Search

Solid‐state methods for cooling and heating promise a sustainable alternative to current compression cycles of greenhouse gases and inefficient fuel‐burning heaters. Barocaloric effects (BCE) driven by hydrostatic pressure (p) are especially encouraging in terms of large adiabatic temperature changes (|ΔT| ≈ 10 K) and isothermal entropy changes (|ΔS| ≈ 100 J K−1 kg−1). However, BCE typically require large pressure shifts due to irreversibility issues, and sizeable |ΔT| and |ΔS| seldom are realized in a same material. Here, the existence of colossal and reversible BCE in LiCB11H12 is demonstrated near its order‐disorder phase transition at ≈380 K. Specifically, for Δp ≈ 0.23 (0.10) GPa, |ΔSrev| = 280 (200) J K−1 kg−1 and |ΔTrev| = 32 (10) K are measured, which individually rival with state‐of‐the‐art BCE figures. Furthermore, pressure shifts of the order of 0.1 GPa yield huge reversible barocaloric strengths of ≈2 J K−1 kg−1 MPa−1. Molecular dynamics simulations are performed to quantify the role of lattice vibrations, molecular reorientations, and ion diffusion on the disclosed BCE. Interestingly, lattice vibrations are found to contribute the most to |ΔS| while the diffusion of lithium ions, despite adding up only slightly to the entropy change, is crucial in enabling the molecular order–disorder phase transition. [ABSTRACT FROM AUTHOR]

Tietz albinism‐deafness syndrome (TADS) is a rare and severe manifestation of Waardenburg syndrome that is primarily linked to mutations in MITF. In this report, we present a case of TADS resulting from a novel c.637G>C mutation in MITF (p.Glu213Gln; GenBank Accession number: NM_000248). A 3‐year‐old girl presented with congenital generalized hypopigmentation of the hair, skin, and irides along with complete sensorineural hearing loss. Histopathological and electron microscopy investigations indicated that this variant did not alter the number of melanocytes in the skin but significantly impaired melanosome maturation within melanocytes. Comprehensive melanin analysis revealed marked reductions in both eumelanin (EM) and pheomelanin (PM) rather than changes in the EM‐to‐PM ratio observed in oculocutaneous albinism. We conducted an electrophoretic mobility shift assay to investigate the binding capability of the identified variant to DNA sequences containing the E‐box motif along with other known variants (p.Arg217del and p.Glu213Asp). Remarkably, all three variants exhibited dominant‐negative effects, thus providing novel insights into the pathogenesis of TADS. This study sheds light on the genetic mechanisms underlying TADS and offers a deeper understanding of this rare condition and its associated mutations in MITF. [ABSTRACT FROM AUTHOR]

Seborrheic keratosis (SK) is a common benign tumour, often associated with hyperpigmentation. To investigate the mechanism of melanin accumulation in SK, we have conducted comprehensive gene expression and histological analyses. We obtained five pairs of skin samples, including non‐lesional and SK samples, from the backs of three male Japanese participants aged 40–59 years. To examine melanocytes and keratinocytes in SK, three pairs of skin samples were separated by laser capture microdissection into the basal layer and the other layer in the epidermis. We performed a comprehensive gene expression analysis to identify differentially expressed genes between non‐lesional and SK skin, followed by gene ontology and pathway analysis. We found abnormal morphogenesis and cell proliferation in the basal layer, along with increased immune response and impaired cell differentiation and metabolism in the other layer of SK. We focused on cell proliferation and differentiation, as these are directly associated with melanin accumulation. Immunohistochemical analyses of Ki67, keratin 10, and keratin 14 demonstrated the decreases in the proliferation and early differentiation of the epidermis. Contrarily, no significant changes were observed in terminal differentiation markers, filaggrin and loricrin. Although the number of melanocytes was higher in SK than in non‐lesional skin, melanogenic activity showed no difference. These results indicated that melanin accumulation in SK is caused by delayed melanin excretion due to reduced turnover around the basal and spinous layers of the epidermis and melanin production due to an increased number of melanocytes. Our findings provide new insights for therapeutic approaches in SK. [ABSTRACT FROM AUTHOR]

Ultraviolet (UV)‐induced skin photoaging is caused by qualitative and quantitative degradation of dermal extracellular matrix components such as collagen and elastic fibers. Elastic fibers are important for maintaining cutaneous elasticity, despite their small amount in the skin. Previously, microfibril‐associated protein 4 (MFAP‐4), which is downregulated in photoaging dermis, has been found to be essential for elastic fiber formation by interaction with both fibrillin‐1 and elastin, which are core components of elastic fiber. In addition, enhanced cutaneous MFAP‐4 expression in a human skin‐xenografted murine photoaging model protects against UV‐induced photodamage accompanied by the prevention of elastic fiber degradation and aggravated elasticity. We therefore hypothesized that the upregulation of MFAP‐4 in dermal fibroblasts may more efficiently accelerate elastic fiber formation. We screened botanical extracts for MFAP‐4 expression‐promoting activity in normal human dermal fibroblasts (NHDFs). We found that rosemary extract markedly promotes early microfibril formation and mature elastic fiber formation along with a significant upregulation of not only MFAP‐4 but also fibrillin‐1 and elastin in NHDFs. Furthermore, rosmarinic acid, which is abundant in rosemary extract, accelerated elastic fiber formation via upregulation of transforming growth factor β‐1. This was achieved by the induction of cAMP response element‐binding protein phosphorylation, demonstrating that rosmarinic acid represents one of the active ingredients in rosemary extract. Based on the findings in this study, we conclude that rosemary extract and rosmarinic acid represent promising materials that exert a preventive or ameliorative effect on skin photoaging by accelerating elastic fiber formation. [ABSTRACT FROM AUTHOR]

