bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial and single-cell transcriptomics onSSPOPTV mutant mice reveals SCO-spondin’s function in mood regulation through brain barriers
Authors: Gao Yue , Xu Jiahui , Li Shuangyan , Yi Wenjuan , Xiao Liuyan , Feng Fei , Zhang Bin , Li Jiahui , Yang Xinping
Published: April 2024

The schizoaffective disorder presents mixed symptoms of schizophrenia and a mood disorder, posing an enormous challenge to its taxonomy and etiology. A recent hypothesis proposes independent genetic risk components from schizophrenia and affective disorders. By whole exome sequencing of a family with schizoaffective disorder, we identified four genes with protein-truncating variants (PTVs) that fit autosomal dominant inheritance model. Among these four genes,SSPO(encoding SCO-spondin) has exclusive expression in the subcommissural organ (SCO), a functionally highly intriguing organ in the brain, known to be potentially involved in CSF homeostasis. We generated a knock-in mouse model for the identified PTV ofSSPO, and the mutant mice exhibited enhanced anxiety-like and anti-depression-like behaviors. We further performed multilayer transcriptomics analyses on the mouse brain, and found that the genes involved in stress response, anxiety, depression and bipolar disorder are dysregulated in the SCO and brain barriers, which have direct contact with CSF. Several cell-cell communication pathways involving brain barrier cells, including the WNT signaling pathways, are altered in the mutant mice. Our results demonstrate that SCO-spondin plays a key role in stress response and mood regulation through modulating brain barriers, and thus strongly suggest that the PTV ofSSPOmay contribute to the affective symptoms of schizoaffective disorder.
Consensus guideline for the management of patients with appendiceal tumors Part 1: Appendiceal tumors without peritoneal involvement
Authors:   PSM Appendiceal Tumor Writing Group,   PSM Consortium Group, Turaga Kiran K
Published: April 2024

Background

Appendiceal tumors comprise a heterogeneous group of tumors which may be localized or disseminate throughout the peritoneum. Limited high quality clinical data exists and many practices have been extrapolated from colorectal cancer without validation in appendiceal cohorts. Many controversies exist regarding their treatment, and practices vary widely between centers and care settings. A national consensus update of best management practices for appendiceal malignancies was performed to better standardize care.

Methods

The 2018 Chicago consensus guideline was updated via modified Delphi consensus, performed over two rounds using nationally circulated surveys. Supporting evidence was evaluated using rapid systematic reviews. Key systemic therapy concepts were summarized by content experts.

Results

Most supporting literature consists of observational studies, but increasingly high-quality studies are becoming available to drive management. Two consensus-based pathways were generated for localized appendiceal tumors, one for epithelial mucinous neoplasms and another for appendiceal adenocarcinoma. Of 138 participants responding in the first round, 133 (96%) engaged in the second round. Over 90% consensus was achieved for all pathway blocks. Key points include minimizing intervention invasiveness where permitted by pathologic classification and margin status, and determining what margin and pathologic findings are indications for consideration of cytoreduction with or without intraperitoneal chemotherapy. Surveillance and systemic therapy recommendations are also presented.

Conclusion

With growing but still primarily observational evidence currently dictating care, these consensus recommendations provide expert guidance in the treatment of appendiceal tumors without peritoneal involvement.
Synaptic gene expression changes in frontotemporal dementia due to theMAPT10+16 mutation
Authors: Dando Owen , McGeachan Robert , McQueen Jamie , Baxter Paul , Rockley Nathan , McAlister Hannah , Prasad Adharsh , He Xin , King Declan , Rose Jamie , Jones Phillip B , Tulloch Jane , Chandran Siddharthan , Smith Colin , Hardingham Giles , Spires-Jones Tara L
Published: April 2024

Mutations in theMAPTgene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer’s disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by theMAPTintronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in humanMAPT10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau cortex as well as a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau caused by theMAPT10+16 mutation.
The PS4-Likelihood Ratio Calculator: Flexible allocation of evidence weighting for case-control data in variant classification
Authors: Rowlands Charlie F. , Garrett Alice , Allen Sophie , Durkie Miranda , Burghel George J. , Robinson Rachel , Callaway Alison , Field Joanne , Frugtniet Bethan , Palmer-Smith Sheila , Grant Jonathan , Pagan Judith , McDevitt Trudi , McVeigh Terri , Hanson Helen , Whiffin Nicola , Jones Michael , Turnbull Clare ,   CanVIG-UK
Published: April 2024

Background

Within the 2015 American College of Medical Genetics/Association of Molecular Pathology (ACMG/AMP) variant classification framework, case-control observations can only be scored dichotomously as ‘strong’ evidence (PS4) towards pathogenicity or ‘nil’.

Methods

We developed the PS4-likelihood ratio calculator (PS4-LRCalc) for quantitative evidence assignment based on the observed variant frequencies in cases and controls. Binomial likelihoods are computed for two models, each defined by pre-specified odds ratio (OR) thresholds. Model one represents the hypothesis of association between variant and phenotype (e.g. OR≥5) and model two represents the hypothesis of non-association (e.g. OR≤1).

Results

PS4-LRCalc enables continuous quantitation of evidence for variant classification expressed as a likelihood ratio (LR), which can be log-converted into log LR (evidence points). Using PS4-LRCalc, observed data can be used to quantify evidence towards either pathogenicity or benignity. Variants can also be evaluated against models of different penetrance. The approach is applicable to balanced datasets generated for more common phenotypes and smaller datasets more typical in very rare disease variant evaluation.

