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Detailed analysis of antibody responses to SARS-CoV-2 vaccination and infection in macaques
Get PDFMacaques are a commonly used model for studying immunity to human viruses, including for studies of SARS-CoV-2 infection and vaccination. However, it is unknown whether macaque antibody responses resemble the response in humans. To answer this question, we employed a phage-based deep mutational scanning approach (Phage-DMS) to compare which linear epitopes are targeted on the SARS-CoV-2 Spike protein in convalescent humans, convalescent (re-infected) rhesus macaques, mRNA-vaccinated humans, and repRNA-vaccinated pigtail macaques. We also used Phage-DMS to determine antibody escape pathways within each epitope, enabling a granular comparison of antibody binding specificities at the locus level. Overall, we identified some common epitope targets in both macaques and humans, including in the fusion peptide (FP) and stem helix-heptad repeat 2 (SH-H) regions. Differences between groups included a response to epitopes in the N-terminal domain (NTD) and C-terminal domain (CTD) in vaccinated humans but not vaccinated macaques, as well as recognition of a CTD epitope and epitopes flanking the FP in convalescent macaques but not convalescent humans. There was also considerable variability in the escape pathways among individuals within each group. Sera from convalescent macaques showed the least variability in escape overall and converged on a common response with vaccinated humans in the SH-H epitope region, suggesting highly similar antibodies were elicited. Collectively, these findings suggest that the antibody response to SARS-CoV-2 in macaques shares many features with humans, but with substantial differences in the recognition of certain epitopes and considerable individual variability in antibody escape profiles, suggesting a diverse repertoire of antibodies that can respond to major epitopes in both humans and macaques. Differences in macaque species and exposure type may also contribute to these findings
Prediction of Major Histocompatibility Complex Binding with Bilateral and Variable Long Short Term Memory Networks
Get PDFAs an important part of immune surveillance, major histocompatibility complex (MHC) is a set of proteins that recognize foreign molecules. Computational prediction methods for MHC binding peptides have been developed. However, existing methods share the limitation of fixed peptide sequence length, which necessitates the training of models by peptide length or prediction with a length reduction technique. Using a bidirectional long short-term memory neural network, we constructed BVMHC, an MHC class I and II binding prediction tool that is independent of peptide length. The performance of BVMHC was compared to seven MHC class I prediction tools and three MHC class II prediction tools using eight performance criteria independently. BVMHC attained the best performance in three of the eight criteria for MHC class I, and the best performance in four of the eight criteria for MHC class II, including accuracy and AUC. Furthermore, models for non-human species were also trained using the same strategy and made available for applications in mice, chimpanzees, macaques, and rats. BVMHC is composed of a series of peptide length independent MHC class I and II binding predictors. Models from this study have been implemented in an online web portal for easy access and use
Model-Guided Metabolic Rewiring for Gamma-Aminobutyric Acid and Butyrolactam Biosynthesis in Corynebacterium glutamicum ATCC13032
Get PDFGamma-aminobutyric acid (GABA) can be used as a bioactive component in the pharmaceutical industry and a precursor for the synthesis of butyrolactam, which functions as a monomer for the synthesis of polyamide 4 (nylon 4) with improved thermal stability and high biodegradability. The bio-based fermentation production of chemicals using microbes as a cell factory provides an alternative to replace petrochemical-based processes. Here, we performed model-guided metabolic engineering of Corynebacterium glutamicum for GABA and butyrolactam fermentation. A GABA biosynthetic pathway was constructed using a bi-cistronic expression cassette containing mutant glutamate decarboxylase. An in silico simulation showed that the increase in the flux from acetyl-CoA to α-ketoglutarate and the decrease in the flux from α-ketoglutarate to succinate drove more flux toward GABA biosynthesis. The TCA cycle was reconstructed by increasing the expression of acn and icd genes and deleting the sucCD gene. Blocking GABA catabolism and rewiring the transport system of GABA further improved GABA production. An acetyl-CoA-dependent pathway for in vivo butyrolactam biosynthesis was constructed by overexpressing act-encoding ß-alanine CoA transferase. In fed-batch fermentation, the engineered strains produced 23.07 g/L of GABA with a yield of 0.52 mol/mol from glucose and 4.58 g/L of butyrolactam. The metabolic engineering strategies can be used for genetic modification of industrial strains to produce target chemicals from α-ketoglutarate as a precursor, and the engineered strains will be useful to synthesize the bio-based monomer of polyamide 4 from renewable resources
