biobank Diabetes Risk Score” (UKB-DRS), which substantially outperformed the clinical CDRS. As only very limited clinical information and a blood sample are needed for the UKB-DRS, and as high-throughput NMR metabolomics are becoming increasingly available at low costs, this model has considerable potential for routine clinical application in diabetes risk assessment.

Key Points

Question

Can the inclusion of metabolites measured in blood samples with NMR spectroscopy improve the accuracy of the clinical Cambridge Diabetes Risk Score (CDRS), which is already a good prediction model including the main diabetes risk indicator HbA1c?

Findings

The novel UK Biobank Diabetes Risk Score (UKB-DRS), which includes traditional diabetes risk factors and 11 metabolites, demonstrated significantly enhanced predictive performance compared to the clinical CDRS, both in the UK Biobank and the German ESTHER cohort.

Meaning

The novel UKB-DRS could significantly improve the validity of early identification of individuals at risk for type 2 diabetes and guide clinicians and people at risk of diabetes in the choice of preventive measures.
DNA methylation models of protein abundance across the lifecourse
Authors: Waterfield Scott , Yousefi Paul , Suderman Matt
Published: June 2024

Background

Multiple studies have shown that DNA methylation (DNAm) models of protein abundance can be informative about exposure, phenotype and disease risk. Here we investigate the capacity of DNAm to capture non-genetic variation in protein abundance across the lifecourse.

Methods

We evaluated the performance of 14 previously published DNAm models of protein abundance (episcores) in peripheral blood from a large adult population using the Avon Longitudinal Study of Parents and Children (ALSPAC) at ages 7-24 and their mothers antenatally and in middle age (N range = 145-1464). Episcore-protein associations were evaluated with and without adjustment for genetics. New age-specific episcores were trained in ALSPAC and evaluated at different ages.

Results

Of the 14 Gadd episcores, 10 generated estimates associated with abundance in middle age, 9 at age 24, and none at age 9. Eight of these episcores explained variation beyond genotype in adulthood (6 at age 24; 7 at midlife). At age 9, the abundances of 22 proteins could be modelled by DNAm, 7 beyond genotype of which one trained model generated informative estimates at ages 24 and in middle age. At age 24, 31 proteins could be modelled by DNAm, 19 beyond genotype, of which 5 trained models generated informative estimates at age 9 and 8 in middle age. In middle age, 23 proteins could be modelled, 13 beyond genotype, of which 3 were informative at age 9 and 7 at age 24.

Conclusions

We observed that episcores performed better at older ages than in children with several episcores capturing non-genetic variation at all ages.
Investigating the variability of physiological response functions across individuals and brain regions in functional magnetic resonance imaging
Authors: Carlton Laura B. , Mitsis Georgios D. , Kassinopoulos Michalis
Published: June 2024

Functional magnetic resonance imaging (fMRI) is a valuable neuroimaging tool for studying brain function and functional connectivity between brain regions. However, the blood oxygen level dependent (BOLD) signal used to generate the fMRI images can be influenced by various physiological factors, such as cardiac and respiratory activity. These physiological effects, in turn, influence the resulting functional connectivity patterns, making physiological noise correction a crucial step in the preprocessing of fMRI data. When concurrent physiological recordings are available, researchers often generate nuisance regressors to account for the effect of heart rate and respiratory variations by convolving physiological response functions (PRF) with the corresponding physiological signals. However, it has been suggested that the PRF characteristics may vary across subjects and different regions of the brain, as well as across scans of the same subject. To investigate the dependence of PRFs on these factors, we examine the performance of several different PRF models, in terms of BOLD variance explained, using resting-state fMRI data from the Human Connectome Project (N=100). We examined both one-input (heart rate or respiration) and two-input (heart rate and respiration) PRF models and show that allowing PRF curves to vary across subjects and brain regions generally improves PRF model performance. For one-input models, the improvement in model performance gained by allowing spatial variability was most prominent for respiration, particularly for a subset of the subjects (about a third) examined. Allowing for subject-specific or regional variability in the cardiac response function resulted in a significant model performance improvement only when using a two-input PRF model. Overall, our results highlight the importance of considering spatial and subject-specific variability in PRFs when analyzing fMRI data, particularly regarding respiratory-related fluctuations.
A bovine model of rhizomelic chondrodysplasia punctata caused by a deep intronic splicing mutation in theGNPATgene
Authors: Boulling Arnaud , Corbeau Julien , Grohs Cécile , Barbat Anne , Mortier Jérémy , Taussat Sébastien , Plassard Vincent , Leclerc Hélène , Fritz Sébastien , Leymarie Cyril , Bourgeois-Brunel Lorraine , Ducos Alain , Guatteo Raphaël , Boichard Didier , Boussaha Mekki , Capitan Aurélien
Published: June 2024

