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Ion conduction through graphene oxide (GO) nanosheets that is pH-switchable between H+ (in acid) and OH− (in base) ions is demonstrated. This finding is the first observation of this type for ion conductive materials and demonstrates an example of stimuli-driven ion-conduction switching. [ABSTRACT FROM AUTHOR]

Proton‐dependent oligopeptide transporters (POTs) belong to the major facilitator superfamily (MFS) and transport dipeptides and tripeptides from the extracellular environment into the target cell. The human POTs PepT1 and PepT2 are also involved in the absorption of various orally ingested drugs. Previously reported structures revealed that the bacterial POTs possess 14 helices, of which H1–H6 and H7–H12 constitute the typical MFS fold and the residual two helices are involved in the cytoplasmic linker. PepTSo2 from Shewanella oneidensis is a unique POT which reportedly assembles as a 200 kDa tetramer. Although the previously reported structures suggested the importance of H12 for tetramer formation, the structural basis for the PepTSo2‐specific oligomerization remains unclear owing to the lack of a high‐resolution tetrameric structure. In this study, the expression and purification conditions for tetrameric PepTSo2 were optimized. A single‐particle cryo‐EM analysis revealed the tetrameric structure of PepTSo2 incorporated into Salipro nanoparticles at 4.1 Å resolution. Furthermore, a combination of lipidic cubic phase (LCP) crystallization and an automated data‐processing system for multiple microcrystals enabled crystal structures of PepTSo2 to be determined at resolutions of 3.5 and 3.9 Å. The present structures in a lipid bilayer revealed the detailed mechanism for the tetrameric assembly of PepTSo2, in which a characteristic extracellular loop (ECL) interacts with two asparagine residues on H12 which were reported to be important for tetramerization and plays an essential role in oligomeric assembly. This study provides valuable insights into the oligomerization mechanism of this MFS‐type transporter, which will further pave the way for understanding other oligomeric membrane proteins. [ABSTRACT FROM AUTHOR]

Proton‐dependent oligopeptide transporters (POTs) belong to the major facilitator superfamily (MFS) and transport dipeptides and tripeptides from the extracellular environment into the target cell. The human POTs PepT1 and PepT2 are also involved in the absorption of various orally ingested drugs. Previously reported structures revealed that the bacterial POTs possess 14 helices, of which H1–H6 and H7–H12 constitute the typical MFS fold and the residual two helices are involved in the cytoplasmic linker. PepTSo2 from Shewanella oneidensis is a unique POT which reportedly assembles as a 200 kDa tetramer. Although the previously reported structures suggested the importance of H12 for tetramer formation, the structural basis for the PepTSo2‐specific oligomerization remains unclear owing to the lack of a high‐resolution tetrameric structure. In this study, the expression and purification conditions for tetrameric PepTSo2 were optimized. A single‐particle cryo‐EM analysis revealed the tetrameric structure of PepTSo2 incorporated into Salipro nanoparticles at 4.1 Å resolution. Furthermore, a combination of lipidic cubic phase (LCP) crystallization and an automated data‐processing system for multiple microcrystals enabled crystal structures of PepTSo2 to be determined at resolutions of 3.5 and 3.9 Å. The present structures in a lipid bilayer revealed the detailed mechanism for the tetrameric assembly of PepTSo2, in which a characteristic extracellular loop (ECL) interacts with two asparagine residues on H12 which were reported to be important for tetramerization and plays an essential role in oligomeric assembly. This study provides valuable insights into the oligomerization mechanism of this MFS‐type transporter, which will further pave the way for understanding other oligomeric membrane proteins. [ABSTRACT FROM AUTHOR]

Aims/Introduction: To investigate the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus, with a focus on hypoglycemia. Materials and Methods: Type 2 diabetes mellitus patients who started sitagliptin therapy and were followed for 52 weeks were enrolled in the Impact of Sitagliptin on Diabetes Mellitus in Japanese Elderly Patients study. The frequency of hypoglycemia and knowledge of hypoglycemia were analyzed using a questionnaire. Results: In total, 5,130 patients (aged 73.8 ± 6.1 years) were analyzed. A significant reduction in glycated hemoglobin (−0.7 ± 1.1%, P < 0.001) and glycoalbumin levels (−2.2 ± 3.8%, P < 0.001) was observed at week 52. The percentage of patients with hypoglycemia did not increase from the baseline (3.3%) to week 52 (2.8%) of sitagliptin administration. Hypoglycemia incidence was significantly higher for combination therapy with insulin (odds ratio 17.75, P < 0.001) or sulfonylurea (odds ratio 2.22, P < 0.001). The increase in sitagliptin dose for combination therapy with antidiabetic drug(s) increased the percentage of patients with hypoglycemia (5.6% in sitagliptin increased subgroup, 2.4% in sitagliptin maintained subgroup, P < 0.01). The awareness of hypoglycemia symptoms and attitude to carry glucose as a countermeasure to prevent hypoglycemia increased during the study. Conclusions: Sitagliptin did not increase the percentage of patients with hypoglycemia among elderly patients with type 2 diabetes mellitus. However, hypoglycemia occurred more frequently in add‐on therapy to sulfonylurea or when the sitagliptin dose was increased in combination therapy, showing that sitagliptin should be used with caution. Sitagliptin did not increase hypoglycemia frequency in elderly patients with type 2 diabetes mellitus. However, the frequency of hypoglycemia increased in add‐on therapy to sulfonylurea or when sitagliptin dose was increased in combination therapy, indicating that sitagliptin should be used with caution. [ABSTRACT FROM AUTHOR]

