bluuebunny/crossref_metadata_2025 huggingface dataset:
Clonal spread ofPlasmodium falciparumcandidate artemisinin partial resistanceKelch13622I mutation and co-occurrence withpfhrp2/3deletions in Ethiopia
Authors: Fola Abebe A. , Feleke Sindew M. , Mohammed Hussein , Brhane Bokretsion G. , Hennelly Christopher M. , Assefa Ashenafi , Crudal Rebecca M. , Reichert Emily , Juliano Jonathan J. , Cunningham Jane , Mamo Hassen , Solomon Hiwot , Tasew Geremew , Petros Beyene , Parr Jonathan B , Bailey Jeffrey A.
Published: March 2023

The emergence and spread of drug- and diagnostic-resistantPlasmodium falciparumare major impediments to malaria control and elimination. We deep sequenced known drug resistance mutations and other informative loci across the genome of 609 samples collected during a study across three regions of Ethiopia. We found that 8.0% (95% CI 7.0-9.0) of malaria cases were caused byP. falciparumcarrying the candidate artemisinin partial-resistanceK13622I mutation, which occurred less commonly in diagnostic-resistantpfhrp2/3-deleted than normal non-deleted parasites (p=0.03). Identity-by-descent analysis showed that 622I parasites were significantly more related than wild-type (p<0.001), consistent with recent expansion and spread.Pfhrp2/3-deleted parasites were also highly related, with evidence of clonal transmissions at the district level. Parasites carrying bothpfhrp2/3deletion and 622I mutation were observed in some sites. These findings raise concern for future spread of combined drug- and diagnostic-resistant parasites and warrant close monitoring.
Visit-to-visit blood pressure variability and progression of white matter hyperintensities over 14 years
Authors: Janssen Esther , van Dalen Jan-Willem , Cai Mengfei , Jacob Mina A. , Marques José , Duering Marco , Richard Edo , Tuladhar Anil M. , de Leeuw Frank-Erik , Hilkens Nina
Published: March 2023

There is evidence that blood pressure variability (BPV) is associated with cerebral small vessel disease (SVD) and may therefore increase the risk of stroke and dementia. It remains unclear if BPV is associated with SVD progression over years. We examined whether visit-to-visit BPV is associated with White Matter Hyperintensity (WMH) progression over 14 years and MRI markers after 14 years.

We included participants with SVD from the Radboud University Nijmegen Diffusion tensor Magnetic resonance imaging Cohort (RUNDMC) who underwent baseline assessment in 2006 and follow-up in 2011, 2015 and 2020. BPV was calculated as coefficient of variation of BP at all visits. Association between WMH progression rates over 14 years and BPV was examined using linear-mixed effects model. Regression models were used to examine association between BPV and MRI markers at final visit in participants.

A total of 199 participants (60.5 SD 6.6 years) who underwent four MRI scans and blood pressure measurements were included, with mean follow-up of 13.7 (SD 0.5) years. Systolic BPV was associated with higher progression of WMH (β = 0.013, 95% CI 0.005 – 0.022) and higher risk of incident lacunes (OR: 1.10, 95% CI 1.01-1.21). There was no association between systolic BPV and grey and white matter volumes, Peak Skeleton of Mean Diffusivity (PSMD) or microbleed count after 13.7 years.

Visit-to-visit systolic BPV is associated with increased progression of WMH volumes and higher risk of incident lacunes over 14 years in participants with SVD. Future studies are needed to examine causality of this association.
A meta-analysis of genome-wide association studies of childhood wheezing phenotypes identifiesANXA1as a susceptibility locus for persistent wheezing
Authors: Granell R , Curtin JA , Haider S , Kitaba N , Mathie S , Gregory L , Yates LL , Tutino M , Hankinson J , Perretti M , Vonk JM , Arshad SH , Cullinan P , Fontanella S , Roberts G , Koppelman GH , Simpson A , Turner S , Murray CS , Lloyd CM , Holloway JW , Custovic A
Published: March 2023

Background

Many genes associated with asthma explain only a fraction of its heritability. Most genome-wide association studies (GWASs) used a broad definition of “doctor-diagnosed asthma”, thereby diluting genetic signals by not considering asthma heterogeneity. The objective of our study was to identify genetic associates of childhood wheezing phenotypes.

Methods

We conducted a novel multivariate GWAS meta-analysis of wheezing phenotypes jointly derived using unbiased analysis of data collected from birth to 18 years in 9,568 individuals from five UK birth-cohorts.

Results

44 independent SNPs were associated with early-onset persistent, 25 with preschool remitting, 33 with mid-childhood remitting and 32 with late onset wheeze. We identified a novel locus on chr9q21.13 (close to annexin 1 (ANXA1), p<6.7×10−9), associated exclusively with early-onset persistent wheeze. We identified rs75260654 as the most likely causative single nucleotide polymorphism (SNP) using Promoter Capture Hi-C loops, and then showed that the risk allele (T) confers a reduction inANXA1expression. Finally, in a murine model of house dust mite (HDM)-induced allergic airway disease, we demonstrated that anxa1 protein expression increased and anxa1 mRNA was significantly induced in lung tissue following HDM exposure. Using anxa1−/−deficient mice, we showed that loss of anxa1 results in heightened airway hyperreactivity and Th2 inflammation upon allergen challenge.