A PTEN deficiency leads to the activation of phospho‐Akt at serine 473 (p‐Akt) and promotes the tumorigenesis of melanomas by coupling with NUAK2 amplification. We tested the prognostic impact of p‐Akt and/or NUAK2 expression on the relapse‐free survival (RFS) and overall survival (OS) of melanoma patients. Primary tumors from patients with acral melanomas (112), Low‐cumulative sun damage (CSD) melanomas (38), and High‐CSD melanomas (18) were examined using immunohistochemistry and their prognostic significance was analyzed statistically. The expression of p‐Akt was found in 32.1%, 68.4%, and 55.6% of acral, Low‐CSD, and High‐CSD melanomas, while NUAK2 expression was found in 46.4%, 76.3%, and 50.0%, respectively. Either p‐Akt or NUAK2 expression was inversely correlated with the RFS of primary melanoma patients and acral melanoma patients (p‐Akt: p <.0001, p <.0001; NUAK2; p =.0005, p <.0001, respectively). Strikingly, multivariate analyses revealed that p‐Akt had a significant impact on RFS (Hazard ratio = 4.454; p <.0001), while NUAK2 did not. Further subset analyses revealed that p‐Akt expression had an inferior RFS of patients with acral melanomas (Hazard ratio = 4.036; p =.0005). We conclude that the expression of p‐Akt has a significant impact on RFS of patients with primary melanomas and can predict the relapse of patients with acral melanomas. Research Highlights: The expression of p‐Akt has a significant impact on relapse‐free survival in primary melanoma patients and can predict the relapse of acral melanoma patients. The expression of p‐Akt can be a promising biomarker to stratify acral melanomas for clinical trials. [ABSTRACT FROM AUTHOR]

Background: The treatment of vitiligo can be challenging. Up‐to‐date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. Objectives: To develop internationally agreed‐upon expert‐based recommendations for the treatment of vitiligo. Methods: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. Results: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak‐inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB‐UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. Conclusions: This international consensus statement culminated in expert‐based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs. [ABSTRACT FROM AUTHOR]

An 82‐year‐old man was treated with ipilimumab and nivolumab for malignant pleural mesothelioma. Although he was previously treated with prednisolone (1 mg/kg/day) for immune‐related adverse event (irAE) hepatitis by a previous doctor, he still had worsening liver function and was transferred to our hospital. Blood tests and imaging findings were negative for autoimmune and infectious hepatitis, and liver biopsy results were consistent with irAE hepatitis. Steroid pulse therapy improved liver function, but tapering to prednisolone (1 mg/kg/day) again worsened his liver function. Concomitant use of mycophenolate mofetil was initiated, but no improvement in liver function was observed, therefore azathioprine, a thiopurine immunosuppressant, was administered in combination with steroids. During the course of treatment, hepatic dysfunction due to azathioprine was suspected, and the concomitant use of mercaptopurine and prednisolone was started. Afterward, the liver function improved, and the prednisolone dose was gradually reduced to 10 mg/day. This is a rare case in which a thiopurine‐based immunosuppressant was effective against irAE hepatitis, therefore thiopurine‐based immunosuppressants may be effective against steroid‐refractory hepatitis. [ABSTRACT FROM AUTHOR]

An 83‐year‐old woman with RET fusion‐positive advanced lung adenocarcinoma was administered selpercatinib 320 mg/day. Despite the shrinking of the tumour, fever, fatigue, and anorexia developed on day 17. Selpercatinib administration was interrupted. On day 21, elevated blood aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were observed. On day 28, AST and ALT levels increased to demonstrate Grade 4 in CTCAE Ver.5. The patient received a glycyrrhizin‐compounding agent and steroid treatment, and AST and ALT levels gradually decreased. On day 63, selpercatinib 160 mg/day was restarted after improvement of the hepatic disorder. Since then, selpercatinib was continued without any severe adverse events. Selpercatinib is a reasonable treatment option for RET fusion‐positive advanced non‐small cell lung cancer even in older patients. However, old age may be a risk factor for adverse events including hepatic disorders. For safe treatment in such patients, careful follow‐up is required. [ABSTRACT FROM AUTHOR]

An iridium‐catalyzed asymmetric synthesis of branched allylic phosphine compounds under mild conditions is reported. Products bearing various functional groups can be synthesized with excellent stereoselectivity (up to 99.9 % ee) and regioselectivity. The employment of phosphine sulfides with relatively low deactivation capacity against metal catalysts is crucial for the success of this reaction. [ABSTRACT FROM AUTHOR]

