bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbes with higher metabolic independence are enriched in human gut microbiomes under stress
Authors: Veseli Iva , Chen Yiqun T. , Schechter Matthew S. , Vanni Chiara , Fogarty Emily C. , Watson Andrea R. , Jabri Bana A. , Blekhman Ran , Willis Amy D. , Yu Michael K. , Fernandez-Guerra Antonio , Fussel Jessika , Eren A. Murat
Published: May 2023

A wide variety of human diseases are associated with loss of microbial diversity in the human gut, inspiring a great interest in the diagnostic or therapeutic potential of the microbiota. However, the ecological forces that drive diversity reduction in disease states remain unclear, rendering it difficult to ascertain the role of the microbiota in disease emergence or severity. One hypothesis to explain this phenomenon is that microbial diversity is diminished as disease states select for microbial populations that are more fit to survive environmental stress caused by inflammation or other host factors. Here, we tested this hypothesis on a large scale, by developing a software framework to quantify the enrichment of microbial metabolisms in complex metagenomes as a function of microbial diversity. We applied this framework to over 400 gut metagenomes from individuals who are healthy or diagnosed with inflammatory bowel disease (IBD). We found that high metabolic independence (HMI) is a distinguishing characteristic of microbial communities associated with individuals diagnosed with IBD. A classifier we trained using the normalized copy numbers of 33 HMI-associated metabolic modules not only distinguished states of health versus IBD, but also tracked the recovery of the gut microbiome following antibiotic treatment, suggesting that HMI is a hallmark of microbial communities in stressed gut environments.
Immunoglobulin A as a key immunological molecular signature of post-COVID-19 conditions
Authors: Sousa Graziele F. , Carpes Raphael M. , Silva Carina A. O. , Pereira Marcela E. P. , Silva Amanda C. V. F. , Coelho Viktoria A. G. S. , Costa Evenilton P. , Mury Flávia B. , Gestinari Raquel S. , Menezes Jackson S. , Silva Manuela L. , Nepomuceno-Silva José L. , Tanuri Amilcar , Júnior Orlando C. F. , Monteiro-de-Barros Cintia
Published: May 2023

COVID-19 has infected humans worldwide, causing millions of deaths or prolonged symptoms in survivors. The transient or persistent symptoms after SARS-CoV-2 infection have been defined as post-COVID-19 conditions (PCC). We conducted a study of 151 Brazilian PCC patients to analyze symptoms and immunoglobulin profiles, taking into account gender, vaccination, hospitalization and age. Fatigue and myalgia were the most common symptoms and lack of vaccination, hospitalization, and neuropsychiatric and metabolic comorbidities were relevant for the development of PCC. Analysis of serological immunoglobulins showed that IgA was higher in PCC patients, especially in the adult and elderly groups. Also, non-hospitalized and hospitalized PCC patients produced high and similar levels of IgA. Our results indicated that the detection of IgA antibodies against SARS-CoV-2 during the course of the disease could be associated with the development of PCC and may be an immunological signature to predict prolonged symptoms in COVID-19 patients.
Understanding COVID-19 Vaccine Uptake and Hesitancy Among People With HIV in Freetown, Sierra Leone: A Cross-sectional Study
Authors: Cummings Peterlyn E. , Lakoh Sulaiman , Yendewa Sahr A. , Massaquoi Samuel P.E. , James Peter B. , Sahr Foday , Deen Gibrilla F. , Gevao Pelema , Yendewa George A.
Published: May 2023

Objectives

People living with HIV (PWH) are at increased risk of COVID-19 related morbidity and mortality, yet less is known about COVID-19 vaccination uptake and hesitancy, especially in sub-Saharan Africa. We aimed to evaluate COVID-19 vaccine uptake and hesitancy among PWH in Sierra Leone.

Methods

We conducted a cross-sectional study in a convenience sample of PWH in routine care at Connaught Hospital in Freetown, Sierra Leone from April through June 2022. We collected sociodemographic and health-related data. We used the VAX Scale, a validated instrument to assess attitudes towards COVID-19 vaccination. From the responses, we constructed hesitancy (VAX) scores, with higher scores implying negative attitudes towards vaccination. We used generalized linear models to identify factors associated with vaccine hesitancy.

Results

A total of 490 PWH were enrolled (71.4% female, median age 38 years, median CD4 count 412 cells/mm3, 83.9% virologically suppressed). About 17.3% had received at least one dose of a COVID-19 vaccine. The mean VAX score was 43.14 ± 7.05, corresponding to 59.9% participants classified as vaccine hesitant. Preference for natural immunity (65.8%) and concerns about commercial profiteering (64.4%) were the commonest reasons for hesitancy, followed by mistrust of vaccine benefits (61.4%) and worries about future side effects (48.0%). In adjusted regression analysis, being Muslim (β = 2.563, p < 0.001) and residence in urban areas (β = 1.709, p = 0.010) were associated with greater vaccine hesitancy, while having tested ever for COVID-19 was associated with lesser vaccine hesitancy (β = -3.417, p = 0.027).