Evaluation of Safety and Efficacy of Traction, Closed Reduction, and Subsequent Hip Fixation in Hilgenreiner Brace in Patients with Severe Forms of Hip Developmental Dysplasia
Get PDFBackground. Hilgenreiner brace (Hb) was developed to improve hip reduction rate and reduce the incidence of femoral head avascular necrosis (AVN). In children under the age of 18 months with unstable hip joints or a dislocated hip joint, the treatment method involves nonsurgical treatment in most cases. Objectives. To evaluate the effectiveness and safety of traction, closed reduction, and hip fixation in Hb in patients with severe forms of hip developmental dysplasia (DDH) in follow-up. Materials and Methods. Prospective, clinical, cohort observation and retrospective matched-pair analysis. Analysis of medical records was conducted to evaluate the effectiveness of using Hb for treatment of dislocated hip joints in <18-month-old children. The investigated cases were of the dislocated hip joint since DDH was confirmed through clinical and imaging diagnosis and treated by the application of the close reduction method together with Hb, in a nonhuman position (hip joint in 90 degrees of flexion and 80 degrees of abduction). Analysis was carried out using the modified Berkeley’s Mckay criteria and hip joint centralization, and evaluation was done using X-ray images according to the basic modified Severin classification system. Results. The use of Hb applied after overhead traction to (mean 22.8 days, confidence level (95%)) 68 hip joints showed a significant improvement (92%) in the treated hips. In summary, only one brace replacement was performed due to swelling of the thigh and fixation pressure, three cases suffered from hip joint redislocation after removing the Hb (5%), and one patient had bilateral avascular necrosis (2.8%). Conclusions. The use of Hb reduced avascular necrosis of the femur head, maintained higher hygiene conditions, and lowered both the risk of cast breakage and skin complications over the use of hip spica as compared to Hb. Hb is more cost-effective, and radiolucency is an additional advantage for this technique. Closed reduction and application of Hb after oral administration of a bolus dose of chlorpromazine chloride or phenobarbital resulted in complication avoidance of total anaesthesia
Incidence of Mortality among Under-Five-Year-Old Children Born to Women Living with HIV and Those Born to Women Not Living with HIV in Botswana: A 5-Year Retrospective Study
Get PDFBackground. Child mortality is a core indicator for child health and wellness. Botswana reported an under-five-year-old children (UFC) mortality rate of 48 deaths per 1000 live births in 2017 against 152 deaths per 1000 live births in 1971. This was a commendable accomplishment. However, given the current country situation whereby 23% of children are born to women living with HIV, the incidence of mortality among UFC born to women living with and not living with HIV and their survival are better health metrics to inform decision making. Nevertheless, such data are still very scarce in Botswana. The study’s objective was to estimate the incidence of UFC mortality among children born to women living with and not living with HIV and to compare UFC survival between the two groups. Methods. A retrospective cohort study of mortality among UFC was conducted in Botswana, including all UFC born between January 2014 and June 2018. Data were extracted from the National Under-Five Mortality Audit Committee (NUFMAC) database using a standardized data collection tool. The incidence rate of UFC death was estimated as a function of the duration from birth to death. Survival functions of UFC born to women living with and not living with HIV were plotted and compared using Kaplan–Meier survival analysis. Results. The overall incidence of UFC death was 4.63/1000 child months (CM) (95% CI 4.36–4.90). The incidence of UFC death among children born to women living with HIV was 6.96/1000 CM (95% CI 6.47–7.45) and that of UFC born to women not living with HIV was 4.34/1000 CM (95% CI 4.03–4.65). The overall average and standard error (SE) time to event/death for UFC born to women living with and not living with HIV was 54.80 (0.18) months. The mean (SE) time to death for UFC born to women living with HIV was 52.79 (0.41) months and that of UFC born to women not living with HIV was 55.44 (0.19) months (log-rank X2 = 37.59, ). Prematurity or low birth weight was the leading cause of UFC death in both groups; but, it was higher in UFC born to women not living with HIV subgroup than their counterparts. Four cases only or 0.5% of the 806 death cases reported by reporting physicians were attributable to HIV-related complications. Conclusion. Despite the commendable efforts made in reducing UFC death, the incidence of UFC death among UFC born to women living with HIV in Botswana is still higher, and their survival is shorter compared to UFC born to women not living with HIV. Child survival interventions should prioritize UFC born to women living with HIV to improve their survival
