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Multiple Sclerosis (MS) is a complex multifactorial autoimmune disease, whose sex- and age-adjusted prevalence in Sardinia (Italy) is among the highest worldwide. To date, 233 loci were associated with MS and almost 20% of risk heritability is attributable to common genetic variants, but many low-frequency and rare variants remain to be discovered. Here, we aimed to contribute to the understanding of the genetic basis of MS by investigating potentially functional rare variants. To this end, we analyzed thirteen multiplex Sardinian families with Immunochip genotyping data. For five families, Whole Exome Sequencing (WES) data were also available. Firstly, we performed a non-parametric Homozygosity Haplotype analysis for identifying the Region from Common Ancestor (RCA). Then, on these potential disease-linked RCA, we searched for the presence of rare variants shared by the affected individuals by analyzing WES data. We found: (i) a variant (43181034 T > G) in the splicing region on exon 27 of CUL9; (ii) a variant (50245517 A > C) in the splicing region on exon 16 of ATP9A; (iii) a non-synonymous variant (43223539 A > C), on exon 9 of TTBK1; (iv) a non-synonymous variant (42976917 A > C) on exon 9 of PPP2R5D; and v) a variant (109859349-109859354) in 3′UTR of MYO16.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.

Background: A wealth of single-nucleotide polymorphisms (SNPs) responsible for multiple sclerosis (MS) susceptibility have been identified; however, they explain only a fraction of MS heritability. Objectives: We contributed to discovery of new MS susceptibility SNPs by studying a founder population with high MS prevalence. Methods: We analyzed ImmunoChip data from 15 multiplex families and 94 unrelated controls from the Nuoro Province, Sardinia, Italy. We tested each SNP for both association and linkage with MS, the linkage being explored in terms of identity-by-descent (IBD) sharing excess and using gene dropping to compute a corresponding empirical p-value. By targeting regions that are both associated and in linkage with MS, we increase chances of identifying interesting genomic regions. Results: We identified 486 MS-associated (p < 1 × 10–4) and 18,426 MS-linked (p < 0.05) SNPs. A total of 111 loci were both linked and associated with MS, 18 of them pointing to 14 non-major histocompatibility complex (MHC) genes, and 93 of them located in the MHC region. Conclusion: We discovered new suggestive signals and confirmed some previously identified ones. We believe this to represent a significant step toward an understanding of the genetic basis of MS. [ABSTRACT FROM AUTHOR]

Objective: The clinical characteristics of multiple sclerosis (MS) are not well defined in Hispanic populations. We hypothesized that disease presentation in Hispanic white (HW) patients will be different from non-Hispanic white (NHW) patients given their ancestral background and reported lower disease prevalence. This study was undertaken to compare HW of primarily Caribbean ancestry to NHW on clinical characteristics of MS. Methods: We assessed 312 HW and 312 NHW patients with definite MS for clinical disease characteristics obtained through consented review of medical records. In order to assess the relationship between age-related phenotypes and ethnicity, linear regression was used. Logistic regression was used to assess the relationship between ethnicity and descriptors of disease presentation and severity as well as presence of neurological symptoms. Results: We observed a significantly younger age at diagnosis (p = 1.38E-02) and age at exam (p = 2.36E-05) in HW. However, age at first symptom did not differ significantly between the two groups. Furthermore, within HW, the mean age at first symptom and age at diagnosis was significantly younger in those born in the United States (p < 1.00E-03 for both). Interestingly, we noted an increase in ambulatory disability in HW patients, primarily among those with relapsing disease (p = 4.18E-03). Conclusions: We found several differences in age-related phenotypes and disease severity between HW of primarily Caribbean origin and NHW patients. To our knowledge, this is the largest study to date that examined the clinical characteristics of MS in Hispanic patients of largely Caribbean origin. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The list of genomic loci associated with multiple sclerosis (MS) susceptibility outside the major histocompatibility complex (MHC) in patients of Northern European (NE) ancestry has increased to 103. Despite the extraordinarily high MS prevalence in the isolated Sardinian population, the contribution of genetic risk factors to MS in Sardinia is largely not understood. Objective: The objective of this paper is to examine the relevance of non-MHC MS susceptibility variants in Sardinia. Methods: We examined a log-additive MS-specific genetic burden score (MSGB) using 110 NE-derived risk alleles in a dataset of 75 Sardinian cases, 346 Sardinian controls and 177 cases and 1967 controls from the United States (US). Results: Sardinian cases demonstrate a heavier non-MHC MSGB load than Sardinian controls and US cases (p = 2E-06, p = 1E-06, respectively). Furthermore, Sardinian controls carry a heavier burden than US controls (p = 2E-14). Our results confirm the limited ability of the 110-SNP MSGB to predict disease status in Sardinia (AUROC = 0.629). Conclusions: Risk alleles discovered in samples of NE ancestry are relevant to MS in Sardinia. Our results suggest a general enrichment of MS susceptibility alleles in Sardinians, encouraging the pursuit of further studies of MS in this population. [ABSTRACT FROM AUTHOR]

