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Immune response genes are highly polymorphic in humans and mice, with heterogeneity amongst loci driving strain-specific host defence responses. The inadvertent retention of polymorphic loci can introduce confounding phenotypes, leading to erroneous conclusions, and impeding scientific advancement. In this study, we employ a combination of RNAseq and variant calling analyses to identify a substantial region of 129S genome, including the highly polymorphic Nlrp1 locus, proximal to Nlrp3, in one of the most commonly used mouse models of NLRP3 deficiency (Nlrp3 tm1Flv ). We show that the presence of the Nlrp1 129S locus leads to an increase in NLRP1B protein expression, and a sensitising of Nlrp3 tm1Flv macrophages to NLRP1 inflammasome activation, independent of NLRP3 deficiency. Retention of 129S genome further leads to protein sequence differences and altered gene regulation across multiple cell types, including of the key tissue-resident macrophage marker, TIM4. Using alternative models of NLRP3 deficiency, including a previously undescribed conditional Nlrp3 allele enabling precise temporal and cell-type specific control over Nlrp3 deletion, we further show that NLRP3 contributes to Talabostat-driven IL-1β release. Our study also establishes a generic framework to identify functionally relevant SNPs and assess genomic contamination in transgenic mice using RNAseq data. This allows for unambiguous attribution of phenotypes to the target gene and advances the precision and reliability of research in the field of host defence responses., (© 2024. The Author(s).)

The coronavirus disease 2019 (COVID-19) has been a global pandemic for more than 2 years and it still impacts our daily lifestyle and quality in unprecedented ways. A better understanding of immunity and its regulation in response to SARS-CoV-2 infection is urgently needed. Based on the current literature, we review here the various virus mutations and the evolving disease manifestations along with the alterations of immune responses with specific focuses on the innate immune response, neutrophil extracellular traps, humoral immunity, and cellular immunity. Different types of vaccines were compared and analyzed based on their unique properties to elicit specific immunity. Various therapeutic strategies such as antibody, anti-viral medications and inflammation control were discussed. We predict that with the available and continuously emerging new technologies, more powerful vaccines and administration schedules, more effective medications and better public health measures, the COVID-19 pandemic will be under control in the near future., (© 2022. The Author(s).)

Cohesin and CTCF are major drivers of 3D genome organization, but their role in neurons is still emerging. Here, we show a prominent role for cohesin in the expression of genes that facilitate neuronal maturation and homeostasis. Unexpectedly, we observed two major classes of activity-regulated genes with distinct reliance on cohesin in mouse primary cortical neurons. Immediate early genes (IEGs) remained fully inducible by KCl and BDNF, and short-range enhancer-promoter contacts at the IEGs Fos formed robustly in the absence of cohesin. In contrast, cohesin was required for full expression of a subset of secondary response genes characterized by long-range chromatin contacts. Cohesin-dependence of constitutive neuronal genes with key functions in synaptic transmission and neurotransmitter signaling also scaled with chromatin loop length. Our data demonstrate that key genes required for the maturation and activation of primary cortical neurons depend on cohesin for their full expression, and that the degree to which these genes rely on cohesin scales with the genomic distance traversed by their chromatin contacts., Competing Interests: LC, FW, JB, MO, RG, YW, TC, GD, WG, KT, Vd, CW, MU, AF, JP, MM No competing interests declared, (© 2022, Calderon et al.)

Cornelia de Lange Syndrome (CdLS) is a human developmental disorder caused by mutations that compromise the function of cohesin, a major regulator of 3D genome organization. Cognitive impairment is a universal and as yet unexplained feature of CdLS. We characterize the transcriptional profile of cortical neurons from CdLS patients and find deregulation of hundreds of genes enriched for neuronal functions related to synaptic transmission, signalling processes, learning and behaviour. Inducible proteolytic cleavage of cohesin disrupts 3D genome organization and transcriptional control in post-mitotic cortical mouse neurons, demonstrating that cohesin is continuously required for neuronal gene expression. The genes affected by acute depletion of cohesin belong to similar gene ontology classes and show significant numerical overlap with genes deregulated in CdLS. Interestingly, reconstitution of cohesin function largely rescues altered gene expression, including the expression of genes deregulated in CdLS.

Adult-onset hearing loss is very common, but we know little about the underlying molecular pathogenesis impeding the development of therapies. We took a genetic approach to identify new molecules involved in hearing loss by screening a large cohort of newly generated mouse mutants using a sensitive electrophysiological test, the auditory brainstem response (ABR). We review here the findings from this screen. Thirty-eight unexpected genes associated with raised thresholds were detected from our unbiased sample of 1,211 genes tested, suggesting extreme genetic heterogeneity. A wide range of auditory pathophysiologies was found, and some mutant lines showed normal development followed by deterioration of responses, revealing new molecular pathways involved in progressive hearing loss. Several of the genes were associated with the range of hearing thresholds in the human population and one, SPNS2, was involved in childhood deafness. The new pathways required for maintenance of hearing discovered by this screen present new therapeutic opportunities., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: ZP is employed by Ambry Genetics, and exome sequencing is among the commercially available tests. The other authors have declared that no competing interests exist.

