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Background: This study aimed to examine whether the non-weight-bearing tunnel view X-ray is effective for short-term evaluation of medial meniscus posterior root tear (MMPRT) by assessing the X-ray characteristics at the initial and follow-up visits. Methods: This was a retrospective longitudinal study of 26 enrolled knees diagnosed with MMPRT on magnetic resonance imaging. The distance between the medial tibial eminence and medial femoral condyle (MTE–MFC distance) and medial tibiofemoral joint (MTFJ) width were measured by obtaining non-weight-bearing tunnel view and frontal view X-ray radiographs. The initial and follow-up values at a median interval of 17 days were compared. Additionally, the correlations between the MTE–MFC distance increase rate and body mass index (BMI), age, femorotibial angle (FTA), and posterior tibial slope (PTS) were evaluated using linear regression analysis. Results: The tunnel view images of the initial and follow-up X-rays showed a significant increase in the MTE–MFC distance and a significant decrease in the MTFJ width. Furthermore, a moderate correlation was observed between the change in the MTE–MFC distance and the time interval between X-rays. However, no substantial correlation was observed for the change in the MTFJ width over time. Moreover, no significant correlation was observed between the change in the MTE–MFC distance in the non-weight-bearing tunnel view and BMI, age, FTA, and PTS. Conclusions: The non-weight-bearing tunnel view is highly beneficial for evaluating MMPRT progression in the short term. [ABSTRACT FROM AUTHOR]

Background and Aims: This study aimed to determine the safety and efficacy of atezolizumab + bevacizumab therapy in hepatocellular carcinoma patients receiving anti‐platelet agents or anticoagulants. Methods: Patients were divided into those using (IM out) and those not using (IM in) anti‐platelet agents or anticoagulants, who violated the exclusion criteria of the IMbrave150 trial, and were retrospectively examined. Results: The study included 185 patients (IM in: 157; IM out: 28). For first‐line treatment, progression‐free survival was 184 days for IM in and 266 days for IM out (p =.136). Overall survival was 603 days for IM in and not reached for IM out (p =.265), with no significant between‐group difference. Similarly, there were no significant between‐group differences in progression‐free survival or overall survival for later‐line treatment. Haemorrhagic adverse events of ≥grade 3 were observed in 11 IM in patients and 3 IM out patients. No significant factors associated with haemorrhagic adverse events of ≥grade 3 were identified in the multivariate analysis including IM out classification, whose p value was.547. Regarding thrombotic/embolic adverse events in the IM out group, one case of exacerbation of portal vein thrombosis was observed. No deaths were directly attributable to bleeding events or exacerbations of thrombosis. Conclusion: Atezolizumab + bevacizumab therapy shows similar safety and efficacy in patients receiving and those not receiving anti‐platelet agents or anticoagulants; therefore, it can be considered for patients with hepatocellular carcinoma receiving anti‐platelet agents or anticoagulants. [ABSTRACT FROM AUTHOR]

Background: Tocotrienols exhibit antioxidant and anti-inflammatory activities. RhoA, a small GTPase protein, plays a crucial role in regulating contractility in airway smooth muscle (ASM). Previous studies have demonstrated that γ-tocotrienols reduce ASM proliferation and migration by inhibiting the activation of RhoA. In this present study, we investigate the effect of another vitamin E isoform, β-tocotrienols, on human ASM cell proliferation and migration stimulated by platelet-derived growth factor-BB (PDGF-BB). Methods: Human ASM cells were pre-treated with β-tocotrienol prior to being stimulated with PDGF-BB to induce ASM cell proliferation and migration. The proliferation and migration of PDGF-BB-induced human ASM cells were assessed using colorimetric and transwell migration assays. The intracellular ROS assay kit was employed to quantify reactive oxygen species (ROS) in human ASM cells. Additionally, we explored the effect of β-tocotrienols on the signaling pathways involved in PDGF-BB-induced ASM proliferation and migration. Results: β-tocotrienol inhibited PDGF-BB-induced ASM cell proliferation and migration by reducing RhoA activation and ROS production. However, in this present study, β-tocotrienol did not affect the signaling pathways associated with cyclin D1, phosphorylated Akt1, and ERK1/2. Conclusions: In conclusion, the inhibition of RhoA activation and ROS production by β-tocotrienol, resulting in the reduction in human ASM proliferation and migration, suggests its potential as a treatment for asthma airway remodeling. [ABSTRACT FROM AUTHOR]

It is a problem that influenza virus infection increases susceptibility to secondary bacterial infection in lungs leading to lethal pneumonia. We previously reported that exopolysaccharides (EPS) derived from Lactobacillus delbrueckii ssp. bulgaricus OLL1073R-1 (OLL1073R-1) could prevent against influenza virus infection followed by secondary bacterial infection in vitro. Therefore, the present study assessed whether EPS derived OLL1073R-1 protects the alveolar epithelial barrier disfunction caused by influenza virus infection. After A549 cells treated with EPS or without EPS were infected influenza virus A/Puerto Rico/8/34 (IFV) for 12 h, the levels of tight junction genes expression and inflammatory genes expression were measured by reverse transcription polymerase chain reaction. As results, EPS treatment could protect against low-titer IFV infection, but not high-titer IFV infection, followed by suppression of the increased expression of inflammatory cytokine gene levels and recovery of the decrease in the expression level of ZO-1 gene that was caused by low-titer IFV infection, leading to an improvement trend in the barrier function. Our findings showed that EPS derived from OLL1073R-1 could inhibit low-titer IFV infection leading to maintenance of the epithelial barrier function through the suppression of inflammatory cytokine genes expression. [ABSTRACT FROM AUTHOR]

