bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid, Near Point-of-Care Assay for HLA-B*57:01 Genotype Associated with Severe Hypersensitivity Reaction to Abacavir
Authors: Wallner Jackson J. , Beck Ingrid A. , Panpradist Nuttada , Ruth Parker S. , Valenzuela-Ponce Humberto , Soto-Nava Maribel , Ávila-Ríos Santiago , Lutz Barry R. , Frenkel Lisa M.
Published: June 2021

Objective

The nucleoside reverse transcriptase inhibitor abacavir is commonly used to treat young children with HIV infection. Abacavir can trigger a severe hypersensitivity reaction in people who are homozygous or heterozygous for HLA-B*57:01. Testing for HLA-B*57:01 prior to abacavir initiation is standard-of-care in high-resource settings, but current tests are too costly for resource-limited settings. To address this gap, we developed an inexpensive, simple-to-use rapid assay to detect HLA-B*57:01.

Methods

We designed and optimized a multiplexed PCR to amplify HLA-B*57 subtypes and the human beta-globin gene. Subsequently, probes annealed to the amplicon and were ligated when specific for the HLA-B*57:01 allele. Ligated products were detected by immunocapture in a lateral flow strip. Cell lines with known HLA genotypes were used to optimize the assay. The assay was then evaluated by comparing the genotype of clinical specimens (n=60) enriched for individuals with HLA-B*57:01 by the new assay to that from sequencing.

Results

The optimized multiplex PCR for B*57 and beta-globin resulted in a 40-minute, 35-cycle amplification, followed by a 20-minute ligation reaction and 15-minute detection step. Evaluation of the HLA-B*57:01 oligonucleotide ligation assay using clinical specimens had a sensitivity of 100% (n=27/27 typed as B*57:01) and specificity of 100% (n=33/33 typed as non-B*57:01) by visual interpretation of lateral flow strips.

Conclusions

This rapid and economical assay can accurately detect the presence of HLA-B*57:01 in clinical specimens. Use of this assay could expand access to HLA-B*57:01 genotyping and facilitate safe same-day initiation of abacavir-based treatment.
Prevalence of persistent symptoms in children during the COVID-19 pandemic: evidence from a household cohort study in England and Wales
Authors: Miller Faith , Nguyen Vincent , Navaratnam Annalan MD , Shrotri Madhumita , Kovar Jana , Hayward Andrew C , Fragaszy Ellen , Aldridge Robert W , Hardelid Pia
Published: June 2021

Using data from 4678 children participating in VirusWatch, a household cohort study, we estimated the prevalence of persistent symptoms lasting ≥4 weeks as 1.7%, and 4.6% in children with a history of SARS-CoV-2 infection. Persistent symptom prevalence was higher in girls, teenagers and children with long-term conditions.
Changes in amygdalar functional connectivity following the water load symptom provocation task (WL-SPT) in youth with functional abdominal pain disorders
Authors: Cunningham Natoshia R , Averbuch Hadas Nahman , Lee Gregory R. , King Christopher , Coghill Robert C.
Published: June 2021

Pediatric functional abdominal pain disorders (FAPD) are highly prevalent, difficult to diagnose and challenging to treat. The brain mechanisms supporting FAPD remain poorly understood. This investigation examined the neuromechanisms of FAPD during a well-tolerated visceral pain induction task, the water load symptom provocation task (WL-SPT). Youth between the ages of 11 and 17 years participated. Functional connectivity (FC) was examined via the Blood Oxygenation Level Dependent (BOLD) effect using the left and right amygdala (AMY) as seed regions. Relationships of the time courses within these seeds with voxels across the whole brain were evaluated. Arterial spin labeling (ASL) was used to assess regional brain activation by examining cerebral blood flow. Increased FC between the left AMY with regions associated with nociceptive processing (e.g., thalamus), and right AMY FC changes with areas associated with cognitive functioning (dorsolateral prefrontal cortex) and the default mode network (DMN; parietal lobe) were observed in youth with FAPD following the WL-SPT. These changes were related to changes in pain unpleasantness. AMY FC changes post WL-SPT were also related to changes in pain intensity. AMY FC with the DMN in youth with FAPD also differed from healthy controls. Global CBF changes were also noted between FAPD and controls, but no significant differences in grey matter were detected either between groups or during the WL-SPT in youth with FAPD. Findings confirm youth with FAPD have changes in brain connectivity that could support the development of biomarkers to enhance understanding of the mechanisms of pain and treatment response.
COVID Oximetry @home: evaluation of patient outcomes
Authors: Boniface Michael , Burns Daniel , Duckworth Chris , Ahmed Mazen , Duruiheoma Franklin , Armitage Htwe , Ratcliffe Naomi , Duffy John , O’Keeffe Caroline , Inada-Kim Matt
Published: June 2021

Background

COVID-19 has placed unprecedented demands on hospitals. A clinical service, COVID Oximetry @home (CO@h) was launched in November 2020 to support remote monitoring of COVID-19 patients in the community. Remote monitoring through CO@h aims to identify early patient deterioration and provide timely escalation for cases of silent hypoxia, while reducing the burden on secondary care.

