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We have investigated the low-energy electronic state of boron-doped diamond thin film by the laser-excited photoemission spectroscopy. A clear Fermi-edge is observed for samples doped above the semiconductor–metal boundary, together with the characteristic structures at 150×n meV possibly due to the strong electron–lattice coupling effect. In addition, for the superconducting sample, we observed a shift of the leading edge below Tc indicative of a superconducting gap opening. We discuss the electron–lattice coupling and the superconductivity in doped diamond.

The dispersion of acoustic and optical phonons in highly boron-doped diamond has been measured by inelastic X-ray scattering at an energy resolution of 6.4 meV. The sample is doped in the metallic regime and shows superconductivity below 4.2 K (midpoint). The data are compared to pure and nitrogen-doped diamond that represent the non-metallic state. No difference is found for the acoustic phonons in the three samples, while the optical phonons show a shift of the dispersion (softening) in qualitative agreement with earlier results from Raman spectroscopy. The presence of boron and nitrogen incorporated into the diamond lattice leads to structural disorder. Evidence for this is found both in the observation of otherwise symmetry-forbidded Bragg intensity at (0 0 2) and intensity from acoustic phonon modes in the vicinity of (0 0 2).

We have performed soft X-ray angle-resolved photoemission spectroscopy (SXARPES) of microwave plasma-assisted chemical vapor deposition diamond films with different B concentrations in order to study the origin of the metallic behavior of superconducting diamond. SXARPES results clearly show valence band dispersions with a bandwidth of ~23 eV and with a top of the valence band at gamma point in the Brillouin zone, which are consistent with the calculated valence band dispersions of pure diamond. Boron concentration-dependent band dispersions near the Fermi level (EF) exhibit a systematic shift of EF, indicating depopulation of electrons due to hole doping. These SXARPES results indicate that diamond bands retain for heavy boron doping and holes in the diamond band are responsible for the metallic states leading to superconductivity at low temperature. A high-resolution photoemission spectroscopy spectrum near EF of a heavily boron-doped diamond superconductor is also presented.

We have investigated an origin of the superconductivity discovered in boron (B)-doped diamonds by means of 11B-NMR on heteroepitaxially grown (1 1 1) and (1 0 0) films and polycrystalline film. The characteristic difference of B-NMR spectral shape for the (1 1 1) and (1 0 0) thin films is demonstrated as arising from the difference in the concentration (nB(1)) of boron substituted for carbon. It is revealed from a scaling between a superconducting transition temperature Tc and nB(1) that the holes doped into diamond via the substitution of boron for carbon are responsible for the onset of superconductivity. The result suggests that the superconductivity in boron-doped diamond is mediated by the electron–phonon interaction brought about a high Debye temperature ~1860 K characteristic for the diamond structure.

Bohring-Opitz syndrome (BOS) is a rare disease with a characteristic facial appearance and limb position. This report describes a case of BOS complicated by persistent pulmonary hypertension of the newborn (PPHN) and formation of abnormal alveoli that was confirmed by autopsy. A female neonate was born by cesarean section at 37 weeks and 2 days of gestation and found to have a nevus flammeus, exophthalmos, abnormal palate, retraction of the mandible, and a posture characteristic of BOS. The patients had severe PPHN requiring inhalation of nitric oxide. Genetic testing revealed a de novo frameshift variant in ASXL1. Autopsy revealed that the lung was at the saccular stage, equivalent to 28-34 weeks of gestation. This is the first report to present pathological evidence of immaturity of the lung that may be associated with PPHN in a patient with BOS caused by a variant in ASXL1., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2024. Published by Elsevier Masson SAS.)

