bluuebunny/crossref_metadata_2025 huggingface dataset:
The Telomerase Connection of the Brain and Its Implications for Neurodegenerative Diseases
Authors: Saretzki Gabriele
Published: November 2022

Telomerase, consisting of the protein subunit telomerase reverse transcriptase (TERT) and RNA component TERC, is best known for maintaining and extending human telomeres, the ends of linear chromosomes, in tissues, where it is active, such as stem cells, germline cells, lymphocytes and endothelial cells. This function is considered as canonical. However, various non-canonical functions for the protein part TERT have been discovered. There are multiple such roles which can interfere with several signaling pathways, cancer development and many other processes. One of these non-canonical functions includes shuttling of the TERT protein out of the nucleus upon increased oxidative stress into the cytoplasm and organelles such as mitochondria. Mitochondrial TERT is able to protect cells from oxidative stress, DNA damage and apoptosis although the exact mechanisms are incompletely understood. Recently, a protective role for TERT was described in brain neurons. Here TERT is able to counteract effects of toxic neurodegenerative proteins via changes in gene expression, activation of neurotrophic factors as well as activation of protein degrading pathways such as autophagy. Protein degradation processes are prominently involved in degrading toxic proteins in the brain like amyloid-β, pathological tau and α-synuclein that are responsible for various neurodegenerative diseases. These new findings can have implications for the development of novel treatment strategies for neurodegenerative diseases. The current review summarizes our knowledge on the role of the telomerase protein TERT in brain function, in particular, under the aspect of age-related neurodegenerative diseases. It also describes various strategies to increase TERT levels in the brain.
When can a refusal to consent to the exercise of a power be challenged?
Authors: Hayton David
Published: November 2022

This update, prepared for a January 2022 session with the Bahamian judiciary, casts light upon three alternative approaches where someone’s consent is required before trustees can exercise particular powers; the rights of protectors to information necessary for them properly to exercise their functions; the large scope for trustees not to follow a settlor’s letter of wishes; distinctions between shams, rights indistinguishable from ownership and revocable trusts; difficulties finding that a large company has dishonestly assisted in a breach of equitable duties; the scope of exoneration clauses and of equitable compensation.
Mediating effects of resilience on frailty and depression among older Chinese people living with HIV/AIDS: a cross-sectional study in Hunan
Authors: Yao Meng , Chen Dan , Meng Lijun , Zhou Cui , Li Xingli
Published: November 2022

Background

Little is known about the ambiguous and complex relationship between frailty, resilience and depression in older adults living with HIV (OALHIV). Thus, the current study aimed to further clarify the relationship, as well as to investigate whether resilience plays a mediating role and to quantify the mediating effect.

Methods

A cross-sectional study was conducted on patients who were aged ≥50 y with HIV/AIDS at the First Hospital of Changsha City from June to August 2019. The sociodemographic characteristics of participants, depression, resilience and frailty were evaluated by the self-developed questionnaire, the 10-item Center for Epidemiological Studies Depression Scale, the 10-item Connor-Davidson Resilience Scale and Tilburg Frailty Indicator, respectively. SPSS macro model 4 was used to analyse the mediation of resilience between frailty and depression.

Results

A total of 175 OALHIV (120 males and 55 females) were investigated in this study. The prevalence of frailty and depression was 31.4% and 30.9%, respectively. Additionally, the mediation analysis model showed that frailty could contribute to depression directly, and that it also affected depression through resilience, suggesting that resilience partially mediated the relationship between frailty and depression among OALHIV.

Conclusions

Our findings suggest that resilience appears to be a protective factor for depression. Effective and targeted intervention on resilience is available and is crucial to improve the life quality of OALHIV.
Content Validity and Interrater Reliability of a Newborn Fall Risk Assessment Tool
Authors: Savage Krystal , Antista Hannah , Diamond Taylor , Knepp Alyssa , Oja Kenneth
Published: November 2022

Background:

Newborn falls are a safety concern in the acute care setting. To our knowledge, a valid and reliable tool for assessing newborn fall risk has not been developed.

Purpose:

To evaluate the content validity and interrater reliability of a tool for nurses to assess the fall risk of newborns in the acute care setting.

Methods:

Content validity was established using a modified Delphi technique with neonatal intensive care unit (NICU) nurses (n = 27). Item-level content validity indices and an average scale content validity index were calculated. For interrater reliability, pairs (n = 130) of NICU nurses simultaneously assessed multiple newborns using the tool, and an intraclass correlation coefficient was calculated.

Results:

The initial tool had 28 items classified in 2 sections (newborn and caregiver variables). Fourteen items met predefined cut-off values for content validity. This resulted in the tool (KAnt Fall) having 7 items for assessing newborns and 7 items for caregivers. The intraclass correlation coefficient was 0.99 indicating excellent interrater reliability.

Implications for Practice:

The tool will help assist nurses in systematically identifying newborns at high risk for falls. This assessment will allow nurses to identify and implement timely preventive actions for hospitalized newborns at high risk for falls.