Methods

We conducted a retrospective service evaluation of COVID-19 patients onboarded to CO@h from November 2020 to March 2021 in the North Hampshire (UK) community led service (a collaboration of 15 GP practices covering 230,000 people). We have compared outcomes for patients admitted to Basingstoke & North Hampshire Hospital who were CO@h patients (COVID-19 patients with home monitoring of SpO2 (n=115)), with non-CO@h patients (those directly admitted without being monitored by CO@h (n=633)). Crude and adjusted odds ratio analysis was performed to evaluate the effects of CO@h on patient outcomes of 30-day mortality, ICU admission and hospital length of stay greater than 3, 7, 14, and 28 days.

Results

Adjusted odds ratios for CO@h show an association with a reduction for several adverse patient outcome: 30-day hospital mortality (p<0.001 OR 0.21 95% CI 0.08-0.47), hospital length of stay larger than 3 days (p<0.05, OR 0.62 95% CI 0.39-1.00), 7 days (p<0.001 OR 0.35 95% CI 0.22-0.54), 14 days (p<0.001 OR 0.22 95% CI 0.11-0.41), and 28 days (p<0.05 OR 0.21 95% CI 0.05-0.59). No significant reduction ICU admission was observed (p>0.05 OR 0.43 95% CI 0.15-1.04). Within 30 days of hospital admission, there were no hospital readmissions for those on the CO@h service as opposed to 8.7% readmissions for those not on the service.

Conclusions

We have demonstrated a significant association between CO@h and better patient outcomes; most notably a reduction in the odds of hospital lengths of stays longer than 7, 14 and 28 days and 30-day hospital mortality.
Functional Rating Scales in Spinal and Bulbar Muscular Atrophy: A Systematic Review, Meta-Analysis and Critical Appraisal of their Measurement Properties
Authors: Abrahao Agessandro , Phung Liane , Freitas Eliza , Borkhoff Cornelia M. , Zinman Lorne
Published: June 2021

Tracking disease progression and treatment effect of spinal bulbar muscular atrophy, or Kennedy’s disease, is challenging given its slowly progressive nature. To achieve success in SBMA clinical trials, a reliable, responsive, and validated patient-reported motor function scale must capture progression of SBMA-specific motor dysfunction. Here, we conducted a systematic review, meta-analysis, and appraisal of core measurement properties of the SBMA functional rating scale (SBMAFRS). We established that the SBMAFRS has satisfactory internal consistency, inter-rater reliability, and construct validity for measuring progressive motor dysfunction over similar neurodegenerative motor function scales but inadequate sensitivity to change over time. Further development to validate and improve the SBMAFRS’ ability to capture longitudinal responsiveness in larger cohorts is warranted.
Analytical comparison of nine SARS-CoV-2 antigen-detecting rapid diagnostic tests for emerging SARS-CoV-2 variants
Authors: Bekliz Meriem , Adea Kenneth , Essaidi-Laziosi Manel , Sacks Jilian A , Escadafal Camille , Kaiser Laurent , Eckerle Isabella
Published: June 2021

Several SARS-CoV-2 variants of concern/interest (VOC/VOI) emerged recently, with VOCs outcompeting earlier lineages on a global scale. To date, few data on routine diagnostic performance for VOC/VOIs are available. Here, we investigate the analytical performance of nine commercially available antigen-detecting rapid diagnostic tests (Ag-RDTs) for VOC B.1.1.7, B.1.351, P.1 and VOI P.2 with cultured SARS-CoV-2. Comparable or higher sensitivity was observed for VOC/VOI compared to a non-VOC/VOI early-pandemic virus for all Ag-RDTs.
Immunological dysfunction persists for 8 months following initial mild-moderate SARS-CoV-2 infection
Authors: Phetsouphanh Chansavath , Darley David , Wilson Daniel B , Howe Annett , Ling Munier C. Mee , Patel Sheila K , Juno Jennifer A , Burrell Louise M , Kent Stephen J , Dore Gregory J , Kelleher Anthony D , Matthews Gail V
Published: June 2021

A proportion of patients surviving acute COVID-19 infection develop post-COVID syndrome (long COVID) encompassing physical and neuropsychiatric symptoms lasting longer than 12 weeks. Here we studied a prospective cohort of individuals with long COVID compared to age/gender matched subjects without long COVID (from the ADAPT study), healthy donors and individuals infected with other non-SARS CoV2 human coronaviruses (the ADAPT-C study). We found highly activated innate immune cells and an absence of subsets of un-activated naïve T and B cells in peripheral blood of long COVID subjects, that did not reconstitute over time. These activated myeloid cells may contribute to the elevated levels of type I (IFN-β) and III interferon (IFN-λ1) that remained persistently high in long COVID subjects at 8 months post-infection. We found positive inter-analyte correlations that consisted of 18 inflammatory cytokines in symptomatic long COVID subjects that was not observed in asymptomatic COVID-19 survivors. A linear classification model was used to exhaustively search through all 20475 combinations of the 29 analytes measured, that had the strongest association with long COVID and found that the best 4 analytes were: IL-6, IFN-γ, MCP-1 (CCL2) and VCAM-1. These four inflammatory biomarkers gave an accuracy of 75.9%, and an F1 score of 0.759, and have also previously been associated with acute severe disease. In contrast, plasma ACE2 levels, while elevated in the serum of people previously infected with SARS-CoV-2 were not further elevated in subjects with long COVID symptoms. This work defines immunological parameters associated with long COVID and suggests future opportunities to prevention and treatment.
Factors associated with home birth in Peru: An analysis of the Demographic and Health Survey, 2019
Authors: Huapaya-Torres Jackeline , Santos-Rosales Yuly , Moquillaza-Alcántara Victor
Published: June 2021

Objective

To determine the proportion and factors associated with home birth in Peru, 2019.