Conclusion

PS4-LRCalc enables flexible evidence quantitation on a continuous scale for observed case-control data. The converted LR is amenable to incorporation into the now widely used 2018 updated Bayesian ACMG/AMP framework.
Accumulating harm and waiting for crisis: Parents perspectives of accessing Child and Adolescent Mental Health Services for their autistic child experiencing mental health difficulties
Authors: Ashworth Emma , Bray Lucy , Hanlon Claire , Stanway Harvey , Pavlopoulou Georgia , Moore David , Donaghy Bethany , Coen Elizabeth , Firth Ellen
Published: April 2024

Background Autistic children and young people are at increased risk of mental health difficulties, but often face barriers when seeking help from Child and Adolescent Mental Health Services (CAMHS). There is limited literature exploring the accessibility of CAMHS for autistic young people, particularly from parents perspectives. The present study aimed to 1) explore the experiences of parents/carers seeking help from CAMHS for their autistic childs mental health difficulties, and 2) gain parents perceptions of the accessibility of CAMHS support for their child and understand what could be improved. Methods A mixed-methods survey design was used to learn from parents/carers. 300 parents/carers took part from across the UK between June and October 2023. Quantitative data were analysed using descriptive statistics, and qualitative data using qualitative content analysis. Results Findings demonstrated the ongoing struggles that parents/carers faced when seeking professional help from CAMHS for their child. Many were not referred to CAMHS or were rejected without an assessment, often due to issues relating to diagnostic overshadowing, a high threshold for assessment, or a lack of professional knowledge about autism and care pathways. Those who were referred reported a lack of reasonable adjustments and offers of ineffective or inappropriate therapies, leaving young people unable to engage, and thus not benefiting. Ultimately, parents felt their childs mental health difficulties either did not improve or declined to the point of crisis. However, there was a recognition that some professionals were kind and compassionate, and provided the validation that parents needed. Conclusions There is a need for a more neuro-inclusive and personalised approach in CAMHS, from the professionals themselves, in the adjustments that are offered, and in the therapies that are provided. Further research, funding, and training are urgently needed to ensure mental health support is accessible, timely, and effective for autistic CYP.
MONITORING OF RESPIRATORY VIRUS COINFECTION IN SOUTHERN BRAZIL DURING COVID-19 PANDEMIC
Authors: Padilha Dayane Azevedo , Barazzetti Fernando Hartmann , Schörner Marcos André , Filho Vilmar Benetti , Kawagoe Eric Kazuo , Marques Souza Doris Sobral , Bazzo Maria Luiza , Wagner Glauber , Fongaro Gislaine
Published: April 2024

Since December 2019, the COVID-19 pandemic caused by SARS-CoV-2 has reached approximately 769 million people, leading to more than 7 million deaths worldwide. Faced with the possible presence of other respiratory pathogens that could co-infect and modify the clinical response of patients detected for SARS-CoV-2, some researchers have explored this line of investigation. The relationship between these co-infections remains unclear, leading to a need to deepen our knowledge about interactions among pathogens, and between pathogens and the host. Thus, the present study employed RT-qPCR to assess the presence of Human Adenovirus (HAdV), Influenza A (Flu A), Influenza B (Flu B), Human Metapneumovirus (HMPV), Respiratory Syncytial Virus (RSV), Human Rhinovirus (HRV), and Parainfluenza Virus (PIV). A total of 187 nasopharyngeal samples from adult patients exhibiting respiratory symptoms were collected between February 2021 and November 2022 at the University Hospital Polydoro Ernani de Sao Thiago in Florianopolis, SC, Brazil. Our findings revealed that 25.16% of samples tested positive for non-SARS-CoV-2 respiratory viruses (29.8% - HRV, 5.3% - PIV, 4.3%-RSV, and 1.1% - HMPV). From the 74.84% of SARS-CoV-2 positive patients, the presence of co-infection was observed in 9,7% of patients, with 7.5% being HRV, 1.1% HAdV and 1.1% Flu A. Since co-infections can potentially alter patient prognoses and impact local epidemiological dynamics, this study highlights the significance of ongoing monitoring and epidemiological assessment through genomic surveillance of other clinically relevant respiratory pathogens.
Conditional Survival and Nomogram for Elderly Non-Metastatic Colon Cancer Patients Following Colectomy
Authors: Gao Yadong , Wang Huimin , Zhang Yi , Zhao Jing , Feng Sujuan , Qiu Jianwei
Published: April 2024

Background

This study aimed to evaluate the conditional survival (CS) of elderly patients with non-metastatic colon cancer who underwent colectomy and build conditional nomograms that can accommodate varying survival periods and estimate survival rates.

Methods

Data from 9302 patients between 2004 and 2017 were obtained from the Surveillance, Epidemiology, and End Results database. CS was used to assess overall survival and colon-specific survival rates in patients who survived beyond a certain time period. Cox regression was used to select factors for nomogram development, and performance was evaluated using area under the receiver operating characteristic curve (AUC), calibration plot, and decision curve analysis (DCA).

