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We present a novel, eco-friendly and one-pot approach for synthesizing unsymmetrical oxalamides with the aid of dichloroacetamide and amine/amides in the presence of CBr 4 in a basic medium. The use of water as a potent supplement for the oxygen atom source and the detailed mechanism have been disclosed. Moreover, the protocol involves triple cleavage of CCl 2 Br and the formation of new C-O/C-N bonds, with the advantage of achieving selective bromination using CBr 4 with good to excellent yield under mild conditions. The method also demonstrates promise for industrial use, as proven by its effective implementation in gram-scale synthesis conducted in a batch process, along with its utilization in a continuous-flow system.

Toltrazuril (TZR) is currently the only registered chemotherapeutic drug in the European Union for the treatment of Cystoisospora suis. This study investigated the comparative pharmacokinetics and tissue concentration-time profiles of TZR and its active metabolite, toltrazuril sulfone (TZR-SO 2 ), after oral (per os, p.o.) and intramuscular (i.m.) administration to suckling piglets. Following a single administration of TZR orally at 50 mg/piglet or intramuscularly at 45 mg/piglet, higher concentrations of TZR and TZR-SO 2 were observed in all three investigated tissues after p.o. administration. The mean TZR concentration in serum peaked at 14 μg/mL (34.03 h) and 5.36 μg/mL (120 h), while TZR-SO 2 peaked at 14.12 μg/mL (246 h) and 9.92 μg/mL (330 h) after p.o. and i.m. administration, respectively. TZR was undetectable in the liver after p.o. administration (18 days) and in the jejunum (24 days) after i.m. injection, while TZR-SO 2 was still detectable in all three tissues after 36 days regardless of administration routes. This study showed that p.o. formulation exhibited faster absorption and higher serum/tissue TZR/TZR-SO 2 concentrations than i.m. formulation. Both formulations generated sufficient therapeutic concentrations in the serum and jejunum, and sustained enough time to protect against Cystoisospora suis infection in the piglets., (© 2023 John Wiley & Sons Ltd.)

In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes + Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes + Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes + Th cells in the CNS. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration.

Background: A critical role in cellular proliferation is played by Casitas B-lineage Lymphoma proto-oncogene (CBL). Germline heterozygous CBL variants give rise to CBL syndrome, which is phenotypically similar to RASopathy. Somatic mutations in CBL have been reported in patients with juvenile myelomonocytic leukemia (JMML)., Methods: Exome analysis was performed in a patient with immunodeficiency who developed Pneumocystis jirovecii pneumonia., Results: Exome analysis identified a homozygous CBL missense variant. Cell biological analysis of this CBL variant confirmed attenuated function., Conclusion: Spontaneous regression of hematological proliferation has been observed in patients with CBL-mutated JMML and in patients with CBL syndrome. Intriguingly, immunological impairment was spontaneously ameliorated by aging in this patient., (© 2022 Japan Pediatric Society.)

The flower of Abelmoschus manihot L. is mainly used for the treatment of chronic kidney diseases, and has been reported to have bioactivities such as antioxidant, anti-inflammatory, antiviral, and antidepressant activities. This study used wild-type adult zebrafish as an animal model to elucidate the potential bioactivity of A. manihot flower ethanol extract (AME) in enhancing their sexual and reproductive functions. Zebrafish were fed AME twice a day at doses of 0.2%, 1%, and 10% for 28 days, and were then given the normal feed for an additional 14 days. The hormone 17-β estradiol was used as the positive control. Sexual behavioral parameters such as the number of times males chased female fish, the production of fertilized eggs, and the hatching rate of the fertilized eggs were recorded at days 0.33, 7, 14, 21, 28, and 42. The expression levels of sex-related genes—including lhcgr, ar, cyp19a1a, and cyp19a1b—were also examined. The results showed that the chasing number, fertilized egg production, and hatching rate were all increased with the increase in the AME treatment dose and treatment time. After feeding with 1% and 10% AME for 28 days, the chasing number in the treated group as compared to the control group increased by 1.52 times and 1.64 times, respectively; the yield of fertilized eggs increased by 1.59 times and 2.31 times, respectively; and the hatching rate increased by 1.26 times and 1.69 times, respectively. All three parameters exhibited strong linear correlations with one another (p < 0.001). The expression of all four genes was also upregulated with increasing AME dose and treatment duration. When feeding with 0.2%, 1%, and 10% AME for 28 days, the four sex-related genes were upregulated at ranges of 1.79−2.08-fold, 2.74−3.73-fold, and 3.30−4.66-fold, respectively. Furthermore, the effect of AME was persistent, as the promotion effect continued after the treatment was stopped for at least two weeks. The present findings suggest that AME can enhance the endocrine system and may improve libido and reproductive performance in zebrafish.

