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Pediatric graft-versus-host-disease (GVHD)-related dry eye disease (DED) is often overlooked due to a lack of subjective symptoms and reliable testing, leading to irreversible corneal damage. To study the clinical findings contributing to the accurate detection of pediatric GVHD-related DED, a retrospective study of pediatric patients treated with hematopoietic stem cell transplantation (HSCT) at Keio University Hospital between 2004 and 2017 was conducted. Association and diagnostic values of ophthalmological findings for DED were analyzed. Twenty-six patients who had no ocular complications before HSCT were included in the study. Eleven (42.3%) patients developed new-onset DED. The cotton thread test showed excellent diagnostic accuracy in detecting DED (area under the receiver operating curve, 0.96; sensitivity, 0.95; specificity, 0.85) with a cut-off of 17 mm, which was higher than the conventional threshold of 10 mm. Additionally, the presence of filamentary keratitis (FK) and pseudomembranous conjunctivitis (PC) were significantly associated with the diagnosis of DED (p value, 0.003 and 0.001 for FK and PC, respectively) and displayed good diagnostic performance (sensitivity, 0.46 and 0.54; specificity, 0.97 and 0.97 for FK and PC, respectively). In conclusion, the cotton thread test with a new threshold, the presence of PC and FK, could be helpful for promptly detecting pediatric GVHD-related DED., (© 2023. The Author(s).)

The aim of this study was to evaluate the influence of skin distortion due to surgical positioning on the clinical accuracy of the navigation system. The distance errors were measured in four fiducial markers (anterior, posterior, right, and left of the head) after the registration of the navigation system. The distance errors were compared between the surface-merge registration (SMR) method using preoperative imaging and the automatic intraoperative registration (AIR) method using intraoperative imaging. The comparison of the distance errors were performed in various surgical positions. The AIR method had the significant accuracy in the lateral markers than the SMR method (lateral position, 3.8 mm vs. 8.95 mm; p < 0.0001; prone position, 4.5 mm vs. 13.9 mm; p = 0.0001; 5.2 mm vs. 11.5 mm; p = 0.0070). The smallest distance errors were obtained close to the surgical field in the AIR method (3.25-3.85 mm) and in the forehead in the SMR method (3.3-8.1 mm). The AIR method was accurate and recommended for all the surgical positions if intraoperative imaging was available. The SMR method was only recommended for the supine position, because skin distortion was frequently observed in the lateral region., (© 2023. The Author(s).)

Since the advent of graphene, a variety of studies have been performed to elucidate its fundamental physics, or to explore its practical applications. Gate-tunable resistance is one of the most important properties of graphene and has been studied in 1-3 layer graphene in a number of efforts to control the band gap to obtain a large on-off ratio. On the other hand, the transport property of multilayer graphene with more than three layers is less well understood. Here we show a new aspect of multilayer graphene. We found that four-layer graphene shows intrinsic peak structures in the gate voltage dependence of its resistance at zero magnetic field. Measurement of quantum oscillations in magnetic field confirmed that the peaks originate from the specific band structure of graphene and appear at the carrier density for the bottoms of conduction bands and valence bands. The intrinsic peak structures should generally be observed in AB-stacked multilayer graphene. The present results would be significant for understanding the physics of graphene and making graphene FET devices.

How atoms acquire three-dimensional bulk character is one of the fundamental questions in materials science. Before addressing this question, how atomic layers become a bulk crystal might give a hint to the answer. While atomically thin films have been studied in a limited range of materials, a recent discovery showing how to mechanically exfoliate bulk crystals has opened up the field to study the atomic layers of various materials. Here, we show systematic variation in the band structure of high mobility graphene with one to seven layers by measuring the quantum oscillation of magnetoresistance. The Landau fan diagram showed distinct structures that reflected differences in the band structure, as if they were finger prints of multilayer graphene. In particular, an even-odd layer number effect was clearly observed, with the number of bands increasing by one for every two layers and a Dirac cone observed only for an odd number of layers. The electronic structure is significantly influenced by the potential energy arising from carrier screening associated with a gate electric field.

