Diet is a modifiable risk factor that may influence cognition in people with HIV.
We examined the association between dietary intake and cognition in women with HIV (WWH) and HIV-seronegative women.
...An 18-item dietary National Cancer Institute screener was completed by 729 WWH and 346 HIV-seronegative Women’s Interagency HIV Study participants. Daily intake frequencies of processed meats, sweet beverages, fish, whole milk, and vegetables were calculated. Participants completed biennial neuropsychological (NP) testing. NP domains included attention/working memory, executive function, processing speed, memory, learning, fluency, and motor function. NP impairment was defined as demographically adjusted T-scores (mean = 50; SD = 10) ≤40 at ≥1 visit after completing the dietary screener. Multivariable logistic regression, stratified by HIV serostatus, examined associations between intake frequency tertile (referent = lowest intake) and NP performance.
Dietary intake frequencies of individual food line items were similar between WWH and HIV-seronegative women, except for sweet beverages, for which HIV-seronegative women reported higher intake frequencies than WWH (P values < 0.05). In WWH, multivariable-adjusted models indicated higher odds of NP impairment with higher intake frequencies of processed meat P = 0.006; ORupper tertile = 1.91 (95% CI: 1.23–2.95; P = 0.003); ORmiddle tertile = 1.66 (95% CI: 1.14–2.42; P = 0.01), sweet beverages P = 0.02; ORupper tertile = 1.75 (95% CI: 1.17–2.64; P = 0.007), fish P = 0.01; ORupper tertile = 1.70 (95% CI: 1.10–2.64; P = 0.02), and whole milk P = 0.029; ORupper tertile = 1.66 (95% CI: 1.14–2.42; P = 0.008). Lower odds of NP impairment P = 0.005; ORupper tertile = 0.65 (95% CI: 0.45–0.95; P = 0.02); ORmiddle tertile = 0.42 (95% CI: 0.24–0.73; P = 0.002) were associated with higher vegetable intakes. In HIV-seronegative women, multivariable-adjusted models did not show associations between food line items/diet quality score and NP outcomes.
Intakes of processed meat, sweet beverages, whole milk, fish, and vegetables may be associated with NP functions among WWH. Associations among WWH are not directly comparable to those among HIV-seronegative women, because models were conducted on each group separately given controls for HIV-specific covariates in WWH. Further studies are needed using more rigorous dietary assessment methods and lengthier longitudinal follow-ups.
Donor-to-donor variability in primary human organoid cultures has not been well characterized. As these cultures contain multiple cell types, there is greater concern that variability could lead to ...increased noise. In this work we investigated donor-to-donor variability in human gut adult stem cell (ASC) organoids. We examined intestinal developmental pathways during culture differentiation in ileum- and colon-derived cultures established from multiple donors, showing that differentiation patterns were consistent among cultures. This finding indicates that donor-to-donor variability in this system remains at a manageable level. Intestinal metabolic activity was evaluated by targeted analysis of central carbon metabolites and by analyzing hormone production patterns. Both experiments demonstrated similar metabolic functions among donors. Importantly, this activity reflected intestinal biology, indicating that these ASC organoid cultures are appropriate for studying metabolic processes. This work establishes a framework for generating high-confidence data using human primary cultures through thorough characterization of variability.
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•Developmental gene expression patterns were used to assess organoid variability•Organoid differentiation patterns were consistent among independent donors•Metabolic state of organoids was developmentally controlled•Variability of hormone secretion and metabolic activity in organoids was minimal
In this work, Lieberman and colleagues investigate donor-to-donor variability patterns using intestinal organoids from various donors. They show that developmental gene expression patterns, hormone secretion, and metabolic activity are consistent among multiple donors. Taken together, this article provides pathway and functional evidence for limited variability among intestinal organoid cultures, which enables robust and reliable interpretation of results.
The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed ...as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs), which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq) was used to evaluate HERV expression following the exposure of primary CD4
T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33) were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose-response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity.
BACKGROUNDTuberculosis (TB) kills more people than any other infection, and new diagnostic tests to identify active cases are required. We aimed to discover and verify novel markers for TB in ...nondepleted plasma.METHODSWe applied an optimized quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation combined with high-resolution mass spectrometry to study nondepleted plasma of 11 patients with active TB compared with 10 healthy controls. Prioritized candidates were verified in independent UK (n = 118) and South African cohorts (n = 203).RESULTSWe generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We analyzed the predominantly low-molecular weight subproteome, identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide FDR ≤ 1%, q ≤ 0.05). Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in 2 independent cohorts. Receiver operating characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP, and SAA1) exhibited discriminatory power in distinguishing TB from other respiratory diseases (AUC = 0.81).CONCLUSIONWe report the most comprehensive TB plasma proteome to date, identifying novel markers with verification in 2 independent cohorts, leading to a 5-protein biosignature with potential to improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic triage test.FUNDINGColciencias, Medical Research Council, Innovate UK, NIHR, Academy of Medical Sciences, Program for Advanced Research Capacities for AIDS, Wellcome Centre for Infectious Diseases Research.
