bluuebunny/crossref_metadata_2025 huggingface dataset:
The intestinal stem cell as a target: A review
Authors: Faizo Nisreen Lutfi
Published: August 2024

Human intestinal epithelium handles several events that may affect health. It is composed of villi and crypts, which contain different types of cells. Each cell type plays an essential role in intestinal functions, including absorption, defense, self-renewal, and regeneration. Intestinal stem cells (ISCs), located at the base of intestinal crypts, play an important role in intestinal homeostasis and renewal. Any disruption in intestinal homeostasis, in which ISCs alter their function, may result in tumor growth. As Wnt and Notch signaling pathways are essential for ISCs homeostasis and for maintaining self-renewal, any defects in these pathways could increase the risk of developing colorectal cancer (CRC). Lgr5+ cells have been identified as intestinal stem cells expressing a leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5), which is involved in the regulation of Wnt signaling. Several studies have reported upregulated expression of LGR5 in CRC. Hence, in this review, we discuss the relationship between LGR5, Wnt signaling, and Notch signaling and the development of CRC, as well as recent therapeutic strategies targeting LGR5, cancer stem cells (CSCs), and the aforementioned signaling pathways.
A novel AI-based diagnostic model for pertussis pneumonia
Authors: Cai Yihong , Fu Hong , Yin Jun , Ding Yang , Hu Yanghong , He Hong , Huang Jing
Published: August 2024

It is still very difficult to diagnose pertussis based on a doctor’s experience. Our aim is to develop a model based on machine learning algorithms combined with biochemical blood tests to diagnose pertussis. A total of 295 patients with pertussis and 295 patients with non-pertussis lower respiratory infections between January 2022 and January 2023, matched for age and gender ratio, were included in our study. Patients underwent a reverse transcription polymerase chain reaction test for pertussis and other viruses. Univariate logistic regression analysis was used to screen for clinical and blood biochemical features associated with pertussis. The optimal features and 3 machine learning algorithms including K-nearest neighbor, support vector machine, and eXtreme Gradient Boosting (XGBoost) were used to develop diagnostic models. Using univariate logistic regression analysis, 18 out of the 27 features were considered optimal features associated with pertussis The XGBoost model was significantly superior to both the support vector machine model (Delong test, P = .01) and the K-nearest neighbor model (Delong test, P = .01), with the area under the receiver operating characteristic curve of 0.96 and an accuracy of 0.923. Our diagnostic model based on blood biochemical test results at admission and XGBoost algorithm can help doctors effectively diagnose pertussis.
Impact of the COVID-19 pandemic on the financial performance of hospitals according to hospital characteristics in Korea: An observational study
Authors: Lee Ji-Hoon
Published: August 2024

The coronavirus disease-19 (COVID-19) pandemic had a profound effect on society and various industries. Moreover, hospitals experienced huge financial losses owing to COVID-19 prevention efforts. This study aims not only to comprehensively inspect the financial impact of the pandemic on Korean hospitals but also to consider financial performance by hospital characteristics. Data were collected from 255 general hospitals that uploaded their income statements on the website, and 1530 data points were collected from 2016 to 2021. We used the paired t-test, linear mixed-effects (LME) model in R software (Ver. 4.3.2). We then selected operating margin ratio (OMR) and total margin ratio (TMR) to measure financial performance and used location, type of hospital, and ownership as hospital characteristics. We found that OMR and TMR worsened after COVID-19 breakout, and the labor and management cost ratios increased. According to the LME model with hospital characteristics, the OMR of hospitals located in the capital area worsened more than that of hospitals in noncapital areas (β5 = −6.3, P < .01). Regarding type of hospitals, tertiary general hospitals maintained a surplus and recorded a better OMR than general hospitals during the pandemic (β6 = 9.5, P < .01). The OMR of public hospitals worsened more than that of private hospitals during the pandemic (β7 = −25.4, P < .01), but the TMR of public hospitals increased compared to that of private hospitals (β7 = 3.9, P < .01). We confirmed that the COVID-19 pandemic had a negative impact on the financial status of hospitals. Considering hospital characteristics, the impact of the pandemic on hospital financial performance differed based on location, type of hospital, and ownership. As the contributions of this study, the government could establish support policies such as government subsidies based on hospital characteristics and hospital administrators could set a contingency plan to mitigate national disasters.
Treatment Complications Associated With Hospital Admission in Oropharyngeal Cancer Patients
Authors: McLaughlin Laura , Chrusciel Timothy , Khemthong Usa
Published: August 2024

Background

Oropharyngeal cancer (OPC) survivorship is a nursing priority because patients are living longer while significant short-term and long-term treatment complications that require nursing care are increasing. Hospital readmission is costly and reflects the quality of care patients receive.

Objectives

This secondary analysis aimed to determine the prevalence of treatment complications resulting in hospital admissions among persons with OPC and examine the relationship between treatment complications resulting in hospital admission among persons with OPC and all other persons with head and neck cancer.

Methods

Using the National Inpatient Survey 2008–2019 database, we identified persons with relevant head and neck cancer diagnoses using specific International Classification of Disease ICD-9 and ICD-10 codes. Complications were operationalized by diagnosis-related codes; persons with codes for major elective surgery were excluded as our focus was posttreatment symptoms requiring hospitalization. Descriptive statistics were used to characterize persons with OPC hospitalized between 2008 and 2019. Binary logistic regression was used to assess complications using crude comparisons. The Elixhauser Comorbidity Index was used for controlling for comorbidities.

