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1.
ACS Appl Mater Interfaces ; 16(19): 24987-24998, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38712685

RESUMO

For traditional ferroelectric field-effect transistors (FeFETs), enhancing the polarization domain of bulk ferroelectric materials is essential to improve device performance. However, there has been limited investigation into the enhancement of polarization field in two-dimensional (2D) ferroelectric material such as CuInP2S6 (CIPS). In this study, similar to bulk ferroelectric materials, CIPS exhibited enhanced polarization field upon application of external cyclic voltage. Moreover, unlike traditional ferroelectric materials, the polarization enhancement of CIPS is not due to redistribution of the defect but rather originates from a mechanism: the long-distance migration of Cu ions. We termed this mechanism the "wake-up-like effect". After incorporating the wake-up-like effect into the graphene/CIPS/WSe2 FeFET device, we successfully increased the hysteresis window and enhanced the current on/off ratio by 4 orders of magnitude. Moreover, the FeFET yielded remarkable achievements, such as multilevel nonvolatile memory with 21 distinct conductance levels, a high on/off ratio exceeding 106, a long retention time exceeding 103 s, and neuromorphic computing with 93% accuracy at recognizing handwritten digits. Introducing the wake-up-like effect to 2D CIPS may pave the way for innovative approaches to achieve advanced multilevel nonvolatile memory and neuromorphic computing capabilities for next-generation micro-nanoelectronic devices.

2.
Nano Lett ; 24(20): 6192-6200, 2024 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-38666542

RESUMO

Creating artificial synapses that can interact with biological neural systems is critical for developing advanced intelligent systems. However, there are still many difficulties, including device morphology and fluid selection. Based on Micro-Electro-Mechanical System technologies, we utilized two immiscible electrolytes to form a liquid/liquid interface at the tip of a funnel nanochannel, effectively enabling a wafer-level fabrication, interactions between multiple information carriers, and electron-to-chemical signal transitions. The distinctive ionic transport properties successfully achieved a hysteresis in ionic transport, resulting in adjustable multistage conductance gradient and synaptic functions. Notably, the device is similar to biological systems in terms of structure and signal carriers, especially for the low operating voltage (200 mV), which matches the biological neural potential (∼110 mV). This work lays the foundation for realizing the function of iontronics neuromorphic computing at ultralow operating voltages and in-memory computing, which can break the limits of information barriers for brain-machine interfaces.


Assuntos
Nanotecnologia , Sinapses , Sinapses/fisiologia , Nanotecnologia/instrumentação , Eletrólitos/química , Nanoestruturas/química , Neurônios/fisiologia , Condutividade Elétrica
3.
Phys Chem Chem Phys ; 25(42): 28716-28726, 2023 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-37850228

RESUMO

Two-dimensional (2D) materials are excellent candidates for advanced flexible electronics and gas sensors. Herein, we systematically investigate the layer-dependent electronic structures, mechanical properties and gas sensing characteristics of the newly synthesized γ-SnSe based on first-principles calculations. Bulk γ-SnSe is a typical van der Waals layered material with an indirect narrow band gap, while monolayer and multilayer γ-SnSe can be obtained through mechanical exfoliation due to its low cleavage energy. The band gap of γ-SnSe gradually increases with decreasing layers, reaching a value of 2.25 eV for the monolayer due to weakened interlayer coupling. Mechanical analysis reveals strong anisotropy in multilayer γ-SnSe, whereas the monolayer exhibits a negative Poisson's ratio (-0.023/-0.025). Additionally, based on the analysis of electronic structures, adsorption energies and charge transfer of the host materials after adsorption of various gases, it is found that the γ-SnSe monolayer demonstrates enhanced sensitivity and selectivity towards NO, NO2, and SO2 compared to CO, CO2, H2S and NH3. These findings highlight the potential of γ-SnSe as an excellent gas-sensitive material for the detection of nitrogen oxides and sulfur dioxide.