In this study, we investigated specific and characteristic findings of the surface layer of surgical resected disc specimens in human temporomandibular joint osteoarthritis cases by transmission electron microscopy (TEM). Specimens were surgically removed from the TMJ of 5 cases (4 female patients: 5 cases) clinically osteoarthritis. Following findings were observed by TEM. Images were photographed on a JEM1400-Flash Electron microscope (JEOL, Japan) equipped with an EM-14661FLASH high-sensitivity digital complementary metal–oxide–semiconductor camera. Following findings were observed by TEM. The surface is covered with plump fibroblastic and histiocytoid cells. Collagen fiber bundles and collagenous matrix are exposed onto the eroded disc surface. Fibrinous dense material is observed on the eroded disc surface. Bundles of collagen fibers are densely observed. Collagen bundles are rich around capillary vessels. Synovial surface cells reveal features of activated macrophages with vacuole formation. Especially, plump fibroblastic and histiocytoid cells, and activated macrophages with vacuole, which were significant findings of the surface layer. These findings might have a significant effect on the regulation of synovial fluid. [ABSTRACT FROM AUTHOR]

Ethanol (EtOH) effectively inactivates enveloped viruses in vitro, including influenza and severe acute respiratory syndrome coronavirus 2. Inhaled EtOH vapor may inhibit viral infection in mammalian respiratory tracts, but this has not yet been demonstrated. Here we report that unexpectedly low EtOH concentrations in solution, approximately 20% (vol/vol), rapidly inactivate influenza A virus (IAV) at mammalian body temperature and are not toxic to lung epithelial cells on apical exposure. Furthermore, brief exposure to 20% (vol/vol) EtOH decreases progeny virus production in IAV-infected cells. Using an EtOH vapor exposure system that is expected to expose murine respiratory tracts to 20% (vol/vol) EtOH solution by gas-liquid equilibrium, we demonstrate that brief EtOH vapor inhalation twice a day protects mice from lethal IAV respiratory infection by reducing viruses in the lungs without harmful side effects. Our data suggest that EtOH vapor inhalation may provide a versatile therapy against various respiratory viral infectious diseases. [ABSTRACT FROM AUTHOR]

There are a few reports on the treatment of nonunited tibial anterior cruciate ligament (ACL) avulsion fractures. To our knowledge, this is the first report of a case of nonunited tibial ACL avulsion fracture 30 years after injury. A 36-year-old woman injured her knee during a road traffic accident 30 years ago. Since then, she had persistent knee instability that was left untreated. She presented to our clinic because of knee pain she had been experiencing for a week. Radiography and computed tomography revealed tibial ACL avulsion fracture nonunions. Screw fixation with arthroscopy was performed, and bone fusion was obtained. The knee injury and osteoarthritis outcome score improved from 24 points preoperatively to 83 points postoperatively. The nonunion of intercondylar eminence fractures of the tibia, even up to 30 years after the initial injury, can be treated by osteosynthesis with arthroscopy. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to investigate whether NKT cells play an important role in preventing or exacerbating diseases caused by high-fat diet (HFD) using CD1d-knockout (KO) mice which lack NKT cells.Methods: Five-week-old male Balb/c (wild-type; WT) or CD1dKO mice were fed with control-diet (CTD) or HFD for 16 weeks.Results: The present study revealed four main findings. First, CD1dKO mice were susceptible to obesity caused by HFD in comparison to WT mice. Second, clinical conditions of fatty liver caused by HFD were comparable between CD1dKO mice and WT mice. Third, HFD-fed WT mice showed high levels of serum biochemical markers, involved in lipid metabolisms, in comparison to WT mice fed a CTD. Notably, the serum concentrations of ALT, T-CHO, TG and HDL-C in CD1dKO mice fed a HFD were almost comparable to those of CD1dKO mice fed a CTD. Fourth, the expression of peroxisome proliferator-activated receptor (PPAR) γ, low-density lipoprotein receptor (LDLR), CD36 of epididymal adipose tissue enhanced and proprotein convertase subtilisin/kexin type (PCSK) 9 in serum decreased.Conclusion: NKT cells were responsible for protection against HFD-induced obesity. However, CD1dKO mice were resistant to serum biochemical marker abnormalities after HFD feeding. One possible explanation is that the epididymal adipose tissue of CD1dKO mice could take up greater amounts of excess lipids in serum in comparison to WT mice. [ABSTRACT FROM AUTHOR]

As the number of agricultural workers is decreasing, there are a lot of demands on the robotics automation of agricultural tasks, including the automation of repacking and shipping in vegetable factories. A soft robot hand is suitable for such tasks because of its less damaging to vegetables and adaptability to variety in size and weight of vegetables. However, most of soft robotic hands are actuated by the air pressure, and the output force is not sufficient for heavy vegetables that are often dealt with in a vegetable factory. To solve this problem, we developed a prototype of a hydraulic soft robot hand in our previous research. Selecting an oil as the hydraulic source, the prototype was actuated by a compact built-in pump, we showed that the prototype could hold 2 or 3 kg cabbage with 1 MPa pressure control. In this paper, we develop a compact water pump that can generate maximum 3 MPa , and update the prototype selecting the water as the hydraulic source. We experimentally show that the soft hand can grasp and hold a cabbages, assuming a real situation in a vegetable factory. [ABSTRACT FROM AUTHOR]

Background and Objectives: Type V tibial tubercle avulsion fractures are extremely rare; therefore, information on them remains limited. Furthermore, although these fractures are intra-articular, to the best of our knowledge, there are no reports on their assessment via magnetic resonance imaging (MRI) or arthroscopy. Accordingly, this is the first report to describe the case of a patient undergoing detailed evaluation via MRI and arthroscopy. Case Presentation: A 13-year-old male adolescent athlete jumped while playing basketball, experienced discomfort and pain at the front of his knee, and fell down. He was transported to the emergency room by ambulance after he was unable to walk. The radiographic examination revealed a Type Ⅴ tibial tubercle avulsion fracture that was displaced. In addition, an MRI scan revealed a fracture line extending to the attachment of the anterior cruciate ligament (ACL); moreover, high MRI intensity and swelling due to ACL were observed, suggesting an ACL injury. On day 4 of the injury, open reduction and internal fixation were performed. Furthermore, 4 months after surgery, bone fusion was confirmed, and metal removal was performed. Simultaneously, an MRI scan obtained at the time of injury revealed findings suggestive of ACL injury; therefore, an arthroscopy was performed. Notably, no parenchymal ACL injury was observed, and the meniscus was intact. The patient returned to sports 6 months postoperatively. Conclusion: Type V tibial tubercle avulsion fractures are known to be extremely rare. Based on our report, we suggest that MRI should be performed without hesitation if intra-articular injury is suspected. [ABSTRACT FROM AUTHOR]

