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Sepsis-induced endothelial acute respiratory distress syndrome is related to microvascular endothelial dysfunction caused by endothelial glycocalyx disruption. Recently, recombinant antithrombin (rAT) was reported to protect the endothelial glycocalyx from septic vasculitis; however, the underlying mechanism remains unknown. Here, we investigated the effect of rAT administration on vascular endothelial injury under endotoxemia. Lipopolysaccharide (LPS; 20 mg/kg) was injected intraperitoneally into 10-week-old male C57BL/6 mice, and saline or rAT was administered intraperitoneally at 3 and 24 hours after LPS administration. Subsequently, serum and/or pulmonary tissues were examined for inflammation and cell proliferation and differentiation by histologic, ultrastructural, and microarray analyses. The survival rate was significantly higher in rAT-treated mice than in control mice 48 hours after LPS injection (75% versus 20%; P

To evaluate the effect of cryoprecipitate (CRYO) transfusion in women referred for postpartum hemorrhage (PPH). This retrospective cohort study included patients with primary PPH referred to Gifu University Hospital between April 2013 and March 2020. We analyzed the effect of CRYO transfusion on fluid balance 24 h after the initial examination using a multivariable linear regression model adjusted for several confounding variables. To evaluate whether outcomes were modified by active bleeding, an interaction term of CRYO*active bleeding was incorporated into the multivariable model. We identified 157 women: 38 in the CRYO group (cases) and 119 in the control group. Fluid balance in the aforementioned period tended to decrease in the CRYO group compared with that in the control group (coefficient − 398.91; 95% CI − 1298.08 to + 500.26; p = 0.382). Active bleeding on contrast-enhanced computed tomography affected the relationship between CRYO transfusion and fluid balance (p = 0.016). Other outcomes, except for the overall transfusion requirement, were not significantly different; however, the interaction effect of active bleeding was significant (p = 0.016). CRYO transfusion may decrease the fluid balance in the first 24 h in PPH patients, especially in those without active bleeding.

Background: Post hoc analysis was used to investigate the effects of renal function on the efficacy and safety of landiolol using data from the J-Land II study, which evaluated landiolol in patients with hemodynamically unstable ventricular tachycardia (VT) or ventricular fibrillation (VF) who were refractory to Class III antiarrhythmic drugs. Methods and Results: Patient data from the J-Land II study (n=29) were stratified by renal function (estimated glomerular filtration rate [eGFR]

Glycocalyx is present on the surface of healthy endothelium, and the concentration of serum syndecan-1 can serve as an injury marker. This study aimed to evaluate the hemodialysis-associated changes in the serum syndecan-1 concentration. This was a single-center, retrospective, observational study. Between March 2017 and December 2019, 145 patients who underwent hemodialysis at the Gifu University Hospital were enrolled. The median dialysis period and dialysis time were 63 months and 3.7 hours, respectively. The serum syndecan-1 concentration increased from 124.6 ± 107.8 ng/mL before hemodialysis to 229.0 ± 138.1 ng/mL after hemolysis (P

Drug-induced phospholipidosis, a side effect of drugs, is associated with drug–membrane binding. Hydrophobic interactions of the drug with the membrane and polar interactions of the drug with the membrane are involved. For risk predictions, membrane binding studies often give false results for strongly hydrophobic compounds and basic hydrophilic compounds because the effects of the hydrophobic interactions overshadow the effects of the polar interactions. Therefore, separate assessments of hydrophobic partitioning and polar interactions are needed. However, a screening method focusing on the polar interactions between drugs and membranes has not yet been reported. In the present study, the retention behavior of an immobilized artificial membrane (IAM) column using a binary mobile phase with a high acetonitrile content was studied to clarify the contribution of the analyte partition to the water-rich layer on the surface of the packed material, which may interfere with the assessment of the polar interactions with the membrane. For acetonitrile contents greater than 50%, the retention factor of propranolol increased as a result of the hydrophilic interactions. The Van’t Hoff plot suggested that the adsorptive retention of the analyte became dominant with high acetonitrile content in the mobile phase, in contrast to the hydrophobic partitioning that occurred for low acetonitrile content. Hydrophilic neutral compounds (e.g., thiourea and mesityl oxide) were not retained. The addition of salts to the mobile phase decreased the propranolol retention. Even with the addition of a kosmotropic salt, the decreased retention indicated that hydrophilic partitioning to the water-enriched layer was unlikely to be the major mechanism. In addition to ionic interactions, other polar interactions were presumed to be involved. The relationships between the retention factor and the log P or pKa values also supported this conclusion. The results of this study suggest that there is potential for IAM chromatography to be used as a tool to estimate the contribution of the polar interactions in overall drug–membrane interactions, which can aid in predicting the risk of phospholipidosis.

