bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss ofEsr1Does Not Affect Hearing and Balance
Authors: Simms Shion S , Milani Marcus N , Kim Mi-Jung , Husain Ryan , Infante Laura , Cooke Paul S , Someya Shinichi
Published: March 2024

Although estrogen affects the structure and function of the nervous system and brain and has a number of effects on cognition, its roles in the auditory and vestibular systems remain unclear. The actions of estrogen are mediated predominately through two classical nuclear estrogen receptors, estrogen receptor 1 (ESR1) and estrogen receptor 2 (ESR2). In the current study, we investigated the roles of ESR1 in normal auditory function and balance performance using 3-month-old wild-type (WT) andEsr1knockout (KO) mice on a CBA/CaJ background, a normal-hearing strain. As expected, body weight ofEsr1KO females was lower than that ofEsr1KO males. Body weight ofEsr1KO females was higher than that of WT females, while there was no difference in body weight between WT andEsr1KO males. Similarly, head diameter was higher inEsr1KO vs. WT females. Contrary to our expectations, there were no differences in auditory brainstem response (ABR) thresholds, ABR waves I-V amplitudes and ABR waves I-V latencies at 8, 16, 32, and 48 kHz, distortion product otoacoustic emission (DPOAE) thresholds and amplitudes at 8, 16, and 32 kHz, and rotarod balance performance (latency to fall) between WT andEsr1KO mice. Furthermore, there were no sex differences in ABRs, DPOAEs, and rotarod balance performance inEsr1KO mice. Taken together, our findings show thatEsr1deficiency does not affect auditory function or balance performance in normal hearing mice, and suggest that loss ofEsr1is likely compensated by ESR2 or other estrogen receptors to maintain the structure and function of the auditory and vestibular systems under normal physiological conditions.

Highlights

Head diameter of femaleEsr1KO mice was higher than that of female WT mice.

ABRs and DPOAEs were not different in WT andEsr1KO mice.

There were no sex differences in ABRs and DPOAEs inEsr1KO mice.

Rotarod balance performance was not different in WT andEsr1KO mice.

There were no sex differences in rotarod balance performance inEsr1KO mice.

Loss ofEsr1does not affect auditory function or balance performance under normal physiological conditions.
Self-Other Voice Discrimination Task: A - Neuropsychological Tool For Clinical Assessment of Self-Related Deficits
Authors: Voruz Philippe , Orepic Pavo , Coll Selim Yahia , Haemmerli Julien , Blanke Olaf , Péron Julie Anne , Schaller Karl , Iannotti Giannina Rita
Published: March 2024

Background

Deficits in self are commonly described through different neuro-pathologies, based on clinical evaluations and experimental paradigms. However, currently available approaches lack appropriate clinical validation, making objective evaluation and discrimination of self-related deficits challenging.

Methods

We applied a statistical standardized method to assess the clinical discriminatory role of a Self-Other Voice Discrimination (SOVD) task. This task, validated experimentally as a marker for self-related deficits, was administered to 17 patients eligible for neurosurgery due to focal hemispheric brain tumors or epileptic lesions.

Results

The clinical discriminatory capacity of the SOVD task was evident in three patients who exhibited impairments for self-voice perception that could not be predicted by other neuropsychological performances. Impairments in other-voice perception were linked to inhibitory neuropsychological alterations, suggesting a potential association with executive deficits in voice recognition.

Conclusions

This exploratory study highlights the clinical discriminatory potential of the SOVD task and suggests that it could complement the standard neuropsychological assessment, paving the way for enhanced diagnoses and tailored treatments for self-related deficits.
Spinal Cord Motor Neuron Phenotypes and Polygenic Risk Scores in Sporadic Amyotrophic Lateral Sclerosis: Deciphering the Disease Pathology and Therapeutic Potential of Ropinirole Hydrochloride
Authors: Kato Chris , Morimoto Satoru , Takahashi Shinichi , Namba Shinichi , Wang Qingbo S. , Okada Yukinori , Okano Hideyuki
Published: March 2024

This study investigated the genetic factors associated with the onset of amyotrophic lateral sclerosis (ALS) and the mechanism of action of Ropinirole hydrochloride (ROPI) in ALS treatment. Firstly, ALS is a neurodegenerative disease characterized by the degeneration of both upper and lower motor neurons (MNs), and identifying the genetic factors of sporadic ALS (SALS) has been challenging. However, ALS-like phenotypes have been observed in induced pluripotent stem cell-derived lower MNs (iPSC-LMNs) of SALS patients, suggesting a polygenic contribution to SALS pathogenesis, and ROPI has emerged as a novel therapeutic candidate for ALS treatment. Moreover, recent genome-wide association studies (GWAS) have suggested an association between high levels of blood total cholesterol (bTC) and ALS. The study aimed to combine iPSC-LMN phenotypes and polygenic risk scores (PRS) to quantify the genetic background of patients and analyze the mechanism of action of ROPI in ALS treatment. Twenty SALS patients were included in the study, and iPSC-LMN phenotypes, PRS for 58 quantitative traits, and ALS were calculated. The results indicated that patients with a higher PRS for bTC showed changes in iPSC-LMN phenotypes, particularly a higher response to ROPI. Additionally, a correlation was observed between bTC levels and the expression of cholesterol biosynthesis (CB) enzymes in MNs, suggesting their involvement in the pathogenesis of SALS. Furthermore, the study compared the liver and spinal cord expression of CB enzymes and found a correlation between bTC levels and CB enzyme expression, particularly in MNs, which may partly explain the MN-specific pathogenesis of SALS. In conclusion, the study suggests that high bTC levels and increased CB activity may contribute to the pathogenesis of SALS, and CB suppression may be a potential therapeutic strategy for ALS, supported by the mechanism of action of ROPI in ALS treatment.
Genetic patterns, sublineages and dynamics of tuberculosis transmission in Cuba, a low burden country
Authors: Martinez-Rodriguez Ileana Margarita , Herrera-Avila Yoslany Mercedes , Goza-Valdes Roxana , Rodriguez-Bertheau Andrea Maria , Diaz-Rodriguez Raul
Published: March 2024

Context

In Cuba, a country with a low incidence of tuberculosis (TB), there is no information on the dynamics of transmission of the disease for two decades.