Background

Genetic defects that occur naturally in livestock species provide valuable models for investigating the molecular mechanisms underlying rare human diseases. Livestock breeds are subject to the regular emergence of recessive genetic defects, due to their low genetic variability, while their large population sizes provide easy access to case and control individuals, as well as massive amounts of pedigree, genomic and phenotypic information recorded for selection purposes. In this study, we investigated a lethal form of recessive chondrodysplasia observed in 21 stillborn calves of the Aubrac breed of beef cattle.

Results

Detailed clinical examinations revealed proximal limb shortening, epiphyseal calcific deposits and other clinical signs consistent with human rhizomelic chondrodysplasia punctata, a rare peroxisomal disorder caused by recessive mutations in one of five genes (AGPS, FAR1,GNPAT,PEX5andPEX7). Using homozygosity mapping, whole genome sequencing of two affected individuals, and filtering for variants found in 1,867 control genomes, we reduced the list of candidate variants to a single deep intronic substitution inGNPAT(g.4,039,268G>A on Chromosome 28 of the ARS-UCD1.2 bovine genome assembly). For verification, we performed large-scale genotyping of this variant using a custom SNP array and found a perfect genotype-phenotype correlation in 21 cases and 26 of their parents, and a complete absence of homozygotes in 1,195 Aubrac controls. The g.4,039,268A allele segregated at a frequency of 2.6% in this population and was absent in 375,535 additional individuals from 17 breeds. Then, usingin vivoandin vitroanalyses, we demonstrated that the derived allele activates cryptic splice sites within intron 11 resulting in abnormal transcripts. Finally, by mining the wealth of records available in the French bovine database, we demonstrated that this deep intronic substitution was responsible not only for stillbirth but also for juvenile mortality in homozygotes and had a moderate but significant negative effect on muscle development in heterozygotes.

Conclusions

We report the first spontaneous large animal model of rhizomelic chondrodysplasia punctata and provide both a diagnostic test to counter-select this defect in cattle and interesting insights into the molecular consequences of complete or partial GNPAT insufficiency in mammals.
Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice
Authors: Prateek G.V. , Chen Zhenghao , Wright Kevin , Di Francesco Andrea , Jojic Vladimir , Churchill Gary A. , Raj Anil
Published: June 2024

Dense temporal measurements of physiological health using simple and consistent assays are essential to characterize biological processes associated with aging and evaluate the effectiveness of interventions on these processes. We measured body weight in 960 genetically diverse mice, every 7-10 days over the full course of their lifespan. We used a state space model to characterize the trajectories of body weight throughout life and derived 10 novel traits capturing the dynamics of body weight that are both associated with lifespan and heritable. Genetic mapping of these traits identified 12 genomic loci, none of which were previously mapped to body weight. We observed that the ability to stabilize body weight, despite fluctuations in energy intake and expenditure, is positively associated with lifespan and mapped to a genomic locus linked to energy homeostasis. Our results highlight the importance of dense longitudinal measurements of physiological traits for monitoring health and aging.
Olive mill wastewater as a source of by-products promoting plant defense against microbial pathogens
Authors: Salvati Ascenzo , Sciubba Fabio , Diomaiuti Alessandra , Leone Gian Paolo , Pizzichini Daniele , Bellincampi Daniela , Pontiggia Daniela
Published: June 2024

