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Targeting PD-1/PD-L1 has shown the ability to improve overall survival in urothelial carcinoma; however, there are cases of nonresponse and resistance. In this study, we evaluated time-course changes in all tumor locations after pembrolizumab treatment to examine the differences in immune checkpoint inhibitor efficacy in different organs. We also examined the usefulness of neutrophil-to-lymphocyte ratio, CRP, and kinetics as prognostic biomarkers in urothelial carcinoma treated with pembrolizumab. Introduction: Since tumors in different human organs may have different tumor microenvironments, we evaluate timecourse changes in all tumor locations after pembrolizumab treatment in urothelial carcinoma (UC) to examine the differences in efficacy of pembrolizumab per organ. Further, we uncover the usefulness of inflammatory markers such as neutrophil-to-lymphocyte ratio (NLR), CRP, and kinetics of these markers to predict pembrolizumab success and relation to overall survival (OS) in UC. Patients and Methods: A total of 115 cancerous lesions from 44 UC patients were measurable based on RECIST 1.1 cr iter ia. The ser um CRP and NLR levels were measured at baseline prior to pembrolizumab treatment and at least every 3 weeks just prior to pembrolizumab administration. Results: Site-specific success (ie, patients with CR/PR/SD by RESIST 1.1) rates for pembrolizumab treatments were as follows: primary tumors: 67%, lymph node: 70%, lung: 44%, liver: 40%, and peritoneal metastasis: 56%. Focusing on the major metastasis sites, lymph nodes and lungs, we examined the relationships between NLR, CRP, or that kinetics and pembrolizumab success. In lymph nodes, both early NLR kinetics (P = .005) and CRP kinetics (P = .035) was a predictor for pembrolizumab success. On the other hand, none of 4 was not in lung metastases. Regarding to the mortality, the multivariate analysis revealed that early NLR kinetics was a prognostic biomarker for OS among the 4, independent of performance status and liver metastasis. Conclusion: We revealed that site-specific pembrolizumab success in UC. Early NLR kinetics was a predictor for lymph node pembrolizumab success and OS in our cohorts. [ABSTRACT FROM AUTHOR]

A new species, Impatiens katjae Nob. Tanaka & J. J. Verm. (Balsaminaceae), from Mandalay Region, central Myanmar, is described and illustrated. This species is similar to I. oblongata Ruchis. & Niet in floral morphology, but differs in having distinctly smaller flowers, 2-flowered axillary inflorescences, much paler pinkish-white flowers, two lateral sepals, and a spurless lower sepal. This new species is assigned to Impatiens L. subg. Impatiens sect. Uniflorae Hook. f. & Thomson. [ABSTRACT FROM AUTHOR]

In the course of our intensive floristic inventories for the flora of Myanmar, a new species of the genus Sapria (Rafflesiaceae), S. myanmarensis Nob. Tanaka, Nagam., Tagane & M.M. Aung is described and photographed. In addition, S. himalayana Griff. f. albovinosa Banziger & B. Hansen is newly recorded in the country. A key to the species of Sapria presently occurring in Myanmar is provided. [ABSTRACT FROM AUTHOR]

This article describes a low latency dynamic bandwidth allocation (DBA) method with high bandwidth efficiency that is intended for use in campus area networks and mobile fronthaul based on TDM-PON (time division multiplexing passive optical network). These network systems require low latency of under 100 μs and high bandwidth efficiency. Our method involves only three steps for allocation and employs an adaptive DBA cycle depending on the traffic load. The DBA cycle length, which is proportional to the latency, can be minimized because the simple allocation steps are appropriate for hardware implementation. Our DBA method automatically optimizes the cycle length to reduce the latency and improve bandwidth efficiency. We implemented it on a 10-gigabit Ethernet passive optical network (10G-EPON) media access control system-on-a-chip and evaluated the allocation results and the latency on the 10G-EPON system. Our DBA achieved a minimum latency of 60 μs with priority control and high bandwidth efficiency, depending on traffic. [ABSTRACT FROM AUTHOR]

