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Probiotics are widely used in food for their health benefits to the host. Inactivated probiotics also reportedly improve the intestinal environment and immune regulation. Our previous studies showed that heat‐killed Lacticaseibacillus paracasei MCC1849 (hk‐MCC1849) effectively induced IL‐12 production in mouse spleen cells and significantly reduced cold symptoms in clinical trial subjects. To further elucidate the mechanism of host immune regulation by hk‐MCC1849, human peripheral blood mononuclear cells (PBMCs) were cocultured with hk‐MCC1849. The Toll‐like receptor 9 ligands CpG‐ODN 2216 and hk‐MCC1849 and the heat‐killed Lacticaseibacillus rhamnosus ATCC53103 were used as positive and negative controls, respectively. The results showed that, compared with the control, hk‐MCC1849 significantly increased the expression of the plasmacytoid dendritic cell (pDC) marker CD86 (p <.0001) and the pDC marker HLA‐DR (p <.001) in PBMCs. The expression levels of the IL‐12p40, IFNα, IFNα1, IFNγ, and ISG15 genes were significantly increased after coculture with hk‐MCC1849 (p <.05, p <.05, p <.05, p <.05, and p <.05, respectively, vs. control). Furthermore, to confirm whether hk‐MCC1849 directly interacted with pDCs, DCs were enriched with PBMCs following 24 h of coculture with hk‐MCC1849. Phagocytosis of fluorescently labeled hk‐MCC1849 by pDCs was observed, and there were significant increases in CD86 (p <.05) and HLA‐DR (p <.0001) expression in pDCs. These results suggest that hk‐MCC1849 exerts a potential immunomodulatory effect on the host through the activation of peripheral pDCs. [ABSTRACT FROM AUTHOR]

Modeling radiative transfer in a 3D cloudy atmosphere is critical to climate projections. A recently developed fast 3D radiation parameterization scheme gains some success in quantifying horizontal radiative transfer through cloud sides using cloud area fraction. Based on 3D Monte Carlo simulations of radiative transfer through an idealized single‐layer cloud with Koch‐shaped fractal geometry edges, here we show that radiative energy transport through cloud sides correlates more significantly with cloud area fraction than with cloud perimeter length. The results exemplify the importance of accounting for the horizontal radiative energy exchanges between cloud‐free and cloudy regions with cloud area fraction. Results from additional sensitivity simulations show that increased cloud vertical extent often enhances cloud‐side sunlight leak more significantly than cloud‐side sunlight interception. At low sun elevations, cloud‐side sunlight interception is enhanced more than cloud‐side sunlight leak does with the increase of cloud mass. Plain Language Summary: Understanding how sunlight transports through three‐dimensional clouds is crucial for robust climate predictions. A new fast method to estimate this transport has achieved success by using the cloud area fraction, which is a measure of how much of an area is covered by clouds. We demonstrate that the cloud area fraction is a better predictor to quantify the sunlight transport through the sides of clouds than the length of the cloud edges, using detailed simulations of how light passes through clouds with complex edges. The present finding supports the use of cloud area fraction in models studying how sunlight transfers between clear and cloudy areas. Additional simulations showed that when clouds are thicker, they tend to let more sunlight leak through their sides. However, when the sun is low in the sky, an increase in cloud mass allows the cloud sides to intercept more sunlight rather than facilitating sunlight leaking. Key Points: Radiative transfer through Koch‐shaped cloud sides correlates more significantly with cloud fraction than with cloud perimeterIncreased cloud vertical extent often enhances cloud‐side leak of radiation more than cloud‐side interception of radiationCloud‐free‐to‐cloudy region horizontal radiative transfer increases with increasing cloud mass at low sun elevations [ABSTRACT FROM AUTHOR]

Kekulene, a cycloarene composed of 12 fused benzene rings in a circular arrangement, exhibits a highly planar and robust structure. Kekulene has been the subject of investigation into its aromaticity and electronic structure, particularly in relation to the cyclic benzenoid. We have successfully synthesized novel bowl‐shaped kekulene analogues with five‐membered rings incorporated into the kekulene structure. The results of DFT calculations and VT‐NMR spectra indicate that inversion of their concave‐convex structures occurs at room temperature. The NICS and AICD plots predict that the Clar's type resonance structure is found in a manner analogous to the pristine kekulene, albeit with the interruption of the π‐conjugation on the sp3 carbons at the five‐membered rings. Despite the presence of the Clar's resonance structure, the Diels‐Alder reaction proceeded smoothly with a dienophile, in contrast to the behavior of planar kekulene derivatives. This study will lead to the creation of novel bowl‐shaped compounds and development of reactivity in aromatic compounds. [ABSTRACT FROM AUTHOR]

Background: The prevalence and risk factors of cholelithiasis in individuals with severe or profound intellectual and motor disabilities (SPIMD) are poorly characterised. Thus, we aimed to investigate the prevalence and risk determinants of cholelithiasis in a cohort with SPIMD under medical care in a residential facility. Methods: We categorised 84 patients in a residential hospital for persons with SPIMD into groups: those with (Group CL) and without (Group N) cholelithiasis. Gallstones were detected via computed tomography, ultrasonography or both. We evaluated gastrostomy status, nutritional and respiratory support, constipation, and bladder and kidney stones. Data were significantly analysed using univariate and multivariate logistic regression analyses. Results: The prevalence rate of cholelithiasis in our SPIMD cohort was 27%. There were no significant differences in sex, age, weight, height, or Gross Motor Function Classification System between the two groups. However, more patients received enteral nutrition (39.13% vs. 6.56%; P = 0.000751) and were on ventilator support (56.52% vs. 19.67%; P = 0.00249) in Group CL than in Group N. Enteral nutrition [odds ratio (OR) 10.4, 95% confidence interval (CI) 1.98–54.7] and ventilator support (OR 20.0, 95% CI 1.99–201.0) were identified as independent risk factors for the prevalence of cholelithiasis in patients with SPIMD. Conclusions: Patients with SPIMD demonstrated an increased prevalence of cholelithiasis, with a notable association between nutritional tonic use and respiratory support. Therefore, to emphasise the need for proactive screening, it is crucial to devise diagnostic and therapeutic strategies specific to patients with SPIMD. Further investigation is essential to validate our findings and explore causative factors. [ABSTRACT FROM AUTHOR]

We herein evaluate a biological applicability of 1,3‐substituted cuneanes as an isostere of m‐substituted benzenes based on its structural similarity. An investigation of a method to obtain 1,3‐substituted cuneanes by selective isomerization of 1,4‐substituted cubanes enables this attempt by giving a key synthetic step to obtain a cuneane analogs of pharmaceuticals having m‐substituted benzene moiety. Biological evaluation of the synthesized analogs and in silico study of the obtained result revealed a potential usage of cuneane skeleton in medicinal chemistry. [ABSTRACT FROM AUTHOR]

