The oncoprotein TBX3 is controlling severity in experimental arthritis

Abstract Background Development of autoimmune diseases is the result of a complex interplay between hereditary and environmental factors, with multiple genes contributing to the pathogenesis in human disease and in experimental models for disease. The T-box protein 3 is a transcriptional repressor essential during early embryonic development, in the formation of bone and additional organ systems, and in tumorigenesis. Methods With the aim to find novel genes important for autoimmune inflammation, we have performed genetic studies of collagen-induced arthritis (CIA), a mouse experimental model for rheumatoid arthritis. Results We showed that a small genetic fragment on mouse chromosome 5, including Tbx3 and three additional protein-coding genes, is linked to severe arthritis and high titers of anti-collagen antibodies. Gene expression studies have revealed differential expression of Tbx3 in B cells, where low expression was accompanied by a higher B cell response upon B cell receptor stimulation in vitro. Furthermore, we showed that serum TBX3 levels rise concomitantly with increasing severity of CIA. Conclusions From these results, we suggest that TBX3 is a novel factor important for the regulation of gene transcription in the immune system and that genetic polymorphisms, resulting in lower expression of Tbx3, are contributing to a more severe form of CIA and high titers of autoantibodies. We also propose TBX3 as a putative diagnostic biomarker for rheumatoid arthritis

The polygenic nature of telomere length and the anti-ageing properties of lithium

Telomere length is a promising biomarker for age-related disease and a potential anti-ageing drug target. Here, we study the genetic architecture of telomere length and the repositioning potential of lithium as an anti-ageing medication. LD score regression applied to the largest telomere length genome-wide association study to-date, revealed SNP-chip heritability estimates of 7.29%, with polygenic risk scoring capturing 4.4% of the variance in telomere length in an independent cohort (p = 6.17 × 10-5). Gene-enrichment analysis identified 13 genes associated with telomere length, with the most significant being the leucine rich repeat gene, LRRC34 (p = 3.69 × 10-18). In the context of lithium, we confirm that chronic use in a sample of 384 bipolar disorder patients is associated with longer telomeres (p = 0.03). As complementary evidence, we studied three orthologs of telomere length regulators in a Caenorhabditis elegans model of lithium-induced extended longevity and found all transcripts to be affected post-treatment (p  0.05). Consequently, this suggests that lithium may be catalysing the activity of endogenous mechanisms that promote telomere lengthening, whereby its efficacy eventually becomes limited by each individual's inherent telomere maintenance capabilities. Our work indicates a potential use of polygenic risk scoring for the prediction of adult telomere length and consequently lithium's anti-ageing efficacy

Associations between childhood maltreatment and inflammatory markers.

BACKGROUND:Childhood maltreatment is one of the strongest predictors of adulthood depression and alterations to circulating levels of inflammatory markers is one putative mechanism mediating risk or resilience.AimsTo determine the effects of childhood maltreatment on circulating levels of 41 inflammatory markers in healthy individuals and those with a major depressive disorder (MDD) diagnosis. METHOD:We investigated the association of childhood maltreatment with levels of 41 inflammatory markers in two groups, 164 patients with MDD and 301 controls, using multiplex electrochemiluminescence methods applied to blood serum. RESULTS:Childhood maltreatment was not associated with altered inflammatory markers in either group after multiple testing correction. Body mass index (BMI) exerted strong effects on interleukin-6 and C-reactive protein levels in those with MDD. CONCLUSIONS:Childhood maltreatment did not exert effects on inflammatory marker levels in either the participants with MDD or the control group in our study. Our results instead highlight the more pertinent influence of BMI.Declaration of interestD.A.C. and H.W. work for Eli Lilly Inc. R.N. has received speaker fees from Sunovion, Jansen and Lundbeck. G.B. has received consultancy fees and funding from Eli Lilly. R.H.M.-W. has received consultancy fees or has a financial relationship with AstraZeneca, Bristol-Myers Squibb, Cyberonics, Eli Lilly, Ferrer, Janssen-Cilag, Lundbeck, MyTomorrows, Otsuka, Pfizer, Pulse, Roche, Servier, SPIMACO and Sunovian. I.M.A. has received consultancy fees or has a financial relationship with Alkermes, Lundbeck, Lundbeck/Otsuka, and Servier. S.W. has sat on an advisory board for Sunovion, Allergan and has received speaker fees from Astra Zeneca. A.H.Y. has received honoraria for speaking from Astra Zeneca, Lundbeck, Eli Lilly, Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion, Janssen; and research grant support from Janssen. A.J.C. has received honoraria for speaking from Astra Zeneca, honoraria for consulting with Allergan, Livanova and Lundbeck and research grant support from Lundbeck

Genetic Risk for Psychiatric Disorders and Telomere Length

Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample.Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking).Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p ≤ 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p ≤ 0.05).Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants

Proteome-wide Mendelian randomization identifies causal links between blood proteins and severe COVID-19.