Metal–Organic Cages: Applications in Organic Reactions
Get PDFSupramolecular metal–organic cages, a class of molecular containers formed via coordination-driven self-assembly, have attracted sustained attention for their applications in catalysis, due to their structural aesthetics and unique properties. Their inherent confined cavity is considered to be analogous to the binding pocket of enzymes, and the facile tunability of building blocks offers a diverse platform for enzyme mimics to promote organic reactions. This minireview covers the recent progress of supramolecular metal–organic coordination cages for boosting organic reactions as reaction vessels or catalysts. The developments in the utilizations of the metal–organic cages for accelerating the organic reactions, improving the selectivity of the reactions are summarized. In addition, recent developments and successes in tandem or cascade reactions promoted by supramolecular metal–organic cages are discussed
Environmental pesticide exposure and non-Hodgkin lymphoma survival: a population-based study
Get PDFThere is evidence indicating that pesticide exposure is a risk factor for non-Hodgkin lymphoma (NHL) development. However, the association between pesticide exposure and NHL survival is not well-established.
Methods
Using the California Cancer Registry, we identified patients with a first primary diagnosis of NHL from 2010 to 2016 and linked these patients with CalEnviroScreen 3.0 to obtain production agriculture pesticide exposure to 70 chemicals from the state-mandated Pesticide Use Reporting (PUR) by census tract from 2012 to 2014. In addition, data from PUR was integrated into a geographic information system that employs land-use data to estimate cumulative exposure to specific pesticides previously associated with NHL (glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt) between 10 years prior up to 1 year after NHL diagnosis. Multivariable Cox proportional hazards regression models were used to evaluate the association between total pesticide exposure from CalEnviroScreen 3.0 and individual pesticide exposure from geographic land use data and lymphoma-specific and overall survival.
Results
Among 35,808 NHL patients identified, 44.2% were exposed to pesticide in their census tract of residence. Glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4-dimethylamine salt exposure was observed in 34.1%, 26.0%, 10.6%, 14.0%, and 12.8% of NHL patients, respectively. Total pesticide exposure at the time of diagnosis was not associated with lymphoma-specific or overall survival. In addition, no association was consistently found between glyphosate, organophosphorus, carbamate, phenoxyherbicide, and 2,4 dimethylamine salt exposure and lymphoma-specific or overall survival.
Conclusions
Although we found no consistent associations between agricultural pesticide exposure at the neighborhood level and worse survival, these results provide a platform for designing future studies to determine the association between pesticide and NHL
A healthy dietary metabolic signature is associated with a lower risk for type 2 diabetes and coronary artery disease
Get PDFThe global burden of cardiovascular disease and type 2 diabetes could be decreased by improving dietary factors, but identification of groups suitable for interventional approaches can be difficult. Reporting of dietary intake is prone to errors, and measuring of metabolites has shown promise in determining habitual dietary intake. Our aim is to create a metabolic signature that is associated with healthy eating and test if it associates with type 2 diabetes and coronary artery disease risk.
Methods
Using plasma metabolite data consisting of 111 metabolites, partial least square (PLS) regression was used to identify a metabolic signature associated with a health conscious food pattern in the Malmö Offspring Study (MOS, n = 1538). The metabolic signature’s association with dietary intake was validated in the Malmö Diet and Cancer study (MDC, n = 2521). The associations between the diet-associated metabolic signature and incident type 2 diabetes and coronary artery disease (CAD) were tested using Cox regression in MDC and logistic regression in Malmö Preventive Project (MPP, n = 1083). Modelling was conducted unadjusted (model 1), adjusted for potential confounders (model 2) and additionally for potential mediators (model 3).