Conclusion

We observed a low COVID-19 vaccine uptake and high hesitancy among PWH in Sierra Leone. Our findings underscore the need to address vaccine hesitancy as a critical element of efforts to boost COVID-19 vaccine uptake among this population in Sierra Leone.
Assessment of Adverse Childhood Experiences in the South Bronx on Risk of Developing Chronic Disease as Adults
Authors: Njoroge Alexander , Shariff Masood A , Khan Hira W , Gordillo Victor , Eclarinal Brian , Vargas Jose , Faiz Mohammad , Kasubhai Moiz , Jackson Tranice
Published: May 2023

Background

Adverse Childhood Experiences (ACE) have a negative impact on health outcomes. Using a cross-sectional study design, our objective was to identify the prevalence of ACEs among residents of the South Bronx and the relationship between such childhood stressors and prevalence of both chronic disease and modifiable high-risk behavior in adulthood.

Methods

We recruited patients from a hospital-based adult primary care clinic in the metropolitan area of South Bronx. A cross-sectional survey was conducted between September 2017 and January 2018, using a modified ACE Questionnaire, that included nine ACE categories (Physical Abuse, Sexual Abuse, Household Substance Abuse, Separation from Parents, Incarcerated Household Member, Parental Separation/Divorce, and Bullying), and in addition to questions on demographics, high-risk behavior, and diagnosis of chronic disease. Our primary objective was to gather incidence of ACEs organized by domains. Secondary objectives were to demonstrate any expected increase (as Odds Ratio) in Chronic Disease or maladaptive social habits when compared to patients with no ACEs within the cohort.

Results

A total of 454 patients completed the survey. The average age was 53.1±14.2 years and females were 49% of the sample. Hispanics were 61% followed by Blacks at 34%. Participants reported high-risk behavior in 24%, had a high prevalence of chronic illness (82%) and ACE events at 70%. We found a significant relationship between ACE events and having a chronic disease diagnosis and engagement in high-risk behavior with higher odds of reporting chronic illnesses among participants with exposure to childhood stressors (OR 1.26, 95% confidence interval 1.1-1.5, p=0.002). Of the nine ACE categories many were independently associated with one or more chronic diseases in adulthood.

Conclusion

According to our survey data, ACE events in our patient population were more prevalent (30% with 4 or more exposures), higher than the proposed average of 1 out of 6 Americans with 4 or more exposures nationally according to the national statistics. These childhood stressors appear to have a strong association with development of high-risk behavior and chronic illnesses.
Spatial inequities in access to medications for treatment of opioid use disorder highlight scarcity of methadone providers under counterfactual scenarios
Authors: Tatara Eric , Lin Qinyun , Ozik Jonathan , Kolak Marynia , Collier Nicholson , Halpern Dylan , Anselin Luc , Dahari Harel , Boodram Basmattee , Schneider John
Published: May 2023

Access to treatment and medication for opioid use disorder (MOUD) is essential in reducing opioid use and associated behavioral risks, such as syringe sharing among persons who inject drugs (PWID). Syringe sharing among PWID carries high risk of transmission of serious infections such as hepatitis C and HIV. MOUD resources, such as methadone provider clinics, however, are often unavailable to PWID due to barriers like long travel distance to the nearest methadone provider and the required frequency of clinic visits. The goal of this study is to examine the uncertainty in the effects of travel distance in initiating and continuing methadone treatment and how these interact with different spatial distributions of methadone providers to impact co-injection (syringe sharing) risks. A baseline scenario of spatial access was established using the existing locations of methadone providers in a geographical area of metropolitan Chicago, Illinois, USA. Next, different counterfactual scenarios redistributed the locations of methadone providers in this geographic area according to the densities of both the general adult population and according to the PWID population per zip code. We define different reasonable methadone access assumptions as the combinations of short, medium, and long travel distance preferences combined with three urban/suburban travel distance preference. Our modeling results show that when there is a low travel distance preference for accessing methadone providers, distributing providers near areas that have the greatest need (defined by density of PWID) is best at reducing syringe sharing behaviors. However, this strategy also decreases access across suburban locales, posing even greater difficulty in regions with fewer transit options and providers. As such, without an adequate number of providers to give equitable coverage across the region, spatial distribution cannot be optimized to provide equitable access to all PWID. Our study has important implications for increasing interest in methadone as a resurgent treatment for MOUD in the United States and for guiding policy toward improving access to MOUD among PWID.
Development and validation of composite inflammaging metrics: Findings from two prospective cohort studies
Authors: Li Chenxi , Ge Yumeng , Yang Zhenqing , Yang Gan , Cao Xingqi , Fu Jinjing , Liu Zuyun
Published: May 2023

Background

Aging-related inflammation is associated with chronic diseases and mortality. This study aimed to: 1) develop composite inflammaging metrics (CIMs) in UK biobank (UKB), and validate them in UKB and National Health and Nutrition Examination Survey (NHANES); 2) estimate mortality and CVD risk predictions of CIMs; 3) compare CIMs with single inflammatory blood biomarkers and conventional inflammatory indexes; 4) examine associations between lifestyles and CIMs.

