p38 MAPK activation is downstream of the loss of intercellular adhesion in pemphigus vulgaris

Pemphigus vulgaris (PV) is a potentially fatal blistering disease characterized by autoantibodies against the desmosomal adhesion protein desmoglein (Dsg) 3. Whether autoantibody steric hindrance or signaling through pathways such as p38 MAPK is primary in disease pathogenesis is controversial. PV mAbs that cause endocytosis of Dsg3 but do not dissociate keratinocytes because of compensatory adhesion by Dsg1 do not activate p38. The same mAbs plus exfoliative toxin to inactivate Dsg1 but not exfoliative toxin alone activate p38, suggesting that p38 activation is secondary to loss of adhesion. Mice with epidermal p38α deficiency blister after passive transfer of PV mAbs; however, acantholytic cells retain cell surface Dsg3 compared with wild-type mice. In cultured keratinocytes, p38 knockdown prevents loss of desmosomal Dsg3 by PV mAbs, and exogenous p38 activation causes internalization of Dsg3, desmocollin 3, and desmoplakin. p38α MAPK is therefore not required for the loss of intercellular adhesion in PV, but may function downstream to augment blistering via Dsg3 endocytosis. Treatments aimed at increasing keratinocyte adhesion could be used in conjunction with immunosuppressive agents, potentially leading to safer and more effective combination therapy regimens.     

PHOSPHATIDYLSERINE SYNTHASE1 is required for microspore development in Arabidopsis thaliana

Phosphatidylserine (PS) has many important biological roles, but little is known about its role in plants, partly because of its low abundance. We show here that PS is enriched in Arabidopsis floral tissues and that genetic disruption of PS biosynthesis decreased heterozygote fertility due to inhibition of pollen maturation. At1g15110, designated PSS1, encodes a base-exchange-type PS synthase. Escherichia coli cells expressing PSS1 accumulated PS in the presence of l-serine at 23°C. Promoter-GUS assays showed PSS1 expression in developing anther pollen and tapetum. A few seeds with pss1-1 and pss1-2 knockout alleles escaped embryonic lethality but developed into sterile dwarf mutant plants. These plants contained no PS, verifying that PSS1 is essential for PS biosynthesis. Reciprocal crossing revealed reduced pss1 transmission via male gametophytes, predicting a rate of 61.6%pss1-1 pollen defects in PSS1/pss1-1 plants. Alexander's staining of inseparable qrt1-1 PSS1/pss1-1 quartets revealed a rate of 42% having three or four dead pollen grains, suggesting sporophytic pss1-1 cell death effects. Analysis with the nuclear stain 4',6-diamidino-2-phenylindole (DAPI) showed that all tetrads from PSS1/pss1-1 anthers retain their nuclei, whereas unicellular microspores were sometimes anucleate. Transgenic Arabidopsis expressing a GFP-LactC2 construct that binds PS revealed vesicular staining in tetrads and bicellular microspores and nuclear membrane staining in unicellular microspores. Hence, distribution and/or transport of PS across membranes were dynamically regulated in pollen microspores. However, among unicellular microspores from PSS1/pss1-2 GFP-LactC2 plants, all anucleate microspores showed little GFP-LactC2 fluorescence, suggesting that pss1-2 microspores are more sensitive to sporophytic defects or show partial gametophytic defects.     

Mental health problems and influencing factors in Japanese women 4?months after delivery

Background

Postpartum mental health problems are a major public health issue; however, studies on the mental health status of mothers and its influencing factors between 8 weeks and 1 year postpartum are scarce. Furthermore, it would be necessary to examine the factors influencing mothers’ mental health in order to evaluate their physiological adaptations to the nursing environment.

Methods

We examined the mental health status of postpartum women and the factors influencing poor mental health at 4 months after delivery. A cross-sectional study of 584 postpartum women was conducted. Information on mental health status, delivery, and other factors was collected using a self-administered questionnaire. Women were asked about their age, height, weight, gestational or marital status, whether they were eating regular meals, appetite, frequency of going out, financial difficulty, stressful life events, and history of depression. The Japanese version of the 12-item General Health Questionnaire (GHQ-12) was used to identify potential poor mental health status. Participants with GHQ-12 scores of ≥4 were classified as the high GHQ-12 score group (poor mental health status) and participants with GHQ-12 scores of ≤3 were classified as the low GHQ-12 score group (good mental health status).