Conclusions

We discovered a novel locus uniquely associated with early-onset persistent wheeze, identified the most likely causative variant, and showed thatANXA1may play a role in regulating the pulmonary immune response to allergens. Targeting this pathway in persistent disease may represent an exciting therapeutic prospect.
Trends in Antibody Titers after SARS-CoV-2 Vaccination - Insights from a Self-Paid Tests at a General Internal Medicine Clinic
Authors: Kusunoki Hiroshi , Ekawa Kazumi , Ekawa Masakazu , Kato Nozomi , Yamasaki Keita , Motone Masaharu , Shimizu Hideo
Published: March 2023

Background

The rise in antibody titers against the novel coronavirus (SARS-CoV-2), and its duration is considered an important indicator for confirming the efficacy of the COVID-19 vaccine, and self-paid tests of antibody titer are conducted at many facilities nationwide.

Methods

The relationship between the number of days after the second and third dose of vaccines, age, and antibody titer was determined from the medical records of general internal medicine clinics that conducted self-paid testing of SARS-CoV-2 antibody titer using Elecsys Anti-SARS-CoV-2 S (Roche Diagnostics), as well as the relationship between the number of days after two or more dose of vaccines and antibody titer. We also examined antibody titers in cases of spontaneous infection with SARS-CoV-2 after two or more doses of the vaccine.

Results

Age and antibody titer were negatively correlated in 86 subjects whose antibody titer was measured within 1 month after the second vaccination with the COVID-19 vaccine. In 31 subjects whose antibody titer was measured within one month after the third dose of vaccine, age and antibody titer showed a negative correlation (p<0.01). The mean antibody titer after the third vaccination was 20704.9±16820.7 U/mL, more than 10 times the mean antibody titer after the second dose of vaccine of 1601.9±1297.9 U/mL. There were also cases of infection after the third or fourth dose of vaccine, with antibody titers in the tens of thousands after infection, but they still received further booster vaccinations after infection.

Discussion

SARS-CoV-2 antibody titers measured within 1 month of the second or third dose of vaccine showed a negative correlation with age, and antibody titers also showed a negative correlation trend with the number of days after the second dose of vaccine. It is considered that many people in Japan received further booster vaccinations after spontaneous infection, even though they already had antibody titers in the tens of thousands U/mL by “hybrid immunity” after spontaneous infection following two or more dose of vaccine.

Conclusion

After measuring SARS-CoV-2 antibody titers, booster vaccination of those with low antibody titers should be done on a priority basis.
Timing of selective serotonin reuptake inhibitor use and risk for preterm birth and related adverse events
Authors: Hwang Yeon Mi , Roper Ryan T. , Piekos Samantha N. , Enquobahrie Daniel A. , Hebert Mary F. , Paquette Alison G. , Baloni Priyanka , Price Nathan D. , Hood Leroy , Hadlock Jennifer J.
Published: March 2023

Purpose

There is uncertainty around the safety of SSRIs for treating depression during pregnancy. We aimed 1) to address confounding by indication, as well as socioeconomic and environmental factors associated with depression and 2) evaluate associations of timing of SSRI exposure in pregnancy with the risk of preterm birth and related outcomes (small for gestational age and low birthweight) among women with depression before pregnancy.

Methods

We conducted propensity score-adjusted regression to calculate odds ratios (OR) of preterm birth, small for gestational age, and low birth weight. We accounted for maternal/pregnancy characteristics, pre-pregnancy comorbidity/depression severity, social vulnerability, rural health disparity, and pre-natal depression severity. We additionally conducted a drug-specific analysis and assessed the impact of other classes of antidepressants within our cohort of interest.

Results

Among women with a history of depression, we identified women with indication of depression ≤ 180 days before pregnancy (n=6,408). Women with no SSRI order during pregnancy (n=3,122) constituted the unexposed group (no SSRI exposure group). The late SSRI exposure group consisted of women with an SSRI order after the first trimester (n=2,596). The early-only SSRI exposure group consisted of women with SSRI orders only in the first trimester (n=691). Late SSRI exposure group had an increased risk of preterm birth of OR=1.7 ([1.3,2.2], p<0.0001), and low birth weight of OR = 1.7 ([1.3,2.4], p<0.001), relative to the no SSRI exposure group.

Conclusions

These findings suggest associations between preterm birth/low birthweight and SSRI exposure is dependent on exposure timing during pregnancy. Small for gestational age is not associated with SSRI exposure.
SOD1-ALS-Browser: a web-utility for investigating the clinical phenotype inSOD1amyotrophic lateral sclerosis
Authors: Spargo Thomas P , Opie-Martin Sarah , Hunt Guy P , Kalia Munishikha , Khleifat Ahmad Al , Topp Simon D , Shaw Christopher E , Al-Chalabi Ammar , Iacoangeli Alfredo
Published: March 2023

Objective

Variants in the superoxide dismutase (SOD1) gene are among the most common genetic causes of amyotrophic lateral sclerosis. Reflecting the wide spectrum of putatively deleterious variants that have been reported to date, it has become clear thatSOD1-linked ALS presents a highly variable age at symptom onset and disease duration.