Material and methods

Cross-sectional analytical design study where the 2019 Peruvian Demographic and Family Health Survey was analyzed. The association was evaluated using Poisson Regression, supplemented with the crude prevalence ratio (cPR) and adjusted (aPR).

Results

The records of 18,401 women were evaluated, where 5.39% (95%CI:4.83-6.03%) presented home birth. The probability of a home birth occurs increases when the pregnant woman is from the andean (aPR:1.24; 95%CI:1.02-1.48) and amazon region (aPR:1.38; 95%CI:1.16-1.64), resides in rural areas (aPR:3.34; 95%CI:2.61-4.29), presents less than 6 prenatal care (aPR:1.66; 95%CI:1.39 -1.96), it is very poor (aPR:9.62; 95%CI:5.13-18.1) or poor (aPR:2.39; 95%CI:1.26-4.52), it has not studied (aPR:2.66; 95%CI:2.02-3.50) or reached primary education (aPR:2.18: 95%CI:1.85-2.58) and has 2 children (aPR:1.64; 95%CI:1.46-1.85) or 3 or more children (aPR:2.18; 95%CI:1.67-2.87). On the other hand, having higher educational instruction (aPR:0.49; 95%CI:0.31-0.78) is associated with a lower probability of a home birth.

Conclusions

There is a low proportion of home births; however, this indicator increases significantly according to various geographical, sociodemographic, and obstetric factors that have been identified.

HIGHLIGHTS

The proportion of home births in Peru is low, although it reaches high values in the amazon and rural areas.

Sociodemographic determinants such as poverty and low educational level are risk factors for home birth.

Obstetric determinants such as having few prenatal controls or had having previously multiple deliveries are risk factors for home birth.
Occupational inequalities in the prevalence of COVID-19: A longitudinal observational study of England, August 2020 to January 2021
Authors: Green Mark A. , Semple Malcolm G.
Published: June 2021

Background

The COVID-19 pandemic has reinforced, amplified and created new health inequalities. There is less evidence on how COVID-19 prevalence varies by measures of work and occupation which represent a key social determinant of health. The aim of the study is to evaluate how occupational inequalities in the prevalence of COVID-19 varies across England and their possible explanatory factors.

Methods

We used data for 363,651 individuals (2,178,835 observations) aged 18 years and over between 1st May 2020 and 31st January 2021 from the ONS Covid Infection Survey, a representative longitudinal survey of individuals in England. We focus on two measures of work; employment status for all adults, and work sector of individuals currently working. Multi-level binomial regression models were used to estimate the likelihood of testing positive of COVID-19, adjusting for known explanatory covariates.

Results

0.9% of participants tested positive for COVID-19 over the study period. COVID-19 prevalence was higher among adults who were students or furloughed (i.e., temporarily not working). Among adults currently working, COVID-19 prevalence was highest in adults employed in the hospitality sector, with higher prevalence for individuals employed in transport, social care, retail, health care and educational sectors. Inequalities by work were not consistent over time.

Conclusions

We find an unequal distribution of infections relating to COVID-19 by work and employment status. Our findings demonstrate the need for greater workplace interventions to protect employees, but also that a large proportion of SARS-CoV-2 transmission occurs outside of work. In particular, populations who experienced social and economic harms through being furloughed were also more likely to experience a double burden of increased likelihood of COVID-19.
Choosing questions before methods in dementia research with competing events and causal goals
Authors: Rojas-Saunero L. Paloma , Young Jessica G. , Didelez Vanessa , Ikram M. Arfan , Swanson Sonja A.
Published: June 2021

Several of the hypothesized or studied exposures that may affect dementia risk are known to increase the risk of death. This may explain counterintuitive results, where exposures that are known to be harmful for mortality risk sometimes seem protective for the risk of dementia. Authors have attempted to explain these counterintuitive results as biased, but the bias associated with a particular analytic method cannot be defined or assessed if the causal question is not explicitly specified. Indeed, we can consider several causal questions when competing events like death, which cannot be prevented by design, are present. Current dementia research guidelines have not explicitly considered what constitutes a meaningful causal question in this setting or, more generally, how this choice justifies and should drive particular analytic decisions. To contextualize current practices, we first perform a systematic review of the conduct and interpretation of longitudinal studies focused on dementia outcomes where death is a competing event. We then describe and demonstrate how to address different causal questions (referred here as “the total effect” and “the controlled direct effect”) with traditional analytic approaches under explicit assumptions. Our application focuses on smoking cessation in late-midlife. To illustrate core concepts, we discuss this example both in terms of a hypothetical randomized trial and with an emulation of such a trial using observational data from the Rotterdam Study.
Effects of Acute Normovolemic Hemodilution on Post-Cardiopulmonary Bypass Coagulation Tests and Allogeneic Blood Transfusion in Thoracic Aortic Repair Surgery: An Observational Cohort Study
Authors: Mladinov Domagoj , Eudailey Kyle W. , Padilla Luz A. , Norman Joseph B. , Leahy Benjamin , Enslin Jacob , Parker Keli , Cornelius Katherine F. , Davies James E.
Published: June 2021

Background and Aim

Perioperative blood transfusion is associated with increased morbidity and mortality. Acute normovolemic hemodilution (ANH) is a blood conservation strategy associated with variable success, and rarely studied in more complex cardiac procedures. The study aim was to evaluate whether acute ANH improves coagulopathy and reduces blood transfusions in thoracic aortic surgeries.