Reporting reactions to death in nonhuman primates can provide valuable information for understanding the evolutionary origin of human ways of dealing with death. Although many studies have reported nonhuman primates' reactions to infant corpses, less is known about their reactions toward dead adults or adolescents. The deaths of adult primates, who usually form complex social relationships, may have social impacts. Here, we described in detail the reactions of Japanese macaques (Macaca fuscata) to the corpse of an adult female in a free-ranging multi-male multi-female group. We analyzed quantitative data on the whole group to determine how death-related behaviors were related to social relationships. Most group members in this case, including social partners of the deceased, exhibited no notable interest in the corpse. Only one adult female, who was not a grooming partner of the female before she died, touched and groomed the corpse. We examined four possible reasons why this female groomed the corpse: unawareness of death, learning about death, desire to consume insects, and reputation-building with other group members. This study highlights the potential value of closer examination of associations between reactions to dead adults or adolescents and social relationships before and after death in primate groups. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-prolyl hydroxylase (HIF-PHD) inhibitors are therapeutic agents for renal anemia that work through HIF2-mediated upregulation of erythropoietin (EPO) and have also been reported to suppress renal fibrosis. Group 2 innate lymphoid cells (ILC2s) have been proven to be involved in the pathogenesis of fibrosis in various organs, including the kidney. However, the relationship between the HIF pathway, renal fibrosis, and kidney ILC2s remains unclear. In the present study, we found that HIF activation by HIF-PHD inhibitors suppressed type 2 cytokine production from kidney ILC2s. The enhanced HIF pathway downregulated the IL-33 receptor ST2L on ILC2s, and phosphorylation of downstream p38 MAPK was attenuated. M2 macrophages that promote renal fibrosis were polarized by ILC2 supernatants, but reduced cytokine production from ILC2s treated with HIF-PHD inhibitors suppressed this polarization. Our findings suggest that HIF-PHD inhibitors are potential therapeutic agents for renal fibrosis that are mediated by the alteration of ILC2 function. [ABSTRACT FROM AUTHOR]

Clonal expansion and differentiation of various T helper subsets, such as Th1, Th2, and Th17 cells, depend on a complex of transcription factors, IRF4 and a BATF-containing AP-1 heterodimer. A major BATF heterodimeric partner, JunB, regulates Th17 differentiation, but the role of JunB in other T helper subsets is not well understood. Here we demonstrate that JunB is required for clonal expansion of Th1, Th2 and Th17 cells. In mice immunized with lipopolysaccharide (LPS), papain, or complete Freund's adjuvant (CFA), which induce predominantly Th1, Th2 and Th17 cells, respectively, accumulation of antigen-primed, Junb -deficient CD4+ T cells is significantly impaired. TCR-stimulated Junb -deficient CD4+ T cells are more sensitive to apoptosis, although they showed largely normal proliferation and cellular metabolism. JunB directly inhibits expression of genes involved in apoptosis, including Bcl2l11 (encoding Bim), by promoting IRF4 DNA binding at the gene locus. Taken together, JunB serves a critical function in clonal expansion of diverse T helper cells by inhibiting their apoptosis. [ABSTRACT FROM AUTHOR]

We developed a chiral symmetry breaking method for monoacylated meso diols. The X‐ray crystal structure analysis of monoacylated 1,4‐anhydroerythritols, meso cyclic diols with a cis configuration, revealed that the O‐(p‐anisoyl) derivative crystallized as a racemic conglomerate of the P212121 crystal system. It was confirmed that the substrate racemized by intramolecular transfer of the acyl group in the presence of a catalytic amount of base. Evaporating the solvent gradually from the solution or Viedma ripening to promote crystallization‐induced deracemization efficiently led to enantiomer crystals. These results provide the first successful example of asymmetric expression and amplification by deracemization of sugar derivatives without an external chemical chiral source. Furthermore, we applied this methodology to acyclic meso‐1,2‐diols. Three O‐monoacylated substrates were successfully deracemized to 99 % ee by Viedma ripening. We also developed asymmetric desymmetrization of meso‐1,2‐diols by combining acylation and crystallization‐induced deracemization. [ABSTRACT FROM AUTHOR]

We developed a chiral symmetry breaking method for monoacylated meso diols. The X‐ray crystal structure analysis of monoacylated 1,4‐anhydroerythritols, meso cyclic diols with a cis configuration, revealed that the O‐(p‐anisoyl) derivative crystallized as a racemic conglomerate of the P212121 crystal system. It was confirmed that the substrate racemized by intramolecular transfer of the acyl group in the presence of a catalytic amount of base. Evaporating the solvent gradually from the solution or Viedma ripening to promote crystallization‐induced deracemization efficiently led to enantiomer crystals. These results provide the first successful example of asymmetric expression and amplification by deracemization of sugar derivatives without an external chemical chiral source. Furthermore, we applied this methodology to acyclic meso‐1,2‐diols. Three O‐monoacylated substrates were successfully deracemized to 99 % ee by Viedma ripening. We also developed asymmetric desymmetrization of meso‐1,2‐diols by combining acylation and crystallization‐induced deracemization. [ABSTRACT FROM AUTHOR]

Atroposelective resolution for axially chiral nicotinamides was achieved by dynamic chiral salt formation with L‐DBTA using six types of nicotinamides that could not be optically resolved by the preferential crystallization method. Kinetic studies of their racemization indicated that the chiral conformation was retained for a significant period of time. Two methods of crystallization‐induced asymmetric transformation were examined by dynamic diastereomeric salt formation: solvent evaporation from a supersaturated solution, and attrition‐enhanced asymmetric transformation. The attrition method was more effective for asymmetric amplification of diastereomeric salts of axially chiral materials. Attrition of equimolar amount of the nicotinamide salts with L‐DBTA converged to one diastereomer salts, and the corresponding enantiomers in 87–99 % ee were obtained after the chiral acid was removed. Changing the ratio of two of the nicotinamides with L‐DBTA to 1 : 2 inverted the axial chirality. [ABSTRACT FROM AUTHOR]

