BACKGROUNDDespite growing evidence that bariatric/metabolic surgery powerfully improves type 2 diabetes (T2D), existing diabetes treatment algorithms do not include surgical options. AIMThe 2nd Diabetes Surgery Summit (DSS-II), an international consensus conference, was convened in collaboration with leading diabetes organizations to develop global guidelines to inform clinicians and policymakers about benefits and limitations of metabolic surgery for T2D. METHODSA multidisciplinary group of 48 international clinicians/scholars (75% nonsurgeons), including representatives of leading diabetes organizations, participated in DSS-II. After evidence appraisal (MEDLINE [1 January 2005-30 September 2015]), three rounds of Delphi-like questionnaires were used to measure consensus for 32 data-based conclusions. These drafts were presented at the combined DSS-II and 3rd World Congress on Interventional Therapies for Type 2 Diabetes (London, U.K., 28-30 September 2015), where they were open to public comment by other professionals and amended face-to-face by the Expert Committee. RESULTSGiven its role in metabolic regulation, the gastrointestinal tract constitutes a meaningful target to manage T2D. Numerous randomized clinical trials, albeit mostly short/midterm, demonstrate that metabolic surgery achieves excellent glycemic control and reduces cardiovascular risk factors. On the basis of such evidence, metabolic surgery should be recommended to treat T2D in patients with class III obesity (BMI ‡40 kg/m 2 ) and in those with class II obesity (BMI 35.0-39.9 kg/m 2 ) when hyperglycemia is inadequately controlled by lifestyle and optimal medical therapy. Surgery should also be considered for patients with T2D and BMI 30.0-34.9 kg/m 2 if hyperglycemia is inadequately controlled despite optimal treatment with either oral or injectable medications. These BMI thresholds should be reduced by 2.5 kg/m 2 for Asian patients. CONCLUSIONSAlthough additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity. To date, the DSS-II guidelines have been formally endorsed by 45 worldwide medical and scientific societies. Health care regulators should introduce appropriate reimbursement policies.

Two mammalian genes, Kcnt1 and Kcnt2, encode pore-forming subunits of Na+-dependent K+ (KNa) channels. Progress in understanding KNa channels has been hampered by the absence of specific tools and methods for rigorous KNa identification in native cells. Here, we report the genetic disruption of both Kcnt1 and Kcnt2, confirm the loss of Slo2.2 and Slo2.1 protein, respectively, in KO animals, and define tissues enriched in Slo2 expression. Noting the prevalence of Slo2.2 in dorsal root ganglion, we find that KO of Slo2.2, but not Slo2.1, results in enhanced itch and pain responses. In dissociated small diameter DRG neurons, KO of Slo2.2, but not Slo2.1, abolishes KNa current. Utilizing isolectin B4+ neurons, the absence of KNa current results in an increase in action potential (AP) firing and a decrease in AP threshold. Activation of KNa acts as a brake to initiation of the first depolarization-elicited AP with no discernible effect on afterhyperpolarizations.DOI: http://dx.doi.org/10.7554/eLife.10013.001

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendrocyte loss, whereas T-cell checkpoint inhibition worsened the aging response. In addition, we identified a subpopulation of lymphocyte-dependent, IFN-responsive microglia in the vicinity of the CD8+ T cells in aging white matter. In summary, we provide evidence that CD8+ T-cell-induced, IFN-responsive oligodendrocytes and microglia are important modifiers of white matter aging.

Antimicrobial peptides act as a host defense mechanism and regulate the commensal microbiome. To obtain a comprehensive view of genes contributing to long-term memory we performed mRNA sequencing from single Drosophila heads following behavioral training that produces long-lasting memory. Surprisingly, we found that Diptericin B, an immune peptide with antimicrobial activity, is upregulated following behavioral training. Deletion and knock down experiments revealed that Diptericin B and another immune peptide, Gram-Negative Bacteria Binding Protein like 3, regulate long-term but not short-term memory or instinctive behavior in Drosophila. Interestingly, removal of DptB in the head fat body and GNBP-like3 in neurons results in memory deficit. That putative antimicrobial peptides influence memory provides an example of how some immune peptides may have been repurposed to influence the function of nervous system.

Transforming growth factor-beta (TGF-beta) signaling is known to depend on the formation of Smad2/3-Smad4 transcription regulatory complexes. However, the signaling functions of Smad2/3-Smad4 during TGF-beta-induced responses are obscure as TGF-beta also initiates a number of other signaling pathways. In this study, we systematically assessed the contribution of TGF-beta-Smad2/3-Smad4 signaling to both target gene transcription and apoptosis. Individual Smads were selectively knocked down in Hep3B cells by stable RNA interference (RNAi). We identified TGF-beta-responsive genes using genome-wide oligonucleotide microarrays and confirmed their dependency on Smad2, Smad3, or Smad4 by the combination of RNAi and microarray assay. The major finding from our microarray analysis was that of the 2,039 target genes seen to be regulated via TGF-beta induction, 190 were differentially transcriptionally controlled by Smad2-Smad4 and Smad3-Smad4 signaling and the latter control mechanism appeared to be functionally more important. We also found indirect evidence of competition between Smad2 and Smad3 for their activation when controlling the transcription of target genes. Functional analysis revealed that Smad3 and Smad4 were the predominant mediators of TGF-beta-induced apoptosis in Hep3B cells. We provide evidence that up-regulation of Bcl-2-interacting mediator of cell death (Bim), under the transcriptional control of Smad3-Smad4 signaling, is crucial to TGF-beta-induced apoptosis in Hep3B cells.