Methods

Single-center observational cohort study comparing ANH and standard institutional practice in patients who underwent thoracic aortic repair from 2019 to 2021.

Results

89 patients underwent ANH and 116 standard practice. There were no significant differences between the groups in terms of demographic or major perioperative characteristics. In the ANH group coagulation tests before and after transfusion of autologous blood showed decreased INR and increased platelets, fibrinogen, all with p<0.0005. Coagulation results in the ANH and control groups were not statistically different. The average number of transfused allogeneic products per patient was lower in the ANH vs control group: FFP 1.1 ±1.6 vs 1.9 ±2.3 (p=0.003), platelets 0.6 ±0.8 vs 1.2 ±1.3 (p=0.0008), and cryoprecipitate 0.3 ±0.7 vs 0.7 ±1.1 (p=0.008). Reduction in RBC transfusion was not statistically significant. The percentage of patients who received any transfusion was 53.9% in ANH and 59.5% in the control group (p=0.42). There was no significant difference in major adverse outcomes.

Conclusions

ANH is a safe blood conservation strategy for surgical repairs of the thoracic aorta. Laboratory data suggests that ANH can improve coagulopathy after separation from CPB, and significantly reduce the number of transfused FFP, platelets and cryoprecipitate.
Interaction of a photochromic UV sensor protein Rc-PYP with PYP-binding protein
Authors: Kim Suhyang , Nakasone Yusuke , Takakado Akira , Yamazaki Yoichi , Kamikubo Hironari , Terazima Masahide
Published: June 2021

Photoactive yellow protein (PYP) from Halorhodospira halophila is one of typical light sensor proteins. Although its photoreaction has been extensively studied, no downstream partner protein has been identified to date. In this study, the intermolecular interaction dynamics observed between PYP from Rhodobacter capsulatus (Rc-PYP) and a possible downstream protein, PYP-binding protein (PBP), were studied. It was found that UV light-induced a long-lived product (pUV*), which interacts with PBP to form a stable hetero-hexamer (Complex-II). The reaction scheme for this interaction was revealed using transient absorption and transient grating methods. Time-resolved diffusion detection showed that a hetero-trimer (Complex-I) is formed transiently, which produced Complex-II via a second-order reaction. Any other intermediates, including those from pBL do not interact with PBP. The reaction scheme and kinetics are determined. Interestingly, long-lived Complex-II dissociates upon excitation with blue light. These results demonstrate that Rc-PYP is a photochromic and new type of UV sensor, of which signaling process is similar to that of other light sensor proteins in the visible light region. The photochromic heterogeneous intermolecular interactions formed between PYP and PBP can be used as a novel and useful tool in optogenetics.

Graphical Abstract
DNase treatment improves viral enrichment in agricultural soil viromes
Authors: Sorensen Jackson W. , Zinke Laura A. , ter Horst Anneliek M. , Santos-Medellin Christian , Schroeder Alena , Emerson Joanne B.
Published: June 2021

The small genomes of most viruses make it difficult to fully capture viral diversity in metagenomes dominated by DNA from cellular organisms. Viral size-fraction metagenomics (viromics) protocols facilitate enrichment of viral DNA from environmental samples, and these protocols typically include a DNase treatment of the post-0.2 μm viromic fraction to remove contaminating free DNA prior to virion lysis. However, DNase may also remove desirable viral genomic DNA (e.g., contained in virions compromised due to frozen storage or laboratory processing), suggesting that DNase-untreated viromes might be useful in some cases. In order to understand how virome preparation with and without DNase treatment influences the resultant data, here we compared 15 soil viromes (7 DNase-treated, 8 untreated) from 8 samples collected from agricultural fields prior to tomato planting. DNase-treated viromes yielded significantly more assembled viral contigs, contained significantly less non-viral microbial DNA, and recovered more viral populations (vOTUs) through read mapping. However, DNase-treated and untreated viromes were statistically indistinguishable, in terms of ecological patterns across viral communities. Although results suggest that DNase treatment is preferable where possible, in comparison to previously reported total metagenomes from the same samples, both DNase-treated and untreated viromes were significantly enriched in viral signatures by all metrics compared, including a ~225 times greater proportion of viral reads in untreated viromes compared to total metagenomes. Thus, even without DNase treatment, viromics was preferable to total metagenomics for capturing viral diversity in these soils, suggesting that preparation of DNase-untreated viromes can be worthwhile when DNase treatment is not possible.