Search and harvesting use cases on harmonised metadata play an important role in several activities on National Research Data Infrastructures (NFDI). The working group Search and Harvesting of the NFDI section (meta)data, terminologies and provenance works on a common understanding of user needs (for search) and service requirements (for harvesting), analysis of the data sources landscape, and recommendations concerning common and specific needs, e.g., for spatial or sensitive data. Here, we present search and harvesting gaps and challenges across NFDI consortia and beyond, which were identified and structured in the Search and Harvesting Working Group, and the recommendations for the NFDI we derive from them. Our goal is to foster a common vision for search and harvesting in the NFDI. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis is a leading cause of non-traumatic neurological disability among young adults worldwide. Prior studies have identified modifiable risk factors for multiple sclerosis in cohorts of White ethnicity, such as infectious mononucleosis, smoking, and obesity during adolescence/early adulthood. It is unknown whether modifiable exposures for multiple sclerosis have a consistent impact on risk across ethnic groups. Aim: To determine whether modifiable risk factors for multiple sclerosis have similar effects across diverse ethnic backgrounds. Methods: We conducted a nested case–control study using data from the UK Clinical Practice Research Datalink. Multiple sclerosis cases diagnosed from 2001 until 2022 were identified from electronic healthcare records and matched to unaffected controls based on year of birth. We used stratified logistic regression models and formal statistical interaction tests to determine whether the effect of modifiable risk factors for multiple sclerosis differed by ethnicity. Results: We included 9662 multiple sclerosis cases and 118,914 age-matched controls. The cohort was ethnically diverse (MS: 277 South Asian [2.9%], 251 Black [2.6%]; Controls: 5043 South Asian [5.7%], 4019 Black [4.5%]). The age at MS diagnosis was earlier in the Black (40.5 [SD 10.9]) and Asian (37.2 [SD 10.0]) groups compared with White cohort (46.1 [SD 12.2]). There was a female predominance in all ethnic groups; however, the relative proportion of males was higher in the South Asian population (proportion of women 60.3% vs 71% [White] and 75.7% [Black]). Established modifiable risk factors for multiple sclerosis—smoking, obesity, infectious mononucleosis, low vitamin D, and head injury—were consistently associated with multiple sclerosis in the Black and South Asian cohorts. The magnitude and direction of these effects were broadly similar across all ethnic groups examined. There was no evidence of statistical interaction between ethnicity and any tested exposure, and no evidence to suggest that differences in area-level deprivation modifies these risk factor-disease associations. These findings were robust to a range of sensitivity analyses. Conclusions and relevance: Established modifiable risk factors for multiple sclerosis are applicable across diverse ethnic backgrounds. Efforts to reduce the population incidence of multiple sclerosis by tackling these risk factors need to be inclusive of people from diverse ethnicities. [ABSTRACT FROM AUTHOR]

