bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the Risk of Conflict on Recent Ebola Outbreaks in Guinea and the Democratic Republic of the Congo
Authors: Charnley Gina E C , Green Nathan , Kelman Ilan , Malembaka Espoir B , Gaythorpe Katy A M
Published: June 2023

Background

Reducing Ebola virus transmission relies on the ability to identify cases and limit contact with infected bodily fluids through biosecurity, safe sex practices, safe burial and vaccination. Armed conflicts can complicate outbreak detection and interventions due to widespread disruption to governments and the populations. Guinea and the Democratic Republic of the Congo (DRC) have historically reported the largest and the most recent Ebola virus outbreaks. Understanding if conflict played a role in these outbreaks may help in identifying key risks factors to improve disease control.

Methods

We used data from a range of publicly available data sources for both Ebola virus cases and conflict events from 2018 to 2021 in Guinea and the DRC. We fitted these data to conditional logistic regression models using the Self-Controlled Case Series methodology to evaluate the magnitude in which conflict increased the risk of reported Ebola virus cases in terms of incidence rate ratio. We re-ran the analysis sub-nationally, by conflict sub-event type and tested any lagged effects.

Results

Conflict was significantly associated with an increased risk of reported Ebola virus cases in both the DRC and Guinea in recent outbreaks. The effect was of a similar magnitude at 1.88- and 1.98-times increased risk for the DRC and Guinea, respectively. The greatest effects (often higher than the national values) were found in many conflict prone areas and during protest/riot-related conflict events. Conflict was influential in terms of Ebola virus risk from 1 week following the event and remained important by 10 weeks.

Conclusion

Extra vigilance is needed following protests and riot-related conflict events in terms of Ebola virus transmission. These events are highly disruptive, in terms of access to transportation and healthcare and are often in urban areas with high population densities. Additional public health messaging around these types of conflict events, relating to the risks and clinical symptoms may be helpful in reducing transmission. Future work should aim to further understand and quantify conflict severity and intensity, to evaluate dose-response relationships in terms of disease risk.
Provider-led community Antiretroviral Therapy distribution in Malawi: Retrospective cohort study of retention, viral load suppression, and costs
Authors: Songo John , Whitehead Hannah , Nichols Brooke , Makwaya Amos , Njala Joseph , Phiri Sam , Hoffman Risa M. , Dovel Kathryn , Phiri Khumbo , van Oosterhout Joep J.
Published: June 2023

Background

Outcomes of community antiretroviral therapy (ART) distribution (CAD), in which provider–led ART teams deliver integrated HIV services at health posts in communities, have been mixed in sub-Saharan African countries. CAD outcomes and costs relative to facility-based care have not been reported from Malawi.

Methods

We performed a retrospective cohort study in two Malawian districts (Lilongwe and Chikwawa districts), comparing CAD with facility-based ART care. We selected an equal number of clients in CAD and facility-based care who were aged >13 years, had an undetectable viral load (VL) result in the last year and were stable on first-line ART for ≥1 year. We compared retention in care (alive and no period of ≥60 days without ART) using Kaplan-Meier survival analysis and Cox regression and maintenance of VL suppression (<1,000 copies/mL) during follow-up using logistic regression. We also compared costs (in US$) from the health system and client perspectives for the two models of care. Data were collected in October and November 2020.

Results

700 ART clients (350 CAD, 350 facility-based) were included. The median age was 43 years (IQR 36-51), median duration on ART was 7 years (IQR 4-9), and 75% were female. Retention in care did not differ significantly between clients in CAD (89.4% retained) and facility-based care (89.3%), p=0.95. No significant difference in maintenance of VL suppression were observed between CAD and facility-based care (aOR: 1.24, 95% CI: 0.47-3.20, p=0.70). CAD resulted in slightly higher health system costs than facility-based care: $118/year vs. $108/year per person accessing care; and $133/year vs. $122/year per person retained in care. CAD decreased individual client costs compared to facility-based care: $3.20/year vs. $11.40/year per person accessing care; and $3.60/year vs. $12.90/year per person retained in care.

Conclusion

Clients in provider-led CAD care in Malawi had very good retention in care and VL suppression outcomes, similar to clients receiving facility-based care. While health system costs were somewhat higher with CAD, costs for clients were reduced substantially. More research is needed to understand the impact of other differentiated service delivery models on costs for the health system and clients.
Intrinsic functional brain connectivity changes following aerobic exercise, computerized cognitive training and their combination in healthy late-middle-aged adults: the Projecte Moviment
Authors: Dimitriadis Stavros I. , Castells-Sánchez Alba , Roig-Coll Francesca , Dacosta-Aguayo Rosalía , Lamonja-Vicente Noemí , Torán-Monserrat Pere , García-Molina Alberto , Monte-Rubio Gemma , Stillman Chelsea , Perera - Lluna Alexandre , Mataró Maria
Published: June 2023