Results
The metabolic signature was associated with lower risk for type 2 diabetes in both MDC (hazard ratio: 0.58, 95% CI 0.52–0.66, per 1 SD increment of the metabolic signature) and MPP (odds ratio: 0.54, 95% CI 0.44–0.65 per 1 SD increment of the metabolic signature) in model 2. The results were attenuated but remained significant in model 3 in both MDC (hazard ratio 0.73, 95% CI 0.63–0.83) and MPP (odds ratio 0.70, 95% CI 0.55–0.88). The diet-associated metabolic signature was also inversely associated with lower risk of CAD in both MDC and MPP in model 1, but the association was non-significant in model 3.
Conclusions
In this proof-of-concept study, we identified a healthy diet-associated metabolic signature, which was inversely associated with future risk for type 2 diabetes and coronary artery disease in two different cohorts. The association with diabetes was independent of traditional risk factors and might illustrate an effect of health conscious dietary intake on cardiometabolic health
The association of neurodevelopmental abnormalities, congenital heart and renal defects in a tuberous sclerosis complex patient cohort
Get PDFTuberous sclerosis complex (TSC) is a rare multi-system genetic disorder characterised by the presence of benign tumours throughout multiple organs including the brain, kidneys, heart, liver, eyes, lungs and skin, in addition to neurological and neuropsychiatric complications. Intracardiac tumour (rhabdomyoma), neurodevelopmental disorders (NDDs) and kidney disorders (KD) are common manifestations of TSC and have been linked with TSC1 and TSC2 loss-of-function mutations independently, but the dynamic relationship between these organ manifestations remains unexplored. Therefore, this study aims to characterise the nature of the relationship specifically between these three organs’ manifestations in TSC1 and TSC2 mutation patients.
Methods
Clinical data gathered from TSC patients across South Wales registered with Cardiff and Vale University Health Board (CAV UHB) between 1990 and 2020 were analysed retrospectively to evaluate abnormalities in the heart, brain and kidney development. TSC-related abnormalities such as tumour prevalence, location and size were analysed for each organ in addition to neuropsychiatric involvement and were compared between TSC1 and TSC2 mutant genotypes. Lastly, statistical co-occurrence between organ manifestations co-morbidity was quantified, and trajectories of disease progression throughout organs were modelled.
Results
This study found a significantly greater mutational frequency at the TSC2 locus in the cohort in comparison to TSC1. An equal proportion of male and female patients were observed in this group and by meta-analysis of previous studies. No significant difference in characterisation of heart involvement was observed between TSC1 and TSC2 patients. Brain involvement was seen with increased severity in TSC2 patients, characterised by a greater prevalence of cortical tubers and communication disorders. Renal pathology was further enhanced in TSC2 patients, marked by increased bilateral angiomyolipoma prevalence. Furthermore, co-occurrence of NDDs and KDs was the most positively correlated out of investigated manifestations, regardless of genotype. Analysis of disease trajectories revealed a more diverse clinical outcome for TSC2 patients: however, a chronological association of rhabdomyoma, NDD and KD was most frequently observed for TSC1 patients
Effects of providing free hearing aids on multiple health outcomes among middle-aged and older adults with hearing loss in rural China: a randomized controlled trial
Get PDFHearing loss has been associated with serious health problems around the globe. Previous studies have found the positive effects of fitting hearing aids on health, but few studies were conducted in developing countries. The aim of this study is to examine the effects of hearing aids on multiple health outcomes among middle-aged and older adults with hearing loss in rural China.
Methods
In this randomized controlled trial (RCT), participants aged 45 and above were randomly assigned to the treatment group prescribing with hearing aids or to the control group with no intervention. Trial outcomes for 385 participants were collected during the 20-month follow-up study. Using the difference-in-difference approach, our primary outcomes were hearing-related quality of life (QoL) and generic QoL.
Results
The intervention led to improvements in hearing-related QoL, presenting as the reduction in Hearing Handicap Inventory for the Elderly Screening Version (HHIE-S) scores (interaction coefficient = − 2.86, p = 0.005), HHIE-S-Emotional scores (interaction coefficient = − 1.42, p = 0.029), and HHIE-S-Situational scores (interaction coefficient = − 1.43, p = 0.007). The intervention was also effective in alleviating the increase in depressive symptoms (interaction coefficient = − 0.14, p = 0.042). Subgroup analysis revealed that the effects were only shown among people with social activities or active social networks