Aims

Determine the genetic patterns and sublineages ofMycobacterium tuberculosiscomplex (MTBC) isolates circulating in 2009 and their relationship with the epidemiological data of the patients.

Settings and Design

A retrospective descriptive study was carried out in Cuba with 178 MTBC isolates.

Materials and methods

Spoligotyping and mycobacterial interspersed repetitive-unit– variable-number tandem-repeat (MIRU-VNTR) typing with 24 loci were performed. For statistical analysis, non-parametric methods, analysis of variance and homogeneity test, were used.

Results

Spoligotyping produced 39 spoligotypes. The S, Beijing, LAM and Haarlem sublineages prevailed. The clustering rate was 75.84% and the Hunter-Gaston discriminatory index (HGDI): 0.8734. MIRU-VNTR typing with 24-loci defined 154 genetic patterns: six grouped 30 isolates and 148 showed unique patterns. The clustering rate was 14.60% and the HGDI: 0.9926. There was a predominance of sublineages by region: S, Beijing and LAM in the West, Center and East, respectively.

Conclusions

The dynamics of TB transmission in Cuba in 2009 is reported, inferring that this occurs in a limited manner and belonging to risk groups does not favor transmission. It serves to evaluate a megaproject of the Global Fund to reduce the transmission of TB in this country. The population genetic structure of MTBC resembles that of an Ibero-American country, with the exception of the high frequency of the Beijing and S sublineages.
Shared Medical Appointments in Heart Failure For Post-hospitalization Follow-up: A Randomized Controlled Trial
Authors: Taveira Tracey H. , Cohen Lisa B. , Laforest Sherry K. , Oliver Karen , Parent Melanie , Hearns Rene , Ball Sherry L. , Dev Sandesh , Wu Wen-Chih
Published: March 2024

Background

Shared medical appointments (SMAs) in heart failure (HF) are medical visits where several patients with HF meet with multidisciplinary providers at the same time for efficient and comprehensive care. It is unknown whether HF-SMAs can improve overall and cardiac health status for high-risk patients discharged with HF.

Methods

A 3-site, open-label, randomized-controlled-trial was conducted. Participants within 12 weeks of HF hospitalization were randomized to receive either HF-SMA or usual HF clinical care (usual-care) on a 1:1 ratio. The HF-SMA team, which consisted of a nurse, nutritionist, psychologist, nurse practitioner and/or a clinical pharmacist, provided four 2-hour session HF-SMAs that met every other week for 8 weeks. Primary outcomes were the overall health status measured by EQ5D-VAS and cardiac health status by KCCQ, 180 days post-randomization.

Results

Of the 242 patients enrolled (HF-SMA n=117, usual-care n=125, mean age 69.3±9.4 years, 71.5% white, 94.6% male), 84% of participants completed the study (n=8 HF-SMA and n=9 usual-care patients died). After 180 days, both HF-SMA and usual-care participants had similar and significant improvements from baseline in KCCQ, but only HF-SMA participants had significant improvements in EQ5D-VAS (mean change = 7.2 ± 15.8 in HF-SMA versus -0.4 ± 19.0 points in usual-care, p<0.001).

Conclusion

Both HF-SMA and usual care in HF participants achieved significant improvements in cardiac health status, but only a team approach through HF-SMA achieved significant improvements in overall health status. A larger population and a longer follow-up time are needed in future studies to evaluate re-hospitalization and death outcomes.

Clinical Perspective

This randomized controlled trial represents the first multi-site study to rigorously assess the outcomes of a multidisciplinary team intervention in a group medical clinic setting to improve patient-centered self-reported outcomes of high-risk patients with a recent heart failure hospitalization.

Shared medical appointments can improve cardiac specific and overall health status in high-risk patients with heart failure.
STRIPAK controls cell-cell communication by promoting cytoneme biogenesis through the membrane-sculpting function of Slik
Authors: Rambaud Basile , Joseph Mathieu , Tsai Feng-Ching , De Jamblinne Camille , Del Guidice Emmanuelle , Sabelli Renata , Bassereau Patricia , Hipfner David R , Carréno Sébastien
Published: March 2024