Methods

Here we describe an open access web-tool for comparative phenotype analysis in ALS:https://sod1-als-browser.rosalind.kcl.ac.uk/. The tool contains a built-in dataset of clinical information from 1,383 people with ALS harbouring aSOD1variant resulting in one of 162 unique amino acid sequence alterations, and from a non-SOD1comparator ALS cohort of 13,469 individuals. We present two examples of analyses possible with this tool, testing how the ALS phenotype relates toSOD1variants which alter amino acid residue hydrophobicity, and distinct variants at the 94thresidue of SOD1 which has six variants sampled at the same position.

Results and conclusions

The tool provides immediate access to the datasets and enables bespoke analysis of phenotypic trends associated with different gene variants, including the option for users to upload their own datasets for integration with the server data. The tool can be used to studySOD1-ALS as well as an analytical framework to study the differences between other user-uploaded ALS groups and our large reference database ofSOD1and non-SOD1ALS. The tool is designed to be useful for clinicians and researchers, including those without programming expertise, and is highly flexible in the analyses that can be conducted.
BDNF, inflammatory and oxidative levels in treatment-naïve ADHD children treated with methylphenidate: An open cohort protocol
Authors: de Lucca Marina Silva , Tonon Laira Lopes , Ferreira Jordânia Alves , Cabral Bárbara Silva , Raimundo Cleuberton Kenedy Oliveira , Cardoso Sílvia Almeida , de Miranda Débora Marques
Published: March 2023

The attention-deficit hyperactivity disorder (ADHD) has a complex etiology, involving the interaction between biological, genetic, and environmental factors. The ADHD pathophysiology remains unknown even though there are hypotheses that inflammatory, hormonal, oxidative and neurotrophic factors are associated. This clinical trial aims to evaluate the contribution of brain derived neurotrophic factor (BDNF), inflammatory and oxidative levels before and after 12 and 24 weeks of methylphenidate use.

Methods

Patients will be screened upon their entry into Child and Adolescent Psychiatry Teaching Outpatient Clinic of the Medical Course at the Federal University of Viçosa in Minas Gerais, Brazil. One hundred and fifty ADHD treatment-naïve children of both sexes, between 6–14 years old, will be invited to participate, after the ADHD diagnosis by an experienced psychiatrist and the child fulfilling the inclusion criteria. Children and their caregivers will answer questionnaires regarding mental health and the children will undergo neuropsychological tests, physical, nutritional and activity assessment, in addition to blood sampling at baseline, 12 and 24 weeks of methylphenidate use respectively.

Discussion

This clinical trial intends to verify how the pharmacological treatment changes the plasma BDNF, inflammatory and oxidative levels in treatment-naïve Brazilian children diagnosed for ADHD.

Trial Registration

Submitted for registration on Brazilian Registry of Clinical Trials (ReBEC). Trial identifier: 13612

Registry name: Níveis de neurotrofina, perfil inflamatório e oxidativo em crianças com TDAH tratadas com metilfenidato.
Epigenetic, psychological, and EEG changes after a 1-week retreat based on mindfulness and compassion for stress reduction: Study protocol of a cross-over randomized controlled trial
Authors: Diez Gustavo G. , Martin-Subero Ignacio , Zangri Rosaria M. , Kulis Marta , Andreu Catherine , Blanco Ivan , Roca Pablo , Cuesta Pablo , García Carola , Garzón Jesús , Herradón Carlos , Riutort Miguel , Baliyan Shishir , Venero César , Vázquez Carmelo
Published: March 2023

Introduction

The main objective of the study will be to evaluate the effects of two widely used standardized mindfulness-based programs [Mindfulness-Based Stress Reduction (MBSR) and Compassion Cultivation Training (CCT)], on epigenetic, neurobiological, psychological, and physiological variables.

Methods

The programs will be offered in an intensive retreat format in a general population sample of healthy volunteer adults. During a 7-day retreat, participants will receive MBSR and CCT in a crossover design where participants complete both programs in random order. After finishing their first 3-day training with one of the two programs, participants will be assigned to the second 3-day training with the second program.

The effects of the MBSR and CCT programs, and their combination, will be measured by epigenetic changes (i.e., DNA methylation biomarkers), neurobiological and psychophysiological measures (i.e., EEG resting state, EKG, respiration patterns, and diurnal cortisol slopes), self-report questionnaires belonging to different psychological domains (i.e., mindfulness, compassion, well-being, distress, and general functioning), and stress tasks (i.e., an Arithmetic Stress Test and the retrieval of negative autobiographical memories). These measures will be collected from both groups on the mornings of day 1 (pre-program), day 4 (after finishing the first program and before beginning the second program), and day 7 (post-second program). We will conduct a 3-month follow-up using only the set of self-report measures.

Discussion

This study aims to shed light on the neurobiological and psychological mechanisms linked to meditation and compassion in the general population. The protocol was registered atclinicaltrials.gov(Identifier:NCT05516355; August 23, 2022).
Early life exposure to cigarette smoke primes lung function and DNA methylation changes atCyp1a1upon exposure later in life
Authors: Onuzulu Chinonye Doris , Lee Samantha , Basu Sujata , Comte Jeannette , Hai Yan , Hizon Nikho , Chadha Shivam , Fauni Maria Shenna , Kahnamoui Shana , Xiang Bo , Halayko Andrew J. , Dolinsky Vernon W. , Pascoe Christopher , Jones Meaghan J.
Published: March 2023