Purpose: Early detection of medial meniscus posterior root tear (MMPRT) is important in preventing the rapid onset and progression of degenerative knee disease. Diagnosis is facilitated by the availability of non-weight-bearing X-ray view, but information on the X-ray characteristics of MMPRT is scarce. Here, we conducted a pilot study of the X-ray characteristics of MMPRT on non-weight-bearing tunnel view. Methods: We retrospectively reviewed 43 consecutive patients treated in the outpatient department for medial knee pain or popliteal pain. Patients were divided into MMPRT (21 knees) and non-MMPRT groups (22 knees). We investigated X-ray characteristics and magnetic resonance imaging findings. Femorotibial angle, posterior tibial slope, medial tibial eminence (MTE)–medial femoral condyle (MFC) distance (contralateral and affected sides, and difference between the two), medial tibiofemoral joint (MTFJ) width (contralateral and affected sides, and difference between the two), and meniscus radial dislocation between the groups were evaluated using the Mann–Whitney U test. The association between X-ray characteristics and MMPRT was determined using univariate and multivariate logistic regression analyses. Results: A highly significant difference between the affected and contralateral sides was seen in MTFJ width and MTE–MFC distance on non-weight-bearing tunnel view between the MMPRT and non-MMPRT groups. Moreover, a difference in MTFJ width of <−0.575 mm and in MTE–MFC distance of >0.665 mm between the affected and contralateral sides was useful in predicting MMPRT. Conclusions: The non-weight-bearing tunnel view is useful for the initial diagnosis of MMPRT. Prospective evaluation in a larger population is warranted. [ABSTRACT FROM AUTHOR]

Summary: Stromules are dynamic membrane‐bound tubular structures that emanate from plastids. Stromule formation is triggered in response to various stresses and during plant development, suggesting that stromules may have physiological and developmental roles in these processes. Despite the possible biological importance of stromules and their prevalence in green plants, their exact roles and formation mechanisms remain unclear. To explore these issues, we obtained Arabidopsis thaliana mutants with excess stromule formation in the leaf epidermis by microscopy‐based screening. Here, we characterized one of these mutants, stromule biogenesis altered 1 (suba1). suba1 forms plastids with severely altered morphology in a variety of non‐mesophyll tissues, such as leaf epidermis, hypocotyl epidermis, floral tissues, and pollen grains, but apparently normal leaf mesophyll chloroplasts. The suba1 mutation causes impaired chloroplast pigmentation and altered chloroplast ultrastructure in stomatal guard cells, as well as the aberrant accumulation of lipid droplets and their autophagic engulfment by the vacuole. The causal defective gene in suba1 is TRIGALACTOSYLDIACYLGLYCEROL5 (TGD5), which encodes a protein putatively involved in the endoplasmic reticulum (ER)‐to‐plastid lipid trafficking required for the ER pathway of thylakoid lipid assembly. These findings suggest that a non‐mesophyll‐specific mechanism maintains plastid morphology. The distinct mechanisms maintaining plastid morphology in mesophyll versus non‐mesophyll plastids might be attributable, at least in part, to the differential contributions of the plastidial and ER pathways of lipid metabolism between mesophyll and non‐mesophyll plastids. Significance Statement: We show that TGD5, which encodes a protein putatively involved in endoplasmic reticulum (ER)‐to‐plastid lipid trafficking, is the causal gene of suba1, an Arabidopsis stromule hyperformation mutant. Our data suggest that the regulation of stromule formation is linked to the ER pathway of plastidial glycolipid synthesis, prompting us to propose a hypothesis that partially explains the difference in stromule formation activity between mesophyll chloroplasts (relatively inactive) and non‐mesophyll plastids (generally active). [ABSTRACT FROM AUTHOR]

The aim of this study is to reveal the morphological property about the loose bodies (LBs) of temporomandibular joint (TMJ) by scanning electron microscope (SEM). We obtained specimens from two female cases of released loose body by surgical operation. These specimens were fixed by soaking in a mixture of 5% glutaraldehyde or 4% formaldehyde for one week. They were cut into half pieces. These specimens were observed at an accelerating voltage of 3 kV under a SEM (JSM-5500, JEOL, Tokyo). In the electron microscopic findings, it seems to be separated into two different parts as inside part and outside part. On the inside part, collagen fibers were running very densely in the same direction in an orderly neatly manner. Whereas, we observed waved collagen fibers running irregularly with many spaces on the outside part. Outside part seems to be porous pattern compared with inside part. It might be that the surface and outside part included many active fibroblasts. As results, it seems that the LBs might develop in a multi-layer style, in which fibrous tissues were piled up loosely around the inside part. The proliferating activity of LBs grows from the inside to outside of SC in TMJ. [ABSTRACT FROM AUTHOR]

Attrition‐enhanced deracemization of two axially chiral nicotinamides, crystallizing as a conglomerate of a P21 crystal system, was performed. N,N‐Dialkylnicotinamides with substituents on the 2‐ and 4‐positions of the pyridine ring exhibited stable axial chirality due to rotationally restricted scaffolds for the Ar–C(=O)N bond. Crystallization of the racemic mixtures from the melt or attrition‐enhanced deracemization led to the chiral breaking of symmetry to give 95–96 % ee of enantiomorphic crystals. [ABSTRACT FROM AUTHOR]

