Host lactosylceramide enhances Edwardsiella tarda infection.

Edwardsiella tarda is a Gram-negative bacterium causing economic damage in aquaculture. The interaction of E. tarda with microdomains is an important step in the invasion, but the target molecules in microdomains remain undefined. Here, we found that intraperitoneal injection of E. tarda altered splenic glycosphingolipid patterns in the model host medaka (Oryzias latipes) accompanied by alteration of glycosphingolipid metabolism-related gene expressions, suggesting that glycosphingolipid levels are involved in E. tarda infection. To ascertain the significance of glycosphingolipids in the infection, fish cell lines, DIT29 cells with a high amount of lactosylceramide (LacCer) and glucosylceramide (GlcCer), and GAKS cells with a low amount of these lipids, were treated with methyl-ß-cyclodextrin to disrupt the microdomain. E. tarda infection was suppressed in DIT29 cells, but not in GAKS cells, suggesting the involvement of microdomain LacCer and GlcCer in the infection. DL-threo-1-phenyl-2-palmitoylamino-3-morpholino-1-propanol, an inhibitor of glycosphingolipid-synthesis, attenuated the infection in DIT29 cells, while Neu3-overexpressing GAKS cells, which accumulated LacCer, enhanced the infection. E. tarda possessed binding ability towards LacCer, but not GlcCer, and LacCer preincubation declined the infection towards fish cells, possibly due to the masking of binding sites. The present study suggests that LacCer may be a positive regulator of E. tarda invasion.

Role of the Transcription Factor MAFA in the Maintenance of Pancreatic ß-Cells.

Pancreatic ß-cells are specialized to properly regulate blood glucose. Maintenance of the mature ß-cell phenotype is critical for glucose metabolism, and ß-cell failure results in diabetes mellitus. Recent studies provide strong evidence that the mature phenotype of ß-cells is maintained by several transcription factors. These factors are also required for ß-cell differentiation from endocrine precursors or maturation from immature ß-cells during pancreatic development. Because the reduction or loss of these factors leads to ß-cell failure and diabetes, inducing the upregulation or inhibiting downregulation of these transcription factors would be beneficial for studies in both diabetes and stem cell biology. Here, we discuss one such factor, i.e., the transcription factor MAFA. MAFA is a basic leucine zipper family transcription factor that can activate the expression of insulin in ß-cells with PDX1 and NEUROD1. MAFA is indeed indispensable for the maintenance of not only insulin expression but also function of adult ß-cells. With loss of MAFA in type 2 diabetes, ß-cells cannot maintain their mature phenotype and are dedifferentiated. In this review, we first briefly summarize the functional roles of MAFA in ß-cells and then mainly focus on the molecular mechanism of cell fate conversion regulated by MAFA.

Oxysterol-binding protein-related protein (ORP) 6 localizes to the ER and ER-plasma membrane contact sites and is involved in the turnover of PI4P in cerebellar granule neurons.

Oxysterol-binding protein (OSBP)-related proteins (ORPs) are conserved lipid binding proteins found in organisms ranging from yeast to mammals. Recent findings have indicated that these proteins mainly localize to contact sites of 2 different membranous organelles. ORP6, a member of the ORP subfamily III, is one of the least studied ORPs. Using approaches in molecular cell biology, we attempted to study the characteristics of ORP6 and found that ORP6 is abundantly expressed in mouse cultured neurons. Deconvolution microscopy of cultured cerebellar granular cells revealed that ORP6 is localized to the endoplasmic reticulum (ER) and ER-plasma membrane (PM) contact sites, where it co-localized with extended synaptotagmin2 (E-Syt2), a well-known ER-PM contact site marker. E-Syt2 also co-localized with ORP3, another subfamily III member, and ORP5, a subfamily IV member. However, ORP5 does not distribute to the same ER-PM contact sites as subfamily III members. Also, the co-expression of ORP3 but not ORP5 altered the distribution of ORP6 into the processes of cerebellar neurons. Immunoprecipitation demonstrated binding between the intermediate region of ORP6 and ORP3 or ORP6 itself. Additionally, the localization of ORP6 in the PM decreased when co-expressed with the intermediate region of ORP6, in which the pleckstrin homology (PH) domain and OSBP-related ligand binding domain (ORD) are deleted. Over-expression of this intermediate region shifted the location of a phophtidylinositol-4-phosphate (PI4P) marker from the Golgi to the PM. Knockdown of ORP6 resulted in the same shift of the PI4P marker. Collectively, our data suggests that the recruitment of ORP6 to ER-PM contact sites is involved in the turnover of PI4P in cerebellar granular neurons.