This research addresses the growing social importance of data from an educational perspective through data literacy (DL), seeking to integrate it into the broader information literacy (Infolit) movement. For this purpose, a systematic review was carried out of the papers in the main collection of the Web of Science that contain both concepts (DL and Infolit) and that were indexed up until March 2023. External aspects, such as the growth of the research and the identity, nationality, professional scope, and productivity of the authors, were taken into account. In addition, internal aspects, such as context (theory, frameworks, definitions, models, and related disciplines), objectives, methodology, results, conclusions, and recommendations, were analyzed to obtain a detailed perspective of the scientific research process adopted. A synchronic and diachronic analysis of the corpus of selected articles is offered, focusing on the aforementioned aspects. The researchers' consensus on the urgency of addressing data training both generally and specifically in the different disciplines, languages, environments, and levels is evident. The emergent, multisectoral, and interdisciplinary nature of data literacy as part of Infolit, which is being applied in the education of students at different levels, viz. professionals and citizens, is noted, although the training limitations of students and many professionals are evident. Consequently, it is imperative to include DL in curricula and training programs to contribute to the acquisition and development of these competencies in different areas. To this end, the joint work of teachers, librarians, researchers, and other professionals is imperative. There is a need to deepen the theoretical, practical, and applied fields, as well as to reach a common definition, form a basic model of DL competencies within Infolit, and create submodels that take into consideration the idiosyncrasies of each area of application. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) clinical trials have included low numbers of patients from racial and ethnic minority populations; therefore, it is uncertain whether differences exist in response to disease-modifying therapies. We evaluated the real-world safety and effectiveness of dimethyl fumarate (DMF) treatment over 5 years in four patient cohorts: Black, non-Black, Hispanic, and non-Hispanic people with relapsing–remitting MS. Methods: ESTEEM is an ongoing, 5-year, multinational, prospective study evaluating the long-term safety and effectiveness of DMF in people with MS. The analysis included patients newly prescribed DMF in routine practice at 393 sites globally. Results: Overall, 5251 patients were analyzed (220 Black, 5031 non-Black; 105 Hispanic, 5146 non-Hispanic). Median (min−max) months of follow-up was 32 (0–72) for Black, 29 (1–77) for Hispanic, and 41 (0–85) for both the non-Black and non-Hispanic populations. In total, 39 (18%) Black and 29 (28%) Hispanic patients reported adverse events leading to treatment discontinuation versus 1126 (22%) non-Black and 1136 (22%) non-Hispanic patients; gastrointestinal disorders were the most common in all subgroups. Median lymphocyte counts decreased by 37% in Black, 40% in non-Black, 10% in Hispanic, and 39% in non-Hispanic patients in the first year, then remained stable and above the lower limit of normal in most patients. Annualized relapse rates (ARRs) (95% confidence intervals) up to 5 years were 0.054 (0.038–0.078) for Black, 0.077 (0.072–0.081) for non-Black, 0.069 (0.043–0.112) for Hispanic, and 0.076 (0.072–0.081) for non-Hispanic populations, representing reductions of 91–92% compared with ARR 12 months before study entry (all p < 0.0001). Conclusion: The safety profile of DMF in these subgroups was consistent with the overall ESTEEM population. Relapse rates remained low in Black and Hispanic patients, and consistent with non-Black and non-Hispanic patients. These data demonstrate a comparable real-world treatment benefit of DMF in Black and Hispanic patients. Trial Registration: ClinicalTrials.gov identifier NCT02047097. [ABSTRACT FROM AUTHOR]

Background: Black and Hispanic patients with multiple sclerosis (MS) have been shown to accumulate greater multiple sclerosis–associated disability (MSAD) than White patients. Disparities in social determinants of health (SDOH) among these groups have also been reported. Objective: To determine the extent to which associations of race and ethnicity with MSAD may be attributable to differences in SDOH. Methods: Retrospective chart analysis of patients at an academic MS center grouped by self-identified Black (n = 95), Hispanic (n = 93), and White (n = 98) race/ethnicity. Individual patient addresses were geocoded and matched with neighborhood-level area deprivation index (ADI) and social vulnerability index (SVI). Results: Average Expanded Disability Status Scale (EDSS) scores at last-recorded evaluations of White patients (1.7 ± 2.0) were significantly lower than Black (2.8 ± 2.4, p = 0.001) and Hispanic (2.6 ± 2.6, p = 0.020) patients. Neither Black race nor Hispanic ethnicity was significantly associated with EDSS in multivariable linear regression models that included individual-level SDOH indicators and either ADI or SVI. Conclusion: Black race and Hispanic ethnicity are not significantly associated with EDSS in models that include individual and neighborhood-level SDOH indicators. Further research should elucidate mechanisms by which structural inequities affect MS disease course. [ABSTRACT FROM AUTHOR]