The tumor microenvironment (TME) consists of cancer cells surrounded by stromal components including tumor vessels. Transforming growth factor‐β (TGF‐β) promotes tumor progression by inducing epithelial–mesenchymal transition (EMT) in cancer cells and stimulating tumor angiogenesis in the tumor stroma. We previously developed an Fc chimeric TGF‐β receptor containing both TGF‐β type I (TβRI) and type II (TβRII) receptors (TβRI‐TβRII‐Fc), which trapped all TGF‐β isoforms and suppressed tumor growth. However, the precise mechanisms underlying this action have not yet been elucidated. In the present study, we showed that the recombinant TβRI‐TβRII‐Fc protein effectively suppressed in vitro EMT of oral cancer cells and in vivo tumor growth in a human oral cancer cell xenograft mouse model. Tumor cell proliferation and angiogenesis were suppressed in tumors treated with TβRI‐TβRII‐Fc. Molecular profiling of human cancer cells and mouse stroma revealed that K‐Ras signaling and angiogenesis were suppressed. Administration of TβRI‐TβRII‐Fc protein decreased the expression of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), interleukin‐1β (IL‐1β) and epiregulin (EREG) in the TME of oral cancer tumor xenografts. HB‐EGF increased proliferation of human oral cancer cells and mouse endothelial cells by activating ERK1/2 phosphorylation. HB‐EGF also promoted oral cancer cell‐derived tumor formation by enhancing cancer cell proliferation and tumor angiogenesis. In addition, increased expressions of IL‐1β and EREG in oral cancer cells significantly enhanced tumor formation. These results suggest that TGF‐β signaling in the TME controls cancer cell proliferation and angiogenesis by activating HB‐EGF/IL‐1β/EREG pathways and that TβRI‐TβRII‐Fc protein is a promising tool for targeting the TME networks. [ABSTRACT FROM AUTHOR]

Phytoplasmas infect a wide variety of plants and can cause distinctive symptoms including the conversion of floral organs into leaf‐like organs, known as phyllody. Phyllody is induced by an effector protein family called phyllogens, which interact with floral MADS‐box transcription factors (MTFs) responsible for determining the identity of floral organs. The MTF/phyllogen complex then interacts with the proteasomal shuttle protein RADIATION SENSITIVE23 (RAD23), which facilitates delivery of the MTF/phyllogen complex to the host proteasome for MTF degradation. Previous studies have indicated that the MTF degradation specificity of phyllogens is determined by their ability to bind to MTFs. However, in the present study, we discovered a novel mechanism determining the degradation specificity through detailed functional analyses of a phyllogen homologue of rice yellow dwarf phytoplasma (PHYLRYD). PHYLRYD degraded a narrower range of floral MTFs than other phyllody‐inducing phyllogens, resulting in compromised phyllody phenotypes in plants. Interestingly, PHYLRYD was able to bind to some floral MTFs that PHYLRYD was unable to efficiently degrade. However, the complex of PHYLRYD and the non‐degradable MTF could not interact with RAD23. These results indicate that the MTF degradation specificity of PHYLRYD is correlated with the ability to form the MTF/PHYLRYD/RAD23 ternary complex, rather than the ability to bind to MTF. This study elucidated that phyllogen target specificity is regulated by both the MTF‐binding ability and RAD23 recruitment ability of the MTF/phyllogen complex. [ABSTRACT FROM AUTHOR]

KDM4B (MIM*609765, NM_015015.3, formerly JMJD2B) encodes a histone demethylase and regulates gene expression via demethylation, mainly of H3K9 tri‐methylation. Heterozygous KDM4B loss‐of‐function variants cause autosomal dominant intellectual developmental disorder 65 (MIM#619320), which is characterized by global developmental delay, intellectual disability, language and gross motor delays, structural brain anomalies, characteristic facial features, and clinodactyly. Although the majority of reported patients have de novo pathogenic variants, some patients inherit pathogenic variants from affected parents. To our knowledge, only 23 patients with heterozygous KDM4B variants have been reported to date, and there are no reports of patients with biallelic KDM4B pathogenic variants. Herein, we report a female patient with a biallelic KDM4B frameshift variant (NM_015015.3: c.1384_1394delinsGGG, p.(Leu462Glyfs*43)) located at exon 12 of 23 protein‐coding exons, which is thought to be subject to nonsense‐mediated mRNA decay and no protein production. She presented developmental and language delays and a hypotonic and characteristic face. The patient's phenotype was more obvious than that of her mother, who is heterozygous for the same variant. Although declining birth rate (embryonic lethality in male mice) in homozygous knockout mice has been demonstrated, our report suggests that homozygous KDM4B frameshift variants can be viable in humans at least female. [ABSTRACT FROM AUTHOR]

Aims: To assess the impact of various patient characteristics on the dynamics of liver glucose metabolism using automated multiparametric imaging with whole‐body dynamic 18F‐fluorodeoxyglucose (FDG)‐positron emission tomography (PET). Materials and Methods: We retrospectively enrolled 540 patients who underwent whole‐body dynamic FDG‐PET. Three quantitative indices representing hepatic glucose metabolism [mean standardized uptake value normalized by lean body mass (SULmean), metabolic glucose rate (kinetic index) and distribution volume (DV)] were measured from multiparametric PET images produced automatically based on the Patlak plot model. Patient characteristics including age, sex, body mass index, fasting time, blood glucose level, and the presence of diabetes mellitus (DM) or hepatic steatosis (HS) were collected. We examined the correlations between the characteristic factors and three quantitative indices using multiple regression analysis. Results: The success rate of kinetic analysis using multiparametric PET imaging was 93.3% (504/540). Hepatic SULmean was significantly correlated with age (p <.001), sex (p <.001) and blood glucose level (p =.002). DV was significantly correlated with age (p =.033), sex (p <.001), body mass index (p =.002), fasting time (p =.043) and the presence of HS (p =.002). The kinetic index was significantly correlated with age (p <.001) and sex (p =.004). In the comparison of the healthy, DM and HS groups, patients with DM had a significantly increased SULmean, whereas patients with HS had a significantly decreased DV. Conclusions: Our results showed that liver glucose metabolism was influenced by various patient characteristic factors. Multiparametric FDG‐PET imaging can be used to analyse the kinetics of liver glucose metabolism in routine clinical practice. [ABSTRACT FROM AUTHOR]

Eribulin inhibits microtubule polymerization and improves the overall survival of patients with recurrent metastatic breast cancer. A subgroup analysis revealed a low neutrophil to lymphocyte ratio (NLR) (<3) to be a prognostic factor of eribulin treatment. We thus hypothesized that eribulin might be related to the immune response for breast cancer cells and we analyzed the effects of eribulin on the immune system. Immunohistochemical staining revealed that human leukocyte antigen (HLA) class I expression was increased in clinical samples after eribulin treatment. In vitro assays revealed that eribulin treatment increased HLA class I expression in breast cancer line cells. RNA‐sequencing demonstrated that eribulin treatment increased the expression of the NOD‐like family CARD domain‐containing 5 (NLRC5), a master regulator of HLA class I expression. Eribulin treatment increased the NY‐ESO‐1‐specific T‐cell receptor (TCR) transduced T (TCR‐T) cell response for New York oesophageal squamous cell carcinoma 1 (NY‐ESO‐1) overexpressed breast cancer cells. The eribulin and TCR‐T combined therapy model revealed that eribulin and immunotherapy using TCR‐T cells has a synergistic effect. In summary, eribulin increases the expression of HLA class 1 via HLA class 1 transactivatior NLRC5 and eribulin combination with immunotherapy can be effective for the treatment of breast cancer. [ABSTRACT FROM AUTHOR]

Cytotrienin A, an ansamycin‐class antibiotic, exhibits potent apoptosis‐inducing activity and has attracted much attention as a lead compound for anticancer drugs. Herein, we report a new asymmetric synthetic route to cytotrienin A, employing an unexplored approach involving the late‐stage installation of a C11 side chain onto the macrolactam core. In this strategy, we utilized the redox properties of hydroquinone and installed a side chain on the sterically hindered C11 hydroxy group by the traceless Staudinger reaction. This study also demonstrated that the boron‐Wittig/iterative Suzuki–Miyaura cross‐coupling sequence was effective for the concise and selective construction of the (E,E,E)‐conjugated triene moiety. The developed route opens new opportunities for the structure–activity relationship studies of the side chains of these ansamycin antibiotics and the preparation of other synthetic analogs and chemical probes for further biological studies. [ABSTRACT FROM AUTHOR]