The length of a telomere is regulated via elongation and shortening processes. Telomeric DNA and telomeric repeat-containing RNA (TERRA), which both contain G-rich repeated sequences, form G-quadruplex structures. Previously, translocated in liposarcoma (TLS) protein, also known as fused in sarcoma (FUS) protein, was found to form a ternary complex with the G-quadruplex structures of telomeric DNA and TERRA. We then showed that the third RGG motif of TLS, the RGG3 domain, is responsible for the complex formation. However, the structural basis for their binding remains obscure. Here, NMR-based binding assaying revealed the interactions in the binary and ternary complexes of RGG3 with telomeric DNA or/and TERRA. In the ternary complex, tyrosine bound exclusively to TERRA, while phenylalanine bound exclusively to telomeric DNA. Thus, tyrosine and phenylalanine each play a central role in the recognition of TERRA and telomeric DNA, respectively. Surprisingly in the binary complexes, RGG3 used both tyrosine and phenylalanine residues to bind to either TERRA or telomeric DNA. We propose that the plastic roles of tyrosine and phenylalanine are important for RGG3 to efficiently form the ternary complex, and thereby regulate the telomere shortening.

Detailed structural analyses of the mushroom body which plays critical roles in olfactory learning and memory revealed that it is directly connected with multiple primary sensory centers in Drosophila. Connectivity patterns between the mushroom body and primary sensory centers suggest that each mushroom body lobe processes information on different combinations of multiple sensory modalities. This finding provides a novel focus of research by Drosophila genetics for perception of the external world by integrating multisensory signals.

This study aimed to investigate the effects of reproducing an ultrasonic sound above 20 kHz on the subjective impressions of water sounds using psychological and physiological information obtained by the semantic differential method and electroencephalography (EEG), respectively. The results indicated that the ultrasonic component affected the subjective impression of the water sounds. In addition, regarding the relationship between psychological and physiological aspects, a moderate correlation was confirmed between the EEG change rate and subjective impressions. However, no differences in characteristics were found between with and without the ultrasound component, suggesting that ultrasound does not directly affect the relationship between subjective impressions and EEG energy at the current stage. Furthermore, the correlations calculated for the left and right channels in the occipital region differed significantly, which suggests functional asymmetry for sound perception between the right and left hemispheres. [ABSTRACT FROM AUTHOR]

Idiopathic normal pressure hydrocephalus (iNPH) is a treatable disease in older adults. The association between gait and cognition has recently become a topic of interest. Sequential changes in this association were investigated in patients with iNPH using a newly developed statistical method. Data were extracted from the SINPHONI-2 multicenter study on iNPH. Fifty patients who underwent shunt surgery were included in this study. Gait and cognition were assessed using the Timed Up and Go (TUG) and Mini-Mental State Examination (MMSE) tests. In addition to the MMSE total score, changes in the sub-item scores were examined. The ordinal sub-items of the MMSE are usually treated as continuous or categorical; however, both are unsuitable. An ordinal smoothing penalty with a generalized additive model enables precise statistical inference of ordinal and binary predictors. The TUG time improved significantly at 3, 6, and 12 months after surgery. The MMSE total scores increased without statistical significance. Preoperatively, there was no association between TUG time and MMSE sub-items. At 3 months, the "Registration," "3-step command," "Read," and "Copy" sub-items were statistically significant. The number of significant sub-items increased after 12 months. Thus, the association between gait and cognition gradually increased after surgery in patients with iNPH. [ABSTRACT FROM AUTHOR]

In recent decades, the detrimental effects of environmental contaminants on human health have become a serious public concern. Organophosphate (OP) pesticides are widely used in agriculture, and the negative impacts of OP and its metabolites on human health have been demonstrated. We hypothesized that exposure to OPs during pregnancy could impose damaging effects on the fetus by affecting various processes. We analyzed sex-specific epigenetic responses in the placenta samples obtained from the mother–child PELAGIE cohort. We assayed the telomere length and mitochondrial copy numbers using genomic DNA. We analyzed H3K4me3 by using chromatin immunoprecipitation followed by qPCR (ChIP‒qPCR) and high-throughput sequencing (ChIP-seq). The human study was confirmed with mouse placenta tissue analysis. Our study revealed a higher susceptibility of male placentas to OP exposure. Specifically, we observed telomere length shortening and an increase in γH2AX levels, a DNA damage marker. We detected lower histone H3K9me3 occupancy at telomeres in diethylphosphate (DE)-exposed male placentas than in nonexposed placentas. We found an increase in H3K4me3 occupancy at the promoters of thyroid hormone receptor alpha (THRA), 8-oxoguanine DNA glycosylase (OGG1) and insulin-like growth factor (IGF2) in DE-exposed female placentas. H3K4me3 occupancy at PPARG was increased in both male and female placentas exposed to dimethylphosphate (DM). The genome-wide sequencing of selected samples revealed sex-specific differences induced by DE exposure. Specifically, we found alterations in H3K4me3 in genes related to the immune system in female placenta samples. In DE-exposed male placentas, a decrease in H3K4me3 occupancy at development-related, collagen and angiogenesis-related genes was observed. Finally, we observed a high number of NANOG and PRDM6 binding sites in regions with altered histone occupancy, suggesting that the effects were possibly mediated via these factors. Our data suggest that in utero exposure to organophosphate metabolites affects normal placental development and could potentially impact late childhood. [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]