Cytonemes are signaling filopodia that facilitate long-range cell-cell communication by forming synapses between cells. Initially discovered in Drosophila for transporting morphogens during embryogenesis, they have since been identified in mammalian cells and recently implicated in carcinogenesis. Yet, despite their importance, the mechanisms controlling cytoneme biogenesis remain elusive. Here, we demonstrate that the Ser/Thr kinase Slik drives remote cell proliferation by promoting cytoneme formation. We discovered that this function depends on the coiled-coil domain of Slik (SlikCCD), which directly sculpts membranes into tubules. Importantly, Slik plays paradoxical roles in cytoneme biogenesis. While its membrane-sculpting activity promotes cytoneme formation, it is counteracted by its kinase activity, which enhances actin association with the plasma membrane via Moesin phosphorylation.In vivo, SlikCCDenhances formation of cytonemes in one epithelial layer of the wing disc to promote cell proliferation in an adjacent layer. Finally, we found that this function relies on the STRIPAK complex, which controls cytoneme formation and governs proliferation at a distance by regulating Slik association with the plasma membrane. Our study unveils the first family of kinases that directly sculpts membranes, a function crucial for cytoneme-mediated control of cell proliferation.
The sodium-proton exchangers sNHE and NHE1 control plasma membrane hyperpolarization in mouse sperm
Authors: Novero Analia G , Rodríguez Paulina Torres , De la Vega Beltrán José L , Schiavi-Ehrenhaus Liz J , Luque Guillermina M , Carruba Micaela , Stival Cintia , Gentile Iñaki , Ritagliati Carla , Santi Celia M , Nishigaki Takuya , Krapf Diego , Buffone Mariano G , Darszon Alberto , Treviño Claudia L , Krapf Dario
Published: March 2024

Sperm capacitation, crucial for fertilization, occurs in the female reproductive tract and can be replicatedin vitrousing a medium rich in bicarbonate, calcium, and albumin. These components trigger the cAMP-PKA signaling cascade, proposed to promote hyperpolarization of the mouse sperm plasma membrane through activation of SLO3 K+channel. Hyperpolarization is a hallmark of capacitation: proper membrane hyperpolarization renders higherin vitrofertilizing ability, whileSlo3KO mice are infertile. However, the precise regulation of SLO3 opening remains elusive. Our study challenges the involvement of PKA in this event and reveals the role of Na+/H+exchangers. During capacitation, calcium increase through CatSper channels activates NHE1, while cAMP directly stimulates the sperm-specific NHE, collectively promoting the alkalinization threshold needed for SLO3 opening. Hyperpolarization then feeds back Na+/H+activity. Our work is supported by pharmacology, and a plethora of KO mouse models, and proposes a novel pathway leading to hyperpolarization.

Teaser

Alkalinization of sperm cytoplasm activates potassium channels to hyperpolarize the plasma membrane in a PKA independent cascade.
External task switches activate default mode regions without enhanced processing of the surrounding scene
Authors: Zhou Ashley X , Duncan John , Mitchell Daniel J
Published: March 2024

Default mode network (DMN) activity, measured with fMRI, typically increases during internally directed thought, and decreases during tasks that demand externally focused attention. However, Crittenden et al. (2015) and Smith et al. (2018) reported increased DMN activity during demanding external task switches between different cognitive domains, compared to within-domain switches and task repeats. This finding is hard to reconcile with many dominant views of DMN function. Here, we aimed to replicate this DMN task-switch effect in a similar paradigm and test whether it reflects increased representation of broader context, specifically of a scene presented behind the focal task. In Core DMN, we found significant activity for all task switches, compared to task repeats, and stronger activity for switches between rest and task. Although the content of the background scene was attended, recalled, and neurally decodable, there was no evidence that this differed by switch type. Therefore, external task switches activated DMN without enhanced processing of the surrounding scene. Surprisingly, DMN activity at within-domain switches was no less than at between-domain switches. We suggest that modulation of DMN activity by task switches reflects a shift in the current cognitive model and depends on the overall complexity of that model.
Venomics and Peptidomics of Palearctic vipers: Clade-wide analysis of seven taxa of the generaVipera,Montivipera,MacroviperaandDaboiaacross Türkiye
Authors: Damm Maik , Karış Mert , Petras Daniel , Nalbantsoy Ayse , Göçmen Bayram , Süssmuth Roderich D.
Published: March 2024

Snake venom variations are a crucial factor to understand the consequences of snakebite envenoming worldwide and therefore it’s important to know about toxin composition alterations between taxa. Palearctic vipers of the generaVipera,Montivipera,MacroviperaandDaboiahave high medical impacts across the Old World. One hotspot for their occurrence and diversity is Türkiye on the border between the continents, but many of their venoms remain still understudied. Here, we present the venom compositions of seven Turkish viper taxa. By complementary mass spectrometry-based bottom-up and top-down workflows, the venom profiles were investigated on proteomics and peptidomics level. This study includes the first venom descriptions ofVipera berus barani,Vipera darevskii,Montivipera bulgardaghica albizonaandMontivipera xanthina, as well as first snake venomics profiles of TurkishMacrovipera lebetinus obtusaandDaboia palaestinae, including an in-depth reanalysis ofMontivipera bulgardaghica bulgardaghicavenom. Additionally, we identified the modular consensus sequence pEXW(PZ1–2P(EI)/(KV)PPLE for bradykinin-potentiating peptides (BPP) in viper venoms. For better insights into variations and potential impacts of medical significance the venoms were compared against other Palearctic viper proteomes, including the first genus-wideMontiviperavenom comparison. This will help the risk assessment of snakebite envenoming by these vipers and aid in predicting the venoms pathophysiology and clinical treatments.
GENOTYPIC SPECTRUM OF ALBINISM IN MALI
Authors: Diallo Modibo , Sylla Ousmane , Sidibé Mohamed Kole , Plaisant Claudio , Mercier Elina , Sequeira Angèle , Javerzat Sophie , Hadid Aziz , Lasseaux Eulalie , Michaud Vincent , Arveiler Benoit
Published: March 2024