Results

The 5-year conditional overall survival rates initially increased slightly but then decreased over time. The rates at different time points after diagnosis (baseline and 1-5 years) were 62.5, 63.2, 62.8, 62.1, 61.6, and 59.8%. In contrast, 5-year conditional colon-specific survival rates consistently improved over the same period. These rates were 78.1, 80.9, 84.2, 86.9, 89.3, and 90.9%, respectively. Nomograms were developed for baseline measurements and for patients who survived 1, 3, and 5 years. The performance of these nomograms, assessed using AUC, calibration curves, and DCA, indicated good predictive capabilities.

Conclusion

CS provides valuable information on the medium- and long-term survival probabilities of elderly patients with non-metastatic colon cancer who underwent colectomy. The developed conditional nomograms allowed for the estimation of survival probabilities across different timeframes, facilitating a comprehensive understanding of prognosis and collaborative decision making.
Development and Internal Validation of Models Predicting the Health Insurance Status of Participants in the German National Cohort
Authors: Hrudey Ilona , Swart Enno , Baurecht Hansjörg , Becher Heiko , Damms-Machado Antje , Hoffmann Wolfgang , Jöckel Karl-Heinz , Kartschmit Nadja , Katzke Verena , Keil Thomas , Kollhorst Bianca , Leitzmann Michael , Meinke-Franze Claudia , Michels Karin B. , Mikolajczyk Rafael , Niedermaier Tobias , Pigeot Iris , Schipf Sabine , Schmidt Börge , Walter Barbara , Willich Stefan , Wolff Robert , Stallmann Christoph
Published: April 2024

Background

In Germany, all citizens must purchase health insurance, in either statutory (SHI) or private health insurance (PHI). Because of the division into SHI and PHI, person insurance’s status is an important variable for studies in the context of public health research. In the German National Cohort (NAKO), the variable on self-reported health insurance status of the participants has a high proportion of missing values (55.4%). The aim of our study was to develop and internally validate models to predict the health insurance status of NAKO baseline survey participants in order to replace missing values. In this respect, our research interest was focused on the question to which extent socio-demographic characteristics are suitable for predicting health insurance status.

Methods

We developed two prediction models including 53,796 participants to estimate the probability that a participant is either member of a SHI (model 1) or PHI (model 2). We identified eight predictors by literature research: occupation, income, education, sex, age, employment status, residential area, and marital status. The predictive performance was determined in the internal validation considering discrimination and calibration. Discrimination was assessed based on the Area Under the Curve (AUC) and the Receiver Operating Characteristic (ROC) curve and calibration was assessed based on the calibration slope and calibration plot.

Results

In model 1, the AUC was 0.91 (95% CI: 0.91-0.92) and the calibration slope was 0.97 (95% CI: 0.97-0.97). Model 2 had an AUC of 0.91 (95% CI: 0.90-0.91) and a calibration slope of 0.97 (95% CI: 0.97-0.97). Based on the calculated performance parameters both models turned out to show an almost ideal discrimination and calibration. Employment status and household income and to a lesser extent educational level, age, sex, marital status, and residential area are suitable for predicting health insurance status.

Conclusions

Socio-demographic characteristics especially employment status and household income assessed at NAKO’s baseline were suitable for predicting the statutory and private health insurance status. However, before applying the prediction models in other studies, an external validation in population-based studies is recommended.
Optimization of1H MR spectroscopy methods for large volume acquisition of low concentration downfield resonances at 3T and 7T
Authors: Wilson Neil E. , Elliott Mark A. , Reddy Nanga Ravi Prakash , Swago Sophia , Witschey Walter R. , Reddy Ravinder
Published: April 2024

Purpose

This goal of this study was to optimize spectrally selective1H MRS methods for large volume acquisition of low concentration metabolites with downfield resonances at 7T and 3T, with particular attention paid to detection of nicotinamide adenine dinucleotide (NAD+) and tryptophan.

Methods

Spectrally selective excitation was used to avoid magnetization transfer effects with water, and various sinc pulses were compared to a pure-phase E-BURP pulse. Localization using a single slice selective pulse was compared to voxel-based localization that used three orthogonal refocusing pulses, and low bandwidth refocusing pulses were used to take advantage of the chemical shift displacement of water. A technique for water sideband removal was added, and a method of coil channel combination for large volumes was introduced.

Results

Proposed methods were compared qualitatively to previously-reported techniques at 7T. Sinc pulses resulted in reduced water signal excitation and improved spectral quality, with a symmetric, low bandwidth-time product pulse performing best. Single slice localization allowed shorter TEs with large volumes, enhancing signal, while low bandwidth slice selective localization greatly reduced the observed water signal. Gradient cycling helped remove water sidebands, and frequency aligning and pruning individual channels narrowed spectral linewidths. High quality brain spectra of NAD+and tryptophan are shown in four subjects at 3T.

Conclusion

Improved spectral quality with higher downfield signal, shorter TE, lower nuisance signal, reduced artifacts, and narrower peaks was realized at 7T. These methodological improvements allowed for previously unachievable detection of NAD+and tryptophan in human brain at 3T in under five minutes.
Parametrization of Worldwide Covid-19 data for multiple variants: How is the SAR-Cov2 virus evolving?
Authors: Foerster Dietrich , Bhatkar Sayali , Bhanot Gyan
Published: April 2024

