Racemization of the substrate and product by serine palmitoyltransferase from Sphingobacterium multivorum yields two enantiomers of the product from d-serine.

Serine palmitoyltransferase (SPT) catalyzes the pyridoxal-5'-phosphate (PLP)-dependent decarboxylative condensation of l-serine and palmitoyl-CoA to form 3-ketodihydrosphingosine (KDS). Although SPT was shown to synthesize corresponding products from amino acids other than l-serine, it is still arguable whether SPT catalyzes the reaction with d-serine, which is a question of biological importance. Using high substrate and enzyme concentrations, KDS was detected after the incubation of SPT from Sphingobacterium multivorum with d-serine and palmitoyl-CoA. Furthermore, the KDS comprised equal amounts of 2S and 2R isomers. 1H-NMR study showed a slow hydrogen-deuterium exchange at Cα of serine mediated by SPT. We further confirmed that SPT catalyzed the racemization of serine. The rate of the KDS formation from d-serine was comparable to those for the α-hydrogen exchange and the racemization reaction. The structure of the d-serine-soaked crystal (1.65 Å resolution) showed a distinct electron density of the PLP-l-serine aldimine, interpreted as the racemized product trapped in the active site. The structure of the α-methyl-d-serine-soaked crystal (1.70 Å resolution) showed the PLP-α-methyl-d-serine aldimine, mimicking the d-serine-SPT complex prior to racemization. Based on these enzymological and structural analyses, the synthesis of KDS from d-serine was explained as the result of the slow racemization to l-serine, followed by the reaction with palmitoyl-CoA, and SPT would not catalyze the direct condensation between d-serine and palmitoyl-CoA. It was also shown that the S. multivorum SPT catalyzed the racemization of the product KDS, which would explain the presence of (2R)-KDS in the reaction products.

Structural insights into the substrate recognition of serine palmitoyltransferase from Sphingobacterium multivorum.

Serine palmitoyltransferase (SPT) is a key enzyme of sphingolipid biosynthesis, which catalyzes the pyridoxal-5'-phosphate-dependent decarboxylative condensation reaction of l-serine (l-Ser) and palmitoyl-CoA (PalCoA) to form 3-ketodihydrosphingosine called long chain base (LCB). SPT is also able to metabolize l-alanine (l-Ala) and glycine (Gly), albeit with much lower efficiency. Human SPT is a membrane-bound large protein complex containing SPTLC1/SPTLC2 heterodimer as the core subunits, and it is known that mutations of the SPTLC1/SPTLC2 genes increase the formation of deoxy-type of LCBs derived from l-Ala and Gly to cause some neurodegenerative diseases. In order to study the substrate recognition of SPT, we examined the reactivity of Sphingobacterium multivorum SPT on various amino acids in the presence of PalCoA. The S. multivorum SPT could convert not only l-Ala and Gly but also l-homoserine, in addition to l-Ser, into the corresponding LCBs. Furthermore, we obtained high-quality crystals of the ligand-free form and the binary complexes with a series of amino acids, including a nonproductive amino acid, l-threonine, and determined the structures at 1.40 to 1.55 Å resolutions. The S. multivorum SPT accommodated various amino acid substrates through subtle rearrangements of the active-site amino acid residues and water molecules. It was also suggested that non-active-site residues mutated in the human SPT genes might indirectly influence the substrate specificity by affecting the hydrogen-bonding networks involving the bound substrate, water molecules, and amino acid residues in the active site of this enzyme. Collectively, our results highlight SPT structural features affecting substrate specificity for this stage of sphingolipid biosynthesis.

[A case of intestinal myiasis in a bedridden elderly patient].

A 75-year-old man with type 2 diabetes and a history of previous empyema surgery was admitted to our hospital due to difficulty moving caused by chronic obstructive pulmonary disease and dehydration. During the first two days of hospitalization, intestinal myiasis was diagnosed after maggots were found in his diapers. After the maggots disappeared, he developed a fever, prompting antibiotic therapy for a suspected secondary infection, resulting in clinical improvement. Despite thorough home cleaning, no flies or maggots were found, and the source of infection and the fly species remained unknown. Recent reports suggest a higher prevalence of myiasis among the elderly, even with overall improvement in hygiene. While myiasis is typically mild, it is a condition that requires consideration in an aging society. Myiasis is a disease that should be considered in the differential diagnosis of the elderly, especially in people who are bedridden or frail.