Methods

We utilized algorithms including multiple linear regression, principal component analysis (PCA), allostatic load (AL), and Klemera and Doubal method (KDM), to develop four CIMs from five inflammatory blood biomarkers, using data of 438,321 adults (40-70 years) from UK Biobank (UKB). We validated these CIMs in UKB and 10,667 adults (20-84 years) from NHANES IV. We performed a parametric proportional hazard model based on Gompertz distribution to estimate CVD and mortality risk predictions of CIMs. Areas under receiver operating characteristic curves (AUCs) were calculated to compare the predictive abilities of CIMs. Multiple linear regression models were used to access associations between lifestyles and CIMs.

Results

With adjustment for age and sex, four CIMs were significantly associated with higher risks of all-cause mortality and incident CVD in UKB, among which CIMKDMoutperformed the others (all-cause mortality: hazard ratio [HR] = 1.48, 95% confidence interval [CI] = 1.46, 1.50; incident CVD: HR = 1.34, 95% CI = 1.33, 1.36). CIMKDMhad the best discriminative ability for predicting 10-year survival and incident CVD in UKB (all-cause mortality: AUC = 0.728; incident CVD: AUC = 0.712). CIMs were responsive to lifestyle variables. For example, in UKB, compared to never smokers, current smokers had a significant increment in CIMKDM(coefficient = 0.30 SD,P< 0.001). Similar results were well validated in NHANES IV.

Conclusions

We developed and validated four novel CIMs that were predictive of mortality and CVD risk. CIMKDMoutperformed the others and had the potential to be used in aging related preventive and intervention programs. Intervention programs targeting lifestyles could slow inflammaging and further reduce disease burden.
A comprehensive Indian clinical and imaging Coronary Artery Disease Dataset: ICADD
Authors: Bohra Akanksha , Barthur Ashita , Patil Rahul , Ansumali Santosh
Published: May 2023

Background & objectives

Coronary artery disease (CAD) is one of the leading causes of mortality worldwide and contributes significantly to the disease burden in India. The dearth of datasets for Indian patients with CAD is an obstacle to further development and collaborative work in clinical research. The purpose of this study was to create a comprehensive dataset of diagnostic information on CAD in Indian patients. We present Indian Coronary Artery Disease Dataset (ICADD) with CT and invasive FFR data to aid innovation and improvement of non-invasive diagnostic procedures.

Methods

The data was collected in a tertiary care centre in South India. The patients with suspected CAD who underwent coronary CT-angiography (CCTA) and invasive angiography (ICA) with the measurement of fractional flow reserve (FFR) were included in the study.

Results

The data from 70 patients were collected between April 2018 and Dec 2021. The dataset contains 70 CCTA, 70 ICA scans along with FFR, and echocardiography and haematology reports. It includes 54 (77.14%) male and 16 (22.85%) female patients. The mean age of participants is 50.7±8.8years.

Conclusions

To the best of our knowledge, ICADD is the first of its kind database in India. This dataset can be used to create a benchmark database, serve as reference for performance and evaluation of clinical utility of novel non-invasive diagnostic methods and additionally serve as a database for clinical research.
Functional Neural Networks Stratify the Parkinson’s Disease Patients Across the Spectrum of Cognitive Impairment
Authors: Hajebrahimi Farzin , Budak Miray , Sarıcaoğlu Mevhibe , Hanoğlu Lütfü , Bayraktaroğlu Zübeyir , Yıldırım Süleyman
Published: May 2023

Cognitive Impairment (CI) in Parkinson’s disease (PD) is one of the important non-motor symptoms that can begin even before the motor symptoms manifest. As the disease progresses into advance stages, however, virtually all patients suffer from cognitive decline. PD Patients hypothetically progress across PD with no CI (PD-NC), Mild Cognitive Impairment (PD-MCI), and PD dementia (PDD). The CI symptoms in PD are linked to different brain regions including dysfunctional subcortical regions and poorly elucidated neural pathways. However, it is still unknown how functional dysregulation in some brain regions correlates to CI progression in PD. Recently, rsfMRI has been shown to be a promising neuroimaging technique that can enable discovery of CI biomarkers in PD. Here, we investigated the differences in the clinical measures and the resting-state Functional Connectivity (FC) of three CI subtypes of PD. We included a total of 114 participants, (26 PD-NC, 32 PD-MCI, 31 PDD, and 26 Healthy Controls (HC), and performed intra- and inter-network FC analysis together with comprehensive clinical cognitive assessment. Our results showed the importance of several neural networks including Default Mode Network (DMN), Frontoparietal Network (FPN), Dorsal Attention Network (DAN), and Visual Network (VN) and their inter-intra network FC distinguishing between PD-MCI and PDD. Additionally, our results showed the importance of Sensory Motor Network (SMN), VN, DMN, and Salience Network (SN) in the discriminating PD-NC from PDD. Finally, in comparison to HC, we found DMN, FPN, VN, and SN as important networks for further differential diagnosis of CI subtypes of PD. We propose that resting state networks can be used in stratifying the CI subtypes of PD patients in the clinic.
Community knowledge, attitudes and practices related to Taenia solium taeniosis and cysticercosis in Zambia
Authors: Zulu Gideon , Mwape Kabemba E. , Welte Tamara M. , Simunza Martin , Hachangu Alex , Mutale Wilbroad , Chembensofu Mwelwa , Sikasunge Chummy , Phiri Isaac K. , Winkler Andrea S.
Published: May 2023

Background

Several studies onTaenia soliumtaeniosis / cysticercosis (TSTC) have been conducted in Zambia. However, none has assessed community knowledge, attitudes and practices related to TSTC and epilepsy.