Results

The final analysis samples included 751,533: 164,770 persons with OPC and 586,763 with other head and cancers. The most prevalent diagnoses observed in those with OPC were esophagitis, nutrition disorder, hematological disorder, and renal failure; the least common diagnoses were sepsis, respiratory tract infection, and pneumonia. Binary regression revealed that persons with OPC experienced significantly more esophagitis, nutrition disorders, hematological disorders, and renal failure compared to persons with other head and neck cancers.

Discussion

Treatment of survivors of OPC requires more intensive monitoring for early symptoms associated with treatment, including esophagitis, nutrition disorders, bleeding disorders, and renal failure, than persons with other head and neck cancers. Monitoring laboratory values and clinical manifestations of these conditions is imperative. Nurses may encounter persons with OPC in emergency departments, outpatient radiology, or inpatient general medicine floors to manage swallowing difficulties, dehydration, malnutrition, and bleeding. Delayed or ineffective treatment of these conditions contributes to readmission, financial burden, and impairment of patient’s quality of life. Future research should investigate the relationship between targeted treatment for expected complications and readmission rates in persons with OPC.
Anti-inflammatory diets
Authors: Day Mercedes , Sing Erin , Spencer Michelle , Moellenberg Kara , Mello Inola , Moore Amy
Published: August 2024

This article reviews inflammatory versus anti-inflammatory foods, autoimmune and inflammatory disorders, the benefits of specific anti-inflammatory diets, and strategies for nurses to partner with individuals, while considering culture and food preferences, to promote healthy eating habits and prevent diseases.
Immunohistochemical Evaluation of Schlafen 11 (SLFN11) Expression in Cancer in the Search of Biomarker-Informed Treatment Targets
Authors: Kaczorowski Maciej , Ylaya Kris , Chłopek Małgorzata , Taniyama Daiki , Pommier Yves , Lasota Jerzy , Miettinen Markku
Published: August 2024

Schlafen 11 (SLFN11), a DNA/RNA helicase, acts as a regulator of cellular response to replicative stress and irreversibly triggers replication block and cell death. Several preclinical in vitro studies and clinical trials established that SLFN11 expression predicts outcomes in patients with advanced cancer treated with DNA-damaging chemotherapeutics and more recently with poly(ADP-ribose) polymerase inhibitors. SLFN11 expression status remains unknown in many cancer types, especially in mesenchymal tumors. This study evaluated a cohort of well characterized 3808 epithelial and 2850 mesenchymal and neuroectodermal tumors for SLFN11 expression using immunohistochemistry. Nuclear SLFN11 expression was rare in some of the most common carcinomas, for example, hepatocellular (1%), prostatic (2%), colorectal (5%), or breast (16%) cancers. In contrast, other epithelial tumors including mesotheliomas (92%), clear cell renal cell carcinomas (79%), small cell lung cancers (76%), squamous cell carcinomas of the tonsil (89%) and larynx (71%), or ovarian serous carcinomas (69%) were mostly SLFN11-positive. Compared with epithelial malignancies, SLFN11 expression was overall higher in neuroectodermal and mesenchymal tumors. Most positive entities included desmoplastic small round cell tumor (100%), Ewing sarcoma (92%), undifferentiated sarcoma (92%), solitary fibrous tumor (91%), dedifferentiated liposarcoma (89%), synovial sarcoma (86%), and malignant peripheral nerve sheath tumor (85%). Also, this study identifies tumors with potentially worse response to DNA-damaging drugs including antibody drug conjugates due to the absence of SLFN11 expression. Such entities may benefit from alternative treatments or strategies to overcome SLFN11 deficiency-related drug resistance. Our approach and results should serve as a foundation for future biomarker-associated clinical trials.
Outcomes of Daytime and Night-Time Appendectomies: A Systematic Review and Meta-Analysis
Authors: Shen Lifang , Zhang Liangfeng , Shi Huili
Published: August 2024

Background:

Acute appendicitis is a common surgical emergency characterized by appendix inflammation. Surgery remains the gold standard for treatment with laparoscopy gaining in popularity. However, the optimal timing for appendectomy remains unclear. We are not aware of studies evaluating potential differences in clinical outcomes among appendectomies performed during the daytime and at night.

Methods:

We followed the PRISMA guidelines and searched the ScienceDirect, Medline, and Google Scholar databases for studies published in English before June 2023. We included prospective and retrospective studies reporting appendectomy outcomes. We categorized the appendectomy procedure times as daytime or night-time based on each study’s definitions. We extracted baseline characteristics and outcomes and assessed the quality of the studies included using the Newcastle-Ottawa Scale. We calculated pooled risk ratios (RRs) and weighted mean differences (WMDs) using random-effects models; and, we assessed heterogeneity using the I
2 statistic.

Results:

We analyzed data from 12 studies for systematic review (n=19,183) including daytime (n=11,839) and night-time (n=7344) appendectomies. For the meta-analysis, we included 9 studies, that evaluated outcomes such as mortality (pooled RR, 0.44; 95% CI, 0.09-2.01; I
2=43.7%; P=0.11), hospital stay (WMD, −0.02; 95% CI, −0.24 to 0.20; I
2=93.3%; P <0.001), and complications (pooled RR, 0.96; 95% CI, 0.64-1.45; I
2=65.1%; P =0.02). We found similar mortality rates, hospital stay lengths, and complications for the appendectomies, regardless of the time of day of the operation. The baseline characteristics of the patients were also similar, except for the duration of symptoms and the presence of an appendiceal abscess.