Thermal plasticity of wing size and wing spot size in Drosophila guttifera.

Thermal plasticity of melanin pigmentation patterns in Drosophila species has been studied as a model to investigate developmental mechanisms of phenotypic plasticity. The developmental process of melanin pigmentation patterns on wings of Drosophila is divided into two parts, prepattern specification during the pupal period and wing vein-dependent transportation of melanin precursors after eclosion. Which part can be affected by thermal changes? To address this question, we used polka-dotted melanin spots on wings of Drosophila guttifera, whose spot areas are specified by wingless morphogen. In this research, we reared D. guttifera at different temperatures to test whether wing spots show thermal plasticity. We found that wing size becomes larger at lower temperature and that different spots have different reaction norms. Furthermore, we changed the rearing temperature in the middle of the pupal period and found that the most sensitive developmental periods for wing size and spot size are different. The results suggest that the size control mechanisms for the thermal plasticity of wing size and spot size are independent. We also found that the most sensitive stage for spot size was part of the pupal period including stages at which wingless is expressed in the polka-dotted pattern. Therefore, it is suggested that temperature change might affect the prepattern specification process and might not affect transportation through wing veins.

Urokinase-type plasminogen activator promotes corneal epithelial migration and nerve regeneration.

Urokinase-type plasminogen activator (uPA) is a serine protease that plays a central role in the pericellular fibrinolytic system, mediates the degradation of extracellular matrix proteins and activation of growth factors, and contributes to the regulation of various cellular processes including cell migration and adhesion, chemotaxis, and angiogenesis. The corneal epithelium responds rapidly to injury by initiating a wound healing process that involves cell migration, cell proliferation, and tissue remodeling. It is innervated by sensory nerve endings that play an important role in the maintenance of corneal epithelial homeostasis and in the wound healing response. We here investigated the role of uPA in corneal nerve regeneration and epithelial resurfacing after corneal injury with the use of uPA-deficient mice. Both the structure of the corneal epithelium and the pattern of corneal innervation in uPA-/- mice appeared indistinguishable from those in uPA+/+ mice. Whereas the cornea was completely resurfaced by 36-48 h after epithelial scraping in uPA+/+ mice, however, such resurfacing required at least 72 h in uPA-/- mice. Restoration of epithelial stratification was also impaired in the mutant mice. Fibrin zymography revealed that the expression of uPA increased after corneal epithelial scraping and returned to basal levels in association with completion of re-epithelialization in wild-type animals. Staining of corneal whole-mount preparations for ßIII-tubulin also revealed that the regeneration of corneal nerves after injury was markedly delayed in uPA-/- mice compared with uPA+/+ mice. Our results thus demonstrate an important role for uPA in both corneal nerve regeneration and epithelial migration after epithelial debridement, and they may provide a basis for the development of new treatments for neurotrophic keratopathy.

Urokinase-type plasminogen activator negatively regulates α-smooth muscle actin expression via Endo180 and the uPA receptor in corneal fibroblasts.

Corneal fibroblasts are embedded within an extracellular matrix composed largely of collagen type 1, proteoglycans, and other proteins in the corneal stroma, and their morphology and function are subject to continuous regulation by collagen. During wound healing and in various pathological conditions, corneal fibroblasts differentiate into myofibroblasts characterized by the expression of α-smooth muscle actin (α-SMA). Endo180, also known as urokinase-type plasminogen activator (uPA) receptor-associated protein (uPARAP), is a collagen receptor. Here we investigated whether targeting of Endo180 and the uPA receptor (uPAR) by uPA might play a role in the regulation of α-SMA expression by culturing corneal fibroblasts derived from uPA-deficient (uPA-/-) or wild-type (uPA+/+) mice in a collagen gel or on plastic. The expression of α-SMA was upregulated, the amounts of full-length Endo180 and uPAR were increased, and the levels of both transforming growth factor-ß (TGF-ß) expression and Smad3 phosphorylation were higher in uPA-/- corneal fibroblasts compared with uPA+/+ cells under the collagen gel culture condition. Antibodies to Endo180 inhibited these effects of uPA deficiency on α-SMA and TGF-ß expression, whereas a TGF-ß signaling inhibitor blocked the effects on Smad3 phosphorylation and α-SMA expression. Our results suggest that uPA deficiency might promote the interaction between collagen and Endo180 and thereby increase α-SMA expression in a manner dependent on TGF-ß signaling. Expression of α-SMA is thus negatively regulated by uPA through targeting of Endo180 and uPAR.