Plasma amino acids and their transporters constitute an important part of the feedback loop between the liver and pancreatic α-cell function, and glucagon regulates hepatic amino acid turnover. Disruption of hepatic glucagon receptor action activates the loop and results in high plasma amino acids and hypersecretion of glucagon associated with α-cell hyperplasia. In the present study, we report a technique to rescue implanted human pancreatic islets from the mouse kidney capsule. Using this model, we have demonstrated that expression of the amino acid transporter SLC38A4 increases in α-cells after administration of a glucagon receptor blocking antibody. The increase in SLC38A4 expression and associated α-cell proliferation was dependent on mechanistic target of rapamycin pathway. We confirmed increased α-cell proliferation and expression of SLC38A4 in pancreas sections from patients with glucagon cell hyperplasia and neoplasia (GCHN) with loss-of-function mutations in the glucagon receptor. Collectively, using a technique to rescue implanted human islets from the kidney capsule in mice and pancreas sections from patients with GCHN, we found that expression of SLC38A4 was increased under conditions of disrupted glucagon receptor signaling. These data provide support for the existence of a liver-human α-cell endocrine feedback loop.

Background Heat-related illnesses include symptoms such as heat syncope/cramps, heat exhaustion, and life-threatening heat stroke. Usually, a heat stroke causes cerebellar ataxia, cognitive impairment, dysphagia, and aphasia. We report a very rare case of a patient who developed severe heat stroke complicated by multiple cerebral infarctions. Case presentation An 80-year-old Asian woman was found lying unconscious at her house, with no air conditioner and closed windows; the highest outside temperature was 36.1 °C. She was brought to our hospital unconscious with a high bladder temperature (42.5 °C) and disseminated intravascular coagulation (DIC score 4). She was diagnosed with severe heat stroke and managed with rapid cooling, intravenous fluids therapy, antibiotic therapy, and anti-coagulation therapy for DIC. Anti-coagulation therapy consisted of treatment with recombinant thrombomodulin for 4 days (days 1–4) and recombinant antithrombin for 1 day (day 1). A head computed tomography (CT) and magnetic resonance imaging (MRI) examination were performed on day 3, because she was still unconscious. Diffuse-weighted imaging showed high-signal intensities, indicating multiple lesions. An intracranial magnetic resonance angiography showed normal results. Imaging indicated new multiple cerebellar infarctions complicated with DIC. A tracheotomy was performed on day 9 because her conscious condition had not improved. She was transferred to another hospital for subacute care on day 23. Conclusions Early management of heat stroke using anti-DIC, anti-bacterial, and fluid resuscitation therapy can help prevent complications such as intracranial hemorrhaging.

Background: An open penetrating external laryngotracheal injury (LTI) is a rare life-threatening injury requiring immediate intervention. Penetrating injuries may cause tissue loss, which makes wound closure difficult sometimes. Here, we report the case of a patient who developed an open penetrating external LTI and abdominal trauma by suicide attempt, which required surgical intervention.Case presentation: A 38-year-old Asian man with depression was found lying on the floor after cutting his neck and abdomen by himself. The emergency services found multiple deep lacerations on his anterior neck and abdomen. He was brought by a helicopter with a physician onboard to a regional trauma center and immediately intubated at the emergency department to secure his airway and prevent airway obstruction. On arrival, his blood pressure was 120/90 mmHg, and his heart rate was 120 beats/min. A pre-shock status was presumed, but other vital signs were normal. Physical examination revealed cut wounds (three lines on the neck and two lines on the abdomen) and no dysphonia. The patient was diagnosed with an open penetrating external LTI, classified as group 5 on the Schaefer classification system and zone Ⅱ on Roon and Christensen’s modification. He was also suspected with a mesenteric injury. We performed an emergency primary laryngotracheal repair and exploratory laparotomy. There was no obvious blood vessel injury, but soft and cartilage tissues were crushed and disconnected completely. On day 8, he underwent wound closure and tracheostomy on the caudal side of the wound. He was successfully weaned from mechanical ventilation on day 9, transferred to the general ward on day 13, decannulated on day 63, and discharged from the hospital thereafter for subacute care.Conclusions: This case was a severe neck injury with complete laryngotracheal separation, but tissue losses due to knife-stabbing were relatively minimal. Wound closure was presumed to occur early during primary repair, even though the purpose of primary repair was originally to secure the airway or manage blood vessel injury. Thus, in the absence of blood vessel injury, wound closure may occur early in patients who developed an open penetrating external LTI by suicide attempt.