Aims/Introduction: It is unclear how changes in body composition induced by sodium–glucose cotransporter 2 (SGLT2) inhibitor treatment correlate with metabolic profile changes. We aimed to clarify how metabolic profile changes correlate with body component changes, and if SGLT2 inhibitor treatment causes sarcopenia and bone mineral content (BMC) loss. Materials and Methods: Moderately obese Japanese type 2 diabetes patients, treated with luseogliflozin for a year, were observed prospectively and evaluated for body composition changes. We analyzed the changes in the individual body components during treatment, and their correlation with other clinical variables. Results: The efficacy analysis set comprised 37 of 43 enrolled patients. The total fat mass significantly decreased early in the treatment at and after week 4, with a mean decrease of −1.97 kg (95% confidence interval −2.66 to −1.28) at week 24. The visceral fat area at week 24 showed an average downward trend, although this was not significant. The changes in visceral fat area in individual patients showed a significant negative correlation with the extent of the baseline visceral fat area (r = −0.399, P = 0.023). The skeletal muscle mass index showed a significant but small change at and after week 36. The BMC profile showed a transient significant decrease only at week 12. No significant change in BMC was noted at other time‐points. Conclusions: Luseogliflozin treatment brought about favorable changes in body composition and metabolism of moderately obese Japanese type 2 diabetes patients, accompanied by body fat reduction, and minimal muscle and BMC reduction. Luseogliflozin treatment was found to be capable of controlling T2D with favorable changes in the body composition and metabolism accompanied by minimal muscle and BMC reduction, even in moderately obese patients. The changes in the visceral fat area at Week 24 in individual patients showed a significant negative correlation with the respective visceral fat area levels at the baseline (r = −0.457, P = 0.0085). [ABSTRACT FROM AUTHOR]

Cancer cells increase glucose metabolism to support aerobic glycolysis. However, only some cancer cells are acutely sensitive to glucose withdrawal, and the underlying mechanism of this selective sensitivity is unclear. We showed that glucose deprivation initiates a cell death pathway in cancer cells that is dependent on the kinase RIPK1. Glucose withdrawal triggered rapid plasma membrane depolarization and an influx of extracellular calcium into the cell through the L-type calcium channel Cav1.3 (CACNA1D), followed by activation of the kinase CAMK1. CAMK1 and the demethylase PPME1 were required for the subsequent demethylation and inactivation of the catalytic subunit of the phosphatase PP2A (PP2Ac) and the phosphorylation of RIPK1. Plasma membrane depolarization, PP2Ac demethylation, and cell death were prevented by glucose and, unexpectedly, by its nonmetabolizable analog 2-deoxy-d-glucose (2-DG), a glycolytic inhibitor. These findings reveal a previously unknown function of glucose as a signaling molecule that protects cells from death induced by plasma membrane depolarization, independently of its role in glycolysis. Components of this cancer cell death pathway represent potential therapeutic targets against cancer. [ABSTRACT FROM AUTHOR]

The formation of Ge 1− x − y Si x Sn y /Ge 1− x Sn x /Ge 1− x − y Si x Sn y double heterostructures with strain-controlled Ge 1− x − y Si x Sn y layers and their crystalline properties were investigated. We achieved the epitaxial growth of double heterostructures consisting of a Ge 1− x Sn x layer with a Sn content of 9% sandwiched between compressive- or tensile-strained Ge 1− x − y Si x Sn y layers. The strain sign of the Ge 1− x − y Si x Sn y epitaxial layer influenced the crystallinity of the double heterostructures. Compressive-strained Ge 1− x − y Si x Sn y layers provided double heterostructures with higher crystallinity than the tensile-strained ones. The magnitude of strain in the Ge 1− x − y Si x Sn y layers also affected the surface roughness of the double heterostructures. Low surface roughness was achieved by decreasing the magnitude of strain in the Ge 1− x − y Si x Sn y layers. Moreover, the strain sign and/or Si content in Ge 1− x − y Si x Sn y influenced the thermal stability of the double heterostructures. Compressive-strained Ge 1− x − y Si x Sn y and/or a low Si content in Ge 1− x − y Si x Sn y improved the thermal stability of the double heterostructures to withstand annealing temperatures as high as 400 °C. [ABSTRACT FROM AUTHOR]