Nevin Manimala

Front Immunol. 2023 Aug 14;14:1171176. doi: 10.3389/fimmu.2023.1171176. eCollection 2023.

ABSTRACT

Decades of research have probed the molecular and cellular mechanisms that control the immune response to malaria. Yet many studies offer conflicting results on the functional impact of innate immunity for controlling parasite replication early in infection. We conduct a meta-analysis to seek consensus on the effect of innate immunity on parasite replication, examining three different species of rodent malaria parasite. Screening published studies that span four decades of research we collate, curate, and statistically analyze infection dynamics in immune-deficient or -augmented mice to identify and quantify general trends and reveal sources of disagreement among studies. Additionally, we estimate whether host factors or experimental methodology shape the impact of immune perturbations on parasite burden. First, we detected meta-analytic mean effect sizes (absolute Cohen’s h) for the difference in parasite burden between treatment and control groups ranging from 0.1475 to 0.2321 across parasite species. This range is considered a small effect size and translates to a modest change in parasitaemia of roughly 7-12% on average at the peak of infection. Second, we reveal that variation across studies using P. chabaudi or P. yoelii is best explained by stochasticity (due to small sample sizes) rather than by host factors or experimental design. Third, we find that for P. berghei the impact of immune perturbation is increased when young or female mice are used and is greatest when effector molecules (as opposed to upstream signalling molecules) are disrupted (up to an 18% difference in peak parasitaemia). Finally, we find little evidence of publication bias suggesting that our results are robust. The small effect sizes we observe, across three parasite species, following experimental perturbations of the innate immune system may be explained by redundancy in a complex biological system or by incomplete (or inappropriate) data reporting for meta-analysis. Alternatively, our findings might indicate a need to re-evaluate the efficiency with which innate immunity controls parasite replication early in infection. Testing these hypotheses is necessary to translate understanding from model systems to human malaria.

PMID:37646037 | PMC:PMC10461630 | DOI:10.3389/fimmu.2023.1171176

Front Immunol. 2023 Aug 14;14:1211980. doi: 10.3389/fimmu.2023.1211980. eCollection 2023.

ABSTRACT

BACKGROUND: Clinically, some patients whose HBsAg becomes negative owing to antiviral therapy or spontaneously still show a low level of HBV DNA persistence in serum. T-lymphocyte subsets, cytokine levels and HBV S gene sequences were analyzed in this study.

METHODS: A total of 52 HBsAg-negative and HBV DNA-positive patients(HBsAg-/HBV DNA+ patients), 52 persistently HBsAg-positive patients(HBsAg+/HBV DNA+ patients) and 16 healthy people were evaluated. T-lymphocyte subsets of these patients were detected by flow cytometry, serum cytokines and chemokines were detected by the Luminex technique, and the HBV S region was evaluated by Sanger sequencing. T%, T-lymphocyte, CD8+ and CD4+T lymphocyte were lower in the HBsAg-negative group than in the HC group. Compared with the HBsAg-positive group, the HBsAg-negative group had lower levels in T lymphocyte %, CD8+T lymphocyte %, CD8+T lymphocyte and CD4/CD8. These difference were statistically significant (P<0.05). Serum IFN-γ, IFN-α and FLT-3L levels were significantly higher in the HBsAg-negative group than in the HBsAg-positive group (P<0.05). However, levels of many cytokines related to inflammation (i.e., IL-6, IL-8, IL10, IL-12, IL-17A) were lower in the HBsAg-negative group. Fifty-two HBsAg-negative samples were sequenced, revealing high-frequency amino acid substitution sites in the HBV S protein, including immune escape mutations (i.e., Y100C, S114T, C124Y, P127L, G130R, T131N, M133T, C137S, G145A) and TMD region substitutions (i.e., E2K/R/D, G7D/R, G10D, A17R, F20L/S, L21V, L22V).

CONCLUSIONS: According to the results of T-lymphocyte subsets and serum cytokines, it can be deduced that the cellular immune function of HBsAg-negative patients is superior to that of HBsAg-positive patients, with attenuation of liver inflammation. HBsAg-negative patients may show a variety of mutations and amino acid replacement sites at high frequency in the HBV S region, and these mutations may lead to undetectable HBsAg, HBsAg antigenic changes or secretion inhibition.

PMID:37646026 | PMC:PMC10461097 | DOI:10.3389/fimmu.2023.1211980

Front Immunol. 2023 Aug 14;14:1235914. doi: 10.3389/fimmu.2023.1235914. eCollection 2023.

