bluuebunny/crossref_metadata_2025 huggingface dataset:
Reasons underlying the intention to vaccinate children aged 5-11 against COVID-19: A cross-sectional study of parents in Israel, November 2021
Authors: Morozov Nicole G. , Dror Amiel A. , Daoud Amani , Eisenbach Netanel , Kaykov Edward , Barhoum Masad , Sheleg Tsvi , Sela Eyal , Edelstein Michael
Published: March 2022

Vaccination is a key tool to mitigate impacts of the COVID-19 pandemic. In Israel, COVID-19 vaccines became available to adults in December 2020 and to 5–11-year-old children in November 2021. Ahead of the vaccine roll-out in children, we aimed to determine whether surveyed parents intended to vaccinate their children and describe reasons for their intentions. We collected information on parental socio-demographic characteristics, COVID-19 vaccine history, intention to vaccinate their children against COVID-19, and reasons for parental decisions using an anonymous online survey. We identified associations between parental characteristics and plans to vaccinate children using a logistic regression model and described reasons for intentions to vaccinate or not. Parental non-vaccination and having experienced major vaccination side effects were strongly associated with non-intention to vaccinate their children (OR 0.09 and 0.18 respectively, p<0.001). Parents who were younger, lived in the socio-economically deprived periphery, and belonged to the Arab population had lower intentions to vaccinate their children. Reasons for non-intention to vaccinate included concerns about vaccine safety and efficacy (53%, 95%CI 50-56) and the belief that COVID-19 is a mild disease (73%, 95%CI 73-79), while a frequent motive for vaccination was the return to normal social and educational life (89%, 95%CI 87-91). Understanding rationales for COVID-19 vaccine rejection or acceptance, as well as parental demographic data, can pave the way for intentional educational campaigns to encourage not only vaccination against COVID-19, but also regular childhood vaccine programming.

Highlights

Parental intention to vaccinate children aged 5-11 is much lower than vaccine coverage in parental age groups

Being unvaccinated and having experienced side effects following vaccination were the greatest negative predictors in parents of intention to vaccinate their children

Parents were more likely to accept a COVID-19 vaccine for their children to allow them to return to daily social life and to ensure economic security in the family

Parents were more likely to reject a COVID-19 vaccination for health reasons such as safety concerns or due the belief that COVID-19 was a mild disease in children
Testing Frequency Matters | An Evaluation of the Diagnostic Performance of a SARS-CoV-2 Rapid Antigen Test in United States Correctional Facilities
Authors: Lind Margaret L. , Schultes Olivia L. , Robertson Alexander J. , Houde Amy J. , Cummings Derek A.T. , Ko Albert I. , Kennedy Byron S. , Richeson Robert P.
Published: March 2022

Background

The CDC recommends serial rapid antigen assay collection within congregate facilities for screening and outbreak testing. Though modeling and observational studies from community and long-term care facilities have shown serial collection provides adequate sensitivity and specificity, the diagnostic accuracy of this testing strategy within correctional facilities remains unknown.

Methods

Using Connecticut Department of Corrections (DOC) data from November 21st2020 to June 15th2021, we estimated the accuracy of a rapid assay, BinaxNOW, under three collection strategies, a single test in isolation and two and three serial tests separated by 1-4 day intervals. Diagnostic accuracy metrics were estimated in relation to RT-PCRs collected within one day before the first or after the last included rapid antigen tests in a series.

Results

Of the 17,669 residents who contributed at least one RT-PCR or rapid antigen during the study period, 3,979 contributed ≥1 paired rapid antigen test series. In relation to RT-PCR, the three-rapid antigen test strategy had a sensitivity of 89.6% (95% confidence intervals: 86.1-92.6%) and specificity of 97.2% (CI: 95.1-98.3%). The sensitivities for two and one-rapid antigen test strategy were 75.2% and 52.8%, respectively, and the specificities were 98.5% and 99.4%, respectively. The sensitivity was higher among symptomatic residents and when the RT-PCR was collected before the rapid antigen tests.

Conclusions

We found the serial collection of an antigen test resulted in high diagnostic accuracy. These findings support serial testing within correctional facilities for outbreak investigation, screening, and when rapid detection is required (such as intakes or transfers).
Immunogenicity and Safety of Booster Dose of S-268019-b or Tozinameran in Japanese Participants: An Interim Report of Phase 2/3, Randomized, Observer-Blinded, Noninferiority Study
Authors: Shinkai Masaharu , Sonoyama Takuhiro , Kamitani Akari , Shibata Risa , Seki Naomi , Omoto Shinya , Shinoda Masahiro , Sato Takashi , Ishii Naoki , Igarashi Kenji , Ariyasu Mari
Published: March 2022

In this randomized, observer-blinded, phase 2/3 study, S-268019-b (n=101), a recombinant spike protein vaccine, was analyzed for noninferiority versus tozinameran (n=103), when given as a booster ≥6 months after 2-dose tozinameran regimen in Japanese adults without prior COVID-19 infection. Interim results showed noninferiority of S-268019-b versus tozinameran in co-primary endpoints for neutralizing antibodies on day 29: geometric mean titer (GMT) (124.97 versus 109.70; adjusted-GMT ratio [95% CI], 1.14 [0.94-1.39]; noninferiority P-value, <0.0001) and seroresponse rate (both 100%; noninferiority P-value, 0.0004). Both vaccines elicited anti-spike-protein immunoglobulin G antibodies, and produced T-cell response (n=29/group) and neutralizing antibodies against Delta and Omicron pseudovirus and live virus variants (n=24/group) in subgroups. Most participants reported low-grade reactogenicity on days 1-2, the most frequent being fatigue, fever, myalgia, and injection-site pain. No serious adverse events were reported. In conclusion, S-268019-b was safe and showed robust immunogenicity as a booster, supporting its use as COVID-19 booster vaccine.