Background: Interactions between the tumor necrosis factor (TNF) ligand superfamily and TNF receptor superfamily play critical roles in B-cell development and maturation. A proliferation-inducing ligand (APRIL), a member of the TNF ligand superfamily, is secreted from myeloid cells and known to induce the differentiation of memory B cells to plasmacytes., Objective: We sought to elucidate the role of APRIL in B-cell differentiation and immunoglobulin production through the analysis of complete APRIL deficiency in human., Methods: We performed whole exome sequencing in a patient with adult common variable immunodeficiency. His parents were in a consanguineous marriage. TNFSF13 mRNA and protein expression were analyzed in the primary cells and plasma from the patient and in cDNA-transfected cells and supernatants of the cultures in vitro. Immunologic analysis was performed by using flow cytometry and next-generation sequencing. Monocyte-derived dendritic cells differentiated from induced pluripotent stem cells (iPSC-moDCs) were cocultured with memory B cells from healthy controls to examine in vitro plasmacyte differentiation., Results: We identified a homozygous frameshift mutation in TNFSF13, the gene encoding APRIL, in the patient. APRIL mRNA and protein were completely absent in the monocytes and iPSC-moDCs of the patient. In contrast to the results of previous animal model studies, the patient showed hypogammaglobulinemia with a markedly reduced level of plasmacytes in peripheral blood and a clearly increased level of circulating marginal zone B cells. Although iPSC-moDC-induced in vitro plasmacyte differentiation was reduced in the patient, recombinant APRIL supplementation corrected this abnormality., Conclusion: The first APRIL deficiency in an adult patient with common variable immunodeficiency revealed the role of APRIL in lifelong maintenance of plasmacytes and immunoglobulin production in humans., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Owing to recent technological advancements, using next-generation sequencing (NGS) and the accumulation of clinical experiences worldwide, more than 420 genes associated with inborn errors of immunity (IEI) have been identified, which exhibit large genotypic and phenotypic variations. Consequently, NGS-based comprehensive genetic analysis, including whole-exome sequencing (WES), have become more valuable in the clinical setting and have contributed to earlier diagnosis, improved treatment, and prognosis. However, these approaches have the following disadvantages that need to be considered: a relatively low diagnostic rate, high cost, difficulties in the interpretation of each variant, and the risk of incidental findings. Thus, the objective of this study is to review our WES results of a large number of patients with IEI and to elucidate patient characteristics, which are related to the positive WES result., Methods: We performed WES for 136 IEI patients with negative conventional screening results for candidate genes and classified these variants depending on validity of their pathogenicity., Results: We identified disease-causing pathogenic mutations in 36 (26.5%) of the patients which were found in known IEI-causing genes. Although the overall diagnostic rate was not high and was not apparently correlated with the clinical subcategories and severity, we revealed that earlier onset with longer duration of diseases were associated with positive WES results, especially in pediatric cases., Conclusions: Most of the disease-causing germline mutations were located in the known IEI genes which could be predicted using patients' clinical characteristics. These results may be useful when considering appropriate genetic approaches in the clinical setting.