Reactions of Pd(PPh3)4with P(E)(NiPr2)(naph) (6, E = S; 7, E = O) (naph = 1,8-naphthylene) having a strained four-membered P(V)-phosphacycle gave dimeric complexes [Pd{κ2P,C-μ2-PE- P(E)(NiPr2)(naph)}(PPh3)]2(9, E = S; 10, E = O), in which a Pd metal has been inserted into a P−C bond of the phosphacycle to form a phosphapalladacycle having a P(V) donor, and the two phosphapalladacycle units have been mutually bridged with EP groups, as confirmed by X-ray structure analysis for thermodynamically more stable racemic isomers 9aand 10a. The meso-to-racemic isomerization observed for the simultaneously formed meso isomer 9b, and probably also for the corresponding meso isomer 10b, indicated partial dissociation of 9and 10taking place to their monomer units in solution, which were actually trapped as [Pd{κ2P,C-P(E)(NiPr2)(naph)}(dppe)] by treatment with bidentate dppe (dppe = 1,2-bis(diphenylphosphino)ethane). On the other hand, a similar treatment of 9awith monodentate PMe3and PEt2Ph resulted in a trivial substitution of both PPh3ligands to give dimeric PMe3and PEt2Ph analogues of 9a, respectively. 10awas found to react with O2to form an unprecedented oxidation product, [Pd{κ2P,O-μ2-PO-PO(O)(NiPr2)(naph)}(PPh3)]2, 17, in which an oxygen atom has been inserted into each P(V)−Pd bond. 9aand 10aexhibited moderate catalytic activities for a Heck reaction between PhI and styrene. The mercury test indicated that metallic Pd nanoparticles released from 9aand 10awould be practical catalysts. [ABSTRACT FROM AUTHOR]

A thermochemical water-splitting iodine–sulfur process offers the potential for mass-producing hydrogen at high-efficiency levels, and it uses high-temperature heat sources, including high-temperature gas-cooled reactors, solar heat, and waste heat of industries. The raw material (H 2 O) is split into H 2 and O 2 by combining three chemical reactions using sulfur and iodine. Currently, R&D tasks are essential to confirm the integrity of the components that are made of practical structural materials and the stability of hydrogen production in harsh working conditions. A test facility for producing hydrogen was constructed from corrosion-resistant components that are developed using industrial materials. In addition, for stable hydrogen production, technical issues for instrumental improvements (i.e., stable pumping of the hydrogen iodide (HI)–I 2 –H 2 O solution without locking the shaft seal, prevention of leakage by improving the quality control of glass-lined steel, prevention of I 2 precipitation using a water removal technique in a Bunsen reactor) were solved. The entire process was successfully operated for 150 h at the rate of ca. 30 L/h. The integrity of components made of practical structural materials and the operational stability of the hydrogen production facility in harsh working conditions were demonstrated. • A test facility was constructed by using corrosion-resistant structural materials. • Prevention of I 2 precipitation (clogging), and pumping of HI–I 2 mixture were devised. • The entire process was successfully operated for 150 h at rates of ca. 10–30 L-H 2 /h. • Operational stability of H 2 production in handling of HI–I 2 was demonstrated. [ABSTRACT FROM AUTHOR]

Endolysosomal defects in neurons are central to the pathogenesis of prion and other neurodegenerative disorders. In prion disease, prion oligomers traffic through the multivesicular body (MVB) and are routed for degradation in lysosomes or for release in exosomes, yet how prions impact proteostatic pathways is unclear. We found that prion-affected human and mouse brain showed a marked reduction in Hrs and STAM1 (ESCRT-0), which route ubiquitinated membrane proteins from early endosomes into MVBs. To determine how the reduction in ESCRT-0 impacts prion conversion and cellular toxicity in vivo, we prion-challenged conditional knockout mice (male and female) having Hrs deleted from neurons, astrocytes, or microglia. The neuronal, but not astrocytic or microglial, Hrs-depleted mice showed a shortened survival and an acceleration in synaptic derangements, including an accumulation of ubiquitinated proteins, deregulation of phosphorylated AMPA and metabotropic glutamate receptors, and profoundly altered synaptic structure, all of which occurred later in the prion-infected control mice. Finally, we found that neuronal Hrs (nHrs) depletion increased surface levels of the cellular prion protein, PrPC, which may contribute to the rapidly advancing disease through neurotoxic signaling. Taken together, the reduced Hrs in the prionaffected brain hampers ubiquitinated protein clearance at the synapse, exacerbates postsynaptic glutamate receptor deregulation, and accelerates neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: No previous study has addressed the efficacy of NF-κB blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κB activation and therapeutic impact of NF-κB blockade by the novel NF-κB inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. Methods: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. Results: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. Conclusion: There was a distinct change in the activation level of NF-κB between T24 and T24PR cells, suggesting strong nuclear localization of NF-κB could be a promising target after developing acquired platinum-resistance in bladder cancer. [ABSTRACT FROM AUTHOR]