A cornerstone technique in the study of hearing is the Auditory Brainstem Response (ABR), an electrophysiologic technique that can be used as a quantitative measure of hearing function. Previous ...studies have published databases of baseline ABR thresholds for mouse strains, providing a valuable resource for the study of baseline hearing function and genetic mapping of hearing traits in mice. In this study, we further expand upon the existing literature by characterizing the baseline ABR characteristics of 100 inbred mouse strains, 47 of which are newly characterized for hearing function. We identify several distinct patterns of baseline hearing deficits and provide potential avenues for further investigation. Additionally, we characterize the sensitivity of the same 100 strains to noise exposure using permanent thresholds shifts, identifying several distinct patterns of noise-sensitivity. The resulting data provides a new resource for studying hearing loss and noise-sensitivity in mice.
•We conducted a superficial screening study for hearing function in 100 inbred strains of mice.•Several distinct patterns of baseline hearing impairment are observed, and possible avenues of research are discussed.•We also characterize the sensitivity of the same 100 strains to damaging levels of noise.•Several distinct patterns of noise-sensitivity are observed, and possible avenues of research are discussed.•The combined dataset is made available for general use.
Abstract Small cohort sizes and modest levels of gene expression changes in brain tissue have plagued the statistical approaches employed in microarray studies investigating the mechanism of ...schizophrenia. To combat these problems a combined analysis of six prior microarray studies was performed to facilitate the robust statistical analysis of gene expression data from the dorsolateral prefrontal cortex of 107 patients with schizophrenia and 118 healthy subjects. Multivariate permutation tests identified 144 genes that were differentially expressed between schizophrenia and control groups. Seventy of these genes were identified as differentially expressed in at least one component microarray study but none of these individual studies had the power to identify the remaining 74 genes, demonstrating the utility of a combined approach. Gene ontology terms and biological pathways that were significantly enriched for differentially expressed genes were related to neuronal cell–cell signaling, mesenchymal induction, and mitogen-activated protein kinase signaling, which have all previously been associated with the etiopathogenesis of schizophrenia. The differential expression of BAG3 , C4B , EGR1 , MT1X , NEUROD6 , SST and S100A8 was confirmed by real-time quantitative PCR in an independent cohort using postmortem human prefrontal cortex samples. Comparison of gene expression between schizophrenic subjects with and without detectable levels of antipsychotics in their blood suggests that the modulation of MT1X and S100A8 may be the result of drug exposure. In conclusion, this combined analysis has resulted in a statistically robust identification of genes whose dysregulation may contribute to the mechanism of schizophrenia.
Rationale Maternal age at birth has been associated with increased incidence of asthma, food allergy, and diabetes in children and young adults. Methods In peripheral blood samples from the Isle of ...Wight (IoW) Birth Cohort (10 (N=138) and 18 (N=367) years) and cord-blood samples from 200 subjects from the IoW 3rd Generation Cohort, methylation was assessed using Illumina HumanMethylation450 and EPIC Beadchips and analyzed with linear models.
Logistic regression was implemented with asthma transition status as the response variable, controlled for potential confounders including gender, family history of asthma, gestational maternal ...smoking, allergy, current smoking, birthweight, farm living, paracetamol use, social class, pet exposure, breast feeding, height and BMI changes. Results DNAm at 7 Cytosine-Phosphate-Guanine (CPG) sites was associated with negative transition, 17 with positive transition, and 3 with persistent asthma.
Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently ...available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in patients with sepsis. Our findings identify differentially expressed mature and immature neutrophil subsets in patients with sepsis. These subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in patients with sepsis. These results enabled the construction of a statistical model based on weighted multi-omics linear regression analysis for sepsis biomarker identification. These findings could help inform early patient stratification and treatment options, and facilitate further mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.
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•Integrated systems immunology approach reveals unique neutrophil subsets in sepsis•Multi-omics modeling reveals biomarkers including neutrophil CD10, PTX3, and lysoPC•These findings could enable future mechanistic studies and patient stratification
Immunity; Components of the immune system; Cell biology; Systems biology
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