Implications for Research:

Since this was a single-center study in 1 NICU, future research is needed in other hospitals and types of newborn settings (eg, labor and delivery and postpartum units). Further testing of KAnt Fall is also needed to establish additional psychometric properties.
Sensitivity analysis for live birth bias in the Ulaanbaatar Gestation and Air Pollution Research study
Authors: McCandless Lawrence C. , Gombojav Enkhjargal , Allen Ryan W.
Published: November 2022

Background:

The Ulaanbaatar Gestation and Air Pollution Research (UGAAR) study is a randomized controlled trial of the effects of portable high efficiency particulate air (HEPA) filter air cleaner use during pregnancy on fetal growth and child health outcomes. A challenge with the study is that the outcome variables cannot be measured in the absence of a live birth. Thus pregnancy loss is a competing event for the outcome variables that can obscure the intervention-outcome relationship. This phenomenon is called “live birth bias” in the epidemiological literature, and it is an example of selection bias due to adjustment for variables affected by previous exposure.

Methods:

In this investigation, we reanalyzed data from the UGAAR study and examined the impacts of the intervention on three health outcomes: preterm birth (PTB), birth weight, and full-scale IQ (FSIQ) measured with the Wechsler Preschool and Primary Scale of Intelligence III when children were four years old, while accounting for live birth bias. Specifically, we used a novel multiple imputation approach to simulate scenarios in which pregnancy losses had instead been born alive and experienced a range of health outcomes.

Results:

After accounting for live birth bias, the association between the intervention and PTB diminished. Additionally, the magnitude of intervention effect on birth weight and FSIQ increased. FSIQ was less sensitive to live birth bias than birth weight.

Conclusion:

We introduced a novel analysis approach to examine the role of live birth bias, and the findings will be useful in environmental epidemiology studies of birth cohorts.
Fall risk management using clinical decision support in a rural nursing-led primary care practice
Authors: Schentrup Denise , Middlemas Amelie , Shear Kristen , Bjarnadottir Ragnhildur I. , Lucero Robert J.
Published: November 2022

Background:

The leading cause of injuries among older adults in the United States is unintentional falls. The American Geriatrics Society/British Geriatrics Society promote fall risk management in primary care; however, this is challenging in low-resource settings.

Local Problem:

Archer Family Health Care (AFHC), an Advanced Practice Registered Nurse (APRN)–managed and federally designated rural health clinic, identified a care gap with falls adherence to guidelines for patients at higher risk for falls.

Methods:

The aim of this quality improvement effort was to integrate an evidence-based fall risk management tool in a rural nurse-managed primary care practice. A standardized fall risk management process with a new brief paper-based clinical decision support (CDS) tool was developed and tested in two phases.

Intervention:

Phase 1 focused on developing a fall risk management CDS tool, identifying the primary care visit workflow, communicating the workflow patterns to the AFHC staff, and collaborating with the staff to identify when and who should implement the tool. Phase 2 focused on implementation of the fall risk management CDS tool into standard practice among older adults aged 65 years and older.

Results:

We found that integrating the tool did not disrupt the workflow of primary care visits at AFHC. The most common recommended intervention for patients at risk of falling was daily vitamin D supplementation.

Conclusion:

This project revealed that it is feasible to introduce a brief fall risk management decision support tool in an APRN-managed rural primary care practice.
“Quantifying the Effective Lift of Skin Only, SMAS Plication (Lateral SMASectomy), and Extended SMAS Facelift Techniques in a Cadaveric Comparison Study”
Authors: Rao Vinay , Basta Marten N. , Jehle Charles C. , Crozier Joseph W. , Woo Albert S.
Published: November 2022

Purpose:

Rhytidectomies are performed to rejuvenate the aging face. Various techniques exist to achieve soft tissue elevation and skin tightening. This study analyzes three common facelift techniques – Skin Only, superficial musculoaponeurotic system (SMAS) Plication, and Extended SMAS lifts. We characterize effective facial changes with each procedure in a cadaver model.

Methods:

We performed facelift procedures on 18 cadaver hemi-faces. Each face was measured along horizontal and vertical vectors. The primary outcome was change along these vectors. Skin Only, SMAS Plication, and Extended SMAS lifts were performed sequentially on each hemi-face. SMAS Plication was used to approximate a Lateral SMASectomy procedure. Parameter measurements were compared.

Results:

All three procedures exhibited a significant tightening along horizontal vectors. SMAS procedures provided a significant lift along all vertical vectors while the Skin Only lift failed to demonstrate significant vertical elevation. SMAS procedures achieved significantly greater composite horizontal and vertical lifts compared to the Skin Only operation. There was only an incremental increase in lift between the SMAS Plication and Extended SMAS procedures in the upper and midface regions. The Extended SMAS led to the greatest lift in the lower face.