Conclusion:

Our results showed that the timing of an appendectomy (daytime vs. night-time) does not significantly affect its outcomes. Surgeon availability or fatigue, and patient severity may not significantly impact the operation results. Standardized protocols and perioperative care ensure consistent outcomes.
Beyond American College of Surgeons Verification: Quality Metrics Associated with High Performance at Level I and II Trauma Centers
Authors: Cho Nam Yong , Choi Jeff , Mallick Saad , Barmparas Galinos , Machado-Aranda David , Tillou Areti , Margulies Daniel , Benharash Peyman ,   for the Academic Trauma Research Consortium (ATRIUM)
Published: August 2024

BACKGROUND:

The American College of Surgeons (ACS) Committee on Trauma has established a framework for trauma center quality improvement. Despite efforts, recent studies show persistent variation in patient outcomes across national trauma centers. We aimed to investigate whether risk-adjusted mortality varies at the hospital level and if high-performing centers demonstrate better adherence to ACS Verification, Review, and Consultation (VRC) program quality measures.

STUDY DESIGN:

We analyzed data from the 2018 to 2021 ACS TQIP Participant Use Files, focusing on adult admissions at ACS-verified level I or II trauma centers for blunt, penetrating, or isolated traumatic brain injury. We used mixed-effects models to assess center-specific risk-adjusted mortality and identified high-performing centers (HPTCs), defined as those with the lowest decile of overall risk-adjusted mortality. We compared patient and hospital characteristics, outcomes, and adherence to ACS-VRC quality measures between HPTC and non-HPTC.

RESULTS:

During the study period, 1,498,602 patients across 442 level I and II trauma centers met inclusion criteria: 65.3% presenting with blunt injury, 9.3% with penetrating injury, and 25.4% with isolated TBI. Management at HPTC was associated with lower odds of major complications, failure to rescue, and takeback. Additionally, HPTC status was associated with increased odds of adherence to several ACS-VRC quality measures, including balanced resuscitation (odds ratio [OR] 1.40, 95% CI 1.29 to 1.51), appropriate pediatric admissions (OR 1.88, 95% CI 1.07 to 3.68), and substance abuse screening (OR 1.14, 95% CI 1.12 to 1.16).

CONCLUSIONS:

Significant variation in risk-adjusted mortality persists across trauma centers. Given the association between adherence to quality measures and high performance, multidisciplinary efforts to refine and implement guidelines are warranted.
Managing the heat: In-Vessel Components
Authors: Cane Jenny , Barth Alan , Farrington Jaime , Flynn Ethan , Kirk Simon , Lilburne James , Vizvary Zsolt
Published: August 2024

The Spherical Tokamak for Energy Production (STEP) programme aims to deliver a first-of-a-kind fusion prototype powerplant (SPP). The SPP plasma places extreme heat, particle and structural loads onto the plasma-facing components (PFCs) of the divertor, limiters and inboard and outboard sections of the first wall. The PFCs must manage the heat and particle loads and wider powerplant requirements relating to safety, net power generation, tritium breeding and plant availability. To enable STEP PFC concepts to be identified that satisfy these wide-ranging requirements, an iterative design (‘Decide & Iterate’) methodology has been used to synchronize a prioritized set of decisions, within the fast-paced, iterative, whole plant concept design schedule. This paper details the ‘Decide and Iterate’ methodology and explains how it has enabled the identification of the SPP PFC concepts. These include innovative PFC solutions such as a helium-cooled discrete and panel limiter design to increase tritium breeding while providing sufficient coverage and enabling individual limiter replacement; the integration of the outboard first wall with the breeding zone to enhance fuel self-sufficiency and power generation; and the use of heavy water (D
2
O) within the inboard first wall and divertor PFCs to increase tritium breeding within the outboard breeding zone.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Maturing the design: challenges in maturing a first of a kind fusion power plant
Authors: Kempton Debbie , Waldon Chris
Published: August 2024

The design, delivery and operation of a large-scale infrastructure project are challenging at best. For the Spherical Tokamak for Energy Production (STEP) prototype powerplant (SPP), the challenges increased dramatically. In addition to being a large-scale infrastructure project, it is a cutting edge, first of a kind (FOAK) technology demonstrator. The design teams are working in a volatile, uncertain, complex and ambiguous environment, where technology is constantly emerging, maturing and changing. STEP will be unlike any power plant ever built and requires the development of new technologies and capabilities, but also a novel approach to planning and maturing the design. By taking a holistic view of the engineering life cycle from the start, the programme will be better positioned to achieve an SPP that is fit for purpose and can be used to show a path to ultimate commercial viability for subsequent power plants. This paper will review the key challenges in maturing a FOAK fusion power plant and look in depth at how the STEP team are maturing the required capabilities and planning to ensure successful delivery of the SPP.

This article is part of the theme issue ‘Delivering Fusion Energy – The Spherical Tokamak for Energy Production (STEP)’.
Genetic underpinnings of predicted changes in cardiovascular function using self supervised learning
Authors: Levine Zachary , Lutsker Guy , Godneva Anastasia , Weinberger Adina , Pompan Maya , Talmor-Barkan Yeela , Reisner Yotam , Rossman Hagai , Segal Eran
Published: August 2024

Background

The genetic underpinnings of cardiovascular disease remain elusive. Contrastive learning algorithms have recently shown cutting-edge performance in extracting representations from electrocardiogram (ECG) signals that characterize cross-temporal cardiovascular state. However, there is currently no connection between these representations and genetics.