4.
Front Neurol ; 14: 1241678, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37681004

RESUMO

Background and objective: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited cerebral microvascular disease characterized by the development of vascular dementia and lacunar infarctions. This study aimed to identify the genetic and clinical features of CADASIL in Japan. Methods: We conducted genetic analysis on a case series of patients clinically diagnosed with CADASIL. Clinical and imaging analyses were performed on 32 patients with pathogenic mutations in the NOTCH3 gene. To assess the presence of cerebral microbleeds (CMBs), we utilized several established rating scales including the Fazekas scale, Scheltens rating scale, and Microbleed Anatomical Rating Scale, based on brain MRI images. Results: Among the 32 CADASIL patients, 24 cases were found carrying the R75P mutation in NOTCH3, whereas the remaining eight cases had other NOTCH3 mutations (R75Q, R110C, C134F, C144F, R169C, and R607C). The haplotype analysis of the R75P mutation uncovered the presence of a founder effect. A brain MRI analysis revealed that cases with the R75P mutation had a significantly higher total number of CMBs, particularly in the thalamus when compared to patients with other NOTCH3 mutations. Among 15 out of 24 cases with the R75P mutation, we observed a notable clustering of CMBs in the thalamus, termed microbleed clustering in thalamus sign (MCT sign). Conclusion: We propose that the MCT sign observed in NOTCH3 R75P-related CADASIL patients may serve as a potentially characteristic imaging feature. This finding offers further insights into the interactions between genotypes and phenotypes between NOTCH3 and CADASIL.

5.
J Peripher Nerv Syst ; 28(4): 597-607, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37555797

RESUMO

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.


Assuntos
Eritromelalgia , Doenças do Sistema Nervoso Periférico , Humanos , Células HEK293 , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Eritromelalgia/genética , Eritromelalgia/patologia , Dor , Mutação/genética
6.
Micromachines (Basel) ; 14(7)2023 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-37512718

RESUMO

Two-dimensional (2D) materials with novel structures and electronic properties are promising candidates for the next generation of micro- and nano-electronic devices. Herein, inspired by the recent experimental synthesis of penta-NiN2 (ACS Nano, 2021, 15, 13539-13546), we propose for the first time a novel ternary penta-NiPN monolayer with high stability by partial element substitution. Our predicted penta-NiPN monolayer is a quasi-direct bandgap (1.237 eV) semiconductor with ultrahigh carrier mobilities (103-105 cm2V-1s-1). Furthermore, we systematically studied the adsorption properties of common gas molecules (CO, CO2, CH4, H2, H2O, H2S, N2, NO, NO2, NH3, and SO2) on the penta-NiPN monolayer and its effects on electronic properties. According to the energetic, geometric, and electronic analyses, the penta-NiPN monolayer is predicted to be a promising candidate for NO and NO2 molecules. The excellent electronic properties of and the unique selectivity of the penta-NiPN monolayer for NO and NO2 adsorption suggest that it has high potential in advanced electronics and gas sensing applications.

7.
Nat Commun ; 14(1): 2808, 2023 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-37198176

RESUMO

Lead halide perovskites have recently emerged as promising X/γ-ray scintillators. However, the small Stokes shift of exciton luminescence in perovskite scintillators creates problems for the light extraction efficiency and severely impedes their applications in hard X/γ-ray detection. Dopants have been used to shift the emission wavelength, but the radioluminescence lifetime has also been unwantedly extended. Herein, we demonstrate the intrinsic strain in 2D perovskite crystals as a general phenomenon, which could be utilized as self-wavelength shifting to reduce the self-absorption effect without sacrificing the radiation response speed. Furthermore, we successfully demonstrated the first imaging reconstruction by perovskites for application of positron emission tomography. The coincidence time resolution for the optimized perovskite single crystals (4 × 4 × 0.8 mm3) reached 119 ± 3 ps. This work provides a new paradigm for suppressing the self-absorption effect in scintillators and may facilitate the application of perovskite scintillators in practical hard X/γ-ray detections.

8.
J Neurol Neurosurg Psychiatry ; 94(8): 622-630, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-36948577

RESUMO

BACKGROUND: NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs. METHOD: Among 2692 Japanese patients clinically diagnosed with IPN/Charcot-Marie-Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR. RESULTS: NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8-59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7-61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear. CONCLUSIONS: These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.