Lifestyle interventions have positive neuroprotective effects in aging. However, there are still open questions about how changes in resting-state functional connectivity (rsFC) contribute to cognitive improvements. The Projecte Moviment is a 12-weeks randomized controlled trial of a multimodal data acquisition protocol that investigated the effects of aerobic exercise (AE), computerized cognitive training (CCT), and their combination (COMB). An initial list of 109 participants was recruited from which a total of 82 participants (62% female; age = 58.38 ± 5.47) finished the intervention with a level of adherence > 80%. We report intervention-related changes in rsFC, and their potential role as mediators of cognitive benefits. For the AE group, we revealed a limited network of 11 connections showing an increased rsFC that involved mainly the anterior default mode network (aDMN), the posterior default mode network (pDMN : left middle temporal gyrus, and right precuneus), and a decreased rsFC that involved the pDMN (left fusiform gyrus (pDMN), right middle temporal gyrus (pDMN), left and right precentral gyrus), the hippocampus, bilateral supplementary motor areas, and the right thalamus. For the CCT group, we untangled a limited network of 6 connections as a combination of increased and decreased rsFC between brain areas located mainly in the aDMN and pDMN. In the COMB group, we revealed an extended network of 33 connections that involved an increased and decreased rsFC within and between the aDMN/pDMN and a reduced rsFC between the bilateral supplementary motor areas and the right thalamus. No global and especially local rsFC changes due to any intervention mediated the cognitive benefits detected in the AE and COMB groups. Projecte Moviment provides evidence of the clinical relevance of lifestyle interventions and the potential benefits when combining them.
LncRNA antigens- a novel resource to improve immunotherapy efficacy predictions in Melanoma
Authors: Malik Sumaira , Golden Aaron
Published: June 2023

Background

ICI (immune checkpoint inhibitor) therapy is one of the most promising treatments for melanoma. ICI response however varies among patients, emphasizing the importance of identifying genomic biomarkers to predict likely therapeutic efficacy in advance of treatment. We hypothesised that a lncRNA based immunogencity (lnc-IM) score could be used to predict individual response to ICI treatment, and that this could complement the existing criterion for ICI selection based on tumor mutation burden (TMB).

Methodology

The TCGA-SKCM (n=101) and the ICI treated UCLA (n=25), MSKCC (n=16) and DFCI (n=40) melanoma cohorts were used in this study, involving both clinical and transcriptomic data. Each patient was assigned an lnc-IM score based on the number of lncRNA sORF derived peptides predicted to be presented by their tumor’s MHC-I genotype. For the ICI treated cohorts, a combined antigen score was defined as a sum of neo-antigen load (derived from TMB) and lnc-IM score. A logistic regression-based classifier was used to predict ICI responses based on these combined antigen scores.

Results

Survival analysis showed improved overall survival among patients with low lnc-IM scores (HR= 0.39, p=0.009) in the TCGA-SKCM cohort. We also observed a negative association between tumor immune cell concentration and lnc-IM scores, with low lnc-IM groups showing higher anti-tumor immune cell concentrations . Using the ICI treated cohorts, we demonstrated that a classifier based on combined antigen scoring improved the prediction of immunotherapy outcomes as compared to using TMB alone, yielding an area under the curve (AUC) of 0.71 with an accuracy of 0.54 and recall of 1. We also demonstrated a reduced rate of false negatives (14%) by using a combined antigen score as compared to the use of TMB alone (33%) in ICI treated cohorts.

Conclusion

Our findings suggest that the use of combined antigen scores (using lnc-IM scores along with TMB derived neoantigen load) have potential in improving immunotherapy efficacy predictions. Prospective validation in larger cohort sizes is warranted.

KEY MESSAGES:

What is already known on this topic

Previous studies have established actionable associations between TMB neoantigen load and immunotherapy responses.

What this study adds

This study introduces lnc-IM scores as a novel metric that predicts patients antigen load based on translatable lncRNAs expression. These lnc-IM scores when combined with TMB associated neoantigen load indicate an improvement in immunotherapy efficacy predictions.

How this study might affect research, practice or policy

Future research is needed to further validate lnc-IM scores as a predictive biomarker for immunotherapy response in various cancer types. The use of lnc-IM scores can empower clinicians to make more informed decisions about administering immunotherapy treatments, improvingpatient outcomes.
CURRENT TRENDS IN HOSPICE CARE USAGE FOR DIALYSIS PATIENTS IN THE USA
Authors: Soipe Ayorinde I , Leggat John E , Abioye Ajibola I , Devkota Kriti , Oke Fausat , Bhuta Kunal , Omotayo Moshood O
Published: June 2023

Background

This study examined the predictors and latest trends in hospice utilization, adequate duration of hospice care, and dialysis discontinuation without hospice enrollment among patients with end stage renal disease (ESRD).

Methods

Data from the United States Renal Data System (USRDS) for ESRD patients who died between January 1, 2012, and December 31, 2019, were analyzed. Chi-square and logistic regression were used to evaluate associations between outcomes of interest and predictors while Joinpoint regression was used to examine trends.

Results

Among 803,049 patients, the median (IQR) age was 71 (17) years, 57% were male, 27% enrolled in hospice, 8% discontinued dialysis before death without hospice enrollment, and 7% remained in hospice for ≥15 days. Patients older than 64 years (adjusted odds ratio [aOR]: 2.75, 95% CI: 2.71-2.79) and white race (aOR: 1.79, 95% CI: 1.77-1.81) were more likely to enroll in hospice. White patients (aOR: 0.75, 95% CI: 0.73-0.76) and those who never received a kidney transplant (aOR: 0.75, 95% CI: 0.73-0.78) were less likely to have adequate duration of hospice care. Hospice enrollment and standardized duration of hospice care increased over time, with an average annual percentage change (AAPC) of 1.1% (95% CI:0.6 – 1.6) and 5% (95% CI:2.6 – 7.4) respectively.