Importance

Viromics is becoming an increasingly popular method for characterizing soil viral communities. DNase treatment of the viral size fraction prior to DNA extraction is meant to reduce contaminating free DNA and is a common step within viromics protocols to ensure sequences are of viral origin. However, some samples may not be amendable to DNase treatment due to viral particles being compromised either in storage (i.e. frozen) or during other sample processing. To date, the effect of DNase treatment on the recovery of viruses and downstream ecological interpretations of soil viral communities is not thoroughly understood. This work sheds light on these questions and indicates that while DNase treatment of soil viromes improves recovery of viral populations, this improvement is modest in comparison to the gains made by viromics over total soil metagenomics. Further, DNase treatment may not be necessary to observe the ecological patterns structuring soil viral communities.
Association between Maternal Depression during Pregnancy and Newborn DNA Methylation
Authors: Drzymalla Emily , Gladish Nicole , Koen Nastassja , Epstein Michael P. , Kobor Michael S. , Zar Heather J. , Stein Dan J. , Huels Anke
Published: June 2021

Around 15% to 65% of women globally experience depression during pregnancy, prevalence being particularly high in low- and middle-income countries. Prenatal depression has been associated with adverse birth and child development outcomes. DNA methylation (DNAm) may aid in understanding this association. In this project, we analyzed associations between prenatal depression and DNAm from cord blood from participants of the South African Drakenstein Child Health Study. We examined DNAm in an epigenome wide association study (EWAS) of 248 mother child pairs. DNAm was measured using the Infinium MethylationEPIC (N=145) and the Infinium HumanMethylation450 (N=103) arrays. Prenatal depression scores, obtained with the Edinburgh Postnatal Depression Scale (EPDS) and the Beck Depression Inventory II (BDI-II), were analyzed as continuous and dichotomized variables. We used linear robust models to estimate associations between depression and newborn DNAm, adjusted for measured (smoking status, household income, sex, preterm birth, cell type proportions, and genetic principal components) and unmeasured confounding using Cate and Bacon algorithms. Bonferroni correction was used to adjust for multiple testing. DMRcate was used to test for differentially methylated regions (DMRs). Differential DNAm in GNAS (cg22798925, Δ beta per IQR(EPDS)=0.0066, p= 1.06 × 10−7) was significantly associated with EPDS. For dichotomized BDI-II thresholds, Differential DNAm in CTNNA2 (cg04859497, Δ beta=-0.064, p= 8.09 × 10−10) and OSBPL10 (cg27278221, Δ beta=-0.020, p= 5.40 × 10−8) was significantly associated with the dichotomized BDI-II variables. Eight DMRs were associated with at least two depression scales. Further studies are needed to replicate these findings and investigate their biological impact.
CorCast: A Distributed Architecture for Bayesian Epidemic Nowcasting and its Application to District-Level SARS-CoV-2 Infection Numbers in Germany
Authors: Hildebrandt Anna-Katharina , Bob Konstantin , Teschner David , Kemmer Thomas , Leclaire Jennifer , Schmidt Bertil , Hildebrandt Andreas
Published: June 2021

Timely information on current infection numbers during an epidemic is of crucial importance for decision makers in politics, medicine, and businesses. As information about local infection risk can guide public policy as well as individual behavior, such as the wearing of personal protective equipment or voluntary social distancing, statistical models providing such insights should be transparent and reproducible as well as accurate. Fulfilling these requirements is drastically complicated by the large amounts of data generated during exponential growth of infection numbers, and by the complexity of common inference pipelines. Here, we present CorCast – a stable and scalable distributed architecture for the reproducible estimation of nowcasts suitable for pandemic scenarios – and its application to the inference of district-level SARS-CoV-2 infection numbers in Germany.
Antiviral Effect of Hyunggaeyungyo-tang on A549 Cells Infected with Human Coronavirus
Authors: Won Seo-Young , Seol In-Chan , Yoo Ho-Ryong , Kim Yoon-Sik
Published: June 2021

Background

Herbal medicine is widely recommended to treat viral infectious diseases. Over 123,000,000 individuals have been infected with the coronavirus since a worldwide pandemic was declared in March 2020. We conducted this research to confirm the potential of herbal medicine as a treatment for coronavirus.

Methods

We infected the A549 cell line with beta coronavirus OC43 then treated with 100 μg/mL Hyunggaeyungyo-tang (HGYGT) or distilled water with a control of HGYGT. We measured the mRNA expression levels of pro-inflammatory cytokines and interferon stimulated genes (ISGs) to confirm the effectiveness of HGYGT upon coronavirus infection.

Results

We found the effects of HYGYT decrease the expression level of pPKR, peIF2α, IFI6, IFI44, IFI44L, IFI27, IRF7, OASL and ISG15 when administered to cells with coronavirus infection. The expressions of IL-1, TNF-α, COX-2, NF-κB, iNOS and IKK mRNA were also significantly decreased in the HGYGT group than in the control group.

Conclusion

Through the reduction of the amount of coronavirus RNA, our research indicates that HGYGT has antiviral effects. The reduction of IKK and iNOS mRNA levels indicate that HGYGT reduces coronavirus RNA expression and may inhibits the replication of coronavirus by acting on NF-kB/Rel pathways to protect oxidative injury. In addition, decreases in mRNA expression levels of pro-inflammatory cytokines indicate that the HGYGT may relieve the symptoms of coronavirus infections.
Tatajuba ― Exploring the distribution of homopolymer tracts
Authors: de Oliveira Martins Leonardo , Bloomfield Samuel , Stoakes Emily , Grant Andrew , Page Andrew J. , Mather Alison E.
Published: June 2021