Assuntos
Doença de Charcot-Marie-Tooth , Disautonomias Primárias , Humanos , Doença de Charcot-Marie-Tooth/genética , Corpos de Inclusão Intranuclear/genética , Japão , Fenótipo
9.
Front Neurol ; 14: 1078195, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36779057

RESUMO

Introduction: Genetic factors are recognized as the major reason for patients with periodic paralysis. The goal of this study was to determine the genetic causes of periodic paralysis in Japan. Methods: We obtained a Japanese nationwide case series of 119 index patients (108 men and 11 women) clinically suspected of periodic paralysis, and a gene panel analysis, targeting CACNA1S, SCN4A, and KCNJ2 genes, was conducted. Results: From 34 cases, 25 pathogenic/likely pathogenic/unknown significance variants were detected in CACNA1S (nine cases), SCN4A (19 cases), or KCNJ2 (six cases), generating a molecular diagnostic rate of 28.6%. In total, seven variants have yet been found linked to periodic paralysis previously. The diagnostic yield of patients with hypokalemic and hyperkalemic periodic paralyzes was 26.2 (17/65) and 32.7% (17/52), respectively. A considerably higher yield was procured from patients with than without positive family history (18/25 vs. 16/94), onset age ≤20 years (24/57 vs. 9/59), or recurrent paralytic attacks (31/94 vs. 3/25). Discussion: The low molecular diagnostic rate and specific genetic proportion of the present study highlight the etiological complexity of patients with periodic paralysis in Japan.

10.
J Neurophysiol ; 129(3): 609-618, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-36722722

RESUMO

Despite extensive study, the mechanisms underlying pain after axonal injury remain incompletely understood. Pain after corneal refractive surgery provides a model, in humans, of the effect of injury to trigeminal afferent nerves. Axons of trigeminal ganglion neurons that innervate the cornea are transected by laser-assisted in situ keratomileusis (LASIK). Although most patients do not experience postoperative pain, a small subgroup develop persistent ocular pain. We previously carried out genomic analysis and determined that some patients with persistent pain after axotomy of corneal axons during refractive surgery carry mutations in genes that encode the electrogenisome of trigeminal ganglion neurons, the ensemble of ion channels and receptors that regulate excitability within these cells, including SCN9A, which encodes sodium channel Nav1.7, a threshold channel abundantly expressed in sensory neurons that has been implicated in a number of pain-related disorders. Here, we describe the biophysical and electrophysiological profiling of the P610T Nav1.7 mutation found in two male siblings with persistent ocular pain after refractive surgery. Our results indicate that this mutation impairs the slow inactivation of Nav1.7. As expected from this proexcitatory change in channel function, we also demonstrate that this mutation produces increased spontaneous activity in trigeminal ganglion neurons. These findings suggest that this gain-of-function mutation in Nav1.7 may contribute to pain after injury to the axons of trigeminal ganglion neurons.NEW & NOTEWORTHY Mechanisms underlying pain after axonal injury remain elusive. A small subgroup of patients experience pain after corneal refractive surgery, providing a human pain model after well-defined injury to axons. Here we analyze a mutation (P610T) in Nav1.7, a threshold sodium channel expressed in nociceptors, found in two siblings with persistent ocular pain after refractive surgery. We show that it impairs channel slow inactivation, thereby triggering inappropriate repetitive activity in trigeminal ganglion axons that signal eye pain.


Assuntos
Dor Ocular , Irmãos , Humanos , Masculino , Axônios , Córnea , Gânglios Espinais , Mutação , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Neurônios/fisiologia , Dor
11.
Plant Biotechnol J ; 21(1): 14-16, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36221906

RESUMO

PoDPBT, an O-benzoyltransferase belonging to the BAHD family, can catalyze the benzoylation of 8-debenzoylpaeoniflorin to paeoniflorin. PoDPBT is the first enzyme demonstrated to be involved in the modification stage of paeoniflorin biosynthesis. DFGGG, a new DFGWG-like motif, was revealed in the BAHD family. The transcriptome database provides a resource for further investigation of other enzyme genes involved in paeoniflorin biosynthesis.