Prenatal and early life exposure to cigarette smoke (CS) have repeatedly been shown to induce stable, long-term changes in DNA methylation (DNAm) in offspring. It has been hypothesized that these changes might be functionally related to the known outcomes of prenatal and early life CS exposure, which include impaired lung development, altered lung function and increased risk of asthma and wheeze. However, to date, few studies have examined DNAm changes induced by prenatal CS in tissues of the lung, and even fewer have attempted to examine the specific influences of prenatal versus early postnatal exposures. Here, we have established a mouse model of CS exposure which isolates the effects of prenatal and early postnatal CS exposures in early life. We have used this model to measure the effects of prenatal and/or postnatal CS exposures on lung function and immune cell infiltration as well as DNAm and expression ofCyp1a1, a candidate gene previously observed to demonstrate DNAm differences upon CS exposure in humans. Our study revealed that exposure to CS prenatally and in the early postnatal period cause long-lasting differences in offspring lung function, gene expression and lungCyp1a1DNAm, which wane over time but are reestablished upon re-exposure to CS in adulthood. This study creates a testable mouse model which can be used to investigate the effects of prenatal and early postnatal CS exposures and will contribute to the design of intervention strategies to mediate these detrimental effects.
Spatial and temporal transcriptomics of SHH-medulloblastoma with chromothripsis identifies multiple genetic clones that resist to treatment and lead to relapse
Authors: Kats Ilia , Schreiber Hannah Sophia , Simovic Milena , Sant Pooja , Mallm Jan-Philipp , Li Albert , Velmurugan Pravin , Weil Sophie , Devens Frauke , Sill Martin , Jugold Manfred , Moustafa Mahmoud , Abdollahi Amir , Winkler Frank , Korshunov Andrey , Pfister Stefan M , Stegle Oliver , Ernst Aurélie
Published: March 2023

Paediatric medulloblastomas with chromothripsis are characterised by high genomic instability and are among the tumours with the worst prognosis. However, the determinants of their aggressiveness and the molecular makeup of chromothriptic medulloblastoma are not well understood. Here, we applied spatial transcriptomics to profile a cohort of 13 chromothriptic and non-chromothriptic medulloblastomas from the same molecular subgroup. Our data reveal a higher extent of spatial intra-tumour heterogeneity in chromothriptic medulloblastomas, which is associated with increased proliferation and stemness, but lower immune infiltration and differentiation. Spatial mapping of genetic subclones of the same tumour identify a regionally distinct architecture and clone-specific phenotypic features, with distinct degrees of differentiation, proliferation and immune infiltration between clones. We conducted temporal profiling of 11 patient-derived xenografts from chromothriptic medulloblastomas, covering the transition from the minimal residual disease stage to treatment-resistant regrown tumours. In chromothriptic medulloblastoma, an ecosystem of cells from multiple genetic clones resisting treatment and leading to relapse highlighted the importance of multi-clone interplay. Finally, we identified a potential role for tumour microtubes in treatment resistance in chromothriptic medulloblastoma, suggesting cell network communication as a putative target.

Highlights

Biological insights

Medulloblastomas with chromothripsis are characterised by higher spatial intra-tumour heterogeneity, proliferation and stemness, but lower immune infiltration and differentiation, as compared with non-chromothriptic medulloblastomas

Spatially aware genetic clone assignment identifies phenotypic features such as degree of differentiation, proliferation and immune infiltration enriched in specific clones

Cells from distinct genetic clones resist to treatment and give rise to relapse in patient-derived xenografts of medulloblastoma with chromothripsis

Tumour microtubes point to putative molecular processes implicated in treatment resistance in chromothriptic medulloblastoma

Technological advances

Validation of the spatial representation of patient-derived xenograft models, providing novel insights into the faithfulness of such models to study cancer

Spatial mapping of clones based on spatial transcriptomics and copy-number variant profiling
Quantifying tumor specificity using Bayesian probabilistic modeling for drug target discovery and prioritization
Authors: Li Guangyuan , Bhattacharjee Anukana , Salomonis Nathan
Published: March 2023

In diseases such as cancer, the design of new therapeutic strategies requires extensive, costly, and unfortunately sometimes deadly testing to reveal life threatening off target effects. A crucial first step in predicting toxicity are analyses of normal RNA and protein tissue expression, which are now possible using comprehensive molecular tissue atlases. However, no standardized approaches exist for target prioritization, which instead rely on ad-hoc thresholds and manual inspection. Such issues are compounded, given that genomic and proteomic data detection sensitivity and accuracy are often problematic. Thus, quantifiable probabilistic scores for tumor specificity that address these challenges could enable the creation of new predictive models for combinatorial drug design and correlative analyses. Here, we propose a Bayesian Tumor Specificity (BayesTS) score that can naturally account for multiple independent forms of molecular evidence derving from both RNA-Seq and protein expression while preserving the uncertainty of the inference. We applied BayesTS to 24,905 human protein-coding genes across 3,644 normal samples (GTEx and TCGA) spanning 63 tissues. These analyses demonstrate the ability of BayesTS to accurately incorporate protein, RNA and tissue distribution evidence, while effectively capturing the uncertainty of these inferences. This approach prioritized well-established drug targets, while deemphasizing those which were later found to induce toxicity. BayesTS allows for the adjustment of tissue importance weights for tissues of interest, such as reproductive and physiologically dispensable tissues (e.g., tonsil, appendix), enabling clinically translatable prioritizations. Our results show that BayesTS can facilitate novel drug target discovery and can be easily generalized to unconventional molecular targets, such as splicing neoantigens. We provide the code and inferred tumor specificity predictions as a database available online (https://github.com/frankligy/BayesTS). We envision that the widespread adoption of BayesTS will facilitate improved target prioritization for oncology drug development, ultimately leading to the discovery of more effective and safer drugs.
Internal Translation of p53 Oncoproteins During Integrated Stress Response Confers Survival Advantage on Cancer Cells
Authors: López-Iniesta Maria José , Lacerda Rafaela , Ramalho Ana Catarina , Parkar Shrutee N. , Marques-Ramos Ana , Pereira Bruna , Miyawaki Lina , Fujita Jun , Hrstka Roman , Romão Luísa , Candeias Marco M
Published: March 2023