We mapped the 2020-2023 daily Covid-19 case data from the World Health Organization (WHO) to the original SIR model of Karmack and McKendrick for multiple pandemic recurrences due to the evolution of the virus to different variants in forty countries worldwide. The aim of the study was to determine how the SIR parameters are changing as the virus evolved into variants. Each peak in cases was analyzed separately for each country and the parameters: reff(pandemic R-parameter), Leff(average number of days an individual is infective) and α (the rate of infection for contacts between the set of susceptible persons and the set of infected persons) were computed. Each peak was mapped to circulating variants for each country and the SIR parameters (reff, Leff, α) were averaged over each variant using their values in peaks where 70% of the variant sequences identified belonged to a single variant. This analysis showed that on average, compared to the original Wuhan variant (α = 0.2), the parameter α has increased to α = 0.5 for the Omicron variants. The value of reffhas decreased from around 3.8 to 2.0 and Leffhas decreased from 15 days to 10 days. This is as would be expected of a virus that is coming to equilibrium by evolving to increase its infectivity while reducing the effects of infections on the host.
Design of the COMEBACK and BACKHOME Studies, Longitudinal Cohorts for Comprehensive Deep Phenotyping of Adults with Chronic Low-Back Pain (cLBP): a part of the BACPAC Research Program
Authors: Hue Trisha F. , Lotz Jeffrey C. , Zheng Patricia , Black Dennis M. , Bailey Jeannie , Ewing Susan K. , Fields Aaron J. , Mehling Wolf , Scheffler Aaron , Strigo Irina , Petterson Thomas , Wu Lucy A. , O’Neill Conor ,   The UCSF REACH Center,   the CoRe CEnter for PAtient-Centric Mechanistic PHenotyping in Chronic Low Back Pain
Published: April 2024

Objective

The University of California, San Francisco (UCSF) Core Center for Patient-centric, Mechanistic Phenotyping in Chronic Low Back Pain (REACH) is one of the three NIH Back Pain Consortium (BACPAC) Research Programs Mechanistic Research Centers (MRCs). The goal of UCSF REACH is to define cLBP phenotypes and pain mechanisms that can lead to effective, personalized treatments for patients across the population. The primary objective of this research project is to address the critical need for new diagnostic and prognostic markers, and associated patient classification protocols for chronic low back pain (cLBP) treatment.

Design

To meet this objective, REACH is conducting two large investigator-initiated translational research cohort studies called: The Longitudinal Clinical Cohort for Comprehensive Deep Phenotyping of Chronic Low-Back Pain (cLBP) Adults Study (comeBACK) and the Chronic Low-Back Pain (cLBP) in Adults Study (BACKHOME).

Setting

comeBACK is a longitudinal multicenter in-person observational study of 450 adults with chronic low back pain designed to perform comprehensive deep phenotyping. While, the BACKHOME study is a site-less longitudinal observational e-cohort of approximately 3000 U.S. adults with cLBP. To our knowledge, BACKHOME is the largest prospective remote registry of nationwide adults with cLBP.

Methods

Both the comeBACK and BACKHOME studies are collecting a robust and comprehensive set of risk factors, outcomes, and covariates in order to perform deep phenotyping of cLBP patients based on combined biopsychosocial variables to: define cLBP subtypes, establish phenotyping tools for routine clinical evaluation, and lead to improved cLBP outcomes in the future. The data from both studies will be used to establish techniques to develop a patient-centric definition of treatment success and to analyze cLBP patient traits to define clinically useful cLBP phenotypes, using a combination of traditional data analyses and deep learning methods.

Conclusions

These 2 pivotal studies, in conjunction with the ancillary studies being performed in both comeBACK and BACKHOME, and the other BACPAC-consortium research projects, we will be able to address a number of diagnostic and therapeutic issues in this complex and diverse patient population with cLBP. These studies will help clarify biopsychosocial mechanisms of cLBP with the aim to provide a foundation to improve the evaluation of treatment effectiveness and to spur new avenues of therapeutic research, including personalized outcome measures that constitute a clinically meaningful treatment effect for individual cLBP patients.
Ablation STrategies for Repeat PrOcedures in Atrial Fibrillation Recurrences despite Durable Pulmonary Vein Isolation ASTRO - AF Trial
Authors: Schmidt Boris , Bordignon Stefano , Metzner Andreas , Sommer Philipp , Steven Daniel , Dahme Tilmann , Busch Matthias , Tilz Roland Richard , Schaack David , Rillig Andreas , Sohns Christian , Sultan Arian , Weinmann-Emhardt Karolina , Hummel Astrid , Vogler Julia , Fink Thomas , Lueker Jakob , Pott Alexander , Heeger Christian , Julian Chun KR
Published: April 2024

Background

Ablation strategies for patients with symptomatic atrial fibrillation (AF) and isolated pulmonary veins (PV) vary and their impact on arrhythmia recurrence remains unclear. This prospective randomized German multi—center trial sought to compare two ablation strategies in this patient cohort.

Methods

Patients with AF despite durable PV isolation were randomly assigned at seven centers to undergo low-voltage area (LVA) ablation using 3D mapping and irrigated radiofrequency current ablation (group A) or empirical left atrial appendage isolation (LAAI) utilizing the cryoballoon (CB) followed by staged interventional LAA closure (group B). The primary endpoint was freedom from atrial tachyarrhythmias between 91 and 365 days after index ablation. The study was powered for superiority of LAAI compared to LVA.

Results

Patients (40% female, mean age 68.8±8 years) with paroxysmal (32%) or persistent AF (68%) were randomized to undergo LVA ablation (n=79) or CB guided LAAI (n=82). After a planned interim analysis enrollment was halted on January 10th2023.