Albinism is a phenotypically and genetically heterogeneous condition characterized by a variable degree of hypopigmentation and by ocular features leading to reduced visual acuity. Whereas numerous genotypic studies have been conducted throughout the world, very little is known about the genotypic spectrum of albinism in Africa and especially in Sub-Saharan Western Africa. Here we report the analysis of all 20 known albinism genes in a series a 23 patients originating from Mali. Four were diagnosed with OCA 1 (oculocutaneous albinism type 1), 17 with OCA 2, and 2 with OCA 4.OCA2variant NM_000275.3:c.819_822delinsGGTC was most frequently encountered. Four novel variants were identified (2 inTYR, 2 inOCA2). A deep intronic variant was found to alter splicing of theOCA2RNA by inclusion of a pseudo exon. Of note, theOCA2exon 7 deletion commonly found in eastern, central and southern Africa was absent from this series. African patients with OCA 1 and OCA 4 had only been reported twice and once respectively in previous publications. This study constitutes the first report of the genotypic spectrum of albinism in a western Sub-Saharan country.
Effect of blood collection tube containing protease inhibitors on the pre-analytical stability of Alzheimer’s disease plasma biomarkers
Authors: Chen Yijun , Zeng Xuemei , Lee Jihui , Sehrawat Anuradha , Lafferty Tara K. , Boslett James J. , Klunk William E. , Pascoal Tharick A. , Villemagne Victor L. , Cohen Annie D. , Lopez Oscar , Yates Nathan A. , Karikari Thomas K.
Published: March 2024

INTRODUCTION

The reliability of plasma Alzheimer’s disease (AD) biomarkers can be compromised by protease-induced degradation. This limits the feasibility of conducting plasma biomarker studies in environments that lack the capacity for immediate processing and appropriate storage of blood samples. We hypothesized that blood collection tube supplementation with protease inhibitors can improve the stability of plasma biomarkers at room temperatures (RT). This study conducted a comparative analysis of blood biomarker stability in traditional ethylenediaminetetraacetic acid (EDTA) tubes versus BD™ P100 collection tubes, the latter being coated with a protease inhibitor cocktail. The stability of six plasma AD biomarkers was evaluated over time under RT conditions.

METHODS

We evaluated three experimental approaches. In Approach 1, pooled plasma samples underwent storage at RT for up to 96 hours. In Approach 2, plasma samples isolated upfront from whole blood collected into EDTA or P100 tubes were stored at RT for 0h or 24h before biomarker measurements. In Approach 3, whole blood samples were collected into paired EDTA or P100 tubes, followed by storage at RT for 0h or 24h before isolating the plasma for analyses. Biomarkers were measured with Single Molecule Array (Simoa) and immunoprecipitation-mass spectrometry (IP-MS) assays.

RESULTS

Both the IP-MS and Simoa methods revealed that the use of P100 tubes significantly improved the stability of Aβ42 and Aβ40 across all approaches. Additionally, the Aβ42/Aβ40 ratio levels were significantly stabilized only in the IP-MS assay in Approach 3. No significant differences were observed in the levels of plasma p-tau181, GFAP, and NfL for samples collected using either tube type in any of the approaches.

CONCLUSION

Supplementation of blood collection tubes with protease inhibitors could reduce the protease-induced degradation of plasma Aβ42 and Aβ40, and the Aβ ratio for IP-MS assay. This has crucial implications for preanalytical procedures, particularly in resource-limited settings.
Fetal-maternal interactions with gluten immunogenic peptides during pregnancy: a new determinant on the coeliac exposome
Authors: Moreno María de Lourdes , González-Rovira María , Martínez-Pancorbo Cristina , Martín-Cameán María , Nájar-Moyano Ana María , Romero Mercedes , de la Hoz Esther , López-Beltrán Cristina , Mellado Encarnación , Bartha José Luis , Brodin Peter , Rodríguez-Herrera Alfonso , Sainz-Bueno José Luís , Sousa Carolina
Published: March 2024

The increasing incidence of coeliac disease is leading to a growing interest in active search for associated factors, even the intrauterine and early life. The exposome approach to disease encompasses a lifecourse perspective from conception onwards has recently been highlighted. Knowledge of early exposure to gluten immunogenic peptides (GIP) in utero could challenge the chronology of early prenatal tolerance or inflammation, rather than after the infant’s solid diet after birth. We developed an accurate and specific immunoassay to detect GIP in amniotic fluid (AF) and studied their accumulates, excretion dynamics and foetal exposure resulting from AF swallowing. 119 pregnant women with different gluten diets and gestational ages were recruited. GIP were detectable in AF from at least the 16th gestational week in gluten-consuming women. Although no significant differences in GIP levels were observed during gestation, amniotic GIP late pregnancy was not altered by maternal fasting, suggesting closed-loop entailing foetal swallowing of GIP-containing AF and subsequent excretion via the foetal kidneys. The study shows evidence, for the first time, of the fetal exposure to gluten immunogenic peptides, and establish a positive correlation with maternal gluten intake. The results obtained point to a novel physiological concept as they describe a closed-loop circuit entailing fetal swallowing of GIP contained in AF, and its subsequent excretion through the fetal kidneys. The study adds important new information to understanding the coeliac exposome.
Assessment of the evidence yield for the calibrated PP3/BP4 computational recommendations
Authors: Stenton Sarah L. , Pejaver Vikas , Bergquist Timothy , Biesecker Leslie G. , Byrne Alicia B. , Nadeau Emily , Greenblatt Marc S. , Harrison Steven , Tavtigian Sean , Radivojac Predrag , Brenner Steven E. , O’Donnell-Luria Anne ,   ClinGen Sequence Variant Interpretation Working Group
Published: March 2024

Purpose

To investigate the number of rare missense variants observed in human genome sequences by ACMG/AMP PP3/BP4 evidence strength, following the calibrated PP3/BP4 computational recommendations.