Conclusion:

SMAS procedures provided a greater lift along both horizontal and vertical vectors than the Skin lift alone. The increased dissection in the Extended SMAS technique resulted in only a modest increase in lift compared to SMAS Plication. The Extended SMAS approach appears to offer the most benefit at the lower face and may be the best choice for targeting this region.
DNA Methylation Study in Presbycusis Patients
Authors: Roche Marie Valerie , Yan Denise , Godrich Dana , Hamad Naser , Tang Pei-Ciao , Young Juan , Blanton Susan , Gong Feng , Liu Xue Zhong
Published: November 2022

Background

Presbycusis, also known as age-related hearing loss (ARHL), is the most frequent sensory disability affecting elderly adults worldwide.ARHL is typified by a bilateral, progressive, sensorineural hearing loss that is pronounced in high frequency. Conventional factors associated with ARHL include diabetes, hypertension, and family history of hereditary hearing loss. The severity of hearing impairment varies between individuals. The accurate causative molecular pathogenesis for ARHL is unknown, therefore the investigation of the underlying pathogenic mechanisms involved in ARHL is imperative for the development of effective therapeutic approaches. Epigenetics is the study of phenotypic changes caused by modification of genetic expression rather than alteration of DNA sequence. It is hypothesized that ARHL could result from unclarified epigenetic susceptibility, nevertheless, there is a shortage of information on the exact contribution of epigenetic modifications to ARHL. Here we present an investigation on the involvement of DNA methylation with Age-related hearing loss.

Results

In the present study the Illumina Infinium® Methylation EPIC Beadchip has been used to identify regions with aberrant levels of methylation across genomes from ARHL patients. Hearing measurements were used to determine the audioprofiles. Clinical, audiometric patterns, DNA testing, and methylation pattern screening were undertaken. Our results demonstrate a strong correlation between patients’ hearing measurements and CpG sites methylation inESPNandTNFRSF25. A Methylation Polymerase chain reaction (PCR) assay was used to confirm methylation levels at specific gene locus in ARHL patients.

Conclusion

Aberrant DNA methylation and its impact on gene expression have been implicated in many biological processes. By interrogating methylation status across the genome at single-nucleotide resolution of hearing loss patients, our study can help establish the association between audiometric patterns and methylation status in age-related hearing loss patients.
Clinical study type classification, validation, and PubMed filter comparison with natural language processing and active learning
Authors: van IJzendoorn David G P , Habets Philippe C , Vinkers Christiaan H , Otte Willem M
Published: November 2022

Each day, many thousands of new studies are published. Identifying specific study types with high sensitivity and specificity may improve searchability and accelerate updating systematic reviews and meta-analyses. Machine learning transformer models could facilitate this identification process if sufficient training data is available.

We used an active learning strategy to construct a large training set (n=50,000) and fine-tuned the PubMedBERT language model to classify PubMed abstracts as randomized controlled trials, human studies, systematic reviews with and without meta-analyses, protocols, and rodent studies. In an external dataset (n=5,000), the average sensitivity and specificity across study types were 0.94 and 0.96, respectively. PubMed’s internal filters had a low sensitivity for both systematic reviews with meta-analysis (0.175, CI: 0.057–0.293) and randomized controlled trials (0.256, CI: 0.119–0.393). We applied this labeling to all 34 million PubMed abstracts currently available and provide the results within an online meta-information platform (EvidenceHunt).

In conclusion, we show that study type classification in PubMed is opportune, given the available language models. The high accuracy in this study invites extending these models to more elaborate and hierarchical identification schemes.
Population-based sero-epidemiological estimates of real-world vaccine effectiveness against Omicron infection in an infection-naive population, Hong Kong, January to July 2022
Authors: Lau Jonathan J , Cheng Samuel MS , Leung Kathy , Lee Cheuk Kwong , Hachim Asmaa , Tsang Leo CH , Yam Kenny WH , Chaothai Sara , Kwan Kelvin KH , Chai Zacary YH , Lo Tiffany HK , Mori Masashi , Wu Chao , Valkenburg Sophie , Amarasinghe Gaya K , Lau Eric HY , Hui David S , Leung Gabriel M , Peiris Malik , Wu Joseph T
Published: November 2022

The SARS-CoV-2 Omicron variant has demonstrated enhanced transmissibility and escape of vaccine-derived immunity. While current vaccines remain effective against severe disease and death, robust evidence on vaccine effectiveness (VE) against all Omicron infections (i.e. irrespective of symptoms) remains sparse. We addressed this knowledge-gap using a community-wide serosurvey with 5,310 subjects by estimating how vaccination histories modulated risk of infection in Hong Kong (which was largely infection naïve) during a large wave of Omicron epidemic during January-July 2022. We estimated that Omicron infected 45% (41-48%) of the Hong Kong population. Three and four doses of BNT162b2 or CoronaVac were effective against Omicron infection (VE of 47% (95% credible interval 34-68%) and 70% (43-99%) for three and four doses of BNT162b2 respectively; VE of 31% (1-73%) and 59% (10-99%) for three and four doses of CoronaVac respectively) seven days after vaccination, but protection waned with half-lives of 15 (3-47) weeks for BNT162b2 and 5 (1-37) weeks for CoronaVac. Our findings suggest that booster vaccination can temporarily enhance population immunity ahead of anticipated waves of infections.
Effect of maternal and infant selenium status on child growth in a birth cohort from Dhaka, Bangladesh
Authors: Mehta Rukshan , Krupa Christine , Ahmed Tahmeed , Hamer Davidson H. , Mahmud Abdullah Al
Published: November 2022

Deficiency of selenium, an essential trace element, has been implicated in adverse birth outcomes and the growth of infants and young children.