Digital clubbing is characterized by bulbous enlargement of the terminal segments of the fingers. Hypotheses including hypoxia have been proposed for the pathogenesis of digital clubbing, but the exact pathogenesis of digital clubbing is still uncertain. Lysinuric protein intolerance (LPI) is caused by pathogenic variants in SLC7A7 and is often associated with interstitial lung disease. Previously two patients of LPI with digital clubbing but without hypoxia have been reported. It is unclear whether digital clubbing in LPI is secondary to hypoxia or directly related to SLC7A7 deficiency. Here we report a 6-year-old Japanese boy presented with digital clubbing without hypoxia. He had episodic vomiting, each episode consisting of a single vomiting event occurring once a month, and his growth had been delayed. He had interstitial lung disease and hepatomegaly. He had compound heterozygous pathogenic variants in the SLC7A7, leading to the diagnosis of LPI. Together with the two previously reported patients mentioned above, we conclude that digital clubbing can occur in the absence of hypoxia. Digital clubbing in the absence of hypoxia has been observed in two genetic disorders related to prostaglandin (PG) E2, HPGD and SLCO2A1. PGE2 synthesis is primarily regulated by the cyclooxygenase 2, which plays a critical role in the control of inflammation. A high urine PGE level in the patient was compatible with the notion that PGE2 production may be increased in LPI. The occurrence of digital clubbing in the absence of hypoxia in LPI patients with SLC7A7 may be attributed to the mechanism of increased PGE2 production., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Red river hogs (RRHs) ( Potamochoerus porcus ), a wild species of Suidae living in Africa with a major distribution in the Guinean and Congolian forests, are natural reservoirs of African swine fever virus (ASFV) and typically are asymptomatic. Since blood and tissue macrophages of suid animals are target cell lineages of ASFV, RRH-derived macrophages are expected to play an important role in suppressing disease development in infected individuals. In the present study, we successfully isolated RRH-derived blood macrophages using co-culture techniques of RRH blood cells with porcine kidney-derived feeder cells and immortalized them by transferring SV40 large T antigen and porcine telomerase reverse transcriptase genes. The newly established macrophage cell line of the RRH-derived blood cell origin (RZJ/IBM) exhibited an Iba1-, CD172a-, and CD203a-positive typical macrophage-like phenotype and up-regulated the phosphorylation of nuclear factor-κB p65 subunit and p38 mitogen-activated protein kinase in response to the bacterial cell wall components, lipopolysaccharide (LPS) and muramyl dipeptide. In addition, RZJ/IBM cells produced the precursor form of interleukin (IL)-1β and IL-18 upon a stimulation with LPS, leading to the conversion of IL-18, but not IL-1β, into the mature form. Time-lapse live cell imaging with pHrodo dye-conjugated Escherichia coli BioParticles demonstrated the phagocytotic activity of RZJ/IBM cells. It is important to note that RZJ/IBM cells are clearly susceptible to ASFV infection and support viral replication in vitro . Therefore, the RZJ/IBM cell line provides a unique model for investigating the pathogenesis of ASFV., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Takenouchi, Masujin, Ikeda, Haraguchi, Suzuki, Uenishi, Onda and Kokuho.)

Cockayne syndrome (CS) is a rare autosomal recessive disorder caused by mutations in ERCC8 or ERCC6. Most pathogenic variants in ERCC8 are single nucleotide substitutions. Structural variants (SVs) have been reported in patients with ERCC8-related CS. However, comprehensive molecular detection, including SVs of ERCC8, in CS patients remains problematic. Herein, we present three Japanese patients with ERCC8-related CS in whom causative SVs were identified using whole-exome-based copy number variation (CNV) detection tools. One patient showed compound heterozygosity for a 259-kb deletion and a deletion of exon 4 which has previously been reported as an Asia-specific variant. The other two patients were homozygous for the same exon 4 deletion. The exon 4 deletion was detected only by the ExomeDepth software. Intrigued by the discrepancy in the detection capability of various tools for the SVs, we evaluated the analytic performance of four whole-exome-based CNV detection tools using an exome data set from 337 healthy individuals. A total of 1,278,141 exons were predicted as being affected by the 4 CNV tools. Interestingly 95.1% of these affected exons were detected by one tool alone. Thus, we expect that the use of multiple tools may improve the detection rate of SVs from aligned exome data., (© 2024. The Author(s).)

We previously showed that several polymorphisms in genes encoding pattern recognition receptors that cause amino acid substitutions alter pathogen recognition ability and disease susceptibility in pigs. In this study, we expanded our analysis to a wide range of immune-related genes and investigated polymorphism distribution and its influence on pneumonia in multiple commercial pig populations. Among the polymorphisms in 42 genes causing 634 amino acid substitutions extracted from the swine genome database, 80 in 24 genes were found to have a minor allele frequency of at least 10% in Japanese breeding stock pigs via targeted resequencing. Of these, 62 single nucleotide polymorphisms (SNPs) in 23 genes were successfully genotyped in 862 pigs belonging to four populations with data on pneumonia severity. Association analysis using a generalized linear mixed model revealed that 12 SNPs in nine genes were associated with pneumonia severity. In particular, SNPs in the cellular receptor for immunoglobulin G FCGR2B and the intracellular nucleic acid sensors IFI16 and LRRFIP1 were found to be associated with mycoplasmal pneumonia of swine or porcine pleuropneumonia in multiple populations and may therefore have wide applications in the improvement of disease resistance in pigs. Functional analyses at the cellular and animal levels are required to clarify the mechanisms underlying the effects of these SNPs on disease susceptibility.