JRCT ID

jRCT2031210470

Highlights

Third COVID-19 vaccine dose (booster) enhances immune response

Interim phase 2/3 data for booster ≥6 months after the 2nd dose in Japan are shown

S-268019-b was noninferior to tozinameran in inducing neutralizing antibodies

Sera boosted with either vaccines neutralized Delta and Omicron virus variants

S-268019-b was safe, and results support its use as a booster in vaccinated adults
Assessment of Aerosol Persistence in ICUs via Low-cost Sensor Network and Zonal Models
Authors: Glenn K , He J , Rochlin R , Teng S , Hecker JG , Novosselov I
Published: March 2022

The COVID-19 pandemic raised public awareness about airborne particulate matter (PM) due to the spread of infectious diseases via the respiratory route. The persistence of potentially infectious aerosols in public spaces and the spread of nosocomial infections in medical settings deserve careful investigation; however, a systematic approach characterizing the fate of aerosols in clinical environments has not been reported. This paper presents a methodology for mapping aerosol propagation using a low-cost PM sensor network in ICU and adjacent environments and the subsequent development of the data-driven zonal model. Mimicking aerosol generation by a patient, we generated trace NaCl aerosols and monitored their propagation in the environment. In positive (closed door) and neutral-pressure (open door) ICUs, up to 6% or 19%, respectively, of all PM escaped through the door gaps; however, the outside sensors did not register an aerosol spike in negative-pressure ICUs. The K-means clustering analysis of temporospatial aerosol concentration data suggests that ICU can be represented by three distinct zones: (1) near the aerosol source, (2) room periphery, and (3) outside the room. The data suggests two-phase plume behavior: dispersion of the original aerosol spike throughout the room, followed by an evacuation phase where “well-mixed” aerosol concentration decayed uniformly. Decay rates were calculated for positive, neutral, and negative pressure operations, with negative-pressure rooms clearing out nearly twice as fast. These decay trends closely followed the air exchange rates. This research demonstrates the methodology for aerosol monitoring in medical settings. This study is limited by a relatively small data set and is specific to single-occupancy ICU rooms. Future work needs to evaluate medical settings with high risks of infectious disease transmission.
Individualised Profiling of White Matter Organisation in Moderate-to-Severe Traumatic Brain Injury Patients Using TractLearn: A Proof-of-Concept Study
Authors: Clemente Adam , Attyé Arnaud , Renard Félix , Calamante Fernando , Burmester Alex , Imms Phoebe , Deutscher Evelyn , Akhlaghi Hamed , Beech Paul , Wilson Peter H , Poudel Govinda , Dominguez D Juan F , Caeyenberghs Karen
Published: March 2022

Approximately 65% of moderate-to-severe traumatic brain injury (m-sTBI) patients present with poor long-term behavioural outcomes, which can significantly impair activities of daily living. Numerous diffusion-weighted MRI studies have linked these poor outcomes to decreased white matter integrity of several commissural tracts, association fibres and projection fibres in the brain. However, these studies focused on group-based analyses, which are unable to deal with the substantial between-patient heterogeneity in m-sTBI. As a result, there is increasing interest in conducting individualised neuroimaging analyses. Here, we generated a detailed subject-specific characterisation of microstructural organisation of white matter tracts in 5 chronic patients with m-sTBI (29 – 49y, 2 females). We developed an imaging analysis framework using fixel-based analysis and TractLearn to determine whether the values of fibre density of white matter tracts at the individual patient level deviate from the healthy control group (n = 12, 8F, Mage=35.7y, age range 25 – 64y). Our individualised analysis confirmed unique white matter profiles, and the heterogeneous nature of m-sTBI to properly characterise the extent of brain abnormality. Future studies incorporating clinical data, as well as utilising larger reference samples and examining the test-retest reliability of the fixel-wise metrics are warranted. This proof-of-concept study suggests that these resulting individual profiles may assist clinicians in planning personalised training programs for chronic m-sTBI patients, which is necessary to achieve optimal behavioural outcomes and improved quality of life.
SARS-CoV-2 Seroprevalence among health care workers after the first and second pandemic wave
Authors: Visscher Nathalie de , Holemans Xavier , Gillain Aline , Kornreich Anne , Lagasse Raphael , Piette Philippe , Ventura Manfredi , Thys Frédéric
Published: March 2022

Background

The Grand Hôpital de Charleroi is a large non-academic Belgian hospital that treated a large number of COVID-19 inpatients. In the context of this pandemic, all professions-combined healthcare workers (HCWs), and not only direct caregivers, are a frontline workforce in contact with suspected and confirmed COVID-19 cases and seem to be a high-risk group for exposure. The aim of our study was to estimate the prevalence of anti-SARS-CoV-2 antibodies in HCWs in our hospital after the first and the second pandemic wave and also to characterize the distribution of this seroprevalence in relation to various criteria.