We used data from a randomized controlled trial to examine associations between selenium biomarkers in whole blood (WBSe), serum and selenoprotein P (SEPP1) in maternal delivery and venous cord (VC) blood, and birth weight, and adverse birth outcomes. Furthermore, we examined associations between selenium biomarkers and infant growth outcomes (age adjusted length, weight, head circumference and weight-for-length z-scores) at birth, one, and two years of age using linear regression.

WB and serum selenium in delivery and VC specimens were negatively associated with birth weight (adjusted β, 95% CI: WBSe delivery: -26.6 (−44.3, -8.9); WBSe VC: -19.6 (−33.0, -6.1)); however, delivery SEPP1 levels (adjusted β: -37.5 (−73.0, -2.0)) and VC blood (adjusted β: 82.3 (30.0, 134.7)) showed inconsistent associations across biomarkers. We found small to moderate associations between infant growth and WBSe VC (LAZ β, 95% CI, at birth: -0.05 (−0.1, -0.01)); 12-months (β: -0.05 (−0.08, -0.007)). WAZ also showed weak negative associations with delivery WBSe (at birth: -0.07 (−0.1, -0.02); 12-months: -0.05 (−0.1, -0.005)) and in WBSe VC (β at birth: -0.05 (−0.08, -0.02); 12-months: -0.05 (−0.09, -0.004)).

Mechanisms connected to redox biology and its antioxidant effects have been causally associated with selenium’s protective properties. Given the fine balance between nutritional and toxic properties of selenium, it is possible that WB and serum selenium may negatively impact growth outcomes, both in utero and postpartum.
Non-Contact Molecular Chemical Imaging Assessment of Tissue Congestion: A Validation Study Compared to MRI
Authors: Saltman Adam E , Ghosh Richik N , Eckman Peter M. , Chappuis Michael , Collins Jeremy D , Morley Pamela , Mazis Holly , Schweitzer Robert , Enriquez-Sarano Maurice , Tazik Shawna K , Gomer Heather , Nelson Matthew , Treado Patrick J
Published: November 2022

Background

Heart failure (HF) is a healthcare problem burdening patients, care teams, and health care systems. A relentless, downward spiral of decompensation, hospital admission, and functional deterioration is challenging to break, partly because of the lack of an objective, inexpensive tool to aid the clinician’s physical examination. We studied performance of a shortwave infrared (SWIR) molecular chemical imaging (MCI) tool to measure relative tissue congestion (TC) in HF patients’ shins, compared to MRI Dixon sequence TC measurements as ground truth.

Methods

Forty-seven (47) subjects underwent paired SWIR MCI and MRI measurements of their lower extremities. Thirty-six (36) subjects were hospitalized with decompensated HF while 11 healthy outpatients served as controls. A partial least squares (PLS) regression model was trained to ingest the SWIR MCI spectra and produce a CardioVerification Index (CVI) that mirrored MRI measurements.

Results

The SWIR MCI model reflected MRI TC measurements accurately for all subjects with a 0.743 linear correlation coefficient. Surprisingly, the MRI results identified a significant fraction of non-HF subjects with elevated TC levels, so a sub-analysis was performed on “Low TC” subjects with low and undetectable levels of extremity edema. This subpopulation’s linear correlation between MRI and CVI was 0.674. A logistic classifier model differentiated HF from non-HF subjects; the area under the receiver operating characteristic curves was 0.906 for the entire subject group and 0.821 for the Low TC subpopulation.

Conclusion

SWIR MCI techniques can be used in a TC-measuring tool that replicates MRI TC measurements. Clinicians could use such tools to help guide therapy for HF patients during in-hospital management of acute HF decompensation and for outpatient monitoring. SWIR MCI’s ability to identify elevated TC in otherwise normal subjects may also meet the unmet need for a novel, widely applicable HF screening tool.
Effect of intranasal administration of neuroEPO in the histological structure of the olfactory mucosa of rats Wistar
Authors: Borrás Ketty Suárez , Peña Gisselle Fernández , Seguí Giselle Puldón , Hernández Carlos Luis Pérez , Cruz Yamila Rodríguez
Published: November 2022

Introduction

Strokes and neurodegenerative diseases are major global health problems. Not only because they cause high mortality and disability, but to the lack of effective therapies. NeuroEPO, a variant of recombinant human erythropoietin (rHu-EPO) with a low sialic acid content, has shown encouraging results as a potential neuroprotective agent when administered intranasally.

Objective

To determine the effect of intranasal administration of NeuroEPO on the histological structure of the olfactory mucosa of Wistar rats.

Materials and Methods

An experimental, prospective, and longitudinal study was conducted in Wistar rats. Ten healthy animals were randomly distributed into two groups of five each. The control group received a vehicle (0.3 μl/g/day) and the treated group received NeuroEPO (300 μg/kg/day). Both treatments were administered intranasally for 28 days. The histological characteristics of the olfactory mucosa were evaluated. The medians of the study groups were compared using the Mann-Whitney U test.

Results

There were no alterations in the histological characteristics of the olfactory epithelium. However, at the level of the lamina propria in the group treated with NeuroEPO, slight hypertrophy, and hyperplasia of the Bowman’s glands was observed.