Length variation of homopolymeric tracts, which induces phase variation, is known to regulate gene expression leading to phenotypic variation in a wide range of bacterial species. There is no specialised bioinformatics software which can, at scale, exhaustively explore and describe these features from sequencing data. Identifying these is non-trivial as sequencing and bioinformatics methods are prone to introducing artefacts when presented with homopolymeric tracts due to the decreased base diversity. We present tatajuba, which can automatically identify potential homopolymeric tracts and their putative phenotypic impact, allowing for rapid investigation. We use it to detect all tracts in two separate datasets, one of Campylobacter jejuni and one of three Bordetella species, and to highlight those tracts that are polymorphic across samples. With this we confirm homopolymer tract variation with phenotypic impact found in previous studies and additionally find many more with potential variability. The software is written in C and is available under the open source license GNU GPL version 3 from https://github.com/quadram-institute-bioscience/tatajuba.
Inactivation of EMILIN-1 by proteolysis and secretion in small extracellular vesicles favors melanoma progression and metastasis
Authors: Lopez Ana Amor , Mazariegos Marina S. , Capuano Alessandra , Ximénez-Embún Pilar , Hergueta-Redondo Marta , Ángel Recio Juan , Muñoz Eva , Al-Shahrour Fátima , Muñoz Javier , Megías Diego , Doliana Roberto , Spessotto Paola , Peinado Héctor
Published: June 2021

Several studies have demonstrated that melanoma-derived extracellular vesicles (EVs) are involved in lymph node metastasis; however, the molecular mechanisms involved are not defined completely. Here, we found that EMILIN-1 is proteolyzed and secreted in small EVs (sEVs) as a novel mechanism to reduce its intracellular levels favoring metastasis in lymph node metastatic cells. Interestingly, we observed that EMILIN-1 has intrinsic tumor and metastasis suppressive-like properties reducing effective migration, cell viability, primary tumor growth and metastasis in mouse melanoma models. Finally, analysis in human melanoma samples showed that tumor cells with high levels of EMILIN-1 are reduced in metastatic lesions compared to primary tumors or nevi. Overall, our analysis suggests that the inactivation of EMILIN-1 by proteolysis and secretion in sEVs reduce its intrinsic tumor suppressive activities in melanoma favoring tumor progression and metastasis.
Real-time individual benefit from social interactions before and during the lockdown: The crucial role of personality, neurobiology and genes
Authors: Monninger Maximilian , Aggensteiner Pascal-M. , Pollok Tania M. , Reinhard Iris , Hall Alisha S.M. , Zillich Lea , Streit Fabian , Witt Stephanie-H. , Reichert Markus , Ebner-Priemer Ulrich , Meyer-Lindenberg Andreas , Tost Heike , Brandeis Daniel , Banaschewski Tobias , Holz Nathalie E.
Published: June 2021

Background:

Social integration is a major resilience factor for staying healthy. However, the COVID-19-pandemic led to unprecedented restrictions in social life. The consequences of these social lockdowns on momentary well-being are yet not fully understood.

Method:

We investigated the individual affective benefit from social interactions in a longitudinal birth cohort study. We used two real-time, real-life ecological momentary assessments once before and once during the initial lockdown of the pandemic (N~6800 total observations) to determine the protective role of social interactions on well-being. Moreover, we used a multimethod approach combining the ecological assessment data with individual risk and resilience factors to analyze the moderating mechanisms of personality, neurobiology and genes.

Results:

Social contacts were linked to higher positive affect both during normal times and during the COVID-19 pandemic, highlighting the beneficial role of social embedding. Moreover, this relationship was moderated by amygdala volume, neuroticism and polygenic risk for schizophrenia. In detail, participants with a larger left amygdala volume and higher trait neuroticism exhibited an affective benefit from more social interactions prior to the pandemic. This pattern changed during the pandemic with participants with smaller amygdala volumes and lower neurotic traits showing a social affective gain during the pandemic. Moreover, participants with low genetic risk for schizophrenia showed an affective benefit from social interactions irrespective of the time point.

Conclusion:

Our results highlight the protective role of social integration on momentary well-being. Thereby, we offer new insights into how this relationship is differently affected by a person’s, neurobiology, personality, and genes under adverse circumstances.
“Metabolic dysregulations of cancer cells with metastatic potential”
Authors: Kader Sara Abdul , Dib Shaima , Achkar Iman W. , Thareja Gaurav , Suhre Karsten , Rafii Arash , Halama Anna
Published: June 2021

Metastasis is the primary cause of cancer related deaths due to the limited number of efficient druggable targets. Signatures of dysregulated cancer metabolism could serve as a roadmap for the determination of new treatment strategies, given their vital role in cancer cell responses to multiple challenges, including nutrient and oxygen availability. However, the metabolic signatures of metastatic cells remain vastly elusive. We conducted untargeted metabolic profiling of cells and growth media of five selected triple negative breast cancer cell lines with high metastatic potential (HMP) (MDA-MB-231, MDA-MB-436, MDA-MB-468) and low metastatic potential (LMP) (BT549, HCC1143). We identified 92 metabolites in cells and 22 in growth medium that display significant differences between LMP and HMP. The HMP cell lines had elevated level of molecules involved in glycolysis, TCA cycle and lipid metabolism. We identified metabolic advantages of cell lines with HMP beyond enhanced glycolysis by pinpointing the role of branched chain amino acids (BCAA) catabolism as well as molecules supporting coagulation and platelet activation as important contributors to the metastatic cascade. The landscape of metabolic dysregulations, characterized in our study, could serve in the future as a roadmap for the identification of treatment strategies targeting cancer cells with enhanced metastatic potential.
The Mechanism of Replication Stalling and Recovery within Repetitive DNA
Authors: Casas-Delucchi Corella S , Daza-Martin Manuel , Williams Sophie L , Coster Gideon
Published: June 2021