Results

Forty-five women (7.7%) were classified as having high GHQ-12 scores. Multiple logistic regression analysis revealed that older age, not eating meals regularly, and history of depression were significantly associated with poor mental health. Financial difficulty had a borderline association with poor mental health in this model.

Conclusions

These risk factors might help practitioners identify women at high risk of poor mental health after delivery.     

Uridine Prevents Fenofibrate-Induced Fatty Liver

Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate-induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD⁺/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD) and acyl-CoA oxidase 1 (ACOX1), and induces excessive accumulation of long chain fatty acids (LCFA) and very long chain fatty acids (VLCFA). Uridine co-administration at a daily dosage of 400 mg/kg raises NAD⁺/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate-induced fatty liver.     

Performance of Young Children on ‘‘Traveling Salesperson’’ Navigation Tasks Presented on a Touch Screen

Background

The traveling salesperson problem (TSP) refers to a task in which one finds the shortest path when traveling through multiple spatially distributed points. Little is known about the developmental course of the strategies used to solve TSPs. The present study examined young children''s performance and route selection strategies in one-way TSPs using a city-block metric. A touch screen-based navigation task was applied.

Methodology/Principal Findings

Children (39–70 months) and adults (21–35 years) made serial responses on a touch screen to move a picture of a dog (the target) to two or three identical pictures of a bone (the goals). For all the versions of the tasks, significant improvement in measures of performance was observed from younger to older participants. In TSPs in which a specific route selection strategy such as the nearest-neighbor strategy minimized the total traveling distance, older participants used that strategy more frequently than younger ones. By contrast, in TSPs in which multiple strategies equally led to the minimal traveling distance, children tended to use strategies different from those used by adults, such as traveling straight to the farthest goal first.

Conclusions/Significance

The results primarily suggest development of efficient route selection strategies that can optimize total numbers of movements and/or solution time. Unlike adults, children sometimes prioritized other strategies such as traveling straight ahead until being forced to change directions. This may reflect the fact that children were either less attentive to the task or less efficient at perceiving the overall shape of the problem and/or the relative distance from the starting location to each goal.     

Label-free Evaluation of Hepatic Microvesicular Steatosis with Multimodal Coherent Anti-Stokes Raman Scattering Microscopy

Hepatic microvesicular steatosis is a hallmark of drug-induced hepatotoxicity and early-stage fatty liver disease. Current histopathology techniques are inadequate for the clinical evaluation of hepatic microvesicular steatosis. In this paper, we explore the use of multimodal coherent anti-Stokes Raman scattering (CARS) microscopy for the detection and characterization of hepatic microvesicular steatosis. We show that CARS microscopy is more sensitive than Oil Red O histology for the detection of microvesicular steatosis. Computer-assisted analysis of liver lipid level based on CARS signal intensity is consistent with triglyceride measurement using a standard biochemical assay. Most importantly, in a single measurement procedure on unprocessed and unstained liver tissues, multimodal CARS imaging provides a wealth of critical information including the detection of microvesicular steatosis and quantitation of liver lipid content, number and size of lipid droplets, and lipid unsaturation and packing order of lipid droplets. Such information can only be assessed by multiple different methods on processed and stained liver tissues or tissue extracts using current standard analytical techniques. Multimodal CARS microscopy also permits label-free identification of lipid-rich non-parenchymal cells. In addition, label-free and non-perturbative CARS imaging allow rapid screening of mitochondrial toxins-induced microvesicular steatosis in primary hepatocyte cultures. With its sensitivity and versatility, multimodal CARS microscopy should be a powerful tool for the clinical evaluation of hepatic microvesicular steatosis.     

Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness

We established a diphtheria toxin (DT)-based conditional deletion system using Il4 enhancer elements previously shown to be specific for IL-4 production in mast cells (MCs) or basophils (Mas-TRECK and Bas-TRECK mice). DT treatment of Bas-TRECK mice resulted in specific deletion of basophils, whereas both MCs and basophils were deleted in Mas-TRECK mice. DT-treated Mas-TRECK mice had impaired passive cutaneous anaphylaxis, IgE-mediated passive systemic anaphylaxis, and IgE-mediated chronic allergic inflammation, whereas DT-treated Bas-TRECK mice had impaired IgE-mediated chronic allergic inflammation. Using these mice, we also sought to tease out the role of MCs and basophils in airway hyperresponsiveness (AHR). Although MC deletion resulted in a slight increase in basal Ag-specific IgE levels and significant increases in basal IgE levels, we found that this deletion markedly impaired the AHR effector phase and was accompanied by decreased histamine levels. By contrast, basophil deletion had no effect on the AHR effector phase or on IgE production induced by systemic OVA immunization. Our results, using these newly established Mas-TRECK and Bas-TRECK models, demonstrated an indispensable role for MCs as effector cells in AHR.     

Shortening the breeding cycle of papaya (<Emphasis Type="Italic">Carica papaya</Emphasis> L.) by culturing embryos treated with ethrel

To shorten the breeding cycle of papaya by embryo culture, we attempted to improve the embryo quality (dimensions, germination ability, and/or seedling vigor) by treating fruits (attached to plants) with ethrel solution. Forty-five-, 60-, and 75-day-old fruits (DOF) were treated with 100 μl l⁻¹ ethrel for 10 or 20 days. The fruits treated with ethrel tended to be lighter in weight compared to those treated with water (the control). Seed coat coloration in 85 DOF (75 DOF plus 10 days of ethrel treatment [DET]) and 95 DOF (75 DOF plus 20 DET) was clearly promoted by the ethrel treatment. Embryo development was enhanced by ethrel treatments in 55 DOF (10 DET), i.e., the ethrel-treated embryos progressed to the mature cotyledon stage earlier than those in the control. The embryo size (length and width) was significantly larger in 55 DOF treated with ethrel than those of the control. In 55 and 65 DOF (20 DET), the embryo germination rates were higher in the ethrel-treated group than those in the control. The seedlings in the ethrel group grew more vigorously than those in the control. Therefore, we found that the embryo quality was improved by the ethrel treatment in 65–95 DOF. The breeding cycle of papaya could be shortened by embryo culture using embryos qualitatively improved by ethrel treatment, i.e., the period (generally 6–9 months) from pollination to seedling establishment could be shortened by approximately 3 months using these breeding techniques.     

Genome screening for reducing type I polyketide synthase genes in tropical fungi associated with medicinal plants

The aim of this work was to employ primers, which encode ketosynthase (KS) domains designed to detect Lovastatin-type PKSs (highly reduced molecules), to identify fungal species that have the potential for polyketide production. Using this strategy we have identified twenty-three KS sequences from twenty different fungal strains associated with medicinal plants found in Thailand. Phylogenetic analysis based on these sequences suggested that rapid screening provided the potential to explore significant PKS structural diversity. With this primer set a unique subclade of reducing type I PKS was identified. This encodes uncharacterized functional enzyme systems, which may suggest a novel function for these pks. Two fungi, Eupenicillium shearii and Myrothecium pandanicola within this novel clade, were investigated for polyketide synthesis. Three compounds, p-hydroxyphenopyrrozin (1) phenopyrrozin (2), and 2,3-dihydro-5-methoxy-2-methylchromen-4-one (3), were identified.     

Chronic Uridine Administration Induces Fatty Liver and Pre-Diabetic Conditions in Mice

Uridine is a pyrimidine nucleoside that exerts restorative functions in tissues under stress. Short-term co-administration of uridine with multiple unrelated drugs prevents drug-induced liver lipid accumulation. Uridine has the ability to modulate liver metabolism; however, the precise mechanism has not been delineated. In this study, long-term effects of uridine on liver metabolism were examined in both HepG2 cell cultures and C57BL/6J mice. We report that uridine administration was associated with O-GlcNAc modification of FOXO1, increased gluconeogenesis, reduced insulin signaling activity, and reduced expression of a liver-specific fatty acid binding protein FABP1. Long-term uridine feeding induced systemic glucose intolerance and severe liver lipid accumulation in mice. Our findings suggest that the therapeutic potentials of uridine should be designed for short-term acute administration.