Genome-wide profiling of histone H3K27 acetylation featured fatty acid signalling in pancreatic beta cells in diet-induced obesity in mice.

AIMS/HYPOTHESIS: Epigenetic regulation of gene expression has been implicated in the pathogenesis of obesity and type 2 diabetes. However, detailed information, such as key transcription factors in pancreatic beta cells that mediate environmental effects, is not yet available. METHODS: To analyse genome-wide cis-regulatory profiles and transcriptome of pancreatic islets derived from a diet-induced obesity (DIO) mouse model, we conducted chromatin immunoprecipitation coupled with high-throughput sequencing (ChIP-Seq) of histone H3 lysine 27 acetylation (histone H3K27ac) and high-throughput RNA sequencing. Transcription factor-binding motifs enriched in differential H3K27ac regions were examined by de novo motif analysis. For the predicted transcription factors, loss of function experiments were performed by transfecting specific siRNA in INS-1, a rat beta cell line, with and without palmitate treatment. Epigenomic and transcriptional changes of possible target genes were evaluated by ChIP and quantitative RT-PCR. RESULTS: After long-term feeding with a high-fat diet, C57BL/6J mice were obese and mildly glucose intolerant. Among 39,350 islet cis-regulatory regions, 13,369 and 4610 elements showed increase and decrease in ChIP-Seq signals, respectively, significantly associated with global change in gene expression. Remarkably, increased H3K27ac showed a distinctive genomic localisation, mainly in the proximal-promoter regions, revealing enriched elements for nuclear respiratory factor 1 (NRF1), GA repeat binding protein α (GABPA) and myocyte enhancer factor 2A (MEF2A) by de novo motif analysis, whereas decreased H3K27ac was enriched for v-maf musculoaponeurotic fibrosarcoma oncogene family protein K (MAFK), a known negative regulator of beta cells. By siRNA-mediated knockdown of NRF1, GABPA or MEF2A we found that INS-1 cells exhibited downregulation of fatty acid ß-oxidation genes in parallel with decrease in the associated H3K27ac. Furthermore, in line with the epigenome in DIO mice, palmitate treatment caused increase in H3K27ac and induction of ß-oxidation genes; these responses were blunted when NRF1, GABPA or MEF2A were suppressed. CONCLUSIONS/INTERPRETATION: These results suggest novel roles for DNA-binding proteins and fatty acid signalling in obesity-induced epigenomic regulation of beta cell function. DATA AVAILABILITY: The next-generation sequencing data in the present study were deposited at ArrayExpress. RNA-Seq: Dataset name: ERR2538129 (Control), ERR2538130 (Diet-induced obesity) Repository name and number: E-MTAB-6718 - RNA-Seq of pancreatic islets derived from mice fed a long-term high-fat diet against chow-fed controls. ChIP-Seq: Dataset name: ERR2538131 (Control), ERR2538132 (Diet-induced obesity) Repository name and number: E-MTAB-6719 - H3K27ac ChIP-Seq of pancreatic islets derived from mice fed a long-term high-fat diet (HFD) against chow-fed controls.

Paternal allelic mutation at the Kcnq1 locus reduces pancreatic ß-cell mass by epigenetic modification of Cdkn1c.