Methods

We designed a new metric, denoted as Delta ECG, which measures temporal shifts in patients’ cardiovascular state, and inherently adjusts for inter-patient differences at baseline. We extracted this measure for 4,782 patients in the Human Phenotype Project using a novel self-supervised learning model, and quantified the associated genetic signals with Genome-Wide-Association Studies (GWAS). We predicted the expression of thousands of genes extracted from Peripheral Blood Mononuclear Cells (PBMCs). Downstream, we ran enrichment and overrepresentation analysis of genes we identified as significantly predicted from ECG.

Findings

In a Genome-Wide Association Study (GWAS) of Delta ECG, we identified five associations that achieved genome-wide significance. From baseline embeddings, our models significantly predict the expression of 57 genes in men and 9 in women. Enrichment analysis showed that these genes were predominantly associated with the electron transport chain and the same immune pathways as identified in our GWAS.

Conclusions

We validate a novel method integrating self-supervised learning in the medical domain and simple linear models in genetics. Our results indicate that the processes underlying temporal changes in cardiovascular health share a genetic basis with CVD, its major risk factors, and its known correlates. Moreover, our functional analysis confirms the importance of leukocytes, specifically eosinophils and mast cells with respect to cardiac structure and function.
Heterogeneous group of genetically determined auditory neuropathy spectrum disorders
Authors: Buianova Anastasiia A. , Bazanova Marina V. , Belova Vera A. , Ilyina Galit A. , Samitova Alina F. , Shmitko Anna O. , Balakina Anna V. , Pavlova Anna S. , Suchalko Oleg N. , Korostin Dmitriy O. , Machalov Anton S. , Daikhes Nikolai A. , Rebrikov Denis V.
Published: August 2024

Background

Auditory Neuropathy Spectrum Disorder (ANSD) is often missed by common hearing screening tests, still accounting for up to 10% of hearing impairments. ANSD has an underlying genetic factor being mostly caused by pathogenic variants in 13 genes.

Methods

We examined 122 children with impaired hearing, including 102 pediatric patients (mean age was 3.7±4.1 years) with sensorineural hearing loss (SNHL) of varying severity and 20 children with a clinically confirmed ANSD (mean age was 5.65±4.63 years). For children with SNHL, we genotyped the most frequent variants (c.35delG, c.167delT, c.235delC, c.313-326del14 and c.358-360delGAG) in theGJB2gene using quantitative PCR. For children with a clinically confirmed ANSD, we performed the whole exome sequencing and studied the obtained variants in a custom panel of 248 genes.

Results

Our findings show that fifty-six (54.9%) SNHL patients carried homozygous variants inGJB2gene. In 12 (60%) ANSD patients, we detected variants in nucleotide sequences of theOTOF(25%),CDH23, TMC1, COL11A1, PRPS1andHOMER2genes (8 of which had not been previously described). Transient Evoked Otoacoustic Emissions testing revealed differences at 500 Hz (AS, p = 0.04181) and 4000 Hz (AD, p = 0.00126) between the ANSD and SNHL patient groups. The Auditory Steady-State Response (ASSR) test demonstrated significant differences at all frequencies (p < 0.01). When comparing the results obtained from the pure-tone audiometry and ASSR tests in ANSD patients revealed statistically significant differences at 500 (AD, AS) and 1000 (AD) Hz.

Conclusions

These findings indicate that audiologists and otorhinolaryngologists should use the ASSR test in clinical practice for differential diagnosis of auditory neuropathies. According to the survey data from the parents of hearing-impaired children, rehabilitation was more successful in SNHL patients compared to ANSD patients.
Gestational Hypertension in Adolescent Mothers: A 2016-2022 Trend Analysis
Authors: Oloyede Oluwapelumi , Xu Lulu , Adepoju Omolola
Published: August 2024

Hypertensive disorders in pregnancy (HDPs) significantly contribute to maternal and fetal complications, particularly in adolescent pregnancies. This study examines the prevalence and predictors of gestational hypertension (gHTN) among U.S. adolescents between 2016 and 2022, using data from the CDC’s Birth Data Files. The analysis included various maternal factors, such as age, race, education, BMI, prenatal care, and participation in the Women, Infants, and Children (WIC) Nutritional Program. Logistic Regression and Random Forest models were employed to evaluate these predictors, with Random Forest showing superior predictive performance. The study found that gHTN prevalence increased from 6.72% in 2016 to 9.51% in 2022, with BMI, month prenatal visits began, WIC participation, and race emerging as key predictors. The findings highlight the importance of early prenatal care and targeted support for adolescents to manage gHTN, emphasizing the need for interventions that address modifiable risk factors such as BMI and access to nutritional programs. This research underscores the critical need for continued efforts to mitigate the rising trend of gHTN in adolescent pregnancies and improve maternal and fetal outcomes in this vulnerable population. Future studies should focus on identifying additional predictors and tailoring interventions to meet the unique needs of adolescent mothers.
Immediate TMS-EEG responses reveal motor cortex excitability
Authors: Stango Antonietta , Zazio Agnese , Barchiesi Guido , Dognini Elisa , Marcantoni Eleonora , Bortoletto Marta
Published: August 2024

Background

Combined transcranial magnetic stimulation and electroencephalography (TMS-EEG) is widely used to probe cortical excitability at the network level, but technical challenges have prevented its application to investigate local excitability of the stimulated area. A recent study revealed immediate TMS-evoked potentials (i-TEPs) after primary motor cortex (M1) stimulation, suggesting that it may represent a local response. Here, we aimed at testing if this activity is physiological in nature and what it represents.