The authors reflect on the multiple sclerosis genetic burden (MSGB) and its epidemiology. They discuss two papers within the issue of "Multiple Sclerosis Journal," one by Hadjixenofontos and colleagues and another by Barizzone and colleagues, which explore the role of known MS genetic risk factors in the population in Sardinia, Italy. They suggest that the components of the genetic burden contribute to the risk and phenotype of the disease, particularly the human leukocyte antigen (HLA) burden.

Mendelian randomization (MR) is a powerful approach for assessing the causal effect of putative risk factors on an outcome, using genetic variants as instrumental variables. The methodology and application developed in the framework of MR have been dramatically improved, taking advantage of the many public genome‐wide association study (GWAS) data. The availability of summary‐level data allowed to perform numerous MR studies especially for complex diseases, pinpointing modifiable exposures causally related to increased or decreased disease risk. Multiple sclerosis (MS) is a complex multifactorial disease whose aetiology involves both genetic and non‐genetic risk factors and their interplay. Previous observational studies have revealed associations between candidate modifiable exposures and MS risk; although being prone to confounding, and reverse causation, these studies were unable to draw causal conclusions. MR analysis addresses the limitations of observational studies and allows to establish reliable and accurate causal conclusions. Here, we systematically reviewed the studies evaluating the causal effect, through MR, of genetic and non‐genetic exposures on MS risk. Among 107 papers found, only 42 were eligible for final evaluation and qualitative synthesis. We found that, above all, low vitamin D levels and high adult body mass index (BMI) appear to be uncontested risk factors for increased MS risk. [ABSTRACT FROM AUTHOR]

Heritability studies represent an important tool to investigate the main sources of variability for complex diseases, whose etiology involves both genetics and environmental factors. In this paper, we aimed to estimate multiple sclerosis (MS) narrow-sense heritability (h2), on a liability scale, using extended families ascertained from affected probands sampled in the Sardinian province of Nuoro, Italy. We also investigated the sources of MS liability variability among shared environment effects, sex, and categorized year of birth (<1946, ≥1946). The latter can be considered a proxy for different early environmental exposures. To this aim, we implemented a Bayesian liability threshold model to obtain posterior distributions for the parameters of interest adjusting for ascertainment bias. Our analysis highlighted categorized year of birth as the main explanatory factor, explaining ~70% of MS liability variability (median value = 0.69, 95% CI: 0.64, 0.73), while h2 resulted near to 0% (median value = 0.03, 95% CI: 0.00, 0.09). By performing a year of birth-stratified analysis, we found a high h2 only in individuals born on/after 1946 (median value = 0.82, 95% CI: 0.68, 0.93), meaning that the genetic variability acquired a high explanatory role only when focusing on this subpopulation. Overall, the results obtained highlighted early environmental exposures, in the Sardinian population, as a meaningful factor involved in MS to be further investigated. [ABSTRACT FROM AUTHOR]

With increasing life expectancy, a growing number of individuals are being affected by Parkinson's Disease (PD), a Neurodegenerative Disease (ND). Approximately, 5–10% of PD is explained by genetic causes linked to known PD genes. With improvements in genetic testing and high-throughput technologies, more PD-associated susceptibility genes have been reported in recent years. However, a comprehensive review of the pathogenic mechanisms and physiological roles of these genes is still lacking. This article reviews novel genes with putative or confirmed pathogenic mutations in PD reported since 2019, summarizes the physiological functions and potential associations with PD. Newly reported PD-related genes include ANK2, DNAH1, STAB1, NOTCH2NLC, UQCRC1, ATP10B, TFG, CHMP1A, GIPC1, KIF21B, KIF24, SLC25A39, SPTBN1 and TOMM22. However, the evidence for pathogenic effects of many of these genes is inconclusive. A variety of novel PD-associated genes have been identified through clinical cases of PD patients and analysis of Genome-Wide Association Studies (GWAS). However, more evidence is needed in confirm the strong association of novel genes with disease. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an acquired demyelinating disease of the central nervous system (CNS). Historically, research on MS has focused on White persons with MS. This preponderance of representation has important possible implications for minority populations with MS, from developing effective therapeutic agents to understanding the role of unique constellations of social determinants of health. A growing body of literature involving persons of historically underrepresented races and ethnicities in the field of multiple sclerosis is assembling. Our purpose in this narrative review is to highlight two populations in the United States: Black and Hispanic persons with multiple sclerosis. We will review the current understanding about the patterns of disease presentation, genetic considerations, response to treatment, roles of social determinants of health, and healthcare utilization. In addition, we explore future directions of inquiry as well as practical methods of meeting these challenges. [ABSTRACT FROM AUTHOR]