Although stress significantly impacts on various metabolic syndromes, including diabetes mellitus, most stress management techniques are based on psychological and subjective approaches. This study examined how the presence or absence of the inaudible high-frequency component (HFC) of sounds, which activates deep-brain structures, affects glucose tolerance in healthy participants using the oral glucose tolerance test (OGTT). Sounds containing HFC suppressed the increase in glucose levels measured by incremental area under the curve in the OGTT compared with the otherwise same sounds without HFC. The suppression effect of HFC was more prominent in the older age group and the group with high HbA1c. This suggests that sounds with HFC are more effective in improving glucose tolerance in individuals at a higher risk of glucose intolerance. [ABSTRACT FROM AUTHOR]

Low priority on waste management has impacted the complex environmental issue of plastic waste pollution, as evident by results of this study where it was found that 24.3% of waste generation in Jakarta and Bandung is emitted into the waterway due to the high intensity of human activity in the urban area. In this study, we investigated the viable integration between material flow analysis and leakage hotspot modeling to improve management strategies for plastic pollution in water systems and open environments. Using a multi-criteria assessment of plastic leakage from current waste management, a material flow analysis was developed on a city-wide scale defining the fate of plastic waste. Geospatial analysis was assigned to develop a calculation for identification and hydrological analysis while identifying the potential amount of plastic leakage to the river system. The results show that 2603 tons of plastic accumulated along the mainstream of the Ciliwung River on an annual basis, and a high-density population like that in Bandung discarded 1547 tons in a one-year period to the Cikapundung River. The methods and results of this study are applicable towards improving the control mechanisms of river rejuvenation from plastic leakage by addressing proper management in concentrated locations. [ABSTRACT FROM AUTHOR]

The existence of three independent binary systems for conditional gene expression (Gal4/UAS; LexA/LexAop; QF/QUAS) has greatly expanded versatile genetic analyses in the Drosophila melanogaster; however, the experimental application of these tools is limited by the need to generate multiple collections of noninterchangeable transgenic fly strains for each inducible gene expression system. To address this practical limitation, we developed a modular vector that contains the regulatory elements from all three binary systems, enabling Gal4-, LexA- or QF-dependent expression of transgenes. Our methods also incorporate DNA elements that facilitate independent site-specific recombination and elimination of regulatory UAS, LexAop or QUAS modules with spatial and temporal control, thus offering unprecedented possibilities and logistical advantages for in vivo genetic modulation and efficient interconversion of overexpression transgenic fly lines. [ABSTRACT FROM AUTHOR]

Head-and-neck squamous cell carcinomas (HNSCCs) are relatively common in patients with Fanconi anemia (FA), a hereditary chromosomal instability disorder. Standard chemo-radiation therapy is not tolerated in FA due to an overall somatic hypersensitivity to such treatment. The question is how to find a suitable alternative treatment. We used whole-exome and whole genome mRNA sequencing to identify major genomic and transcriptomic events associated with FA-HNSCC. CRISPR-engineered FA-knockout models were used to validate a number of top hits that were likely to be druggable. We identified deletion of 18q21.2 and amplification of 11q22.2 as prevailing copy-number alterations in FA HNSCCs, the latter of which was associated with strong overexpression of the cancer-related genes YAP1, BIRC2, BIRC3 (at 11q22.1-2). We then found the drug AZD5582, a known small molecule inhibitor of BIRC2-3, to selectively kill FA tumor cells that overexpressed BIRC2-3. This occurred at drug concentrations that did not affect the viability of untransformed FA cells. Our data indicate that 11q22.2 amplifications are relatively common oncogenic events in FA-HNSCCs, as holds for non FA-HNSCC. Therefore, chemotherapeutic inhibition of overexpressed BIRC2-3 may provide the basis for an approach to develop a clinically realistic treatment of FA-HNSCCs that carry 11q22.2 amplifications. [ABSTRACT FROM AUTHOR]