In the LAAI group 77/82 LAAs were successfully isolated with subsequent LAAC in 57 patients. Procedure related complications occurred in 4 (5%) and 11 (13.5%) patients in group A and B, respectively (P=0.10). The median follow-up was 367 (IQR 359-378) days. The Kaplan Meier point estimate for the freedom from a primary endpoint event was 51.7% (CI 40.9-65.4%) for group A and 55.5% (CI 44.4-69.2%; p=0.8069).

Conclusions

The present study did not detect superiority of CB guided LAAI over LVA ablation in patients with AF despite durable PVI.

It was registered athttps://clinicaltrials.gov/study/NCT04056390

Clinical Perspectives

What is new?

This is the first randomized multi-center study to compare two different ablation strategies in AF patients with durable PVI.

Empirical LAAI was not associated with better outcome in comparison to low-voltage area ablation.

What are the clinical implications?

LAAI should not be advocated as a stand-alone ablation strategy for patients with AF recurrences after prior ablation.

The patient with AF recurrence after prior catheter ablation should be informed that if all PVs are found durably isolated the optimal ablation strategy remains uncertain.
School Neighborhood Deprivation is Associated with a Higher Prevalence of Hypertension
Authors: Onugha Elizabeth A. , Banerjee Ankona , Nobleza Kenneth J. , Nguyen Duc T. , Rosales Omar , Oluyomi Abiodun , Dave Jayna M. , Samuels Joshua
Published: April 2024

Abstract

Background

Hypertension, a major modifiable risk factor for cardiovascular disease, is increasing among adolescents. While socioeconomic factors have been shown to contribute to hypertension risk in adults, similar data in children is lacking. We examined the association between socioeconomic characteristics of school neighborhoods and the prevalence of hypertension in adolescents.

Methods

School neighborhood socioeconomic status (SES) was assessed via the area deprivation index (ADI), a composite measure of area-level socioeconomic deprivation. Using data from a school BP surveillance program implemented in the Houston metropolitan area, we performed a cross-sectional analysis using both univariate and multivariable regression analyses.

Results

Among 21,392 students aged 10 to 19 years during the 2000 through 2017 academic years, the prevalence of sustained hypertension was 2.6%. Although 85% of students attended schools located in neighborhoods in quartiles 1 (Q1) and 2 (Q2) (higher ADI represents more deprivation), Hispanics and African Americans were overrepresented in the schools located inside more deprived neighborhoods. The highest sustained hypertension rate (4.6%) was observed among students attending Q 3 and Q4 schools compared to 2.3% in Q 1 and Q2 schools (p < 0.001). Multivariable regression analysis showed that being male, obese, and attending school in a disadvantaged neighborhood were significantly associated with an increased prevalence of hypertension.

Conclusions

Attending school in neighborhoods with lower SES may account for the increased hypertension prevalence in minority adolescents. Characteristics of school neighborhoods play an important role in the disparities observed in hypertension prevalence, providing direct opportunities to encourage improved dietary intake and physical activity, both of which are important determinants of hypertension.
Microbiota-derived inosine programs protective CD8+T cell responses against influenza in newborns
Authors: Stevens Joseph , Culberson Erica , Kinder Jeremy , Ramiriqui Alicia , Gray Jerilyn , Bonfield Madeline , Shao Tzu-Yu , Al Gharabieh Faris , Peterson Laura , Steinmeyer Shelby , Zacharias William , Pryhuber Gloria , Paul Oindrila , Sengupta Shaon , Alenghat Theresa , Way Sing Sing , Deshmukh Hitesh
Published: April 2024

The immunological defects causing susceptibility to severe viral respiratory infections due to early-life dysbiosis remain ill-defined. Here, we show that influenza virus susceptibility in dysbiotic infant mice is caused by CD8+T cell hyporesponsiveness and diminished persistence as tissue-resident memory cells. We describe a previously unknown role for nuclear factor interleukin 3 (NFIL3) in repression of memory differentiation of CD8+T cells in dysbiotic mice involving epigenetic regulation of T cell factor 1 (TCF 1) expression. Pulmonary CD8+T cells from dysbiotic human infants share these transcriptional signatures and functional phenotypes. Mechanistically, intestinal inosine was reduced in dysbiotic human infants and newborn mice, and inosine replacement reversed epigenetic dysregulation ofTcf7and increased memory differentiation and responsiveness of pulmonary CD8+T cells. Our data unveils new developmental layers controlling immune cell activation and identifies microbial metabolites that may be used therapeutically in the future to protect at-risk newborns.
PGC-1α drives small cell neuroendocrine cancer progression towards an ASCL1-expressing subtype with increased mitochondrial capacity
Authors: Varuzhanyan Grigor , Chen Chia-Chun , Freeland Jack , He Tian , Tran Wendy , Song Kai , Wang Liang , Cheng Donghui , Xu Shili , Dibernardo Gabriella A. , Esedebe Favour N , Bhatia Vipul , Han Mingqi , Abt Evan R. , Park Jung Wook , Memarzadeh Sanaz , Shackelford David , Lee John K. , Graeber Thomas , Shirihai Orian , Witte Owen
Published: April 2024