Methods

We analyzed a TMS-EEG dataset from 28 healthy participants recorded at 9.6 kHz including two M1 stimulation conditions with opposite biphasic current directions. We localized the brain sources of i-TEPs, calculated the immediate TMS-related power (i-TRP) to distinguish between two oscillatory components that may contribute to i-TEPs, and investigated the relationship between i-TRP and motor-evoked potentials (MEPs). In an additional recording, we stimulated a control site evoking a muscular response to understand the contribution of the TMS-related muscle artifact.

Results

Results confirmed i-TEPs with similar characteristics as previously described. The i-TRP revealed strong activity in two ranges 600-800 Hz and 100-200 Hz; The former was positively associated with MEPs amplitude for both current direction conditions. Moreover, i-TEPs were localized in the precentral gyrus of the stimulated hemisphere and the muscular response generated by the control stimulation site differed from i-TEPs and i-TRP.

Discussion

These findings provide first evidence on the physiological nature of i-TEPs and i-TRP following M1 stimulation and that i-TRP represents a direct measure of excitability of the stimulated cortex.
Signal peptidase SpsB coordinates staphylococcal cell cycle, surface protein septal trafficking and LTA synthesis
Authors: Zhang Ran , Jia Yaosheng , Scaffidi Salvatore J. , Madsen Jesper J. , Yu Wenqi
Published: August 2024

Many cell wall anchored surface proteins of Gram-positive bacteria harbor a highly conserved YSIRK/G-S signal peptide (SPYSIRK+), which deposits surface protein precursors at the cell division septum where they are subsequently anchored to septal peptidoglycan. Previously we identified that LtaS-mediated lipoteichoic acid (LTA) synthesis regulates septal trafficking of YSIRK+ proteins inS. aureus. Interestingly, both LtaS and SPYSIRK+are cleaved by the signal peptidase SpsB, but the biological implications remain unclear. Here we show that SpsB is required for cleaving SPSpA(YSIRK+)of staphylococcal surface protein A (SpA). Depletion ofspsBnot only diminished SPSpAprocessing but also abolished SpA septal localization. The mis-localization is attributed to the cleavage activity of SpsB, as an A37P mutation of SPSpAthat disrupted SpsB cleavage also abrogated SpA septal localization. Strikingly, depletion ofspsBled to aberrant cell morphology, cell cycle arrest and daughter cell separation defects. Localization studies showed that SpsB predominantly localized at the septum of dividing staphylococcal cells. Finally, we show that SpsB spatially regulates LtaS asspsBdepletion enriched LtaS at the septum. Collectively, the data suggest a new dual-mechanism model mediated by SpsB: the abundant YSIRK+ proteins are efficiently processed by septal localized SpsB; SpsB cleaves LtaS at the septum, which spatially regulates LtaS activity contributing to YSIRK+ proteins septal trafficking. The study identifies SpsB as a novel and key regulator orchestrating protein secretion, cell cycle and cell envelope biogenesis.

Importance

Surface proteins containing a YSIRK/G-S positive signal peptide are widely distributed in Gram-positive bacteria and play essential roles in bacterial pathogenesis. They are highly expressed proteins that are enriched at the septum during cell division. The biogenesis of these proteins is coordinated with cell cycle and LTA synthesis. The current study identified the staphylococcal signal peptidase SpsB as a key determinant in regulating surface protein septal trafficking. Furthermore, this study highlights the novel functions of SpsB in coordinating LtaS-mediated LTA production and regulating staphylococcal cell cycle. As SpsB, YSIRK+ proteins and LTA synthesis are widely distributed and conserved, the mechanisms identified here may be shared across Gram-positive bacteria.
Exposure profiles of social-environmental neighborhood factors and psychotic-like experiences
Authors: Ku Benson , Yuan Qingyue , Christensen Grace M. , Dimitrov Lina , Risk Benjamin , Huels Anke
Published: August 2024

Importance

Recent research has demonstrated that domains of social determinants of health (SDOH) (e.g., air pollution and social context) are associated with psychosis. However, SDOHs have often been studied in isolation.

Objective

To identify distinct exposure profiles, estimate their associations with persistent distressing psychotic-like experiences (PLE), and evaluate whether involvement with physical activities partially explains this association.

Design, Setting, and Participants

This population-based study used data from the Adolescent Brain and Cognitive Development (ABCD) Study. Participants were recruited from 22 US sites between September 2016 and January 2022. Data from baseline and three follow-ups were included.

Exposures

Area-level geocoded variables spanning various domains of SDOH, including socioeconomic status (SES), education, crime, built environment, social context, and crime, were clustered using a self-organizing map method to identify exposure profiles.

Main Outcomes and Measures

Persistent distressing PLE was derived from the Prodromal Questionnaire-Brief Child Version across four years. Generalized linear mixed modeling tested the association between exposure profiles and persistent distressing PLE as well as physical activities (i.e., team and individual sports), adjusting for individual-level covariates including age, sex, race/ethnicity, highest level of parent education, family-relatedness, and study sites.