Conclusions

The administration of the nasal formulation of NeuroEPO did not induce histological alterations of the olfactory mucosa of Wistar rats under the experimental conditions of this research.
Quartet metabolite reference materials for assessing inter-laboratory reliability and data integration of metabolomic profiling
Authors: Zhang Naixin , Zhang Peipei , Chen Qiaochu , Zhou Kejun , Liu Yaqing , Wang Haiyan , Xie Yongming , Ren Luyao , Hou Wanwan , Yang Jingcheng , Yu Ying , Zheng Yuanting , Shi Leming
Published: November 2022

Various laboratory-developed metabolomic methods lead to big challenges in inter-laboratory comparability and effective integration of diverse datasets. As part of the Quartet Project, we established a publicly available suite of four metabolite reference materials derived from B-lymphoblastoid cell lines from a family quartet of parents and monozygotic twin daughters. We generated comprehensive LC-MS based metabolomic data from the Quartet reference materials using targeted and untargeted strategies in different laboratories. High variabilities in the qualitative and quantitative metabolomic measurements were observed across laboratories. Moreover, the Quartet multi-sample-based quality metrics were developed for objectively assessing the reliability of metabolomic profiling in detecting intrinsic biological differences among difference groups of samples. Importantly, the ratio-based metabolomic profiling, by scaling the absolute values of a study sample relative to those of a universal reference sample, enables data integration in long-term measurements across difference laboratories or platforms. Thus, we constructed the ratio-based high-confidence reference datasets between two reference samples, providing “ground truth” for inter-laboratory proficiency test, which enables objective assessment of various metabolomic methods. Our study provided the community with rich resources and best practice for objective assessment of inter-laboratory measurements and data integration, ensuring reliable large-scale and longitudinal metabolomic profiling.
S-BEAM: A Semi-Supervised Ensemble Approach to Rank Potential Causal Variants and Their Target Genes in Microglia for Alzheimer’s Disease
Authors: Khaire Archita , Wen Jia , Yang Xiaoyu , Zhou Haibo , Shen Yin , Li Yun
Published: November 2022

Alzheimer’s disease (AD) is the leading cause of death among individuals over 65. Despite many AD genetic variants detected by large genome-wide association studies (GWAS), a limited number of causal genes have been confirmed. Conventional machine learning techniques integrate functional annotation data and GWAS signals to assign variants functional relevance probabilities. Yet, a large proportion of genetic variation lies in the non-coding genome, where unsupervised and semi-supervised techniques have demonstrated greater advantage. Furthermore, cell-type specific approaches are needed to better understand disease etiology. Studying AD from a microglia-specific lens is more likely to reveal causal variants involved in immune pathways. Therefore, in this study, we developed S-BEAM: a semi-supervised ensemble approach using microglia-specific data to prioritize non-coding variants and their target genes that play roles in immune-related AD mechanisms. We designed a transductive positive-unlabeled and negative-unlabeled learning model that employs a bagging technique to learn from unlabeled variants, generating multiple predicted probabilities of variant risk. Using a combined homogeneous-heterogeneous ensemble framework, we aggregated the predictions. We applied our model to AD variant data, identifying 11 risk variants acting in well-known AD genes, such asTSPAN14,INPP5D, andMS4A2. These results validated our model’s performance and demonstrated a need to study these genes in the context of microglial pathways. We also proposed further experimental study for 37 potential causal variants associated with less-known genes. Our work has utility in predicting AD relevant genes and variants functioning in microglia and can be generalized for application to other complex diseases or cell types.
Integrating Network Pharmacology And Experimental Verification To Explore The Mechanism Of Qionggui Power Against Atherosclerosis
Authors: Wang Yuqing , Man Yonghong , Jiang Xu , Shui Dong , Zhao Qing , Li Shujiao , Zhuang Guo
Published: November 2022

Qionggui Power (QP), a classic prescription in Traditional Chinese Medicine (TCM), has shown potential in the treatment of atherosclerosis during the past decades. However, the mechanism that mediates these cardiovascular benefits remains to be fully elucidated. Here, we investigated the effects and mechanisms of QP against atherosclerosis with network pharmacology approaches andin vitromodel. The active ingredients and related targets of QP were collected from public databases. The hub targets and signaling pathways of QP against AS were defined by extensive application of bioinformatics approaches, including the protein-protein interaction (PPI) network, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG). The predicted major targets were validated in LPS-stimulated murine macrophages RAW264.7. The anti-inflammatory properties of QP were also evaluated in this model.In silicoinvestigation of QP resulted in the identification of 18 active ingredients and 49 chemical targets intersecting with AS-related genes. And KEGG pathway analysis revealed a high enrichment in the Lipid and Atherosclerosis pathway of these chemical targets. Biochemical analysis showed marked effects of QP on the expression of predicted chemical targets (PPARr, CAT, PTGS2) and LPS-induced inflammatory genes (IL1, IL6, and TNFα). And these inhibitory effects were linked to the suppression of the NF-κB signaling pathway, which was activated by the LPS stimulus. Our findings revealed the therapeutic potential of QP in the prevention and treatment of atherosclerosis.