Methods

Missense variants from the genome sequences of 300 probands from the Rare Genomes Project with suspected rare disease were analyzed using computational prediction tools able to reach PP3_Strong and BP4_Moderate evidence strengths (BayesDel, MutPred2, REVEL, and VEST4). The numbers of variants at each evidence strength were analyzed across disease-associated genes and genome-wide.

Results

From a median of 75.5 rare (≤1% allele frequency) missense variants in disease-associated genes per proband, a median of one reached PP3_Strong, 3-5 PP3_Moderate, and 3-5 PP3_Supporting. Most were allocated BP4 evidence (median 41-49 per proband) or were indeterminate (median 17.5-19 per proband). Extending the analysis to all protein-coding genes genome-wide, the number of PP3_Strong variants increased approximately 2.6-fold compared to disease-associated genes, with a median per proband of 1-3 PP3_Strong, 8-16 PP3_Moderate, and 10-17 PP3_Supporting.

Conclusion

A small number of variants per proband reached PP3_Strong and PP3_Moderate in 3,424 disease-associated genes, and though not the intended use of the recommendations, also genome-wide. Use of PP3/BP4 evidence as recommended from calibrated computational prediction tools in the clinical diagnostic laboratory is unlikely to inappropriately contribute to the classification of an excessive number of variants as Pathogenic or Likely Pathogenic by ACMG/AMP rules.
COVID-19 Vaccination Booster Uptake Is Related to End of Pandemic Perception: Population-Based Survey in Four Provinces in Indonesia
Authors: Maula Ahmad Watsiq , Indriani Citra , Arisanti Risalia Reni , Testamenti Vincentius Arca , Praptiningsih Catharina Yekti , Merril Rebecca , Ansariadi  , Wahyono Tri Yunis Miko , Hidajah Atik Choirul , Ahmad Riris Andono
Published: March 2024

Global COVID-19 booster vaccination uptake has been low, particularly in low-middle-income countries (LMICs). However, studies on the determinants of COVID-19 booster vaccination remain limited, especially in LMIC settings. This study aims to describe the determinants of COVID-19 booster vaccination uptake in an LMIC context. We analyzed data from a cross-sectional survey that was conducted in September 2022 in four provinces in Indonesia. Participants (n=2,223) were recruited using multiple-stage cluster sampling. Multivariable logistic regression analysis was used to identify factors associated with booster vaccination status. The proportion of COVID-19 booster vaccination among fully vaccinated adults was 29.5%, while fear of transmission (12.4%) and perceived risk of getting a COVID-19 infection (33.5%) were low. Multivariable analysis showed that people living on Java Island (aOR: 2.45, 95% CI: 1.87-3.24), living in the urban area (aOR: 2.04, 95% CI: 1.60-2.61), being an employee in the formal sector (aOR: 3.99, 95% CI: 1.93 - 8.58), experiencing a side effect from previous vaccination (aOR: 1.71, 95% CI: 1.40-2.09), having a history of SARS-COV2 infection (aOR: 2.10, 95%CI: 1.27-3.50), having perception on the upcoming new wave of COVID-19 (aOR: 1.37, 95% CI: 1.07 -1.76), and believing the pandemic has not ended (aOR: 1.29, 95% CI: 1.01, 1.64) were associated with booster shot uptake. Low educational level (aOR: 0.6, 95% CI: 0.39-0.93) inhibited booster vaccination uptake. Current booster dose coverage was considerably lower than the primary vaccination dosage. The low booster vaccination uptake in four provinces was associated with a belief the pandemic has no longer, which might hinder the catch up of wide-population target coverage and COVID-19 control for reduced disease severity and hospitalization. Thus, efforts need to be prioritized in reaching the COVID-19 vulnerable population, which includes elderly and those with comorbidities.
International consensus on fluoride programmes for Early Childhood Caries prevention in early education settings
Authors: Abuhaloob Lamis , Conay David I , Blokland Alex , Ross Al
Published: March 2024

Background

The World Health Organisation has set out a clear priority for the implementation of interventions to reduce the burden of Early Childhood Caries (ECC), a global public health problem affecting over 500 million children around the world and having a substantial impact on child well-being and health system expenditure.

The aim of this study was to assess and develop international expert consensus on the evidence for fluoride-based interventions in early-year education settings (kindergartens/nursery and primary schools) for reducing ECC and to synthesise clear programme-level recommendations with regard to ECC prevention in this setting.

Methods

A systematic overview of systematic reviews, trials, and observational studies was performed to identify and critically appraise the available evidence on the effectiveness and cost-effectiveness of fluoride-based interventions in early-years education settings to prevent ECC.

This was followed by a three-stage modified Delphi panel study (n= 21) consisting of: round 1, an online survey to gather opinions on safety, effectiveness and feasibility of interventions; round 2, an iterative survey to consider collated group opinion and gather feedback on review findings; and finally, an online workshop with presentations and facilitated in-depth, recorded group discussions.

Results

There was high-quality evidence and consensus on delivering supervised toothbrushing in kindergartens (nurseries) and primary/elementary schools; this is safe and cost-effective, shows greater benefit to more disadvantaged children, helps child social development, and is feasible in high and low/middle-income countries. There was more moderate support for the effectiveness and cost-effectiveness of fluoride varnish application in this setting (especially where supervised toothbrushing with fluoride is in place). It was agreed that policy makers should prioritise at-risk groups where resources are limited, and that systemic fluoride interventions (Fluoride tablets, drops, milk, and salt) in this setting are no longer a priority.