ABSTRACT

INTRODUCTION: SARS-CoV-2 elicits a hyper-inflammatory response that contributes to increased morbidity and mortality in patients with COVID-19. In the case of HIV infection, despite effective anti-retroviral therapy, people living with HIV (PLWH) experience chronic systemic immune activation, which renders them particularly vulnerable to the life-threatening pulmonary, cardiovascular and other complications of SARS-CoV-2 co-infection. The focus of the study was a comparison of the concentrations of systemic indicators of innate immune dysfunction in SARS-CoV-2-PCR-positive patients (n=174) admitted with COVID-19, 37 of whom were co-infected with HIV.

METHODS: Participants were recruited from May 2020 to November 2021. Biomarkers included platelet-associated cytokines, chemokines, and growth factors (IL-1β, IL-6, IL-8, MIP-1α, RANTES, PDGF-BB, TGF-β1 and TNF-α) and endothelial associated markers (IL-1β, IL-1Ra, ICAM-1 and VEGF).

RESULTS: PLWH were significantly younger (p=0.002) and more likely to be female (p=0.001); median CD4+ T-cell count was 256 (IQR 115 -388) cells/μL and the median HIV viral load (VL) was 20 (IQR 20 -12,980) copies/mL. Fractional inspired oxygen (FiO2) was high in both groups, but higher in patients without HIV infection (p=0.0165), reflecting a greater need for oxygen supplementation. With the exception of PDGF-BB, the levels of all the biomarkers of innate immune activation were increased in SARS-CoV-2/HIV-co-infected and SARS-CoV-2/HIV-uninfected sub-groups relative to those of a control group of healthy participants. The magnitudes of the increases in the levels of these biomarkers were comparable between the SARS-CoV-2 -infected sub-groups, the one exception being RANTES, which was significantly higher in the sub-group without HIV. After adjusting for age, sex, and diabetes in the multivariable model, only the association between HIV status and VEGF was statistically significant (p=0.034). VEGF was significantly higher in PLWH with a CD4+ T-cell count >200 cells/μL (p=0.040) and those with a suppressed VL (p=0.0077).

DISCUSSION: These findings suggest that HIV co-infection is not associated with increased intensity of the systemic innate inflammatory response during SARS-CoV-2 co-infection, which may underpin the equivalent durations of hospital stay, outcome and mortality rates in the SARS-CoV-2/HIV-infected and -uninfected sub-groups investigated in the current study. The apparent association of increased levels of plasma VEGF with SARS-CoV-2/HIV co-infection does, however, merit further investigation.

PMID:37646024 | PMC:PMC10461055 | DOI:10.3389/fimmu.2023.1235914

HGG Adv. 2023 Aug 1;4(4):100228. doi: 10.1016/j.xhgg.2023.100228. eCollection 2023 Oct 12.

ABSTRACT

Clinician bias negatively impacts the healthcare received by marginalized communities. In this study, we explored factors that influence clinician and trainee bias against individuals with intellectual disabilities and its impact on clinical judgment in prenatal genetic testing settings. Specifically, we examined bias toward a fetus with a higher chance of developing a disability. We compared genetics specialists with their non-expert counterparts. This web-based study included clinical vignettes, implicit association tests (IATs), and an educational module. 595 participants were recruited via their institution or professional society. We conducted statistical analyses, including regression models controlling for key demographic characteristics, to analyze recommendation patterns and degree of change after the module. Genetics expertise strongly correlated with appropriate testing recommendation when the patient would not consider pregnancy termination (r = 1.784 pre-module, r = 1.502 post-module, p < 0.01). Factors that influenced pre-module recommendation to test include increased age (r = -0.029, p < 0.05), high religiosity (r = 0.525, p < 0.05), and participant personal preference against testing (r = 1.112, p < 0.01). Responses among participants without genetics expertise improved after the educational module (Z = -4.435, p < 0.01). 42% of non-experts who answered inappropriately changed their answer to match guidelines after the module. Individual bias, along with structural and institutional bias, permeates family planning encounters and significantly decreases quality of care. We demonstrate here that anti-bias training is effective, particularly for non-expert providers, and it can improve the care provided to individuals with intellectual disability. Evidence-based training such as this one can help providers make appropriate genetic counseling recommendations.

PMID:37646012 | PMC:PMC10461018 | DOI:10.1016/j.xhgg.2023.100228

bioRxiv. 2023 Aug 17:2023.05.03.539321. doi: 10.1101/2023.05.03.539321. Preprint.