Enamel is the outermost layer of the tooth that protects it from invasion. In general, an acidic environment accelerates tooth demineralization, leading to the formation of cavities. Scanning electron microscopy (SEM) is conventionally used as an in vitro tool for the observation of tooth morphology changes with acid attacks. Yet, SEM has intrinsic limitations for the potential application of in vivo detection in the early demineralization process. In this study, a high-resolution optical coherence tomography (OCT) system with the axial and transverse resolutions of 2.0 and 2.7 μm in teeth has been utilized for characterizing the effect of the acidic environment (simulated by phosphoric acid) on the enamel topology. The scattering coefficient and the surface roughness of enamel can be directly derived from the OCT results, enabling a quantitative evaluation of the topology changes with demineralization. The dynamic process induced by the acid application is also recorded and analyzed with OCT, depicting the evolution of the demineralization process on enamel. Notably, the estimated enamel scattering coefficient and surface roughness significantly increase with the application time of acid and the results illustrate that the values of both parameters after demineralization are significantly larger than those obtained before the demineralization, illustrating both parameters could be effective to differentiate the healthy and demineralized teeth and determine the severity. The obtained results unambiguously illustrate that demineralization of the tooth surface can be successfully detected by OCT and further used as an indicator of early-stage cavity formation.

The application of random lasers has been restricted due to the absence of a well-defined resonant cavity, as the lasing action mainly depends on multiple light scattering induced by intrinsic disorders of the laser medium to establish the required optical feedback that hence increases the difficulty in efficiently tuning and modulating random lasing emissions. This study investigated whether the transport mean free path of emitted photons within disordered scatterers composed of ZnO nanowires is tunable by a curvature bending applied to the flexible polyethylene terephthalate (PET) substrate underneath, thereby creating a unique light source that can be operated above and below the lasing threshold for desirable spectral emissions. For the first time, the developed curvature-tunable random laser is implemented for in vivo biological imaging with much lower speckle noise compared to the non-lasing situation through simple mechanical bending, which is of great potential for studying the fast-moving physiological phenomenon such as blood flow patterns in mouse ear skin. It is expected that the experimental demonstration of the curvature-tunable random laser can provide a new route to develop disorder-based optoelectronic devices.

Background: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined., Objective: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT., Methods: We reviewed retrospectively the medical records of cohorts undergoing HSCT at collaborating facilities., Results: Thirty-year overall survival was 86.1%, but event-free survival was 39.6%. Life-threatening events, such as severe infections or lymphoproliferation, were frequent in childhood and adolescence and were common indications for HSCT. Nine patients underwent HSCT with fludarabine-based reduced-intensity conditioning. Seven patients survived after frequent adverse complications and engraftment failure. Most symptoms improved after HSCT., Conclusion: Patients with APDS1 showed variable clinical manifestations. Life-threatening progressive combined immunodeficiency and massive lymphoproliferation were common indications for HSCT. Fludarabine-based reduced-intensity conditioning-HSCT ameliorated clinical symptoms, but transplantation-related complications were frequent, including graft failure., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

This paper presents a method to inhibit B16F10 cancer cells using extremely low-frequency electromagnetic fields (ELF-EMFs) and to evaluate cell viability using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The study examined the effect of a natural EMF resonance frequency (7.83 Hz) and a power line frequency (60 Hz) on B16F10 cancer cells for 24 and 48 h. The B16F10 cancer cells were also exposed to sweep frequencies in several sweep intervals to quantitatively analyze the viability of cancer cells. The results yielded a 17% inhibition rate under 7.83 Hz compared with that of the control group. Moreover, sweep frequencies in narrow intervals (7.83 ± 0.1 Hz for the step 0.05 Hz) caused an inhibition rate of 26.4%, and inhibitory effects decreased as frequency sweep intervals increased. These results indicate that a Schumann resonance frequency of 7.83 Hz can inhibit the growth of cancer cells and that using a specific frequency type can lead to more effective growth inhibition.