CCP110 (centriolar coiled coil protein 110, also known as CP110) is one of the essential proteins localized in the centrosome that plays critical roles in the regulation of the cell cycle and also in the initiation of ciliogenesis. So far, no human congenital disorders have been identified to be associated with pathogenic variants of CCP110. Mice with biallelic loss-of-function variants of Ccp110 (Ccp110 -/- ) are known to manifest multiple organ defects, including a small body size, polydactyly, omphalocele, congenital heart defects, cleft palate, short ribs, and a small thoracic cage, a pattern of abnormalities closely resembling that in "ciliopathies" in humans. Herein, we report a 7-month-old male infant who presented with growth failure and skeletal abnormalities, including a narrow thorax and severe brachydactyly. Trio exome analysis of the genomic DNA of the patient and his parents showed that the patient was a compound heterozygote for truncating variants of CCP110, including a frameshift variant NM_001323572.2:c.856_857del, p.(Val286Leufs*5) inherited from the father, and a nonsense variant NM_001323572.2:c.1129C>T, p.(Arg377*) inherited from the mother. The strikingly similar pattern of malformations between Ccp110 -/- mice and the 7-month-old male infant reported herein carrying unequivocal truncating CCP110 variants strongly supports the contention that CCP110 is a novel disease-causative gene., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Pathogenic variants in WDR45 on chromosome Xp11 cause neurodegenerative disorder beta-propeller protein-associated neurodegeneration (BPAN). Currently, there is no effective therapy for BPAN. Here we report a 17-year-old female patient with BPAN and show that antisense oligonucleotide (ASO) was effective in vitro. The patient had developmental delay and later showed extrapyramidal signs since the age of 15 years. MRI findings showed iron deposition in the globus pallidus and substantia nigra on T2 MRI. Whole genome sequencing and RNA sequencing revealed generation of pseudoexon due to inclusion of intronic sequences triggered by an intronic variant that is remote from the exon-intron junction: WDR45 (OMIM #300526) chrX(GRCh37):g.48935143G > C, (NM_007075.4:c.235 + 159C > G). We recapitulated the exonization of intron sequences by a mini-gene assay and further sought antisense oligonucleotide that induce pseudoexon skipping using our recently developed, a dual fluorescent splicing reporter system that encodes two fluorescent proteins, mCherry, a transfection marker designed to facilitate evaluation of exon skipping and split eGFP, a splicing reaction marker. The results showed that the 24-base ASO was the strongest inducer of pseudoexon skipping. Our data presented here have provided supportive evidence for in vivo preclinical studies., (© 2024. The Author(s).)

We herein report a typical case of alopecia neoplastica secondary to breast cancer. Alopecia neoplastica is a rare form of alopecia resulting from metastasis of a primary tumour to the scalp and is often misdiagnosed as alopecia areata., Competing Interests: None to declare., (© 2023 The Authors. Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