Assuntos
Paeonia , Paeonia/genética , Aciltransferases/genética , Monoterpenos , Catálise
12.
Proc Natl Acad Sci U S A ; 119(38): e2119630119, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36095216

RESUMO

Trigeminal neuralgia (TN) is a unique pain disorder characterized by intense paroxysmal facial pain within areas innervated by the trigeminal nerve. Although most cases of TN are sporadic, familial clusters of TN suggest that genetic factors may contribute to this disorder. Whole-exome sequencing in patients with TN reporting positive family history demonstrated a spectrum of variants of ion channels including TRP channels. Here, we used patch-clamp analysis and Ca2+ and Na+ imaging to assess a rare variant in the TRPM7 channel, p.Ala931Thr, within transmembrane domain 3, identified in a man suffering from unilateral TN. We showed that A931T produced an abnormal inward current carried by Na+ and insensitive to the pore blocker Gd3+. Hypothesizing that replacement of the hydrophobic alanine at position 931 with the more polar threonine destabilizes a hydrophobic ring, near the voltage sensor domain, we performed alanine substitutions of F971 and W972 and obtained results suggesting a role of A931-W972 hydrophobic interaction in S3-S4 hydrophobic cleft stability. Finally, we transfected trigeminal ganglion neurons with A931T channels and observed that expression of this TRPM7 variant lowers current threshold and resting membrane potential, and increases evoked firing activity in TG neurons. Our results support the notion that the TRPM7-A931T mutation located in the S3 segment at the interface with the transmembrane region S4, generates an omega current that carries Na+ influx in physiological conditions. A931T produces hyperexcitability and a sustained Na+ influx in trigeminal ganglion neurons that may underlie pain in this kindred with trigeminal neuralgia.


Assuntos
Proteínas Serina-Treonina Quinases , Canais de Cátion TRPM , Gânglio Trigeminal , Neuralgia do Trigêmeo , Alanina/genética , Humanos , Masculino , Mutação , Neurônios/fisiologia , Proteínas Serina-Treonina Quinases/genética , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Gânglio Trigeminal/fisiopatologia , Neuralgia do Trigêmeo/genética
13.
Front Neurol ; 13: 986504, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36061987

RESUMO

Non-coding repeat expansions within RFC1 and NOTCH2NLC genes have lately been linked to multisystem neurodegenerative diseases, which also shed light on yet undiagnosed patients with inherited peripheral neuropathies. The aim of this study was to identify the genetic basis of patients with hereditary sensory and autonomic neuropathy (HSAN). We collected 79 unrelated DNA samples clinically suspected with HSAN from multiple regions of Japan. Mutation screening was first performed using gene panel sequencing and whole-exome sequencing. Pathogenic/likely pathogenic variants were identified from genes of WNK1/HSN2 (6 cases), SCN9A (3 cases), NTRK1 (3 cases), and DNMT1 (2 cases). Subsequently, long-range flanking PCR and repeat-primed PCR were applied to analyze repeat expansions in RFC1 and NOTCH2NLC. Bi-allelic RFC1 repeat expansions were detected from 20 adult-onset HSAN patients, consisting of [(AAGGG)exp/(AAGGG)exp] (8 cases), [(ACAGG)exp/(ACAGG)exp] (8 cases), and [(AAGGG)exp/(ACAGG)exp] (4 cases). GGC repeat expansion in NOTCH2NLC was found in 1 case. Single-nucleotide variant-based haplotype analysis of patients harboring disease-associated repeat expansions in RFC1 revealed distinguishable haplotypes among subgroups with different repeat genotypes. These findings substantially redefine the genetic spectrum of HSAN, where multi-type RFC1 repeat expansions account for 25.3% of all patients, highlighting the necessity of genetic screening, particularly for adult-onset patients.