Genetic factors are important determinants of the onset and progression of diabetes mellitus. Numerous susceptibility genes for type 2 diabetes, including potassium voltage-gated channel, KQT-like subfamily Q, member1 (KCNQ1), have been identified in humans by genome-wide analyses and other studies. Experiments with genetically modified mice have also implicated various genes in the pathogenesis of diabetes. However, the possible effects of the parent of origin for diabetes susceptibility alleles on disease onset have remained unclear. Here, we show that a mutation at the Kcnq1 locus reduces pancreatic ß-cell mass in mice by epigenetic modulation only when it is inherited from the father. The noncoding RNA KCNQ1 overlapping transcript1 (Kcnq1ot1) is expressed from the Kcnq1 locus and regulates the expression of neighboring genes on the paternal allele. We found that disruption of Kcnq1 results in reduced Kcnq1ot1 expression as well as the increased expression of cyclin-dependent kinase inhibitor 1C (Cdkn1c), an imprinted gene that encodes a cell cycle inhibitor, only when the mutation is on the paternal allele. Furthermore, histone modification at the Cdkn1c promoter region in pancreatic islets was found to contribute to this phenomenon. Our observations suggest that the Kcnq1 genomic region directly regulates pancreatic ß-cell mass and that genomic imprinting may be a determinant of the onset of diabetes mellitus.

Mechanism of the Dendritic Translation and Localization of Brain-derived Neurotrophic Factor.

Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor critical for synaptic plasticity, neuronal development and neurite extension. BDNF mRNA is transported to dendrites and axons, where it is expressed locally. We previously reported that dendritic targeting elements in the BDNF 3' UTR are necessary for dendritic transport and interact with cytoplasmic polyadenylation element binding protein 1. Here, we demonstrated that the short 3' UTR directs local translation of BDNF and that locally synthesized BDNF exists in a novel compartment that does not co-localize with markers of endosomes, endoplasmic reticulum, Golgi or the trans-Golgi network. Further, locally synthesized BDNF vesicles co-localized with Bicaudal-D2 (BicD2), a member of dynein motor complex proteins. Silencing BicD2 significantly reduced BDNF local synthesis in dendrites. These new findings may underlie the mechanism of local neuronal response to environmental stimuli.

[Severe Hemostatic Dysfunction during Multiple Spinal Fusion Surgery in a Patient with Multiple Myeloma].

We report a patient with multiple myeloma who developed severe hemostatic dysfunction during spinal fusion surgery. A 74-year-old man presented with lower limb paralysis due to thoracic supine pathological fracture and was scheduled for spinal fusion surgery. He suffered from multiple myeloma for decades but did not present with any significant abnormalities in a preoperative blood exam. Prothrombin time international normalized ratio (PT-INR, 0.97) and activated partial thromboplastin time (APTT, 31 sec) were normal. Surgeons confronted hemostatic difficulty during surgery. At the point of 1,000 ml blood loss, PT-INR was 9.99, APTT was 300 sec, and platelet count was 116,000 x µl(-1). The patient was administered 1,400 ml of frozen plasma concentrate; PT-INR and APTT recovered to 1.04 and 39.6 sec, respectively. Hemostatic dysfunction in this patient may have resulted from an inherent coagulation deficiency associated with multiple myeloma.

MafA is critical for maintenance of the mature beta cell phenotype in mice.