Conclusions

Approximately one in every four ESRD patients who died between 2012 and 2019 had a history of hospice enrollment, while one in every 12 discontinued dialysis before death without hospice enrollment. There was an upward trend in the standardized duration of hospice care.
Machine Learning Interpretability Methods to Characterize the Importance of Hematologic Biomarkers in Prognosticating Patients with Suspected Infection
Authors: Upadhyaya Dipak P , Tarabichi Yasir , Prantzalos Katrina , Ayub Salman , Kaelber David C , Sahoo Satya S
Published: June 2023

Abstract Early detection of sepsis in patients admitted to the emergency department (ED) is an important clinical objective as early identification and treatment can help reduce morbidity and mortality rate of 20% or higher. Hematologic changes during sepsis-associated organ dysfunction are well established and a new biomarker called Monocyte Distribution Width (MDW) has been recently approved by the US Food and Drug Administration for sepsis. However, MDW, which quantifies monocyte activation in sepsis patients, is not a routinely reported parameter and it requires specialized proprietary laboratory equipment. Further, the relative importance of MDW as compared to other routinely available hematologic parameters and vital signs has not been studied, which makes it difficult for resource constrained hospital systems to make informed decisions in this regard. To address this issue, we analyzed data from a cohort of ED patients (n=10,229) admitted to a large regional safety-net hospital in Cleveland, Ohio with suspected infection who later developed poor outcomes associated with sepsis. We developed a new analytical framework consisting of seven data models and an ensemble of high accuracy machine learning (ML) algorithms (accuracy values ranging from 0.83 to 0.90) for the prediction of outcomes more common in sepsis than uncomplicated infection (3-day intensive care unit stay or death). To characterize the contributions of individual hematologic parameters, we applied the Local Interpretable Model-Agnostic Explanation (LIME) and Shapley Additive Value (SHAP) interpretability methods to the high accuracy ML algorithms. The ML interpretability results were consistent in their findings that the value of MDW is grossly attenuated in the presence of other routinely reported hematologic parameters and vital signs data. Further, this study for the first time shows that complete blood count with differential (CBC-DIFF) together with vital signs data can be used as a substitute for MDW in high accuracy ML algorithms to screen for poor outcomes associated with sepsis.
Evaluating ChatGPT-4 in Otolaryngology–Head and Neck Surgery Board Examination using the CVSA Model
Authors: Long Cai , Lowe Kayle , Santos André dos , Zhang Jessica , Alanazi Alaa , O’Brien Daniel , Wright Erin , Cote David
Published: June 2023

Background

ChatGPT is among the most popular Large Language Models (LLM), exhibiting proficiency in various standardized tests, including multiple-choice medical board examinations. However, its performance on Otolaryngology–Head and Neck Surgery (OHNS) board exams and open-ended medical board examinations has not been reported. We present the first evaluation of LLM (ChatGPT-4) on such examinations and propose a novel method to assess an artificial intelligence (AI) model’s performance on open-ended medical board examination questions.

Methods

Twenty-one open end questions were adopted from the Royal College of Physicians and Surgeons of Canada’s sample exam to query ChatGPT-4 on April 11th, 2023, with and without prompts. A new CVSA (concordance, validity, safety, and accuracy) model was developed to evaluate its performance.

Results

In an open-ended question assessment, ChatGPT-4 achieved a passing mark (an average of 75% across three trials) in the attempts. The model demonstrated high concordance (92.06%) and satisfactory validity. While demonstrating considerable consistency in regenerating answers, it often provided only partially correct responses. Notably, concerning features such as hallucinations and self-conflicting answers were observed.

Conclusion

ChatGPT-4 achieved a passing score in the sample exam, and demonstrated the potential to pass the Canadian Otolaryngology–Head and Neck Surgery Royal College board examination. Some concerns remain due to its hallucinations that could pose risks to patient safety. Further adjustments are necessary to yield safer and more accurate answers for clinical implementation.
EHR-QC: A streamlined pipeline for automated electronic health records standardisation and preprocessing to predict clinical outcomes
Authors: Ramakrishnaiah Yashpal , Macesic Nenad , Peleg Anton Y. , Tyagi Sonika
Published: June 2023

The adoption of electronic health records (EHRs) has created opportunities to analyze historical data for predicting clinical outcomes and improving patient care. However, non-standardized data representations and anomalies pose major challenges to the use of EHRs in digital health research. To address these challenges, we have developed EHR-QC, a tool comprising two modules: the data standardization module and the preprocessing module. The data standardization module migrates source EHR data to a standard format using advanced concept mapping techniques, surpassing expert curation in benchmarking analysis. The preprocessing module includes several functions designed specifically to handle healthcare data subtleties. We provide automated detection of data anomalies and solutions to handle those anomalies. We believe that the development and adoption of tools like EHR-QC is critical for advancing digital health. Our ultimate goal is to accelerate clinical research by enabling rapid experimentation with data-driven observational research to generate robust, generalisable biomedical knowledge.