Hepatocyte-specific fibroblast growth factor 21 overexpression ameliorates high-fat diet-induced obesity and liver steatosis in mice.

Fibroblast growth factor (FGF) 21 is an endocrine growth factor mainly secreted by the liver in response to a ketogenic diet and alcohol consumption. FGF21 signaling requires co-receptor ß-klotho (KLB) co-acting with FGF receptors, which has pleiotropic metabolic effects, including induced hepatic fatty acid oxidation and ketogenesis, in human and animal models of obesity. We examined the hepatocyte-specific enhancer/promoter of FGF21 expression plasmids in high-fat diet-fed mice for 12 weeks. Hydrodynamic injection for FGF21 delivery every 6 weeks sustained high circulating levels of FGF21, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and liver steatosis. FGF21-induced lipolysis in the adipose tissue enabled the liver to be flooded with fat-derived FFAs. The hepatic expression of Glut2 and Bdh1 was upregulated, whereas that of gluconeogenesis-related genes, G6p and Pepck, and lipogenesis-related genes, Srebp-1 and Srebp-2, was significantly suppressed. FGF21 induced the phosphorylation of AMPK at Thr172 and Raptor at ser792 and suppressed that of mTOR at ser2448, which downregulated mTORC1 signaling and reduced IRS-1 phosphorylation at ser1101. Finally, in the skeletal muscle, FGF21 increased Glut4 and Mct2, a membrane protein that acts as a carrier for ketone bodies. Enzymes for ketone body catabolism (Scot) and citrate cycle (Cs, Idh3a), and a marker of regenerating muscle (myogenin) were also upregulated via increased KLB expression. Thus, FGF21-induced lipolysis was continuously induced by a high-fat diet and fat-derived FFAs might cause liver damage. Hepatic fatty acid oxidation and ketone body synthesis may act as hepatic FFAs' disposal mechanisms and contribute to improved liver steatosis. Liver-derived ketone bodies might be used for energy in the skeletal muscle. The potential FGF21-related crosstalk between the liver and extraliver organs is a promising strategy to prevent and treat metabolic syndrome-related nonalcoholic steatohepatitis.

Real-world outcomes of molecular targeted agents for patients with hepatocellular carcinoma over 80 years old.

AIM: There is insufficient evidence regarding the safety and efficacy of molecular targeted agents (MTAs) for elderly patients with hepatocellular carcinoma (HCC), who are likely to be vulnerable to adverse events (AEs) of therapy. The aim of this study was to compare sorafenib and lenvatinib use in elderly patients with HCC from the viewpoint of overall survival (OS) and rate of AE-induced MTA discontinuation. METHODS: This retrospective study included patients with HCC over 80 years old who received first-line molecular targeted therapy (MTT) at four hospitals between June 2009 and September 2019. They were divided into three groups according to the era and type of first-line MTA: E1-Sora (sorafenib, between 2009 and 2016), E2-Sora (sorafenib, between 2017 and 2019), and E2-Len (lenvatinib, between 2017 and 2019). RESULTS: The study included 173 patients (E1-Sora, n = 79; E2-Sora, n = 50; E2-Len, n = 44) with a median age of 81.9 years (range, 80-93 years). Median OS was 15.1 months in the entire cohort (E1-Sora, 12.7 months; E2-Sora, 20.5 months; E2-Len, 10.3 months). The rate of treatment discontinuation due to AEs was high in the entire cohort, especially in E1-Sora and E2-Len (49.4% in E1-Sora, 28.0% in E2-Sora, and 54.6% in E2-Len, p = 0.0753). More E2-Sora patients received subsequent MTT than E2-Len patients (E2-Sora, 50%; E2-Len, 28.6%; p = 0.0111). CONCLUSION: Both sorafenib and lenvatinib were effective and feasible for elderly patients with HCC. In terms of discontinuation due to AEs and subsequent MTT, sorafenib might be more desirable for elderly patients with HCC over 80 years.