p53is the most known and studied tumour suppressor gene. Yet we have recently shown thatp53is also a proto-oncogene, as it encodes the Δ160p53 oncoprotein. Integrated stress response (ISR) is a survival pathway frequently activated in cancers, marked by the phosphorylation of eukaryotic initiation factor 2alpha (eIF2α) and a defined reprogramming in mRNA translation. Here we identified ISR as a powerful trigger of p53 oncogene, leading to the induction of not only Δ160p53 but also Δ133p53, another protein variant of thep53gene. Upon ISR the two isoforms were translated internally from p53 full-length (FL) transcript through an internal regulator of expression site (IRES) located in the vicinity of codon 160. Frameshift mutations upstream of codons 133 and 160 demonstrated that FLp53 protein synthesis is not required for making Δ133p53 and Δ160p53. Instead, targeting IRES(160) with an antisense oligo was sufficient to efficiently and specifically impair the expression of these isoforms without affecting FLp53 levels. This in turn averted ISR’s protective program culminating in cancer cell cycle arrest and death. Mechanistically, FLp53 showed 3 times more affinity to Δ160p53 than to other isoforms, Δ40p53 or Δ133p53. During ISR Δ160p53 localized to the nucleus and strongly inhibited FLp53-mediated activation of pro-apoptotic genep53 upregulated modulator of apoptosis(PUMA). Our results uncover a new branch of the ISR network essential for cancer cell survival and growth and establish the proof of concept for a new strategy to target cancer.
PI3K block restores age-dependent neurovascular coupling defects associated with cerebral small vessel disease
Authors: Thakore Pratish , Yamasaki Evan , Ali Sher , Solano Alfredo Sanchez , Labelle-Dumais Cassandre , Gao Xiao , Chaumeil Myriam M. , Gould Douglas B. , Earley Scott
Published: March 2023

Neurovascular coupling (NVC), a vital physiological process that rapidly and precisely directs localized blood flow to the most active regions of the brain, is accomplished in part by the vast network of cerebral capillaries acting as a sensory web capable of detecting increases in neuronal activity and orchestrating the dilation of upstream parenchymal arterioles. Here, we report aCol4a1mutant mouse model of cerebral small vessel disease (cSVD) with age-dependent defects in capillary-to-arteriole dilation, functional hyperemia in the brain, and memory. The fundamental defect in aged mutant animals was the depletion of the minor membrane phospholipid phosphatidylinositol 4,5 bisphosphate (PIP2) in brain capillary endothelial cells, leading to the loss of inwardly rectifier K+(Kir2.1) channel activity. Blocking phosphatidylinositol-3-kinase (PI3K), an enzyme that diminishes the bioavailability of PIP2by converting it to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), restored Kir2.1 channel activity, capillary-to-arteriole dilation, and functional hyperemia. In longitudinal studies, chronic PI3K inhibition also improved the memory function of agedCol4a1mutant mice. Our data suggest that PI3K inhibition is a viable therapeutic strategy for treating defective NVC and cognitive impairment associated with cSVD.

One-sentence summary

PI3K inhibition rescues neurovascular coupling defects in cerebral small vessel disease.
Ecosystem connectivity and configuration can mediate instability at a distance in metaecosystems
Authors: Tadiri Christina P. , Negrín Dastis Jorge O. , Cristescu Melania E. , Gonzalez Andrew , Fussmann Gregor F.
Published: March 2023

Ecosystems are connected by flows of nutrients and organisms. Changes to connectivity and nutrient enrichment may destabilise ecosystem dynamics far from the nutrient source. We used gradostats to examine the effects of trophic connectivity (movement of consumers and producers) versus nutrient-only connectivity in different metaecosystem configurations (linear vs dendritic) on dynamics ofDaphnia pulex(consumers) and an algae (resources). We found that peak population size and instability (coefficient of variation; CV) ofDaphniapopulations increased as distance from the nutrient input increased, but were lower in metaecosystems connected by all trophic levels compared to nutrient-only connected systems and in dendritic systems compared to linear ones. We examined the effects of trophic connectivity (i.e. how many trophic levels are moving rather than one or the other) using a generic model to qualitatively assess patterns of ecosystem dynamics. Our model predicted increased population sizes and fluctuations in ecosystems with nutrient connectivity, with this pattern being more pronounced in linear rather than dendritic systems. These results confirm that connectivity may propagate and even amplify instability over a metaecosystem to communities far from the source disturbance, and suggest a pathway for future experiments, that recreate conditions closer to those found in natural systems.
Management factors influenceSalmonellapersistence in reused poultry litter over three successive flocks
Authors: Woyda Reed , Oladeinde Adelumola , Endale Dinku , Strickland Timothy , Lawrence Jodie Plumblee , Abdo Zaid
Published: March 2023