Highlights

EHR-QC accepts EHR data from a relational database or as a flat file and provide an easy-to-use, customized, and comprehensive solution for data handling activities.

It offers a modular standardization pipeline that can convert any EHR data to a standardized data model i.e. OMOP-CDM.

It includes an innovative algorithmic solution for clinical concept mapping that surpasses the current expert curation process.

We have demonstrated that the imputation performance depends on the nature and missing proportion, hence as part of EHR-QC we included a method that searches for the best imputation method for the given data.

It also contains an end-to-end solution to handle other anomalies such as outliers, errors, and other inconsistencies in the EHR data.
Single-cell Spatial Metabolic and Immune Phenotyping of Head and Neck Cancer Tissues Identifies Tissue Signatures of Response and Resistance to Immunotherapy
Authors: Jhaveri Niyati , Cheikh Bassem Ben , Nikulina Nadezhda , Ma Ning , Klymyshyn Dmytro , DeRosa James , Mihani Ritu , Pratapa Aditya , Kassim Yasmin , Bommakanti Sidharth , Shang Olive , He Yan , Zheng Yi , Monkman James , Cooper Caroline , O’Byrne Ken , Anand Bhaskar , Prater Michael , Basu Subham , Hughes Brett G.M. , Kulasinghe Arutha , Braubach Oliver
Published: June 2023

Head and neck squamous cell carcinomas (HNSCC) are the seventh most common cancer and represent a global health burden. Immune checkpoint inhibitors (ICIs) have shown promise in treating recurrent/metastatic cases, with durable benefit in ∼30% of patients. Current biomarkers for head and neck tumors are limited in their dynamic ability to capture tumor microenvironment (TME) features, with an increasing need for deeper tissue characterization. Therefore, new biomarkers are needed to accurately stratify patients and predict responses to therapy. Here, we have optimized and applied an ultra-high plex, single-cell spatial protein analysis in HNSCC. Tissues were simultaneously analyzed with a panel of 101 antibodies that targeted biomarkers related to tumor immune, metabolic and stress microenvironments. Our data uncovered a high degree of intra-tumoral heterogeneity intrinsic to head and neck tumors and provided unique insights into the biology of the tumor. In particular, a cellular neighborhood analysis revealed the presence of 6 unique spatial tumor-immune neighborhoods enriched in functionally specialized immune cell subsets across the patient tissue. Additionally, functional phenotyping based on key metabolic and stress markers identified four distinct tumor regions with differential protein signatures. One tumor region was marked by infiltration of CD8+ cytotoxic T cells and overexpression of BAK, a proapoptotic regulator, suggesting strong immune activation and stress. Another adjacent region within the same tumor had high expression of G6PD and MMP9, known drivers of tumor resistance and invasion respectively. This dichotomy of immune activation-induced death and tumor progression in the same sample demonstrates the heterogenous niches and competing microenvironments that underpin clinical responses of therapeutic resistance. Our data integrate single-cell ultra-high plex spatial information with the functional state of the tumor microenvironment to provide insights into a partial response to immune checkpoint inhibitor therapy in HNSCC. We believe that the approach outlined in this study will pave the way towards a new understanding of TME features associated with response and sensitivity to ICI therapies.
A semi-quantitative, rapid, point of care SARS-CoV-2 serologic assay predicts neutralizing antibody levels
Authors: Markmann Alena J. , Bhowmik D. Ryan , Jiang Baowei , Van Hoy Michael , Wang Frank , Hou Yixuan J. , Baric Ralph S. , de Silva Aravinda M. , Bartelt Luther A.
Published: June 2023

The ongoing COVID-19 pandemic has caused millions of deaths and the continued emergence of new variants suggests continued circulation in the human population. In the current time of vaccine availability and new therapeutic development, including antibody-based therapies, many questions about long-term immunity and protection remain uncertain. Identification of protective antibodies in individuals is often done using highly specialized and challenging assays such as functional neutralizing assays, which are not available in the clinical setting. Therefore, there is a great need for the development of rapid, clinically available assays that correlate with neutralizing antibody assays to identify individuals who may benefit from additional vaccination or specific COVID-19 therapies. In this report, we apply a novel semi-quantitative method to an established lateral flow assay (sqLFA) and analyze its ability to detect the presence functional neutralizing antibodies from the serum of COVID-19 recovered individuals. We found that the sqLFA has a strong positive correlation with neutralizing antibody levels. At lower assay cutoffs, the sqLFA is a highly sensitive assay to identify the presence of a range of neutralizing antibody levels. At higher cutoffs, it can detect higher levels of neutralizing antibody with high specificity. This sqLFA can be used both as a screening tool to identify individuals with any level of neutralizing antibody to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), or as a more specific tool to identify those with high neutralizing antibody levels who may not benefit from antibody-based therapies or further vaccination.
A framework for identifying fertility gene targets for mammalian pest control
Authors: Clark Anna C , Alexander Alana , Edison Rey , Esvelt Kevin , Kamau Sebastian , Dutoit Ludovic , Champer Jackson , Champer Samuel E , Messer Philipp W , Gemmell Neil J
Published: June 2023

Fertility-targeted gene drives have been proposed as an ethical genetic approach for managing wild populations of vertebrate pests for public health and conservation benefit.