Methods

A community-based cross-sectional study was conducted between November and December 2022. The design consisted of a questionnaire-based survey conducted in each of the 25 purposely selected villages in Chiparamba Rural Health Centre (RHC) catchment area in Chipata district of the Eastern Province.

Results

A total of 588 participants comprising 259 (44%) males and 329 (56%) females with median age of 42 years (range 17 to 92 years) were interviewed. Awareness of the signs and symptoms of taeniosis and human cysticercosis (HCC), including transmission and prevention measures was very low. Whilst the majority had heard about epilepsy, they were not able to link HCC to epilepsy. Most participants were aware of cysticerci in pigs (PCC) including its predilection sites but were not aware of mode of transmission and prevention measures. The pork meat inspection by trained professionals was also not a common practice in the area. Risk perception ofT. soliuminfections was thus very low. Overall knowledge, attitude and practice scores related toT. soliuminfections and to epilepsy were very low with median scores of 0.38 (IQR 0.25 - 0.54) for knowledge, 0.25 (0.25 - 0.50) for attitudes, and 0.31 (0.25 - 0.44) for practices. Males had better knowledge on TSTC (median = 0.42, p = 0.017, r = 0.098) and better practice scores (median = 0.38, p = < 0.001, r = 0.154) compared to females though the effect size was small. With regards to sanitation and hygiene washing with soap and water was reported by many but only few had a hand washing facility near their latrines.

Conclusion

The study shows overall poor knowledge, attitudes and practices related to TSTC among the community of Chiparamba RHC in Chipata district of the Eastern Province of Zambia. This poses a serious challenge for control and elimination ofT. soliuminfections and thus efforts to improve knowledge, attitudes and practices should be made using a One Health approach for the control and elimination of TSTC. Educational programs about TSTC transmission, signs and symptoms, prevention, management and control need to be scaled up in the study area and Zambia as a whole.
A progesterone derivative linked to a stable phospholipid activates breast cancer cell response without leaving the cell membrane
Authors: Font-Mateu Jofre , Sanllehí Pol , Sot Jesús , Abad Beatriz , Mateos Nicolas , Torreno-Pina Juan Andres , Ferrari Roberto , Wright Roni H.G. , Garcia-Parajo Maria , Joglar Jesús , Goñi Félix M. , Beato Miguel
Published: May 2023

In hormone-responsive breast cancer cells, progesterone (P4) has been shown to act via its nuclear receptor (PR), a ligand-activated transcription factor. A small fraction of PR is palmitoylated and anchored to the cell membrane (mbPR) forming a complex with estrogen receptor alpha (ERα). Upon hormone exposure, either directly or via interaction with ERα mbPR activates the SRC/RAS/ERK kinase pathway leading to phosphorylation of PR by ERK. Kinase activation is essential for P4 gene regulation, as the ERK and MSK1 kinases are recruited by the PR to its genomic binding sites and trigger chromatin remodeling. An interesting open question is whether activation of mbPR can result in gene regulation in the absence of ligand binding to intracellular PR. This matter has been investigated in the past using P4 attached to serum albumin, but the attachment is leaky and albumin can be endocytosed and degraded, liberating P4. Here we propose a more stringent approach to address this issue by ensuring attachment of P4 to the cell membrane via covalent binding to a stable phospholipid. This strategy identifies the actions of P4 independent of hormone binding to intracellular PR. We found that a membrane-attached progestin can activate mbPR, the ERK signalling pathway leading to PR phosphorylation, initial gene regulation and entry into the cell cycle, in the absence of detectable intracellular progestin.
Metformin an anti-diabetic drug, possess ACE-2 receptor-SARS-Cov-2 RBD binding antagonist activity, anti-inflammatory and cytokine inhibitory properties suitable for treatment of COVID-19
Authors: Saxena Uday , Meher Kranti , Saranya K , Vangala Subrahmanyam
Published: May 2023

Metformin is a widely used and is a safe anti-diabetic drug. It has also been shown to have anti-inflammatory and anti-viral activities in humans and animal models. Specifically we explored its activity in SARS-CoV-2 initiated COVID19 disease. Here we show that metformin 1. blocks the binding of SARS-CoV-2 spike protein receptor binding domain RBD to human ACE2 receptor 2. We also show that it has anti-inflammatory effects and reduces cytokine secretion as well as blocks the recruitment of monocytes to endothelial cells 3. Finally we show its activity in a hamster in vivo model of SARS-CoV-2 infection as a nasal formulation. Based on the safety and the therapeutic properties relevant to COVID-19 it is feasible to propose a nasal spray of metformin that can be used in treatment of this disease. A nasal spray would deliver the drug to the target organ lung and spare other organs which get exposed upon oral dosing.
Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis
Authors: Middha Pooja , Thummalapalli Rohit , Betti Michael J. , Yao Lydia , Quandt Zoe , Balaratnam Karmugi , Bejan Cosmin A. , Cardenas Eduardo , Falcon Christina J. , Faleck David M. ,   Princess Margaret Lung Group, Gubens Matthew A. , Huntsman Scott , Johnson Douglas B. , Kachuri Linda , Khan Khaleeq , Li Min , Lovly Christine M. , Murray Megan H. , Patel Devalben , Werking Kristin , Xu Yaomin , Zhan Luna Jia , Balko Justin M. , Liu Geoffrey , Aldrich Melinda C. , Schoenfeld Adam J. , Ziv Elad
Published: May 2023