Graphical Abstract
Age-related changes in brain metabolites underlie slowing of speed-accuracy trade-off
Authors: Revie Lauren , Metzler-Baddeley Claudia
Published: November 2022

Aging leads to response slowing but the underpinning cognitive and neural mechanisms remain elusive. We studied cognitive components of response speed with a diffusion drift model to estimate nondecision, boundary-separation, and drift-rate contributions to choice reaction times of older (62-80 years) and younger (18-29 years) adults (n=25 each). We characterised age-related differences in the metabolic and microstructural profile of cortical regions and white matter (WM) pathways of visuo-perceptual and attention networks with magnetic resonance spectroscopy and multi-shell diffusion-weighted imaging. Aging was associated with increased non-decision time and boundary-separation, reduced N-acetyl aspartate (NAA) concentrations in anterior cingulate (ACC) and posterior parietal cortices, and reduced WM microstructure in the optic radiation (OR), inferior and superior longitudinal fasciculus (ILF, SLF) and fornix. NAA in ACC and diffusivities in OR and SLF predicted non-decision time, while restricted diffusivity signal fraction in the ILF and fornix, and diffusivity in OR predicted boundary-separation. These results suggest that age-related deterioration of neuronal health and WM microstructure in visuo-perceptual and attention networks contribute to response slowing in aging.
An information theoretic approach to detecting spatially varying genes
Authors: Jones Daniel C. , Danaher Patrick , Kim Youngmi , Beechem Joseph M. , Gottardo Raphael , Newell Evan W.
Published: November 2022

Identifying genes with spatially coherent expression patterns is a key task in spatial transcriptomics. We adopt an information theoretic perspective on this problem by equating the degree of spatial coherence with the mutual information between nearby expression measurements. To avoid the notoriously difficult problem of computing mutual information, we use modern methods of approximation, in a method we call maximization of spatial information (Maxspin). As well as being highly scalable, we demonstrate improved accuracy across several spatial transcriptomics platforms and a variety of simulations when compared to both existing specialized methods and traditional spatial statistics methods. We use the method to analyze a renal cell carcinoma sample profiled using CosMx Spatial Molecular Imaging, revealing previously undescribed gene expression patterns.
Now you see it: fixation-related electrical potentials during a free visual search task reveal the timing of visual awareness
Authors: Qiu Zeguo , Xia Hongfeng , Becker Stefanie I. , Hamblin-Frohman Zachary , Pegna Alan J.
Published: November 2022

It has been repeatedly claimed that emotional faces capture attention readily, and that they are processed without awareness. Yet some observations cast doubt on these assertions. Part of the problem may lie in the experimental paradigms employed. Here, we used a free viewing visual search task and simultaneously recorded electroencephalography and eye-movements. Fixation-related potentials were computed for fearful and neutral facial expressions, and the electrical response compared when participants were aware or unaware of the fixated stimulus. We showed that the P300 increased across repeated fixations on the unseen targets, culminating in a conscious report, likely reflecting evidence accumulation. Awareness of the stimulus was associated with electrical changes emerging at around 130 ms, with emotions of the stimulus being dissociated only after awareness had arisen. These results suggest that the earliest electrical correlate of awareness emerges at around 130 ms in visual search and that emotion processing requires visual awareness.
Statistical analysis and simulation allowing simultaneously positive, negative, and no crossover interference in multilocus recombination data
Authors: Sapielkin Shaul , Frenkel Zeev , Privman Eyal , Korol Abraham B.
Published: November 2022

Crossover interference (COI) is a widespread feature of homologous meiotic recombination. It can be quantified by the classical coefficient of coincidence (CoC) `but this characteristic is highly variable and specific to the pair of chromosomal intervals considered. Several models were proposed to characterize COI on a chromosome-wise level. In the gamma model, the strength of interference is characterized by a shape parameterν, while the gamma-sprinkled two-pathway model (GS) accounts for both interference-dependent and independent crossover (CO) events by fitting a mixture of gamma distributions withv>1 andv=1, correspondingly, and mixture proportions 1-pandp. In reality, COI can vary along chromosomes resulting in low compliance of the fitted model to real data. Additional inconsistency can be caused by common neglecting of possible negative COI in the model, earlier reported for several organisms. In this work, we propose an extension of the GS-model to take possible negative COI into account. We propose a way for data simulation and parameter estimation for such situations.
The inhibitory control of traveling waves in cortical networks
Authors: Palkar Grishma , Wu Jian-young , Ermentrout Bard
Published: November 2022

Propagating waves of activity can be evoked and can occur spontaneouslyin vivoandin vitro. We examine the properties of these waves as inhibition varies in a cortical slice and then develop several computational models. We first show that in the slice, inhibition controls the velocity of propagation as well as the magnitude of the local field potential. We introduce a spiking model of sparsely connected excitatory and inhibitory theta neurons which are distributed on a one-dimensional domain and illustrate both evoked and spontaneous waves. The excitatory neurons have an additional spike-frequency adaptation current which limits their maximal activity. We show that increased inhibition slows the waves down and limits the participation of excitatory cells in this spiking network. Decreased inhibition leads to large amplitude faster moving waves similar to those seen in seizures. To gain further insight into the mechanism that control the waves, we then systematically reduce the model to a Wilson-Cowan type network using a mean-field approach. We simulate this network directly and by using numerical continuation to follow traveling waves in a moving coordinate system as we vary the strength and spread of inhibition and the strength of adaptation. We find several types of instability (bifurcations) that lead to the loss of waves and subsequent pattern formation. We approximate the smooth nonlinearity by a step function and obtain expressions for the velocity, wave-width, and stability.