The thermodynamic properties of few-layer graphene arbitrarily stacked on LiNbO3 crystal were characterized by measuring the parameters of a surface acoustic wave as it passed through the graphene/LiNbO3 interface. The parameters considered included the propagation velocity, frequency, and attenuation. Mono-, bi-, tri-, tetra-, and penta-layer graphene samples were prepared by transferring individual graphene layers onto LiNbO3 crystal surfaces at room temperature. Intra-layer lattice deformation was observed in all five samples. Further inter-layer lattice deformation was confirmed in samples with odd numbers of layers. The inter-layer lattice deformation caused stick–slip friction at the graphene/LiNbO3 interface near the temperature at which the layers were stacked. The thermal expansion coefficient of the deformed few-layer graphene transitioned from positive to negative as the number of layers increased. To explain the experimental results, we proposed a few-layer graphene even–odd layer number stacking order effect. A stable pair-graphene structure formed preferentially in the few-layer graphene. In even-layer graphene, the pair-graphene structure formed directly on the LiNbO3 substrate. Contrasting phenomena were noted with odd-layer graphene. Single-layer graphene was bound to the substrate after the stable pair-graphene structure was formed. The pair-graphene structure affected the stacking order and inter-layer lattice deformation of few-layer graphene substantially. [ABSTRACT FROM AUTHOR]

Identification of a quantitative trait locus (QTL) related to a chronic respiratory disease such as Mycoplasmal pneumonia of swine (MPS) and immune-related traits is important for the genetic improvement of disease resistance in pigs. The objective of this study was to detect a novel QTL for a total of 22 production, respiratory disease, and immune-related traits in Landrace pigs. A total of 874 Landrace purebred pigs, which were selected based on MPS resistance, were genotyped using the Illumina PorcineSNP60 BeadChip. We performed single nucleotide polymorphism (SNP)-based and haplotype-based genome-wide association studies (GWAS) to detect a novel QTL and to evaluate the possibility of a pleiotropic QTL for these traits. SNP-based GWAS detected a total of six significant regions in backfat thickness, ratio of granular leucocytes to lymphatic cells, plasma concentration of cortisol at different ages, and complement alternative pathway activity in serum. The significant region detected by haplotype-based GWAS was overlapped across the region detected by SNP-based GWAS. Most of these detected QTL regions were novel regions with some candidate genes located in them. With regard to a pleiotropic QTL among traits, only three of these detected QTL regions overlapped among traits, and many detected regions independently affected the traits. [ABSTRACT FROM AUTHOR]

In Bell's palsy, electrodiagnosis by electroneurography (ENoG) is widely used to predict a patient's prognosis. The therapeutic options for patients with poor prognostic results remain controversial. Here, we investigated whether early intervention with intratympanic steroid therapy (ITST) is an effective treatment for Bell's palsy patients with poor electrodiagnostic test results (≤ 10% electroneurography value). Patients in the concurrent ITST group (n = 8) received the standard systemic dose of prednisolone (410 mg total) and intratympanic dexamethasone (16.5 mg total) and those in the control group (n = 21) received systemic prednisolone at the standard dose or higher (average dose, 605 ± 27 mg). A year after onset, the recovery rate was higher in the ITST group than in the control group (88% vs 43%, P = 0.044). The average House-Brackmann grade was better in the concurrent ITST group (1.13 ± 0.13 vs 1.71 ± 0.16, P = 0.035). Concurrent ITST improves the facial nerve outcome in patients with poor electroneurography test results, regardless of whether equivalent or lower glucocorticoid doses were administered. This may be ascribed to a neuroprotective effect of ITST due to a higher dose of steroid reaching the lesion due to dexamethasone transfer in the facial nerve. [ABSTRACT FROM AUTHOR]