The liver plays a critical role in maintaining ammonia homeostasis. Urea cycle defects, liver injury, or failure and glutamine synthetase (GS) deficiency result in hyperammonemia, serious clinical conditions, and lethality. In this study we used a mouse model with a defect in the urea cycle enzyme ornithine transcarbamylase (Otcspf-ash) to test the hypothesis that glucagon receptor inhibition using a monoclonal blocking antibody will reduce the hyperammonemia and associated lethality induced by a high-protein diet, which exacerbates disease. We found reduced expression of glutaminase, which degrades glutamine and increased expression of GS in livers of Otcspf-ash mice treated with the glucagon receptor blocking antibody. The gene expression changes favor ammonia consumption and were accompanied by increased circulating glutamine levels and diminished hyperammonemia. Otcspf-ash mice treated with the glucagon receptor-blocking antibody gained lean and body mass and had increased survival. These data suggest that glucagon receptor inhibition using a monoclonal antibody could reduce the risk for hyperammonemia and other clinical manifestations of patients suffering from defects in the urea cycle, liver injury, or failure and GS deficiency.

Rationale: Glucagon is a key hormone that regulates the adaptive metabolic responses to fasting. In addition to maintaining glucose homeostasis, glucagon participates in the regulation of cholesterol metabolism; however, the molecular pathways underlying this effect are incompletely understood. Objective: We sought to determine the role of hepatic Gcgr (glucagon receptor) signaling in plasma cholesterol regulation and identify its underlying molecular mechanisms. Methods and Results: We show that Gcgr signaling plays an essential role in LDL-C (low-density lipoprotein cholesterol) homeostasis through regulating the PCSK9 (proprotein convertase subtilisin/kexin type 9) levels. Silencing of hepatic Gcgr or inhibition of glucagon action increased hepatic and plasma PCSK9 and resulted in lower LDLR (LDL receptor) protein and increased plasma LDL-C. Conversely, treatment of wild-type (WT) mice with glucagon lowered LDL-C levels, whereas this response was abrogated in Pcsk9 −/− and Ldlr −/− mice. Our gain- and loss-of-function studies identified Epac2 (exchange protein activated by cAMP-2) and Rap1 (Ras-related protein-1) as the downstream mediators of glucagon’s action on PCSK9 homeostasis. Moreover, mechanistic studies revealed that glucagon affected the half-life of PCSK9 protein without changing the level of its mRNA, indicating that Gcgr signaling regulates PCSK9 degradation. Conclusions: These findings provide novel insights into the molecular interplay between hepatic glucagon signaling and lipid metabolism and describe a new posttranscriptional mechanism of PCSK9 regulation.

Background Neurogenic acute respiratory failure is usually caused by either infection or vascular insufficiency. We report the case of a patient who developed acute respiratory failure secondary to a spinal tumor. Case Presentation A 32‐year‐old man, presenting with numbness and muscle weakness in his legs for 2 weeks, was transferred to our hospital with worsening quadriplegia and development of respiratory symptoms. We carried out emergent spinal decompression and initiated steroid pulse therapy, with no resolution of symptoms; a tumor incision biopsy after contrast cervical magnetic resonance imaging revealed an intraspinal tumor with a pathological diagnosis of World Health Organization grade IV glioma. The patient developed bradycardia, severe sepsis, status epilepticus, and cardiopulmonary arrest due to hypoxemia and was treated with chemoradiotherapy under mechanical ventilation. He was later transferred to another hospital for subacute care. Conclusion Acute respiratory failure caused by spinal tumors is uncommon. However, acute care practitioners should be mindful of neoplastic lesions as a potential cause., Neurogenic acute respiratory failure caused by spinal tumors is uncommon. However, acute care practitioners should be mindful of neoplastic lesions as a potential cause.