14.
Front Plant Sci ; 13: 980854, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119574

RESUMO

Paeoniflorin, a monoterpene glucoside, is increasingly used in the clinical treatment of many diseases because it has a variety of pharmacological activities. Besides, paeoniflorin has been considered the characteristic chemical constituent of Paeoniaceae plants since it was first reported in 1963. Therefore, how to better develop and utilize paeoniflorin in Paeoniaceae has always been a research hotspot. We reviewed the current knowledge on paeoniflorin in Paeoniaceae, with particular emphasis on its distribution and influencing factors. Moreover, the limited understanding of the biosynthesis pathway has restricted the production of paeoniflorin by synthetic biology. This review provides insights into the post-modification pathway of paeoniflorin biosynthesis and proposes directions for further analysis in the future.

15.
J Phys Condens Matter ; 34(40)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35856860

RESUMO

It is known that the Kohn-Sham eigenvalues do not characterize experimental excitation energies directly, and the band gap of a semiconductor is typically underestimated by local density approximation (LDA) of density functional theory (DFT). An embarrassing situation is that one usually uses LDA+Ufor strongly correlated materials with rectified band gaps, but for non-strongly-correlated semiconductors one has to resort to expensive methods like hybrid functionals orGW. In spite of the state-of-the-art meta-generalized gradient approximation functionals like TB-mBJ and SCAN, methods with LDA-level complexity to rectify the semiconductor band gaps are in high demand. DFT-1/2 stands as a feasible approach and has been more widely used in recent years. In this work we give a detailed derivation of the Slater half occupation technique, and review the assumptions made by DFT-1/2 in semiconductor band structure calculations. In particular, the self-energy potential approach is verified through mathematical derivations. The aims, features and principles of shell DFT-1/2 for covalent semiconductors are also accounted for in great detail. Other developments of DFT-1/2 including conduction band correction, DFT+A-1/2, empirical formula for the self-energy potential cutoff radius, etc, are further reviewed. The relations of DFT-1/2 to hybrid functional, sX-LDA,GW, self-interaction correction, scissor's operator as well as DFT+Uare explained. Applications, issues and limitations of DFT-1/2 are comprehensively included in this review.

16.
J Neurol ; 269(12): 6406-6415, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35907044

RESUMO

Non-dystrophic myotonias (NDM) are rare skeletal muscle channelopathies, mainly linked to two voltage-gated ion channel genes, CLCN1 and SCN4A. The aim of this study is to identify the clinical and genetic features of patients with NDM in Japan. We collected a Japanese nationwide case series of patients with clinical diagnosis of NDM (1999-2021). Among 71 out of 88 pedigrees, using Sanger and next-generation sequencing targeting both CLCN1 and SCN4A genes, variants classified as pathogenic/likely pathogenic/unknown significance were detected from CLCN1 (31 probands), SCN4A (36 probands), or both genes (4 probands), and 11 of them were novel. Pedigrees carrying mono-allelic CLCN1 variants were more commonly seen than that with bi-allelic/double variants (24:7). Compared to patients with CLCN1 variants, patients harboring SCN4A variants showed younger onset age (5.64 ± 4.70 years vs. 9.23 ± 5.21 years), fewer warm-up phenomenon, but more paramyotonia, hyperCKemia, transient muscle weakness, and cold-induced myotonia. Haplotype analysis verified founder effects of the hot spot variants in both CLCN1 (p.T539A) and SCN4A (p.T1313M). This study reveals variants in CLCN1 and SCN4A from 80.7% of our case series, extending genetic spectrum of NDM, and would further our understanding of clinical similarity/diversity between CLCN1- and SCN4A-related NDM, as well as the genetic racial differences.


Assuntos
Miotonia Congênita , Miotonia , Humanos , Lactente , Pré-Escolar , Criança , Miotonia/genética , Efeito Fundador , Canal de Sódio Disparado por Voltagem NAV1.4/genética , Japão , Canais de Cloreto/genética , Mutação/genética , Miotonia Congênita/genética
17.
Ann Clin Transl Neurol ; 9(5): 747-755, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35482004