[Successful Surgical Correction of Partial Atrioventricular Septal Defect in an Elderly Patient:Report of a Case].

There are only few reports on surgery for partial atrioventricular septal defect( pAVSD) in patients aged over 70 years. This report is about successful surgical correction of pAVSD in a 79-year-old women. Echocardiography showed left-sided atrioventricular valve regurgitation with cleft and ostium primum atrial septal defect, but without ventricular septal defect. Accordingly, she was diagnosed with pAVSD. Treatment plan included direct cleft closure, patch closure for the ostium primum atrial septal defect, and right atrioventricular annuloplasty. The postoperative course was uneventful. She was followed up without complications for four years. To the best of our knowledge, our patient is the oldest to undergo such surgical techniques in Japan to date.

Requirement for the collagen receptor Endo180 in collagen gel contraction mediated by corneal fibroblasts.

The interaction of keratocytes with extracellular matrix components plays an important role in the maintenance of corneal transparency and shape as well as in the healing of corneal wounds. In particular, the interaction of these cells with collagen and cell-mediated collagen contraction contribute to wound closure. Endo180 is a receptor for collagen that mediates its cellular internalization. We have now examined the role of Endo180 in collagen contraction mediated by corneal fibroblasts (activated keratocytes). Antibodies to Endo180 inhibited the contractile activity of mouse corneal fibroblasts embedded in a three-dimensional collagen gel and cultured in the presence of serum, with this effect being both concentration and time dependent and essentially complete at an antibody concentration of 0.2 µg/ml. Whereas corneal fibroblasts cultured in a collagen gel manifested a flattened morphology with prominent stress fibers under control conditions, they showed a spindlelike shape with few stress fibers in the presence of antibodies to Endo180. Antibodies to Endo180 had no effect on the expression of α-smooth muscle actin or the extent of collagen degradation in collagen gel cultures of corneal fibroblasts. Immunohistofluorescence analysis did not detect the expression of Endo180 in the unwounded mouse cornea. However, Endo180 expression was detected in keratocytes migrating into the wound area at 3 days after a corneal incisional injury. Together, our results suggest that Endo180 is required for the contraction of collagen matrix mediated by corneal fibroblasts and that its expression in these cells may contribute to the healing of corneal stromal wounds.

Attenuated effect of PNPLA3 on hepatic fibrosis by HSD17B13 in Japanese patients with non-alcoholic fatty liver disease.

BACKGROUND & AIMS: PNPLA3 rs738409 has been associated with increased risks of fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Recently, carriage of the rs6834314 G allele, which is in high linkage with rs72613567 of 17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13), was reported to be associated with a reduced risk of liver injury in NAFLD patients. We estimated the impact of these genetic variants on hepatic fibrosis in Japanese patients with NAFLD. METHODS: We analysed the associations of these genetic variants with liver histology in 290 Japanese patients with biopsy-proven NAFLD diagnosed during 2002-2019. During follow-up, 14 patients (4.8%) developed hepatocellular carcinoma. RESULTS: Prevalences of the PNPLA3 rs738409 genotypes were 0.17 for CC, 0.41 for CG, 0.42 for GG, and those for HSD17B13 rs6834314 were 0.54 for AA, 0.39 for AG and 0.07 for GG. There was no significant interaction between the PNPLA3 and HSD17B13 genotypes. Prevalences of advanced fibrosis according to PNPLA3/HSD17B13 genotypes were 0.16 for CC,CG/AG,GG, 0.20 for CC,CG/AA, 0.30 for GG/AG,GG and 0.37 for GG/AA. Multivariate analysis identified PNPLA3 GG as a predictor of advanced fibrosis (stage 3/4) in carriers of HSD17B13 AA (odds ratio 2.4, P = .041), but not HSD17B13 AG/GG (P = .776). The HSD17B13 genotype G was significantly associated with lower prevalences of severe inflammation and ballooning and tended to be associated with a higher prevalence of advanced steatosis. CONCLUSIONS: In Japanese patients with NAFLD, carriage of the HSD17B13 rs6834314 G allele attenuated the effect of the PNPLA3 rs738409 GG genotype on advanced hepatic fibrosis.