Endothelial glycocalyx coats healthy vascular endothelium and plays an important role in vascular homeostasis. Although cerebral capillaries are categorized as continuous, as are those in the heart and lung, they likely have specific features related to their function in the blood brain barrier. To test that idea, brains, hearts and lungs from C57BL6 mice were processed with lanthanum-containing alkaline fixative, which preserves the structure of glycocalyx, and examined using scanning and transmission electron microscopy. We found that endothelial glycocalyx is present over the entire luminal surface of cerebral capillaries. The percent area physically covered by glycocalyx within the lumen of cerebral capillaries was 40.1 ± 4.5%, which is significantly more than in cardiac and pulmonary capillaries (15.1 ± 3.7% and 3.7 ± 0.3%, respectively). Upon lipopolysaccharide-induced vascular injury, the endothelial glycocalyx was reduced within cerebral capillaries, but substantial amounts remained. By contrast, cardiac and pulmonary capillaries became nearly devoid of glycocalyx. These findings suggest the denser structure of glycocalyx in the brain is associated with endothelial protection and may be an important component of the blood brain barrier.

Background Management of diabetes remains a major health and economic challenge, demanding test systems in which to develop new therapies. These studies assessed different methodologies for determining glucose tolerance in green monkeys. Methods Twenty‐eight African green monkeys between 4 and 24 years old underwent single or repeat intravenous glucose tolerance testing (IVGTT), oral glucose tolerance testing (OGTT), and/or graded glucose infusion testing. Results Geriatric monkeys exhibited glucose intolerance with impaired glucose‐stimulated insulin secretion following IVGTT. Repeat IVGTT and OGTT assessments were inconsistent. Monkeys with low glucose‐stimulated insulin secretion after graded glucose infusion exhibited elevated blood glucose levels. Conclusion IVGTT and graded glucose infusion protocols revealed differences in glucose tolerance among green monkeys at single time points, including age‐dependent differences suggestive of shifts in pancreatic beta‐cell functional capacity, but care should be applied to study design and the interpretation of data in the setting of longitudinal studies.

Chiral BINOL-derived pyrophosphoric acid catalysts were developed and used for the regio- and enantioselective aza-Friedel–Crafts reaction of phenols with aldimines. ortho/para-Directing phenols could react at the para-position selectively with moderate to good enantioselectivities. Moreover, the gram-scale transformation of a product into the key intermediate for the antifungal agent (R)-bifonazole was demonstrated., ファイル公開：2019/12/01

Pancreatic α cells proliferate at a low rate, and little is known about the control of this process. Here we report the characterization of human α cells by large-scale, single-cell RNA sequencing coupled with pseudotime ordering. We identified two large subpopulations and a smaller cluster of proliferating α cells with increased expression of genes involved in cell-cycle regulation. The proliferating α cells were differentiated, had normal levels of GCG expression, and showed no signs of cellular stress. Proliferating α cells were detected in both the G1S and G2M phases of the cell cycle. Human α cells proliferate at a fivefold higher rate than human β cells and express lower levels of the cell-cycle inhibitors CDKN1A and CDKN1C. Collectively, this study provides the gene signatures of human α cells and the genes involved in their cell division. The lower expression of two cell-cycle inhibitors in human α cells could account for their higher rate of proliferation compared with their insulin-producing counterparts.

We report on a comprehensive measurement system for mobility and energy states of charge carriers in matter under dynamic chemical doping. The temporal evolution of the iodine doping process of poly(3-hexylthiophene) (P3HT) was monitored directly through electron paramagnetic resonance (EPR) and optical absorption spectroscopy, as well as differential electrical conductivity by the microwave conductivity measurement. The increase in conductivity was observed after the EPR intensity reached a maximum and declined thereafter, and the conductivity finally reached ∼80 S cm–1. The carrier species changed from a paramagnetic polaron with an estimated mobility of μP+ ≈ 2 × 10–3 cm2 V–1 s–1 to an antiferromagnetic polaron pair with μPP+ ≈ 0.6 cm2 V–1 s–1. The technique presented here can be a ubiquitous method for rapid and direct observation of charge carrier mobility and energy states in p-type semiconducting materials as a completely noncontact, experimental, and quantitative technique.

Significance The lobules are the functional units of the liver. They consist of 15–25 layers of hepatocytes with specialized metabolic functions and gene expression patterns relative to their position along the lobule, a phenomenon referred to as metabolic zonation. The Wnt/β-catenin pathway regulates hepatocyte function but how the zonation is controlled to meet the metabolic demands of the liver is unclear. Glucagon regulates hepatic function. We now demonstrate that glucagon contributes to liver zonation by interacting and opposing the actions of the Wnt/β-catenin pathway., Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal function. Wnt/β-catenin signaling controls metabolic zonation by activating genes in the perivenous hepatocytes, while suppressing genes in the periportal counterparts. We now demonstrate that glucagon opposes the actions of Wnt/β-catenin signaling on gene expression and metabolic zonation pattern. The effects were more pronounced in the periportal hepatocytes where 28% of all genes were activated by glucagon and inhibited by Wnt/β-catenin. The glucagon and Wnt/β-catenin receptors and their signaling pathways are uniformly distributed in periportal and perivenous hepatocytes and the expression is not regulated by the opposing signal. Collectively, our results show that glucagon controls gene expression and metabolic zonation in the liver through a counterplay with the Wnt/β-catenin signaling pathway.