Evasion from immunity is a major obstacle to the achievement of successful cancer immunotherapy. Hybrids derived from cell–cell fusion are theoretically associated with tumor heterogeneity and progression by conferring novel properties on tumor cells, including drug resistance and metastatic capacity; however, their impact on immune evasion remains unknown. Here, we investigated the potency of tumor–macrophage hybrids in immune evasion. Hybrids were established by co‐culture of a melanoma cell line (A375 cells) and type 2 macrophages. The hybrids showed greater migration ability and greater tumorigenicity than the parental melanoma cells. The hybrids showed heterogeneous sensitivity to New York esophageal squamous cell carcinoma‐1 (NY‐ESO‐1)‐specific T‐cell receptor‐transduced T (TCR‐T) cells and two out of four hybrid clones showed less sensitivity to TCR‐T compared with the parental cells. An in vitro tumor heterogeneity model revealed that the TCR‐T cells preferentially killed the parental cells compared with the hybrids and the survival rate of the hybrids was higher than that of the parental cells, indicating that the hybrids evade killing by TCR‐T cells efficiently. Analysis of a single‐cell RNA sequencing dataset of patients with melanoma revealed that a few macrophages expressed RNA encoding melanoma differentiation antigens including melan A, tyrosinase, and premelanosome protein, which indicated the presence of hybrids in primary melanoma. In addition, the number of potential hybrids was correlated with a poorer response to immune checkpoint blockade. These results provide evidence that melanoma–macrophage fusion has a role in tumor heterogeneity and immune evasion. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Lanceolate nerve endings (LNEs) surrounding hair follicles (HFs) play an important role in detecting hair deflection. Complexes of the LNEs form a palisade‐like structure along the longitudinal axis of hair roots in which axons are sandwiched between two processes of terminal Schwann cells (tSCs) at the isthmus of HFs. The structure and molecular mechanism of LNEs in animal sinus hair, pelage, and human vellus hairs have been investigated. Despite the high density of HFs in human scalp skin, the LNEs in human terminal HFs have not been investigated. In this study, we aimed to reveal the distribution and ultrastructure of LNEs in terminal HFs of human scalp skin. Using light‐sheet microscopy and immunostaining, the LNEs were observed at one terminal HF but not at the other terminal HFs in the same follicular unit. The ultrastructure of the LNEs of terminal HFs in human scalp skin was characterized using correlated light and electron microscopy (CLEM). Confocal laser microscopy and transmission electron microscopy of serial transverse sections of HFs revealed that LNEs were aligned adjacent to the basal lamina outside the outer root sheath (ORS), at the isthmus of terminal HFs, and adjacent to CD200‐positive ORS cells in the upper bulge region. Moreover, axons with abundant mitochondria were sandwiched between tSCs. Three‐dimensional CLEM, specifically confocal laser microscopy and focused ion beam scanning electron microscopy, of stained serial transverse sections revealed that LNEs were wrapped with type I and type II tSCs, with the processes protruding from the space between the Schwann cells. Moreover, the ultrastructures of LNEs at miniaturized HFs were similar to those of LNEs at terminal HFs. Preembedding immunoelectron microscopy revealed that Piezo‐type mechanosensitive ion channel component 2 (Piezo2), a gated ion channel, was in axons and tSCs and adjacent to the cell membrane of axons and tSCs, suggesting that LNEs function as mechanosensors. The number of LNEs increased as the diameter of the ORS decreased, suggesting that LNEs dynamically adapt to the HF environment as terminal HFs miniaturize into vellus‐like hair. These findings will provide insights for investigations of mechanosensory organs, aging, and re‐innervation during wound healing. [ABSTRACT FROM AUTHOR]

Aim: Little is known about early manifestations of autism spectrum disorders (ASD) in females, including those who may be overlooked by the current diagnostic criteria. We longitudinally explored sex differences in the trajectories of cognitive and motor functions and adaptive behaviors in children with different levels of autistic traits. Methods: The participants were 824 children from the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), Japan, who were classified into three autistic trait groups—low, moderate, and high—based on the Social Responsiveness Scale–Second Edition. Cognitive and motor functions were measured at seven time‐points from 0.5 to 3.5 years of age using the Mullen Scales of Early Learning. Adaptive behaviors were measured at five time‐points from 2.7 to 9 years of age using the Vineland Adaptive Behavior Scales–Second Edition. Trajectories were depicted using latent growth curve modeling. Results: Sex‐specific trajectories were observed in the high‐autistic‐trait group, with only males showing a temporary decline in expressive language around the age of 2 years and a slight improvement thereafter. They also showed a slight improvement around 3 years in the adaptive behavior communication domain but a gradual downward trend later. Females in the high‐autistic‐trait group showed no distinct manifestation before the age of 3 years but showed a downward trend after 3.5 years in the adaptive behavior communication domain. Conclusion: Females and males with higher autistic traits than their same‐sex peers, independent of clinical diagnosis, may have different phenotypes in certain neurodevelopmental domains during infancy and early childhood. [ABSTRACT FROM AUTHOR]

The pathological mechanism responsible for EGFR inhibitor (EGFRI)‐induced skin rash remains unclear. Recent studies reveal associations between skin dysbiosis and skin inflammatory diseases. This study aimed to examine whether skin dysbiosis is associated with EGFRI‐induced skin rash. Bacterial swabs were taken from the forehead of 17 cancer patients at baseline and at several time points after EGFRIs initiation, as well as from 20 healthy controls. The skin microbiome was analysed using 16S rRNA sequencing. The severity of the skin rash was assessed using the rash grade. Skin surface parameters (pH, water capacitance, and sebum level) were also measured. Compared with baseline, the abundance of Cutibacterium acnes decreased in 13 of 15 cases, and that of Staphylococcus aureus, Corynebacterium spp., Staphylococcus epidermidis or Proteobacteria increased in 13 of 15 cases after EGFRIs initiation. Skin pH increased significantly in parallel with a decrease in water capacitance after EGFRI initiation. Also, the composition of the skin microbiome of patients with severe rash was significantly different from that of healthy controls. In addition, the skin dysbiosis did not return to baseline during EGFRIs treatment for >1 year. These longitudinal observations indicate that skin dysbiosis is associated with development of skin rash. [ABSTRACT FROM AUTHOR]

Concise synthesis and structure‐activity relationships study of 4‐substituted 2‐azaadamantane N‐oxyls reveals that 4‐chloro‐2‐azaadamantane N‐oxyl (4‐Cl‐AZADO) is an efficient organocatalyst toward the aerobic oxidation of alcohols in the presence of NOx as a co‐catalyst. The organocatalyst was easily synthesized from 2‐adamantanone in five steps, and it showed high activity compared with many previously reported nitroxyl radical catalysts. [ABSTRACT FROM AUTHOR]

The reciprocal interaction between pain and negative affect is acknowledged but pain‐related alterations in brain circuits involved in this interaction, such as the mediodorsal thalamus (MDThal), still require a better understanding. We sought to investigate the relationship between MDThal circuitry, negative affect and pain severity in chronic musculoskeletal pain. For these analyses, participants with chronic knee pain (CKP, n = 74) and without (n = 36) completed magnetic resonance imaging scans and questionnaires. Seed‐based MDThal functional connectivity (FC) was compared between groups. Within CKP group, we assessed the interdependence of MDThal FC with negative affect. Finally, post hoc moderation analysis explored whether burden of pain influences affect‐related MDThal FC. The CKP group showed altered MDThal FC to hippocampus, ventromedial prefrontal cortex and subgenual anterior cingulate. Furthermore, in CKP group, MDThal connectivity correlated significantly with negative affect in several brain regions, most notably the medial prefrontal cortex, and this association was stronger with increasing pain burden and absent in pain‐free controls. In conclusion, we demonstrate mediodorsal thalamo‐cortical dysconnectivity in chronic pain with areas linked to mood disorders and associations of MDThal FC with negative affect. Moreover, burden of pain seems to enhance affect sensitivity of MDThal FC. These findings suggest mediodorsal thalamic network changes as possible drivers of the detrimental interplay between chronic pain and negative affect. [ABSTRACT FROM AUTHOR]