Conclusion

Supervised toothbrushing with fluoridated toothpaste is the most effective, cost-effective, feasible and safest mechanism for children in early education settings. Universal coverage is preferred but where resources are limited targeting based on need is indicated. Panel consensus is that it remains appropriate in water fluoridated areas and is largely feasible in low/middle-income countries.
Depressive Symptoms and its Associated Factors among Health Care Workers in Saint Paul’s Hospital Millennium Medical College, Ethiopia
Authors: Tesema Melese Bahiru , Woldeamanue Berhanu Teshome , Mekonen Eyoel Berhane , Melese Kidest Getu
Published: March 2024

Background

Depression is a mental disorder that presents with a depressed mood, loss of pleasure or interest, decrease in energy, feeling of guilt or low self-worth, disturbed sleep, loss of appetite, and poor-concentration. Healthcare professionals are more susceptible to depression because they face higher amounts of professional stress in their job and academic lives. However, there is limited knowledge regarding health professionals’ level of depressive disorder in Ethiopia. This study aimed to assess the prevalence of depression and associated factors among health professionals, at Saint Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia.

Methods

We conducted an institution-based cross-sectional study among 439 randomly selected health care worker using interviewer-administered patient health questionnaire-9 from April to May 2023. Ordinal logistic regression was performed to identify predictors of depressive disorder.

Result

The overall prevalence of depressive symptoms among health care workers was 56.5% (95% CI (51.8%, 61.1%)). There were reports of mild (35%), moderate (13%) and severe (9%) depression, respectively. Marital status of being single (AOR=7.78, 95%CI: 1.123, 49.01), history of childhood abuse (AOR=2.57, 95%CI:1.49, 4.42), history of suicidal attempt (AOR=2.66, 95%CI:1.25,5.67), having history of stressful life event (AOR=1.527, 95%CI: 1.02,2.3), back pain over the past 30 days (AOR=2, 95%CI: 1.30,3.11), working for more than 8 hours (AOR=3.03, 95%CI: 1.12,8.24), and having experience of 5-10 year (AOR=4, 95%CI: 1.05,15.27) and 10-15 years (AOR= 4.24, 95%CI: 1.08,16.58) and poor social support (AOR= 2.09, 95%CI: 1.09,3.99) were statistically associated with increased level of depressive disorder.

Conclusion

Healthcare professionals’ higher rate of depression was due to the higher work load, childhood abuse, history of stressful life, back pain, and poor social support. Thus, the hospital or ministry of health should give special attention to health care workers who has high work load, childhood abuse, history of stressful life, back pain, and poor social support to reduce the burden of depressive disorder among health professionals. Furthermore, early depression screening and treatment in hospitals is needed.
Regulation of virion production by the ORF8 signal peptide across SARS-CoV-2 variants
Authors: Khalid Mir M , Chen Irene , Soveg Frank S , Taha Taha Y , Tabata Takako , Suryawanshi Rahul , Syed Abdullah M. , Ciling Alison , McCavitt-Malvido Maria , Schulze-Gahmen Ursula , Hayashi Jennifer , Kim Ik-Jung , Fong Seiw Wai , Batra Jyoti , Kumar G. Renuka , Laurent Renia , NG Lisa FP , Krogan Nevan J , Doudna Jennifer A. , Verdin Eric , Ott Melanie
Published: March 2024

The open reading frame 8 (ORF8), an accessory protein of SARS-CoV-2, is prone to deletions and mutations across different viral variants, which was first described in several Singapore variants. The reason why viral evolution favors loss or inactivation of ORF8 is not fully understood, although the effects of ORF8 on inflammation, immune evasion, and disease severity have been described. Here we show using clinical ORF8 deficient viral isolates, virus like particles (VLPs) and viral replicons that ORF8 expression dampens viral particle production. ORF8 physically interacts with the viral Spike protein and induces Golgi fragmentation, overall contributing to less virus particle production. Using systematic ORF8 deletions, we mapped the particle reducing function to its N terminal signal peptide. Interestingly, this part of ORF8 is severely truncated in the recent XBB.1.5 variant, and when restored, suppresses viral particle production in the context of the entire viral genome. Collectively, our data support the model that evolutionary pressure exists to delete ORF8 sequence and expression across SARS-CoV-2 variants to fully enable viral particle production.
Human Anterior Insular Cortex Encodes Multiple Electrophysiological Representations of Anxiety-Related Behaviors
Authors: Lee A Moses , Sturm Virginia E , Dawes Heather , Krystal Andrew D , Chang Edward F
Published: March 2024

Anxiety is a common symptom across psychiatric disorders, but the neurophysiological underpinnings of these symptoms remain unclear. This knowledge gap has prevented the development of circuit-based treatments that can target the neural substrates underlying anxiety. Here, we conducted an electrophysiological mapping study to identify neurophysiological activity associated with self-reported state anxiety in 17 subjects implanted with intracranial electrodes for seizure localization. Participants had baseline anxiety traits ranging from minimal to severe. Subjects volunteered to participate in an anxiety induction task in which they were temporarily exposed to the threat of unpredictable shock during intracranial recordings. We found that anterior insular beta oscillatory activity was selectively elevated during epochs when unpredictable aversive stimuli were being delivered, and this enhancement in insular beta was correlated with increases in self-reported anxiety. Beta oscillatory activity within the frontoinsular region was also evoked selectively by cues-predictive of threat, but not safety cues. Anterior insular gamma responses were less selective than gamma, strongly evoked by aversive stimuli and had weaker responses to salient threat and safety cues. On longer timescales, this gamma signal also correlated with increased skin conductance, a measure of autonomic state. Lastly, we found that direct electrical stimulation of the anterior insular cortex in a subset of subjects elicited self-reported increases in anxiety that were accompanied by enhanced frontoinsular beta oscillations. Together, these findings suggest that electrophysiologic representations of anxiety- related states and behaviors exist within anterior insular cortex. The findings also suggest the potential of reducing anterior insular beta activity as a therapeutic target for refractory anxiety-spectrum disorders.
Integrating mechanism-based T cell phenotypes into a model of tumor-immune cell interactions
Authors: Tangella Neel , Cess Colin G. , Ildefonso Geena V. , Finley Stacey D.
Published: March 2024