Mutations in the RNA-binding protein FUS cause familial amyotropic lateral sclerosis (ALS). Several mutations that affect the proline-tyrosine nuclear localization signal (PY-NLS) of FUS cause severe juvenile ALS. FUS also undergoes liquid–liquid phase separation (LLPS) to accumulate in stress granules when cells are stressed. In unstressed cells, wild type FUS resides predominantly in the nucleus as it is imported by the importin Karyopherin-β2 (Kapβ2), which binds with high affinity to the C-terminal PY-NLS of FUS. Here, we analyze the interactions between two ALS-related variants FUS(P525L) and FUS(R495X) with importins, especially Kapβ2, since they are still partially localized to the nucleus despite their defective/missing PY-NLSs. The crystal structure of the Kapβ2·FUS(P525L)PY-NLS complex shows the mutant peptide making fewer contacts at the mutation site, explaining decreased affinity for Kapβ2. Biochemical analysis revealed that the truncated FUS(R495X) protein, although missing the PY-NLS, can still bind Kapβ2 and suppresses LLPS. FUS(R495X) uses its C-terminal tandem arginine-glycine-glycine regions, RGG2 and RGG3, to bind the PY-NLS binding site of Kapβ2 for nuclear localization in cells when arginine methylation is inhibited. These findings suggest the importance of the C-terminal RGG regions in nuclear import and LLPS regulation of ALS variants of FUS that carry defective PY-NLSs. [ABSTRACT FROM AUTHOR]

High-resolution digital audio is believed to produce a better listening experience than the standard quality audio, such as compact disks (CDs) and digital versatile disks (DVDs). One common belief is that high-resolution digital audio is superior due to the higher frequency (> 22 kHz) of its sound components, a characteristic unique to this audio. This study examined whether sounds with high-frequency components were processed differently from similar sounds without these components in the auditory cortex. Mismatch negativity (MMN), an electrocortical index of auditory deviance detection in sensory memory, was recorded in young adults with normal hearing (N = 38) using two types of white noise bursts: original sound and digitally filtered sound from which high-frequency components were removed. The two sounds did not produce any MMN response and could not be discriminated behaviourally. In conclusion, even if high-resolution audio is superior to the standard format, the difference is apparently not detectable at the cortical level. [ABSTRACT FROM AUTHOR]

In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4+ T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFNγ were expressed in liver tissue. IL-33 induced strong activation and expression of type 2 cytokines as well as IL-6 by hepatic ILC2 while IFNγ suppressed cytokine production. Interestingly, this inhibitory effect was overcome by IL-33. The phenotype of activated hepatic ILC2 were stable since they did not show functional plasticity in response to liver inflammation-induced cytokines. Moreover, hepatic ILC2 induced a Th2 phenotype in activated CD4+ T cells, which increased ILC2-derived cytokine expression via IL-2. In contrast, Th1 cells inhibited survival of ILC2 by production of IFNγ. Thus, hepatic ILC2 function is regulated by IL-33, IL-2, and IFNγ. While IL-33 and IL-2 support hepatic ILC2 activation, their inflammatory activity in immune-mediated hepatitis might be limited by infiltrating IFNγ-expressing Th1 cells. [ABSTRACT FROM AUTHOR]

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score-matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.

In immune-mediated hepatitis, type 2 innate lymphoid cells (ILC2) as well as effector CD4 + T cells have been shown to drive disease pathology. However, less is known about mechanisms involved in the regulation of ILC2 function during liver inflammation. We showed that in homeostasis, hepatic ILC2 constituted a very small population with a naive, inactive phenotype. During immune-mediated hepatitis, the cytokines IL-33 and IFNγ were expressed in liver tissue. IL-33 induced strong activation and expression of type 2 cytokines as well as IL-6 by hepatic ILC2 while IFNγ suppressed cytokine production. Interestingly, this inhibitory effect was overcome by IL-33. The phenotype of activated hepatic ILC2 were stable since they did not show functional plasticity in response to liver inflammation-induced cytokines. Moreover, hepatic ILC2 induced a Th2 phenotype in activated CD4 + T cells, which increased ILC2-derived cytokine expression via IL-2. In contrast, Th1 cells inhibited survival of ILC2 by production of IFNγ. Thus, hepatic ILC2 function is regulated by IL-33, IL-2, and IFNγ. While IL-33 and IL-2 support hepatic ILC2 activation, their inflammatory activity in immune-mediated hepatitis might be limited by infiltrating IFNγ-expressing Th1 cells.