Immune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRSUCpredicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76,P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35,P=0.01). PRSCDwas not associated with IMC or severe IMC. The association between PRSUCand IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRSUCpredicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53,P=0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.
Routine respiratory metagenomics service for intensive care unit patients
Authors: Charalampous Themoula , Alcolea-Medina Adela , Snell Luke B. , Alder Christopher , Tan Mark , Williams Tom G.S. , Al-Yaakoubi Noor , Humayun Gul , Meadows Christopher I.S. , Wyncoll Duncan L.A. , Richard Paul , Hemsley Carolyn J. , Jeyaratnam Dakshika , Newsholme William , Goldenberg Simon , Patel Amita , Tucker Fearghal , Nebbia Gaia , Wilks Mark , Chand Meera , Cliff Penelope R. , Batra Rahul , O’Grady Justin , Barrett Nicholas A. , Edgeworth Jonathan D.
Published: May 2023

Background

Respiratory metagenomics (RMg) needs evaluation in a pilot service setting to determine utility and inform implementation into clinical practice.

Methods

Feasibility, performance and clinical impacts on antimicrobial prescribing and infection control were recorded during a pilot RMg service for patients with suspected lower respiratory tract infection (LRTI) on two general and one specialist respiratory intensive care units (ICU) at Guy’s & St Thomas NHS foundation Trust, London.

Results

RMg was performed on 128 samples from 87 patients during the first 15-weeks providing same-day results for 110 samples (86%) with median turnaround time of 6.7hrs (IQR 6.1-7.5 hrs). RMg was 92% sensitive and 82% specific for clinically-relevant pathogens compared with routine testing. 48% of RMg results informed antimicrobial prescribing changes (22% escalation; 26% de-escalation) with escalation based on speciation in 20/24 cases and detection of acquired-resistance genes in 4/24 cases. Fastidious or unexpected organisms were reported in 21 samples including anaerobes (n=12),Mycobacterium tuberculosis, Tropheryma whipplei, cytomegalovirus andLegionella pneumophilaST1326, which was subsequently isolated from the bed-side water outlet. Application to consecutive severe community-acquired LRTI cases identifiedStaphylococcus aureus(two withSCCmecand three withlukF/S virulence determinants),Streptococcus pyogenes(emm1-M1uk clone),S. dysgalactiaesubspecies equisimilis (STG62647A) andAspergillus fumigatuswith multiple treatments and public-health impacts.

Conclusions

RMg provides frequent diverse benefits for treatment, infection control and public health. The combination of rapid comprehensive results, alongside revealing and characterising a hidden burden of infections makes the case for expediting routine service implementation.
Single-cell RNA sequencing data reveals rewiring of transcriptional relationships in Alzheimer’s Disease associated with risk variants
Authors: Bouland Gerard A. , Marinus Kevin I. , van Kesteren Ronald E. , Smit August B. , Mahfouz Ahmed , Reinders Marcel J.T.
Published: May 2023

Understanding how genetic risk variants contribute to Alzheimer’s Disease etiology remains a challenge. Single-cell RNA sequencing (scRNAseq) allows for the investigation of cell type specific effects of genomic risk loci on gene expression. Using seven scRNAseq datasets totalling >1.3 million cells, we investigated differential correlation of genes between healthy individuals and individuals diagnosed with Alzheimer’s Disease. Using the number of differential correlations of a gene to estimate its involvement and potential impact, we present a prioritization scheme for identifying probable causal genes near genomic risk loci. Besides prioritizing genes, our approach pin-points specific cell types and provides insight into the rewiring of gene-gene relationships associated with Alzheimer’s.
Inferring Skin-Brain-Skin Connections from Infodemiology Data using Dynamic Bayesian Networks
Authors: Scutari Marco , Kerob Delphine , Salah Samir
Published: May 2023

Background

The relationship between skin diseases and mental illnesses has been extensively studied using cross-sectional epidemiological data. Typically, such data can only measure association (rather than causation) and include only a subset of the diseases we may be interested in.

Objective

In this paper, we complement the evidence from such analyses by learning an overarching causal network model over twelve health conditions from the Google Search Trends Symptoms public data set.

Methods

We learned the causal network model using a dynamic Bayesian network, which can represent both cyclic and acyclic causal relationships, is easy to interpret and accounts for the spatio-temporal trends in the data in a probabilistically rigorous way.