Breast cancer gene 1 (BRCA1) plays roles in DNA repair and centrosome regulation and is involved in DNA damage‐induced centrosome amplification (DDICA). Here, the centrosomal localization of BRCA1 and the kinases involved in centrosome duplication were analyzed in each cell cycle phase after treatment with DNA crosslinker cisplatin (CDDP). CDDP treatment increased the centrosomal localization of BRCA1 in early S–G2 phase. BRCA1 contributed to the increased centrosomal localization of Aurora A in S phase and that of phosphorylated Polo‐like kinase 1 (PLK1) in late S phase after CDDP treatment, resulting in centriole disengagement and overduplication. The increased centrosomal localization of BRCA1 and Aurora A induced by CDDP treatment involved the nuclear export of BRCA1 and BRCA1 phosphorylation by ataxia telangiectasia mutated (ATM). Patient‐derived variants and mutations at phosphorylated residues of BRCA1 suppressed the interaction between BRCA1 and Aurora A, as well as the CDDP‐induced increase in the centrosomal localization of BRCA1 and Aurora A. These results suggest that CDDP induces the phosphorylation of BRCA1 by ATM in the nucleus and its transport to the cytoplasm, thereby promoting the centrosomal localization Aurora A, which phosphorylates PLK1. The function of BRCA1 in the translocation of the DNA damage signal from the nucleus to the centrosome to induce centrosome amplification after CDDP treatment might support its role as a tumor suppressor. [ABSTRACT FROM AUTHOR]

Spinocerebellar degenerations (SCDs) are a diverse group of rare and slowly progressive neurological diseases that include spinocerebellar ataxia type 1 (SCA1), SCA2, SCA3, SCA6, SCA7, dentatorubral‐pallidoluysian atrophy (DRPLA) and multiple system atrophy (MSA). They are often inherited, and affect the cerebellum and related pathways. The combination of clinical findings and lesion distribution has been the gold‐standard for classifying SCDs. This conventional approach has not been very successful in providing a solid framework shared among researchers because their points of views have been quite variable. After identification of genetic abnormalities, classification was overwhelmed by genotyping, replacing the conventional approach far behind. In this review, we describe a stepwise operational approach that we constructed based only on macroscopic findings without microscopy to classify SCDs into three major groups: pure cerebellar type for SCA6 and SCA31; olivopontocerebellar (OPC) type for SCA1, SCA2, SCA7 and MSA; and dentatorubral‐pallidoluysian (DRPL) type for SCA1, SCA3, DRPLA and progressive supranuclear palsy (PSP). Spinocerebellar tract involvement distinguishes SCA1 and SCA3 from DRPLA. Degeneration of the internal segment of the pallidum is accentuated in SCA3 and PSP, while degeneration of the external segment is accentuated in SCA1 and DRPLA. These contrasts are helpful in subdividing OPC and DRPL types to predict their genotypes. Lesion distribution represents disease‐specific selective vulnerability, which is readily differentiated macroscopically using our stepwise operational approach. Precise prediction of the major genotypes will provide a basis to understand how genetic abnormalities lead to corresponding phenotypes through disease‐specific selective vulnerabilities. [ABSTRACT FROM AUTHOR]

As the worldwide prevalence of colorectal cancer (CRC) increases, it is vital to reduce its morbidity and mortality through early detection. Saliva‐based tests are an ideal noninvasive tool for CRC detection. Here, we explored and validated salivary biomarkers to distinguish patients with CRC from those with adenoma (AD) and healthy controls (HC). Saliva samples were collected from patients with CRC, AD, and HC. Untargeted salivary hydrophilic metabolite profiling was conducted using capillary electrophoresis–mass spectrometry and liquid chromatography–mass spectrometry. An alternative decision tree (ADTree)‐based machine learning (ML) method was used to assess the discrimination abilities of the quantified metabolites. A total of 2602 unstimulated saliva samples were collected from subjects with CRC (n = 235), AD (n = 50), and HC (n = 2317). Data were randomly divided into training (n = 1301) and validation datasets (n = 1301). The clustering analysis showed a clear consistency of aberrant metabolites between the two groups. The ADTree model was optimized through cross‐validation (CV) using the training dataset, and the developed model was validated using the validation dataset. The model discriminating CRC + AD from HC showed area under the receiver‐operating characteristic curves (AUC) of 0.860 (95% confidence interval [CI]: 0.828‐0.891) for CV and 0.870 (95% CI: 0.837‐0.903) for the validation dataset. The other model discriminating CRC from AD + HC showed an AUC of 0.879 (95% CI: 0.851‐0.907) and 0.870 (95% CI: 0.838‐0.902), respectively. Salivary metabolomics combined with ML demonstrated high accuracy and versatility in detecting CRC. [ABSTRACT FROM AUTHOR]

Obesity is accompanied by and accelerated with chronic inflammation in adipose tissue, especially visceral adipose tissue (VAT). This low‐level inflammation predisposes the host to the development of metabolic disease, most notably type 2 diabetes. We have focused on the capacity of glycolipid‐reactive, CD1d‐restricted natural killer T (NKT) cells to modulate obesity and its associated metabolic sequelae. We previously reported that CD1d knockout (KO) mice are partially protected against the development of obesity‐associated insulin resistance, and these findings were recapitulated in mice with an adipocyte‐specific CD1d deficiency, suggesting that NKT cell–adipocyte interactions play a critical role in exacerbating disease. However, many other CD1d‐expressing cells contribute to the in vivo responses of NKT cells to lipid antigens. In the present study, we examined the role of CD1d expression by macrophages (Mϕ) in the development of obesity‐associated metabolic inflammation using LysMcre‐cd1d1f/f mice where the CD1d1 gene is disrupted in a Mϕ‐specific manner. Unexpectedly, these animals contained a higher frequency of T‐bet+ CD4+ T cells in VAT with increased production of Th1 cytokines that aggravated VAT inflammation. Mϕ from mutant mice displayed increased production of IL‐12p40, suggesting M1 polarization. These findings indicate that interactions of CD1d on Mϕ with NKT cells play a beneficial role in obesity‐associated VAT inflammation and insulin resistance with a sharp contrast to an aggravating role of CD1d in another type of antigen‐presenting cell, dendritic cells. [ABSTRACT FROM AUTHOR]

A 54‐year‐old woman presented to our hospital with a fever and cough. The patient had a medical history of follicular lymphoma treated with obinutuzumab. She was infected with an omicron variant of coronavirus disease 2019 and developed viral pneumonia. Antibiotics, molnupiravir, sotrovimab, and prednisolone were administered but were ineffective. The patient's symptoms and pneumonia persisted. She could not produce antibodies against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) because she was administered obinutuzumab. Finally, when we administered 300 mg of tixagevimab and cilgavimab, pneumonia immediately improved. However, the infection was prolonged for more than 4 months. Patients treated with anti‐CD20 monoclonal antibodies may have a prolonged SARS‐CoV‐2 infection. In such cases, tixagevimab/cilgavimab may be effective. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous genetic disease characterized by progressive weakness and spasticity predominantly affecting the lower limbs. Complex HSP is a subset of HSP presenting with additional neuronal and/or non‐neuronal phenotypes. Here, we identify a homozygous ABHD16A nonsense variant in two affected children in a Chilean family. Very recently, two groups reported patients with biallelic ABHD16A whose clinical presentation was similar to that of our patients. By reviewing the clinical features of these reports and our patients, ABHD16A‐related HSP can be characterized by early childhood onset, developmental delay, intellectual disability, speech disturbance, extrapyramidal signs, psychiatric features, no sphincter control, skeletal involvement, thin corpus callosum, and high‐intensity signals in white matter on T2‐weighted brain MRI. In addition, our affected siblings showed a characteristic face, sleep disturbance, and nodular and hyperpigmented skin lesions, which have not previously been reported in this condition. [ABSTRACT FROM AUTHOR]