This is the first paper to report a series of bismuth oxyfluoride/bismuth oxyiodide (BiO p F q /BiO x I y ) nanocomposites with different F/I molar ratios, pH values, and reaction temperatures that were synthesized through a template-free and controlled hydrothermal method. These nanocomposites were characterized through scanning electron microscope energy dispersive microscopy (SEM-EDS), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier-transform infrared (FT-IR), X-ray photoelectron spectroscopy (XPS), Brunauer-Emmett-Teller (BET), and diffuse reflectance spectroscopy (DRS). Under visible-light irradiation, the BiO p F q /BiO x I y composites exhibited excellent photocatalytic activities in the degradation of crystal violet (CV) and 2-hydroxybenzoic acid (HBA). The order of rate constants was BiOF/BiOI > BiOI ≫ BiOF. The photocatalytic activity of BiOF/BiOI composites reached a maximum rate constant of 0.2305 h -1 , 1.2 times higher than that of BiOI and 100 times higher than that of BiOF. Thus, the derived BiOF/BiOI is crucial for photocatalytic activity enhancement. After the removal of CV in the third cycle, no apparent deficits in photocatalytic activity were observed, and the observed deficit was 8.2% during the fifth run. Overall, the catalytic activity and stability observed for the proposed composites were determined to be adequate under visible-light irradiation. For various scavengers, the noted quenching effects demonstrated that reactive O 2 - has a notable role in the degradation of the applied CV., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive primary immunodeficiency. Hypogammaglobulinemia is a major manifestation of ICF syndrome, but immunoglobulin replacement therapy does not seem to be effective for some ICF patients. Therefore, we aimed to reassess the immunological characteristics of this syndrome., Methods: Eleven Japanese patients with ICF syndrome were enrolled. We performed whole-exome sequencing in four cases and homozygosity mapping using SNP analysis in two. We evaluated their clinical manifestations and immunological status., Results: We newly diagnosed six ICF patients who had tentatively been diagnosed with common variable immunodeficiency. We identified two novel mutations in the DNMT3B gene and one novel mutation in the ZBTB24 gene. All patients showed low serum IgG and/or IgG 2 levels and were treated by periodic immunoglobulin replacement therapy. Three of the six patients showed worse results of the mitogen-induced lymphocyte proliferation test. Analyses of lymphocyte subpopulations revealed that CD19 + CD27 + memory B cells were low in seven of nine patients, CD3 + T cells were low in three patients, CD4/8 ratio was inverted in five patients, CD31 + recent thymic emigrant cells were low in two patients, and CD19 + B cells were low in four patients compared with those in the normal controls. ICF2 patients showed lower proportions of CD19 + B cells and CD16 + 56 + NK cells and significantly higher proportions of CD3 + T cells than ICF1 patients. T cell receptor excision circles were undetectable in two patients. Despite being treated by immunoglobulin replacement therapy, three patients died of influenza virus, fatal viral infection with persistent Epstein-Barr virus infection, or JC virus infection. One of three dead patients showed normal intelligence with mild facial anomaly. Two patients presented with autoimmune or inflammatory manifestations. Infectious episodes decreased in three patients who were started on trimethoprim-sulfamethoxazole and/or antifungal drugs in addition to immunoglobulin replacement therapy. These patients might have suffered from T cell immunodeficiency., Conclusion: These results indicate that patients with ICF syndrome have a phenotype of combined immunodeficiency. Thus, to achieve a better prognosis, these patients should be treated as having combined immunodeficiency in addition to receiving immunoglobulin replacement therapy.

This paper presents an unprecedented systematic synthetic study of a controlled hydrothermal method for the preparation of bismuth oxychloride/bismuth oxybromide/bismuth oxyiodide ternary composites (BiO x Cl y /BiO m Br n /BiO p I q ). The pH, temperature, and KCl:KBr:KI molar ratio for the reactions were adjusted to control the compositions and morphologies of BiO x Cl y /BiO m Br n /BiO p I q composites. Scanning electron microscopy-energy dispersive X-ray spectroscopy, transmission electron microscopy, X-ray diffraction, ultraviolet-visible diffuse reflectance spectroscopy, Brunauer-Emmett-Teller specific surface areas, photoluminescence spectroscopy, and X-ray photoelectron spectroscopy, and electron paramagnetic resonance spectroscopy were applied to the products. The photocatalytic activities of dispersions were examined by monitoring the 2-hydroxybenzoic acid (HBA) and crystal violet concentrations. Various scavengers demonstrated quenching effects. O 2 - was crucial to HBA degradation, whereas h + and OH played minor roles in HBA degradation. This text hypothesizes possible photodegradation mechanisms., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Some patients with genetic defects develop Epstein-Barr virus (EBV)-associated lymphoproliferative disorder (LPD)/lymphoma as the main feature. Hypomophic mutations can cause different clinical and laboratory manifestations from null mutations in the same genes., Methods: We sought to describe the clinical and immunologic phenotype of a 21-month-old boy with EBV-associated LPD who was in good health until then. A genetic and immunologic analysis was performed., Results: Whole-exome sequencing identified a novel compound heterozygous mutation of ZAP70 c.703-1G>A and c.1674G>A. A small amount of the normal transcript was observed. Unlike ZAP70 deficiency, which has been previously described as severe combined immunodeficiency with nonfunctional CD4+ T cells and absent CD8+ T cells, the patient had slightly low numbers of CD8+ T cells and a small amount of functional T cells. EBV-specific CD8+ T cells and invariant natural killer T (iNKT) cells were absent. The T-cell receptor repertoire, determined using next generation sequencing, was significantly restricted., Conclusions: Our patient showed that a hypomorphic mutation of ZAP70 can lead to EBV-associated LPD and that EBV-specific CD8+ T cells and iNKT cells are critically involved in immune response against EBV infection.