Conventional PD‐L1 immunohistochemical tissue biopsies only predict 20%–40% of non‐small cell lung cancer (NSCLC) patients that will respond positively to anti‐PD‐1/PD‐L1 immunotherapy. Herein, we present an immunogold biochip to quantify single extracellular vesicular RNA and protein (AuSERP) as a non‐invasive alternative. With only 20 μl of purified serum, PD‐1/PD‐L1 proteins on the surface of extracellular vesicles (EVs) and EV PD‐1/PD‐L1 messenger RNA (mRNA) cargo were detected at a single‐vesicle resolution and exceeded the sensitivities of their bulk‐analysis conventional counterparts, ELISA and qRT‐PCR, by 1000 times. By testing a cohort of 27 non‐responding and 27 responding NSCLC patients, AuSERP indicated that the single‐EV mRNA biomarkers surpass the single‐EV protein biomarkers in predicting patient responses to immunotherapy. Dual single‐EV PD‐1/PD‐L1 mRNA detection differentiated responders from non‐responders with an accuracy of 72.2% and achieved an NSCLC diagnosis accuracy of 93.2%, suggesting the potential for AuSERP to provide enhanced immunotherapy predictions and cancer diagnoses within the clinical setting. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+‐dependent Na+/Ca2+ exchanger 5. NCKX5 is involved in the maturation of melanosomes, but its function is still unclear. In this study, we characterized a Japanese patient with OCA6. Genetic analysis revealed compound heterozygous variants in SLC24A5, c.590 + 1dupG, and c.598G>A (p.G200R). To clarify the functional significance of the missense variant, we generated a knock‐in (KI) mouse model carrying the mouse homolog of the G200R variant using the CRISPR/Cas9 system. Chemical analysis showed decreased amounts of eumelanin in the hair and skin of KI mice, while levels of benzothiazine units in pheomelanin were significantly increased in their hair. Retinal pigment was also decreased in KI mice. Notably, a histopathologic study revealed a significant pigment loss in the retinal pigment epithelium (RPE) but not in the choroid. Immunohistochemically, the expression of NCKX5 in the RPE was decreased but was maintained in the choroid of KI mice. These findings could explain the difference in phenotypic severity between eye symptoms and hypopigmentation in the skin/hair. [ABSTRACT FROM AUTHOR]

The reaction of propargyl difluorides R1CF2C≡CR2 with alkylzincs R3ZnCl giving axially chiral fluorinated allenes R1FC=C=CR2R3 with high enantioselectivity (up to 99 % ee) was found to be catalyzed by a chiral diene/rhodium complex. A key step in the catalytic cycle is selective elimination of one of the enantiotopic fluorides at the β‐position of an alkenyl‐Rh intermediate, which is generated by regioselective addition of R3‐Rh onto the triple bond of the starting difluorides. [ABSTRACT FROM AUTHOR]

The hormone melatonin is synthesized from serotonin by two enzymatic reactions (AANAT and ASMT/HIOMT) in the pineal gland following a circadian rhythm with low levels during the day and high levels at night. The robust nightly peak of melatonin secretion is an output signal of the circadian clock to the whole organism. However, so far the regulatory roles of endogenous melatonin in mammalian biological rhythms and physiology processes are poorly understood. Here, we establish congenic mouse lines (>N10 generations) that are proficient or deficient in melatonin synthesis (AH+/+ or AH−/− mice, respectively) on the C57BL/6J genetic background by crossing melatonin‐proficient MSM/Ms with C57BL/6J. AH+/+ mice displayed robust nightly peak of melatonin secretion and had significantly higher levels of pineal and plasma melatonin vs AH−/− mice. Using this mice model, we investigated the role of endogenous melatonin in regulating multiple biological rhythms, physiological processes, and rhythmic behaviors. In the melatonin‐proficient (AH+/+) mice, the rate of re‐entrainment of wheel‐running activity was accelerated following a 6‐hour phase advance of dark onset when comparted with AH−/− mice, suggesting a role of endogenous melatonin in facilitating clock adjustment. Further in the AH+/+ mice, there was a significant decrease in body weight, gonadal weight and reproductive performance, and a significant increase in daily torpor (a hypothermic and hypometabolic state lasting only hours during adverse conditions). Endogenous melatonin, however, had no effect in the modulation of the diurnal rhythm of 2‐[125I]‐iodomelatonin receptor expression in the SCN, free‐running wheel behavior in constant darkness, life span, spontaneous homecage behaviors, and various types of social‐emotional behaviors. The findings also shed light on the role of endogenous melatonin in mice domestication and provide new insights into melatonin's action in reducing energy expenditure during a food shortage. In summary, the congenic mice model generated in this study offers a significant advantage toward understanding of the role of endogenous melatonin in regulating melatonin receptor‐mediated rhythm behaviors and physiological functions. [ABSTRACT FROM AUTHOR]

Overexpression of human dynactin‐associated protein isoform a (dynAPa) transforms NIH3T3 cells. DynAPa is a single‐pass transmembrane protein with a carboxy‐terminal region exposed to the outside of cells. According to the NCBI RefSeq database, there may be two other splicing variants of the encoding gene (dynAPb and c). DynAPa and c differ in some amino‐terminal residues (NH2‐MVA in dynAPa and NH2‐MEYQLL in dynAPc). DynAPb has the same amino‐terminal residues as dynAPc, but lacks 55 residues in the intracellular region. All three isoforms have the same carboxy‐terminal region, including the transmembrane domain. Expression of mRNAs of three splicing variants was found in human cancer cell lines ACHN and Caki‐1. The subcellular localization and in vitro cell transformation ability of the three isoforms were examined using NIH3T3 cells overexpressing each respective isoform. All isoforms were found to be localized to the Golgi apparatus and plasma membrane, where the carboxy‐terminal region was exposed to the outside of cells. Cell transformation was tested using focus formation due to loss of contact inhibition of cell proliferation, and colony formation was examined on soft agar and spheroid formation in ultralow U‐bottomed wells. DynAPa robustly formed foci and colonies on soft agar and spheroid, whereas these abilities were considerably decreased for dynAPb and completely lost in dynAPc. These findings warrant dissection studies to identify the dynAP domain that is required for cell transformation. [ABSTRACT FROM AUTHOR]