Recently, a recessive Arabidopsis thaliana mutant with abundant stromules in leaf epidermal pavement cells was visually screened and isolated. The gene responsible for this mutant phenotype was identified as PARC6 , a chloroplast division site regulator gene. The mutant allele parc6-5 carried two point mutations (G62R and W700stop) at the N- and C-terminal ends of the coding sequence, respectively. Here, we further characterized parc6-5 and other parc6 mutant alleles, and showed that PARC6 plays a critical role in plastid morphogenesis in all cell types of the leaf epidermis: pavement cells, trichome cells, and guard cells. Transient expression of PARC6 transit peptide (TP) fused to the green fluorescent protein (GFP) in plant cells showed that the G62R mutation has no or little effect on the TP activity of the PARC6 N-terminal region. Then, plastid morphology was microscopically analyzed in the leaf epidermis of wild-type (WT) and parc6 mutants (parc6-1 , parc6-3 , parc6-4 and parc6-5) with the aid of stroma-targeted fluorescent proteins. In parc6 pavement cells, plastids often assumed aberrant grape-like morphology, similar to those in severe plastid division mutants, atminE1, and arc6. In parc6 trichome cells, plastids exhibited extreme grape-like aggregations, without the production of giant plastids (>6 µm diameter), as a general phenotype. In parc6 guard cells, plastids exhibited a variety of abnormal phenotypes, including reduced number, enlarged size, and activated stromules, similar to those in atminE1 and arc6 guard cells. Nevertheless, unlike atminE1 and arc6 , parc6 exhibited a low number of mini-chloroplasts (< 2 µm diameter) and rarely produced chloroplast-deficient guard cells. Importantly, unlike parc6 , the chloroplast division site mutant arc11 exhibited WT-like plastid phenotypes in trichome and guard cells. Finally, observation of parc6 complementation lines expressing a functional PARC6-GFP protein indicated that PARC6-GFP formed a ring-like structure in both constricting and non-constricting chloroplasts, and that PARC6 dynamically changes its configuration during the process of chloroplast division. [ABSTRACT FROM AUTHOR]

The vagal activity of infants is represented by heart rate variability (HRV) and associated with both growth and socioemotional development. The enhancement of an infant's vagal tone activity might be beneficial for development. This study explored whether HRV in infants aged 3–8 months can be enhanced by influencing HRV in mothers (40 dyads). The power of the low frequency (LF) component of maternal HRV was facilitated using slow-paced breathing. We investigated whether the change in maternal HRV affected the LF component in infants held by their mothers. In older infants (N = 14, 6–8 months) the LF power showed an increase during maternal paced breathing, whereas a delayed increase occurred after termination of maternal paced breathing in younger infants (N = 16, 3–5 months). These results show that the effects of maternal cardiac activity on the infant's HRV are age-dependent. This age-dependent reactivity of the infant's HRV could be due to the development of the inner model in infants which regulates physiological functions, including cardiac activity. This finding might help develop efficient methods for enhancing vagal nerve activity in infants. [ABSTRACT FROM AUTHOR]

A fixed‐dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (nonnucleoside NS5B inhibitor) was approved for hepatitis C virus treatment in Japan. The objectives of the analyses were to develop the daclatasvir, asunaprevir, and beclabuvir population pharmacokinetic models for the combination regimen. First, an original population pharmacokinetic model was developed using the data in non‐Japanese hepatitis C virus–infected subjects. The model was subsequently updated after a phase 3 study in Japanese hepatitis C virus–infected subjects was available. A total of 11,382, 11,300, and 10,728 pharmacokinetic records from 1,228 subjects were included for daclatasvir, asunaprevir, and beclabuvir in the updated model, respectively. Daclatasvir and beclabuvir pharmacokinetics (PK) were described by a 1‐compartment model with linear elimination and asunaprevir PK was described by 2‐compartment model with linear elimination. Cirrhosis, baseline, and time‐varying ALT were significant covariates on asunaprevir apparent oral clearance. Asian subjects had greater asunaprevir and beclabuvir exposures than white subjects. The effects of all covariates on daclatasvir PK were modest and not considered clinically significant. With the exception of race on asunaprevir and beclabuvir PK, no other parameters for daclatasvir, asunaprevir and beclabuvir population PK models were meaningfully impacted during the refinement with Japanese subjects. [ABSTRACT FROM AUTHOR]

Dynamic enantioselective crystallization enabled the chiral symmetry breaking of two spiropyrans and one spirooxazine. The three spiro compounds afforded racemic conglomerate crystals, and easily racemized in alcoholic solution without irradiation. Optically pure enantiomorphic crystals were obtained by vapor‐diffusion crystallization or attrition‐enhanced deracemization (Viedma ripening). Their absolute configurations were determined by single‐crystal X‐ray analysis and each enantiomorphic crystal was correlated with its solid‐state circular dichroism (CD) spectrum. [ABSTRACT FROM AUTHOR]

The intramolecular asymmetric photocycloaddition between 1,4‐naphthoquinone and vinyl ether with a small (R)‐point‐chiral group on the tether was studied. Under photoirradiation, [2+2] cyclobutane products were exclusively obtained for this intramolecular system. The effect of solvent polarity on the stereoselectivity was significant, with predominant formation of the (2R,S3) over the (2R,R3) isomer in non‐polar solvents being reversed in slightly polar dichloromethane. The detailed temperature‐dependent study revealed the dominant diastereo‐differentiating processes, which were switched between the ground‐state equilibrium, the relative rate of bond formation in the triplet manifold, as well as deactivation processes between the pro‐(S3) and pro‐(R3) precursors, depending on the temperature domain examined. The enthalpic contribution (ΔΔH≠) was always compensated by the entropic factor (ΔΔS≠), implying the importance of solvation on the diastereo‐differentiation steps. The mechanism of photocycloaddition, especially for the face‐selective processes, is thoroughly discussed, which is supported by quantum chemical calculations on the ground‐state circular dichroism (CD) spectral behavior as well as on the diastereomeric transition states in the triplet excited state. [ABSTRACT FROM AUTHOR]