Salmonellainfections are a leading cause of bacterial food-borne illness worldwide. Infections are highly associated with the consumption of contaminated food, and in particular, chicken meat. Understanding how management practices and environmental factors influenceSalmonellapopulations in broiler chicken production may aid in reducing the risk of food-borne illness in humans. Utilizing whole genome sequencing with antimicrobial and heavy metal resistance, virulence factor and plasmid identification, we have characterized the genetic diversity ofSalmonella entericaisolates (n = 55) obtained from broiler chicken litter.S. entericaisolates were recovered from the litter of broiler chickens over three consecutive flocks in four broiler houses on a single integrated farm in Georgia, USA. The chickens were raised under a newly adopted “No Antibiotics Ever” program and copper sulfate was administered via drinking water.In-silicoserovar prediction identified threeS. entericaserovars: Enteritidis (n = 12), Kentucky (n = 40) and Senftenberg (n = 3). Antimicrobial susceptibility testing revealed that only oneS. Kentucky isolate was resistant to streptomycin, while the remaining isolates were susceptible to all antibiotics tested. Metal resistance operons, including copper and silver, were identified chromosomally and on plasmids in serovar Senftenberg and Kentucky isolates, respectively. Serovar Kentucky isolates harboring metal resistance operons were the onlySalmonellaisolates recovered from the litter of third flock cohort. These results suggest the addition of copper sulfate to drinking water may have selected forS.Kentucky isolates harboring plasmid-borne copper resistance genes and may explain their persistence in litter from flock to flock.

Importance

Salmonellafoodborne illnesses are the leading cause of hospitalizations and deaths, resulting in a high economic burden on the healthcare system. Globally, chicken meat is one of the highest consumed meats and is a predominant source of foodborne illness. The severity ofSalmonellainfections depends on the presence of antimicrobial resistance genes and virulence factors. While there are many studies which have investigatedSalmonellastrains isolated from post-harvest chicken samples, there is a gap in our understanding of the prevalence and persistence ofSalmonellain pre-harvest and in particular their makeup of antibiotic resistance genes, virulence factors and metal resistance genes. The objective of this study was to determine how on-farm management practices and environmental factors influenceSalmonellapersistence, as well as the antimicrobial resistance genes and virulence factors they harbor. In this study we demonstrate that broiler chickens raised without antibiotics are less likely to harbor antibiotic resistance, however the practice of adding acidified copper sulfate to drinking water may select for strains carrying metal resistant genes.
Sordarin bound eEF2 unlocks spontaneous forward and reverse translocation on CrPV IRES
Authors: Ou Zheren , Petrov Alexey
Published: March 2023

The Intergenic Region Internal Ribosome Entry Sites (IGR IRESs) ofDiscistroviridaepromote protein synthesis without initiation factors, with IRES translocation by elongation factor 2 (eEF2) being the first factor catalyzed reaction. Here, we developed a system that allows for the observation of intersubunit conformation of eukaryotic ribosomes at the single-molecule level. We use it to follow translation initiation and subsequent translocation of the cricket paralysis virus IRES (CrPV IRES). We observed that pre-translocation 80S-IRES ribosomes spontaneously exchanged between non-rotated and semi-rotated conformations but predominantly occupied a semi-rotated conformation. In the presence of eEF2, ribosomes underwent forward and reverse translocation. Both reactions were eEF2 concentration dependent, indicating that eEF2 promoted both forward and reverse translocation. The antifungal sordarin, stabilizes eEF2 on the ribosome after GTP hydrolysis in an extended conformation. 80S-CrPV IRES-eEF2-sordarin complexes underwent multiple rounds of forward and reverse translocations per eEF2 binding event. In the presence of sordarin, GTP hydrolysis or phosphate release were not required for IRES translocation. Together, these results suggest that in the presence of sordarin, eEF2 promotes the mid and late stages of CrPV IRES translocation by unlocking ribosomal movements, with mid and late stages of translocation being thermally driven.
Eye proteome ofDrosophila melanogaster
Authors: Kumar Mukesh , Has Canan , Lam-Kamath Khanh , Ayciriex Sophie , Dewett Deepshe , Bashir Mhamed , Poupault Clara , Schuhmann Kai , Knittelfelder Oskar , Raghuraman Bharath Kumar , Ahrends Robert , Rister Jens , Shevchenko Andrej
Published: March 2023

TheDrosophila melanogastereye is a popular model to elucidate the molecular mechanisms that underlie the structure and function of the eye as well as the causes of retinopathies. For instance, theDrosophilaeye has been used to investigate the impacts of ageing and environmental stresses such as light-induced damage or dietary deficiencies. Moreover, large-scale screens have isolated genes whose mutation causes morphological and functional ocular defects, which includes key components of the phototransduction cascade. However, the proteome of theDrosophilaeye is poorly characterized. Here, we used GeLC-MS/MS to quantify 3516 proteins he adultDrosophila melanogastereye and provide a generic and expandable resource for further genetic, pharmacological, and dietary studies.
Microglia play beneficial roles in multiple experimental seizure models
Authors: Shelton-Gibbs Synphane , Benderoth Jordan , Gaykema Ronald P. , Straub Justyna , Okojie Kenneth A. , Uweru Joseph O. , Lentferink Dennis H. , Rajbanshi Binita , Cowan Maureen N. , Patel Brij , Campos-Salazar Anthony Brayan , Perez-Reyes Edward , Eyo Ukpong B.
Published: March 2023