Adenocarcinomas from multiple tissues can evolve into lethal, treatment-resistant small cell neuroendocrine (SCN) cancers comprising multiple subtypes with poorly defined metabolic characteristics. The role of metabolism in directly driving subtype determination remains unclear. Through bioinformatics analyses of thousands of patient tumors, we identified enhanced PGC-1α—a potent regulator of oxidative phosphorylation (OXPHOS)—in various SCN cancers (SCNCs), closely linked with neuroendocrine differentiation. In a patient-derived prostate tissue SCNC transformation system, the ASCL1-expressing neuroendocrine subtype showed elevated PGC-1α expression and increased OXPHOS activity. Inhibition of PGC-1α and OXPHOS reduced the proliferation of SCN lung and prostate cancer cell lines and blocked SCN prostate tumor formation. Conversely, enhancing PGC- 1α and OXPHOS, validated by small-animal Positron Emission Tomography mitochondrial imaging, tripled the SCN prostate tumor formation rate and promoted commitment to the ASCL1 lineage. These results establish PGC-1α as a driver of SCNC progression and subtype determination, highlighting novel metabolic vulnerabilities in SCNCs across different tissues.

STATEMENT OF SIGNIFICANCE

Our study provides functional evidence that metabolic reprogramming can directly impact cancer phenotypes and establishes PGC-1α-induced mitochondrial metabolism as a driver of SCNC progression and lineage determination. These mechanistic insights reveal common metabolic vulnerabilities across SCNCs originating from multiple tissues, opening new avenues for pan-SCN cancer therapeutic strategies.
CDC42 Inhibitors Alter Patterns of Vessel Arborization in Skin and Tumors in vivo
Authors: Vuong Linh M , Hachey Stephanie , Shiu Jessica , Xie Danny F , Salvador Noel , Brindani Nicoletta , Bertozzi Sine Mandrup , Summa Maria , Bertorelli Rosalia , Armirotti Andrea , Pham Rachel , Ku Vance SH , Nguyen Terry , Choi Bernard , Hughes Christopher CW , De Vivo Marco , Ganesan Anand K
Published: April 2024

Tumors that arise in the epidermis must develop a vascular supply to grow beyond a millimeter in depth. This process requires CDC42 GTPases such as CDC42, RhoJ and RhoQ. Despite this dependence on angiogenesis for growth, melanoma tumors are minimally responsive to current anti-angiogenesis agents, highlighting the need for more effective drugs in this class. Here we integrate antibody infusion, optical tissue clearing, multiphoton imaging, and three-dimensional semi-automated tracing to develop a quantitative approach to measure changes in vascular architecture in skin and skin tumors. This new approach uncovered differences in vessel arborization in the skin of RhoJ KO mice as compared to wild-type mice. Furthermore, novel small molecules that inhibit CDC42 GTPases inhibited both tumor growth and vessel branching within tumors to a similar degree as Braf inhibitors, which are commonly used to treat melanoma. In contrast to Braf inhibitors, however, which only affected tumor vasculature, CDC42 inhibitors affected vascularization in both tumor and normal skin without apparent toxicity to endothelial or stromal cells. These novel CDC42 inhibitors similarly blocked vessel branching in human cell-based micro-physiological models of normal and tumor vessels. RNA sequencing revealed reduced expression of multiple angiogenesis-related genes in drug-treated skin. Taken together, these studies identify a new class of pharmacologic agents that inhibit vessel branching in both normal skin and tumors with potential utility for treating skin cancer and skin diseases characterized by pathologic angiogenesis.
Metabolite accumulation from oral NMN supplementation drives aging-specific kidney inflammation
Authors: Saleh Tara A. , Whitson Jeremy , Keiser Phoebe , Prasad Praveena , Jenkins Brenita C. , Sodeinde Tori , Mann Carolyn N. , Rabinovitch Peter S. , McReynolds Melanie R. , Sweetwyne Mariya T.
Published: April 2024

The mitochondrial-rich renal tubule cells are key regulators of blood homeostasis via excretion and reabsorption of metabolic waste. With age, tubules are subject to increasing mitochondrial dysfunction and declining nicotinamide adenine dinucleotide (NAD+) levels, both hampering ATP production efficiency. We tested two mitochondrial interventions in young (6-mo) and aged (26-mo) adult male mice: (ELAM), a tetrapeptide in clinical trials that improves mitochondrial structure and function, and nicotinamide mononucleotide (NMN), an NAD+intermediate and commercially available oral supplement. Kidneys were analyzed from young and aged mice after eight weeks of treatment with ELAM (3 mg/kg/day), NMN (300 mg/kg/day), or from aged mice treated with the two interventions combined (ELAM+NMN). We hypothesized that combining pharmacologic treatments to ameliorate mitochondrial dysfunction and boost NAD+levels, would more effectively reduce kidney aging than either intervention alone. Unexpectedly, in aged kidneys, NMN increased expression of genetic markers of inflammation (IL-1β and Ccl2) and tubule injury (Kim-1). Metabolomics of endpoint sera showed that NMN-treated aged mice had higher circulating levels of uremic toxins than either aged controls or young NMN-treated mice. ELAM+NMN- treated aged mice accumulated uremic toxins like NMN-only aged mice, but reduced IL-1β and Ccl2 kidney mRNA. This suggests that pre-existing mitochondrial dysfunction in aged kidney underlies susceptibility to inflammatory signaling with NMN supplementation in aged, but not young, mice. These findings demonstrate age and tissue dependent effects on downstream metabolic accumulation from NMN and highlight the need for targeted analysis of aged kidneys to assess the safety of anti-aging supplements in older populations.