This manuscript introduces a framework to identify and evaluate target gene suitability based on biological gene function, gene expression, and results from mouse knockout models.

This framework identified 16 genes essential for male fertility and 12 genes important for female fertility that may be feasible targets for mammalian gene drives and other non-drive genetic pest control technology. Further, a comparative genomics analysis demonstrates the conservation of the identified genes across several globally significant invasive mammals.

In addition to providing important considerations for identifying candidate genes, our framework and the genes identified in this study may have utility in developing additional pest control tools such as wildlife contraceptives.
Deleterious functional consequences of perfluoroalkyl substances accumulation into the myelin sheath
Authors: Butruille L. , Jubin P. , Martin E. , Aigrot MS. , Lhomme M. , Fini JB. , Demeneix B. , Stankoff B. , Lubetzki C. , Zalc B. , Remaud S.
Published: June 2023

Exposure to persistent organic pollutants during the perinatal period is of particular concern because of the potential increased risk of neurological disorders in adulthood. Here we questioned whether exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) could alter myelin formation and regeneration. First, we show that PFOS, and to a lesser extent PFOA, accumulated into the myelin sheath of postnatal day 21 (p21) mice, whose mothers were exposed to either PFOA or PFOS (20mg/L)viadrinking water during late gestation and lactation, suggesting that accumulation of PFOS into the myelin could interfere with myelin formation and function. In fact, PFOS, but not PFOA, disrupted the generation of oligodendrocytes, the myelin-forming cells of the central nervous system, derived from neural stem cells localised in the subventricular zone of p21 exposed animals. Then, cerebellar slices were transiently demyelinated using lysophosphatidylcholine and remyelination was quantified in the presence of either PFOA or PFOS. Only PFOS impaired remyelination, a deleterious effect rescued by adding thyroid hormone (TH). Similarly to our observation in the mouse, we also showed that PFOS altered remyelination inXenopus laevisusing the Tg(Mbp:GFP-ntr) model of conditional demyelination and measuring, then, the number of oligodendrocytes. The functional consequences of PFOS-impaired remyelination were shown by its effects using a battery of behavioural tests. In sum, our data demonstrate that perinatal PFOS exposure disrupts oligodendrogenesis and myelin function through modulation of TH action. PFOS exposure may exacerbate genetic and environmental susceptibilities underlying myelin disorders, the most frequent being multiple sclerosis.

Highlights

Our investigation points the deleterious effects of PFOS incorporation into the myelin sheath

PFOS interfere dramatically with the generation of remyelinating and functional repair of demyelinating lesions

Our study points to a potential link between these persistent pollutants and the recent increase in prevalence of multiple sclerosis
An ethogram method for the analysis of human distress in the aftermath of public conflicts
Authors: Pallante Virginia , Ejbye-Ernst Peter , Lindegaard Marie Rosenkrantz
Published: June 2023

Research on nonhuman animals has widely documented the behavioural expression of distress in a conflict context. In humans, however, this remains largely unknown due to the lack of direct access to real-life conflict events. Here, we took the aftermath of 129 video recorded street fights and applied the ethological method to explore the behavioural cues of people previously involved in a fight. Drawing on observations on nonhuman behaviour and inductively identified behaviours, we developed and inter-coder reliability tested an ethogram for the behavioural repertoire of distress. We further quantitively analysed the behaviours with a correlation matrix and PCA, that revealed that the behaviours we observed were not displayed in combination with each other, showing a variability in how people express distress. Since both human and nonhuman primates react to conflict situations with similar expressions of distress, we suggest a comparative approach to understand the evolutionary roots of human behaviour.
Albumin-binding recombinant human IL-18BP ameliorates macrophage activation syndrome and atopic dermatitis via direct IL-18 inactivation
Authors: Jang Young-Saeng , Lee Kyungsun , Park Mihyun , Park Jin Joo , Choi Ga Min , Kim Chohee , Dehkohneh Shima Barati , Chi Susan , Han Jaekyu , Song Moo Young , Han Yong-Hyun , Cha Sang-Hoon , Kang Seung Goo
Published: June 2023

Given the clinical success of cytokine blockade in managing diverse inflammatory human conditions, this approach could be exploited for numerous refractory or uncontrolled inflammatory conditions by identifying novel targets for functional blockade. IL-18, a pro-inflammatory cytokine, is relatively underestimated as a therapeutic target, despite accumulated evidence indicating the unique roles of IL-18 in acute and chronic inflammatory conditions, such as macrophage activation syndrome. Herein, we designed a new form of IL-18 blockade, i.e., APB-R3, a long-acting recombinant human IL-18BP linked to human albumin-binding Fab fragment, SL335, for extending half-life. We then explored the pharmacokinetics and pharmacodynamics of APB-R3. In addition to an extended serum half-life, APB-R3 alleviates liver inflammation and splenomegaly in a model of the macrophage activation syndrome induced in IL-18BP knockout mice. Moreover, APB-R3 substantially controlled skin inflammation in a model of atopic dermatitis. Thus, we report APB-R3 as a new potent IL-18 blocking agent that could be applied to treat IL-18-mediated inflammatory diseases.
Assessment ofBlighia sapidaon Cholinergic and Antioxidant Enzymes; Possible Use of the Plant Stem-Bark Extract as a Biological Pest Controlling Agent
Authors: Adekola M.B. , Oriyomi O.V.
Published: June 2023

The harmful effects of synthetic pesticides include neurological, behavioural dysfunctions, hormonal imbalances, and water pollution. Hydro-alcohol extract of the stem bark ofB. sapidawas studied for pesticidal effects on Glutathione S-transferases (GST) and acetylcholinesterase (AChE) using a rat model. Various concentrations of the extract were administered to six different groups, of three male and three female groups of rats (50 mg/kg, 100 mg/kg and 150 mg/kg bwt. respectively), two synthetic 10% (w/v) groups and a control group. Blood plasma, liver, and brain were obtained at the end of 28 days sub-acute test, from the Wistar rats for biochemical assay.