Results

The causal network confirms a large number of cyclic relationships between the selected health conditions and the interplay between skin and mental diseases. For acne, we observe a cyclic relationship with anxiety and attention deficit hyperactivity disorder (ADHD) and an indirect relationship with depression through sleep disorders. For dermatitis, we observe directed links to anxiety, depression and sleep disorders and a cyclic relationship with ADHD. We also observe a link between dermatitis and ADHD and a cyclic relationship between acne and ADHD. Furthermore, the network includes several direct connections between sleep disorders and other health conditions, highlighting the impact of the former on the overall health and well-being of the patient. The averageR2for a condition given the values of all conditions in the previous week is 0.67: in particular, 0.42 for acne, 0.85 for asthma, 0.58 for ADHD, 0.87 for burn, 0.76 for erectile dysfunction, 0.88 for scars, 0.57 for alcohol disorders, 0.57 for anxiety, 0.53 for depression, 0.74 for dermatitis, 0.60 for sleep disorders and 0.66 for obesity.

Conclusions

Mapping disease interplay, indirect relationships, and the key role of mediators, such as sleep disorders, will allow healthcare professionals to address disease management holistically and more effectively. Even if we consider all skin and mental diseases jointly, each disease subnetwork is unique, allowing for more targeted interventions.
An amplicon-based nanopore sequencing workflow for rapid tracking of avian influenza outbreaks, France, 2020-2022
Authors: Croville Guillaume , Walch Mathilda , Lèbre Laetitia , Silva Sonia , Filaire Fabien , Guérin Jean-Luc
Published: May 2023

During the recent avian influenza epizootics that occurred in France in 2020/21 and 2021/22, the virus was so contagiousness that it was impossible to control its spread between farms. The preventive slaughter of millions of birds consequently was the only solution available. In an effort to better understand the spread of avian influenza viruses (AIVs) in a rapid and innovative manner, we established an amplicon-based MinION sequencing workflow for the rapid genetic typing of circulating AIV strains.

An amplicon-based MinION sequencing workflow based on a set of PCR primers targeting primarily the hemagglutinin gene but also the entire influenza virus genome was developed. Thirty field samples from H5 HPAIV outbreaks in France, including environmental samples, were sequenced using the MinION MK1C. A real-time alignment of the sequences with MinKNOW software allowed the sequencing run to be stopped as soon as enough data were generated. The consensus sequences were then generated and a phylogenetic analysis was conducted to establish links between the outbreaks.

The whole sequence of the hemagglutinin gene was obtained for the 30 clinical samples of H5Nx HPAIV belonging to clade 2.3.4.4b. The consensus sequences comparison and the phylogenetic analysis demonstrated links between some outbreaks.

While several studies have shown the advantages of MinION for avian influenza virus sequencing, this workflow has been applied exclusively to clinical field samples, without any amplification step on cell cultures or embryonated eggs. As this type of testing pipeline requires only a short amount of time to link outbreaks or demonstrate a new introduction, it could be applied to the real-time management of viral epizootics.
A Resource of Gene Expression Data from a Multiethnic Population Cohort of Induced Pluripotent Cell–Derived Cardiomyocytes
Authors: Lv Wenjian , Babu Apoorva , Morley Michael P. , Musunuru Kirin , Guerraty Marie
Published: May 2023

Induced pluripotent stem cells (iPSCs), upon differentiation into somatic cell types, offer the ability to model the genetic states of tissues in the individuals from whom the iPSCs were derived.1A prior study used a multiethnic cohort of healthy individuals to derive iPSCs and iPSC-hepatocytes and perform gene expression and expression quantitative trait locus (eQTL) analyses, identifying causal genes and variants linked to blood lipid levels.2We sought to use this cohort of iPSC lines to generate a similar resource with iPSC-cardiomyocytes (iPSC-CMs) and make the results available to the community.
TREM2 limits necrotic core formation during atherogenesis by controlling macrophage survival and efferocytosis
Authors: Piollet Marie , Porsch Florentina , Rizzo Giuseppe , Kapser Frederieke , Schulz Dirk J.J. , Kiss Máté G. , Schlepckow Kai , Morenas-Rodriguez Estrella , Sen Mustafa Orkun , Gropper Julius , Roesch Melanie , Göderle Laura , Hladik Anastasiya , Knapp Sylvia , Colonna Marco , Martini Rudolf , Haass Christian , Zernecke Alma , Binder Christoph J. , Cochain Clément
Published: May 2023

Atherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries [1], [2], and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [3]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating several key myeloid cell functions [4], as a highly expressed marker of macrophage foam cells in experimental and human atherosclerosis [5]. However, the function of TREM2 in the development of atherosclerosis is unknown. Here, we show that hematopoietic or global TREM2 deficiency increases necrotic core formation in early experimental atherosclerosis. We further demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, altogether indicating a crucial role of TREM2 in maintaining the balance between foam cell death and their clearance in atherosclerotic lesions, thereby controlling plaque necrosis.
Molecular and evolutionary basis of O-antigenic polysaccharide driven phage sensitivity in environmental pseudomonads
Authors: Vacheron Jordan , Heiman Clara Margot , Garneau Julian R , Kupferschmied Peter , deJonge Ronnie , Garrido-Sanz Daniel , Keel Christoph
Published: May 2023