AIMS/HYPOTHESIS: The plasticity of adult somatic cells allows for their dedifferentiation or conversion to different cell types, although the relevance of this to disease remains elusive. Perturbation of beta cell identity leading to dedifferentiation may be implicated in the compromised functions of beta cells in diabetes, which is a current topic of islet research. This study aims to investigate whether or not v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (MafA), a mature beta cell marker, is involved in maintaining mature beta cell phenotypes. METHODS: The fate and gene expression of beta cells were analysed in Mafa knockout (KO) mice and mouse models of diabetes in which the expression of MafA was reduced in the majority of beta cells. RESULTS: Loss of MafA reduced the beta to alpha cell ratio in pancreatic islets without elevating blood glucose to diabetic levels. Lineage tracing analyses showed reduced/lost expression of insulin in most beta cells, with a minority of the former beta cells converted to glucagon-expressing cells in Mafa KO mice. The upregulation of genes that are normally repressed in mature beta cells or transcription factors that are transiently expressed in endocrine progenitors was identified in Mafa KO islets as a hallmark of dedifferentiation. The compromised beta cells in db/db and multiple low-dose streptozotocin mice underwent similar dedifferentiation with expression of Mafb, which is expressed in immature beta cells. CONCLUSIONS/INTERPRETATION: The maturation factor MafA is critical for the homeostasis of mature beta cells and regulates cell plasticity. The loss of MafA in beta cells leads to a deeper loss of cell identity, which is implicated in diabetes pathology.

Generation and characterization of MafA-Kusabira Orange mice.

MafA and MafB are basic leucine zipper transcription factors expressed in mature pancreatic ß- and α-cells, respectively. MafA is not only an insulin gene transcription factor but is also critical for the maturation and maintenance of ß-cell function, whereas MafB is expressed in immature ß-cells during development and in compromised ß-cells in diabetes. In this study, we developed a mouse model to easily trace the promoter activity of MafA in ß-cells as a tool for studying ß-cell differentiation, maturation, regeneration and function using the expression of the fluorescent protein Kusabira Orange (KOr) driven by the BAC-mafA promoter. The expression of KOr was highly restricted to ß-cells in the transgenic pancreas. By crossing MafA-KOr mice with MafB(GFP/+) reporter mice, simultaneous monitoring of MafA and MafB expressions in the isolated islets was successfully performed. This system can be a useful tool for examining dynamic changes in the differentiation and function of pancreatic islets by visualizing the expressions of MafA and MafB.

Muscle relaxant effects on insertion efficacy of the laryngeal mask ProSeal(®) in anesthetized patients: a prospective randomized controlled trial.

BACKGROUND: Anesthesiologists often encounter LMA-ProSeal(®) (ProSeal) insertion difficulty due to its large cuff size. We performed a randomized clinical trial to examine how insertion efficacy and sealing pressure of ProSeal are affected by muscle relaxant administration in anesthetized patients. METHODS: Our adult patients were either administered rocuronium (0.9 mg kg(-1)) as a muscle relaxant (R group; 40 patients) or not (C group; 40 patients). Anesthesia was induced with propofol and fentanyl. We compared the two groups with regard to the number of attempts required for successful insertion, sealing pressure, and subjective difficulty for insertion. RESULTS: Total insertion attempts required for successful ventilation in the two groups were one (R group, 38 patients; C group, 28 patients), two (R group, one patient; C group, seven patients), and three (R group, one patient; C group, five patients), revealing a significant difference between groups (p < 0.001). Sealing pressure was significantly higher in the R group than in the C group (R group, 27.4 ± 5.4 cmH2O; C group, 21.2 ± 5.2 cmH2O; p < 0.001). Leakage volume by mechanical ventilation was significantly smaller in the R group than in the C group (R group, 17.4 ± 29.1 ml; C group, 46.8 ± 45.5 ml; p < 0.001). Subjective difficulty of insertion was significantly lower in the R group than in the C group (R group, 12.3 ± 23.1 mm; C group, 39.4 ± 31.9 mm; p < 0.001). CONCLUSIONS: Muscle relaxation appears to facilitate ProSeal insertion efficacy by enabling higher successful insertion rates, higher sealing pressure, lower leakage volume, and lower subjective difficulty of insertion in anesthetized patients.

Gene expression of cytokines and prostaglandin metabolism-related proteins in eosinophilic otitis media.

The objective of this study was to investigate the levels of gene expression in the middle ear mucosa of 2 patients diagnosed with eosinophilic otitis media. One patient with severe hearing loss showed high expression levels of genes encoding IL-5 and IL-33 receptors.

Single-housing-induced islet epigenomic changes are related to polymorphisms in diabetic KK mice.