The results showed that there was a significant decrease (P < 0.05) in acetylcholinesterase (AChE) activities in the brain of female rats while that of males was not significant (P > 0.05) compared to control. Also in GST, a significant increase (P < 0.05) in all the doses in liver but only at 100 mg/kg and 150 mg/kg in plasma of female rats, was observed compared to control while in male rats, a significant increase in both liver and plasma at 100 mg/kg and 150 mg/kg but not significant at 50 mg/kg was observed. The non-significant difference was observed in alkaline phosphatase (ALP) aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total protein (TP) activities in both sexes at 50 mg/kg compared to control.

It was concluded that hydro-alcohol extract ofB. sapidasignificantly reduced the levels of AChE and GST activities at higher and lower doses respectively. This property of the plant could be exploited in the formulation of agents useful in pest control.
Remodelling of the endothelial cell transcriptional program via paracrine and DNA-binding activities of MPO
Authors: Zheng Ruiyuan , Moynahan Kyle , Georgomanolis Theodoros , Pavlenko Egor , Geissen Simon , Mizi Athanasia , Grimm Simon , Nemade Harshal , Rehimi Rizwan , Bastigkeit Jil , Lackmann Jan-Wilm , Adam Matti , Rada-Iglesias Alvaro , Nuernberg Peter , Klinke Anna , Poepsel Simon , Baldus Stephan , Papantonis Argyris , Kargapolova Yulia
Published: June 2023

Myeloperoxidase (MPO) is an enzyme that functions in host defence by catalysing the formation of reactive oxygen intermediates. Synthesized majorly by myeloid progenitor cell types and neutrophils, MPO is released into the vascular lumen during inflammation, where it may adhere and subsequently enter endothelial cells coating vascular walls. Here, we show that MPO actually enters the nucleus of these endothelial cells and binds chromatin independently of its enzymatic activity to cause changes in chromatin structure. At its binding sites, MPO drives chromatin decondensation, while enhancing condensation at flanking regions. We further show that MPO binds loci relevant for the activation of the endothelial-to- mesenchymal transition (EndMT) and the migratory potential of ECs. Finally, MPO interacts with the RNA- binding factor ILF3 affecting its relative abundance between cytoplasm and nucleus. This leads to ILF3:MPO- driven transcriptional and post-transcriptional regulation. Accordingly, MPO-knockout mice show reduced EC numbers at scars formed after myocardial infarction, indicating reduced neovascularization. In summary, we describe a non-enzymatic role for MPO in coordinating EndMT and controlling the fate of endothelial cells through direct chromatin binding and association with such co-factors as ILF3.
17α-estradiol Alleviates High-Fat Diet-Induced Inflammatory and Metabolic Dysfunction in Skeletal Muscle of Male and Female Mice
Authors: Bubak Matthew P. , Mann Shivani N. , Borowik Agnieszka K. , Pranay Atul , Batushansky Albert , Mondal Samim Ali , Diodge Stephen M. , Davidyan Arik , Szczygiel Marcelina M. , Peelor Fredrick R. , Rigsby Sandra , Broomfield Matle , Lacy Charles I. , Rice Heather C. , Stout Michael B. , Miller Benjamin F.
Published: June 2023

Skeletal muscle has a central role in maintaining metabolic homeostasis. 17α-estradiol (17α-E2), a naturally-occurring non-feminizing diastereomer of 17β-estradiol that demonstrates efficacy for improving metabolic outcomes in male, but not female, mice. Despite several lines of evidence showing that 17α-E2 treatment improves metabolic parameters in middle-aged obese and old male mice through effects in brain, liver, and white adipose tissue little is known about how 17α-E2 alters skeletal muscle metabolism, and what role this may play in mitigating metabolic declines. Therefore, this study aimed to determine if 17α-E2 treatment improves metabolic outcomes in skeletal muscle from obese male and female mice following chronic high fat diet (HFD) administration. We hypothesized that male, but not female, mice, would benefit from 17α-E2 treatment during HFD. To test this hypothesis, we used a multi-omics approach to determine changes in lipotoxic lipid intermediates, metabolites, and proteins related to metabolic homeostasis. In male mice, we show that 17α-E2 alleviates HFD-induced metabolic detriments of skeletal muscle by reducing the accumulation of diacylglycerol (DAGs) and ceramides, inflammatory cytokine levels, and reduced the abundance of most of the proteins related to lipolysis and beta-oxidation. In contrast to males, 17α-E2 treatment in female mice had little effect on the DAGs and ceramides content, muscle inflammatory cytokine levels, or changes to the relative abundance of proteins involved in beta-oxidation. These data support to the growing evidence that 17α-E2 treatment could be beneficial for overall metabolic health in male mammals.
A generic reference defined by consensus peaks for scATAC-seq data analysis
Authors: Meng Qiuchen , Wu Xinze , Chen Wenchang , Zhao Yubo , Li Chen , Wei Zheng , Li Jiaqi , Xi Xi , Chen Sijie , Zhang Catherine , Chen Shengquan , Li Jiaqi , Wang Xiaowo , Jiang Rui , Wei Lei , Zhang Xuegong
Published: June 2023