The study of diseases of the central nervous system (CNS) at the molecular level is challenging because of the complexity of neural circuits and the huge number of specialized cell types. Moreover, genomic association studies have revealed the complex genetic architecture of schizophrenia and other genetically determined mental disorders. Investigating such complex genetic architecture to decipher the molecular basis of CNS pathologies requires the use of high-throughput models such as cells and their derivatives. The time is coming for high-throughput genetic technologies based on CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)/Cas systems to manipulate multiple genomic targets. CRISPR/Cas systems provide the desired complexity, versatility, and flexibility to create novel genetic tools capable of both altering the DNA sequence and affecting its function at higher levels of genetic information flow. CRISPR/Cas tools make it possible to find and investigate the intricate relationship between the genotype and phenotype of neuronal cells. The purpose of this review is to discuss innovative CRISPR-based approaches for studying the molecular mechanisms of CNS pathologies using cellular models. [ABSTRACT FROM AUTHOR]

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic disease that lacks known pathogenesis, distinctive diagnostic criteria, and effective treatment options. Understanding the genetic (and other) risk factors associated with the disease would begin to help to alleviate some of these issues for patients. Methods: We applied both GWAS and the PrecisionLife combinatorial analytics platform to analyze ME/CFS cohorts from UK Biobank, including the Pain Questionnaire cohort, in a case–control design with 1000 cycles of fully random permutation. Results from this study were supported by a series of replication and cohort comparison experiments, including use of disjoint Verbal Interview CFS, post-viral fatigue syndrome and fibromyalgia cohorts also derived from UK Biobank, and compared results for overlap and reproducibility. Results: Combinatorial analysis revealed 199 SNPs mapping to 14 genes that were significantly associated with 91% of the cases in the ME/CFS population. These SNPs were found to stratify by shared cases into 15 clusters (communities) made up of 84 high-order combinations of between 3 and 5 SNPs. p-values for these communities range from 2.3 × 10–10 to 1.6 × 10–72. Many of the genes identified are linked to the key cellular mechanisms hypothesized to underpin ME/CFS, including vulnerabilities to stress and/or infection, mitochondrial dysfunction, sleep disturbance and autoimmune development. We identified 3 of the critical SNPs replicated in the post-viral fatigue syndrome cohort and 2 SNPs replicated in the fibromyalgia cohort. We also noted similarities with genes associated with multiple sclerosis and long COVID, which share some symptoms and potentially a viral infection trigger with ME/CFS. Conclusions: This study provides the first detailed genetic insights into the pathophysiological mechanisms underpinning ME/CFS and offers new approaches for better diagnosis and treatment of patients. [ABSTRACT FROM AUTHOR]