In this study, we experimentally demonstrated a flexible random laser fabricated on a polyethylene terephthalate (PET) substrate with a high degree of tunability in lasing emissions. Random lasing oscillation arises mainly from the resonance coupling between the emitted photons of gain medium (Rhodamine 6G, R6G) and the localized surface plasmon (LSP) of silver nanoprisms (Ag NPRs), which increases the effective cross-section for multiple light scattering, thus stimulating the lasing emissions. More importantly, it was found that the random lasing wavelength is blue-shifted monolithically with the increase in bending strains exerted on the PET substrate, and a maximum shift of ∼15 nm was achieved in the lasing wavelength, when a 50% bending strain was exerted on the PET substrate. Such observation is highly repeatable and reversible, and this validates that we can control the lasing wavelength by simply bending the flexible substrate decorated with the Ag NPRs. The scattering spectrum of the Ag NPRs was obtained using a dark-field microscope to understand the mechanism for the dependence of the wavelength shift on the exerted bending strains. As a result, we believe that the experimental demonstration of tunable lasing emissions based on the revealed structure is expected to open up a new application field of random lasers.

Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1 , or PTEN , which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19 + B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19 + B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3 + T cells and CD14 + monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19 + B cells, enhanced pAKT was prominently detected in CD10 + immature B cells compared with CD10 - mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.

Objective: In the current study, we aimed to accurately evaluate donor/recipient or male/female chimerism in samples from patients who underwent hematopoietic stem cell transplantation (HSCT)., Methods: We designed the droplet digital polymerase chain reaction (ddPCR) for SRY and RPP30 to detect the male/female chimerism. We also developed mutation-specific ddPCR for four primary immunodeficiency diseases., Results: The accuracy of the male/female chimerism analysis using ddPCR was confirmed by comparing the results with those of conventional methods (fluorescence in situ hybridization and short tandem repeat-PCR) and evaluating dilution assays. In particular, we found that this method was useful for analyzing small samples. Thus, this method could be used with patient samples, especially to sorted leukocyte subpopulations, during the early post-transplant period. Four mutation-specific ddPCR accurately detected post-transplant chimerism., Conclusion: ddPCR-based male/female chimerism analysis and mutation-specific ddPCR were useful for all HSCT, and these simple methods contribute to following the post-transplant chimerism, especially in disease-specific small leukocyte fractions.

Primary immunodeficiencies (PIDs) are a heterogeneous group of inherited diseases of the immune system. The definite diagnosis of PID is ascertained by genetic analysis; however, this takes time and is costly. Flow cytometry provides a rapid and highly sensitive tool for diagnosis of PIDs. Flow cytometry can evaluate specific cell populations and subpopulations, cell surface, intracellular and intranuclear proteins, biologic effects associated with specific immune defects, and certain functional immune characteristics, each being useful for the diagnosis and evaluation of PIDs. Flow cytometry effectively identifies major forms of PIDs, including severe combined immunodeficiency, X-linked agammaglobulinemia, hyper IgM syndromes, Wiskott-Aldrich syndrome, X-linked lymphoproliferative syndrome, familial hemophagocytic lymphohistiocytosis, autoimmune lymphoproliferative syndrome, IPEX syndrome, CTLA 4 haploinsufficiency and LRBA deficiency, IRAK4 and MyD88 deficiencies, Mendelian susceptibility to mycobacterial disease, chronic mucocuneous candidiasis, and chronic granulomatous disease. While genetic analysis is the definitive approach to establish specific diagnoses of PIDs, flow cytometry provides a tool to effectively evaluate patients with PIDs at relatively low cost., (Copyright © 2017 Japanese Society of Allergology. Production and hosting by Elsevier B.V. All rights reserved.)