The rapid advancement of transposase-accessible chromatin using sequencing (ATAC-seq) technology, particularly with the emergence of single-cell ATAC-seq (scATAC-seq), has accelerated the studies of gene regulation. However, the absence of a generic feature reference for ATAC-seq data limits single-cell analyses and hinders the development of comprehensive cell atlases. To address this, we constructed a generic chromatin accessibility reference by aggregating peaks from 624 high-quality bulk ATAC-seq datasets, defining more than 1 million consensus peaks (cPeaks). Leveraging a deep neural network model, we expanded cPeaks to include previously unobserved regions, enhancing their coverage across diverse tissues and cell types. cPeaks exhibit consistent shapes across tissue types, sequencing technologies, and peak-calling methods, indicating that they represent inherent genomic features. Compared to existing feature defining methods and references, cPeaks show superior performance in scATAC-seq analyses, improving cell annotation and rare cell type identification. Additionally, cPeaks provide insights into chromatin dynamics during cellular differentiation and tumor progression. cPeaks can serve as a robust reference for chromatin accessibility studies to promote cross-dataset consistency and accelerate biological discoveries.
Microstructural dynamics of motor learning and sleep-dependent consolidation: a diffusion imaging study
Authors: Stee Whitney , Legouhy Antoine , Guerreri Michele , Villemonteix Thomas , Zhang Hui , Peigneux Philippe
Published: June 2023

Diffusion-weighted magnetic resonance imaging (DWI) allows the observation of (micro)structural brain remodelling in cortical and subcortical regions after time-limited motor learning. Post-learning sleep consolidation should lead to long-term microstructural brain changes, but concrete evidence remains limited. Here, we used both conventional diffusion tensor imaging (DTI) and Neurite Orientation Dispersion & Density Imaging (NODDI), that estimates dendritic and axonal complexity in white and grey matter, to investigate the microstructural brain mechanisms underlying time- and sleep-dependent motor memory consolidation. Sixty-one young healthy adults underwent 2 DWI sessions, with sequential motor training in between, on day 1 followed by the experimental night of total sleep deprivation or regular sleep. After 3 recovery nights at home, they underwent 2 further DWI sessions separated by a motor retraining session. Sequential motor learning resulted in immediate modifications in structural parameters in occipitoparietal and temporal regions, as well as in subcortical regions of interest. Similar changes were observed following relearning but at a smaller magnitude. Regarding delayed consolidation effects, learning-related changes only partially persisted 3 days after initial learning, and no post-learning sleep effect was detected. Our results show rapid motor learning-related remodelling, reflecting temporary processes in learning-related neuronal brain plasticity. Post-learning sleep-related cellular changes remain to be evidenced, possibly using more sophisticated brain imaging measures and spanning more extended timescales to allow the expression of structural changes.
RAMZIS: a bioinformatic toolkit for rigorous assessment of the alterations to glycoprotein structure that occur during biological processes
Authors: Hackett William Edwin , Chang Deborah , Carvalho Luis , Zaia Joseph
Published: June 2023

Motivation

Glycosylation elaborates the structures and functions of glycoproteins; glycoproteins are common post-translationally modified proteins and are heterogeneous and non-deterministically synthesized as an evolutionarily driven mechanism that elaborates the functions of glycosylated gene products. While glycoproteins account for approximately half of all proteins, their macro- and micro-heterogeneity requires specialized proteomics data analysis methods as a given glycosite can be divided into several glycosylated forms, each of which must be quantified. Sampling of heterogeneous glycopeptides is limited by mass spectrometer speed and sensitivity, resulting in missing values. In conjunction with the low sample size inherent to glycoproteomics, this necessitated specialized statistical metrics to identify if observed changes in glycopeptide abundances are biologically significant or due to data quality limitations.

Results

We developed an R package, Relative Assessment ofm/zIdentifications by Similarity (RAMZIS), that uses similarity metrics to guide biomedical researchers to a more rigorous interpretation of glycoproteomics data. RAMZIS uses contextual similarity to assess the quality of mass spectral data and generates graphical output that demonstrates the likelihood of finding biologically significant differences in glycosylation abundance dataset. Investigators can assess dataset quality, holistically differentiate glycosites, and identify which glycopeptides are responsible for glycosylation pattern expression change. Herein RAMZIS approach is validated by theoretical cases and by a proof-of-concept application. RAMZIS enables comparison between datasets too stochastic, small, or sparse for interpolation while acknowledging these issues in its assessment. Using our tool, researchers will be able to rigorously define the role of glycosylation and the changes that occur during biological processes.