Summary Statement

Declining levels of NAD+and increasing mitochondrial dysfunction with age are functionally linked and are popular mechanistic targets of commercially available anti-aging therapeutics. Studies have focused on nicotinamide mononucleotide (NMN), nicotinamide riboside (NR) and nicotinamide (NAM) supplementation to boost cellular NAD+, but a consensus on the dosage and regimen that is beneficial or tolerable has not been reached. We show that although high levels of sustained NMN supplementation are beneficial to liver and heart in aged mice, the same dosing regimen carries age-associated signs of kidney inflammation. Our findings underscore a complex state of age- and tissue-specific metabolic homeostasis and raise questions not only about how much, and for how long, but at what age is NAD+boosting safe.
High-throughput three-dimensional characterization of morphogenetic signals during the formation of the vertebrate retina
Authors: Ledesma-Terrón Mario , Pérez-Dones Diego , Mazó-Durán Diego , Míguez David G.
Published: April 2024

The precise differentiation of neural progenitors during development ensures the correct cognitive, sensory and motor functions of higher organisms. This balance between self-renewal and terminal differentiation is regulated by a complex interplay of signaling pathways, that set the spatial and temporal cues that ultimately shape and organize neurogenic tissues. The developing vertebrate retina is a widely used model to study how these key signaling cascades modulate the mode and rate of division of neural progenitors, despite its complex threedimensional architecture and the asymmetric differentiation dynamics. Here, we present a comprehensive multi-step framework that integratesin totoexperiments with three dimensional image analysis and theoretical tools to provide a quantitative characterization of the dynamics of growth and differentiation of the developing vertebrate retina. Additionally, we use small molecule inhibitors to show that Hh and FGF activation promote differentiation and cell cycle progression, while Wnt and Notch activation respectively increase and decrease the average division rate. These results represent a detailed and accurate quantitative characterization of the development and regulation of the vertebrate retina. We propose that the same framework can be directly used to characterize otherin vitroorin vivotissues.
Do mixed-species groups travel as one? An investigation on large African herbivores using animal-borne video collars
Authors: Dejeante Romain , Valeix Marion , Chamaillé-Jammes Simon
Published: April 2024

Although prey foraging in mixed-species groups benefit from a reduced risk of predation, whether heterospecific groupmates move together in the landscape, and more generally to what extent mixed-species groups remain cohesive over time and space remains unknown. Here, we used GPS collars with video cameras to investigate the movements of plains zebras (Equus quagga) in mixed-species groups. Blue wildebeest (Connochaetes taurinus), impalas (Aepyceros melampus) and giraffes (Giraffa camelopardalis) commonly form mixed-species groups with zebras in savanna ecosystems. We found that zebras adjust their movement decisions solely to the presence of giraffes, being more likely to move in zebra-giraffe herds, and this was correlated to a higher cohesion of such groups. Additionally, zebras moving with giraffes spent longer time grazing, suggesting that zebras follow giraffes to forage in their proximity. Our results provide new insights on animal movements in mixed-species groups, contributing to a better consideration of mutualism in movement ecology.
Satellite glial cells from adult DRG dedifferentiatein vitroand can be reprogrammed into nociceptor-like neurons
Authors: Sodmann Annemarie , Köhler Niels , Esfahani Nastaran M. , Schukraft Nina , Aue Annemarie , Jager Sara E. , Bischler Thorsten , Imdahl Fabian , Gräfenhan Tom , Leipold Enrico , Rittner Heike L. , Blum Robert
Published: April 2024

Loss of sensory neurons in the dorsal root ganglia (DRG) may be a cause of neuropathic pain following traumatic nerve lesion or surgery. To regenerate peripheral sensory neurons, satellite glial cells (SGCs) may be an attractive endogenous cell source. SGCs are known to acquire certain neural progenitor-like properties after injury and are derived from the same neural crest lineage as sensory neurons. Here, we found that adult mouse DRG harbor SGC-like cells that dedifferentiate into glial sensory progenitor cellsin vitro. Surprisingly, forced coexpression of the early developmental transcription factors Neurog1 and Neurog2 was sufficient to induce neuronal and glial cell phenotypes. In the presence of nerve growth factor, the induced neurons developed a nociceptor phenotype characterized by functional expression of marker ion channels such as TrpA1, TrpV1 and TTX-resistant NaVchannels. Our study demonstrates that glial cells harvested from the adult DRG have neural stem cell-like properties, are multipotent, and may be useful for future neural repair strategies in the peripheral nervous system.

Summary statement

The adult dorsal root ganglion carries a satellite glial cell source for generation of induced nociceptor-like neurons. The cells dedifferentiatein vitroand acquire properties of a multipotent peripheral neural progenitor.
Differential Proteomic Analysis of Serum and Bone Marrow Supernatant in Acute myeloid leukemia Patients at Low and Intermediate Altitudes after Chemotherapy
Authors: Sun Qi , Zhou Houfa , Wang Aibo , Li Wenqian , Xie Youbang
Published: April 2024