Accurate chromosomal DNA replication is essential to maintain genomic stability. Genetic evidence suggests that certain repetitive sequences impair replication, yet the underlying mechanism is poorly defined. Replication could be directly inhibited by the DNA template or indirectly, for example by DNA-bound proteins. Here, we reconstituted replication of mono-, di- and trinucleotide repeats in vitro using eukaryotic replisomes assembled from purified proteins. We found that structure-prone repeats are sufficient to impair replication. Whilst template unwinding was unaffected, leading strand synthesis was inhibited, leading to fork uncoupling. Synthesis through hairpin-forming repeats relied on replisome-intrinsic mechanisms, whereas synthesis of quadruplex-forming repeats required an extrinsic accessory helicase. DNA-induced fork stalling was mechanistically similar to that induced by leading strand DNA lesions, highlighting structure-prone repeats as an important potential source of replication stress. Thus, we propose that our understanding of the cellular response to replication stress also applies to stalling induced by repetitive sequences.
Antibacterial Activity and Acute Toxicity Testing of Biosynthesized Silver Nanoparticles against Methicilin-Resistant Staphylococcus aureus and Pseudomonas aeruginosa
Authors: Olobayotan Ifeyomi Wilfred , Akin-Osanaiye Bukola Catherine , Onuh Olukemi A.
Published: June 2021

Antibacterial activity of biosynthesized silver nanoparticles was studied using the macrobroth dilution technique. The silver nanoparticles was significantly active (p > 0.05) against the test organisms at an extract concentration of 75 µg/ml. Concentrations ≤ 50 µg/ml were not as effective as the colony forming units at this concentration, 1.61 × 106 for methicillin-resistant Staphylococcus aureus and concentrations ≤ 25 µg/ml 1.45 × 106 for Pseudomonas aeruginosa respectively, were about the same range as the colony forming units of the controls. The silver nanoparticles inhibited Methicillin-Resistant S. aureus more (MIC of 75 µg/ml and MBC of 100 µg/ml) than they inhibited P. aeruginosa (both MIC and MBC was 100 µg/ml). The LD50 of the synthesized silver nanoparticles after oral administration was seen to be greater than 5000 mg/kg body weight and is therefore thought to be safe. This study supports the use of silver nanoparticles as therapeutic agents.
Mycobacterium tuberculosis H2S functions as a sink to modulate central metabolism, bioenergetics, and drug susceptibility
Authors: Kunota Tafara T.R. , Rahman Md. Aejazur , Truebody Barry E. , Mackenzie Jared S. , Saini Vikram , Lamprecht Dirk A. , Adamson John H. , Sevalkar Ritesh R. , Lancaster Jack R. , Berney Michael , Glasgow Joel N. , Steyn Adrie J.C.
Published: June 2021

H2S is a potent gasotransmitter in eukaryotes and bacteria. Host-derived H2S has been shown to profoundly alter M. tuberculosis (Mtb) energy metabolism and growth. However, compelling evidence for endogenous production of H2S and its role in Mtb physiology is lacking. We show that multidrug-resistant and drug-susceptible clinical Mtb strains produce H2S, whereas H2S production in non-pathogenic M. smegmatis is barely detectable. We identified Rv3684 (Cds1) as an H2S-producing enzyme in Mtb and show that cds1 disruption reduces, but does not eliminate, H2S production, suggesting the involvement of multiple genes in H2S production. We identified endogenous H2S to be an effector molecule that maintains bioenergetic homeostasis by stimulating respiration primarily via cytochrome bd. Importantly, H2S plays a key role in central metabolism by modulating the balance between oxidative phosphorylation and glycolysis, and functions as a sink to recycle sulfur atoms back to cysteine to maintain sulfur homeostasis. Lastly, Mtb-generated H2S regulates redox homeostasis and susceptibility to anti-TB drugs clofazimine and rifampicin. These findings reveal previously unknown facets of Mtb physiology and have implications for routine laboratory culturing, understanding drug susceptibility, and improved diagnostics.
The BLENDS Method for Data Augmentation of 4-Dimensional Brain Images
Authors: Nguyen Kevin P. , Raval Vyom , Minhajuddin Abu , Carmody Thomas , Trivedi Madhukar H. , Dewey Richard B. , Montillo Albert A.
Published: June 2021

Purpose

Data augmentation improves the accuracy of deep learning models when training data is scarce by synthesizing additional samples. This work addresses the lack of validated augmentation methods specific for synthesizing anatomically realistic 4D (3D+time) images for neuroimaging, such as fMRI, by proposing a new augmentation method.

Materials and Methods

The proposed method, BLENDS, generates new nonlinear warp fields by combining intersubject coregistration maps, computed using symmetric normalization, through spatial blending. These new warp fields can be applied to existing 4D fMRI to create new augmented images. BLENDS is tested on two neuroimaging problems using de-identified datasets: 1) the prediction of antidepressant response from task-based fMRI in the EMBARC dataset (n = 163), and 2) the prediction of Parkinson’s Disease symptom trajectory from baseline resting-state fMRI regional homogeneity in the PPMI dataset (n = 43).