X-linked severe combined immunodeficiency (X-SCID), caused by defects in the common gamma chain, is typically characterized by T and NK cell defects with the presence of B cells. T cell dysfunction and impaired class-switch recombination of B cells mean that patients typically have defects in class-switched immunoglobulins (IgG, IgA, and IgE) with detectable IgM. Here, we describe two patients with X-SCID with IgG1 gammopathy, in whom we identified maternal T and B cell engraftment. Exclusively, maternal B cells were found among the IgD - CD27 + class-switched memory B cells, whereas the patients' B cells remained naïve. In vitro stimulation with CD40L+IL-21 revealed that peripheral blood cells from both patients produced only IgG1. Class-switched maternal B cells had restricted receptor repertoires with various constant regions and few somatic hypermutations. In conclusion, engrafted maternal B cells underwent class-switch recombination and produced immunoglobulin, causing hypergammaglobulinemia in patients with X-SCID., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Primary immunodeficiency diseases (PIDDs) are rare inherited diseases that impair the human immune system. We established a multicolor flow cytometric assay to comprehensively evaluate the immune status and immunological characteristics of patients with PIDDs., Methods: Fifty-nine normal controls and 75 patients with PIDDs, including X-linked severe combined immunodeficiency (X-SCID), X-linked agammaglobulinemia (XLA), X-linked hyper IgM syndrome (X-HIGM), ataxia telangiectasia (AT), Wiskott-Aldrich syndrome (WAS), hyper IgE syndrome (HIES), and chronic mucocutaneous candidiasis disease (CMCD), were enrolled in this study. Immunophenotyes were evaluated by multicolor flow cytometry using seven different panels that allowed the detection of major leukocyte populations in peripheral blood., Results: Multicolor flow cytometry revealed distinct leukocyte populations and immunological features of patients with X-SCID, XLA, X-HIGM, AT, WAS, HIES, and CMCD., Conclusions: Immunophenotyping by multicolor flow cytometry is useful to evaluate immune status and contributes to the diagnosis and management of patients with PIDDs.

Caveolin-1 (CAV1), the major constituent of caveolae, plays a pivotal role in various cellular biological functions, including cancer and inflammation. The ubiquitin/proteasomal pathway is known to contribute to the regulation of CAV1 expression, but the ubiquitin ligase responsible for CAV1 protein stability remains unidentified. Here we reveal that E3 ubiquitin ligase ZNRF1 modulates CAV1 protein stability to regulate Toll-like receptor (TLR) 4-triggered immune responses. We demonstrate that ZNRF1 physically interacts with CAV1 in response to lipopolysaccharide and mediates ubiquitination and degradation of CAV1. The ZNRF1-CAV1 axis regulates Akt-GSK3β activity upon TLR4 activation, resulting in enhanced production of pro-inflammatory cytokines and inhibition of anti-inflammatory cytokine IL-10. Mice with deletion of ZNRF1 in their hematopoietic cells display increased resistance to endotoxic and polymicrobial septic shock due to attenuated inflammation. Our study defines ZNRF1 as a regulator of TLR4-induced inflammatory responses and reveals another mechanism for the regulation of TLR4 signalling through CAV1.

Background: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6., Objective: This study aimed to identify novel genes responsible for APDS., Methods: Whole-exome sequencing was performed in Japanese patients with PIDs. Immunophenotype was assessed through flow cytometry. Hyperphosphorylation of AKT, mTOR, and S6 in lymphocytes was examined through immunoblotting, flow cytometry, and multiplex assays., Results: We identified heterozygous mutations of phosphatase and tensin homolog (PTEN) in patients with PIDs. Immunoblotting and quantitative PCR analyses indicated that PTEN expression was decreased in these patients. Patients with PTEN mutations and those with PIK3CD mutations, including a novel E525A mutation, were further analyzed. The clinical symptoms and immunologic defects of patients with PTEN mutations, including lymphocytic AKT, mTOR, and S6 hyperphosphorylation, resemble those of patients with APDS. Because PTEN is known to suppress the PI3K pathway, it is likely that defective PTEN results in activation of the PI3K pathway., Conclusion: PTEN loss-of-function mutations can cause APDS-like immunodeficiency because of aberrant PI3K pathway activation in lymphocytes., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