Author summary

Stimuli and other aspects of neuronal activity are carried across areas in the brain through the concerted activity of recurrently connected neurons. The activity is controlled through negative feedback from both inhibitory neurons and intrinsic currents in the excitatory neurons. Evoked activity often appears in the form of a traveling pulse of activity. In this paper we study the speed, magnitude, and other properteis of these waves as various aspects of the negative feedback are altered. Inhibition enables information to be readily transmitted across distances without the neural activity blowing up into a seizure-like state.
Altering stimulus timing via fast rhythmic sensory stimulation induces STDP-like recall performance in human episodic memory
Authors: Wang Danying , Shapiro Kimron L. , Hanslmayr Simon
Published: November 2022

Animal studies suggest that the strength of synaptic modification depends on spike timing between pre- and post-synaptic neurons on the order of tens of milliseconds, which is termed ‘spike-timing-dependent plasticity’ (STDP). However, evidence for STDP in human episodic memory is lacking. We investigated this using rhythmic sensory stimulation to drive visual and auditory cortices at 37.5 Hz with four phase offsets. Visual relative to auditory cued recall accuracy was significantly enhanced in the 90° condition since the visual stimulus led at the shortest delay (6.67 ms). This pattern was reversed in the 270° condition when the auditory stimulus led the shortest delay. Within cue modality, recall was enhanced when a stimulus of the corresponding modality led the shortest delay as compared to the longest delay (20 ms). Our findings provide novel evidence for STDP in human memory, which builds an important bridge from in-vitro studies in animals to human behaviour.
Eos promotes TH2 differentiation by propagating the IL-2/STAT5 signaling pathway
Authors: Tuazon Jasmine A. , Read Kaitlin A. , Sreekumar Bharath K. , Yaeger Michael J. , Varikuti Sanjay , Jones Devin M. , Warren Robert T. , Powell Michael D. , Rasheed Mustafa N. , Duncan Elizabeth G. , Childs Lauren M. , Gowdy Kymberly M. , Oestreich Kenneth J.
Published: November 2022

The Ikaros zinc finger transcription factor Eos has been commonly implicated in regulatory T cells to promote their immunosuppressive functions. Paradoxically, a new role is emerging for Eos in promoting pro-inflammatory responses of conventional CD4+T cells in the dysregulated setting of autoimmunity. Even so, the precise role of Eos in regulating the differentiation and function of healthy effector CD4+T cell subsets remains unclear. Here, we find that Eos is a positive regulator of CD4+T helper 2 (TH2) cells—effector T cells implicated in the induction of allergic asthma. Using murine in vitro TH2 cells and an in vivo house dust mite asthma model, we found that Eos-deficient T cells had reduced expression of key TH2 transcription factors, effector cytokines, and differentiation receptors. Mechanistically, among various TH2-polarizing pathways, the IL-2/STAT5 axis and its downstream TH2 gene targets emerged as one of the most significantly downregulated networks in Eos deficiency. Using in vitro TH2 cells and overexpression of Eos zinc-finger-domain mutants, we discovered that Eos forms a novel complex with and supports the tyrosine-phosphorylated signaling activity of STAT5. Overall, these data define a novel regulatory mechanism whereby Eos promotes IL-2/STAT5 activity to facilitate TH2 differentiation.
Variability by region and method in human brain sodium concentrations estimated by23Na magnetic resonance imaging: a meta-analysis
Authors: Ridley Ben , Morsillo Filomena , Zaaraoui Wafaa , Nonino Francesco
Published: November 2022

Sodium imaging (23Na-MRI) is of interest in neurological conditions given potential sensitivity to the physiological and metabolic status of tissues. Benchmarks have so far been restricted to parenchyma or grey/white matter (GM/WM). We investigate (1) the availability of evidence, (2) regional pooled estimates and (3) variability attributable to regional/methodology.

MEDLINE literature search for Tissue sodium concentration (TSC) measured in specified ‘healthy’ brain regions returned 127 reports plus 278 retrieved from bibliographies. 28 studies met inclusion criteria, including 400 individuals. Reporting variability led to nested data structure, so we used multilevel meta-analysis and a random effects model to pool effect sizes.

The pooled mean from 141 TSC estimates was 40.51 mM (95% CI: 37.59 - 43.44; p< 0.001, I2Total=99.4%). Tissue as a moderator was significant (F214=65.34, p-val < .01). Six sub-regional pooled means with requisite statistical power were derived. We were unable to consider most methodological and demographic factors sought because of non-reporting, but each factor included beyond tissue improved model fit. Significant residual heterogeneity remained.