Availability

https://github.com/WillHackett22/RAMZIS

Contact

Joseph Zaia, Boston University Medical Campus, 670 Albany St., rm 509, Boston, MA 02118 USA, (e)jzaia@bu.edu, (v) 1-617-358-2429

Supplementary information

Supplementary data are available
Role of XerCD in release of over-replicated DNA through Outer Membrane Vesicles inEscherichia coli
Authors: Mansky Johannes , Wang Hui , Wagner-Döbler Irene , Tomasch Jürgen
Published: June 2023

Outer membrane vesicles (OMVs) are universally produced by prokaryotes and play important roles in symbiotic and pathogenic interactions. Here we show that the GammaproteobacteriumEscherichia coliproduces OMVs that contain DNA enriched for the region around the terminus of replicationter, and specifically for the recognition sequencedifof the two site-specific recombinases XerCD, similar to OMVs from the AlphaproteobacteriumDinoroseobacter shibae. In deletion mutants ofxerCorxerD, the enriched region aroundterbecomes broader while the peak directly at thedifsequence itself is reduced.

Importance

Imprecise termination of replication can lead to over-replicated parts of bacterial chromosomes that have to be excised and removed from the dividing cell. The underlying mechanism is so far poorly understood. Our data suggest a conserved mechanism for repair and removal of over-replicated DNA through outer membrane vesicles and an active role of the site-specific XerCD recombinase complex therein.
Geospatially-resolved public-health surveillance via wastewater sequencing
Authors: Tierney Braden T , Foox Jonathan , Ryon Krista A , Butler Daniel , Damle Namita , Young Benjamin G , Mozsary Christopher , Babler Kristina M. , Yin Xue , Carattini Yamina , Andrews David , Solle Natasha Schaefer , Kumar Naresh , Shukla Bhavarth , Vidovic Dusica , Currall Benjamin , Williams Sion L. , Schürer Stephan C. , Stevenson Mario , Amirali Ayaaz , Beaver Cynthia C. , Kobetz Erin , Boone Melinda M. , Reding Brian , Laine Jennifer , Comerford Samuel , Lamar Walter E. , Tallon John J. , Hirschberg Jeremy Wain , Proszynski Jacqueline , Sharkey Mark E. , Church George M , Grills George S , Solo-Gabriele Helena M. , Mason Christopher E
Published: June 2023

Wastewater, which contains everything from pathogens to pollutants, is a geospatially-and temporally-linked microbial fingerprint of a given population. As a result, it can be leveraged for monitoring multiple dimensions of public health across locales and time. Here, we integrate targeted and bulk RNA sequencing (n=1,419 samples) to track the viral, bacterial, and functional content over geospatially distinct areas within Miami Dade County from 2020-2022. First, we used targeted amplicon sequencing (n=966) to track diverse SARS-CoV-2 variants across space and time, and we found a tight correspondence with clinical caseloads from University students (N = 1,503) and Miami-Dade County hospital patients (N = 3,939 patients), as well as an 8-day earlier detection of the Delta variant in wastewater vs. in patients. Additionally, in 453 metatranscriptomic samples, we demonstrate that different wastewater sampling locations have clinically and public-health-relevant microbiota that vary as a function of the size of the human population they represent. Through assembly, alignment-based, and phylogenetic approaches, we also detect multiple clinically important viruses (e.g.,norovirus) and describe geospatial and temporal variation in microbial functional genes that indicate the presence of pollutants. Moreover, we found distinct profiles of antimicrobial resistance (AMR) genes and virulence factors across campus buildings, dorms, and hospitals, with hospital wastewater containing a significant increase in AMR abundance. Overall, this effort lays the groundwork for systematic characterization of wastewater to improve public health decision making and a broad platform to detect emerging pathogens.
Insufficient serological evidence of the association between chronic kidney disease and leptospirosis in Badulla and Kandy districts, Sri Lanka
Authors: Fonseka Regina Amanda , Senarathne Pavani , Muthusinghe Devinda Shameera , Nanayakkara Nishantha , Gunaratne Lishantha , Yoshimatsu Kumiko , Koizumi Nobuo , Gamage Chandika Damesh
Published: June 2023

Objective

Chronic kidney disease (CKD) and chronic kidney disease of uncertain etiology (CKDu) are chronic kidney diseases that pose a significant health burden in Sri Lanka. Leptospirosis is a bacterial zoonosis that primarily damages renal tissues by colonization ofLeptospiraspp. in the renal tubules and is a suspected etiological agent of CKDu. Since Sri Lanka is an endemic for leptospirosis and outbreaks of the disease have been reported, this study aimed to determine the association between leptospirosis and chronic kidney disease in two geographically distinct regions of Sri Lanka, Badulla (CKDu endemic) and Kandy (CKDu non-endemic) districts.

Results

Eighty-five patients with CKDu and 149 controls from Badulla and 49 patients with CKD and 135 controls from Kandy were serologically tested by microscopic agglutination test with a panel of 11Leptospiraserogroups. The seroprevalence rates for leptospirosis were 7.1% and 13.4% in the CKDu and control groups, respectively, in Badulla and 2.1% and 18.5% in the CKD and control groups, respectively, in Kandy. There were no statistically significant differences between demographic characteristics and leptospirosis seropositivity in the CKD and control groups in either Badulla or Kandy.