We demonstrate a new doping scheme where photo-induced carriers from graphene quantum dots (GQDs) can be injected into GaN and greatly enhance photoluminescence (PL) in GaN epilayers. An 8.3-fold enhancement of PL in GaN is observed after the doping. On the basis of time-resolved PL studies, the PL enhancement is attributed to the carrier transfer from GQDs to GaN. Such a carrier transfer process is caused by the work function difference between GQDs and GaN, which is verified by Kelvin probe measurements. We have also observed that photocurrent in GaN can be enhanced by 23-fold due to photo-induced doping with GQDs. The improved optical and transport properties from photo-induced doping are promising for applications in GaN-based optoelectronic devices.

Background: The molecular mechanism of class-switch recombination (CSR) in human subjects has not been fully elucidated. The CSR-induced mutations occurring in the switch region of the IgM gene (Smu-SHMs) in in vitro CSR-activated and in vivo switched B cells have been analyzed in mice but not in human subjects., Objective: We sought to better characterize the molecular mechanism of CSR in human subjects., Methods: Smu-SHMs were analyzed in vitro and in vivo by using healthy control subjects and patients with molecularly defined CSR defects., Results: We found that Smu-SHMs can be induced in vitro by means of CSR activation in human subjects. We also found large amounts of Smu-SHMs in in vivo class-switched memory B cells, smaller (although significant) amounts in unswitched memory B cells, and very low amounts in naive B cells. In class-switched memory B cells a high frequency of Smu-SHMs was found throughout the Smu. In unswitched memory B cells, the Smu-SHM frequency was significantly decreased in the 5' part of the Smu. The difference between switched and unswitched B cells suggests that the extension of somatic hypermutation (SHM) to the 5' upstream region of the Smu might be associated with the effective induction of CSR. The analysis of the pattern of mutations within and outside the WRCY/RGYW (W, A/T; R, A/G; and Y, C/T) motifs, as well as the Smu-SHMs, in CD27(+) B cells from CD40 ligand (CD40L)-, activation-induced cytidine deaminase (AID)-, and uracil-DNA glycosylase (UNG)-deficient patients revealed the dependence of Smu-SHM on CD40L, AID, UNG, and the mismatch repair system in human subjects., Conclusion: CD40L-, AID-, UNG-, and mismatch repair system-dependent Smu-SHMs and extension to the 5' region of Smu are necessary to accomplish effective CSR in human subjects., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Highly perfect, twin-free GaAs nanosheets grown on (111)B surfaces by selective area growth (SAG) are demonstrated. In contrast to GaAs nanowires grown by (SAG) in which rotational twins and stacking faults are almost universally observed, twin formation is either suppressed or eliminated within properly oriented nanosheets are grown under a range of growth conditions. A morphology transition in the nanosheets due to twinning results in surface energy reduction, which may also explain the high twin-defect density that occurs within some III–V semiconductor nanostructures, such as GaAs nanowires. Calculations suggest that the surface energy is significantly reduced by the formation of {111}-plane bounded tetrahedra after the morphology transition of nanowire structures. By contrast, owing to the formation of two vertical {11[overline]0} planes which comprise the majority of the total surface energy of nanosheet structures, the energy reduction effect due to the morphology transition is not as dramatic as that for nanowire structures. Furthermore, the surface energy reduction effect is mitigated in longer nanosheets which, in turn, suppresses twinning.

The growth mechanism for the formation of GaN nanorods using metalorganic chemical vapor deposition (MOCVD) selective area growth by pulsed source injection is proposed. The pulsed mode procedure and the kinetic model are discussed and experiments performed to support the model are described. The achievement of rod shape nanostructures grown by the pulsed mode can be attributed to two mechanisms: (1) the differences in the adsorption/desorption behavior of Ga adatoms on the c-plane (0001) and the boundary m-planes {11[overline]00}, and (2) the growth behavior of the semi-polar planes (especially the semi-polar {11[overline]00} plane).