Chemotherapy is the primary treatment for patients with acute myeloid leukemia (AML). In addition to factors such as patient age, physical condition, and choice of medication, we have noticed that environmental factors such as altitude may also have a significant impact on post-chemotherapy bone marrow suppression in AML patients in clinical practice. The results indicate that there are differences in the proteomics of the two groups of patients during the bone marrow suppression period after chemotherapy. Differentially expressed proteins are primarily located in the cytoplasm, extracellular space, and nucleus, followed by mitochondria and membranes. These differentially expressed proteins mainly participate in biological processes such as cell and metabolism. For differential protein KEGG pathway enrichment analysis, it was found that metabolic pathways were mainly enriched in the metabolic category, while the PI3K-Akt signaling pathway, HIF-1 signaling pathway, NF-κB signaling pathway, and calcium signaling pathway were enriched in the signaling pathways.
Vascular dysfunction is at the onset of oxaliplatin-induced peripheral neuropathy symptoms in mice
Authors: Taib Sonia , Durand Juliette , Boulay Anne-Cecile , Dehais Vianney , Martin Sabrina , Blugeon Corinne , Jourdren Laurent , Cohen-Salmon Martine , Hazan Jamile , Brunet Isabelle V
Published: April 2024

Oxaliplatin-induced peripheral neuropathy (OIPN) is an adverse side effect of this chemotherapy used for gastrointestinal cancers. The continuous pain experienced by OIPN patients often result in the reduction or discontinuation of chemotherapy, thereby affecting patient survival. Several pathogenic mechanisms involving sensory neurons were shown to participate in the occurrence of OIPN symptoms. However, the dysfunction of the blood-nerve barrier as a source of nerve alteration had not been thoroughly explored. To characterise the vascular contribution to OIPN symptoms, we undertook two comparative transcriptomic analyses from mouse purified brain and sciatic nerve blood vessels (BVs), and nerve BVs after oxaliplatin or control administration. These analyses reveal distinct molecular landscapes between brain and nerve BVs and the upregulation of transcripts involved in vascular contraction after oxaliplatin treatment. Anatomical examination of the nerve yet shows the preservation of BV architecture in acute OIPN mouse model, although treated mice exhibit both neuropathic symptoms and enhanced vasoconstriction reflected by hypoxia. Moreover, vasodilators significantly reduce oxaliplatin-induced neuropathic symptoms and endoneurial hypoxia, establishing the key involvement of nerve blood flow in OIPN.
Transiently Worse Postural Effects After Vestibulo-ocular Reflex Gain-Down Adaptation in Healthy Adults
Authors: Arduino Cesar , Schubert Michael C , Anson Eric R
Published: April 2024

Suffering an acute asymmetry in vestibular function (i.e. vestibular neuritis) causes increased sway. Non-causal studies report associations between lateral semicircular canal function and balance ability, but direct links remains controversial. We investigate the immediate effect on body sway after unilateral vestibulo-ocular reflex (VOR) gain down adaptation simulating acute peripheral vestibular hypofunction. Eighteen healthy adults, mean age 27.4 (SD 12.4), stood wearing an inertial measurement device with their eyes closed on foam before and after incremental VOR gain down adaptation to simulate mild unilateral vestibular neuritis. Active head impulse VOR gain was measured before and after the adaptation to ensure VOR gain adaptation. Percentage change for VOR gain and sway area were determined. Sway area was compared before and after VOR adaptation. VOR gain decreased unilaterally exceeding meaningful change values. Sway area was significantly greater immediately after VOR gain down adaptation, but quickly returned to baseline. In a subset of subjects VOR gain was re-assessed and found to remain adapted despite sway normalization. These results indicate that oculomotor adaptation targeting the lateral semicircular canal VOR pathways have an immediate, albeit transient increase in body sway. Rapid return of body sway to baseline levels suggests dynamic sensory reweighting between vestibular and somatosensory inputs to resolve the undesirable increased body sway.
The subthalamic nucleus contributes causally to perceptual decision-making in monkeys
Authors: Rogers Kathryn , Gold Joshua I. , Ding Long
Published: April 2024

The subthalamic nucleus (STN) plays critical roles in the motor and cognitive function of the basal ganglia (BG), but the exact nature of these roles is not fully understood, especially in the context of decision-making based on uncertain evidence. Guided by theoretical predictions of specific STN contributions, we used single-unit recording and electrical microstimulation in the STN of healthy monkeys to assess its causal, computational roles in visual-saccadic decisions based on noisy evidence. The recordings identified subpopulations of STN neurons with distinct task-related activity patterns that related to different theoretically predicted functions. Microstimulation caused changes in behavioral choices and response times that reflected multiple contributions to an “accumulate-to-bound”-like decision process, including modulation of decision bounds and evidence accumulation, and to non-perceptual processes. These results provide new insights into the multiple ways that the STN can support higher brain function.
Hypothesis-driven interpretable neural network for interactions between genes
Authors: Wang Shuhui , Allauzen Alexandre , Nghe Philippe , Opuu Vaitea
Published: April 2024

Mechanistic models of genetic interactions are rarely feasible due to a lack of information and computational challenges. Alternatively, machine learning (ML) approaches may predict gene interactions if provided with enough data but they lack interpretability. Here, we propose an ML approach for interpretable genotype-to-fitness mapping, the Direct-Latent Interpretable Model (D-LIM). The neural network is built on a strong hypothesis: mutations in different genes cause independent effects in phenotypes, which then interact via non-linear relationships to determine fitness. D-LIM predicts interpretable genotype-to-fitness maps with state-of-the-art accuracy for gene-to-gene and gene-to-environment perturbations in deep mutational scanning of a metabolic pathway, a protein-protein interaction system, and yeast mutants for environmental adaptation. The hypothesis-driven structure of D-LIM offers interpretable features reminiscent of mechanistic models: the inference of phenotypes, identification of trade-offs, and fitness extrapolation outside of the data domain.