Structural disorder represents a key feature in the mechanism of action of RNA-binding proteins (RBPs). Recent insights revealed that intrinsically disordered regions (IDRs) linking globular domains modulate their capability to interact with various sequences of RNA, but also regulate aggregation processes, stress-granules formation, and binding to other proteins. The FET protein family, which includes FUS (Fused in Sarcoma), EWG (Ewing Sarcoma) and TAF15 (TATA binding association factor 15) proteins, is a group of RBPs containing three different long IDRs characterized by the presence of RGG motifs. In this study, we present the characterization of a fragment of FUS comprising two RGG regions flanking the RNA Recognition Motif (RRM) alone and in the presence of a stem-loop RNA. From a combination of EPR and NMR spectroscopies, we established that the two RGG regions transiently interact with the RRM itself. These interactions may play a role in the recognition of stem-loop RNA, without a disorder-to-order transition but retaining high dynamics. [ABSTRACT FROM AUTHOR]

The transcription factor GATA3 is a master regulator that modulates T helper 2 (Th2) cell differentiation and induces expression of Th2 cytokines, such as IL-4, IL-5, and IL-13. Th2 cytokines are involved in the protective immune response against foreign pathogens, such as parasites. However, excessive production of Th2 cytokines results in type-2 allergic inflammation. Therefore, the application of a GATA3 inhibitor provides a new therapeutic strategy to regulate Th2 cytokine production. Here, we established a novel high-throughput screening system for an inhibitor of a DNA-binding protein, such as a transcription factor, and identified pyrrothiogatain as a novel inhibitor of GATA3 DNA-binding activity. Pyrrothiogatain inhibited the DNA-binding activity of GATA3 and other members of the GATA family. Pyrrothiogatain also inhibited the interaction between GATA3 and SOX4, suggesting that it interacts with the DNA-binding region of GATA3. Furthermore, pyrrothiogatain significantly suppressed Th2 cell differentiation, without impairing Th1 cell differentiation, and inhibited the expression and production of Th2 cytokines. Our results suggest that pyrrothiogatain regulates the differentiation and function of Th2 cells via inhibition of GATA3 DNA binding activity, which demonstrates the efficiency of our drug screening system for the development of novel small compounds that inhibit the DNA-binding activity of transcription factors. [ABSTRACT FROM AUTHOR]

YAP (also known as YAP1 or YAP65) is a transcriptional coactivator that interacts with a number of transcription factors including RUNX and TEAD and plays a pivotal role in controlling cell growth. YAP is classified as a proto-oncogene. However, the mechanism by which activated YAP induces cancerous changes is not well known. Here we demonstrate that overexpression of YAP in NIH3T3 cells was sufficient for inducing tumorigenic transformation of cells. Mechanistically, YAP exerts its function in cooperation with the TEAD transcription factor. Our data also show that cMYC is a critical factor that acts downstream of the YAP/TEAD complex. Furthermore, we also found that aberrant activation of YAP is sufficient to drive tumorigenic transformation of non-immortalized mouse embryonic fibroblasts. Together our data indicate that YAP can be categorized as a new type of proto-oncogene distinct from typical oncogenes, such as H-RAS, whose expression in non-immortalized cells is tightly linked to senescence. [ABSTRACT FROM AUTHOR]

We predict the very large spin Hall effect in type-II superconductors whose mechanism is drastically different from the previously known ones. We find that in the flux-flow regime the spin is transported by the spin-polarized Abrikosov vortices moving under the action of the Lorenz force in the direction perpendicular to the applied electric current. Due to the large vortex velocities the spin Hall angle can be of the order of unity in realistic systems based on the high-field superconductors, superconductor/ferromagnet hybrid structures or the recently developed superconductor/ferromagnetic insulator proximity structures. We propose the realization of high-frequency pure spin current generator based on the periodic structure of moving vortex lattices. We find the patterns of charge imbalance and spin accumulation generated by moving vortices, which can be used for the electrical detection of individual vortex motion. The new mechanism of inverse flux-flow spin Hall effect is found based on the driving force acting on the vortices in the presence of injected spin current which results in the generation of transverse voltage. [ABSTRACT FROM AUTHOR]

In Drosophila melanogaster, aversive (electric shock) stimuli have been shown to activate subpopulations of dopaminergic neurons with terminals in the mushroom bodies (MBs) of the brain. While there is compelling evidence that dopamine (DA)-induced synaptic plasticity underpins the formation of aversive memories in insects, the mechanisms involved have yet to be fully resolved. Here we take advantage of the accessibility of MBs in the brain of the honey bee to examine, using fast scan cyclic voltammetry, the kinetics of DA release and reuptake in vivo in response to electric shock, and to investigate factors that modulate the release of this amine. DA increased transiently in the MBs in response to electric shock stimuli. The magnitude of release varied depending on stimulus duration and intensity, and a strong correlation was identified between DA release and the intensity of behavioural responses to shock. With repeated stimulation, peak DA levels increased. However, the amount of DA released on the first stimulation pulse typically exceeded that evoked by subsequent pulses. No signal was detected in response to odour alone. Interestingly, however, if odour presentation was paired with electric shock, DA release was enhanced. These results set the stage for analysing the mechanisms that modulate DA release in the MBs of the bee. [ABSTRACT FROM AUTHOR]