While the role of common genetic variants in multiple sclerosis (MS) has been elucidated in large genome-wide association studies, the contribution of rare variants to the disease remains unclear. Herein, a whole-genome sequencing study in four affected and four healthy relatives of a consanguineous Italian family identified a novel missense c.1801T > C (p.S601P) variant in the GRAMD1B gene that is shared within MS cases and resides under a linkage peak (LOD: 2.194). Sequencing GRAMD1B in 91 familial MS cases revealed two additional rare missense and two splice-site variants, two of which (rs755488531 and rs769527838) were not found in 1000 Italian healthy controls. Functional studies demonstrated that GRAMD1B, a gene with unknown function in the central nervous system (CNS), is expressed by several cell types, including astrocytes, microglia and neurons as well as by peripheral monocytes and macrophages. Notably, GRAMD1B was downregulated in vessel-associated astrocytes of active MS lesions in autopsied brains and by inflammatory stimuli in peripheral monocytes, suggesting a possible role in the modulation of inflammatory response and disease pathophysiology. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is a clinically heterogeneous class of neurodevelopmental conditions with a strong, albeit complex, genetic basis. The genetic architecture of ASD includes different genetic models, from monogenic transmission at one end, to polygenic risk given by thousands of common variants with small effects at the other end. The mitochondrial DNA (mtDNA) was also proposed as a genetic modifier for ASD, mostly focusing on maternal mtDNA, since the paternal mitogenome is not transmitted to offspring. We extensively studied the potential contribution of mtDNA in ASD pathogenesis and risk through deep next generation sequencing and quantitative PCR in a cohort of 98 families. While the maternally-inherited mtDNA did not seem to predispose to ASD, neither for haplogroups nor for the presence of pathogenic mutations, an unexpected influence of paternal mtDNA, apparently centered on haplogroup U, came from the Italian families extrapolated from the test cohort (n = 74) when compared to the control population. However, this result was not replicated in an independent Italian cohort of 127 families and it is likely due to the elevated paternal age at time of conception. In addition, ASD probands showed a reduced mtDNA content when compared to their unaffected siblings. Multivariable regression analyses indicated that variants with 15%-5% heteroplasmy in probands are associated to a greater severity of ASD based on ADOS-2 criteria, whereas paternal super-haplogroups H and JT were associated with milder phenotypes. In conclusion, our results suggest that the mtDNA impacts on ASD, significantly modifying the phenotypic expression in the Italian population. The unexpected finding of protection induced by paternal mitogenome in term of severity may derive from a role of mtDNA in influencing the accumulation of nuclear de novo mutations or epigenetic alterations in fathers' germinal cells, affecting the neurodevelopment in the offspring. This result remains preliminary and needs further confirmation in independent cohorts of larger size. If confirmed, it potentially opens a different perspective on how paternal noninherited mtDNA may predispose or modulate other complex diseases. [ABSTRACT FROM AUTHOR]

RNA binding proteins are important regulators of T cell activation, proliferation, and cytokine production. The zinc finger protein 36 (ZFP36) family genes (Zfp36, Zfp36l1, and Zfp36l2) encode RNA binding proteins that promote the degradation of transcripts containing AU-rich elements. Numerous studies have demonstrated both individual and shared functions of the ZFP36 family in immune cells, but their collective function in T cells remains unclear. Here, we found a redundant and critical role for the ZFP36 proteins in regulating T cell quiescence. T cell–specific deletion of all three ZFP36 family members in mice resulted in early lethality, immune cell activation, and multiorgan pathology characterized by inflammation of the eyes, central nervous system, kidneys, and liver. Mice with T cell–specific deletion of any two Zfp36 genes were protected from this spontaneous syndrome. Triply deficient T cells overproduced proinflammatory cytokines, including IFN-γ, TNF, and GM-CSF, due to increased mRNA stability of these transcripts. Unexpectedly, T cell–specific deletion of both Zfp36l1 and Zfp36l2 rendered mice resistant to experimental autoimmune encephalomyelitits due to failed priming of antigen-specific CD4+ T cells. ZFP36L1 and ZFP36L2 double-deficient CD4+ T cells had poor proliferation during in vitro T helper cell polarization. Thus, the ZFP36 family redundantly regulates T cell quiescence at homeostasis, but ZFP36L1 and ZFP36L2 are specifically required for antigen-specific T cell clonal expansion. ZFP36 proteins: The same, but different RNA binding proteins are an essential component of the regulatory machinery that prevents excessive lymphocyte activation by limiting target transcript translation or promoting mRNA decay. Using a series of conditional knockout mice, Cook et al. systematically investigated the role of the zinc finger protein 36 (ZFP36) family of RNA binding proteins in T cell homeostasis and autoimmunity. T cell–specific deletion of all three Zfp36 genes resulted in lethal, multiorgan inflammation accompanied by excessive production of IFN-γ and TNF, whereas mice deficient in any two family members were protected. Although ZFP36 proteins were redundant in controlling T cells during homeostasis, mice with T cells lacking Zfp36l1 and Zfp36l2 were resistant to development of experimental autoimmune encephalomyelitits, demonstrating that ZFP36 family members can also perform context-specific functions during autoimmunity. [ABSTRACT FROM AUTHOR]