From a mouse triple‐negative breast cancer cell line, 4T1, we previously established 4T1.3 clone with a high capacity to metastasize to bone after its orthotopic injection into mammary fat pad of immunocompetent mice. Subsequent analysis demonstrated that the interaction between cancer cells and fibroblasts in a bone cavity was crucial for bone metastasis focus formation arising from orthotopic injection of 4T1.3 cells. Here, we demonstrated that a member of the adhesion G‐protein–coupled receptor (ADGR) family, G‐protein–coupled receptor 56 (GPR56)/adhesion G‐protein–coupled receptor G1 (ADGRG1), was expressed selectively in 4T1.3 grown in a bone cavity but not under in vitro conditions. Moreover, fibroblasts present in bone metastasis sites expressed type III collagen, a ligand for GPR56/ADGRG1. Consistently, GPR56/ADGRG1 proteins were detected in tumor cells in bone metastasis foci of human breast cancer patients. Deletion of GPR56/ADGRG1 from 4T1.3 cells reduced markedly intraosseous tumor formation upon their intraosseous injection. Conversely, intraosseous injection of GPR56/ADGRG1‐transduced 4T1, TS/A (mouse breast cancer cell line), or MDA‐MB‐231 (human breast cancer cell line) exhibited enhanced intraosseous tumor formation. Furthermore, we proved that the cleavage at the extracellular region was indispensable for GPR56/ADGRG1‐induced increase in breast cancer cell growth upon its intraosseous injection. Finally, inducible suppression of Gpr56/Adgrg1 gene expression in 4T1.3 cells attenuated bone metastasis formation with few effects on primary tumor formation in the spontaneous breast cancer bone metastasis model. Altogether, GPR56/ADGRG1 can be a novel target molecule to develop a strategy to prevent and/or treat breast cancer metastasis to bone. [ABSTRACT FROM AUTHOR]

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This paper proposes a new fish bone detection technique using a convolutional neural network (CNN) and synthetic image generation. Semantic segmentation CNNs with supervised learning generally require a large number of training images and their pixel‐wise teaching signals. In fish bone detection, there are two problems with using semantic segmentation CNNs. One is the manual annotations of fish bones and the other is the difficulty of sampling all variations of fish bones with various lengths, angles, and thicknesses. The proposed method, however, generates them by drawing virtual fish bones on X‐ray images. This technique is very useful for reducing the cost of collecting and annotating a dataset. Experimental results have shown that the average F‐measure for the proposed method is 0.747, while that for a normal training method is 0.493. In the proposed method, the CNN successfully detected actual fish bones despite its training only with virtual fish bones. © 2021 Institute of Electrical Engineers of Japan. Published by Wiley Periodicals LLC. [ABSTRACT FROM AUTHOR]

Clozapine (CLZ) is a key drug in treatment‐resistant schizophrenia. Therapeutic drug monitoring (TDM) of CLZ and its metabolites, N‐desmethylclozapine and clozapine N‐oxide, is required to monitor and manage the risks of side effects. Although quantification methods for TDM have been developed for CLZ and its metabolites, they were not sufficiently accurate for the quantification of CLZ owing to the upper limits of the calibration curves. An analytical method using high‐performance liquid chromatography/electrospray ionization tandem mass spectrometry was developed and validated for the simultaneous measurement of CLZ and its metabolites in human plasma. To expand the concentration range of the calibration curves, we used a linear range shift technique using in‐source collision‐induced dissociation (CID). Using our approach, the linearity and quantitative range were improved compared to those reported by previous studies, and were sufficient for TDM in clinical practice. The intra‐ and inter‐assay accuracy was 84.6%–114.8%, and the intra‐ and inter‐assay precisions were ≤9.1% and ≤9.9%, respectively. Moreover, all samples from patients with treatment‐resistant schizophrenia were successfully quantified. Therefore, our novel analytical method using in‐source CID had the appropriate performance to measure the plasma concentrations of CLZ and its metabolites for TDM in clinical practice. [ABSTRACT FROM AUTHOR]

With a miniaturization of electrical devices, the gap between electrode becomes lower and lower. In order to optimize the insulation design, the understanding of breakdown phenomenon across micrometer-scale gap is essential. In this study, breakdown characteristics across micrometer-scale gap was investigated based on experiment and numerical simulation. The result shows that the breakdown voltage under positive voltage application is 1.5 times higher than the one under the negative voltage application. The polarity effect can be explained by the source of initial electrons. Under negative voltage application, the initial electrons are emitted fromthe cathode surface based on Fowler-Nordheim equation. On the other hand, under positive voltage application, the insulator plays an important role on breakdown voltage. [ABSTRACT FROM AUTHOR]

As the sentinels of innate and adaptive immune system, dendritic cells (DCs) have been considered to hold a great promise for medical application. Among the diverse types of DCs, monocyte‐derived DCs (mo‐DCs) generated in vitro have been most commonly employed. We have been improving the culture protocol and devised a protocol to produce mature interferon‐α‐induced DCs (IFN‐DCs), hereinafter called (mat)IFN‐DCs. While exploring the relationship between the expression of CD56 and the cytotoxic activity of (mat)IFN‐DCs, we unexpectedly found that sorting of (mat)IFN‐DCs with CD56 antibody‐coated microbeads (MB) resulted in fractionating cells with tumoricidal activity into the flow‐through (FT) but not MB‐bound fraction. We uncovered that the FT fraction contains cells expressing low but substantial level of CD56. Moreover, those cells express granzyme B (GrB), perforin (PFN), and serpin B9 at high levels. By employing a specific inhibitor of PFN, we confirmed that direct tumoricidal activity relies on the GrB/PFN pathway. We designated subpopulation in FT fraction as CD56dim and that in CD56 positively sorted fraction as CD56bright, respectively. This is the first time, to our knowledge, to identify subpopulations of CD56‐positive IFN‐DCs with distinct tumoricidal activity which is ascribed to high expression of the components of GrB/PFN pathway. [ABSTRACT FROM AUTHOR]

Temperature is one of the most influential factors for animals. The acclimation (rearing) and challenge temperatures are often more important than the given temperature per se. These effects on physiological responses have been known, but not well understood on immune responses. Here, we investigated the integrated effects of rearing and challenge temperatures on haemocyte populations in larvae of a plusiine moth, Chrysodeixis eriosoma. We hypothesize that the haemocyte concentration is decreased (increased) at higher (lower) temperatures from rearing temperatures and that the proportions of haemocyte types exhibit directional changes at higher (lower) temperatures to compensate for immune reactions. We expect that increasing (decreasing) the challenge temperature from the rearing temperature enhances (reduces) phagocytic activity. We found that higher temperatures slightly decreased the haemocyte concentration. We detected small changes in the proportions of haemocyte types among rearing temperatures, but the changes were non‐directional and most of them were statistically insignificant. We also found the integrated effects only with increases in the challenge temperatures, which resulted in increased phagocytosis, whereas no apparent reactions were detected with decreases in the challenge temperatures. Our results show that the haemocyte concentration is significantly affected by the rearing temperature, which implies that haematopoiesis depends on the ambient temperature. We discuss some adaptive and non‐adaptive components for the positive integrated effects of increases in the challenge temperatures. We also discussed the obtained non‐responsiveness in the integrated effects with decreases in the challenge temperatures. [ABSTRACT FROM AUTHOR]