α-Synuclein (aS) is a major constituent of Lewy bodies, which are not only a pathological marker for Parkinson disease but also a trigger for neurodegeneration. Cumulative evidence suggests that aS spreads from cell to cell and thereby propagates neurodegeneration to neighboring cells. Recently, Nedd4-1 (neural precursor cell expressed developmentally down-regulated protein 4-1), an E3 ubiquitin ligase, was shown to catalyze the Lys-63-linked polyubiquitination of intracellular aS and thereby facilitate aS degradation by the endolysosomal pathway. Because Nedd4-1 exerts its activity in close proximity to the inner leaflet of the plasma membrane, we speculate that after the internalization of aS the membrane resident aS is preferentially ubiquitinated by Nedd4-1. To clarify the role of Nedd4-1 in aS internalization and endolysosomal sequestration, we generated aS mutants, including ΔPR1(1-119 and 129-140), ΔC(1-119), and ΔPR2(1-119 and 134-140), that lack the proline-rich sequence, a putative Nedd4-1 recognition site. We show that wild type aS, but not ΔPR1, ΔPR2, or ΔC aS, is modified by Nedd4-1 in vitro, acquiring a Lys-63-linked ubiquitin chain. Compared with the mutants lacking the proline-rich sequence, wild type-aS is preferentially internalized and translocated to endosomes. The overexpression of Nedd4-1 increased aS in endosomes, whereas RNAi-mediated silencing of Nedd4-1 decreased endosomal aS. Although aS freely passes through plasma membranes within minutes, a pulse-chase experiment revealed that the overexpression of Nedd4-1 markedly decreased the re-secretion of internalized aS. Together, these findings demonstrate that Nedd4-1-linked Lys-63 ubiquitination specifies the fate of extrinsic and de novo synthesized aS by facilitating their targeting to endosomes. [ABSTRACT FROM AUTHOR]

Abstract  We have previously reported that thermal vasodilation following warm-water bathing and low-temperature sauna bathing (LTSB) at 60 °C for 15 min improves the cardiac function in patients with congestive heart failure. Through a comparative before-and-after study, we studied the hemodynamic and clinical effects of single exposure to LTSB in cerebral palsy (CP) patients who usually suffer from chilled extremities and low cardiac output. The study population comprised 16 patients ranging between 19 and 53 years with severe motor and intellectual disabilities. Noninvasive methods were used to estimate the systemic and peripheral circulatory changes before and after LTSB. Using blood flow velocity analysis, the pulsatile and resistive indexes of the peripheral arteries of the patients’ lower limbs were calculated. Following LTSB, the patients’ deep body temperature increased significantly by 1°C. Their heart rates increased and blood pressure decreased slightly. The total peripheral resistance decreased by 11%, and the cardiac output increased by 14%. There was significant improvement in the parameters that are indicative of the peripheral circulatory status, including the skin blood flow, blood flow velocity, pulsatile index, and resistive index. Numbness and chronic myalgia of the extremities decreased. There were no adverse side effects. Thus, it can be concluded that LTSB improves the peripheral circulation in CP patients. [ABSTRACT FROM AUTHOR]

Heterocyphelium triseptatum is newly recorded from Asia. The species was previously known only from South America and Africa. It was collected from the bark of a broadleaf tree at 35 m elevation in the Tanintharyi Region of southern Myanmar. An unidentified substance was newly detected for this species by thin layer chromatography (TLC). This study demonstrates the phylogenetic position of H. triseptatum in the Lecanographaceae using Bayesian and RAxML analyses of mtSSU and nrLSU sequence data. The close relationship with H. leucampyx within the Heterocyphelium clade was confirmed. [ABSTRACT FROM AUTHOR]

The aim of this study was to validate the contemporary grading system. Our follow-up study revealed that men with Gleason score (GS) 4D5 and those with Gleason grade group 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4D5 and GS 5D4 or higher. Gleason grade groups 4 and 5 in the contemporary grading system should be reviewed. Introduction: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. Patients and Methods: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). Results: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4þ5 and 29 patients with GS 5þ4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4þ5, and GS 5þ4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4þ5 than in GS 5þ4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4þ5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5þ4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. Conclusion: Our follow-up study revealed that men with GS 4þ5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4þ5 and GS 5þ4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients. [ABSTRACT FROM AUTHOR]