The current estimates provide an empirical point of departure for better understanding in23Na-MRI. Improving on current estimates supports: (1) larger, more representative data collection/sharing, including (2) regional data, and (3) agreement on full reporting standards.
Artificial Gravity During a Spaceflight Analog Alters Brain Sensory Connectivity
Authors: McGregor Heather R. , Lee Jessica K. , Mulder Edwin R. , De Dios Yiri E. , Beltran Nichole E. , Wood Scott J , Bloomberg Jacob J. , Mulavara Ajitkumar P. , Seidler Rachael D.
Published: November 2022

Spaceflight has numerous untoward effects on human physiology. Various countermeasures are under investigation including artificial gravity (AG). Here, we investigated whether AG alters resting-state brain functional connectivity changes during head-down tilt bed rest (HDBR), a spaceflight analog. Participants underwent 60 days of HDBR. Two groups received daily AG administered either continuously (cAG) or intermittently (iAG). A control group received no AG. We assessed resting-state functional connectivity before, during, and after HDBR. We also measured balance and mobility changes from pre-to post-HDBR. We examined how functional connectivity changes throughout HDBR and whether AG is associated with differential effects. We found differential connectivity changes by group between posterior parietal cortex and multiple somatosensory regions. The control group exhibited increased functional connectivity between these regions throughout HDBR whereas the cAG group showed decreased functional connectivity. This finding suggests that AG alters somatosensory reweighting during HDBR. We also observed brain-behavioral correlations that differed significantly by group. Control group participants who showed increased connectivity between the putamen and somatosensory cortex exhibited greater mobility declines post-HDBR. For the cAG group, increased connectivity between these regions was associated with little to no mobility declines post-HDBR. This suggests that when somatosensory stimulation is provided via AG, functional connectivity increases between the putamen and somatosensory cortex are compensatory in nature, resulting in reduced mobility declines. Given these findings, AG may be an effective countermeasure for the reduced somatosensory stimulation that occurs in both microgravity and HDBR.
Ras-dependent RAF-MAPK hyperactivation by pathogenic RIT1 is a therapeutic target in Noonan syndrome-associated cardiac hypertrophy
Authors: Cuevas-Navarro Antonio , Wagner Morgan , Van Richard , Swain Monalisa , Allison Madeline R. , Cheng Alice , Messing Simon , Simanshu Dhirendra K. , Sale Matthew J. , McCormick Frank , Stephen Andrew G. , Castel Pau
Published: November 2022

RIT1 belongs to the family of Ras guanosine triphosphatases (GTPases) that regulate many aspects of signal transduction and are drivers of cancer and congenital disorders.RIT1gain-of-function mutations are found in lung cancer, leukemia, and in the germline of Noonan syndrome individuals with an increased prevalence of cardiac hypertrophy and other congenital heart defects. Pathogenic RIT1 proteins evade proteasomal degradation and promote MEK/ERK mitogen-activated protein kinase (MAPK) hyperactivation, yet the mechanism remains poorly understood. Here we show that RAF kinases are putative mutant RIT1 effectors necessary for MAPK activation and characterize RIT1 association with plasma membrane lipids and interaction with RAF kinases. We identify critical residues present in the RIT1 hypervariable region that facilitate interaction with negatively charged membrane lipids and show that these are necessary for association with RAF kinases. Although mutant RIT1 binds to RAF kinases directly, it fails to activate RAF-MAPK signaling in the absence of classical Ras proteins. Consistent with aberrant RAF/MEK/ERK activation as a driver of disease, we show that MEK inhibition alleviates cardiac hypertrophy in a mouse model of RIT1-mutant Noonan syndrome. These data shed light on pathogenic RIT1 function and identify avenues for therapeutic intervention.

One Sentence Summary

Electrostatic plasma membrane association facilitates RIT1-mediated Ras-dependent RAF kinase activation to promote pathogenic MAPK signaling.
High growing season temperatures limit winter recovery of grapevines fromXylella fastidiosainfection – implications for epidemiology in hot climates
Authors: Burbank Lindsey , Sisterson Mark S. , Wei Wei , Ortega Brandon , Luna Nathaniel , Naegele Rachel
Published: November 2022

Management of widespread plant pathogens is challenging as climatic differences among crop growing regions may alter key aspects of pathogen spread and disease severity.Xylella fastidiosais a xylem-limited bacterial pathogen that is transmitted by xylem sap feeding insects. Geographic distribution ofX. fastidiosais limited by winter climate and vines infected withX. fastidiosacan recover from infection when held at cold temperatures. California has a long history of research on Pierce’s disease, and significant geographic and climatic diversity among grape-growing regions. This background in combination with experimental disease studies under controlled temperature conditions can inform risk assessment forX. fastidiosaspread and epidemic severity across different regions and under changing climate conditions. California’s grape growing regions have considerable differences in summer and winter climate. In northern and coastal regions, summers are mild and winters cool, conditions favoring winter recovery of infected vines. In contrast, in inland and southern areas summers are hot and winters mild, reducing likelihood of winter recovery. Here, winter recovery of three table grape cultivars (Flame, Scarlet Royal, and Thompson seedless) and three wine grape cultivars (Sauvignon Blanc, Cabernet Sauvignon, and Zinfandel) were evaluated under temperature conditions representative of the San Joaquin Valley, an area with hot summers and mild winters that has been severely impacted by Pierce’s disease, and contains a large portion of California grape production. Mechanically inoculated vines were held in the greenhouse under one of three warming treatments to represent different seasonal inoculation dates prior to being moved into a cold chamber. Winter recovery under all treatments was generally limited, but with some cultivar variation. Given hot summer temperatures of many grape-growing regions worldwide, as well as increasing global temperatures overall, winter recovery of grapevines should not be considered a key factor affectingX. fastidiosaspread and epidemic severity in the majority of cases.