Although the left anterior temporal lobe (ATL) has been associated with semantic processing, the role of this region in syntactic structure building of sentences remains a subject of debate. Functional neuroimaging studies contrasting well‐formed sentences with word lists lacking syntactic structure have produced mixed results. The current functional magnetic resonance imaging study examined whether the left ATL is selectively involved in semantic processing or also plays a role in syntactic structure building by manipulating syntactic complexity and meaningfulness in a novel way. To deprive semantic/pragmatic information from a sentence, we replaced all content words with pronounceable meaningless placeholders. We conducted an experiment with a 2 × 2 factorial design with factors of SEMANTICS (natural sentences [NAT]; sentences with placeholders [SPH]) and SYNTAX (the basic Japanese Subject‐Object‐Verb [SOV] word order; a changed Object‐Subject‐Verb [OSV] word order). A main effect of SEMANTICS (NAT > SPH) was found in the left ATL, as well as in the ventral occipitotemporal regions. The opposite contrast (SPH > NAT) revealed activation in the dorsal regions encompassing Brodmann area 44, the premotor area, and the parietal cortex in the left hemisphere. We found no main effect of SYNTAX (OSV > SOV) in a subregion of the left ATL that was more responsive to natural sentences than meaningless sentences. These results indicate selective involvement of a subregion of the left ATL in semantic/pragmatic processing. [ABSTRACT FROM AUTHOR]

Aims: To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). Methods: A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. Results: The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child–Pugh grade (CP)‐A and CP‐B, respectively, and 26.7% and 0% in VP4 HCC patients with CP‐A and CP‐B, respectively. Estimated median progression‐free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin‐bilirubin grade (hazard ratio 0.372, 95% CI 0.157–0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116–0.889; p = 0.0287) were independently associated with progression‐free survival in patients with tm50%LO HCC. In VP4 HCC, median progression‐free survival was worse in CP‐B (57 days) than in CP‐A patients (137 days, p = 0.0462). Conclusions: Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular‐type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers. [ABSTRACT FROM AUTHOR]

Highly regioselective intramolecular aminolysis of 3,4‐epoxy amines has been achieved. Key features of this reaction are (1) chemoselective activation of epoxides in the presence of unprotected aliphatic amines in the same molecules by a La(OTf)3 catalyst and (2) excellent regioselectivity for anti‐Baldwin 5‐endo‐tet cyclization. This reaction affords 3‐hydroxy‐2‐alkylpyrrolidines stereospecifically in high yields. DFT calculations revealed that the regioselectivity might be attributed to distortion energies of epoxy amine substrates. The use of this reaction was demonstrated by the first enantioselective synthesis of an antispasmodic agent prifinium bromide. [ABSTRACT FROM AUTHOR]

Flower malformation represented by phyllody is a common symptom of phytoplasma infection induced by a novel family of phytoplasma effectors called phyllogens. Despite the accumulation of functional and structural phyllogen information, the molecular mechanisms of phyllody have not yet been integrated with their evolutionary aspects due to the limited data on their homologs across diverse phytoplasma lineages. Here, we developed a novel universal PCR‐based approach to identify 25 phytoplasma phyllogens related to nine "Candidatus Phytoplasma" species, including four species whose phyllogens have not yet been identified. Phylogenetic analyses showed that the phyllogen family consists of four groups (phyl‐A, ‐B, ‐C, and ‐D) and that the evolutionary relationships of phyllogens were significantly distinct from those of phytoplasmas, suggesting that phyllogens were transferred horizontally among phytoplasma strains and species. Although phyllogens belonging to the phyl‐A, ‐C, and ‐D groups induced phyllody, the phyl‐B group lacked the ability to induce phyllody. Comparative functional analyses of phyllogens revealed that a single amino acid polymorphism in phyl‐B group phyllogens prevented interactions between phyllogens and A‐ and E‐class MADS domain transcription factors (MTFs), resulting in the inability to degrade several MTFs and induce phyllody. Our finding of natural variation in the function of phytoplasma effectors provides new insights into molecular mechanisms underlying the aetiology of phytoplasma diseases. [ABSTRACT FROM AUTHOR]

To predict whether populations of marine animals will persist in the face of changing climate conditions, it is informative to understand how past climate conditions have shaped present‐day tolerance thresholds. We examined 4 species of intertidal invertebrates (Nucella lamellosa, Littorina scutulata, Littorina sitkana, and Balanus glandula) inhabiting the coasts of Vancouver Island, Canada, where the east coast experiences historically warmer sea surface temperature (SST), warmer low tide (i.e., emersion) rock surface temperature (RST), and lower sea surface salinity (SSS) than the west coast. To determine if east coast populations have higher tolerance thresholds to acute stress than west coast populations, animals from 3 sites per coast were exposed to stressful temperatures and salinities in common garden experiments. Emersion temperature tolerance differed between populations only in N. lamellosa and B. glandula, tolerance thresholds being 1.4–1.5°C higher on the east coast. Water temperature tolerance differed between populations only in B. glandula and L. scutulata but was highest on the west coast. No differences in salinity tolerance were observed within any species. Thus, there is limited evidence of divergence among east and west coast populations in tolerance of acute stress despite the substantial historical differences in extreme temperature and salinity conditions between coasts. However, based on present‐day summertime SST and RST and known rates of change in these parameters, we predict present‐day tolerance thresholds would be sufficient to allow adults of these populations to tolerate extreme temperatures predicted for the next several hundred years, and that even a slow rate of change in acute tolerance thresholds might suffice to keep up with future temperature extremes. [ABSTRACT FROM AUTHOR]

Objectives: One of the reasons as to why chimeric antigen receptors (CAR)‐T cell therapy for malignancies other than CD19‐ or BCMA‐positive tumors has yet to produce remarkable progress is the paucity of targetable antigens. NKp44 is only expressed by activated natural killer cells and detects a variety of transformed cells, while it reportedly does not react with normal tissues. The aim of this study is to develop CAR‐T cell that can target multiple types of tumor cells. Methods: We created a series of novel CAR constructs in first‐generation (1G) and second‐generation (2G) CAR format with the extracellular immunoglobulin‐like domain of NKp44 (NKp44‐CAR). Results: Transduction of the best 1G construct into human primary T cells led to specific cytotoxic effects and cytokine secretion upon encountering multiple types of neoplastic cells including AML, T‐ALL and childhood solid tumors. Replacement of the extracellular hinge domain of NKp44 with that of CD8α resulted in diminished CAR function. The 1G NKp44‐CAR‐T cells exhibited significantly better tumor control in long‐term co‐culture assays compared with activated NK cells, as well as with NK cells transduced with identical NKp44‐CAR. T cells transduced with the best 2G‐CAR construct with 4‐1BB co‐stimulatory domain proliferated at significantly higher levels upon single antigen exposure and showed significantly better tumor control compared with the 1G‐CAR and 2G‐CAR with CD28 co‐stimulatory domain. Conclusions: NKp44‐based CAR endows T cells with NK cell‐like anti‐tumor specificity. The CAR gene created in this study will be useful for the development of novel gene‐modified T‐cell immunotherapy. [ABSTRACT FROM AUTHOR]