A small proportion of individuals utilizing cosmetics containing rhododendrol developed leukoderma with various pathological conditions, in some cases indistinguishable from vitiligo. In this review, we investigate and evaluate the major considerations for developing rhododendrol‐induced leukoderma based on data from original or review articles published in the literature to provide a wide range of information regarding the pathophysiology, mechanisms, risk evaluation, and possible mechanism‐based treatments. We compile and discuss the latest information, including data related to the cytotoxicity of rhododendrol, cytoprotective functions, and involvement of the immune system, and consider the possibility of novel treatments based on the differences between individual patients and on the mechanism underlying the onset of the condition. Understanding the pathophysiology of rhododendrol‐induced leukoderma helps not only elucidate the mechanisms of non‐segmental vitiligo onset and progression, but also suggests prevention and treatment. [ABSTRACT FROM AUTHOR]

Individuals who used skin‐whitening cosmetics (quasi‐drugs) containing 2% rhododendrol‐containing agents, developed leukoderma at a higher frequency than those who have used other skin‐whitening cosmetics. The Rhododenol Research Team (RD‐Team) was formed and commissioned by Kanebo Cosmetics Inc. to conduct research in treatments of rhododendrol‐induced leukoderma (RDL), to evaluate effective treatment options from a medical standpoint, and provide information to a wide range of people. In this study, we evaluated the efficacy of various treatments for RDL from a medical perspective, based on the information published in the literature as original or review articles. We searched the PubMed (international) and the Igaku Chuo Zasshi (ICHUSHI) (Japanese) databases using the keywords "Rhododenol" and "rhododendrol", for articles published between July 2013 and November 2020. We discuss the main clinical findings and treatments (topical, oral, phototherapy, and surgical) of this condition based on the literature review. We found that ultraviolet light therapy is the most effective treatment for RDL. We have also summarized reports of the efficacy of oral vitamin D3 in RDL. A topical prostaglandin derivative has been reported in a new study to be effective. We have provided guidance for patients using self‐tanning and skin‐whitening agents to improve their quality of life. Finally, we have highlighted the importance of providing patients with information on contact dermatitis and instructing them to discontinue product use immediately if they develop any symptoms of contact dermatitis while using skin‐whitening agents. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA) is the most frequent presentation of albinism, a heterogeneous rare genetic condition generally associated with variable alterations in pigmentation and with a profound visual impairment. There are non‐syndromic and syndromic types of OCA, depending on whether the gene product affected impairs essentially the function of melanosomes or, in addition, that of other lysosome‐related organelles (LROs), respectively. Syndromic OCA can be more severe and associated with additional systemic consequences, beyond pigmentation and vision alterations. In addition to OCA, albinism can also be presented without obvious skin and hair pigmentation alterations, in ocular albinism (OA), and a related genetic condition known as foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA). In this review, we will focus only in the genetics of skin pigmentation in OCA, both in human and mouse, updating our current knowledge on this subject. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA), which is roughly divided into non‐syndromic and syndromic OCA, is a group of autosomal recessive disorders caused by mutations in genes associated with pigmentation. Patients with OCA have hypopigmentation and ocular manifestations such as photophobia, amblyopia, and nystagmus. Hermansky–Pudlak syndrome (HPS), the most common syndromic OCA, is characterized by the additional features of a bleeding tendency and other critical systemic comorbidities such as pulmonary fibrosis and immunodeficiency. NGS‐based gene analyses have identified several new causative genes for OCA and have detected rare subtypes of OCA with high accuracy including Japanese patients. In our survey of 190 Japanese OCA patients/families, OCA4 is the most common subtype (25.3%) followed by OCA1 (20.0%), HPS1 (14.7%), and OCA2 (8.4%). Similar to the A481T variant in OCA2, which is associated with a mild form of OCA2 and skin color variation, the c.‐492_489delAATG variant located in the promoter region of SLC45A2 has been uniquely identified in Japanese patients with a mild form of OCA4. Further, rare OCA subtypes, including OCA3, HPS2, HPS3, HPS4, HPS5, HPS6, and HPS9, have also been identified in Japanese patients. The clinical characteristics and underlying molecular mechanisms of each subtype of OCA are concisely summarized in this review. [ABSTRACT FROM AUTHOR]

SASH1 has been reported as a causal gene of lentiginous phenotypes with and without heredity, including an autosomal dominant type characterized by lentigines predominantly on sun‐exposed areas such as the face and limbs. Recently, cases of dyschromatosis with SASH1 mutations have been reported worldwide; however, only one case has been reported from Japan. Here, we analyzed six Japanese patients who characteristically showed many lentigines on sun‐exposed areas, using next‐generation sequencing. We identified five novel heterozygous mutations in SASH1 (p.I586M, p.S531Y, p.R644W, p.T525R, and p.S516I) in our patients and their families. The p.R644W substitution identified in two unrelated families was the first mutation located in the sterile alpha motif 1 (SAM1) domain. The degree and location of the lentigines were variable across individuals, even if they shared the same SASH1 mutation. All mutations were predicted to be deleterious by six different algorithms used to evaluate the functional impact of a variation. In addition, immunohistopathological findings and RNA sequencing results suggested that SASH1 mutations were associated with an increase in the number of melanocytes, acceleration of melanogenesis, and upregulated hair keratin expression. [ABSTRACT FROM AUTHOR]

Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for research has not been established. In order to analyze the pathomechanism of PIH, we successfully induced PIH in a hairless version of transgenic mice (hk14‐SCF Tg/HRM) that have a human‐type epidermis containing melanin by repeated hapten application of 2,4‐dinitrofluorobenzene. Histopathologic observation showed epidermal hyperplasia, predominant infiltrations of inflammatory cells, and melanin‐containing cells in the dermis just after elicitation of the atopic dermatitis‐like condition. At week 2, the findings were similar to the characteristics of PIH, that is, an increase of melanin without spongiosis or liquid degeneration in the epidermis and an increase in dermal melanophages. Dynamic analysis of melanin showed that the melanin in the dermis remained for a longer duration than in the epidermis. Furthermore, immunohistochemical staining revealed that the majority of cells containing melanin were positive for the anti‐CD68 antibody, but negative for the anti‐F4/80 antibody. These data suggest that novel treatments of PIH should be targeted against macrophages and should eventually lead to the development of new treatment modalities. [ABSTRACT FROM AUTHOR]

A tornado associated with category 5 Super Typhoon Hagibis occurred on October 12, 2019 in Ichihara City, Chiba Prefecture, Japan. An X‐band phased array weather radar revealed the occurrence of the tornado at the south edge of its parent cloud, which had several characteristics of a classic supercell (mesocyclone, hook‐shaped echo, bounded weak echo region, and vault shape). Phased array radar observation also revealed a three‐dimensional multiscale structure of the tornado with a mesocyclone and misocyclone at different altitudes. The misocyclone, the vorticity of which intensified for several minutes under the mesocyclone, resulted in the formation of a tornado and debris ball. The echo top height of the debris ball abruptly increased at the time when the vorticity of the misocyclone maximized at low levels, suggesting a rapid evolution of tornadic vortex and the associated damage on the ground. Plain Language Summary: On October 12, 2019 in Japan, a typhoon‐induced tornado adversely affected human lives and seriously damaged buildings. A phased array weather radar (PAWR), one of the latest weather radar systems having the ability of rapid scanning, observed detailed movements of the tornado and its parent cloud three dimensionally. The PAWR detected larger vortices above the tornado, as well as the tornado itself, before destruction on the ground. Using PAWR data, precision of tornado forecasting can be improved and earlier warnings can be issued. Key Points: A tornado induced by Typhoon Hagibis was generated in a mini‐supercellEnhancement of a misocyclone, which is smaller than a mesocyclone, contributed to the evolution of the tornado in the mini‐supercellThree‐dimensional and rapid evolution process of a debris ball, a signature of tornado damage, was detected from 1 min prior to beginning of damage [ABSTRACT FROM AUTHOR]

Vitiligo is a depigmentation disease characterized by gradual loss of melanin and melanocytes from the epidermis. The mechanism of melanocyte loss is not yet known. In this report, we showed that the expression of discoidin domain receptor 1 and E‐cadherin, known adhesion molecules, was variable or absent in the epidermis of rhododendrol‐induced leukoderma (RDIL) mice during the depigmentation process. Our findings suggest that melanocyte damage by rhododendrol promotes reduction of adhesion molecules not only in melanocytes but also in keratinocytes, and this is associated with the detachment of melanocytes from the basal layer. [ABSTRACT FROM AUTHOR]

A chiral diene‐rhodium complex was found to catalyze the reaction of 1,6‐enynes with ArZnCl to give high yields of 2‐(alkylidene)cyclopentylmethylzincs with high enantioselectivity (95–99 % ee). The enantioenriched alkylzincs were readily converted in a one‐pot approach into a wide variety of functionalized products by taking advantage of their unique reactivity. The catalytic cylcle involves arylrhodation of alkyne, intramolecular alkenylrhodation of alkene, and transmetalation of the alkyl‐rhodium intermediate into alkylzinc. [ABSTRACT FROM AUTHOR]

Pemetrexed (PEM) is a useful drug that can be combined with immune checkpoint blockade therapy for treatment of patients with advanced non–small‐cell lung cancer (NSCLC). However, its effects on anti–cancer immunity, especially the sensitivity of NSCLC cells to cytotoxic immune cells, have not been fully investigated. In this study, we examined the effects of PEM on the sensitivity of human NSCLC cells to two different types of cytotoxic immune cells. Pre‐treatment with PEM increased the sensitivity of two NSCLC cell lines, PC9 and A549, to activated T cells and natural killer (NK) cells, and decreased the expression of anti–apoptotic proteins, including XIAP and Mcl‐1. In addition, PEM treatment increased the cell surface expression of programmed death‐ligand 1 (PD‐L1) on PC9 cells. PEM‐induced upregulation of PD‐L1 on PC9 cells was at least partially ascribed to activation of ERK and the NFκB pathway. In contrast, PEM treatment increased the expression of UL16‐binding proteins (ULBP), ligands for the NKG2D NK receptor, on PC9 and A549 cells, as well as the induction of senescence. Although the addition of anti–programmed cell death 1 antibody showed no effect on the sensitivity of PEM‐treated PC9 and A549 cells to activated T cells, that of anti–NKG2D antibody decreased the enhanced sensitivity of PEM‐treated A549 cells to NK cells. These results indicate that PEM can effectively sensitize human NSCLC cells to cytotoxic immune cells while modulating the expression of immune‐regulatory molecules. [ABSTRACT FROM AUTHOR]