Chiral C2- and C1-symmetric BINOL-derived bis(phosphoric acid) catalysts facilitated the enantioselective aza-Friedel–Crafts reaction of 2-methoxyfuran with α-ketimino esters., Chiral C2- and C1-symmetric BINOL-derived bis(phosphoric acid) catalysts, which have OP( 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O)(OH)2/OP( 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O)(OH)(OR) moieties at the 2,2′-positions, were developed and used for the enantioselective aza-Friedel–Crafts reaction of 2-methoxyfuran with α-ketimino esters for the first time. The intramolecular conjugated double hydrogen bond network is a key to increasing the Brønsted acidity and preventing deactivation of the catalysts. Highly functionalized α-amino acid derivatives with a chiral quaternary carbon center could be transformed into versatile optically active N- and O-heterocycles and an α-aryl-substituted serine.

Cationic amphiphilic drugs (CADs) can induce the hyperaccumulation of phospholipids in cells and tissues. This side effect, which is known as drug-induced phospholipidosis, is sometimes problematic in the development and clinical use of CADs. It is known that CADs generally interact with phospholipids via both hydrophobic and acid-base interactions, and CADs with the larger affinity to phospholipid exhibit the larger induction risk. To develop a chromatographic assay system to predict the phospholipidosis-inducing potential with considering the acid-base interaction between CAD and phosphate group of phospholipid, hydrophilic interaction chromatographic (HILIC) methods were tested in this study. First, a PC HILIC column with phosphocholine groups on a packed material was used. The acid-base or other hydrophilic interactions to the stationary phase differed among basic drugs, and retention to the PC HILIC column did not accurately reflect the induction potential of phospholipidosis. As an alternative HILIC approach, the elution of CADs with the phosphate buffer from an amide column was tested. The elution effect, which is expressed as ratio of retention factors between different phosphate content in the mobile phase, closely correlated with the induction potential. Using the elution effect and retention factor to a reversed-phase HPLC column, the phospholipidosis-inducing drugs were clearly discriminated from the non-inducers. These results suggest that the proposed chromatographic approach can screen phospholipidosis-inducing drugs.

Pancreatic islets comprise of endocrine cells with distinctive hormone expression patterns. The endocrine cells show functional differences in response to normal and pathological conditions. The goal of this protocol is to generate high-quality, large-scale transcriptome data of each endocrine cell type with the use of a droplet-based microfluidic single-cell RNA sequencing technology. Such data can be utilized to build the gene expression profile of each endocrine cell type in normal or specific conditions. The process requires careful handling, accurate measurement, and rigorous quality control. In this protocol, we describe detailed steps for human pancreatic islets dissociation, sequencing, and data analysis. The representative results of about 20,000 human single islet cells demonstrate the successful application of the protocol.

Background We aimed to investigate the efficacy and safety of landiolol in Japanese patients with recurrent hemodynamically unstable ventricular tachycardia or recurrent ventricular fibrillation (recurrent VT/VF).Methods and Results:This was an open-label, uncontrolled, multicenter study. Patients with hemodynamically unstable VT or VF 24 h prior to providing informed consent, and who were refractory to class III antiarrhythmic drugs, were enrolled. Landiolol was started at a dose of 1 μg/kg/min, after VT/VF was suppressed with electrical defibrillation. Landiolol was titrated up to 10 μg/kg/min in 1 h and adjusted between 1 and 40 μg/kg/min for the efficacy assessment (1-49 h). The primary efficacy endpoint was the proportion of patients free from recurrent VT/VF. Secondary efficacy endpoints included the number of recurrent VT/VF events and the survival rate 30 days after the start of landiolol treatment. Adverse events (AEs) were assessed for safety; 27 and 29 patients were analyzed for efficacy and safety, respectively. The proportion of patients free from recurrent VT/VF was 77.8% (95% CI 57.1-89.3). The mean (±standard deviation) number of recurrent VT/VF events was 9.3±7.9. The survival rate was 96.3%. The overall incidence of AEs and of serious AEs was 72.4% and 6.9%, respectively. Conclusions Landiolol may be useful for Japanese patients with recurrent VT/VF who do not respond to class III antiarrhythmic drugs.