A multiprotein complex, THO/TREX, couples the transcription, 3′‐end formation and nuclear export of mRNAs. In this study, we report that crucial factors for mRNA processing, such as XRN2, DDX5/DDX17 and CstF64, are copurified with human THO (hTHO). Using chromatin immunoprecipitation, we found increased cross‐linking of XRN2 and CstF64 to the RNA polymerase II (RNAP II) pause site of the HSPA1A gene upon down‐regulation of THOC5, a metazoan‐specific component of hTHO. As observed in THOC5‐depleted cells, knockdown of XRN2 blocked HSP70 transcript release and increased the amount of CstF64 at the pause site. In addition, our data indicate that DDX5/DDX17 is also required for HSP70 transcript release. As the degradation of read‐through transcripts, but not cleavage at polyadenylation sites per se, was hindered upon THOC5 or DDX5/DDX17 down‐regulation, these factors appear to influence transcriptional termination. Interestingly, over‐expression of RNase H suppressed the accumulation of HSP70 transcripts in nuclear foci in THOC5‐ or DDX5/DDX17‐depleted cells. Thus, we propose a model in which hTHO, along with DDX5/DDX17, restricts the formation of R‐loops, thereby facilitating the XRN2‐mediated transcriptional termination and release of the mature transcript from the HSPA1A locus. [ABSTRACT FROM AUTHOR]

IgG4‐related disease is an evolving entity of immune‐mediated origin. We report a case of IgG4‐related disease mimicking lung cancer with pleural dissemination. A 76‐year‐old male non‐smoker was admitted to our hospital because of chest X‐ray abnormality. Chest computed tomography scan showed a lung nodule measuring 26 × 14 mm with tiny nodules on the adjacent pleural surface. Wedge resection by video‐assisted thoracoscopic surgery (VATS) was performed to aid diagnosis. Pathological findings of the nodule consisted of lymphoid follicular hyperplasia with lymphoplasmacytic infiltrate, fibrosis, and obstructive vasculitis. Focal and scattered thickening of the pleura with lymphoplasmacytic infiltrate was also observed. The IgG4/IgG ratio in the most prominent area exceeded 80%. Thus, we made a diagnosis of IgG4‐related lung and pleural disease. To our knowledge, there has been no report of IgG4‐related lung disease mimicking lung cancer with pleural dissemination. [ABSTRACT FROM AUTHOR]

Abstract: Daclatasvir is a nonstructural protein 5A replication complex inhibitor, and asunaprevir is a nonstructural protein 3 protease inhibitor for hepatitis C virus (HCV). In 2014, the combination therapy of daclatasvir and asunaprevir received the first global approval in Japan as the first nonribavirin, all‐oral therapy for HCV treatment. The population pharmacokinetics (popPK) of daclatasvir and asunaprevir were characterized by nonlinear mixed‐effects modeling using 3801 and 2626 concentration data from 336 and 265 Japanese HCV subjects, respectively. The plasma pharmacokinetic profiles of daclatasvir and asunaprevir were described by a 1‐compartment model. Parameter estimates (interindividual variability) of daclatasvir apparent clearance (CL/F) and apparent volume of the central compartment (V/F) were 5.29 L/h (39.4%) and 64.2 L (38.1%). The effects of all statistically significant covariates on daclatasvir PK parameters were within or overlapped the 80% to 125% boundaries, suggesting a lack of clinical relevance. Parameter estimates (interindividual variability) of asunaprevir CL/F and V/F were 52.1 L/h (41.5%) and 75.1 L (93.4%), respectively. Baseline and time‐varying aspartate aminotransferase (AST) and cirrhosis on CL/F and formulation (soft‐gel capsule or tablet) on F were included as significant covariates in the asunaprevir popPK model. The effects of all covariates exceeded the 80% to 125% boundaries, indicating that the asunaprevir soft‐gel capsule had higher bioavailability than the tablet and that asunaprevir exposure increased with cirrhosis and increasing baseline and time‐varying AST values. The popPK models adequately described the PK profiles of daclatasvir and asunaprevir in Japanese HCV subjects. [ABSTRACT FROM AUTHOR]

Abstract: The treatment of hepatitis C virus (HCV) infection has been revolutionized by the development of all‐oral combination regimens of direct‐acting antiviral agents. The current analysis characterized the relationship between exposures of daclatasvir (DCV; tablets) and asunaprevir (ASV; capsules) and sustained virologic response (SVR) in Japanese patients who are HCV genotype (GT) 1b nonresponders to pegylated interferon (IFN) α/ribavirin or IFNβ/ribavirin, and IFN‐based therapy–ineligible naive/intolerant patients receiving DCV and ASV, and provided insight into patient covariates that were most closely associated with efficacy. The relationship between the probability of achieving SVR at 12 weeks after treatment (SVR12) and average steady‐state plasma concentrations estimated from population pharmacokinetic models for DCV and ASV is described using a logistic regression model with data from a phase 2 and a phase 3 study in Japanese patients infected with HCV GT 1b (N=265). The functional form characterization, which describes a relationship between DCV and ASV average steady‐state plasma concentrations and SVR12, as well as covariate identification (demographic, laboratory, and prognostic and treatment covariates) were investigated during model development. The presence of the signature nonstructural protein 5A Y93H mutation at baseline was the only significant parameter of SVR12 in the final exposure‐response model. Model evaluation plots demonstrate that the final model was able to predict the observed SVR rates. Exposure‐response analysis supports the clinical utility of the combination regimen of 60‐mg once‐daily DCV and 100‐mg twice‐daily ASV in Japanese patients infected with HCV GT 1b. [ABSTRACT FROM AUTHOR]