Hermansky–Pudlak syndrome type 2 (HPS2) is an extremely rare autosomal recessive inherited disease characterized by partial oculocutaneous albinism (OCA), bleeding diathesis due to a storage pool deficiency and immunodeficiency. The disorder is caused by disruption of the adapter protein 3 complex, which is involved in impaired intracellular vesicle transport. Here, we report the first case of a 1‐year‐old girl with HPS2 in Asia. She had no specific symptoms other than OCA and neutropenia. We analyzed her platelet function using transmission electron microscopy and a platelet aggregation test, cytotoxic degranulation assay of her natural killer (NK) cells and bleeding time, the results of which led to the diagnosis of HPS2. Although her NK‐cell cytotoxic degranulation was impaired, she had not developed signs of hemophagocytic lymphohistiocytosis (HLH) or fibrosing lung disease. Molecular genetic analyses showed novel heterozygous mutations (c.188T>A [p.M63K] and c.2546>A [p.L849X]) in AP3B1. When examining patients with OCA, blood tests should be performed to confirm neutrophil count, bleeding time and platelet agglutination. When HPS2 is suspected, detailed immunological tests should be considered, and attention should be paid to HLH and pulmonary lesions immediately and over the long term. [ABSTRACT FROM AUTHOR]

Aim: In Japan, the number of older patients with cancer has been increasing. Assessment of performance status, cognitive function and social background is necessary for the treatment of older patients. The aims of the present study were: (i) to establish an evaluation system using electronic medical records; and (ii) to distinguish older patients as fit versus vulnerable or frail according to a geriatric assessment (GA) system score. Methods: We incorporated GA tools in our electronic medical records system and carried out comprehensive assessments for patients with newly diagnosed lung cancer aged ≥65 years. The decision about primary treatment followed consultation with the clinical team and was not guided by GA scores. Subsequent treatment and outcomes were recorded. Results: A total of 100 patients had completed GA. The average age was 75 years (range 65–94 years). Regarding GA results, 63% were positive on the Comprehensive Geriatric Assessment 7, 39% on the Vulnerable Elderly Survey‐13 and 84% on the Geriatric 8. The percentage of vulnerable patients (positive on all three GA) was significantly higher in the non‐standard therapy group (n = 19) than in the standard therapy group (n = 81; 78.9% vs 21.0%, P < 0.001). Among vulnerable patients who received standard therapy, 47% discontinued chemotherapy as a result of toxicity. Even if a patient was considered vulnerable based on GA scores, chemotherapy is possibly safe for those with EGFR mutations. Conclusions: We confirmed the feasibility of this system. During decision‐making for older patients with cancer, a combination of GA helps prevent undertreatment or overtreatment. Geriatr Gerontol Int 2019; 19: 1108–1111. [ABSTRACT FROM AUTHOR]

Albinism, which is commonly inherited as an autosomal recessive trait, is characterized by a reduction or absence of melanin in the eyes, skin, and hair. To date, more than 20 causal genes for albinism have been identified; thus, the accurate diagnosis of albinism requires next‐generation sequencing (NGS). In this study, we analyzed 46 patients who tested negative for oculocutaneous albinism (OCA)1–4 and Hermansky‐Pudlak syndrome (HPS)1 based on conventional analysis, in addition to 28 new Japanese patients, using NGS‐based targeted resequencing. We identified a genetic background for albinism in 18 of the 46 patients (39%), who were previously tested negative according to the conventional analysis. In addition, we unveiled a genetic predisposition toward albinism in 23 of the 28 new patients (82%). We identified six patients with rare subtypes of albinism, including HPS3, HPS4, and HPS6, and found 12 novel pathological mutations in albinism‐related genes. Furthermore, most patients who were not diagnosed with albinism by the NGS analysis showed mild manifestations of albinism without apparent eye symptoms and harbored only one heterozygous mutation, occasionally in combination with skin‐color associated gene variants. [ABSTRACT FROM AUTHOR]

Currently, vitiligo lacks a validated Physician Global Assessment (PGA) for disease extent. This PGA can be used to stratify and interpret the numeric scores obtained by the Vitiligo Extent Score (VES). We investigated the interrater reliability of a 5‐point PGA scale during an international vitiligo workshop. Vitiligo experts from five different continents rated photographs of non‐segmental vitiligo patients with varying degrees of extent with the PGA score. Good interrater agreements (intraclass correlation coefficient >0.6) were observed between the raters overall and within each continent. All hypotheses to evaluate construct validity were confirmed. Median VES values per category were for limited 1.10 [IQR: 0.21–1.67], moderate 3.17 [IQR: 1.75–6.21], extensive 9.58 [IQR: 6.21–13.03] and very extensive 42.67 [IQR: 21.20–42.67]. Defined categories for vitiligo extent can be valuable for inclusion criteria and may impact future reimbursement criteria. [ABSTRACT FROM AUTHOR]

Senescence is a state of growth arrest induced not only in normal cells but also in cancer cells by aging or stress, which triggers DNA damage. Despite growth suppression, senescent cancer cells promote tumor formation and recurrence by producing cytokines and growth factors; this state is designated as the senescence‐associated secretory phenotype. In this study, we examined the susceptibility of senescent human breast cancer cells to immune cell‐mediated cytotoxicity. Doxorubicin (DXR) treatment induced senescence in 2 human breast cancer cell lines, MDA‐MB‐231 and BT‐549, with the induction of γH2AX expression and increased expression of p21 or p16. Treatment with DXR also induced the expression of senescence‐associated β‐galactosidase and promoted the production of pro‐inflammatory cytokines. Importantly, DXR‐treated senescent MDA‐MB‐231 cells showed increased sensitivity to 2 types of immune cell‐mediated cytotoxicity: cytotoxicity of activated CD4+ T cells and Ab‐dependent cellular cytotoxicity by natural killer cells. This increased sensitivity to cytotoxicity was partially dependent on tumor necrosis factor‐related apoptosis‐inducing ligand and perforin, respectively. This increased sensitivity was not observed following treatment with the senescence‐inducing cyclin‐dependent kinase‐4/6 inhibitor, abemaciclib. In addition, treatment with DXR, but not abemaciclib, decreased the expression of antiapoptotic proteins in cancer cells. These results indicated that DXR and abemaciclib induced senescence in breast cancer cells, but that they differed in their sensitivity to immune cell‐mediated cytotoxicity. These findings could provide an indication for combining anticancer immunotherapy with chemotherapeutic drugs or molecular targeting drugs. [ABSTRACT FROM AUTHOR]