Interactions between cancer cells and immune cells in the tumor microenvironment influence tumor growth and can contribute to the response to cancer immunotherapies. It is difficult to gain mechanistic insights into the effects of cell-cell interactions in tumors using a purely experimental approach. However, computational modeling enables quantitative investigation of the tumor microenvironment, and agent-based modeling in particular provides relevant biological insights into the spatial and temporal evolution of tumors. Here, we develop a novel agent-based model (ABM) to predict the consequences of intercellular interactions. Furthermore, we leverage our prior work that predicts the transitions of CD8+ T cells from a naïve state to a terminally differentiated state using Boolean modeling. Given the detailed incorporated to predict T cell state, we apply the integrated Boolean-ABM framework to study how the properties of CD8+ T cells influence the composition and spatial organization of tumors and the efficacy of an immune checkpoint blockade. Overall, we present a mechanistic understanding of tumor evolution that can be leveraged to study targeted immunotherapeutic strategies.
Exploring the causal role of the human gut microbiome in endometrial cancer: a Mendelian randomization approach
Authors: Fryer Ella , Hatcher Charlie , Knight Rochelle , Wade Kaitlin
Published: March 2024

Endometrial cancer presents a major public health issue, particularly in post-menopausal women. Whilst there are known risk factors for the disease, including oestrogen and obesity, these factors do not fully explain risk variability in cancer outcomes. The identification of novel risk factors may aid in better understanding of endometrial cancer development and, given the link with oestrogen metabolism, obesity and the risk of various cancers, the gut microbiome could be one such risk factor. Mendelian randomization (MR), a method that reduces biases of conventional epidemiological studies (namely, confounding and reverse causation) by using genetic variants to proxy exposures, was used to investigate the effect of gut microbial traits on endometrial cancer risk. Whilst our initial analyses showed that the presence of an unclassified group of bacteria in theErysipelotrichaceaefamily increased the risk of oestrogen-dependent endometrial cancer (odds ratio (OR) per approximate doubling of the genetic liability to presence vs absence: 1.13; 95% CI: 1.01, 1.26; P=0.03), subsequent sensitivity analyses, including colocalisation, suggested these findings were unlikely reflective of causality. This work highlights the importance of using a robust MR analysis pipeline, including sensitivity analyses to assess the validity of causal effect estimates obtained using MR.
IMPROVING ALPHAFOLD2 PERFORMANCE WITH A GLOBAL METAGENOMIC & BIOLOGICAL DATA SUPPLY CHAIN
Authors: Munsamy Geraldene , Bohnuud Tanggis , Lorenz Philipp
Published: March 2024

Scaling laws suggest that more than a trillion species inhabit our planet but only a miniscule and unrepresentative fraction (less than 0.00001%) have been studied or sequenced to date. Deep learning models, including those applied to tasks in the life sciences, depend on the quality and size of training or reference datasets. Given the large knowledge gap we experience when it comes to life on earth, we present a data-centric approach to improving deep learning models in Biology: We built partnerships with nature parks and biodiversity stakeholders across 5 continents covering 50% of global biomes, establishing a global metagenomics and biological data supply chain. With higher protein sequence diversity captured in this dataset compared to existing public data, we apply this data advantage to the protein folding problem by MSA supplementation during inference of AlphaFold2. Our model, BaseFold, exceeds traditional AlphaFold2 performance across targets from the CASP15 and CAMEO, 60% of which show improved pLDDT scores and RMSD values being reduced by up to 80%. On top of this, the improved quality of the predicted structures can yield better docking results. By sharing benefits with the stakeholders this data originates from, we present a way of simultaneously improving deep learning models for biology and incentivising protection of our planet’s biodiversity.
Endocannabinoid and neuroplasticity-related changes as susceptibility factors in a rat model of posttraumatic stress disorder
Authors: Szente Laszlo , Balla Gyula Y , Varga Zoltan K , Toth Blanka , Biro Laszlo , Balogh Zoltan , Hill Matthew N , Toth Mate , Mikics Eva , Aliczki Mano
Published: March 2024