Funder: Cambridge NIHR Biomedical Research CentreFunder: Addenbrooke’s Charities TrustFunder: NIHR Biomedical Research Centre (BRC)Funder: Maudsley NHS Foundation TrustFunder: King’s College LondonIn November 2021, the COVID-19 pandemic death toll surpassed five million individuals. We applied Mendelian randomization including >3,000 blood proteins as exposures to identify potential biomarkers that may indicate risk for hospitalization or need for respiratory support or death due to COVID-19, respectively. After multiple testing correction, using genetic instruments and under the assumptions of Mendelian Randomization, our results were consistent with higher blood levels of five proteins GCNT4, CD207, RAB14, C1GALT1C1, and ABO being causally associated with an increased risk of hospitalization or respiratory support/death due to COVID-19 (ORs = 1.12-1.35). Higher levels of FAAH2 were solely associated with an increased risk of hospitalization (OR = 1.19). On the contrary, higher levels of SELL, SELE, and PECAM-1 decrease risk of hospitalization or need for respiratory support/death (ORs = 0.80-0.91). Higher levels of LCTL, SFTPD, KEL, and ATP2A3 were solely associated with a decreased risk of hospitalization (ORs = 0.86-0.93), whilst higher levels of ICAM-1 were solely associated with a decreased risk of respiratory support/death of COVID-19 (OR = 0.84). Our findings implicate blood group markers and binding proteins in both hospitalization and need for respiratory support/death. They, additionally, suggest that higher levels of endocannabinoid enzymes may increase the risk of hospitalization. Our research replicates findings of blood markers previously associated with COVID-19 and prioritises additional blood markers for risk prediction of severe forms of COVID-19. Furthermore, we pinpoint druggable targets potentially implicated in disease pathology

Para-infectious brain injury in COVID-19 persists at follow-up despite attenuated cytokine and autoantibody responses

To understand neurological complications of COVID-19 better both acutely and for recovery, we measured markers of brain injury, inflammatory mediators, and autoantibodies in 203 hospitalised participants; 111 with acute sera (1–11 days post-admission) and 92 convalescent sera (56 with COVID-19-associated neurological diagnoses). Here we show that compared to 60 uninfected controls, tTau, GFAP, NfL, and UCH-L1 are increased with COVID-19 infection at acute timepoints and NfL and GFAP are significantly higher in participants with neurological complications. Inflammatory mediators (IL-6, IL-12p40, HGF, M-CSF, CCL2, and IL-1RA) are associated with both altered consciousness and markers of brain injury. Autoantibodies are more common in COVID-19 than controls and some (including against MYL7, UCH-L1, and GRIN3B) are more frequent with altered consciousness. Additionally, convalescent participants with neurological complications show elevated GFAP and NfL, unrelated to attenuated systemic inflammatory mediators and to autoantibody responses. Overall, neurological complications of COVID-19 are associated with evidence of neuroglial injury in both acute and late disease and these correlate with dysregulated innate and adaptive immune responses acutely

A study on the functional properties of silk and polyester / lyocell mixed fabric

ABSTRACT Silk is one of the valuable fibers in textile industry. It is used for delicate applications in many areas such as sarees, suitings, curtains and luxurious interiors. To diversify the properties and usages silk is mixed with polyester and lyocell. The fabric is dyed with natural dyes (kum kum, indigo, barberry) as well as synthetic dyes (reactive dye (H), reactive dye (M) and sulphur dye). This mixed fabric is compared with 100% silk for some of the basic properties like absorbency, water retention, wicking, water vapour permeability, air permeability, K/S values, colour fastness and antimicrobial property. The silk mixed fabric gives the appreciable results with the 100% silk fabric