Inactivating mutations in the insulin receptor results in extreme insulin resistance. The resulting hyperglycemia is very difficult to treat, and patients are at risk for early morbidity and mortality from complications of diabetes. We used the insulin receptor antagonist S961 to induce severe insulin resistance, hyperglycemia, and ketonemia in mice. Using this model, we show that glucagon receptor (GCGR) inhibition with a monoclonal antibody normalized blood glucose and β-hydroxybutyrate levels. Insulin receptor antagonism increased pancreatic β-cell mass threefold. Normalization of blood glucose levels with GCGR-blocking antibody unexpectedly doubled β-cell mass relative to that observed with S961 alone and 5.8-fold over control. GCGR antibody blockage expanded α-cell mass 5.7-fold, and S961 had no additional effects. Collectively, these data show that GCGR antibody inhibition represents a potential therapeutic option for treatment of patients with extreme insulin-resistance syndromes.

Pancreatic islet cells are critical for maintaining normal blood glucose levels, and their malfunction underlies diabetes development and progression. We used single-cell RNA sequencing to determine the transcriptomes of 1,492 human pancreatic α, β, δ, and PP cells from non-diabetic and type 2 diabetes organ donors. We identified cell-type-specific genes and pathways as well as 245 genes with disturbed expression in type 2 diabetes. Importantly, 92% of the genes have not previously been associated with islet cell function or growth. Comparison of gene profiles in mouse and human α and β cells revealed species-specific expression. All data are available for online browsing and download and will hopefully serve as a resource for the islet research community.

Novel, triphenylamino benzothiazole-based excited-state intramolecular proton transfer (ESIPT) and non-ESIPT fluorophores were prepared by Suzuki coupling reactions. Their photophysical properties in solution, aqueous suspension, and in the solid state were systematically investigated. High fluorescence quantum efficiencies (Φsol≈95 %; Φsolid≈88 %), moderate Stokes shifts (≈8000 cm−1), microenvironment-sensitive and molecular-framework-dependent emission are the striking features of the protocol described here. Solid-state emission was modulated and interpreted as a crossover effect of π–π interactions using single-crystal X-ray analyses. The nonplanar/twisted framework of the system helps to avoid noncovalent interactions, facilitating the suppression of fluorescence quenching in the solid state with high quantum efficiency over 88 %.

The importance of community-based care systems has increased due to the highly aging population and diversity of disease. To enhance the cooperation among healthcare professionals in community-based care systems, a two-day on-site training program for community pharmacists based on a multidisciplinary team approach was conducted at the Medical Science Hospital of Shiga University from April 2015 to March 2017. There were two professional courses in this training program: the palliative care course and nutrition support course. Both courses consisted of common pharmaceutical care training as follows: regional cooperation among healthcare professionals, pharmacist's clinical activities in the ward, pressure ulcer care, infection control, and aseptic technique for parenteral solutions. Each course was limited to 2 participants. A questionnaire was given to participants in the training program. Seventy-five pharmacists participated in the training and all of them answered the questionnaire. According to the questionnaire, 86% of participants felt that 2 days was an appropriate term for the training program. Positive answers regarding the content of each program and overall satisfaction were given by 100% and 99% of the participants, respectively. In the categorical classification of free comments regarding the expected change in pharmacy practice after the training, both "support for patients under nutritional treatment" and "cooperation with other medical staff" were answered by 24 participants. These results suggested that the 2-day on-site training for community pharmacists facilitated cooperation among healthcare professionals in the community.

Proinsulin is a misfolding-prone protein, making its biosynthesis in the endoplasmic reticulum (ER) a stressful event. Pancreatic β-cells overcome ER stress by activating the unfolded protein response (UPR) and reducing insulin production. This suggests that β-cells transition between periods of high insulin biosynthesis and UPR-mediated recovery from cellular stress. We now report the pseudotime ordering of single β-cells from humans without diabetes detected by large-scale RNA sequencing. We identified major states with 1) low UPR and low insulin gene expression, 2) low UPR and high insulin gene expression, or 3) high UPR and low insulin gene expression. The latter state was enriched for proliferating cells. Stressed human β-cells do not dedifferentiate and show little propensity for apoptosis. These data suggest that human β-cells transition between states with high rates of biosynthesis to fulfill the body’s insulin requirements to maintain normal blood glucose levels and UPR-mediated recovery from ER stress due to high insulin production.