Background: In the UNITY-3 study, 96% sustained virologic response (SVR12) rate was observed in Japanese patients with hepatitis C virus (HCV) genotype (GT)-1 infection treated for 12 weeks with fixed-dose daclatasvir, asunaprevir, and beclabuvir (DCV-TRIO). As HCV clearance may improve liver outcomes, we assessed hepatic fibrosis and alpha-fetoprotein (AFP), a hepatocellular carcinoma risk marker, pre- and post-treatment in UNITY-3.Methods: Treatment-naive or interferon-experienced UNITY-3 patients with HCV GT-1 who received twice-daily DCV-TRIO were assessed for fibrosis [FibroTest; FibroScan; fibrosis-4 index (FIB-4), aspartate-aminotransferase-to-platelet-ratio index] and AFP at baseline and Weeks 4 (FIB-4 only), 12 or 24 post-treatment.Results: Of 217 patients, 99% had GT-1b infection, 46% were aged > 65 years, 21% had compensated cirrhosis, and 26% baseline HCV-RNA > 107 IU/mL. All GT-1b patients treated ≥ 4 weeks achieved SVR12 with (n = 54) or without (n = 144) baseline NS5A polymorphisms associated with DCV resistance (positions 28/30/31/93). Statistically significant post-treatment reductions from baseline were observed for all fibrosis measures and AFP, with numerically greater reductions in cirrhotic patients. FibroTest category improved in 44%, remained stable in 50%, and worsened in 6% of patients; 98% with baseline AFP < 6 μg/L remained < 6 μg/L and 51% with baseline AFP ≥ 6 μg/L were < 6 μg/L post-treatment.Conclusions: DCV-TRIO administered for 12 weeks to Japanese patients with primarily GT-1b infection achieved a high SVR12 rate and resulted in improved measures of hepatic fibrosis and serum AFP that may reduce the risk of future liver disease progression and hepatocellular carcinoma, particularly in those with compensated cirrhosis. [ABSTRACT FROM AUTHOR]

Asymmetric synthesis involving photochemical dimerization of a prochiral flavonoid derivative in solution without any chiral source was achieved. Irradiation of ethyl 6- bromochromonecarboxylate in solution efficiently gave a C2chiral anti-head-to-head dimer in excellent chemical yield with good quantum efficiency (Φ365 = 0.15). X-ray crystallographic analysis revealed that the dimer crystallized as a conglomerate of C2 space group. The crystalline dimer precipitated upon irradiation of the monomer in solution, and indirect racemization of the dimer through a reversible photoreaction in solution and selective crystallization simultaneously occurred to give the C2- chiral dimer in optically active form with up to 80 % ee. Optically active photoproducts could be obtained by simply irradiating achiral materials in solution without an external chiral source. [ABSTRACT FROM AUTHOR]

Background: DCV-TRIO, a fixed-dose combination of daclatasvir (pangenotypic NS5A inhibitor), asunaprevir (NS3/4A protease inhibitor), and beclabuvir (non-nucleoside NS5B inhibitor), has achieved high rates of sustained virologic response at post-treatment Week 12 (SVR12) in phase 3 studies.Methods: In this phase 3 study, DCV-TRIO for 12 weeks and daclatasvir plus asunaprevir (DUAL) for 24 weeks were studied in Japanese patients infected with HCV genotype 1 (99 % genotype 1b).Results: SVR12 rates ≥95 % were achieved in both treatment-naive (N = 152) and interferon-experienced (N = 65) cohorts treated with DCV-TRIO for 12 weeks and were comparable across patient subgroups, including patients aged ≥65 years and those with cirrhosis. DUAL recipients (N = 75) had an SVR12 rate of 87 %. In the absence of baseline resistance-associated polymorphisms at positions NS5A-Y93H or -L31, SVR12 rates were 98 % with DCV-TRIO or DUAL. Among genotype 1b-infected patients with baseline Y93H or L31 polymorphisms, 35/38 (92 %) DCV-TRIO recipients, and 7/16 (44 %) DUAL recipients achieved SVR12. Adverse events, mostly liver related, led to treatment discontinuation in 10 % of DCV-TRIO recipients. In this group, SVR12 was achieved by 3/9 patients who discontinued before Week 4 and by 12/12 patients who completed ≥4 weeks of DCV-TRIO. Treatment-related serious adverse events occurred in 4 and 3 % of DCV-TRIO and DUAL recipients, respectively. Seven patients (9 %) discontinued DUAL due to adverse events. No deaths occurred.Conclusion: SVR12 was achieved by 96 % of Japanese patients with HCV genotype 1 infection after 12 weeks of treatment with the DCV-TRIO regimen. DCV-TRIO and DUAL exhibited comparable safety profiles. [ABSTRACT FROM AUTHOR]

Irradiation of prochiral ( E)-aroylacrylamide with sunlight gave single-handed pyrrolinone quantitatively and with an enantiomeric excess ( ee) of over 99 % under absolutely achiral conditions. The phenomenon was explained by photoisomerization and reversible cyclization followed by dynamic crystallization involving deracemization. [ABSTRACT FROM AUTHOR]

Aerobic glycolysis, a metabolic pathway essential for effector T cell survival and proliferation, regulates differentiation of autoimmune T helper (Th) 17 cells, but the mechanism underlying this regulation is largely unknown. Here, we identify a glycolytic intermediate metabolite, phosphoenolpyruvate (PEP), as a negative regulator of Th17 differentiation. PEP supplementation or inhibition of downstream glycolytic enzymes in differentiating Th17 cells increases intracellular PEP levels and inhibits interleukin (IL)-17A expression. PEP supplementation inhibits expression of signature molecules for Th17 and Th2 cells but does not significantly affect glycolysis, cell proliferation, or survival of T helper cells. Mechanistically, PEP binds to JunB and inhibits DNA binding of the JunB/basic leucine zipper transcription factor ATF-like (BATF)/interferon regulatory factor 4 (IRF4) complex, thereby modulating the Th17 transcriptional program. Furthermore, daily administration of PEP to mice inhibits generation of Th17 cells and ameliorates Th17-dependent autoimmune encephalomyelitis. These data demonstrate that PEP links aerobic glycolysis to the Th17 transcriptional program, suggesting the therapeutic potential of PEP for autoimmune diseases. [Display omitted] • PEP inhibits Th17 generation • PEP regulates the Th17 transcriptional program • PEP interacts with JunB and suppresses DNA binding of JunB/BATF/IRF4 • PEP inhibits in vivo Th17 generation and EAE development Huang et al. demonstrate that a glycolytic intermediate metabolite, PEP, suppresses Th17 generation and Th17-dependent autoimmune encephalomyelitis. Mechanistically, PEP regulates the Th17 transcriptional program by inhibiting DNA-binding activity of the JunB/BATF/IRF4 transcription factor complex. [ABSTRACT FROM AUTHOR]