Methods

At the end of the two recruitment periods, a total of 4008 serological tests were performed in this single-center cross-sectional study. After completing a questionnaire including demographic and personal data, possible previous COVID-19 diagnostic test results and/or the presence of symptoms potentially related to COVID-19, the study participants underwent blood sampling and serological testing using DiaSorin’s LIAISON® SARS-CoV-2 S1/S2 IgG test for the first phase and LIAISON® SARS-CoV-2 TrimericS IgG test for the second phase of this study.

Results

302 study participants (10,72%) in the first round of the study and 404 (33,92%) in the second round were positive for SARS-CoV-2-IgG antibodies. The prevalence of seropositivity observed after the second wave was 3,16 times higher than after the first wave. We confirmed that direct, prolonged and repeated contact with patients or their environment was a predominant seroconversion factor, but more unexpectedly, that this was the case for all HCWs and not only caregivers. Finally, the notion of high-risk contact seemed more readily identifiable in one’s workplace than in one’s private life.

Conclusion

Our study confirmed that HCWs are at a significantly higher risk of contracting COVID-19 than the general population, and suggest that repeated contacts with at-risk patients, regardless of the HCWs’ profession, represent the most important risk factor for seroconversion. (Clinicaltrials.gov number, NCT04723290)
Sero-surveillance for IgG to SARS-CoV-2 at antenatal care clinics in three Kenyan referral hospitals: repeated cross-sectional surveys 2020-21
Authors: Lucinde R. , Mugo D. , Bottomley C. , Karani A. , Gardiner E. , Aziza R , Gitonga J. , Karanja H. , Nyagwange J. , Tuju J. , Wanjiku P. , Nzomo E. , Kamuri E. , Thuranira K. , Agunda S. , Nyutu G. , Etyang A. , Adetifa I. M. O. , Kagucia E. , Uyoga S. , Otiende M. , Otieno E. , Ndwiga L. , Agoti C. N. , Aman R. A. , Mwangangi M. , Amoth P. , Kasera K. , Nyaguara A. , Ng’ang’a W. , Ochola L. B. , Namdala E. , Gaunya O , Okuku R , Barasa E. , Bejon P. , Tsofa B. , Ochola-Oyier L. I. , Warimwe G. M. , Agweyu A. , Scott J. A. G. , Gallagher K. E.
Published: March 2022

Introduction

The high proportion of SARS-CoV-2 infections that have remained undetected presents a challenge to tracking the progress of the pandemic and estimating the extent of population immunity.

Methods

We used residual blood samples from women attending antenatal care services at three hospitals in Kenya between August 2020 and October 2021and a validated IgG ELISA for SARS-Cov-2 spike protein and adjusted the results for assay sensitivity and specificity. We fitted a two-component mixture model as an alternative to the threshold analysis to estimate of the proportion of individuals with past SARS-CoV-2 infection.

Results

We estimated seroprevalence in 2,981 women; 706 in Nairobi, 567 in Busia and 1,708 in Kilifi. By October 2021, 13% of participants were vaccinated (at least one dose) in Nairobi, 2% in Busia. Adjusted seroprevalence rose in all sites; from 50% (95%CI 42-58) in August 2020, to 85% (95%CI 78-92) in October 2021 in Nairobi; from 31% (95%CI 25-37) in May 2021 to 71% (95%CI 64-77) in October 2021 in Busia; and from 1% (95% CI 0-3) in September 2020 to 63% (95% CI 56-69) in October 2021 in Kilifi. Mixture modelling, suggests adjusted cross-sectional prevalence estimates are underestimates; seroprevalence in October 2021 could be 74% in Busia and 72% in Kilifi.

Conclusions

There has been substantial, unobserved transmission of SARS-CoV-2 in Nairobi, Busia and Kilifi Counties. Due to the length of time since the beginning of the pandemic, repeated cross-sectional surveys are now difficult to interpret without the use of models to account for antibody waning.
Burden of Disease from Contaminated Drinking Water in Countries with High Access to Safely Managed Water: A Systematic Review
Authors: Lee Debbie , Gibson Jacqueline MacDonald , Brown Joe , Habtewold Jemaneh , Murphy Heather M.
Published: March 2022

The vast majority of residents of high-income countries (≥90%) reportedly have high access to safely managed drinking water. Owing perhaps to the widely held perception of near universal access to high-quality water services in these countries, the burden of waterborne disease in these contexts is understudied. This systematic review aimed to: identify population-scale estimates of waterborne disease in countries with high access to safely managed drinking water, compare methods to quantify disease burden, and identify gaps in available burden estimates. We conducted a systematic review of population-scale disease burden estimates attributed to drinking water in countries where ≥90% of the population has access to safely managed drinking water per official United Nations monitoring. We identified 24 studies reporting estimates for disease burden attributable to microbial contaminants. Across these studies, the population-weighted average burden of gastrointestinal illness risks attributed to drinking water was ∼3,529 annual cases per 100,000 people. Beyond exposure to infectious agents, we identified 10 studies reporting disease burden—predominantly, cancer risks—associated with chemical contaminants. Across these studies, the pooled population-weighted average of excess cancer cases attributable to drinking water was 1.8 annual cancer cases per 100,000 people. These estimates exceed WHO-recommended normative targets for disease burden attributable to drinking water and highlight that there remains important preventable disease burden in these contexts. However, the available literature was scant and limited in geographic scope, disease outcomes, range of microbial and chemical contaminants, and inclusion of subpopulations (rural, low-income communities; Indigenous or Aboriginal peoples; and populations marginalized due to discrimination by race, ethnicity, or socioeconomic status) that could most benefit from water infrastructure investments. Studies quantifying drinking water-associated disease burden in countries with reportedly high access to safe drinking water, with a focus on specific subpopulations and promoting environmental justice, are needed.
Monocyte, Neutrophil and Whole Blood Transcriptome Dynamics Following Ischemic Stroke
Authors: Carmona-Mora Paulina , Knepp Bodie , Jickling Glen C , Zhan Xinhua , Hakoupian Marisa , Hull Heather , Alomar Noor , Amini Hajar , Sharp Frank R , Stamova Boryana , Ander Bradley P
Published: March 2022