The one‐step synthesis of arylacetaldehydes by carbon–carbon bond formation between formylmethyl and aryl groups has been realized by the reaction of vinylene carbonate with arylboronic acids in the presence of an iridium/bisphosphine catalyst and a catalytic amount of tetrahydroxydiboron. [ABSTRACT FROM AUTHOR]

We study the Na‐ion battery characteristics of SnS as a negative electrode by first‐principles calculations. From energy analyses, we clarify the discharge reaction process of the Na/SnS half‐cell system. We show a phase diagram of Na−Sn−S ternary systems by constructing convex‐hull curves, and show a possible reaction route considering intermediate products in discharge reactions. Voltage‐capacity curves are calculated based on the Na−SnS reaction path that is obtained from the ternary phase diagram. It is found that the conversion reactions and subsequently the alloying reactions proceed in the SnS electrode, contributing to its high capacity compared with the metallic Sn electrode, in which only the alloying reactions progresses stepwise. To verify the calculated reaction process, x‐ray absorption spectra (XAS) are calculated and compared with experimental XAS at S K‐edge, showing meaningful XAS changes associated with Na2S and SnS in discharged and charged states, respectively. By using the first‐principles calculations, we investigate discharge reaction mechanisms in a negative electrode of tin sulfide SnS for sodium‐ion batteries. Possible reaction formulae in Na/SnS during the discharge processes are theoretically shown based on the ternary Na−Sn−S phase diagrams. Theoretical voltage‐capacity curves and x‐ray absorption spectra show reasonable agreements with experiments. [ABSTRACT FROM AUTHOR]

Since localized treatment for vitiligo is as essential as systemic treatment, a reliable instrument for target evaluation is needed besides those for whole body evaluation. We developed the Vitiligo Extent Score for a Target Area (VESTA) using reference images of both marginal and perifollicular repigmentation to measure the repigmentation rate (%) in a target lesion. In the validation study, a total of 65 dermatologists in 10 institutes evaluated 17 pairs of vitiligo images (pre‐ and post‐treatment) using both a rough estimate and the VESTA. The VESTA (concordance correlation coefficient: 0.949, 95% confidence interval [CI] 0.942–0.955) was significantly more accurate than the rough estimate (0.896, 95% CI: 0.883–0.908). It was also associated with better inter‐rater reliability over the rough estimate, albeit not significant. The VESTA can afford intuitive, convenient, and reliable assessment of the treatment response in a target area, and would be useful in clinical practice as well as retrospective studies. [ABSTRACT FROM AUTHOR]

This paper reports on a capacitive MEMS hydrogen sensor using Pd‐based metallic glass (MG) for future hydrogen society. First, we investigate PdCuSi as a Pd‐based MG and show that this material is promising for capacitive MEMS hydrogen sensor. Second, we employ the Pd‐based MG in a hydrogen sensor that has an inverted T‐shaped electrode. The sensor is fabricated by a surface micromachining process. We show that the fabricated hydrogen sensor exhibits hysteresis‐free and fast response properties at room temperature. [ABSTRACT FROM AUTHOR]

The enantioselective synthesis of a series of C2‐symmetric 3,3′‐diarylated 1,1′‐spirobiindane‐7,7′‐diols (3,3′‐diaryl‐SPINOLs) was developed by sequential Rh‐catalyzed twofold asymmetric conjugate arylation/BF3‐promoted diastereoselective spirocyclization (>20:1 d.r. and >99 % ee for all examples). Some phosphoramidite ligands were prepared from the 3,3′‐Ph‐SPINOL and applied to several catalytic asymmetric reactions, and the 3,3′‐diarylated ligands showed higher enantioselectivities than the privileged nonsubstituted ligands. Going for a ′SPIN′: The enantioselective synthesis of a series of 3,3′‐diarylated 1,1′‐spirobiindane‐7,7′‐diols (3,3′‐diaryl‐SPINOLs) was developed using a sequential Rh‐catalyzed twofold asymmetric conjugate arylation/BF3‐promoted diastereoselective spirocyclization. Some phosphoramidite ligands were prepared from the 3,3′‐Ph‐SPINOL and applied to several catalytic asymmetric reactions, and the 3,3′‐diarylated ligands showed higher enantioselectivities than the privileged nonsubstituted ligands. [ABSTRACT FROM AUTHOR]

Background: Rhododendrol (rhododenol), an inhibitor of tyrosinase activity, is used as a skin‐whitening component. Many cases of leukoderma after the application have been reported, termed rhododenol‐induced leukoderma (RIL). The aim of this study was to clarify the pathogenesis of RIL morphologically through comparison with vitiligo. Methods: We examined 14 cases of RIL and 15 cases of vitiligo using routine histopathology and immunohistochemistry. Thirteen cases of RIL, six cases of vitiligo and specimens of the RIL mouse model were evaluated by electron microscopy. Results: There were common findings in RIL and vitiligo at the light‐microscopic level: (a) vacuolar changes in the dermo‐epidermal junction, (b) melanophages in the papillary dermis, (c) perifollicular lymphocyte infiltration, (d) loss or decrease of basal melanin pigment and (e) decrease of melanocytes in the lesions. The ultrastructural observations showed specific findings of RIL: (a) remaining melanocytes in depigmented lesions, (b) inhomogeneous melanization in melanocytes and (c) degenerated melanosomes in melanocytes. Some of the findings were observed in a RIL mouse model. Furthermore, it is notable that cell organelles of melanocytes were intact in our RIL cases. Conclusion: Morphological changes of RIL targeting melanosomes in melanocytes without degeneration of organelles reflect the reversible clinical course of most cases. [ABSTRACT FROM AUTHOR]