Olive oil is a core component of the Mediterranean diet known for its nutritional properties and health benefits. Olive industry is moving to novel extraction systems for higher oil yield and quality and for waste reduction, which is a relevant problem in the process due to its toxicity and high disposal costs. Multi-Phase Decanter (DMF) is a modern two-phase system performed without adding water during the process. Using DMF, a wet by-product indicated as pâté and consisting of the fruit pulp and vegetation water (VW) is recovered. The pâté has a high content of potentially bioactive molecules that may be exploited to promote plant resistance against microbial pathogens. In this work, to identify by/products of biological interest, the VW recovered from the pâté by centrifugation was subjected to fractionation by tangential-flow membrane filtration (TFMF), combining microfiltration (MF) and ultrafiltration (UF). High-resolution NMR spectroscopy indicated the presence of bioactive molecules such as flavonoids, hydroxytyrosol and oleuropein with known antimicrobial activity. High-Performance Anion Exchange Chromatography with Pulsed Amperometric Detection (HPAEC-PAD) was performed to detect the presence of pectic oligosaccharides in the fractions, showing the enrichment, in the UF-concentrate fraction, of oligogalacturonides (OGs), well known for the ability to elicit defense responses and protect plants against pathogen infections.Arabidopsis thalianaplants treated with TFMF fractions displayed induction of defense responses and exhibited resistance against microbial pathogens without adverse effects on growth and fitness. This study shows that pâté by-products can potentially be exploited in agriculture as sustainable plant phyto-protectant.

Graphical abstract

(image created with BioRender)
Positive feedback between demographic and selective fluctuations can greatly amplify the random fluctuation of population size
Authors: Kim Yuseob
Published: June 2024

Population sizes fluctuate over time probably due to random variability in the external environment. However, the severity of such fluctuations should depend on the characteristics of a species shaped in its evolutionary history. Previous studies have suggested that species are likely to evolve to minimize demographic fluctuations because an allele causing a smaller variance in offspring number is advantageous. However, this study finds that evolution in the opposite direction, favoring a mutation causing larger fitness fluctuation, occurs in a simple eco-evolutionary model under a randomly changing environment. This requires that (1) the mutant allele is under fluctuating selection within a subset, the field, of the population but neutral in another subset, the refuge, and (2) the field-to-refuge ratio of the carrying capacity is positively correlated to the fitness of the mutant allele. A general condition for the fixation of such a mutation was derived to depend on the relative strengths of demographic and fitness fluctuations and the mutational effect on the carrying capacity. Multi-locus simulations revealed that positive feedback between demography and selection accelerates the sequential fixations of fluctuation-amplifying mutations, leading to a drastic size fluctuation. This study therefore offers an unconventional explanation for large demographic fluctuations.
Leveraging the transient statistics of quantal content to infer neuronal synaptic transmission
Authors: Vahdat Zahra , Gambrell Oliver , Fisch Jonas , Friauf Eckhard , Singh Abhyudai
Published: June 2024

Quantal parameters of synapses are fundamental for the temporal dynamics of neurotransmitter release, forming the basis of interneuronal communication. We propose a class of models that capture the stochastic dynamics of quantal content (QC) - the number of SV fusion events per action potential (AP). Considering the probabilistic and time-varying nature of SV docking, undocking, and AP-triggered fusion, we derive anexactstatistical distribution for the QC over time. Analyzing this distribution at steady-state and its associated autocorrelation function, we show that QC fluctuation statistics can be leveraged for inferring key presynaptic parameters, such as the probability of SV fusion (release probability), and SV replenishment at empty docking sites (refilling probability). Our model predictions are tested with electrophysiological data obtained from 50-Hz stimulation of auditory MNTB-LSO synapses in brainstem slices of juvenile mice. Our results show that while synaptic depression can be explained by low and constant refilling/release probabilities, this scenario is inconsistent with the statistics of the electrophysiological data that show a low QC Fano factor and almost uncorrelated successive QCs. Our systematic analysis yields a model that couples a high release probability to a time-varying refilling probability to explain both the synaptic depression and its associated statistical fluctuations. In summary, we provide a general approach that exploits stochastic signatures in QCs to infer neurotransmission-regulating processes that are indistinguishable from just analyzing averaged synaptic responses.
Structural Basis of Differential Gene Expression at eQTLs Loci from High-Resolution Ensemble Models of 3D Single-Cell Chromatin Conformations
Authors: Du Lin , Farooq Hammad , Delafrouz Pourya , Liang Jie
Published: June 2024

Motivation

Techniques such as high-throughput chromosome conformation capture (Hi-C) have provided a wealth of information on the organization of the nucleus and the genome important for understanding gene expression regulation. Additionally, Genome-Wide Association Studies (GWASs) have uncovered thousands of loci related to complex traits. Expression quantitative trait loci (eQTL) studies have further linked the genetic variants to alteration in expression levels of associated target genes across individuals. However, the functional roles of many eQTLs located in non-coding regions are unclear. Current joint analyses of Hi-C and eQTLs data lack advanced computational tools, limiting what can be learned from these data.