A lack of social relationships is increasingly recognized as a type 2 diabetes (T2D) risk. To investigate the underlying mechanism, we used male KK mice, an inbred strain with spontaneous diabetes. Given the association between living alone and T2D risk in humans, we divided the non-diabetic mice into singly housed (KK-SH) and group-housed control mice. Around the onset of diabetes in KK-SH mice, we compared H3K27ac ChIP-Seq with RNA-Seq using pancreatic islets derived from each experimental group, revealing a positive correlation between single-housing-induced changes in H3K27ac and gene expression levels. In particular, single-housing-induced H3K27ac decreases revealed a significant association with islet cell functions and GWAS loci for T2D and related diseases, with significant enrichment of binding motifs for transcription factors representative of human diabetes. Although these H3K27ac regions were preferentially localized to a polymorphic genomic background, SNVs and indels did not cause sequence disruption of enriched transcription factor motifs in most of these elements. These results suggest alternative roles of genetic variants in environment-dependent epigenomic changes and provide insights into the complex mode of disease inheritance.

Macroarray expression analysis of cytokines and prostaglandin metabolism-related genes in chronic rhinosinusitis.

Background: Chronic rhinosinusitis (CRS) can be divided into endotypes by functional or pathophysiologic findings. Objective: The aim of this study was to analyze the expression of cytokines, prostaglandin (PG) synthases, and their receptors related to the pathogenesis of CRS, especially those contributing to nasal polyp (NP) formation. Methods: NPs and uncinate tissue (UT) samples were collected from 90 patients who underwent endoscopic sinus surgery. They included 75 patients with CRS (including 45 with eosinophilic CRS [eCRS] and 30 with non-eCRS) and 15 patients without CRS. A total of 30 genes were selected for our original DNA array plate to analyze the levels of expression of 10 cytokines (IFN-γ, IL-4, IL-5, IL-10, IL-13, IL-17A, IL-22, IL-25, IL-33, and TSLP), 4 prostaglandin synthases (prostaglandin D2 [PGD2] synthase, prostaglandin E2 synthase, COX-1, and COX-2), and their 16 receptors. Clustering analysis was performed according to the expression results, and clinical findings of patients from each cluster were investigated. Results: The samples could be divided into 3 clusters. Cluster 1 showed elevated levels of expression of IL4, IL5, IL13, TSLP, IL1RL1 (ST2 [an IL-33 receptor]), HPGDS, and GPR44 (CRTH2, a PGD2 receptor); cluster 2 showed elevated levels of expression of IL17A and PTGES; and cluster 3 showed an elevated level of expression of IL25. Regarding clinical features, the main characteristics of each cluster were as follows: NPs from patients with eCRS for cluster 1, NPs and/or UT samples from patients with non-eCRS for cluster 2, and UTs from patients with non-CRS for cluster 3. Conclusion: The results suggest that there are associations between type 2 inflammation/PGD2 and eCRS and also between type 3 inflammation/prostaglandin E2 and non-eCRS.

Glucocorticoid receptor-NECAB1 axis can negatively regulate insulin secretion in pancreatic ß-cells.

The mechanisms of impaired glucose-induced insulin secretion from the pancreatic ß-cells in obesity have not yet been completely elucidated. Here, we aimed to assess the effects of adipocyte-derived factors on the functioning of pancreatic ß-cells. We prepared a conditioned medium using 3T3-L1 cell culture supernatant collected at day eight (D8CM) and then exposed the rat pancreatic ß-cell line, INS-1D. We found that D8CM suppressed insulin secretion in INS-1D cells due to reduced intracellular calcium levels. This was mediated by the induction of a negative regulator of insulin secretion-NECAB1. LC-MS/MS analysis results revealed that D8CM possessed steroid hormones (cortisol, corticosterone, and cortisone). INS-1D cell exposure to cortisol or corticosterone increased Necab1 mRNA expression and significantly reduced insulin secretion. The increased expression of Necab1 and reduced insulin secretion effects from exposure to these hormones were completely abolished by inhibition of the glucocorticoid receptor (GR). NECAB1 expression was also increased in the pancreatic islets of db/db mice. We demonstrated that the upregulation of NECAB1 was dependent on GR activation, and that binding of the GR to the upstream regions of Necab1 was essential for this effect. NECAB1 may play a novel role in the adipoinsular axis and could be potentially involved in the pathophysiology of obesity-related diabetes mellitus.