Oculocutaneous albinism (OCA) type 4 is one of the most common types of albinism among Japanese population. In some patients who were clinically diagnosed with OCA, we have found a heterozygous pathological mutation in the coding region of SLC45A2, the gene responsible for OCA4, not leading to a DNA‐based diagnosis. In this study, we evaluated pathological variants in the promoter region of SLC45A2 in these patients. The results indicated that the majority of the patients had a 4‐bp deletion in the said region (c.‐492_489delAATG; GenBank accession number: NM_016180; rs984225803) in the contralateral allele. These patients displayed a mild phenotype, especially regarding eye manifestations. The results of the luciferase reporter assay and electrophoretic mobility shift assay supported the pathological role of the variant. In addition, four of 220 alleles in Japanese normal control subjects also showed the deletion variant, indicating that this variant could possibly be a skin color‐associated variant. [ABSTRACT FROM AUTHOR]

Abstract: Age‐dependent changes of the mandible bone in female F344/N rats, aged 22–1196 days, were analyzed using physiological bone properties and morphology. Bone weight, bone area, bone mineral components, and bone mineral density were assessed using dual‐energy X‐ray absorptiometry. The bone weight, bone area, bone mineral components, and bone mineral density increased rapidly until approximately 150 days of age, increased gradually thereafter, and then stabilized or decreased after 910 days of age. The ratio of bone mineral components to bone weight (bone mineral ratio) increased rapidly until approximately 43 days of age and stabilized thereafter. Size of the mandible, which was measured at 13 points on mandible surface, increased with age, and the rate of change showed a similar pattern to the other parameters. From a principal component analysis on morphometric measurements, principal component 1 (size factor) increased proportionally with age, whereas principal component 2 (shape factor) decreased until approximately 88 days of age and then increased after 365 days of age. As a result, the scatter plots for principal component 1 and principal component 2 were V‐shaped, which indicates that the mandible developed in size, with deformation at younger ages, and recovered its original shape later in life. Our results revealed the occurrence of inflection points at approximately 43, 88, 150, 365, and 910 days of age. Some of these ages corresponded to transition points revealed by the age‐dependent changes of the occlusal mandibular condyle and tooth wear in the same rat. [ABSTRACT FROM AUTHOR]

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients’ general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment. [ABSTRACT FROM AUTHOR]

Abstract: Asymmetric benzannulation of 1‐arylalkynes, where the aryl group is an ortho‐substituted aromatic group, with 2‐(cyanomethyl)phenylboronate was catalyzed by a rhodium complex coordinated with a chiral diene ligand to give high yields of axially chiral 2‐aminobiaryls with greater than 90 % ee. [ABSTRACT FROM AUTHOR]

Abstract: Owing to the innovative applications of fluorinated compounds in many areas of technology and medicine, methods for the preparation of C−F quaternary fluorine containing compounds are in extremely high demand. Here, we report the discovery of a general procedure for an SN2 reaction catalyzed by Pd/Ding‐SKP‐type ligands, and that occurs between Colby pro‐enolates with MBH carbonates to afford the corresponding products featuring two consecutive stereogenic carbons, including a C−F quaternary stereogenic center. The reactions readily occur at ambient temperatures with high chemical yields and in excellent chemo‐, diastereo‐ and enantioselective manners. This practically attractive stereochemical outcome, coupled with the operational simplicity and structural generality, bodes well for the synthetic application of this process in the preparation of a novel class of biologically relevant fluorine‐containing compounds. [ABSTRACT FROM AUTHOR]

Although rare, pleuroparenchymal fibroelastosis (PPFE) is a serious late‐onset complication of haematopoietic stem cell transplantation (HSCT). It remains unclear whether graft‐versus‐host disease (GVHD) is involved in the development of PPFE. We report the case of a patient with PPFE after HSCT. The patient experienced pneumothorax repeatedly despite surgical treatment. A surgical specimen demonstrated PPFE findings, without evidence of GVHD. In this case, development of PPFE was not associated with GVHD, and immunosuppressive therapy did not improve pulmonary function. Surgical biopsy is recommended for precise treatment and elucidation of pathogenesis in each suspected PPFE patient. [ABSTRACT FROM AUTHOR]

Summary: Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), a bleeding tendency, and ceroid deposition. Most of the causative genes for HPS encode subunits of the biogenesis of lysosome‐related organelles complex (BLOC). In this study, we identified one patient each with HPS4, HPS6, and HPS9 by whole‐exome sequencing. Next, we analyzed hair samples from the three patients and representative patients with HPS1 and controls using electron microscopy and chemical methods. All HPS patients had fewer, smaller, and more immature melanosomes than healthy controls. Further, all patients showed reduced total melanin content and increased levels of benzothiazine‐type pheomelanin. The results of this study demonstrate the impact of the dysfunctions of BLOCs on the maturation of melanosomes and melanin levels and composition through analysis of their hair samples. [ABSTRACT FROM AUTHOR]