ABSTRACT

Intuitively, combining multiple sources of evidence should lead to more accurate decisions than considering single sources of evidence individually. In practice, however, the proper computation may be difficult, or may require additional data that are inaccessible. Here, based on the concept of conditional independence, we consider expressions that can serve either as recipes for integrating evidence based on limited data, or as statistical benchmarks for characterizing evidence integration processes. Consider three events, A, B , and C . If A and B are conditionally independent with respect to C , then the probability that C occurs given that both A and B are known, P ( C | A, B ), can be easily calculated without the need to measure the full three-way dependency between A, B , and C . This simplified approach can be used in two general ways: to generate predictions by combining multiple (conditionally independent) sources of evidence, or to test whether separate sources of evidence are functionally independent of each other. These applications are demonstrated with four computer-simulated examples, which include detecting a disease based on repeated diagnostic testing, inferring biological age based on multiple biomarkers of aging, discriminating two spatial locations based on multiple cue stimuli (multisensory integration), and examining how behavioral performance in a visual search task depends on selection histories. Besides providing a sound prescription for estimating outcomes, this methodology may be useful for analyzing experimental data of many types.

PMID:37646001 | PMC:PMC10461915 | DOI:10.1101/2023.05.03.539321

bioRxiv. 2023 Aug 14:2023.08.14.553219. doi: 10.1101/2023.08.14.553219. Preprint.

ABSTRACT

Sequencing of viral infections has become increasingly common over the last decade. Deep sequencing data in particular have proven useful in characterizing the roles that genetic drift and natural selection play in shaping within-host viral populations. They have also been used to estimate transmission bottleneck sizes from identified donor-recipient pairs. These bottleneck sizes quantify the number of viral particles that establish genetic lineages in the recipient host and are important to estimate due to their impact on viral evolution. Current approaches for estimating bottleneck sizes exclusively consider the subset of viral sites that are observed as polymorphic in the donor individual. However, allele frequencies can change dramatically over the course of an individual’s infection, such that sites that are polymorphic in the donor at the time of transmission may not be polymorphic in the donor at the time of sampling and allele frequencies at donor-polymorphic sites may change dramatically over the course of a recipient’s infection. Because of this, transmission bottleneck sizes estimated using allele frequencies observed at a donor’s polymorphic sites may be considerable underestimates of true bottleneck sizes. Here, we present a new statistical approach for instead estimating bottleneck sizes using patterns of viral genetic variation that arose de novo within a recipient individual. Specifically, our approach makes use of the number of clonal viral variants observed in a transmission pair, defined as the number of viral sites that are monomorphic in both the donor and the recipient but carry different alleles. We first test our approach on a simulated dataset and then apply it to both influenza A virus sequence data and SARS-CoV-2 sequence data from identified transmission pairs. Our results confirm the existence of extremely tight transmission bottlenecks for these two respiratory viruses, using an approach that does not tend to underestimate transmission bottleneck sizes.

PMID:37645981 | PMC:PMC10462048 | DOI:10.1101/2023.08.14.553219

Res Sq. 2023 Aug 17:rs.3.rs-3242375. doi: 10.21203/rs.3.rs-3242375/v1. Preprint.

ABSTRACT

In this note, we present an innovative approach called “homologous hypothesis tests” that focuses on cross-sectional comparisons of average tumor volumes at different time-points. By leveraging the correlation structure between time-points, our method enables highly efficient per time-point comparisons, providing inferences that are highly efficient as compared to those obtained from a standard two-sample $t$-test. The key advantage of this approach lies in its user-friendliness and accessibility, as it can be easily employed by the broader scientific community through standard statistical software packages.

PMID:37645958 | PMC:PMC10462185 | DOI:10.21203/rs.3.rs-3242375/v1

bioRxiv. 2023 Aug 16:2023.03.20.532813. doi: 10.1101/2023.03.20.532813. Preprint.