Results

Among 8,145 participants (baseline mean [SD] age, 9.92 [0.63] years; 3,868 (47.5%) females; 5,566 (68.3%) White, 956 (11.7%) Black, 159 (2.0%) Asian, and 1,480 (18.4%) Hispanic participants), five exposure profiles were identified. Compared to the reference Profile 1 (suburban affluent areas, 2521 children, 30.9%), Profile 3 (rural areas with low walkability and high ozone; 1459 children, 17.9%; adjusted OR: 1.34, 95% CI: 1.09—1.64) and Profile 4 (urban areas with high SES deprivation, high crime, and high pollution; 715 children, 8.8%; adjusted OR: 1.40, 95% CI: 1.08—1.81), were associated with persistent distressing PLE. Team sports mediated 6.14% of the association for Profile 3.

Conclusion and Relevance

This study found that neighborhoods characterized by rural areas with low walkability and urban areas with high socioeconomic deprivation, air pollutants, and crime were associated with persistent distressing PLE. Further research is needed to explore the pathways through which different environmental factors may impact the development of psychosis.
Safety and immunogenicity of GamEvac-Combi, a heterologous rVSV- and rAd5-vectored Ebola vaccine: a randomized controlled multicenter clinical trial in the Republic of Guinea and Russia
Authors: Logunov DY , Dolzhikova  , Boiro MY , Kovyrshina AV , Dzharullaeva AS , Erokhova AS , Grousova DM , Tukhvatulin AI , Izhaeva FM , Simakova YV , Ordzhonikidze MK , Lubenets NL , Zubkova OV , Scheblyakov DV , Esmagambetov IB , Shmarov MM , Semikhin AS , Tukhvatulina NM , Shcherbinin DN , Tutykhina IL , Prokhorov GS , Khovaev AA , Demidova TN , Malishev NA , Merkulova LN , Voronina OL , Fedyakina IT , Kisteneva LB , Kolobukhina LV , Mishin DV , Elakov AL , Ermolova EI , Krasnoslobodtsev KG , Larichev VF , Kruzhkova IS , Burmistrov EM , Sheremet AB , Tokarskaya EA , Gromov AV , Reshetnikov DA , Fisun AY , Kotiv BN , Ovchinnikov DV , Ivchenko EV , Zhdanov KV , Zakharenko SM , Solovev AN , Ivanov AM , Sukachev VS , Gudkov RV , Maltsev OV , Gabdrahmanov IA , Barsukov AV , Vashchenkov VV , Demianenko NY , Ignatev SB , Asyamov KV , Kirichenko NN , Lyubimov AV , Volkov  , Kryukov EV , Bazarnov NK , Kolodyazhnaya V , Kolomoets EV , Syromyatnikova SI , Chifanov DE , Andrus AF , Kutaev DA , Borisevich SV , Naroditsky BS , Gintsburg AL ,   the GamEvac-Combi trial group
Published: August 2024

Ebola virus disease (EVD) is one of the most dangerous and lethal diseases affecting humans. There are several licensed vaccines against EVD, but it remains one of the priority diseases for research and development of effective vaccines. A double-blind randomized placebo-controlled trial was performed to evaluate safety and immunogenicity of rVSV- and rAd5-vectored vaccine “GamEvac-Combi” in healthy adults of both sexes between 18 and 60 years. Safety and immunogenicity were assessed during the observation period of 12 months. Immunogenicity was assessed with GP-specific ELISA, IFN-γ ELISA, and plaque pseudoneutralization assay. Vaccinated participants showed marked GP-specific IFN-γ response at day 28 and neutralizing response at day 42 (GMT = 32.6, seroconversion rate 96.3%). GP-specific IgG antibody levels in vaccinated participants peaked at day 42 (GMT = 9345) and persisted for a year after vaccination (GMT = 650). The vaccine showed favorable safety profile and induced robust cell-mediated immune response and strong humoral immune response that lasts at least for a year from the start of vaccination. The study was funded by the Ministry of Health of Russian Federation; GamEvac-CombiClinicalTrials.govnumber,NCT03072030, Pan African Clinical Trial Registry PACTR201702002053400.
Reply to: Eigenmodes of the brain: revisiting connectomics and geometry
Authors: Pang James C. , Aquino Kevin M. , Oldehinkel Marianne , Robinson Peter A. , Fulcher Ben D. , Breakspear Michael , Fornito Alex
Published: August 2024

In Pang, Aquino et al. (2023), we presented multiple lines of evidence to indicate that brain geometry plays a previously under-appreciated role in shaping dynamics. Mansour et al. raise concerns about one specific analysis, in which we showed that eigenmodes derived from the geometry of the human cortex can reconstruct diverse activity maps generated with functional magnetic resonance imaging (fMRI) better than eigenmodes derived from connectomes estimated with diffusion MRI (dMRI). Here, we address their concerns and show how our findings and conclusions remain valid.
Wolbachiaintrogression inAe. aegyptiis accompanied by variable loss – a multi-country assessment
Authors: Dainty Kimberley R. , Pacidônio Etiene C. , Lee Elvina , Kyrylos Peter , Baran Nathan , Kay Eleonora , Dong Yi , Pinto Sofia B. , Ribeiro Gabriel S. , Uribe Alexander , Barajas Jovany , O’Neill Scott L. , Velez Ivan D. , Moreira Luciano A. , Simmons Cameron P. , Flores Heather A.
Published: August 2024