MYCN, a member of the MYC proto-oncogene family, regulates cell growth and proliferation. Somatic mutations of MYCN are identified in various tumors, and germline loss-of-function variants are responsible for Feingold syndrome, characterized by microcephaly. In contrast, one megalencephalic patient with a gain-of-function variant in MYCN, p.Thr58Met, has been reported, and additional patients and pathophysiological analysis are required to establish the disease entity. Herein, we report two unrelated megalencephalic patients with polydactyly harboring MYCN variants of p.Pro60Leu and Thr58Met, along with the analysis of gain-of-function and loss-of-function Mycn mouse models. Functional analyses for MYCN-Pro60Leu and MYCN-Thr58Met revealed decreased phosphorylation at Thr58, which reduced protein degradation mediated by FBXW7 ubiquitin ligase. The gain-of-function mouse model recapitulated the human phenotypes of megalencephaly and polydactyly, while brain analyses revealed excess proliferation of intermediate neural precursors during neurogenesis, which we determined to be the pathomechanism underlying megalencephaly. Interestingly, the kidney and female reproductive tract exhibited overt morphological anomalies, possibly as a result of excess proliferation during organogenesis. In conclusion, we confirm an MYCN gain-of-function-induced megalencephaly-polydactyly syndrome, which shows a mirror phenotype of Feingold syndrome, and reveal that MYCN plays a crucial proliferative role, not only in the context of tumorigenesis, but also organogenesis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Anti-PD-1-based immunotherapy is considered a preferred first-line treatment for advanced BRAF V600-mutant melanoma. However, a recent international multi-center study suggested that the efficacy of immunotherapy is poorer in Asian patients in the non-acral cutaneous subtype. We hypothesized that the optimal first-line treatment for Asian patients may be different., Methods: We retrospectively collected data of Asian patients with advanced BRAF V600-mutant melanoma treated with first-line BRAF/MEK inhibitors (BRAF/MEKi), anti-PD-1 monotherapy (Anti-PD-1), and nivolumab plus ipilimumab (PD-1/CTLA-4) between 2016 and 2021 from 28 institutions in Japan., Results: We identified 336 patients treated with BRAF/MEKi (n = 236), Anti-PD-1 (n = 64) and PD-1/CTLA-4 (n = 36). The median follow-up duration was 19.9 months for all patients and 28.6 months for the 184 pa tients who were alive at their last follow-up. For patients treated with BRAF/MEKi, anti-PD-1, PD-1/CTLA-4, the median ages at baseline were 62, 62, and 53 years (p = 0.03); objective response rates were 69%, 27%, and 28% (p < 0.001); median progression-free survival (PFS) was 14.7, 5.4, and 5.8 months (p = 0.003), and median overall survival (OS) was 34.6, 37.0 months, and not reached, respectively (p = 0.535). In multivariable analysis, hazard ratios (HRs) for PFS of Anti-PD-1 and PD-1/CTLA-4 compared with BRAF/MEKi were 2.30 (p < 0.001) and 1.38 (p = 0.147), and for OS, HRs were 1.37 (p = 0.111) and 0.56 (p = 0.075), respectively. In propensity-score matching, BRAF/MEKi showed a tendency for longer PFS and equivalent OS with PD-1/CTLA-4 (HRs for PD-1/CTLA-4 were 1.78 [p = 0.149]) and 1.03 [p = 0.953], respectively). For patients who received second-line treatment, BRAF/MEKi followed by PD-1/CTLA-4 showed poor survival outcomes., Conclusions: The superiority of PD-1/CTLA-4 over BRAF/MEKi appears modest in Asian patients. First-line BRAF/MEKi remains feasible, but it is difficult to salvage at progression. Ethnicity should be considered when selecting systemic therapies until personalized biomarkers are available in daily practice. Further studies are needed to establish the optimal treatment sequence for Asian patients., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Anti-programmed cell death protein 1 (PD-1) monotherapy is one of the standard systemic therapies for advanced melanoma; however, the efficacy of salvage systemic therapies after PD-1 monotherapy failure (PD-1 MF), particularly in acral melanoma (AM), the main clinical melanoma type in Japanese patients, is unclear. This study aimed to investigate the efficacy of salvage systemic therapies in Japanese patients with AM after PD-1 MF., Patients and Methods: The study included 108 patients with advanced AM (palm and sole, 72; nail apparatus, 36) who underwent salvage systemic therapy at 24 Japanese institutions. We mainly assessed the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: Thirty-six (33%) patients received ipilimumab, 23 (21%) received nivolumab and ipilimumab (nivo/ipi), 10 (9%) received cytotoxic chemotherapy, 4 (4%) received BRAF and MEK inhibitors (BRAFi/MEKi), and the remaining 35 (32%) continued with PD-1 monotherapy after disease progression. The ORRs in the ipilimumab, nivo/ipi, cytotoxic chemotherapy, and BRAFi/MEKi groups were 8, 17, 0, and 100%, respectively. The nivo/ipi group showed the longest OS (median, 18.9 months); however, differences in ORR, PFS, and OS between the groups were insignificant. The OS in the nivo/ipi group was higher in the palm and sole groups than in the nail apparatus group (median: not reached vs. 8.7 months, p  < 0.001). Cox multivariate analysis demonstrated that nail apparatus melanoma independently predicted unfavorable PFS and OS ( p  = 0.006 and 0.001). The total OS (from PD-1 monotherapy initiation to death/last follow-up) was insignificant between the groups., Conclusion: Nivo/ipi was not more effective than cytotoxic chemotherapy and ipilimumab after PD-1 MF in patients with advanced AM. The prognosis after PD-1 MF would be poorer for nail apparatus melanoma than for palm and sole melanoma., Competing Interests: TMo and SS have received honoraria from Ono Pharma. KeN has served as a consultant and/or received honoraria from Novartis, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Novartis, and Ono Pharma. NY has received research funding from BMS, MSD, Novartis, Ono Pharma, and Takara Bio, and has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma. YKi, SY, HK, and NF have received honoraria from Novartis and Ono Pharma. OY has received research funding and/or honoraria from Ono Pharma. TIn has received honoraria from BMS, MSD, and Ono Pharma. SF has received research funding from Ono Pharma and honoraria from BMS, MSD, and Novartis. TT, TMae, and SM have received honoraria from BMS, MSD, Novartis, and Ono Pharma. AO has served as a consultant and/or received honoraria from BMS, MSD, Novartis, and Ono Pharma, and has received research funding from Eisai. TIs has served as a consultant and/or received honoraria from Ono Pharma, Pfizer, BMS, and Novartis. YNakamura has served as a consultant and/or received honoraria from BMS, MSD, Maruho, Ono Pharma, Sanofi, Sun Pharma, Tanabe Mitsubishi Pharma, and Torii. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mori, Namikawa, Yamazaki, Kiniwa, Yamasaki, Yoshikawa, Inozume, Kato, Nakai, Fukushima, Takenouchi, Maekawa, Matsushita, Otsuka, Nomura, Baba, Isei, Saito, Fujimoto, Tanaka, Kaneko, Kuwatsuka, Matsuya, Nagase, Onishi, Onuma and Nakamura.)

