TCF7L2 is a master regulator of insulin production and processing.

Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors', we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.

Inactivation of coxsackievirus B4, feline calicivirus and herpes simplex virus type 1: unexpected virucidal effect of a disinfectant on a non-enveloped virus applied onto a surface.

OBJECTIVE: To evaluate the effect of a disinfectant onto viruses in suspension on the one hand and applied onto a surface on the other. METHODS: A system combining flocked swabs to recover viruses dried onto stainless steel carriers and gel filtration to eliminate cytotoxic products has been developed to study the virucidal effect of a quaternary ammonium-based disinfectant towards herpes simplex virus type 1 (HSV-1), coxsackievirus B4 (CVB4) and feline calicivirus F9 (FCV). The recovery of FCV has been estimated by RT real-time PCR. RESULTS: HSV-1, CVB4 and FCV had a titer over 10(4) TCID50 · ml(-1) after 2 h drying and were recovered from the carriers using flocked swabs. HSV-1 was inactivated in suspension and on stainless steel carriers by the disinfectant (a reduction factor of 4 and 2.83 log, respectively) whereas CVB4 was resistant. The reduction of infectious titer was moderate, 1.5 log in 30 min, when FCV was in suspension, whereas it was up to 4 log in 10 min when the virus was dried on a carrier. Dried FCV was efficiently recovered from carriers as demonstrated by RT real-time PCR. CONCLUSION: A non-enveloped virus, FCV, applied on a surface, but not in suspension, was inactivated by a quaternary ammonium-based disinfectant. The resistance of viruses applied onto a surface to the effect of disinfectants should be investigated further.

Inactivation of an enterovirus by airborne disinfectants.

BACKGROUND: The activity of airborne disinfectants on bacteria, fungi and spores has been reported. However, the issue of the virucidal effect of disinfectants spread by fogging has not been studied thoroughly. METHODS: A procedure has been developed to determine the virucidal activity of peracetic acid-based airborne disinfectants on a resistant non-enveloped virus poliovirus type 1. This virus was laid on a stainless carrier. The products were spread into the room by hot fogging at 55°C for 30 minutes at a concentration of 7.5 mL.m(-3). Poliovirus inoculum, supplemented with 5%, heat inactivated non fat dry organic milk, were applied into the middle of the stainless steel disc and were dried under the air flow of a class II biological safety cabinet at room temperature. The Viral preparations were recovered by using flocked swabs and were titered on Vero cells using the classical Spearman-Kärber CPE reading method, the results were expressed as TCID50.ml(-1). RESULTS: The infectious titer of dried poliovirus inocula was kept at 10(5) TCID50.mL(-1) up to 150 minutes at room temperature. Dried inocula exposed to airborne peracetic acid containing disinfectants were recovered at 60 and 120 minutes post-exposition and suspended in culture medium again. The cytotoxicity of disinfectant containing medium was eliminated through gel filtration columns. A 4 log reduction of infectious titer of dried poliovirus inocula exposed to peracetic-based airborne disinfectant was obtained. CONCLUSION: This study demonstrates that the virucidal activity of airborne disinfectants can be tested on dried poliovirus.

The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells.

The transcription factor TCF7L2 remains the most important diabetes gene identified to date and genetic risk carriers exhibit lower insulin secretion. We show that Tcf7l2 regulates the auxiliary subunit of voltage-gated Ca2+ channels, Cacna2d1 gene/α2δ-1 protein levels. Furthermore, suppression of α2δ-1 decreased voltage-gated Ca2+ currents and high glucose/depolarization-evoked Ca2+ signaling which mimicked the effect of silencing of Tcf7l2. This appears to be the result of impaired voltage-gated Ca2+ channel trafficking to the plasma membrane, as Cav1.2 channels accumulated in the recycling endosomes after α2δ-1 suppression, in clonal as well as primary rodent beta-cells. This impaired the capacity for glucose-induced insulin secretion in Cacna2d1-silenced cells. Overexpression of α2δ-1 increased high-glucose/K+-stimulated insulin secretion. Furthermore, overexpression of α2δ-1 in Tcf7l2-silenced cells rescued the Tcf7l2-dependent impairment of Ca2+ signaling, but not the reduced insulin secretion. Taken together, these data clarify the connection between Tcf7l2, α2δ-1 in Ca2+-dependent insulin secretion.

A respiratory syncytial virus isolate enables the testing of virucidal products.

The respiratory syncytial virus (RSV) is known as a major cause of respiratory infections and nosocomial diseases. Testing this virus is rather difficult due to the problems encountered in producing it at a high titer without using any purification method. A RSV isolate which replicates to high level on a Hep-2 cell line with an infectious titer of at least 10(7)TCID(50)mL(-1) in culture supernatant fluids has been identified. Thanks to this isolate, the virucidal effects of two products, a hand rub solution and a surface disinfectant, were conveniently tested according to the EN 14476:2007-02 procedure.