Result

In this work, we developed a computational method for simultaneous analysis of Hi-C and eQTL data. Our method can identify a small set of non-random interactions from all Hi-C interactions. Using these non-random interactions, we reconstruct large ensemble (×105) of high-resolution single-cell 3D chromatin conformations with thorough sampling, which accurately replicate Hi-C measurements. Our results revealed the presence of many-body interactions in chromatin conformation at single-cell level in eQTL locus, offering detailed view into how three-dimensional structures of chromatin form the physical foundation for gene regulation, including how genetic variants of eQTLs affect the expression level of their associated eGenes.

Furthermore, our method can deconvolve chromatin heterogeneity and investigate the spatial associations of eQTLs and eGenes at subpopulation level to reveal their regulatory impacts on gene expression. Together, ensemble modeling of thoroughly sampled single cell chromatin conformations from Hi-C, along with eQTL data, helps to decipher how chromatin 3D structures provide the physical basis for gene regulation, expression control, and aid in understanding of the overall structure-function relationships of genome organization.

Availability and implementation: It is available athttps://github.com/uic-liang-lab/3DChromFolding-eQTL-Loci
Unraveling biological processes and EGFR pathway regulation by the protein tyrosine phosphatase PTPRH in non-small cell lung cancer
Authors: Ortiz Mylena M. O. , Patel Deeya M. , Swiatnicki Matthew , Andrechek Eran
Published: June 2024

The delicate balance of protein phosphorylation is often disrupted in cancers, with hyperactivity of kinases and inactivation of phosphatases driving cell proliferation and survival pathways. PTPRH, a protein tyrosine phosphatase, is deregulated or mutated in certain cancers, including non-small cell lung cancer (NSCLC). However, the biological processes that PTPRH is involved in and how they may contribute to tumorigenesis are unknown. Previous studies have linked PTPRH to the regulation of the EGFR pathway but the full extension of this regulation and the underlying mechanisms remain to be elucidated. We found that PTPRH knockout tends to increase the phosphorylation levels of EGFR at the tyrosine residue 1173 (1197), whereas overexpression of PTPRH wild-type significantly decreases phosphorylation in one of the NSCLC cell lines. Surprisingly, disruption of the extracellular or intracellular domains of the phosphatase leads to EGFR dephosphorylation in a similar manner. Co-immunoprecipitation and proximity-dependent biotinylation (BioID) experiments demonstrated that PTPRH do not directly interact with EGFR, but rather with CDK5RAP3 and EIF2AK2, two proteins reported to regulate the downstream pathway NF-κB. In addition, BioID revealed 55 novel PTPRH interactors in NSCLC cells, which are enrichedin translation and RNA-associated pathways. Guided by RNA sequencing analysis, we observed that overexpression of the phosphatase downregulates multiple oncogenic signature pathways and modulates the gene expression of 34 protein tyrosine phosphatases and 45 tyrosine kinases, EGFR included. Together, these results shed light on the importance of PTPRH in regulating biological and cellular processes and how its inactivation may support cancer progression.
Mealtime alters daily rhythm in nuclear O-GlcNAcome to regulate hepatic gene expression
Authors: Liu Xianhui , Cai Yao D , Mendiola Aron Judd P. , Xu Xuehan , Luo Yige , Zheng Haiyan , Zhao Caifeng , Chen Ching-Hsuan , Xiang Yang K. , Chiu Joanna
Published: June 2024

