Inter-individual DNA methylation variations were frequently hypothesized to alter individual susceptibility to Type 2 Diabetes Mellitus (T2DM). Sequence-influenced methylations were described in T2DM-associated genomic regions, but evidence for direct, sequence-independent association with disease risk is missing. Here, we explore disease-contributing DNA methylation through a stepwise study design: first, a pool-based, genome-scale screen among 1169 case and control individuals revealed an excess of differentially methylated sites in genomic regions that were previously associated with T2DM through genetic studies. Next, in-depth analyses were performed at selected top-ranking regions. A CpG site in the first intron of the FTO gene showed small (3.35%) but significant (P = 0.000021) hypomethylation of cases relative to controls. The effect was independent of the sequence polymorphism in the region and persists among individuals carrying the sequence-risk alleles. The odds of belonging to the T2DM group increased by 6.1% for every 1% decrease in methylation (OR = 1.061, 95% CI: 1.032-1.090), the odds ratio for decrease of 1 standard deviation of methylation (adjusted to gender) was 1.5856 (95% CI: 1.2824-1.9606) and the sensitivity (area under the curve = 0.638, 95% CI: 0.586-0.690; males = 0.675, females = 0.609) was better than that of the strongest known sequence variant. Furthermore, a prospective study in an independent population cohort revealed significant hypomethylation of young individuals that later progressed to T2DM, relative to the individuals who stayed healthy. Further genomic analysis revealed co-localization with gene enhancers and with binding sites for methylation-sensitive transcriptional regulators. The data showed that low methylation level at the analyzed sites is an early marker of T2DM and suggests a novel mechanism by which early-onset, inter-individual methylation variation at isolated non-promoter genomic sites predisposes to T2DM.

Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

Summary Reducing the activity of the Insulin/IGF-1 Signaling pathway (IIS) modifies development, elevates stress resistance, protects from toxic protein aggregation (proteotoxicity) and extends lifespan of worms, flies and mice. In the nematode Caenorhabditis elegans (C. elegans), lifespan extension by IIS reduction is entirely dependent upon the activity of the transcription factors DAF-16 and the Heat Shock Factor-1 (HSF-1). While DAF-16 determines lifespan exclusively during early adulthood it is required for proteotoxicity protection also during late adulthood. In contrast, HSF-1 protects from proteotoxicity during larval development. Despite the critical requirement for HSF-1 for lifespan extension the temporal requirements for this transcription factor as a lifespan determinant are unknown. To establish the temporal requirements of HSF-1 for longevity assurance we conditionally knocked down hsf-1 during larval development and adulthood of C. elegans and found that unlike daf-16, hsf-1 is foremost required for lifespan determination during early larval development, required for a lesser extent during early adulthood and has small effect on longevity also during late adulthood. Our findings indicate that early developmental events affect lifespan and suggest that HSF-1 sets during development the conditions that enable DAF-16 to promote longevity during reproductive adulthood. This study proposes a novel link between HSF-1 and the longevity functions of the IIS.

In the nematode Caenorhabditis elegans, the heat shock response (HSR) is regulated at the organismal level by a network of thermosensory neurons that senses elevated temperatures and activates the HSR in remote tissues. Which neuronal receptors are required for this signaling mechanism and in which neurons they function are largely unanswered questions. Here we used worms that were engineered to exhibit RNA interference hypersensitivity in neurons to screen for neuronal receptors that are required for the activation of the HSR and identified a putative G-protein coupled receptor (GPCR) as a novel key component of this mechanism. This gene, which we termed GPCR thermal receptor 1 ( gtr-1), is expressed in chemosensory neurons and has no role in heat sensing but is critically required for the induction of genes that encode heat shock proteins in non-neural tissues upon exposure to heat. Surprisingly, the knock-down of gtr-1 by RNA interference protected worms expressing the Alzheimer's-disease-linked aggregative peptide A␤ 3-42 from proteotoxicity but had no effect on lifespan. This study provides several novel insights: (1) it shows that chemosensory neurons play important roles in the nematode's HSR-regulating mechanism, (2) it shows that lifespan and heat stress resistance are separable, and (3) it strengthens the emerging notion that the ability to respond to heat comes at the expense of protein homeostasis (proteostasis).

Anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cell (CART) therapy shows remarkable efficacy in patients with relapsed and/or refractory (R/R) multiple myeloma (MM). HBI0101, a novel second generation optimized anti-BCMA CART cell therapy, was developed in an academic setting. We conducted a phase I dose-escalation study of HBI0101 (cohort 1, 150x10^6 CART cells, N=6; cohort 2; 450x10^6 CART cells, N=7 and cohort 3, 800x10^6 CART cells, N=7) (NCT04720313) in 20 heavily pretreated R/R MM patients. Grade 1-2 cytokine release syndrome (CRS) was reported in 18 patients (90%). Neither grade 3-4 CRS, nor neurotoxicity of any grade were observed. No dose-limiting toxicities (DLTs) were observed in any cohort. The overall response rate (ORR), (stringent) complete response (CR/sCR) and very good partial response (VGPR) rates were 75%, 50% and 25%, respectively. Response rates were dose-dependent with 85% ORR, 71% CR and 57% minimal residual disease (MRD) negativity in the high-dose cohort 3. For the entire cohort, the median overall survival (OS) was 308 days (range, 25-466+), with an estimated OS of 55% as of data cutoff June 27th. The median progression-free survival (PFS) was 160 days, with 6 subjects remaining progression free at the time of data cutoff. Our findings demonstrate the manageable safety profile and efficacy of HBI0101. These favorable data are encouraging and support decentralization of CART production at an academic setting, ensuring a sufficient CART supply in the light of the increasing local demand.