Traumatic experiences result in the development of posttraumatic stress disorder (PTSD) in 10-25% of exposed individuals. While human clinical studies suggest that susceptibility is potentially linked to endocannabinoid (eCB) signaling, neurobiological PTSD susceptibility factors are poorly understood. Employing a rat model of PTSD, we characterized distinct resilient and susceptible subpopulations based on generalized fear, a core symptom of PTSD. In these groups, we assessed i.) eCB levels by mass spectrometry and expression variations of eCB system- and iii.) neuroplasticity-related genes by real-time quantitative PCR in the circuitry relevant in trauma-induced changes. Furthermore, employing supervised and semi-supervised machine learning based statistical analytical models, we assessed iv.) gene expression patterns with the most robust predictive power regarding PTSD susceptibility. According to our findings, in our model, generalized fear responses occurred with sufficient variability to characterize distinct resilient and susceptible subpopulations. Susceptible subjects showed lower prelimbic and higher ventral hippocampal levels of eCB 2-arachidonoyl-glycerol (2-AG) compared to resilient subjects. Ventral hippocampal 2-AG content positively correlated with the strength of fear generalization. Furthermore, susceptibility was associated with i.) neuronal prefrontal, hippocampal and amygdalar hypoactivity, ii.) marked decrease in the expression of genes of transcription factors modulating neuroplasticity and iii.) an altered expression pattern of eCB-related genes, including enzymes involved in eCB metabolism. Unsupervised and semi-supervised statistical approaches highlighted that hippocampal gene expression patterns possess strong predictive power regarding susceptibility. Taken together, the marked eCB and neuroplasticity changes in susceptible individuals associated with abnormal activity patterns in the fear circuitry possibly contribute to context coding deficits, resulting in generalized fear.

Highlights

We assessed endocannabinoid and neuroplasticity correlates of PTSD susceptibility

Posttrauma generalized fear strength separates susceptible and resilient individuals

Susceptible individuals show altered endocannabinoid levels in the fear circuitry

Neuroplasticity and endocannabinoid gene expression patterns predict susceptibility
Electrophysiological correlates of divergent projections in the avian superior olivary nucleus
Authors: Baldassano James F. , MacLeod Katrina M.
Published: March 2024

The physiological diversity of inhibitory neurons provides ample opportunity to influence a wide range of computational roles through their varied activity patterns, especially via feedback loops. In the avian auditory brainstem, inhibition originates primarily from the superior olivary nucleus (SON) and so it is critical to understand the intrinsic physiological properties and processing capabilities of these neurons. Neurons in the SON receive ascending input via the cochlear nuclei: directly from the intensity-coding cochlear nucleus angularis (NA) and indirectly via the interaural timing nucleus laminaris (NL), which itself receives input from cochlear nucleus magnocellularis. Two distinct populations of SON neurons provide either inhibitory feedback to ipsilateral NA, NL, and the timing cochlear nucleus NM, or to the contralateral SON. To determine whether these populations correspond to distinct response types, we investigated their electrophysiology in brain stem slices using patch clamp electrophysiology. We identified three phenotypes: single-spiking, chattering tonic, and regular tonic neurons. The two tonic phenotypes displayed distinct firing patterns and different membrane properties. Additionally, fluctuating “noisy” currents were used to probe the capability of SON neurons to encode temporal features. Each of the three phenotypes had a distinct level of sensitivity to this temporally modulated input. By using cell fills and anatomical reconstructions, we could correlate the firing phenotypes with their axonal projection patterns. We found that SON axons exited via three fiber tracts with specific phenotypes comprising each tract. Two ipsilateral tracts exit the SON, with the laterally projecting tract composed entirely of regular tonic neurons and medially projecting tract composed of both regular and chattering tonic neurons. The contralateral projection was composed entirely of single spiking neurons. These results provide a basis for understanding the role of specific inhibitory cell types in auditory function and elucidate the organization of the SON outputs.
Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses possibly at a neurosteroid site on GABAARs
Authors: Phillips Shekinah , Chatham John C. , McMahon Lori L.
Published: March 2024

GABAergic transmission is influenced by post-translational modifications, like phosphorylation, impacting channel conductance, allosteric modulator sensitivity, and membrane trafficking. O-GlcNAcylation is a post-translational modification involving the O-linked attachment of β–N-acetylglucosamine on serine/threonine residues. Previously we reported an acute increase in O-GlcNAcylation elicits a long-term depression of evoked GABAAR inhibitory post synaptic currents (eIPSCs) onto hippocampal principal cells. Importantly, O-GlcNAcylation and phosphorylation can co-occur or compete for the same residue; whether they interact in modulating GABAergic IPSCs is unknown. We tested this by recording IPSCs from hippocampal principal cells and pharmacologically increased O-GlcNAcylation, before or after increasing serine phosphorylation using the adenylate cyclase activator, forskolin. Although forskolin had no significant effect on baseline eIPSC amplitude, we found that a prior increase in O-GlcNAcylation unmasks a forskolin-dependent increase in eIPSC amplitude, reversing the O-GlcNAc-induced eIPSC depression. Inhibition of adenylate cyclase or protein kinase A did not prevent the potentiating effect of forskolin, indicating serine phosphorylation is not the mechanism. Surprisingly, increasing O-GlcNAcylation also unmasked a potentiating effect of the neurosteroids 5α-pregnane-3α,21-diol-20-one (THDOC) and progesterone on eIPSC amplitude, mimicking forskolin. Our findings show under conditions of heightened O-GlcNAcylation, the neurosteroid site on synaptic GABAARs is accessible to agonists, permitting strengthening of synaptic inhibition.
Structural determination and modeling of ciliary microtubules
Authors: Walton Travis , Doran Matthew H. , Brown Alan
Published: March 2024

The axoneme, a microtubule-based array at the center of every cilium, has been the subject of structural investigations for decades, but only recent advances in cryo-EM and cryo-ET have allowed a molecular-level interpretation of the entire complex to be achieved. The unique properties of the nine doublet microtubules and central pair of singlet microtubules that form the axoneme, including the highly decorated tubulin lattice and the docking of massive axonemal complexes, provide opportunities and challenges for sample preparation, 3D reconstruction and atomic modeling. Here, the approaches used for cryo-EM and cryo-ET of axonemes are reviewed, while highlighting the unique opportunities provided by the latest generation of AI-guided tools that are transforming structural biology.