Background

After ischemic stroke (IS), peripheral leukocytes infiltrate the damaged region and modulate the response to injury. Peripheral blood cells display distinctive gene expression signatures post IS and these transcriptional programs reflect changes in immune responses to IS. Dissecting the temporal dynamics of gene expression after IS improves our understanding of immune and clotting responses at the molecular and cellular level that are involved in acute brain injury and may assist with time-targeted, cell-specific therapy.

Methods

The transcriptomic profiles from peripheral monocytes, neutrophils, and whole blood from 38 ischemic stroke patients and 18 controls were analyzed with RNAseq as a function of time and etiology after stroke. Differential expression analyses were performed at 0-24 h, 24-48 h, and >48 h following stroke.

Results

Unique patterns of temporal gene expression and pathways were distinguished for monocytes, neutrophils and whole blood with enrichment of interleukin signaling pathways for different timepoints and stroke etiologies. Compared to control subjects, gene expression was generally up-regulated in neutrophils and generally down- regulated in monocytes over all times for cardioembolic, large vessel and small vessel strokes. Self-Organizing Maps identified gene clusters with similar trajectories of gene expression over time for different stroke causes and sample types. Weighted Gene Co- expression Network Analyses identified modules of co-expressed genes that significantly varied with time after stroke and included hub genes of immunoglobulin genes in whole blood.

Conclusions

Altogether, the identified genes and pathways are critical for understanding how the immune and clotting systems change over time after stroke. This study identifies potential time- and cell-specific biomarkers and treatment targets.
A multi-analyte serum biomarker panel for early detection of pancreatic adenocarcinoma
Authors: Firpo Matthew A. , Boucher Kenneth M. , Bleicher Josh , Khanderao Gayatri D. , Rosati Alessandra , Poruk Katherine E. , Kamal Sama , Marzullo Liberato , De Marco Margot , Falco Antonia , Genovese Armando , Adler Jessica M. , De Laurenzi Vincenzo , Adler Douglas G. , Affolter Kajsa E. , Garrido-Laguna Ignacio , Scaife Courtney L. , Turco M. Caterina , Mulvihill Sean J.
Published: March 2022

Purpose

We determined whether a large, multi-analyte panel of circulating biomarkers can improve detection of early-stage pancreatic ductal adenocarcinoma (PDAC).

Experimental Design

We defined a biologically relevant subspace of blood analytes based on previous identification in premalignant lesions or early-stage PDAC and evaluated each in pilot studies. The 31 analytes that met minimum diagnostic accuracy were measured in serum of 837 subjects (461 healthy, 194 benign pancreatic disease, 182 early stage PDAC). We used machine learning to develop classification algorithms using the relationship between subjects based on their changes across the predictors. Model performance was subsequently evaluated in an independent validation data set from 186 additional subjects.

Results

A classification model was trained on 669 subjects (358 healthy, 159 benign, 152 early-stage PDAC). Model evaluation on a hold-out test set of 168 subjects (103 healthy, 35 benign, 30 early-stage PDAC) yielded an area under the receiver operating characteristic (ROC) curve (AUC) of 0.920 for classification of PDAC from non-PDAC (benign and healthy controls) and an AUC of 0.944 for PDAC vs. healthy controls. The algorithm was then validated in 146 subsequent cases presenting with pancreatic disease (73 benign pancreatic disease, 73 early and late stage PDAC) as well as 40 healthy control subjects. The validation set yielded an AUC of 0.919 for classification of PDAC from non-PDAC and an AUC of 0.925 for PDAC vs. healthy controls.

Conclusions

Individually weak serum biomarkers can be combined into a strong classification algorithm to develop a blood test to identify patients who may benefit from further testing.
Declines and pronounced state-level variation in tapentadol use in the US
Authors: Low Ching Y. , McCall Kenneth L. , Piper Brian J.
Published: March 2022

Background

Tapentadol is an opioid approved for the treatment of moderate-to-severe pain in the United States (US). Tapentadol is unique as it is the only Schedule II prescription drug that has dual modes of action as it combines agonist activity at the µ opioid receptor with norepinephrine reuptake inhibition. This descriptive study characterized tapentadol use in the US.

Methods

Drug distribution data from 2010 to 2020 were extracted for each state from the Drug Enforcement Administration. Use per state, corrected for population, was analyzed. The percentage of distribution channels (pharmacies, hospitals, and providers), the distributed amount of tapentadol, and the final adjusted quota of tapentadol were obtained. Data on tapentadol use as reported by the Medicare and Medicaid programs for 2010 to 2020 were also analyzed.