Background: The Response Evaluation Criteria in Solid Tumors (RECIST) for computed tomography (CT) is preoperatively used to evaluate therapeutic effects. However, it does not reflect the pathological treatment response (PTR) of pancreatic ductal adenocarcinoma (PDAC). The Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) for positron emission tomography (PET)/CT is effective in other cancers. This study aimed to confirm the usefulness of PERCIST and the prognostic utility of PET/CT for PDAC. Methods: Forty‐two consecutive patients with PDAC who underwent neoadjuvant therapy (NAT) and pancreatectomy at our institution between 2014 and 2018 were retrospectively analyzed. We evaluated the treatment response and prognostic significance of PET/CT parameters and other clinicopathological factors. Results: Twenty‐two patients who underwent PET/CT both before and after NAT with the same protocol were included. RECIST revealed stable disease and partial response in 20 and 2 cases, respectively. PERCIST revealed stable metabolic disease, partial metabolic response, and complete metabolic response in 8, 9, and 5 cases, respectively. The PTR was G3, G2, and G1 in 8, 12, and 2 cases, respectively. For comparing the concordance rates between PTR and each parameter, PERCIST (72.7% [16/22]) was significantly superior to RECIST (36.4% [8/22]) (P =.017). The area under the curve survival values of PET/CT parameters were 0.777 for metabolic tumor volume (MTV), 0.500 for maximum standardized uptake value, 0.554 for peak standardized uptake value corrected for lean body mass, and 0.634 for total lesion glycolysis. A 50% cut‐off value for the MTV reduction rate yielded the largest difference in survival between responders and nonresponders. On multivariate analysis, MTV reduction rates < 50% were independent predictors for relapse‐free survival (hazard ratio [HR], 3.92; P =.044) and overall survival (HR, 14.08; P =.023). Conclusions: PERCIST was more accurate in determining NAT's therapeutic effects for PDAC than RECIST. MTV reduction rates were independent prognostic factors for PDAC. [ABSTRACT FROM AUTHOR]

Summary: Nuclear factor (NF)‐κB‐inducing kinase (NIK) is known to be a critical regulator of multiple aspects of the immune response. Although the role of NIK in the development of medullary thymic epithelial cells (mTECs) has been well documented, the impact of NIK on the differentiation and function of cortical thymic epithelial cells (cTECs) remains ambiguous. To investigate the possible involvement of NIK in cTEC differentiation, we have compared the gene expression and function of cTECs from a NIK‐mutant mouse, alymphoplasia (aly/aly) with those of cTECs from wild‐type (WT) mice. Flow cytometric analyses revealed that expression levels of MHC class II, but not MHC class I or other TEC markers, were higher in aly/aly cells than in WT cells. Notably, the proportion of MHC class IIhi+ cTECs was elevated in aly/aly mice. We also demonstrated that expression of Ccl5 mRNA in the MHC class IIhi+ subset of aly/aly cTECs was decreased compared with that in WT cells, implying an abnormal pattern of gene expression in aly/aly cTECs. Analyses of bone marrow chimera using aly/aly or aly/+ mice as hosts suggested that Vβ usage and CD5 expression on WT T‐cells were altered when they matured in aly/aly thymi. These results collectively indicate that NIK may be involved in controlling the function of cTEC in selecting a proper T‐cell repertoire. [ABSTRACT FROM AUTHOR]

A growing body of evidence has indicated that individuals with autism spectrum disorder (ASD) exhibit abnormal reactions to sensory stimuli and impaired face processing. Although behavioral studies have reported that individual differences in sensory processing patterns are correlated with performance in face processing tasks, the neural substrates underlying the association between sensory processing patterns and face processing remain unknown. Using functional magnetic resonance imaging, the present study examined the relationships between sensory processing patterns assessed with the Adolescent/Adult Sensory Profile (AASP) and brain activity during a one‐back task with two types of stimuli (face or house pictures). We enrolled 18 Japanese adults with ASD and 19 age‐ and IQ‐matched controls. Sensation Avoiding scores, which were assessed using the AASP, were positively correlated with right fusiform activity during the presentation of pictures of faces in the ASD group, but not in the control group. This suggests that abnormal sensory processing patterns in ASD are associated with abnormal face‐related brain activity, possibly resulting in impaired face processing. Autism Res 2020, 13: 741–750. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: Sensory abnormalities are one of the most common symptoms in people with autism spectrum disorder (ASD). This study shows that individuals with ASD who react abnormally to sensory stimuli also exhibit atypical brain activity when recognizing faces. Abnormal sensory processing may partly explain the difficulty that people diagnosed with ASD have in identifying others' faces. [ABSTRACT FROM AUTHOR]

The larvae of Japanese rhinoceros beetle, Trypoxylus dichotomus, feed on dead plant material in forest soils that are derived from fallen leaves broken down by basidiomycete fungi. Our previous work provided an understanding of the degradation of polysaccharides in dead plant material by T. dichotomus larvae and reported the complexity of the physicochemical and biochemical environment of the larval gut. Here, we examined ten divisions of the digestive tract of T. dichotomus larvae for physicochemical and biochemical conditions to elucidate site-specifically functional properties along the tract. The distribution of potassium ions, pH, and acetic acid differed markedly along the length of the digestive tract with the potassium ion concentration profile closely reflecting that of pH along the length of the digestive tract. Distinct physicochemical environments were maintained in the digestive tract along with site-specific polysaccharide degradation. Based on these findings, we suggest that there are metabolic relationships between the activities of the enzymes involved in polysaccharide degradation, the presence of intermediate metabolites and location along the digestive tract. Furthermore, we revealed that the anterior region of the gut plays an important role in the degradation of polysaccharides in the digestive tract of T. dichotomus larvae. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?We questioned whether the disruption of invariant natural killer T (iNKT) cells exacerbates left ventricular (LV) remodelling and heart failure after transverse aortic constriction in mice.What are the main findings and their importance?Pressure overload induced by transverse aortic constriction increased the infiltration of iNKT cells in mouse hearts. The disruption of iNKT cells exacerbated LV remodelling and hastened the transition from hypertrophy to heart failure, in association with the activation of mitogen‐activated protein kinase signalling. Activation of iNKT cells modulated the immunological balance in this process and played a protective role against LV remodelling and failure. Chronic inflammation is involved in the development of cardiac remodelling and heart failure (HF). Invariant natural killer T (iNKT) cells, a subset of T lymphocytes, have been shown to produce various cytokines and orchestrate tissue inflammation. The pathophysiological role of iNKT cells in HF caused by pressure overload has not been studied. In the present study, we investigated whether the disruption of iNKT cells affected this process in mice. Transverse aortic constriction (TAC) and a sham operation were performed in male C57BL/6J wild‐type (WT) and iNKT cell‐deficient Jα18 knockout (KO) mice. The infiltration of iNKT cells was increased after TAC. The disruption of iNKT cells exacerbated left ventricular (LV) remodelling and hastened the transition to HF after TAC. Histological examinations also revealed that the disruption of iNKT cells induced greater myocyte hypertrophy and a greater increase in interstitial fibrosis after TAC. The expressions of interleukin‐10 and tumour necrosis factor‐α mRNA and their ratio in the LV after TAC were decreased in the KO compared with WT mice, which might indicate that the disruption of iNKT cells leads to an imbalance between T‐helper type 1 and type 2 cytokines. The phosphorylation of extracellular signal‐regulated kinase was significantly increased in the KO mice. The disruption of iNKT cells exacerbated the development of cardiac remodelling and HF after TAC. The activation of iNKT cells might play a protective role against HF caused by pressure overload. Targeting the activation of iNKT cells might thus be a promising candidate as a new therapeutic strategy for HF. [ABSTRACT FROM AUTHOR]