RESUMO

BACKGROUND: Biallelic POLR3B mutations cause a rare hypomyelinating leukodystrophy. De novo POLR3B heterozygous mutations were recently associated with afferent ataxia, spasticity, variable intellectual disability, and epilepsy, and predominantly demyelinating sensorimotor peripheral neuropathy. METHODS: We performed whole-exome sequencing (WES) of DNA samples from 804 Charcot-Marie-Tooth (CMT) cases that could not be genetically diagnosed by DNA-targeted resequencing microarray using next-generation sequencers. Using WES data, we analyzed the POLR3B mutations and confirmed their clinical features. RESULTS: We identified de novo POLR3B heterozygous missense mutations in two patients. These patients presented with early-onset demyelinating sensorimotor neuropathy without ataxia, spasticity, or cognitive impairment. Patient 1 showed mild cerebellar atrophy and spinal cord atrophy on magnetic resonance imaging and eventually died of respiratory failure in her 50s. We classified these mutations as pathogenic based on segregation studies, comparison with control database, and in silico analysis. CONCLUSION: Our study is the third report on patients with demyelinating CMT harboring heterozygous POLR3B mutations and verifies the pathogenicity of POLR3B mutations in CMT. Although extremely rare in our large Japanese case series, POLR3B mutations should be added to the CMT-related gene panel for comprehensive genetic screening, particularly for patients with early-onset demyelinating CMT.


Assuntos
Doença de Charcot-Marie-Tooth , Ataxia , Atrofia , Doença de Charcot-Marie-Tooth/genética , Feminino , Humanos , Japão , Mutação , Fenótipo , RNA Polimerase III/genética
18.
J Neurol ; 269(8): 4129-4140, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35235001

RESUMO

Mitochondrial disorders are a group of clinically and genetically heterogeneous multisystem disorders and peripheral neuropathy is frequently described in the context of mutations in mitochondrial-related nuclear genes. This study aimed to identify the causative mutations in mitochondrial-related nuclear genes in suspected hereditary peripheral neuropathy patients. We enrolled a large Japanese cohort of clinically suspected hereditary peripheral neuropathy patients who were mutation negative in the prescreening of the known Charcot-Marie-Tooth disease-causing genes. We performed whole-exome sequencing on 247 patients with autosomal recessive or sporadic inheritance for further analysis of 167 mitochondrial-related nuclear genes. We detected novel bi-allelic likely pathogenic/pathogenic variants in four patients, from four mitochondrial-related nuclear genes: pyruvate dehydrogenase beta-polypeptide (PDHB), mitochondrial poly(A) polymerase (MTPAP), hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit (HADHB), and succinate-CoA ligase ADP-forming beta subunit (SUCLA2). All these patients showed sensory and motor axonal polyneuropathy, combined with central nervous system or multisystem involvements. The pathological analysis of skeletal muscles revealed mild neurogenic changes without significant mitochondrial abnormalities. Targeted screening of mitochondria-related nuclear genes should be considered for patients with complex hereditary axonal polyneuropathy, accompanied by central nervous system dysfunctions, or with unexplainable multisystem disorders.


Assuntos
Doença de Charcot-Marie-Tooth , Doenças Mitocondriais , Doença de Charcot-Marie-Tooth/genética , Coenzima A/genética , DNA Mitocondrial , Humanos , Doenças Mitocondriais/genética , Mutação/genética , Oxirredutases/genética
19.
Zhongguo Zhong Yao Za Zhi ; 47(1): 203-223, 2022 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-35178927

RESUMO

This study aims to explore the molecular mechanism of Ganoderma against gastric cancer based on network pharmacology, molecular docking, and cell experiment. The active components and targets of Ganoderma were retrieved from Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform(TCMSP), and gastric cancer-related targets from GeneCards and Online Mendelian Inheritance in Man(OMIM). The protein-protein interaction(PPI) network of the common targets was constructed with STRING, followed by Gene Ontology(GO) term enrichment and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis of the common genes based on Bioconductor and R language. The medicinal-disease-component-target network and medicinal-disease-component-target-pathway network were established by Cytoscape. Molecular docking was performed between ß-sitosterol(the key component in Ganoderma) and the top 15 targets in the PPI network. Cell experiment was performed to verify the findings. A total of 14 active components and 28 targets of Ganoderma were retrieved, and the medicinal and the disease shared 25 targets, including caspase-3(CASP3), caspase-8(CASP8), caspase-9(CASP9), and B-cell lymphoma-2(BCL2). The common targets involved 72 signaling pathways and apoptosis and p53 signaling pathway may play a crucial role in the effect of Ganoderma against gastric cancer. ß-sitosterol had strong binding activity to the top 15 targets in the PPI network. The in vitro cell experiment demonstrated that ß-sitosterol inhibited gastric cancer AGS cell proliferation by inducing cell apoptosis and cell cycle arrest in the S phase, which might be related to the regulation of the p53 pathway. This study shows the multi-component, multi-target, and multi-pathway characteristics of Ganoderma against gastric cancer, which lays a scientific basis for further research on the molecular mechanism.