Seizure disorders are common, affecting both the young and the old. Currently available antiseizure drugs are ineffective in a third of patients and have been developed with a focus on known neurocentric mechanisms, raising the need for investigations into alternative and complementary mechanisms that contribute to seizure generation or its containment. Neuroinflammation, broadly defined as the activation of immune cells and molecules in the central nervous system (CNS), has been proposed to facilitate seizure generation, although the specific cells involved in these processes remain inadequately understood. The role of microglia, the primary inflammation-competent cells of the brain, is debated since previous studies were conducted using approaches that were less specific to microglia or had inherent confounds. Using a selective approach to target microglia without such side effects, we show a broadly beneficial role for microglia in limiting chemoconvulsive, electrical, and hyperthermic seizures and argue for a further understanding of microglial contributions to contain seizures.
A phylogeny-informed characterisation of global tetrapod traits addresses data gaps and biases
Authors: Moura Mario R. , Ceron Karoline , Guedes Jhonny J. M. , Chen-Zhao Rosana , Sica Yanina V. , Hart Julie , Dorman Wendy , Portmann Julia M. , Gonzalez-del-Pliego Pamela , Ranipeta Ajay , Catenazzi Alessandro , Werneck Fernanda P. , Toledo Luís Felipe , Upham Nathan S. , Tonini João F. R. , Colston Timothy J. , Guralnick Robert , Bowie Rauri C. K. , Pyron R. Alexander , Jetz Walter
Published: March 2023

Tetrapods (amphibian, reptiles, birds and mammals) are model systems for global biodiversity science, but continuing data gaps, limited data standardisation, and ongoing flux in taxonomic nomenclature constrain integrative research on this group and potentially cause biased inference. We combined and harmonised taxonomic, spatial, phylogenetic, and attribute data with phylogeny-based multiple imputation to provide a comprehensive data resource (TetrapodTraits 1.0.0) that includes values, predictions, and sources for body size, activity time, micro- and macrohabitat, ecosystem, threat status, biogeography, insularity, environmental preferences and human influence, for all 33,281 tetrapod species covered in recent fully sampled phylogenies. We assess gaps and biases across taxa and space, finding that shared data missing in attribute values increased with taxon-level completeness and richness across clades. Prediction of missing attribute values using multiple imputation revealed substantial changes in estimated macroecological patterns. These results highlight biases incurred by non-random missingness and strategies to best address them. While there is an obvious need for further data collection and updates, our phylogeny--informed database of tetrapod traits can support a more comprehensive representation of tetrapod species and their attributes in ecology, evolution, and conservation research.
Subjective sleep onset latency is influenced by sleep structure and body heat loss in human subjects
Authors: Iijima Ryusei , Kadooka Akari , Sugawara Kairi , Fushimi Momo , Hosoe Mizuki , Aritake-Okada Sayaka
Published: March 2023

Objectives

The current study examined the relationship between subjective SOL, sleep structure, changes in skin and body temperature, and subjective evaluation in healthy young adults to elucidate the pathophysiological mechanisms of insomnia.

Methods

Twenty-eight participants (mean age: 21.5 ± 0.5 years) with no sleep problems participated in a 1-hour polysomnographic recording that obtained objective sleep parameters during the daytime while skin and body temperatures were recorded. The distal–proximal skin temperature gradient (DPG) was calculated. Subjective parameters, such as subjective SOL, sleep time, and restorative sleepiness, were evaluated before and after sleep.

Results

Most participants estimated their sleep latency as being longer than their actual SOL (13.7 min vs. 7.6 min). Objective SOL was significantly correlated with each sleep stage parameter whereas subjective SOL was negatively correlated with stage N2 sleep duration (Rho = −0.454, p = 0.020), slow-wave activity and delta power (Rho = −0.500, p = 0.011, Rho = −0.432, p = 0.031, respectively), and ΔDPG (the degree of reduction of heat loss before and after lights-off). Stepwise regression analysis showed that ΔDPG was the strongest predictive factor in explaining the length of subjective SOL.

Conclusions

The degree of heat dissipation before falling asleep contributed most to the sensation of falling asleep in healthy young adults. This finding may be helpful for elucidating the physiological mechanisms of insomnia and its treatment.

STATEMENT OF SIGNIFICANCE

The time estimate ability is also activated during sleep. However, some insomniacs have abnormalities in this function and suffer from sleep state misperception, which is a discrepancy between subjective and objective sleep time. They often overestimate the sleep onset latency. We investigated the relationship between subjective sleep onset latency, sleep structure, EEG frequency components, and body temperature during the process of falling asleep in healthy adults. It was suggested that the Stage N2 duration, the amounts of slow wave activity around after lights-out, and the degree of heat dissipation before falling asleep may be related to the perception of falling asleep. These results are expected to contribute to the understanding of the pathophysiological mechanisms and to the treatment of insomnia.
Visual field asymmetries vary between adolescents and adults
Authors: Carrasco Marisa , Myers Caroline , Roberts Mariel
Published: March 2023