Proteomic analysis of cerebrospinal fluid before and after intrathecal injection of steroid into patients with postherpetic pain.

Postherpetic neuralgia (PHN) is the most frequent complication of herpes zoster, and the risk of it increases with age. By comparing proteomes of the cerebrospinal fluid (CSF) before and after the treatment, it may be possible to identify proteins that play a role in PHN and to predict responses to various treatments. To address this issue, we enrolled eight outpatients with PHN over 55 years of age and treated them with intrathecal methylprednisolone and lidocaine four times every week, collecting CSF samples before the treatment at each visit. We used 2D DIGE to investigate differentially expressed proteins in the CSF before and after repetitive treatments individually. Of 145 differentially expressed spots, the levels of nine proteins were decreased by the treatment including lipocalin-type prostaglandin D synthase (L-PGDS), and five were increased by it. The time course of alterations in the L-PGDS concentration in the CSF of each patient, detected by a pairwise and sandwich ELISA by SPR constructed here was well correlated with that by 1DE Western blots with anti-L-PGDS antibody, but was not related with that of the pain relief. The present study demonstrates that the real-time ELISA was precise and sensitive enough to measure L-PGDS in the CSF and that the steroid treatment decreased the L-PGDS concentration in CSF.

Activation of pancreatic-duct-derived progenitor cells during pancreas regeneration in adult rats.

The adult pancreas has considerable capacity to regenerate in response to injury. We hypothesized that after partial pancreatectomy (Px) in adult rats, pancreatic-duct cells serve as a source of regeneration by undergoing a reproducible dedifferentiation and redifferentiation. We support this hypothesis by the detection of an early loss of the ductal differentiation marker Hnf6 in the mature ducts, followed by the transient appearance of areas composed of proliferating ductules, called foci of regeneration, which subsequently form new pancreatic lobes. In young foci, ductules express markers of the embryonic pancreatic epithelium - Pdx1, Tcf2 and Sox9 - suggesting that these cells act as progenitors of the regenerating pancreas. The endocrine-lineage-specific transcription factor Neurogenin3, which is found in the developing embryonic pancreas, was transiently detected in the foci. Islets in foci initially resemble embryonic islets in their lack of MafA expression and lower percentage of beta-cells, but with increasing maturation have increasing numbers of MafA(+) insulin(+) cells. Taken together, we provide a mechanism by which adult pancreatic duct cells recapitulate aspects of embryonic pancreas differentiation in response to injury, and contribute to regeneration of the pancreas. This mechanism of regeneration relies mainly on the plasticity of the differentiated cells within the pancreas.

Effect of long-term confinement on metabolic and physiological parameters in mice.

Long-term and mild confinement or isolation in an enclosed environment can occur in situations such as disasters, specific political, economic or social events, nuclear shelters, seabed exploration, polar expeditions, and space travel. To investigate the effects of stress caused by long-term confinement in an enclosed environment in mammals, we divided 8-week-old C57BL/6J mice into four groups that were housed in a closed environment with a narrow metabolic cage (stress group), normal metabolic cage (control group), conventional cage (conventional group) or conventional cage with wire mesh floor (wire mesh group). The phenotypes of the mice were examined for four weeks, followed by behavioral tests. Weight gain suppression was observed in the stress group. Continuous analysis of these mice every two minutes for four weeks using an implanted measuring device showed a significantly decreased amount of spontaneous activity and subcutaneous temperature in the stress group. After housing in each environment for four weeks, the behavioral tests of mice in the stress group also revealed a shorter latency to fall off in the rotarod test and shorter stride length and interstep distance in the footprint test. Interestingly, the lower spontaneous activity of mice in the stress group was rescued by housing in conventional cages. These results suggest a temporary effect of long-term confinement in an enclosed environment as a chronic and mild stress on homeostasis in mammals.