Results

The distributed amount of tapentadol was 3.5 tons in 2020 and on average, the final adjusted production quota was 207.2% greater than the distributed amount between 2010 and 2020. Distributed tapentadol was 1.3% of all Schedule II opioids distributed in 2020. Tapentadol use decreased by −53.8% between 2012 and 2020 in the US whereas New Hampshire was the only state that had a positive change (+13.1%). There were minor changes in the amounts of tapentadol distributed via various distribution channels (Pharmacies = 98.0%, hospitals = 1.9% in 2020). Tapentadol prescribed by Nurse Practitioners experienced the largest increase of +8.7% among all specialties to 18.0%, the highest percentage of Medicare claims of tapentadol in 2019. Diabetes prevalence was significantly correlated with tapentadol distribution in 2012 (r(50) = .44,p< .01) and 2020 (r(50) = .28,p< .05).

Discussion

There has been a substantial decline over the past decade in tapentadol distribution and prescribing to Medicaid patients. The unusual tapentadol prescribing pattern in New Hampshire may warrant investigation regarding differing prescribers’ attitudes towards tapentadol or the employment of tapentadol as part of a step-down therapy for opioid addiction.
Species invasiveness and community invasibility of US freshwater fish fauna revealed via trait-based analysis
Authors: Su Guohuan , Mertel Adam , Brosse Sébastien , Calabrese Justin M.
Published: March 2022

While biological invasions are recognized as a major threat to global biodiversity, determining species’ abilities to invade new areas (species invasiveness) and the vulnerability of those areas to invasions (community invasibility) are still poorly understood. Here, we used trait-based analysis to profile invasive species and quantify the community invasibility for >1,800 North American freshwater fish communities. We show that species with higher reproduction rates, longer life spans and larger sizes tend to be more invasive. Community invasibility peaked when the functional distance among native species was high, leaving unoccupied functional space for the establishment of potential invaders. Invasion success is therefore governed by both the functional traits of non-native species determining their invasiveness, and by the functional characteristics of the invaded community determining its invasibility. Considering those two determinants together will allow better predictions of invasions.
The 13A4 monoclonal antibody to the mouse PROM1 protein recognizes a structural epitope
Authors: Matalkah Fatimah , Rhodes Scott , Ramamurthy Visvanathan , Stoilov Peter
Published: March 2022

Purpose

We endeavored to map the epitope of the rat monoclonal antibody mAB 13A4 to the mouse PROM1 (CD133, AC133) protein. mAB 13A4 is the main reagent used to detect the mouse PROM1 protein. PROM1 is required for the maintenance of primary cilia and mutations in the Prom1 gene are associated with retinal degeneration.

Methods

Epitope tagged clones of splice variants and tiled deletion mutants were used to map the mAB 13A4 epitope and test the predicted tertiary structure of PROM1. The proteins were expressed in Neuro 2a cells and analyzed by Western blot with antibodies to PROM1 and the epitope tag.

Results

Deletions in the second and third extracellular domains of the PROM1 protein disrupted the mAB 13A4 epitope. Furthermore, the affinity of mAB 13A4 to the major PROM1 isoform in photoreceptor cells is significantly reduced due to the inclusion of a photoreceptor-specific alternative exon in the third extracellular domain. Interestingly, a deletion in the photoreceptor specific isoform of six amino acids adjacent to the alternative exon restored the affinity of mAB 13A4 to PROM1.

Conclusion

mAB 13A4 recognizes a structural epitope that is stabilized by two of the extracellular domains of PROM1. The results of our mutagenesis are consistent with the computationally predicted helical bundle structure of PROM1 and point to the utility of mAB 13A4 for evaluating the effect of mutations on the PROM1 structure. We show that the PROM1 isoform composition needs to be considered when interpreting tissue and developmental expression data produced by mAB 13A4.
Feeding desensitizes A1 adenosine receptors in adipose through FOXO1-mediated transcriptional regulation
Authors: Granade Mitchell E. , Hargett Stefan R. , Lemke Michael C. , Luse Melissa A. , Bochkis Irina M. , Linden Joel , Harris Thurl E.
Published: March 2022

Adipose tissue is a critical regulator of energy balance that must rapidly shift its metabolism between fasting and feeding to maintain homeostasis. Adenosine has been characterized as an important regulator of adipocyte metabolism primarily through its actions on A1 adenosine receptors (A1R). We sought to understand the role A1R plays in adipocytes during fasting and feeding to regulate glucose and lipid metabolism by using an inducible, adiponectin-Cre with Adora1 floxed mice (FAdora1−/−), where F designates a fat-specific deletion. Fadora1−/− mice had impairments in the suppression of lipolysis by insulin on normal chow and impaired glucose tolerance on high-fat diet. FAdora1−/− mice also exhibited a higher lipolytic response to isoproterenol than WT controls when fasted, but not after a 4-hour refeeding period. We found that FOXO1 binds to the A1R promoter in adipocytes. Upon feeding, signaling along the insulin-Akt-FOXO1 axis leads to a rapid downregulation of A1R transcript and desensitization of adipocytes to A1R agonism. Obesity also desensitizes adipocyte A1R, and this is accompanied by a disruption of cyclical changes in A1R transcription between fasting and refeeding. We propose that FOXO1 drives high A1R expression under fasted conditions to limit excess lipolysis during stress and augment insulin action upon feeding. Subsequent downregulation of A1R under fed conditions facilitates reentrance into the catabolic state upon fasting.
PANDORA: a fast, anchor-restrained modelling protocol for peptide:MHC complexes
Authors: Parizi Farzaneh Meimandi , Marzella Dario F. , Tilborg Derek Van , Renaud Nicolas , Sybrandi Daan , Buzatu Rafaella , Xue Li C
Published: March 2022

Deeper understanding T-cell mediated adaptive immune responses bears important implications in designing cancer immunotherapies and antiviral vaccines against pandemic outbreaks. T cells fire when they recognize foreign peptides that are presented on the cell surface by Major Histocompatibility Complexes (MHC), forming peptide:MHC (pMHC) complexes. 3D structure of pMHC complexes provides fundamental insight of T-cell recognition mechanism and aids immunotherapy design. High MHC and peptide diversities necessitate efficient computational modelling to enable whole proteome structural analysis.