Specimens of lichens collected from southern Myanmar including Tanintharyi and Yangon Regions were examined. As the result of taxonomic examinations, the following 20 species were identified: Astrothelium macrocarpum, Bulbothrix subscortea, Coccocarpia erythroxyli, C. palmicola, Cruentotrema thailandicum, Dirinaria aegialita, D. consimilis, Dyplolabia afzelii, Flakea papillata, Glyphis cicatricosa, Graphis cf. caesiella, G. desquamescens, G. supracola, Malmidea bakeri, Physcia undulata, Pyrenula mamillana, Pyxine dactyloschmidtii, Sarcographa labyrinthica, Trypethelium eluteriae, and Zwackhia prosodea. All of them, except the two species of Coccocarpia, are new records for Myanmar. The ITS rDNA sequences were successfully obtained from 17 samples for 14 species. The BLAST identities for Myanmar collections with the same species in GenBank range from 89 to 100%. [ABSTRACT FROM AUTHOR]

The extracellular matrix (ECM) surrounding cancer cells becomes stiffer during tumor progression, which influences cancer cell behaviors such as invasion and proliferation through modulation of gene expression as well as remodeling of the actin cytoskeleton. In this study, we show that MMP24 encoding matrix metalloproteinase (MMP)-24 is a novel target gene of Yes-associated protein (YAP), a transcription coactivator known as a mechanotransducer. We first examined the effect of substrate stiffness on MMP24 expression in MCF-7 human breast cancer cells and showed that the expression of MMP24 was significantly higher in cells grown on stiff substrates than that on soft substrates. The MMP24 expression was significantly reduced by knockdown of YAP. In contrast, the expression of constitutively active YAP increased MMP24 promoter activity. In addition, binding of YAP to the MMP24 promoter was confirmed by the chromatin immunoprecipitation (ChIP) assay. These results show that ECM stiffening promotes YAP activation, thereby inducing MMP24 expression. Based on the Human Protein Atlas database, breast cancer patients with lower MMP24 expression exhibit the worse survival rates overall. Thus, MMP24 may negatively regulate the aggressiveness of cancer cells under the stiff ECM environment during tumor progression. [ABSTRACT FROM AUTHOR]

The Keap1-Nrf2 system plays a pivotal role in the oxidative stress response by inducing a number of cytoprotective genes. Under stress, damaged epithelial cells release cytokines that activate type 2 innate lymphoid cells (ILC2s), which mediate the allergic immune response. In this article, we investigated the role of the Keap1-Nrf2 pathway in ILC2 homeostasis and allergic inflammation using Nrf2 knockout mice. ILC2s from Nrf2-deficient mice showed a transient, upregulated IL-33 response and underwent hyperproliferation in response to a combined stimulation of IL-33 with IL-2, IL-7, or TSLP. This enhanced proliferation was correlated with an increased activation of downstream signals, including JAK1, Akt, and Erk1/2. In contrast, activating Nrf2 with a chemical inducer (CDDO-Im) decreased the viability of the wild-type but not of the Nrf2-deficient ILC2s. This effect on viability resembled that exerted by the corticosteroid dexamethasone; however, unlike the latter, the Nrf2-dependent cell death was mediated by neither caspase 3-dependent apoptosis nor necroptosis. Using a mouse intratracheal IL-33 administration allergy model, we found that the activation of Nrf2 by CDDO-Im in vivo decreased the number of pulmonary ILC2s and eosinophils. These findings indicated that Nrf2 is an important regulator of the allergic response by determining the survival and death of ILC2s, and these findings suggest that Nrf2 activation is a potential therapeutic strategy for steroid-resistant allergy alleviation. The Journal of Immunology, 2019, 202: 1331-1339. [ABSTRACT FROM AUTHOR]