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasm caused by human T-cell leukemia virus type I (HTLV-I). Therapeutic interventions have not been associated with satisfactory outcomes. We showed that the porphyrin metabolic pathway preferentially accumulates the endogenous photosensitive metabolite, protoporphyrin IX (PpIX) in ATL, after a short-term culture with 5-aminolevulinic acid (ALA). PpIX accumulated 10-100-fold more in ATL leukemic cells when compared to healthy peripheral blood mononuclear cells (PBMCs). Patient specimens showed dynamic changes in flow cytometry profiles during the onset and progression of ATL. Furthermore, 98.7% of ATL leukemic cell death in the ATL patient specimens could be induced with 10 min of visible light exposure, while 77.5% of normal PBMCs survived. Metabolomics analyses revealed that a specific stage of the metabolic pathway progressively deteriorated with HTLV-I infection and at the onset of ATL. Therefore, this method will be useful in diagnosing and identifying high-risk HTLV-I carriers with single cell resolutions. Photodynamic therapy in the circulatory system may be a potential treatment due to its highly-specific, non-invasive, safe, simultaneous, and repeatedly-treatable modalities. [ABSTRACT FROM AUTHOR]

B7-H3, a new member of the B7 superfamily, acts as both a T cell costimulator and coinhibitor. Recent studies identified B7-H3 plays a critical role in the development of asthma. But the definitive mechanism is not clear. In this study, we further report that B7-H3 participates in the development of OVA-induced asthma in a murine model. And study its mechanism through the vitro and vivo experiment. Exogenous administration of B7-H3 strongly amplified the inflammatory response and augmented proinflammatory cytokines in vitro and vivo. These B7-H3-associated proinflammatory effects were not dependent on TLR2 signaling, as airway inflammation, eosinophils infiltration and cytokins (IL-4, IL-5, IL-13 and IFN-gamma) augment were still amplified in TLR2-deficient mice after administrated recombinant mouse B7-H3. These results indicated an important role for B7-H3 in the development of Th1 and Th2 cells in a murine model of asthma and its proinflammatory effects are not dependent on TLR2 signaling. [ABSTRACT FROM AUTHOR]

Mammalian tetraploid embryos die in early development because of defects in the epiblast. Experiments with diploid/tetraploid chimeric mice, obtained via the aggregation of embryonic stem cells, clarified that while tetraploid cells are excluded from epiblast derivatives, diploid embryos with tetraploid extraembryonic tissues can develop to term. Today, this method, known as tetraploid complementation, is usually used for rescuing extraembryonic defects or for obtaining completely embryonic stem (ES) cell-derived pups. However, it is still unknown why defects occur in the epiblast during mammalian development. Here, we demonstrated that downregulation of p53, a tumour suppressor protein, rescued tetraploid development in the mammalian epiblast. Tetraploidy in differentiating epiblast cells triggered p53-dependent cell-cycle arrest and apoptosis, suggesting the activation of a tetraploidy checkpoint during early development. Finally, we found that p53 downregulation rescued tetraploid embryos later in gestation. [ABSTRACT FROM AUTHOR]

The NR4A nuclear receptor family member Nr4a1 is strongly induced in thymocytes undergoing selection, and has been shown to control the development of Treg cells; however the role of Nr4a1 in CD8+ T cells remains undefined. Here we report a novel role for Nr4a1 in regulating the development and frequency of CD8+ T cells through direct transcriptional control of Runx3. We discovered that Nr4a1 recruits the corepressor, CoREST to suppress Runx3 expression in CD8+ T cells. Loss of Nr4a1 results in increased Runx3 expression in thymocytes which consequently causes a 2-fold increase in the frequency and total number of intrathymic and peripheral CD8+ T cells. Our findings establish Nr4a1 as a novel and critical player in the regulation of CD8 T cell development through the direct suppression of Runx3. [ABSTRACT FROM AUTHOR]