Here we present PANDORA, a robust pMHC structure modelling pipeline. Given a query, PANDORA searches for structural templates in its extensive database and then applies anchor restraints to the modelling process. This restrained energy minimization ensures one of the fastest pMHC modelling pipelines so far. On a set of 835 pMHC-I complexes over 78 MHC types, PANDORA generated models with a median RMSD of 0.68 Å and achieved a 93% success rate in top 10 models. PANDORA performs competitively with three pMHC-I modelling state-of-the-art approaches and outperforms AlphaFold in terms of accuracy while being superior to it in speed. PANDORA is a modularized and user-configurable python package with easy installation. We envision PANDORA to fuel deep learning with large-scale high-quality 3D models to tackle long-standing immunology challenges.
Assembly of functional diversity in an oceanic island flora
Authors: Barajas-Barbosa Martha Paola , Craven Dylan , Weigelt Patrick , Denelle Pierre , Otto Rüdiger , Díaz Sandra , Price Jonathan , Fernández-Palacios José María , Kreft Holger
Published: March 2022

Oceanic island floras are well-known for their morphological peculiarities and exhibit striking examples of trait evolution1,2. These morphological shifts are commonly attributed to insularity and thought to be shaped by biogeographical processes and evolutionary histories of oceanic islands1,3. However, the mechanisms through which biogeography and evolution have shaped the distribution and diversity of plant functional traits remain unclear. Here, we describe the functional trait space of an oceanic island flora (Tenerife, Canary Islands, Spain) using extensive field and laboratory measurements, and relate it to global trade-offs in ecological strategies. We find that the island trait space is concentrated around a functional hotspot dominated by shrubs with a conservative life-history strategy. By dividing the island flora into species groups with distinct biogeographical distributions and diversification histories, our results reveal that long-distance dispersal, and the interplay between inter-island dispersal and archipelago-level speciation processes drive functional divergence and expand trait space. Conversely, speciation via cladogenesis has overall led to functional convergence, densely packing trait space around shrubbiness. Our approach combines ecology, biogeography and evolution and opens avenues for new trait-based insights into how dispersal and speciation shape the assembly of native island floras.
Robust differential composition and variability analysis for multisample cell omics
Authors: Mangiola S , Schulze A , Trussart M , Zozaya E , Ma M , Gao Z , Rubin AF , Speed TP , Shim H , Papenfuss AT
Published: March 2022

Cell omics such as single-cell genomics, proteomics and microbiomics allow the characterisation of tissue and microbial community composition, which can be compared between conditions to identify biological drivers. This strategy has been critical to unveiling markers of disease progression such as cancer and pathogen infection. For cell omic data, no method for differential variability analysis exists, and methods for differential composition analysis only take a few fundamental data properties into account. Here we introduce sccomp, a generalised method for differential composition and variability analyses able to jointly model data count distribution, compositionality, group-specific variability and proportion mean-variability association, with awareness against outliers. Sccomp is an extensive analysis framework that allows realistic data simulation and cross-study knowledge transfer. Here, we demonstrate that mean-variability association is ubiquitous across technologies showing the inadequacy of the very popular Dirichlet-multinomial modelling and provide mandatory principles for differential variability analysis. We show that sccomp accurately fits experimental data, with a 50% incremental improvement over state-of-the-art algorithms. Using sccomp, we identified novel differential constraints and composition in the microenvironment of primary breast cancer.

Significance statement

Determining the composition of cell populations is made possible by technologies like single-cell transcriptomics, CyTOF and microbiome sequencing. Such analyses are now widespread across fields (~800 publications/month, Scopus). However, existing methods for differential abundance do not model all data features, and cell-type/taxa specific differential variability is not yet possible. Increase in the variability of tissue composition and microbial communities is a well-known indicator of loss of homeostasis and disease. A suitable statistical method would enable new types of analyses to identify component-specific loss of homeostasis for the first time. This and other innovations are now possible through our discovery of the mean-variability association for compositional data. Based on this fundamental observation, we have developed a new statistical model, sccomp, that enables differential variability analysis for composition data, improved differential abundance analyses, with cross-sample information borrowing, outlier identification and exclusion, realistic data simulation, based on experimental datasets, cross-study knowledge transfer.
Towards resolution of the intron retention paradox in breast cancer
Authors: Shah Jaynish S. , Milevskiy Michael , Petrova Veronika , Au Amy YM , Wong Justin J.L. , Visvader Jane E. , Schmitz Ulf , Rasko John E.J.
Published: March 2022

After many years of neglect in the field of alternative splicing, the importance of intron retention (IR) in cancer has come into focus following landmark discoveries of aberrant IR patterns in cancer. Many solid and liquid tumours are associated with drastic increases in IR and such patterns have been pursued as both biomarkers and therapeutic targets. Paradoxically, breast cancer (BrCa) is the only tumour type in which IR is reduced compared to adjacent normal breast tissue.