ThewMel andwAlbB strains of the bacterial endosymbiontWolbachiaare being introgressed intoAedes aegyptipopulations as a biocontrol method to reduce the transmission of medically important arboviruses. Successful introgression ofWolbachiarelies on both persistence ofWolbachiathroughout the host life cycle and a high fidelity of maternal transmission ofWolbachiabetween generations.wMel has been introgressed into field populations in 14 countries to date. Monitoring of field sites has shown thatwMel prevalence can fluctuate substantially over time, prompting concerns this could lead to reduced efficacy of the biocontrol method. To explore the fidelity ofwMel persistence and transmission, we developed molecular methods to measure the prevalence ofAe. aegyptinegative forWolbachiainfection but carrying the “founder” mitochondrial haplotype of the single female first transinfected. As all releasedwMel-infected mosquitoes and any subsequent offspring will carry this founder mitochondrial haplotype, any mosquitoes with this mitochondrial haplotype and withoutwMel indicate thatwMel was lost from this lineage at some point. We observed loss ofwMel ranging from 0 to 20.4% measured at various time intervals afterwMel-infected mosquito releases in five different countries. Despite some field sites showingWolbachialoss, overallWolbachiaprevalence was sustained during the time periods studied. We then employed laboratory studies to explore factors that could contribute to the loss ofwMel. Surprisingly, near-perfect maternal transmission was measured across laboratory conditions of early blood feeding, starvation, and salinity. Collectively, these findings underscore that althoughwMel transmission can be imperfect it does not necessarily undermine population-level establishment, providing encouragement that the intervention will be robust in most dengue-endemic environments.
Characterization, enrichment, and computational modeling of cross-linked actin networks in trabecular meshwork cells
Authors: Li Haiyan , Harvey Devon H. , Dai Jiannong , Swingle Steven P. , Compton Anthony M , Sugali Chenna Kesavulu , Dhamodaran Kamesh , Yao Jing , Lin Tsai-Yu , Sulchek Todd , Kim Taeyoon , Ethier C. Ross , Mao Weiming
Published: August 2024

Purpose

Cross-linked actin networks (CLANs) are prevalent in the glaucomatous trabecular meshwork (TM), yet their role in ocular hypertension remains unclear. We used a human TM cell line that spontaneously forms fluorescently-labeled CLANs (GTM3L) to explore the origin of CLANs, developed techniques to increase CLAN incidence in GMT3L cells, and computationally studied the biomechanical properties of CLAN-containing cells.

Methods

GTM3L cells were fluorescently sorted for viral copy number analysis. CLAN incidence was increased by (i) differential sorting of cells by adhesion, (ii) cell deswelling, and (iii) cell selection based on cell stiffness. GTM3L cells were also cultured on glass or soft hydrogel to determine substrate stiffness effects on CLAN incidence. Computational models were constructed to mimic and study the biomechanical properties of CLANs.

Results

All GTM3L cells had an average of 1 viral copy per cell. LifeAct-GFP expression level did not affect CLAN incidence rate, but CLAN rate was increased from ∼0.28% to ∼50% by a combination of adhesion selection, cell deswelling, and cell stiffness-based sorting. Further, GTM3L cells formed more CLANs on a stiff vs. a soft substrate. Computational modeling predicted that CLANs contribute to higher cell stiffness, including increased resistance of the nucleus to tensile stress when CLANs are physically linked to the nucleus.

Conclusions

It is possible to greatly enhance CLAN incidence in GTM3L cells. CLANs are mechanosensitive structures that affect cell biomechanical properties. Further research is needed to determine the effect of CLANs on TM biomechanics and mechanobiology as well as the etiology of CLAN formation in the TM.
A low-cost virtual reality stroke rehabilitation system: development and initial feasibility assessment
Authors: Fisk Aidan , Fox Summer , Floyd Jenna , Blustein Daniel
Published: August 2024

Stroke is a leading cause of disability worldwide. Following a stroke, high doses of intensive motor rehabilitation provide maximal benefit. Barriers to realizing recommended levels of rehabilitation therapy include cost, physical access, and clinical resource availability. Virtual Reality (VR) offers a potential solution to overcome these challenges and enable home-based, self-directed therapy. Here we present a low-cost system utilizing the off-the-shelf Meta Quest 2 headset running custom software to deliver immersive rehabilitation exercises. The system employs movement amplification to partially reduce motor deficits and enable more engaging task completion. It leverages recent advances in VR technology, including inside-out hand tracking, voice recognition, and an AI-driven virtual coach, to create a more accessible environment for users with no prior VR experience. We present the development of the virtual rehabilitation implementation and an initial feasibility assessment to determine if motor amplification increases the visually induced motion sickness experienced by the user. We find that motor amplification does not result in additional reported motion sickness suggesting that low-cost VR systems may serve as a feasible option to increase individualized and guided post-stroke motor rehabilitation.
Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production
Authors: Borges Kleiton S. , Little Donald W. , de Almeida Magalhães Taciani , Ribeiro Claudio , Dumontet Typhanie , Lapensee Chris , Basham Kaitlin J. , Seth Aishwarya , Azova Svetlana , Guagliardo Nick A. , Barrett Paula Q. , Berber Mesut , O’Connell Amy E. , Turcu Adina F. , Lerario Antonio Marcondes , Mohan Dipika R. , Rainey William , Carlone Diana L. , Hirschhorn Joel N. , Salic Adrian , Breault David T. , Hammer Gary D.
Published: August 2024

The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant inWNT2Band an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss ofWnt2bin the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboringWNT2Bloss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications.