Pseudomonas protegens CHA0, a bacterial strain able to suppress plant pathogens as well as efficiently kill lepidopteran pest insects, has been studied as biocontrol agent to prevent ensuing agricultural damage. However, the success of this method is dependent on the efficient plant colonization by the bacterial inoculant while it faces competition from the resident microbiota as well as predators such as bacteriophages. One of these naturally occurring phages, ΦGP100, was found to drastically reduce the abundance of CHA0 once inoculated into plant microcosms, resulting in the loss of plant protection against a phytopathogen. Here, we investigated the molecular determinants implicated in the interaction between CHA0 and the phage ΦGP100 using a high-density transposon-sequencing approach. We show that lipopolysaccharide cell surface decorations, specifically the longer OBC3-type O-antigenic polysaccharide (O-PS, O-antigen) of the two dominant O-PS of CHA0 is essential for the attachment and infection of ΦGP100. Moreover, when exploring the distribution of the OBC3 cluster in bacterial genomes, we identified several parts of this gene cluster that are conserved in phylogenetically distant bacteria. Through heterologous complementation, we integrated an OBC3-type gene copy from a phylogenetically distant bacterium and were able to restore the phage sensitivity of a CHA0 mutant which lacked the ability to form long O-PS. Finally, we evidence that the OBC3 gene cluster of CHA0 displays a high genomic plasticity and likely underwent several horizontal acquisitions and genomic rearrangements. Collectively, this study underlines the complexity of phage-bacteria interaction and the multifunctional aspect of bacterial cell surface decorations.
Putrescine acetyltransferase (PAT/SAT1) dependent GABA synthesis in astrocytes
Authors: Lim Jiwoon , Bhalla Mridula , Park Mingu Gordon , Koh Wuhyun , Lee C. Justin
Published: May 2023

GABA synthesis in astrocytes mediates tonic inhibition to regulate patho-physiological processes in various brain regions. Monoamine oxidase B (MAO-B) has been known to be the most important metabolic enzyme for synthesizing GABA from the putrescine degradation pathway. MAO-B converts N1-acetylputrescine to N1-acetyl-γ-aminobutyraldehyde and hydrogen peroxide (H2O2). Putrescine acetyltransferase (PAT), also known as spermidine and spermine N1-acetyltransferase 1 (SAT1), has been thought to be a feasible candidate enzyme for converting putrescine to N1-acetylputrescine. However, it has not been rigorously investigated or determined whether PAT/SAT1 contributes to GABA synthesis in astrocytes. To investigate the contribution of PAT/SAT1 to GABA synthesis in astrocytes, we conducted sniffer patch and whole-cell patch experiments with gene silencing of PAT/SAT1 bySat1shRNA expression. Our results showed that the gene silencing of PAT/SAT1 significantly decreased the MAO-B-dependent GABA synthesis, which was induced by putrescine incubation, leading to decreased Ca2+-dependent release of GABAin vitro. Additionally, we found that, from the brain sliceex vivo, putrescine incubation induces tonic GABA inhibition in dentate gyrus granule cells, which can be inhibited by MAO-B inhibitor, selegiline. Consistent with ourin vitroresults, astrocytic gene silencing of PAT/SAT1 significantly reduced putrescine incubation-induced tonic GABA current, possibly by converting putrescine to N1-acetylputrescine, a substrate of MAO-B. Our findings emphasize a crucial role of PAT/SAT1 in MAO-B-dependent GABA synthesis in astrocytes.
Cardiopharyngeal Mesoderm specification into cardiac and skeletal muscle lineages in gastruloids
Authors: Argiro Laurent , Chevalier Céline , Choquet Caroline , Nandkishore Nitya , Ghata Adeline , Baudot Anaïs , Zaffran Stéphane , Lescroart Fabienne
Published: May 2023

Cardiopharyngeal mesoderm contributes to the formation of the heart and head muscles. However, the mechanisms governing cardiopharyngeal mesoderm specification remain unclear. Indeed, there is a lack of anin vitromodel replicating the differentiation of both heart and head muscles to study these mechanisms. Such models are required to allow live-imaging and high throughput genetic and drug screening. Here, we show that the formation of self-organizing or pseudo-embryos from mouse embryonic stem cells (mESCs), also called gastruloids, reproduces cardiopharyngeal mesoderm specification towards cardiac and skeletal muscle lineages. By conducting a comprehensive temporal analysis of cardiopharyngeal mesoderm establishment and differentiation in gastruloids and comparing it to mouse embryos, we present the first evidence for skeletal myogenesis in gastruloids. By inferring lineage trajectories from the gastruloids single-cell transcriptomic data, we further suggest that heart and head muscles formed in gastruloids derive from cardiopharyngeal mesoderm progenitors. We identify different subpopulations of cardiomyocytes and skeletal muscles, which most likely correspond to different states of myogenesis with “head-like” and “trunk-like” skeletal myoblasts. These findings unveil the potential of mESC-derived gastruloids to undergo specification into both cardiac and skeletal muscle lineages, allowing the investigation of the mechanisms of cardiopharyngeal mesoderm differentiation in development and how this could be affected in congenital diseases.
Lipase-mediated detoxification of host-derived antimicrobial fatty acids byStaphylococcus aureus
Authors: Tchoupa Arnaud Kengmo , Elsherbini Ahmed M. A. , Fu Xiaoqing , Ghaneme Oumayma , Seibert Lea , Böcker Marieke A. , Lebtig Marco , Camus Justine , Lambidis Stilianos Papadopoulos , Schittek Birgit , Kretschmer Dorothee , Lämmerhofer Michael , Peschel Andreas
Published: May 2023