In this study, we have conducted a pan-cancer analysis of IR with emphasis on BrCa and its subtypes. We explored mechanisms that could cause aberrant and pathological IR and clarified why normal breast tissue has unusually high IR.

Strikingly, we found that reduced IR in BrCa can be largely attributed to normal breast tissue having the highest occurrence of IR events compared to other healthy tissues. Our analyses suggest that low numbers of IR events in breast tumours are associated with poor prognosis, particularly in the luminal B subtype. Interestingly, we found that IR frequencies negatively correlate with cell proliferation in BrCa cells, i.e. rapidly dividing tumour cells have the lowest number of IR events. Aberrant RNA binding protein (RBP) expression and changes in tissue composition are among the causes of low IR in BrCa.

Our results suggest that IR should be considered for therapeutic manipulation in BrCa patients with aberrantly low IR levels and that further work is needed to understand the cause and impact of high IR in other tumour types.
Four tumor micro-environmental niches explain a continuum of inter-patient variation in the macroscopic cellular composition of breast tumors
Authors: Marrahi Anissa El , Lipreri Fabio , Alber David , Hausser Jean
Published: March 2022

The tumor microenvironment is a complex, self-organising tissue whose architecture determines prognostic and response to therapy. There is significant variation in the cellular and spatial architecture of the tumor-microenvironment within and across patients. Are there rules that constrain the architecture of the tumor-microenvironment?

To find out, we develop a quantitative framework of tumor architecture inspired by ideas from satellite imaging, which we apply on deep single-cell profiling and multiplex imaging data in breast tumors. Data analysis shows that inter-patient variation in the macroscopic cellular composition of tumors is structured as a continuum explained by four tumor niches: cancer, inflammatory, tertiary lymphoid structure and fibrotic/necrotic. These niches have their origin in tumor micro-architecture and are shared across patients and tumor subtypes. Niche prevalence depends strongly on the patient, which constraints and explains inter-patient variation.

The present framework will facilitate interpreting inter-patient variation in terms of a tractable number of micro-environmental niches which serve as organizational entities at the meso-scale to bridge the micro- and macro-scales of tumor architecture.
Developmental changes in cerebral NAD and neuroenergetics of an antioxidant compromised mouse model of schizophrenia
Authors: Skupienski Radek , Steullet Pascal , Do Kim Q. , Xin Lijing
Published: March 2022

Defects in essential metabolic regulation for energy supply, increased oxidative stress promoting excitatory/inhibitory imbalance and phospholipid membrane dysfunction have been implicated in the pathophysiology of schizophrenia (SZ). The knowledge about the developmental trajectory of these key pathophysiological components and their interplay is important to develop new preventive and treatment strategies. However, this assertion is so far limited. To investigate the developmental regulations of these key components, we assessed, for the first time, in vivo redox state from the oxidized (NAD+) and reduced (NADH) form of Nicotinamide Adenine Dinucleotide (NAD), energy and membrane metabolites, neurotransmitters (γ-aminobutyrate and glutamate) by 31P and 1H MRS during the neurodevelopment of a SZ animal model with genetically compromised glutathione synthesis (gclm-KO mice). When compared to age-matched wild type (WT), an increase in NAD+/NADH redox ratio was found in gclm-KO mice until early adulthood, followed by a decrease in full adults as observed in patients. Especially, in early postnatal life (P20, corresponding to childhood), levels of several metabolites were altered in gclm-KO mice, including NAD+, ATP, phosphocreatine, intracellular pH, glutamine + glutamate and membrane phospholipids components, suggesting an interactive compensation for redox dysregulation between NAD, energy metabolism, and neurotransmission. The identified temporal neurometabolic regulations provide insights in preventive treatment targets for at-risk individuals, and other neurodevelopmental disorders involving oxidative stress and energetic dysfunction.
Genome Editing Is Induced in a Binary Manner in Single Human Cells
Authors: Takahashi Gou , Kondo Daiki , Maeda Minato , Morishita Yuji , Miyaoka Yuichiro
Published: March 2022

Even when precise nucleotide manipulations are intended, the outcomes of genome editing can be diverse, often including random insertions and deletions. The combinations and frequencies of these different outcomes in single cells are critical not only in the generation of genetically modified cell lines but also in the evaluation of the clinical effects of genome editing therapies. However, current methods only analyze cell populations, not single cells. Here, we utilized the Single Particle isolation System (SPiS) for the efficient isolation of single cells to systematically analyze genome editing results in individual human cultured cells. As a result, we discovered that genome editing induction has a binary nature, that is, the target alleles of cells tend to be all edited or not edited at all. This study enhances our understanding of the induction mechanism of genome editing and provides a new strategy to analyze genome editing outcomes in single cells.
Phenotypic Characterization of Liver Sinusoidal Endothelial Cells on the Human Liver-Chip for Potential in vitro Therapeutic Antibody Pharmacology Applications
Authors: Candarlioglu Pelin L. , Jadalannagari Sushma , Chaff Jake , Velez James , Joshipura Sannidhi R , Kanellias Marianne , Simpson Alexander P. , Kerns S. Jordan , Ewart Lorna , Hegde Manjunath , Ekert Jason
Published: March 2022