Highlights

WNT2Bvariant is associated with increased risk for primary aldosteronism

Wnt2bknock-out mice show defects in adrenal morphology

Wnt2bknock-out mice have hyperreninemic hypoaldosteronism

WNT2B activates non-canonical Wnt/planar cell polarity signaling

WNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism
Amyloid-β deposition in basal frontotemporal cortex is associated with selective disruption of temporal mnemonic discrimination
Authors: Vanderlip Casey R. , Taylor Lisa , Kim Soyun , Harris Alyssa L. , Tuteja Nandita , Meza Novelle , Escalante Yuritza Y. , McMillan Liv , Yassa Michael A. , Adams Jenna N.
Published: August 2024

Cerebral amyloid-beta (Aβ) accumulation, a hallmark pathology of Alzheimer’s disease (AD), precedes clinical impairment by two to three decades. However, it is unclear whether Aβ contributes to subtle memory deficits observed during the preclinical stage. The heterogenous emergence of Aβ deposition may selectively impact certain memory domains, which rely on distinct underlying neural circuits. In this context, we tested whether specific domains of mnemonic discrimination, a neural computation essential for episodic memory, exhibit specific deficits related to early Aβ deposition. We tested 108 cognitively unimpaired human older adults (66% female) who underwent 18F-florbetapir positron emission tomography (Aβ-PET), and a control group of 35 young adults, on a suite of mnemonic discrimination tasks taxing object, spatial, and temporal domains. We hypothesized that Aβ pathology would be selectively associated with temporal discrimination performance due to Aβ’s propensity to accumulate in the basal frontotemporal cortex, which supports temporal processing. Consistent with this hypothesis, we found a dissociation in which generalized age-related deficits were found for object and spatial mnemonic discrimination, while Aβ-PET levels were selectively associated with deficits in temporal mnemonic discrimination. Further, we found that higher Aβ-PET levels in medial orbitofrontal and inferior temporal cortex, regions supporting temporal processing, were associated with greater temporal mnemonic discrimination deficits, pointing to the selective vulnerability of circuits related to temporal processing early in AD progression. These results suggest that Aβ accumulation within basal frontotemporal regions may disrupt temporal mnemonic discrimination in preclinical AD, and may serve as a sensitive behavioral biomarker of emerging AD progression.
Lamellar Schwann cells in the Pacinian corpuscle potentiate vibration perception
Authors: Chen Yuh-Tarng , de Thomas Wagner Dominica , Loutit Alastair J. , Nourizonoz Ali , Croisier-Coeytaux Mary-Claude , Blanc Jérôme , Knott Graham , Lee Kuo-Sheng , Huber Daniel
Published: August 2024

Pacinian corpuscles are among the most sensitive mechanoreceptors found in vertebrates and they are tuned to vibrations in the highest perceptible frequency range (100-2000Hz). One of their anatomical hallmarks is the onion-like cell layers surrounding the central axon. The innermost layers consist of ∼60 densely packed lamellar Schwann cells (LSCs), whose function remains largely unknown. Using high-resolution 3D electron microscopy we found that LSCs in Pacinian corpuscles of the mouse hindlimb do not form concentric rings, but complex, multilayered and intertwining assemblies that are connected via an estimated 5805.1 desmosomes and 4142.5 gap-junctions. LSCs make multiple converging contacts with the afferent axon and its protrusions with desmosomes. Using optogenetic manipulations of LSCs we demonstrate that their activation does not only drive reliable time-locked spiking in the axon, but that their inactivation significantly elevates the thresholds in-situ and increases perceptual thresholds behaviorally. Together these findings provide evidence that LSCs are a key element of somatosensory processing, actively potentiating mechanosensitivity in Pacinian corpuscles.

Highlights

High-resolution electron microscopy reveals details of the Pacinian corpuscle

Lamellar Schwann cells form claw-like structures with converging axonal contacts

Schwann-cell modulation bidirectionally affects neural coding of Pacinian afferent

Inactivation of lamellar Schwann-cells increases perceptual thresholds
Exploring symbiotic legume-rhizobia relationships across tropical species
Authors: Rojas-Jimenez Keilor , Morera-Huertas Jessica , de Bedout-Mora Marianne , Loria-Vinueza Beatriz , Zuniga-Orozco Andres , Molina-Mora Jose Arturo , Solis-Ramos Laura , Blanco Mario A. , Valverde-Barrantes Oscar J.
Published: August 2024

The nitrogen-fixing symbiosis with rhizobia significantly contributes to the successful establishment of legumes in tropical environments. Here, we explored the symbiotic interactions between legumes and rhizobia across 109 tropical species. We evaluated the presence of root nodules in 72 genera spanning four Fabaceae subfamilies, encompassing 53% of the genera in Costa Rica and approximately 9.4% globally. Our analysis revealed root nodules in 78% of the species belonging to Caesalpinioideae (67%) and Papilionoideae (84%). Also, we formulated a predictive model for nodulation in legumes, with fine-root color and flower symmetry as the main predictor criteria. Nodulating taxa consistently presented higher N levels in tissues, thinner roots, and a pronounced phylogenetic influence on nodulation. We also identified the bacterial genera associated with all nodulating legumes. Caesalpinioideae formed symbiotic relationships with ten rhizobial genera, whereas Papilionoideae were associated with only four. Bradyrhizobium emerged as the predominant symbiont in nodules, while Rhizobium, Mesorhizobium, Agrobacterium, Paraburkholderia, and Cupriavidus exhibited a more restricted host range. Furthermore, genomic analysis suggests that 15 out of the 22 sequenced rhizobial strains may represent novel species. Our study enhances the understanding of the different dimensions that comprise legume-rhizobia interactions, incorporating a diverse array of previously unexamined tropical forest legume taxa.