Effect of pemafibrate on fatty acid levels and liver enzymes in non-alcoholic fatty liver disease patients with dyslipidemia: A single-arm, pilot study.

AIM: Dyslipidemia (DL) is commonly associated with non-alcoholic fatty liver disease (NAFLD). Pemafibrate, a selective peroxisome proliferator activated receptor α modulator (SPPARMα), has been shown to improve liver function among patients with DL. The aim of this single-arm prospective study is to evaluate the efficacy of pemafibrate in NAFLD patients with DL. METHODS: Twenty NAFLD patients with DL who received pemafibrate (0.1 mg) twice a day for 12 weeks were prospectively enrolled in this study. The primary end-point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. RESULTS: Serum ALT levels decreased from 75.1 IU/L at baseline to 43.6 IU/L at week 12 (P = 0.001). Significant improvements in triglyceride, high-density lipoprotein cholesterol, total fatty acid, saturated fatty acid (SFA), and unsaturated fatty acid were also noted. The serum level of remnant-like protein cholesterol, SFA, and polyunsaturated / saturated fatty acid ratio (PUFA / SFA ratio) at baseline were correlated with change in ALT level (r = -0.53, r = -0.57, and r = 0.46, respectively). Change in PUFA and change in PUFA / SFA ratio were negatively correlated with change in ALT level (r = -0.49 and r = -0.53). No hepatic or renal adverse events were reported. CONCLUSIONS: Selective peroxisome proliferator activated receptor α could be a promising novel agent for treatment of NAFLD patients with DL by regulating fatty acid composition. A further long-term large-scale trial is warranted to confirm the efficacy of SPPARMα on NAFLD with DL.

Starvation tolerance associated with prolonged sleep bouts upon starvation in a single natural population of Drosophila melanogaster.

Large genetic variations in starvation tolerance in animals indicate that there are multiple strategies to cope with low-nutrient conditions. Fruit flies (Drosophila melanogaster) typically respond to starvation by suppressing sleep and enhancing locomotor activity presumably to search for food. However, we hypothesized that in a natural population, there are costs and benefits to sleep suppression under low-nutrient conditions and that conserving energy through sleep could be a better strategy depending on food availability. In this study, we quantified the variation in sleep-related traits in 21 wild-derived inbred lines from Katsunuma, Japan, under fed and starved conditions and analysed the relationship between those traits and starvation tolerance. Although most of the lines responded to starvation by suppressing the total time in sleep, there were indeed two lines that responded by significantly increasing the sleep-bout durations and thus not reducing the total time in sleep. These genotypes survived longer in acute starvation conditions compared to genotypes that responded by the immediate suppression of sleep, which could be due to the reduced metabolic rate during the long uninterrupted sleep bouts. The coexistence of the enhanced foraging and resting strategies upon starvation within a single population is consistent with the presence of a behavioural trade-off between food search and energy conservation due to unpredictable food availability in nature. These results provide insights into the evolutionary mechanisms that contribute to the maintenance of genetic variations underlying environmental stress resistance.

Inferring the demographic history of Japanese cedar, Cryptomeria japonica, using amplicon sequencing.

The evolution of a species depends on multiple forces, such as demography and natural selection. To understand the trajectory and driving forces of evolution of a target species, it is first necessary to uncover that species' population history, such as past and present population sizes, subdivision and gene flow, by using appropriate genetic markers. Cryptomeria japonica is a long-lived monoecious conifer species that is distributed in Japan. There are two main lines (omote-sugi and ura-sugi), which are distinguished by apparent differences in morphological traits that may have contributed to their local adaptation. The evolution of these morphological traits seems to be related to past climatic changes in East Asia, but no precise estimate is available for the divergence time of these two lines and the subsequent population dynamics in this species. Here, we analyzed the nucleotide variations at 120 nuclear genes in 94 individuals by using amplicon sequencing in combination with high-throughput sequencing technologies. Our analysis indicated that the population on Yakushima Island, the southern distribution limit of C. japonica in Japan, diverged from the other populations 0.85 million years ago (MYA). The divergence time of the other populations on mainland Japan was estimated to be 0.32 MYA suggesting that the divergence of omote-sugi and ura-sugi might have occurred before the last glacial maximum. Although we found modest levels of gene flow between the present populations, the long-term isolation and environmental heterogeneity caused by climatic changes might have contributed to the differentiation of the lines and their local adaptation.