For human adults, visual perception varies around isoeccentric locations (with polar angle at a constant distance from the center of gaze). The same visual information yields better performance along the horizontal than vertical meridian (horizontal vertical anisotropy, HVA) and along the lower than upper vertical meridian (vertical meridian asymmetry, VMA). For children, performance is better along the horizontal than vertical meridian (HVA) but does not differ between the lower and the upper vertical meridian. Here, we investigated whether the extent of the HVA varies and the VMA emerges and fully develops during adolescence, or whether the VMA only emerges in adulthood. We found that for adolescents, performance yields both HVA and VMA, but both are less pronounced than those for adults.
Cannabis and cannabinoids in dermatology: protocol for a systematic review and meta-analysis of quantitative outcomes
Authors: Sermsaksasithorn Pim , Nopsopon Tanawin , Samuthpongtorn Chatpol , Chotirosniramit Korn , Pongpirul Krit
Published: March 2023

Following the discovery of various effects on skin function by modifying endocannabinoid systems, multiple preclinical studies have revealed the promise of cannabis and cannabinoids in the treatment of a variety of skin diseases. However, its clinical efficacy is still debated. This systematic review aims to evaluate the therapeutic efficacy of cannabis and cannabinoids in dermatological conditions and diseases. The protocol has been prepared using the Preferred Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) guidelines and has been registered with the International Prospective Register of Systematic Reviews (PROSPERO: CRD42023397189). PubMed, EMBASE, SCOPUS, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science will be used for the systemic search. The outcomes will be an improvement in dermatological characteristics, including disease-specific composite scores and objective and subjective outcomes of skin conditions. This systematic review will provide valuable information on dermatological therapy of cannabis and cannabinoids and could be the start of future research and medicinal applications.
Modelling the association between neutralizing antibody levels and SARS-CoV-2 viral dynamics : implications to define correlates of protection against infection
Authors: Lingas Guillaume , Planas Delphine , Péré Hélène , Duffy Darragh , Staropoli Isabelle , Porrot Françoise , Guivel-Benhassine Florence , Chapuis Nicolas , Gobeaux Camille , Veyer David , Delaugerre Constance , Goff Jérôme Le , Getten Prunelle , Hadjadj Jérôme , Bellino Adèle , Parfait Béatrice , Treluyer Jean-Marc , Schwartz Olivier , Guedj Jérémie , Kernéis Solen , Terrier Benjamin
Published: March 2023

Background

While anti-SARS-CoV-2 antibody kinetics have been well described in large populations of vaccinated individuals, we still poorly understand how they evolve during a natural infection and how this impacts viral clearance.

Methods

For that purpose, we analyzed the kinetics of both viral load and neutralizing antibody levels in a prospective cohort of individuals during acute infection by Alpha variant.

Results

Using a mathematical model, we show that the progressive increase in neutralizing antibodies leads to a shortening of the half-life of both infected cells and infectious viral particles. We estimated that the neutralizing activity reached 90% of its maximal level within 8 days after symptoms onset and could reduce the half-life of both infected cells and infectious virus by a 6-fold factor, thus playing a key role to achieve rapid viral clearance. Using this model, we conducted a simulation study to predict in a more general context the protection conferred by the existence of pre-existing neutralization, due to either vaccination or prior infection. We predicted that a neutralizing activity, as measured by ED50>103, could reduce by 50% the risk of having viral load detectable by standard PCR assays and by 99% the risk of having viral load above the threshold of cultivable virus.

Conclusions

This threshold value for the neutralizing activity could be used to identify individuals with poor protection against disease acquisition.
LINC01117 inhibits invasion and migration of lung adenocarcinoma through influencing EMT process
Authors: Liu Linjun , Ren Wenjia , Du Licheng , Xu Ke , Zhou Yubai
Published: March 2023

Background

Studying the mechanism of action of LincRNAs in lung adenocarcinoma (LUAD) is of great importance for an in-depth understanding of the molecular mechanism of lung adeno carcinogenesis and development.

Objective

To identify long-stranded non-coding RNAs that are specifically highly expressed in LUAD cells and to investigate their function in LUAD cells to provide new potential targets for targeting LUAD therapy.

Methods

This study used publicly available data downloaded from The Cancer Genome Atlas (TCGA) database. Construction of siRNA and overexpression plasmid-packed lentiviral constructs were used to knock down and increase the expression of LINC01117 in LUAD cells. The effect of LINC01117 on LUAD cell migration and invasion was verified by scratch assays and Transwell assays. Western blot assays were performed to verify the effect of knocking down LINC01117 expression on key proteins of the EMT process.

Results

LINC01117 expression was upregulated in LUAD tissues and cell lines. Clinical correlation and prognostic analyses showed that LINC01117 was associated with poorer clinical features (staging and N classification) and poorer prognosis and could be analyzed as an independent prognostic factor. Cell migration and invasion were significantly inhibited in the knockdown group compared to the control group; in contrast, cell migration and invasion were promoted in the overexpression group. The expression of N-cadherin and vimentin, molecular markers of the EMT process, was elevated in the overexpression group, and the expression of E-cadherin was decreased. Conclusions: LINC01117 was highly expressed in LUAD cells, and inhibition of LINC01117 expression significantly inhibited the migration and invasion of LUAD cells, while overexpression of LINC01117 significantly promoted the migration and invasion of LUAD cells, and may affect the migration ability of LUAD cells through the EMT process. It suggests that LINC01117 may play a key role in the occurrence and development of LUAD.