Lung cancer is the most common cause of cancer mortality, however, efficient methods to culture, expand and transform lung epithelial (LE) cells have not been established. In the present study, an efficient ex vivo method was applied to recapitulate lung carcinogenesis using mouse LE cells. A Matrigel‑assisted three‑dimensional culture was used to isolate and selectively expand LE cells from mouse lungs. Purified LE cells were passaged and expanded for at least 2 to 3 months while maintaining epidermal growth factor‑dependence. LE cells were also easily transformed by genetic manipulations using retroviral vectors. A SV40 large‑T antigen, suppressing p53 and pRB, plus an activated oncogene, such as KrasG12V or EGFRex19del, were required to transform LE cells. Transformed cells formed tumors resembling non‑small cell lung cancer (NSCLC) in allograft models and exhibited strong oncogene addiction. This experimental system provided a unique model system to study lung tumorigenesis and develop novel therapeutics against NSCLC. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease (AD)-linked β-amyloid (Aβ) accumulates in multivesicular bodies (MVBs) with the onset of AD pathogenesis. Alterations in endosomes are among the earliest changes associated with AD but the mechanism(s) that cause endosome enlargement and the effects of MVB dysfunction on Aβ accumulation and tau pathology are incompletely understood. Methods: MVB size and Aβ fibrils in primary neurons were visualized by electron microscopy and confocal fluorescent microscopy. MVB-dysfunction, modelled by expression of dominant negative VPS4A (dnVPS4A), was analysed by biochemical methods and exosome isolation. Results: Here we show that AD transgenic neurons have enlarged MVBs compared to wild type neurons. Uptake of exogenous Aβ also leads to enlarged MVBs in wild type neurons and generates fibril-like structures in endocytic vesicles. With time fibrillar oligomers/fibrils can extend out of the endocytic vesicles and are eventually detectable extracellularly. Further, endosomal sorting complexes required for transport (ESCRT) components were found associated with amyloid plaques in AD transgenic mice. The phenotypes previously reported in AD transgenic neurons, with net increased intracellular levels and reduced secretion of Aβ, were mimicked by blocking recycling of ESCRT-III by dnVPS4A. DnVPS4A further resembled AD pathology by increasing tau phosphorylation at serine 396 and increasing markers of autophagy. Conclusions: We demonstrate that Aβ leads to MVB enlargement and that amyloid fibres can form within the endocytic pathway of neurons. These results are consistent with the scenario of the endosome-lysosome system representing the site of initiation of Aβ aggregation. In turn, a dominant negative form of the CHMP2B-interacting protein VPS4A, which alters MVBs, leads to accumulation and aggregation of Aβ as well as tau phosphorylation, mimicking the cellular changes in AD. [ABSTRACT FROM AUTHOR]

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage. [ABSTRACT FROM AUTHOR]

Background Even among patients considered to be functionally eligible for major lung resection, some experience postoperative dyspnea. Based on our previous study with quantitative computed tomography (CT), we hypothesized that postoperative dyspnea is associated with the collapse of the remaining lung, and thus, prediction of the postoperative lung volume may contribute to risk assessment for postoperative dyspnea. Methods We measured the emphysematous lung volume and functional lung volume (FLV) separately on whole lung CT using an image analysis software in 290 patients undergoing major lung resection for cancer between January 2006 and December 2012. The postoperative FLV was predicted by a stepwise multiple regression analysis. Results Fourteen patients complained of postoperative dyspnea (complicated group), five of them presented with chronic respiratory failure. The postoperatively measured FLV was significantly lower in the complicated group than in the control group (P < 0.01). The postoperative FLV could be calculated using preoperative variables, including the forced vital capacity, number of resected segments, FLV, and emphysematous lung volume. The predicted postoperative FLV was significantly lower in the complicated group than in the control group (P < 0.01, area under the curve = 0.78; sensitivity 86%; specificity 73%). The predicted postoperative FLV was also useful in distinguishing complicated patients from matched-control patients who had similar preoperative pulmonary function (P = 0.02). Conclusions Postoperative dyspnea is likely accompanied by a collapse of the remaining lung. Quantitative assessment of the lung morphology on preoperative CT is useful to screen for patients at risk of postoperative dyspnea. [ABSTRACT FROM AUTHOR]

The ESCRT-0 complex, consisting of the hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and the signaltransducing adaptor molecule (STAM) proteins, recognizes ubiquitylated cargo during the initial step of endosomal sorting. The endosomal accumulation of overexpressed Hrs has been reported previously to be associated with endosome enlargement. In this study, we have found that co-expressing exogenous STAM1 in Hrs-overexpressing cells leads to a diffuse localization for a large part of the Hrs accumulated on endosomes and a recovery of the impaired cargo protein degradation process, thus suggesting that exogenous STAM abrogates the abnormalities of the Hrs-positive endosomes. A fluorescently labeled Hrs, introduced into the cells by membrane permeabilization, exhibited endosomal localization in the absence of STAM1 and gradually dissociated from the endosomes upon the sequential addition of recombinant STAM1. Furthermore, when microinjected into cells, the fluorescently labeled Hrs also showed endosomal accumulation; however, ESCRT-0 complexes formed prior to the microinjection did not. Analysis of the state of the complex in HeLa cells using blue-native PAGE revealed that the membrane- associated Hrs exists partly as a monomer and not only in the STAM1-bound form. Thus, our data suggest that the membrane binding and dissociation cycle of the ESCRT-0 proteins on the endosomal membrane is a critical step during the cargo sorting process. [ABSTRACT FROM AUTHOR]