Liver plays a vital role in the human immune system, in the internalization and catabolic clearance of therapeutic antibodies and antibody-bound immune complexes via Fc-receptor (FcR) binding on the hepatic reticuloendothelial system cells. This Fc portion of the antibody binding to FcR in the liver initiates the clearance of these antibodies or immune complexes, which is vital in the context of half-life, dosing interval, efficacy, and safety of therapeutic antibodies. The liver sinusoidal endothelial cells (LSECs) express scavenging receptors that recognize, bind, and internalize an enormous diversity of extracellular ligands. The Fc gamma receptor FcγRIIB or CD32B on LSECs is responsible for the clearance of a large majority of IgG-bound immune complexes in the liver. Investigating the pharmacological effects of antibody clearance via human liver in vitro has been challenging due to the lack of reliable long-term LSEC culture protocols. Human LSECs downregulate the expression of CD32B rapidly in vitro in traditional 2D LSEC mono- and co-cultures,. We describe a Liver-Chip model with a co-culture of primary human LSECs and hepatocytes to recreate the liver microenvironment and extend the viability and function of LSECs, including CD32B expression levels, for a duration that is relevant for assessing the pharmacokinetics (PK) of therapeutic antibodies. Our results show that the expression of CD32B can differ based on experimental variables such as the source of primary cells (donor), passage number or source of detection antibodies used to visualize CD32B and shear stress. The CD32B expression was maintained for 14 days on the Liver-Chip in a donor-dependent but passage number independent manner. The Scanning Electron Microscopy (SEM) imaging showed the presence of fenestrae structures - one of the hallmarks of LSEC function. Key LSEC markers, including CD32B expression, were validated through flow cytometry.
Pervasive impacts of climate change on the woodiness and ecological generalism of dry forest plant assemblages
Authors: Moura Mario R. , Nascimento Fellipe A. O. do , Paolucci Lucas N. , Silva Daniel P. , Santos Bráulio A.
Published: March 2022

Climate emergency is a significant threat to biodiversity in the 21st century, but species will not be equally affected. In summing up different species’ responses at the local scale, we can assess changes in the species quantity and composition of biotic assemblages. Here we investigated climate change driven variation in species richness and spatial beta-diversity using modelled distributions of 2,841 plant species in Caatinga, the largest dry forest region of South America. More than 99% of plant assemblages were projected to lose species by 2060, with biotic homogenisation ─ the decrease in spatial beta-diversity forecasted in 40% of the Caatinga. Replacement of narrow-range woody species by wide-range non-woody ones should impact at least 85% of Caatinga plant assemblages. The future increase in aridity will change patterns of woodiness and ecological generalism of tropical dry forest plant assemblages, and ultimately erode ecosystem services linked to biomass productivity and carbon storage.
DNA methylation dynamics during stress-response in woodland strawberry (Fragaria vesca)
Authors: López María-Estefanía , Roquis David , Becker Claude , Denoyes Béatrice , Bucher Etienne
Published: March 2022

Environmental stresses can result in a wide range of physiological and molecular responses in plants. These responses can also impact epigenetic information in genomes especially at the level of DNA methylation. DNA methylation is the hallmark heritable epigenetic modification and plays a key role in silencing transposable elements (TEs). Although DNA methylation is an essential epigenetic mechanism, fundamental aspects of its contribution to stress responses and adaptation remain obscure.

We investigated epigenome dynamics of wild strawberry (Fragaria vesca) in response to variable environmental conditions at DNA methylation level. F. vesca methylome responded with great plasticity to ecologically relevant abiotic and hormonal stresses. Thermal stress resulted in substantial genome-wide loss of DNA methylation. Notably, all tested stress conditions resulted in marked hot spots of differential DNA methylation near centromeric or pericentromeric regions, particularly in non-symmetrical DNA methylation context. Additionally, we identified differentially methylated regions (DMRs) within promoter regions of transcription factor (TF) superfamilies involved in plant stress-response and assessed the effects of these changes on gene expression.

These findings improve our understanding on stress-response at the epigenome level by highlighting the correlation between DNA methylation, TEs and gene expression regulation in plants subjected to a broad range of environmental stresses.
Rapid in vivo multiplexed editing (RIME) of the adult mouse liver
Authors: Katsuda Takeshi , Cure Hector , Simeonov Kamen P. , Arany Zoltan , Grompe Markus , Stanger Ben Z.
Published: March 2022

Background & Aims

Assessing mammalian gene function in vivo has traditionally relied on manipulation of the mouse genome in embryonic stem cells or peri-zygotic embryos. These approaches are time consuming and require extensive breeding when simultaneous mutations in multiple genes is desired. The aim of this study is to introduce a Rapid In vivoMultiplexed Editing (RIME), and to provide a proof-of-concept of this system.

Approach & Results

RIME, a system wherein CRISPR/Cas9 technology, paired with adeno-associated viruses (AAVs), permits the inactivation of one or more genes in the adult mouse liver. The method is quick, requiring as little as 1 month from conceptualization to knockout (KO), and highly efficient, enabling editing in >95% of target cells. To highlight its utility, we used this system to inactivate, alone or in combination, genes with functions spanning metabolism, mitosis, mitochondrial maintenance, and cell proliferation.

Conclusion

RIME enables the rapid, efficient, and inexpensive analysis of multiple genes in the mouse liver in vivo.