The liver circadian clock and hepatic transcriptome are highly responsive to metabolic signals generated from feeding-fasting rhythm. Previous studies have identified a number of nutrient-sensitive signaling pathways that could interpret metabolic input to regulate rhythmic hepatic biology. Here, we investigated the role of O-GlcNAcylation, a nutrient-sensitive post-translational modification (PTM) in mediating metabolic regulation of rhythmic biology in the liver. We observed daily oscillation of global nuclear protein O-GlcNAcylation in the liver of mice subjected to natural nighttime-restricted feeding (NRF). O-GlcNAcomic analysis revealed that 11.54% of 719 O-GlcNAcylated proteins are rhythmically O-GlcNAcylated over a 24-hour day-night cycle. Proteins involved in gene expression were enriched among rhythmically O-GlcNAcylated nuclear proteins, suggesting rhythmic O-GlcNAcylation may directly shape the daily rhythmicity of the hepatic transcriptome. Furthermore, we showed that rhythmic O-GlcNAcylation can also indirectly modulate the hepatic transcriptome by interacting with phosphorylation. Specifically, several proteins harboring O-GlcNAcylation-phosphorylation interplay motif exhibit rhythmic O-GlcNAcylation and phosphorylation. We propose that O-GlcNAcylation may occur at a phospho-degron of a key circadian transcriptional activator, circadian locomotor output cycles kaput (CLOCK), thus regulating its stability and transcriptional output. Finally, we report that unnatural day time-restricted feeding (DRF) dampens O-GlcNAcylation rhythm, suggesting the disruption in liver transcriptomic rhythm previously observed in DRF condition could be mediated by dysregulation of daily protein O-GlcNAcylation rhythm. In summary, our results provide new mechanistic insights into metabolic regulation of daily hepatic transcriptomic rhythm via interplay between O-GlcNAcylation and phosphorylation and shed light on the deleterious effects of improper mealtimes.
Clinical exome sequencing data from patients with inborn errors of immunity: cohort level meta-analysis and the benefit of systematic reanalysis
Authors: Vorsteveld Emil E. , Van der Made Caspar I. , Smeekens Sanne P. , Schuurs-Hoeijmakers Janneke H. , Astuti Galuh , Diepstra Heleen , Gilissen Christian , Hoenselaar Evelien , Janssen Alice , van Roozendaal Kees , Sikkema-van Engelen Jettie , Steyaert Wouter , Weiss Marjan M. , Yntema Helger G. , Mantere Tuomo , AlZahrani Mofareh S. , van Aerde Koen , Derfalvi Beata , Faqeih Eissa Ali , Henriet Stefanie S.V. , van Hoof Elise , Idressi Eman , Issekutz Thomas B. , Jongmans Marjolijn C.J. , Keski-Filppula Riikka , Krapels Ingrid , te Loo Maroeska , Mulders-Manders Catharina M. , ten Oever Jaap , Potjewijd Judith , Sarhan Nora Tarig , Slot Marjan C. , Terhal Paulien A. , Thijs Herman , Vandersteen Anthony , Vanhoutte Els K. , van de Veerdonk Frank , van Well Gijs , Netea Mihai G. , Simons Annet , Hoischen Alexander
Published: June 2024

While next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use of exome sequencing is still emerging. We performed a cohort level meta-analysis by revisiting clinical exome data from 1,300 IEI patients using an updatedin-silicogene panel for IEI. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8%. A systematic reanalysis resulted in the identification of variants of interest in 5.2% of undiagnosed patients, of which 75.4% were (candidate) disease-causing, increasing the molecular diagnostic yield to 15.2%. We find a high degree of actionability in IEI patients with a genetic diagnosis (76.4%). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in patients with IEI conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated.
Reconfiguration of the visual code and retinal cell type complement in closely related diurnal and nocturnal mice
Authors: Allen Annette E , Hahn Joshua , Richardson Rose , Pantiru Andreea , Mouland Josh , Baño-Otalora Beatriz , Monavarfeshani Aboozar , Yan Wenjun , Williams Christopher , Wynne Jonathan , Rodgers Jessica , Milosavljevic Nina , Orlowska-Feuer Patrycja , Storchi Riccardo , Sanes Joshua R. , Shekhar Karthik , Lucas Robert J
Published: June 2024

How does evolution act on neuronal populations to match computational characteristics to functional demands? We address this problem by comparing visual code and retinal cell composition in closely related murid species with different behaviours.Rhabdomys pumilioare diurnal and have substantially thicker inner retina and larger visual thalamus than nocturnalMus musculus. High-density electrophysiological recordings of visual response features in the dorsal lateral geniculate nucleus (dLGN) reveals thatRhabdomysattains higher spatiotemporal acuity both by denser coverage of the visual scene and a selective expansion of elements of the code characterised by non-linear spatiotemporal summation. Comparative analysis of single cell transcriptomic cell atlases reveals that realignment of the visual code is associated with increased relative abundance of bipolar and ganglion cell types supporting OFF and ON-OFF responses. These findings demonstrate how changes in retinal cell complement can reconfigure the coding of visual information to match changes in visual needs.