Long-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such asStaphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used byS. aureusto resist AFAs could open new avenues to prevent pathogen colonization. Here, we identify theS. aureuslipase Lip2 as a novel resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. This is reminiscent of the activity of the fatty acid-modifying enzyme (FAME), whose identity has remained elusive for over three decades.In vitro, Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Our genomic analysis revealed that prophage-mediated inactivation of Lip2 was more common in blood and nose isolates than in skin strains, suggesting a particularly important role of Lip2 for skin colonization. Accordingly, in a mouse model ofS. aureusskin colonization, bacteria were protected from sapienic acid - a human-specific AFA - in a cholesterol- and lipase-dependent manner. These results suggest Lip2 is the long-sought FAME that exquisitely manipulates environmental lipids to promote bacterial growth. Our data support a model in whichS. aureusexploits and/or exacerbates lipid disorders to colonize otherwise inhospitable niches.
The ecological characteristics of the safe sites for early-stage establishment ofChamaecyparis obtusavar.formosanaseedlings in Taiwan
Authors: Wei Shuo , Tseng Yu-Pei , Zelený David
Published: May 2023

Chamaecyparis obtusavar.formosanais an ecologically and economically important species in Taiwan, with a high affinity for fog immersion. Our study aims to identify possible stress factors that induced seedling mortality and investigate how different ecological factors influence early-stage safe site requirements of the seedlings. We focused on the effect of large-scale climatic variables, small-scale microhabitat conditions, and biotic interactions on seedling survival and establishment by applying seasonal seedling survival monitoring and establishment survey on both regional and local scale. We identified two alternative ways of seedling death, by environmental-induced mortality and by herbivory. Opposite effects of the same environmental factors on different causes of mortality showed that seedlings might need to balance the risks posed by both causes to optimize their growing conditions. On a regional scale, we observed limited effect of regional climatic variables (namely fog frequency) on seedlings’ establishment and survival but noted a similar seasonal survival pattern among regions. We hypothesize that short-duration droughts during the transition from Plum rain to typhoon season is one of the key mechanisms of environmental-induced mortality. On a local scale, we found that decayed coarse wood debris (CWD) facilitates seedling establishment by providing a “safe site”, likely due to increased colonization of small-stature bryophytes and decreased litterfall accumulation. The effect of bryophytes on seedling establishment varies depending on their thickness, with thicker ones having stronger negative effects. Aside from the bryophytes, the accumulation of litter significantly hindered seedling establishment. We argue that to safeguard the regeneration ofChamaecyparis obtusavar.formosanapopulation, preserving CWD in the forest floor as a safe site for the seedlings after tree-replacing disturbance in natural forests is essential, particularly under ongoing climate change where more frequent and prolonged drought events are predicted.

Highlights

On a local scale, decayed coarse wood debris (CWD) provides “safe site” for the establishment ofChamaecypairs obtusavar.formosanaseedlings.

Regional climatic variables had limited effects on seedlings, but all regions had similar seasonal patterns of seedling mortatlity.

Facilitation effect of small-stature bryophytes and litterfall avoidance might be the underlying mechanisms behind CWD safe sites.

Preserving CWD for seedlings is important in the context of predicted prolong drought events under ongoing climate change.
Dietary fibre reverses adverse post-stroke outcomes in mice via short-chain fatty acids and its sensing receptors GPR41, GPR43 and GPR109A
Authors: Peh Alex , Dinakis Evany , Jama Hamdi , Anderson Dovile , Creek Darren J. , Zheng Gang , de Veer Michael , Mackay Charles R. , Zheng Tenghao , Kemp-Harper Barbara K. , Broughton Brad R.S. , Marques Francine Z.
Published: May 2023

Dietary fibre intake is associated with fewer cases of ischaemic stroke. This is likely via the microbiota-gut-brain axis, where fibre is fermented by the gut microbiota, releasing short-chain fatty acids (SCFAs). However, whether fibre or SCFAs can reverse adverse post-stroke outcomes remains unknown. Here, we demonstrated that a low fibre diet exacerbates post-stroke outcomes in mice. This was reversed by a high fibre diet or direct supplementation with SCFAs (delivered either in the water or a high SCFA-releasing diet) immediately after stroke. These modulated the gut microbiome and improved the gut epithelial barrier integrity, which was associated with fewer activated neutrophils and more neuroblast cells in the brain. We then investigated the SCFA-receptors GPR41/43/109A using a triple knockout mouse model, which exhibited poorer stroke outcomes and recovery. These results show that post-stroke interventions using dietary fibre and/or SCFA supplementation, acting via GPR41/43/109A signalling, may represent new therapeutic strategies for stroke-induced brain injury.