Results

BLENDS readily generates hundreds of new fMRI from existing images, with unique anatomical variations from the source images, that significantly improve prediction performance. For antidepressant response prediction, augmenting each original image once (2x the original training data) significantly increased prediction R2 from 0.055 to 0.098 (p < 1e-6), while at 10x augmentation R2 increased to 0.103. For the prediction of Parkinson’s Disease trajectory, 10x augmentation R2 increased from 0.294 to 0.548 (p < 1e-6).

Conclusion

Augmentation of fMRI through nonlinear transformations with BLENDS significantly improves the performance of deep learning models on clinically relevant predictive tasks. This method will help neuroimaging researchers overcome dataset size limitations and achieve more accurate predictive models.
Enriched sleep environments lengthen lemur sleep duration
Authors: Vining Alexander Q. , Nunn Charles L. , Samson David R.
Published: June 2021

Characteristics of the sleep-site are thought to influence the quality and duration of primate sleep, yet only a handful of studies have investigated these links experimentally. Using actigraphy and infrared videography, we quantified sleep in four lemur species (Eulemur coronatus, Lemur catta, Propithecus coquereli, and Varecia rubra) under two different experimental conditions at the Duke Lemur Center (DLC) in Durham, NC, USA. Individuals from each species underwent three weeks of simultaneous testing to investigate the hypothesis that comfort level of the sleep-site influences sleep. We obtained baseline data on normal sleep, and then, in a pair-wise study design, we compared the daily sleep times of individuals in simultaneous experiments of sleep-site enrichment and sleep-site impoverishment. Over 163 24-hour periods from 8 individuals (2 of each species), we found strong evidence that enriched sleep-sites increased daily sleep times of lemurs, with an average increase of thirty-one minutes. The effect of sleep-site impoverishment was small and not statistically significant. We conclude that properties of a sleep-site enhancing softness or insulation, more than the factors of surface area or stability, influence lemur sleep, with implications regarding the importance of nest building in primate evolution and the welfare and management of captive lemurs.
Targeted degradation of the oncogenic phosphatase SHP2
Authors: Vemulapalli Vidyasiri , Donovan Katherine A. , Seegar Tom C.M. , Rogers Julia M. , Bae Munhyung , Lumpkin Ryan J. , Cao Ruili , Henke Matthew T. , Fischer Eric S. , Cuny Gregory D. , Blacklow Stephen C.
Published: June 2021

SHP2 is a protein tyrosine phosphatase that plays a critical role in the full activation of the Ras/MAPK pathway upon stimulation of receptor tyrosine kinases (RTKs), which are frequently amplified or mutationally activated in human cancer. In addition, activating mutations in SHP2 result in developmental disorders and hematologic malignancies. Several allosteric inhibitors have been developed for SHP2 and are currently in clinical trials. Here, we report the development and evaluation of a SHP2 PROTAC created by conjugating RMC-4550 with pomalidomide using a PEG linker. This molecule is highly selective for SHP2, induces degradation of SHP2 in leukemic cells at sub-micromolar concentration, inhibits MAPK signaling, and suppresses cancer cell growth. SHP2 PROTACs serve as an alternative strategy for targeting ERK-dependent cancers and are useful tools alongside allosteric inhibitors for dissecting the mechanisms by which SHP2 exerts its oncogenic activity.
Localization of TRP channels in healthy oral mucosa from human donors
Authors: Moayedi Yalda , Michlig Stephanie , Park Mark , Koch Alia , Lumpkin Ellen A
Published: June 2021

The oral cavity is exposed to a remarkable range of noxious and innocuous conditions, including temperature fluctuations, mechanical forces, inflammation and environmental and endogenous chemicals. How such changes in the oral environment are sensed by oral cells and tissues is not completely understood. Transient receptor potential (TRP) ion channels are a diverse family of molecular receptors that are activated by chemicals, temperature changes, and tissue damage. In non-neuronal cells, TRP channels play roles in inflammation, as well as tissue development and maintenance. In somatosensory neurons, TRP channels mediate nociception, thermosensation and chemosensation. To assess whether TRP channels might be involved in environmental sensing in the human oral cavity, we investigated the distribution of TRP channels in human tongue and hard palate. Oral biopsies were collected from volunteers and underwent fluorescent immunohistochemistry followed by confocal imaging. We analyzed immunoreactivity of TRP channels in human oral epithelia including TRPV3, TRPV4, TRPV1, TRPM8, and TRPA1. TRPV3 and TRPV4 were expressed in epithelial cells with inverse expression patterns where they are likely to contribute to epithelial development and integrity. TRPA1 immunoreactivity was found in fibroblasts, subsets immune cells, and neurons, consistent with known roles of TRPA1 in sensory transduction, as well as in response to damage and inflammation. TRPM8 immunoreactivity was found in lamina propria cells and some neuronal subpopulations including some neurons within the end bulbs of Krause, consistent with a role in thermal sensation. TRPV1 immunoreactivity was identified in intraepithelial nerve fibers, in some end bulbs of Krause, and in epithelial cells, consistent with roles in nociception and thermosensation. Immunoreactivity of TRPM8 and TRPV1 in end bulbs of Krause suggest that these structures contain a variety of neuronal afferents, including those that mediate nociception, thermosensation and mechanotransduction. Collectively, these studies support the role of TRP channels in oral environmental surveillance and response.