We report a systematic study of carrier dynamics in Al(x)Ga(1-x)As-passivated GaAs nanowires. With passivation, the minority carrier diffusion length (L(diff)) increases from 30 to 180 nm, as measured by electron beam induced current (EBIC) mapping, and the photoluminescence (PL) lifetime increases from sub-60 ps to 1.3 ns. A 48-fold enhancement in the continuous-wave PL intensity is observed on the same individual nanowire with and without the Al(x)Ga(1-x)As passivation layer, indicating a significant reduction in surface recombination. These results indicate that, in passivated nanowires, the minority carrier lifetime is not limited by twin stacking faults. From the PL lifetime and minority carrier diffusion length, we estimate the surface recombination velocity (SRV) to range from 1.7 × 10(3) to 1.1 × 10(4) cm·s(-1), and the minority carrier mobility μ is estimated to lie in the range from 10.3 to 67.5 cm(2) V(-1) s(-1) for the passivated nanowires.

Uniform GaN nanorod arrays are grown vertically by selective area growth on (left angle bracket 0001 right angle bracket) substrates. The GaN nanorods present six nonpolar {1⁻100} facets, which serve as growth surfaces for InGaN-based light-emitting diode quantum well active regions. Compared to growth on the polar {0001} plane, the piezoelectric fields in the multiple quantum wells (MQWs) can be eliminated when they are grown on nonpolar planes. The capability of growing ordered GaN nanorod arrays with different rod densities is demonstrated. Light emission from InGaN/GaN MQWs grown on the nonpolar facets is investigated by photoluminescence. Local emission from MQWs grown on different regions of GaN nanorods is studied by cathodoluminescence (CL). The core-shell structure of MQWs grown on GaN nanorods is investigated by cross-sectional transmission electron microscopy in both axial and radial directions. The results show that the active MQWs are predominantly grown on nonpolar planes of GaN nanorods, consistent with the observations from CL. The results suggest that GaN nanorod arrays are suitable growth templates for efficient light-emitting diodes.

Background: Bronchoconstriction during the night causing nocturnal and early morning wheezing is recognized as a major problem for asthmatics. Oral sustained-release theophyllines (SRTs) were developed to reduce the symptoms. A circadian variation in theophylline kinetics has been demonstrated with many SRTs. The purpose of this study was to evaluate the differences in serum theophylline concentration (STC) caused by morning or evening dosing of Euphyllin Retard, a brand of SRT, for a period of 36 hours following oral administration., Methods: A total of nine non-smoking healthy male volunteers were involved in the study, with a two-period crossover comparison. They were randomly divided into two groups. The first group took a single oral dose of 350 mg Euphyllin Retard at 8:00 A.M. and the second group took it at 8:00 P.M. Blood samples were collected during the 36 hours following administration. Two weeks later, the first group took the drug at night and the second group took it in the morning. The difference in the absorption of theophylline with daytime administration versus night-time administration was assessed using pharmacokinetic parameters derived from the plasma drug concentration vs time curve., Results: The means of unextrapolated area under the concentration vs time curve (AUC) from time 0 to 24 hours (AUCUN) and of the extrapolated AUC from time 0 to infinity (AUCEX) in the night phase were higher than those in the day phase (62.403 micrograms/ml/hr vs 53.081 micrograms/ml/hr, p = 0.9186; 107.21 micrograms/ml/hr vs 98.879 micrograms/ml/hr, p = 0.8807, respectively). The mean of maximum concentration (Cmax) was higher in the night phase than that in the day phase (4.166 micrograms/dl vs 3.451 micrograms/dl, p = 0.9234). Daytime administration showed a delayed time to maximum concentration (Tmax) when compared to that of night-time administration (6.5 hr vs 5.75 hr, p = 0.6244). The terminal elimination rate constant (Kel) was lower in the day phase than in the night phase (0.053 l/hr vs 0.06 l/hr, p = 0.7601). The day phase and night phase data are combined data from the two night and two day groups. The statistical analysis of the results show that the time of administration does not influence the STC., Conclusions: No diurnal variation in theophylline kinetics was found with Euphyllin Retard. This study was performed in a limited number of normal healthy subjects, and the same result is yet to be proved in asthmatic patients and a larger population of normal subjects.