There is increasing evidence that diseases caused by dysfunctional mitochondria (MD) are associated with autism spectrum disorder (ASD). A comprehensive meta-analysis showed that developmental regression was reported in half of the children with ASD and mitochondrial dysfunction which is much higher than in the general population of ASD. The aim of the present exploratory study was to determine lactate concentrations in urine of children with ASD, as a non-invasive large-scale screening method for metabolic abnormalities including mitochondrial dysfunction and its possible association with regression. First, clinical characteristics of MD were examined in 99 children (3–11 years) with ASD. Second, clinical characteristics of MD, severity of ASD and reported regression were compared between children with the 20% lowest lactate concentrations and those with the 20% highest lactate concentrations in urine. Third, clinical characteristics of MD and lactate concentration in urine were compared in children with (n = 37) and without (n = 62) reported regression. An association of urine lactate concentrations with mitochondrial dysfunction and regression could not be demonstrated in our large ASD cohort. However, since ASD children were reported by their parents to show a broad range of phenotypic characteristics of MD (e.g., gastro-intestinal and respiratory impairments), and lactate concentrations in urine are not always increased in individuals with MD, the presence of milder mitochondrial dysfunction cannot be excluded. Development of alternative biomarkers and their implementation in prospective studies following developmental trajectories of infants at elevated likelihood for ASD will be needed in the future to further unravel the association of ASD with mitochondrial dysfunction and eventually improve early detection. [ABSTRACT FROM AUTHOR]

This work aimed at estimating narrow-sense heritability, defined as the proportion of the phenotypic variance explained by the sum of additive genetic effects, via Haseman–Elston regression for a subset of 56 plasma protein levels related to Multiple Sclerosis (MS). These were measured in 212 related individuals (with 69 MS cases and 143 healthy controls) obtained from 20 Sardinian families with MS history. Using pedigree information, we found seven statistically significant heritable plasma protein levels (after multiple testing correction), i.e., Gc ( h 2 = 0.77; 95%CI: 0.36, 1.00), Plat ( h 2 = 0.70; 95%CI: 0.27, 0.95), Anxa1 ( h 2 = 0.68; 95%CI: 0.27, 1.00), Sod1 ( h 2 = 0.58; 95%CI: 0.18, 0.96), Irf8 ( h 2 = 0.56; 95%CI: 0.19, 0.99), Ptger4 ( h 2 = 0.45; 95%CI: 0.10, 0.96), and Fadd ( h 2 = 0.41; 95%CI: 0.06, 0.84). A subsequent analysis was performed on these statistically significant heritable plasma protein levels employing Immunochip genotyping data obtained in 155 healthy controls (92 related and 63 unrelated); we found a meaningful proportion of heritable plasma protein levels' variability explained by a small set of SNPs. Overall, the results obtained, for these seven MS-related proteins, emphasized a high additive genetic variance component explaining plasma levels' variability. [ABSTRACT FROM AUTHOR]

The DNA damage repair (DDR) genes are increasingly gaining attention as potential therapeutic targets in cancers. In this study, we identified the DDR genes associated with the tumor mutation burden (TMB) and prognosis of cervical squamous cell carcinoma (CESC) based on The Cancer Genome Atlas (TCGA) database. Through LASSO Cox regression, the prognostic signature involving five DDR genes (ACTR2, TEX12, UBE2V1, HSF1, and FBXO6) was established, and the risk score was identified as an independent risk factor for CESC. The nomogram consisting of the five genes accurately predicted the overall survival (OS) and the immunotherapeutic response of CESC patients. Finally, the loss of the copies of the transcription factor (TF) SP140 in CESC patients may decrease the expression of FBXO6, improve DNA repair function, and reduce the diversity of neoantigens, thereby lowering the response to immunotherapies. Therefore, the DDR gene signature is a novel prognostic model and a biomarker for immunotherapies in CESC patients. [ABSTRACT FROM AUTHOR]