Rationale: We developed a new high‐throughput method to analyze tegafur (FT) and 5‐fluorouracil (5‐FU) in tear and plasma samples using hydrophilic interaction liquid chromatography (HILIC)/tandem mass spectrometry (MS/MS). Methods: The tear samples (10 μL) spiked with FT, 5‐FU, and 5‐chlorouracil (internal standard) were diluted using 40 μL of 2 M ammonium acetate and 250 μL of acetonitrile with 2% formic acid; 20 μL of plasma spiked with the two drugs and internal standard was diluted with 80 μL of 2 M ammonium acetate and 500 μL of acetonitrile with 2% formic acid. After centrifugation, the clear supernatant extract (15 μL) was directly injected into the HILIC/MS/MS instrument, and each drug was separated on a Unison UK‐Amino column (50 mm × 3 mm i.d., 3 μm particle size) with a linear gradient elution system composed of 10 mM ammonium acetate (pH 6.8) and acetonitrile at a flow rate of 0.7 mL/min. We performed quantification by multiple reaction monitoring (MRM) with negative‐ion atmospheric‐pressure chemical ionization. Results: Distinct peaks were observed for the drugs on each MRM channel within 2 min. The regression equations showed good linearity within the range 0.04–4.0 μg/mL for the tear and plasma samples with detection limits at 0.02–0.04 μg/mL. Recoveries for target analytes (FT and 5‐FU) for the tear and plasma samples were in the 94–128% and 94–104% ranges, respectively. The intra‐ and inter‐day coefficients of variation for the two drugs were lower than 10.8%. The accuracies of quantitation were 97–115% for both samples. Conclusions: We established a high‐throughput, reproducible, and practical procedure for analyzing FT and 5‐FU in human tear and plasma samples using HILIC/MS/MS analysis with an aminopropyl‐bonded mixed‐mode separation column. This method can be applied to the high‐throughput routines used in clinical analyses. [ABSTRACT FROM AUTHOR]

Despite the potential of α‐fluoroethers in medicinal chemistry, their synthetic methods, especially etherification of aliphatic alcohols, have been limited. Herein, we developed two‐ and three‐step gem‐difluoropropargylation of aliphatic alcohols including amino acid derivatives and naturally occurring bioactive molecules. Highly chemoselective etherification proceeded by using the gem‐difluoropropargyl bromide dicobalt complex in the presence of silver triflate and triethylamine. Decomplexation of dicobalt complexes was achieved by using cerium ammonium nitrate or N,N,N′‐trimethylethylenediamine. The thus obtained gem‐difluoropropargyl ethers were converted to various α‐difluoroethers which are expected to be useful for medicinal chemistry. [ABSTRACT FROM AUTHOR]

Aims: The study aims to evaluate the prognostic significance of impaired glucose tolerance (IGT) with reference to albuminuria in patients with chronic heart failure (CHF). Methods and results: We examined 535 CHF patients (mean 66 years, women 25%) in the control arm of our SUPPORT trial, in which we examined additive impact of olmesartan in hypertensive patients with symptomatic CHF treated with β‐blockers and/or angiotensin‐converting enzyme inhibitors. We examined the association between glycaemic abnormality (assessed by 75 g of oral glucose tolerance test) and albuminuria for a composite outcome of all‐cause death, myocardial infarction, stroke, and HF hospitalization. IGT patients (N = 113, mean 67.2 years) were older and more frequently treated with β‐blockers compared with those with normal glucose regulation (N = 142, mean 64.0 years) and those with diabetes mellitus (N = 280, mean 65.7 years). Multivariable Cox proportional hazard models revealed that, as compared with normal glucose regulation (NGR), IGT was associated with increased risk of the outcome when complicated by albuminuria [hazard ratio (HR) 2.25; 95% confidence interval (CI) 1.14–4.42; P = 0.019] but not when uncomplicated by albuminuria (HR 0.76; 95% CI 0.35–1.60, P = 0.47) (P for interaction = 0.041). This was also the case for diabetes mellitus and albuminuria (HR 2.06; 95% CI 1.17–3.61; P = 0.012). Among IGT patients without albuminuria, 21 (29%) developed albuminuria at 1‐year visit, which was again associated with poor prognosis (HR 7.36; 95% CI 1.39–38.98, P = 0.019). Conclusions: These results indicate that IGT is associated with poor prognosis when complicated by albuminuria in CHF patients, demonstrating the importance of combined early stages of glucose intolerance and renal dysfunction in the management of CHF. [ABSTRACT FROM AUTHOR]

Methyl‐selective α‐oxygenation of tertiary amines is a highly attractive approach for synthesizing formamides while preserving the amine substrate skeletons. Therefore, the development of efficient catalysts that can advance regioselective α‐oxygenation at the N‐methyl positions using molecular oxygen (O2) as the terminal oxidant is an important subject. In this study, we successfully developed a highly regioselective and efficient aerobic methyl‐selective α‐oxygenation of tertiary amines by employing a Cu/nitroxyl radical catalyst system. The use of moderately hindered nitroxyl radicals, such as 1,5‐dimethyl‐9‐azanoradamantane N‐oxyl (DMN‐AZADO) and 1‐methyl‐2‐azaadamanane N‐oxyl (1‐Me‐AZADO), was very important to promote the oxygenation effectively mainly because these N‐oxyls have longer life‐times than less hindered N‐oxyls. Various types of tertiary N‐methylamines were selectively converted to the corresponding formamides. A plausible reaction mechanism is also discussed on the basis of experimental evidence, together with DFT calculations. The high regioselectivity of this catalyst system stems from steric restriction of the amine‐N‐oxyl interactions. [ABSTRACT FROM AUTHOR]

A 60‐year‐old woman with stage IV rectal cancer received adoptive cell therapy with autologous cancer antigen (AC‐ACT) causing induction of anti‐oncogenic and anti‐PD‐L1 miRNAs as assessed by miRNA microarray. More than 1 year after AC‐ACT, metastases have been arrested, and the patient reports good quality of life. [ABSTRACT FROM AUTHOR]

The responses of cloud and diagnostic fields to the poleward shift of the local Hadley cell subsiding edge are examined using observational and reanalysis data from December 1982 to February 2016. Over the western North Pacific, the interannual variability of the local Hadley cell subsiding edge is marked by an anomalous rising motion, decreased large‐scale static stability, and corresponding increases of the midlevel cloud fraction over the climatological sinking zone around 35°N. The most sensitive cloud type is identified to be cumulus congestus, with cloud top pressures in the range of 440–680 hPa and optical thicknesses in the range of 23–60. This kind of cloud is estimated to be the main contributor to the net negative top‐of‐atmosphere radiation anomaly and to constrain the distribution of the anomalous precipitation associated with the local HC expansion. Plain Language Summary: The Hadley circulation is a dominant large‐scale circulation that robustly impacts the variability of global and regional climate. The current scientific consensus is that a poleward shift of the Hadley circulation is underway due to the warming climate; however, the magnitude of the shift, the detailed responses of cloud fields, and the underlying mechanisms still need further elucidation. The present study aims to figure out the most responsive cloud type that varies in conjunction with the poleward shift of the local Hadley cell subsiding edge (LHCSE), especially over the western North Pacific in winter. We explored how the interannual variability of the LHCSE modulates the environmental variables that influence cloud formation and how clouds in turn constrain the precipitation pattern over the northeast Asian coastal area. Key Points: The poleward shift of the local Hadley cell subsiding edge (LHCSE) is marked by increases of the midlevel cloud fraction over the climatological sinking zoneLHCSE‐correlated radiation anomalies are mainly contributed by the response of cumulus congestusModulated cumulus congestus and moist instability lead to increased precipitation over the northeast Asian coastal area [ABSTRACT FROM AUTHOR]