ABSTRACT

The D. melanogaster protein coding gene bag of marbles ( bam ) plays a key role in early male and female reproduction by forming complexes with partner proteins to promote differentiation in gametogenesis. Like another germline gene, Sex lethal , bam genetically interacts with the endosymbiont Wolbachia , as Wolbachia rescues the reduced fertility of a bam hypomorphic mutant. Here, we explored the specificity of the bam-Wolbachia interaction by generating 22 new bam mutants, with ten mutants displaying fertility defects. Nine of these mutants trend towards rescue by the w Mel Wolbachia variant, with eight statistically significant at the fertility and/or cytological level. In some cases, fertility was increased a striking 20-fold. There is no specificity between the rescue and the known binding regions of bam , suggesting w Mel does not interact with one singular bam partner to rescue the reproductive phenotype. We further tested if w Mel interacts with bam in a non-specific way, by increasing bam transcript levels or acting upstream in germline stem cells. A fertility assessment of a bam RNAi knockdown mutant reveals that w Mel rescue is specific to functionally mutant bam alleles and we find no obvious evidence of w Mel interaction with germline stem cells in bam mutants.

AUTHOR SUMMARY: Reproduction in the Drosophila melanogaster fruit fly is dependent on the bag of marbles ( bam ) gene, which acts early in the process of generating eggs and sperm. Mutations to this gene negatively impact the fertility of the fly, causing it to be sterile or have fewer progeny. Interestingly, we find that the bacteria Wolbachia , which resides within reproductive cells across a wide range of insects, partially restores the fertility and ovary phenotype of several bam mutants of which the resultant Bam protein is altered from wildtype. The protein function of Bam is further suggested to be important by the lack of rescue for a fly that has a fertility defect due to low expression of a non-mutated bam gene. Previous work makes similar conclusions about Wolbachia with another reproductive gene, Sex lethal ( Sxl ), highlighting the potential for rescue of fertility mutants to occur in a similar way across different genes. An understanding of the ways in which Wolbachia can affect host reproduction provides us with context with which to frame Wolbachia ‘s impact on host genes, such as bam and Sxl, and consider the evolutionary implications of Wolbachia ‘s infection in D. melanogaster fruit flies.

PMID:37645949 | PMC:PMC10461928 | DOI:10.1101/2023.03.20.532813

bioRxiv. 2023 Aug 14:2023.08.11.551770. doi: 10.1101/2023.08.11.551770. Preprint.

ABSTRACT

The nervous system needs to balance the stability of neural representations with plasticity. It is unclear what is the representational stability of simple actions, particularly those that are well-rehearsed in humans, and how it changes in new contexts. Using an electrocorticography brain-computer interface (BCI), we found that the mesoscale manifold and relative representational distances for a repertoire of simple imagined movements were remarkably stable. Interestingly, however, the manifold’s absolute location demonstrated day-to-day drift. Strikingly, representational statistics, especially variance, could be flexibly regulated to increase discernability during BCI control without somatotopic changes. Discernability strengthened with practice and was specific to the BCI, demonstrating remarkable contextual specificity. Accounting for drift, and leveraging the flexibility of representations, allowed neuroprosthetic control of a robotic arm and hand for over 7 months without recalibration. Our study offers insight into how electrocorticography can both track representational statistics across long periods and allow long-term complex neuroprosthetic control.

PMID:37645922 | PMC:PMC10462094 | DOI:10.1101/2023.08.11.551770

bioRxiv. 2023 Aug 21:2023.06.21.545365. doi: 10.1101/2023.06.21.545365. Preprint.

ABSTRACT

Cancerous tumors may contain billions of cells including distinct malignant clones and nonmalignant cell types. Clarifying the evolutionary histories, prevalence, and defining molecular features of these cells is essential for improving clinical outcomes, since intratumoral heterogeneity provides fuel for acquired resistance to targeted therapies. Here we present a statistically motivated strategy for deconstructing intratumoral heterogeneity through multiomic and multiscale analysis of serial tumor sections. By combining deep sampling of IDH-mutant astrocytomas with integrative analysis of single-nucleotide variants, copy-number variants, and gene expression, we reconstruct and validate the phylogenies, spatial distributions, and transcriptional profiles of distinct malignant clones, which are not observed in normal human brain samples. Importantly, by genotyping nuclei analyzed by single-nucleus RNA-seq for truncal mutations identified from bulk tumor sections, we show that existing strategies for inferring malignancy from single-cell transcriptomes may be inaccurate. Furthermore, we identify a core set of genes that is consistently expressed by the truncal clone, including AKR1C3 , whose expression is associated with poor outcomes in several types of cancer. This work establishes a robust and flexible strategy for precisely deconstructing intratumoral heterogeneity in clinical specimens and clarifying the molecular profiles of distinct cellular populations in any kind of solid tumor.

PMID:37645893 | PMC:PMC10461981 | DOI:10.1101/2023.06.21.545365