Assuntos
Ganoderma , Medicina Tradicional Chinesa , Neoplasias Gástricas , Humanos , Simulação de Acoplamento Molecular , Farmacologia em Rede , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética
20.
Front Oncol ; 11: 772636, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956891

RESUMO

PURPOSE: Hepatoid adenocarcinoma of the stomach (HAS) is a highly malignant and aggressive tumor. The purpose of this study was to describe the clinical, computed tomography (CT), and prognostic features of HAS to increase the awareness of this entity and determine its distinguishing features from non-HAS tumors. METHODS: The CT features and clinical data of 47 patients in our hospital with pathologically documented HAS were retrospectively analyzed, and the relevant differences between pure HAS (pHAS) and mixed HAS (mHAS) were determined. In addition, 141 patients with non-HAS tumors in the same T stage in the same period were selected as the control group. The data were compared between the two groups, and factors affecting the prognosis of HAS were analyzed. In addition, we included 9 patients with HAS and 27 patients with non-HAS tumors from another center for external validation. RESULTS: The patients in the HAS group were predominantly men (n = 33), and the tumor location was mostly the cardia or fundus (n = 27). Between the HAS and non-HAS groups, there were observed differences in terms of: sex, serum alpha-fetoprotein (AFP), carbohydrate antigen (CA)-125, and CA-724 levels; longest tumor diameter; degree of differentiation; vascular invasion; N stage, M stage, and tumor-node-metastasis (TNM) stage; thickest tumor diameter; plain CT attenuation; arterial-phase CT attenuation; CT attenuation between the venous and arterial phases; enhancement modes; and degrees of enhancement (all P < 0.05). In the data from another center for external validation, there were observed differences in terms of: age, degree of differentiation, vascular invasion, thickest tumor diameter, the ratio of arterial CT attenuation to CT attenuation of the abdominal aorta at the same level (RA), CT attenuation difference between the venous phase and arterial phase (HUv-a) (all P < 0.05). The results of the multivariate analysis revealed that the independent factors for differentiation were serum AFP level (P = 0.001), M stage (P = 0.038), and tumor enhancement on CT (P = 0.014). Among patients in the HAS group, 72.34% had pHAS and 27.66% had mHAS. The thickest tumor diameter and the longest short diameter of the metastatic lymph nodes of the mHAS group were on average 6.39 cm and 1.45 cm, respectively, which were larger than those in the pHAS group. The median progression-free survival time was 18.25 months in the HAS group, which was shorter than that in the non-HAS group (72.96 months; P = 0.001). The median overall survival time in the HAS group was 24.80 months, which was shorter than that in the non-HAS group (67.96 months; P = 0.001). The factors affecting the prognosis of HAS were M stage (P = 0.001), overall TNM stage (P = 0.048), presence of vascular cancer emboli (P = 0.040), and pHAS type (P = 0.046). Multifactorial analysis revealed that M stage (P = 0.027) and pHAS type (P = 0.009) were independent risk factors affecting the prognosis of HAS. CONCLUSION: Although HAS is a rare clinical entity, it should be considered in the differential diagnosis of gastric tumors. Patients with HAS often have advanced-stage disease at presentation and a worse prognosis than patients with non-HAS tumors. CT findings, combined with laboratory results, can support the diagnosis of HAS. However, the final diagnosis needs to be confirmed with a histopathologic examination. If the postoperative pathologic findings reveal the mHAS type, a rapid clinical intervention and a detailed follow-up with CT are essential.

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