Clinical and pathological features of sarcopenia-related indices in patients with non-alcoholic fatty liver disease.

BACKGROUND: Sarcopenia is diagnosed with the skeletal muscle index (SMI) or the sarcopenia index (SI). We previously reported that the ratio of skeletal muscle mass to body fat mass (SF ratio) was a novel index of sarcopenia in patients with non-alcoholic fatty liver disease (NAFLD). The aim of this retrospective study was to evaluate sarcopenia with these indices in patients with NAFLD. METHODS: One hundred and fifty-six consecutive patients with biopsy-proven NAFLD and alanine aminotransferase (ALT) >40 IU/L were enrolled. Liver function and body composition were evaluated in 121 patients after 12 months. We evaluated the relationship between histological findings, changes in liver function, and the SMI, SI, and SF ratio. RESULTS: Of the 156 patients enrolled, 13.5% and 26.3% were diagnosed with sarcopenia with the SMI and SI. In patients with hepatic fibrosis stage <2, the SI and the SF ratio were significantly greater than in patients with fibrosis stage ≥2. There was no difference in SMI between groups. In the cohort assessed at baseline and 12 months later, transaminase activity and SMI decreased significantly, and the SF ratio increased over time. A multivariate analysis revealed the presence of the PNPLA3 G allele and an increase in SF ratio (odds ratio, 7.406) as predictive factors of ALT reduction >30% from baseline. CONCLUSIONS: Due to the high prevalence of obesity, we should consider both skeletal muscle mass and body fat mass in the diagnosis and treatment of NAFLD. The SF ratio could be a useful index in sarcopenic NAFLD.

Effects of occupational status on social adjustment after laryngectomy in patients with laryngeal and hypopharyngeal cancer.

PURPOSE: This study was performed to examine the relationship of social adjustment with occupation and life changes in patients with laryngeal and hypopharyngeal cancer, from before laryngectomy to 1 year after hospital discharge. METHODS: The subjects were 27 patients with laryngeal and hypopharyngeal cancer who were admitted to hospital for laryngectomy and provided informed consent for participation in the study. The patients answered questionnaire surveys before surgery, and 3, 6, and 12 months after hospital discharge. Regarding social adjustment, social functioning (SF) and mental health (MH) in SF-36V2 were used as dependent variables, and time, occupation status, age, family structure, and sex as independent variables. Repeated measures analysis of variance was used to examine the main effect, and second- and third-order interactions were also examined. RESULTS: The age of the subjects was 62.9 ± 6.4 years and about 30% had an occupation. Loss of voice was the reason for 30% leaving work. In an examination of the main effects of the four variables, only age was significant regarding SF, and SF was favorable in subjects aged ≥ 64 years old. Regarding MH, age and family structure were significant, and MH was higher in older subjects who lived alone. The interaction between time and the other 3 variables was not significant. Only time/age/occupation was significant for MH. Regarding SF, a weak interaction was suggested, but it was not significant. CONCLUSION: Older subjects showed better social adjustment, and those who lived alone had better MH. These findings may have been due to a reduced environmental influence. MH of subjects with an occupation decreased more at 3 months or later after hospital discharge, compared to those without an occupation. Especially for younger patients, development of new approaches is required to allow families and colleagues of patients to understand the difficulties of patients with laryngeal and hypopharyngeal cancer.