Introduction: Persistent medically unexplained symptoms (MUS) are a major burden for health care. Cognitive behaviour therapy (CBT) is efficacious for patients with MUS, with small to medium effects. The current study investigates whether therapy outcomes of a CBT for MUS patients can be improved by complementing it with emotion regulation training., Methods: In a multicentre trial 255 patients with at least three persisting MUS were randomised to 20 sessions of either conventional CBT (n = 128) or CBT complemented with emotion regulation training (ENCERT; n = 127). Somatic symptom severity and secondary outcomes were assessed at pre-treatment, therapy session 8, end of therapy, and 6-month follow-up., Results: Linear mixed-effect models revealed medium to large effects in both study arms for almost all outcomes at the end of therapy and 6-month follow-up. ENCERT and CBT did not differ in their effect on the primary outcome (d = 0.20, 95% CI: -0.04 to 0.44). Significant time × group cross-level interactions suggested ENCERT to be of more benefit than conventional CBT for a few secondary outcomes. Moderator analyses revealed higher effects of ENCERT in patients with co-morbid mental disorders., Discussion/conclusions: Current findings are based on a representative sample. Results demonstrate that both CBT and ENCERT can achieve strong effects on primary and secondary outcomes in MUS patients. Our results do not indicate that adding a training in emotion regulation skills generally improves the effect of CBT across all patients with MUS. Large effect sizes of both treatments and potential specific benefits of ENCERT for patients with co-morbid mental disorders are discussed., (© 2019 S. Karger AG, Basel.)

Cohesin is important for 3D genome organization. Nevertheless, even the complete removal of cohesin has surprisingly little impact on steady-state gene transcription and enhancer activity. Here we show that cohesin is required for the core transcriptional response of primary macrophages to microbial signals, and for inducible enhancer activity that underpins inflammatory gene expression. Consistent with a role for inflammatory signals in promoting myeloid differentiation of hematopoietic stem and progenitor cells (HPSCs), cohesin mutations in HSPCs led to reduced inflammatory gene expression and increased resistance to differentiation-inducing inflammatory stimuli. These findings uncover an unexpected dependence of inducible gene expression on cohesin, link cohesin with myeloid differentiation, and may help explain the prevalence of cohesin mutations in human acute myeloid leukemia.

Objective: Somatoform disorders are characterized by increased health care utilization producing high health costs. The aim of this study was to assess facets of and interdiagnostic differences in health care use in somatoform disorders and to examine health anxiety, symptom-related disability, depression, and phobic anxiety as potential mediating factors of the relationship between somatization and health care use., Method: An outpatient sample of N=254 patients with somatoform disorders was investigated by analyzing different facets of their health care use over the last 12months. Multiple mediation analyses were applied., Results: Participants reported a mean of 28.02 doctor visits over the last year. Patients fulfilling criteria of DSM-IV somatization disorder had a significantly higher number of doctor visits than patients with undifferentiated somatoform, and somatoform pain disorder, all p≤.006. In most health care use variables, patients with comorbid mental disorders did not differ from patients without comorbidities. The mediation model on the effect of all mediator variables on the relationship between somatization and health care use reached significance (b=0.32, 95% CI: 0.0576, 0.6435). Surprisingly, specific mediator effects were found for health anxiety (b=0.06, 95% CI: 0.0004, 0.1505) and disability (b=0.18, 95% CI: 0.0389, 0.3530), but not for depression and phobic anxiety., Conclusions: Health anxiety and symptom-related disability should be further considered when investigating potential etiological factors of increased health care use., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the heterogeneity of illness behavior in patients with medically unexplained physical symptoms (MUPS), we clustered patients in regard to their degree of engaging in different aspects of illness behavior and identified related variables with these behaviors., Method: A sample of N = 224 patients attending treatment in primary care with a history of MUPS (at least two symptoms) was investigated by analyzing different aspects of illness behavior with the self-reported number of doctor visits during the last 6 months and the Scale for the Assessment of Illness Behavior (SAIB; e.g., expression of symptoms)., Results: Two distinct clusters were identified by cluster analysis: a low (n = 106) and a high (n = 118) illness behavior clusters. The high illness behavior cluster exhibited a significantly higher rate of health anxiety than the low illness behavior cluster. Regression analysis revealed a particular effect of sex in the high illness behavior cluster: whereas being male was associated with increased illness behavior as measured by the SAIB, being female was linked to a higher number of doctor visits. Increased health anxiety was associated with the SAIB illness behavior in both clusters. Depression and anxiety did not show incremental associations with all aspects of illness behavior., Conclusion: Knowledge of the pattern of illness behavior in patients with MUPS enables us to improve psychological treatments that directly address specific aspects of illness behavior or health anxiety. Differences between sexes in illness behaviors require more differentiated consideration in future research.