Oncogenic Ras induces cell transformation and promotes an invasive phenotype. The tumor suppressor p53 has a suppressive role in Ras-driven invasion. However, its mechanism remains poorly understood. Here we show that p53 induces activation of the mitochondrial protease high-temperature requirement A2 (HtrA2; also known as Omi) and prevents Ras-driven invasion by modulating the actin cytoskeleton. Oncogenic Ras increases accumulation of p53 in the cytoplasm, which promotes the translocation of p38 mitogen-activated protein kinase (MAPK) into mitochondria and induces phosphorylation of HtrA2/Omi. Concurrently, oncogenic Ras also induces mitochondrial fragmentation, irrespective of p53 expression, causing the release of HtrA2/Omi from mitochondria into the cytosol. Phosphorylated HtrA2/Omi therefore cleaves β-actin and decreases the amount of filamentous actin (F-actin) in the cytosol. This ultimately down-regulates p130 Crk-associated substrate (p130Cas)-mediated lamellipodia formation, countering the invasive phenotype initiated by oncogenic Ras. Our novel findings provide insights into the mechanism by which p53 prevents the malignant progression of transformed cells. [ABSTRACT FROM AUTHOR]

00515.2013.--Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Using the paired-pulse transcranial magnetic stimulation (TMS) paradigm, we can measure interhemispheric inhibition (IHI) and interhemispheric facilitation (IHF) as indexes of the interhemispheric interactions in humans. We investigated how quadripulse transcranial magnetic stimulation (QPS), one form of repetitive TMS (rTMS), on M1 affects the contralateral M1 and the interhemispheric interactions. QPS is able to induce bidirectional plastic changes in M1 depending on the interstimulus intervals (ISIs) of TMS pulses: longterm potentiation (LTP)-like effect by QPS-5 protocol, and long-term depression-like effect by QPS-50, whose numbers indicate the ISI (ms). Twelve healthy subjects were enrolled. We applied QPS over the left M1 and recorded several parameters before and 30 min after QPS. QPS-5, which increased motor-evoked potentials (MEPs) induced by left M1 activation, also increased MEPs induced by right M1 activation. Meanwhile, QPS-50, which decreased MEPs elicited by left M1 activation, did not induce any significant changes in MEPs elicited by right M1 activation. None of the resting motor threshold, active motor threshold, short-interval intracortical inhibition, longinterval intracortical inhibition, intracortical facilitation, and shortinterval intracortical inhibition in right M1 were affected by QPS. IHI and IHF from left to right M1 significantly increased after left M1 QPS-5. The degree of left first dorsal interosseous MEP amplitude change by QPS-5 significantly correlated with the degree of IHF change. We suppose that the LTP-like effect on the contralateral M1 may be produced by some interhemispheric interactions through the corpus callosum. [ABSTRACT FROM AUTHOR]

A correction to the article about the immunostaining of SSdRE-S1 cells that was published in the previous issue, is presented.

IL-21 regulates certain functions of T cells, B cells, NK cells and dendritic cells. Although activated CD4+ T cells produce IL-21, data identifying the specific CD4+ T cell subsets that produce IL-21 are conflicting. In a previous study, mouse IL-21 message was detected in TH2, whereas human IL-21 (hIL-21) message was found in both TH1 and follicular helper T cells. To identify the IL-21-secreting cell populations in human, we established a hybridoma cell line producing an anti-hIL-21 mAb. Intracellular hIL-21-staining experiments showed that hIL-21 was mainly expressed in activated CD4+ central memory T cells and in activated CD4+ effector memory T cells, but not in activated CD4+ naive T cells. Moreover, IL-21 was produced upon activation by some IFN-γ-producing TH1-polarized cells and some IL-17-producing TH17-polarized cells, but not by IL-4-producing TH2-polarized cells. These results suggest that specific CD4+ T cell populations produce IL-21. In the functional analysis, we found that IL-21 significantly enhanced the cytokine-driven proliferation of CD4+ helper T cells synergistically with IL-7 and IL-15 without T cell activation stimuli. Taken together, IL-21 produced from CD4+ memory T cells may have a supportive role in the maintenance of CD4+ T cell subsets. [ABSTRACT FROM AUTHOR]