DExH-box helicases are involved in unwinding of RNA and DNA. Among the 16 DExH-box genes, monoallelic variants of DHX16, DHX30, DHX34, and DHX37 are known to be associated with neurodevelopmental disorders. In particular, DHX30 is well established as a causative gene for neurodevelopmental disorders. Germline variants of DHX9, the closest homolog of DHX30, have not been reported until now as being associated with congenital disorders in humans, except that one de novo heterozygous variant, p.(Arg1052Gln) of the gene was identified during comprehensive screening in a patient with autism; unfortunately, the phenotypic details of this individual are unknown. Herein, we report a patients with a heterozygous de novo missense variant, p.(Gly414Arg) of DHX9 who presented with a short stature, intellectual disability, and ventricular non-compaction cardiomyopathy. The variant was located in the glycine codon of the ATP-binding site, G-C-G-K-T. To assess the pathogenicity of these variants, we generated transgenic Drosophila lines expressing human wild-type and mutant DHX9 proteins: 1) the mutant proteins showed aberrant localization both in the nucleus and the cytoplasm; 2) ectopic expression of wild-type protein in the visual system led to the rough eye phenotype, whereas expression of the mutant proteins had minimal effect; 3) overexpression of the wild-type protein in the retina led to a reduction in axonal numbers, whereas expression of the mutant proteins had a less pronounced effect. Furthermore, in a gene-editing experiment of Dhx9 G416 to R416, corresponding to p.(Gly414Arg) in humans, heterozygous mice showed a reduced body size, reduced emotionality, and cardiac conduction abnormality. In conclusion, we established that heterozygosity for a loss-of-function variant of DHX9 can lead to a new neurodevelopmental disorder., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Masson SAS.)

Competing Interests: None disclosed.

Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM&#95;001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted., (© 2023. The Author(s).)

Background: Individuals with variants of cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial functional-related gene, exhibit symptoms of spinocerebellar ataxia with axonal neuropathy before the age of 20. However, COA7 variants with parkinsonism or adult-onset type cases have not been described., Case Presentation: We report the case of a patient who developed cerebellar symptoms and slowly progressive sensory and motor neuropathy in the extremities, similar to Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58. Exome analysis revealed COA7 missense mutation in homozygotes (NM&#95;023077.2:c.17A > G, NP&#95;075565.2: p.Asp6Gly). Dopamine transporter single-photon emission computed tomography using a 123 I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum. However, 123 I-metaiodobenzylguanidine myocardial scintigraphy showed normal sympathetic nerve function. Levodopa administration improved parkinsonism in this patient., Conclusions: COA7 gene variants may have caused parkinsonism in this case because mitochondrial function-related genes, such as parkin and PINK1, are known causative genes in some familial Parkinson's diseases., (© 2023. The Author(s).)