A novel BICD2 mutation of a patient with Spinal Muscular Atrophy Lower Extremity Predominant 2.

The bicaudal D homolog 2 (BICD2) gene encodes a protein required for the stable complex of dynein and dynactin, which functions as a motor protein working along the microtubule cytoskeleton. Both inherited and de novo variants of BICD2 are reported with autosomal dominant spinal muscular atrophy with lower extremity predominance (SMALED2). Here, we report a male patient with a novel mutation in the BICD2 gene caused by a heterozygous substitution of arginine with cysteine at residue 162 (Arg162Cys); inherited from his asymptomatic mother. The patient showed typical clinical symptoms of SMALED2, which was genetically confirmed by sequencing. The Arg162Cys mutant clusters with four previously reported variants (c.361C>G, p.Leu121Val; c.581A>G, p.Gln194Arg; c.320C>T, p.Ser107Leu; c.565A>T, p.Ile189Phe) in a region that binds to the dynein-dynactin complex (DDC). The BICD2 domain structures were predicted and the Arg162Cys mutation was localized in the N-terminus coiled-coil segment 1 (CC1) domain. Protein modeling of BICD2's CC1 domain predicted that the Arg162Cys missense variant disrupted interactions with dynein cytoplasmic 1 heavy chain 1 within the DDC. The mutant did this by either changing the electrostatic surface potential or making a broader hydrophobic unit with the neighboring residues. This hereditary case supports the complex and broad genotype-phenotype correlation of BICD2 mutations, which could be explained by incomplete penetrance or variable expressivity in the next generation.

Applicability of composite materials for space radiation shielding of spacecraft.

Energetic ion beam experiments with major space radiation elements, 1H, 4He, 16O, 28Si and 56Fe, have been conducted to investigate the radiation shielding properties of composite materials. These materials are expected to be used for parts and fixtures of space vehicles due to both their mechanical strength and their space radiation shielding capabilities. Low Z materials containing hydrogen are effective for shielding protons and heavy ions due to their high stopping power and large fragmentation cross section per unit mass. The stopping power of the composite materials used in this work is intermediate between that of aluminum and polyethylene, which are typical structural and shielding materials used in space. The total charge-changing cross sections per unit mass, σUM, of the composite materials are 1.3-1.8 times larger than that of aluminum. By replacing conventional aluminum used for spacecraft with commercially available composite (carbon fiber / polyether ether ketone), it is expected that the shielding effect is increased by ∼17%. The utilization of composite materials will help mitigate the space radiation hazard on future deep space missions.

Islet cell dedifferentiation is a pathologic mechanism of long-standing progression of type 2 diabetes.

Dedifferentiation has been implicated in ß cell dysfunction and loss in rodent diabetes. However, the pathophysiological significance in humans remains unclear. To elucidate this, we analyzed surgically resected pancreatic tissues of 26 Japanese subjects with diabetes and 11 nondiabetic subjects, who had been overweight during adulthood but had no family history of diabetes. The diabetic subjects were subclassified into 3 disease stage categories, early, advanced, and intermediate. Despite no numerical changes in endocrine cells immunoreactive for chromogranin A (ChgA), diabetic islets showed profound ß cell loss, with an increase in α cells without an increase in insulin and glucagon double-positive cells. The proportion of dedifferentiated cells that retain ChgA immunoreactivity without 4 major islet hormones was strikingly increased in diabetic islets and rose substantially during disease progression. The increased dedifferentiated cell ratio was inversely correlated with declining C-peptide index. Moreover, a subset of islet cells converted into exocrine-like cells during disease progression. These results indicate that islet remodeling with dedifferentiation is the underlying cause of ß cell failure during the course of diabetes progression in humans.