Single-handed α-amino acid derivatives were generated from achiral precursors without an external chiral source. Conjugate addition of phenethylamine to an achiral aroyl acrylamide under homogeneous conditions gave the α-amino amides in quantitative yields, which crystallized as a conglomerate of a P21 crystal system. Dynamic preferential crystallization or attrition-enhanced deracemization resulted in the formation of enantiomorphic crystals of 99 % ee. [ABSTRACT FROM AUTHOR]

To investigate whether the administration of IL-12 is effective against influenza virus infection, mice were intranasally administered IL-12 for three consecutive days and then infected with a non-lethal dose of the influenza virus. The IL-12-treated mice were more resistant to the virus than control mice with respect to the remission of body weight loss, virus burden, pro-inflammatory cytokine production, and inflammatory cell infiltration in the lungs. The number of NK cells and the level of NK cell cytotoxicity significantly increased in the lungs of the mice treated with IL-12 before infection compared to that observed in control mice, leading to promptly eliminate the viral-infected cells. Unexpectedly, all of mice that received IL-12 treatment after being infected with a non-lethal dose of the virus died as a result of their high virus burden and pro-inflammatory cytokine production in the lungs. One possibility of the mechanisms was considered to be activation of myeloid-derived suppressor cell (MDSC), which has immune suppressive function, in the lungs. Thus, IL-12 treatment has opposite effects depending on whether it is administered before or after infection. These results demonstrate the potential risks of immune modulating therapies such as administration of exogenous cytokine or neutralization of cytokine. J. Med. Virol. 88:1487-1496, 2016. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

[ Pasteurella ] pneumotropica is a ubiquitous bacterium frequently isolated from laboratory rodents. Although this bacterium causes various diseases in immunosuppressed animals, little is known about major virulence factors and their roles in pathogenicity. To identify virulence factors, we sequenced the genome of [ P. ] pneumotropica biotype Heyl strain ATCC 12555, and compared the resulting non-contiguous draft genome sequence with the genome of biotype Jawetz strain ATCC 35149. Among a large number of genes encoding virulence-associated factors in both strains, four genes encoding for YadA-like proteins, which are known virulence factors that function in host cell adherence and invasion in many pathogens. In this study, we assessed YadA distribution and biological activity as an example of one of virulence–associated factor shared, with biotype Jawetz and Heyl. More than half of mouse isolates were found to have at least one of these genes; whereas, the majority of rat isolates did not. Autoagglutination activity, and ability to bind to mouse collagen type IV and mouse fibroblast cells, was significantly higher in YadA-positive than YadA-negative strains. To conclude, we identified a large number of candidate genes predicted to influence [ P. ] pneumotropica pathogenesis. [ABSTRACT FROM AUTHOR]

Background and Aim Daclatasvir combined with asunaprevir is the first all-oral, ribavirin-free treatment of hepatitis C virus genotype 1b infection in Japan. This study compared the efficacy and safety of daclatasvir plus asunaprevir versus telaprevir plus peginterferon/ribavirin in Japanese treatment-naive patients infected with hepatitis C virus genotype 1b. Methods Treatment-naive patients (20-70 years; baseline viral load, ≥100,000 IU/mL) were randomly assigned (stratified by IL28B rs8099917 TT/non-TT status) to receive either daclatasvir 60 mg tablets once daily and asunaprevir 100 mg softgel capsules twice daily for 24 weeks or telaprevir 750 mg (3 × 250 mg tablets) three times daily for 12 weeks and peginterferon/ribavirin per Japanese prescribing information for 24 weeks. A cohort of prior relapsers to peginterferon/ribavirin (20-75 years; baseline viral load, ≥100,000 IU/mL) received daclatasvir plus asunaprevir. Results In treatment-naive patients, sustained virologic response at post-treatment week 12 in daclatasvir plus asunaprevir recipients was non-inferior (treatment difference, +25.8% in favor of daclatasvir plus asunaprevir) and higher (89.1%, 106/119) than telaprevir plus peginterferon/ribavirin recipients (62.2%, 69/111); sustained viral response was achieved in 95.5% ( n = 21/22) of relapsers. Numerically, fewer patients receiving daclatasvir plus asunaprevir compared with telaprevir plus peginterferon/ribavirin experienced serious adverse events (4.2% vs. 5.4%), adverse events leading to discontinuation of any drug (5.0% vs. 62.2%), grade 3/4 treatment-related adverse events (14.3% vs. 72.1%), rash-related events (0% vs. 13.5%), or anemia (0% vs. 47.7%). Conclusion Marked differences were observed in the efficacy and safety profile of daclatasvir in combination with asunaprevir, compared with telaprevir plus peginterferon/ribavirin. [ABSTRACT FROM AUTHOR]

Methanogenic archaea are strict anaerobes and demand highly reduced conditions to produce methane in paddy field soil. However, methanogenic archaea survive well under upland and aerated conditions in paddy fields and exhibit stable community. In the present study, methanogenic archaeal community was investigated in fields where paddy rice ( Oryza sativa L.) under flooded conditions was rotated with soybean ( Glycine max [L.] Merr.) under upland conditions at different rotation histories, by polymerase chain reaction (PCR)-denaturing gradient gel electrophoresis (DGGE) and real-time quantitative PCR methods targeting 16S rRNA and mcrA genes, respectively. Soil samples collected from the fields before flooding or seeding, during crop cultivation and after harvest of crops were analyzed. The abundance of the methanogenic archaeal populations decreased to about one-tenth in the rotational plots than in the consecutive paddy (control) plots. The composition of the methanogenic archaeal community also changed. Most members of the methanogenic archaea consisting of the orders Methanosarcinales, Methanocellales, Methanomicrobiales, and Methanobacteriales existed autochthonously in both the control and rotational plots, while some were strongly affected in the rotational plots, with fatal effect to some members belonging to the Methanosarcinales. This study revealed that the upland conversion for one or longer than 1 year in the rotational system affected the methanogenic archaeal community structure and was fatal to some members of methanogenic archaea in paddy field soil. [ABSTRACT FROM AUTHOR]