FIB-4 Index and Diabetes Mellitus Are Associated with Chronic Kidney Disease in Japanese Patients with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). The aim of this retrospective study was to determine the risk factors for progression of CKD in patients with biopsy-proven NAFLD including patatin-like phospholipase domain containing 3 (PNPLA3) polymorphism. A total of 344 patients with biopsy-proven NAFLD were enrolled consecutively in this study. Multivariate analysis identified males (odds ratio (OR) 5.46), age (per 1 year, OR 1.07), and FIB-4 index (≥1.30, OR 3.85) as factors associated with CKD. Of the 154 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min, 30 had a deterioration in CKD stage and 15 developed CKD after 3 years. Multivariate analysis identified diabetes mellitus (OR 2.44) as a risk factor for deterioration in CKD stage, while diabetes mellitus (OR 21.54) and baseline eGFR (per 1 mL/min OR 0.88) were risk factors for development of CKD. PNPLA3 did not affect the change in eGFR. In NAFLD patients, a high FIB-4 index was associated with CKD to increases in the index linked to reductions in eGFR. In order to prevent development of CKD, an appropriate therapy focusing on renal function is needed for NAFLD patients, especially those with diabetes.

An innovative ovipositor for niche exploitation impacts genital coevolution between sexes in a fruit-damaging Drosophila.

Limited attention has been given to ecological factors influencing the coevolution of male and female genitalia. The innovative ovipositor of Drosophila suzukii, an invading fruit pest, represents an appealing case to document this phenomenon. The serrated saw-like ovipositor is used to pierce the hard skin of ripening fruits that are not used by other fruit flies that prefer soft decaying fruits. Here, we highlight another function of the ovipositor related to its involvement in genital coupling during copulation. We compared the morphology and coupling of male and female genitalia in this species to its sibling species, Drosophila subpulchrella, and to an outgroup species, Drosophila biarmipes These comparisons and a surgical manipulation indicated that the shape of male genitalia in D. suzukii has had to be adjusted to ensure tight coupling, despite having to abandon the use of a hook-like structure, paramere, because of the more linearly elongated ovipositor. This phenomenon demonstrates that ecological niche exploitation can directly affect the mechanics of genital coupling and potentially cause incompatibility among divergent forms. This model case provides new insights towards elucidating the importance of the dual functions of ovipositors in other insect species that potentially induce genital coevolution and ecological speciation.

Association between glaucoma severity and driving cessation in subjects with primary open-angle glaucoma.

BACKGROUND: The aim of this study, which included a baseline cross-sectional study and a 3-year follow-up prospective study, was to investigate the association between glaucomatous visual field damage and driving cessation in subjects with primary open-angle glaucoma (POAG). METHODS: A total of 211 POAG subjects divided into 3 groups according to POAG severity (mild, moderate, or severe) in the better eye were enrolled along with 148 control subjects; subjects were asked about changes in their driving status. In the 3-year follow-up study, 185 of the POAG subjects and 80 of the controls annually reported their driving status. Adjusted odds ratios and 95% confidence intervals for the prevalence and incidence of driving cessation were estimated with a multiple logistic regression model. RESULTS: In the original cross-sectional study, 11/148 (7%) members of the control group reported having given up driving over the previous 5 years; the corresponding figures for the mild POAG, moderate POAG, and severe POAG groups were 9/173 (5%), 0/22 (0%), and 5/16 (31%), respectively (p = 0.001, Fisher's exact test), with severe POAG found to be associated with driving cessation after adjustment for age, gender, systemic hypertension, and diabetes mellitus (odds ratio 11.52 [95% CI 2.87-46.35], ref. control, p = 0.001). In the follow-up study, the proportions of subjects who ceased driving were 1/80 (1.3%) in the control group, 8/152 (5.3%) in the mild POAG group, 5/22 (22.7%) in the moderate POAG group, and 2/11 (18.2%) in the severe POAG group (p = 0.001, Fisher's exact test). Moderate POAG and severe POAG in the better eye were found to be associated with driving cessation after adjustment for age, gender, systemic hypertension, and diabetes mellitus (moderate POAG in the better eye: odds ratio 37.7 [95% CI 3.7-383.8], ref. control, p = 0.002, and severe POAG in the better eye: odds ratio 52.8 [95% CI 3.5-797.0], ref. control, p = 0.004). CONCLUSION: Moderate and Severe POAG in the better eye is associated with driving cessation.