Genotype-phenotype correlations of AR-CMT2S in a cohort of axonal Charcot-Marie-Tooth patients from Central South China.

BACKGROUND AND AIMS: This study aimed to report nine Charcot-Marie-Tooth disease (CMT) families with six novel IGHMBP2 mutations in our CMT2 cohort and to summarize the genetic and clinical features of all AR-CMT2S patients reported worldwide. METHODS: General information, clinical and neurophysiological data of 275 axonal CMT families were collected. Genetic screening was performed by inherited peripheral neuropathy related genes panel or whole exome sequencing. The published papers reporting AR-CMT2S from 2014 to 2023 were searched in Pubmed and Wanfang databases. RESULTS: In our CMT2 cohort, we detected 17 AR-CMT2S families carrying IGHMBP2 mutations and eight were published previously. Among these, c.743 T > A (p.Val248Glu), c.884A > G (p.Asp295Gly), c.1256C > A (p.Ser419*), c.2598_2599delGA (p.Lys868Sfs*16), c.1694_1696delATG (p.Asp565del) and c.2509A > T (p.Arg837*) were firstly reported. These patients prominently presented with early-onset typical axonal neuropathy and without respiratory dysfunction. So far, 56 AR-CMT2S patients and 57 different mutations coming from 43 families have been reported in the world. Twenty-nine of 32 missense mutations were clustered in helicase domain and ATPase region. The age at onset ranged from 0.11to 20 years (Mean ± SD: 3.43 ± 3.88 years) and the majority was infantile-onset (<2 years). The initial symptoms included weakness of limbs (19, 29.7%), delayed milestones (12, 18.8%), gait disturbance (11, 17.2%), feet deformity (8, 12.5%), feet drop (8, 12.5%), etc. INTERPRETATION: AR-CMT2S accounted for 6.2% in our CMT2 cohort. We firstly reported six novel IGHMBP2 mutations which expanded the genotypic spectrum of AR-CMT2S. Furthermore, 17 AR-CMT2S families could provide more resources for natural history study, drug research and development.

Molecular Characterization of α- and ß-Thalassemia Among Children Less Than 18 Years Old in Guizhou, China.

BACKGROUND: Thalassemia is an inherited hemolytic disease, the complications and sequelae of which have posed a huge impact on both patients and society. But limited studies have investigated the molecular characterization of α- and ß-thalassemia in children from Guizhou, China. METHODS: Between January 2019 and December 2022, a total of 3301 children, aged 6 months to 18 years, suspected of having thalassemia underwent molecular analysis. RESULTS: Out of the total sample, 824 (25%) children were found to carry thalassemia mutations. The carrier rates of α-thalassemia, ß-thalassemia, and α + ß-thalassemia were determined as 8.1%, 15.6%, and 1.3%, respectively. Approximately 96.5% of the α-thalassemia gene mutations were --SEA (51%), ααCS (20.9%), -α3.7 (19.6%), and -α4.2 (5.0%). The most prevalent mutations of ß-thalassemia were ßCD17(A>T) (41.5%), ßCD41-42(-TTCT) (37.7%), and ßIVS-II-654(C>T) (11.3%). Additionally, we identified rare cases, including one case with ααHb Nunobiki/αα, two cases with triplicated α-thalassemia (one case with ααα/ααα and ßCD41-42/ßN and the other with ααα-3.7/αα and ßE CD26/ßN), and also one case with α Q-Thailandα/-α4.2 and ßCD41-42/ßN. CONCLUSIONS: Our study findings provide important insights into the heterogeneity of thalassemia carrier rates and molecular profiles among children in the Guizhou region. The findings support the development of prevention strategies to reduce the incidence of severe thalassemia in the future.

Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with Charcot-Marie-Tooth Disease.

BACKGROUND: To identify genetic causes in 40 whole exome sequencing (WES)-negative Charcot-Marie-Tooth (CMT) families and provide a summary of the clinical and genetic features of the diagnosed patients. METHODS: The clinical information and sequencing data of 40 WES-negative families out of 131 CMT families were collected, and phenotype-driven reanalysis was conducted using the Exomiser software. RESULTS: The molecular diagnosis was regained in 4 families, increasing the overall diagnosis rate by 3.0%. One family with adolescent-onset pure CMT1 was diagnosed [POLR3B: c.2810G>A (p.R937Q)] due to the novel genotype-phenotype association. One infantile-onset, severe CMT1 family with deep sensory disturbance was diagnosed by screening the BAM file and harbored c.1174C>T (p.R392*) and 875_927delinsCTGCCCACTCTGCCCACTCTGCCCACTCTG (p.V292Afs53) of PRX. Two families were diagnosed due to characteristic phenotypes, including an infantile-onset ICMT family with renal dysfunction harboring c.213_233delinsGAGGAGCA (p.S72Rfs34) of INF2 and an adolescent-onset CMT2 family with optic atrophy harboring c.560C>T (p.P187L) and c.616A>G (p.K206E) of SLC25A46. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the variants of POLR3B and SLC25A46 were classified as likely pathogenic, and the variants of INF2 and PRX were pathogenic. All these variants were first reported worldwide except for p.R392* of PRX. CONCLUSIONS: We identified five novel pathogenic variants in POLR3B, PRX, INF2, and SLC25A46, which broaden their phenotypic and genotypic spectrums. Regular phenotype-driven reanalysis is a powerful strategy for increasing the diagnostic yield of WES-negative CMT patients, and long-term follow-up and screening BAM files for contiguous deletion and missense variants are both essential for reanalysis.

Hepatoid adenocarcinoma of the lung with PD-L1 expression and the response to anti-PD-1 therapy: a case report.

Hepatoid adenocarcinoma of the lung (HAL) is extremely rare; a standardized treatment strategy for HAL has not been established. The prognosis of patients with unresectable HAL is extremely poor. Here, we reported a 64-year-old male patient with unresectable alpha-fetoprotein-producing HAL who showed moderate harboring programmed death ligand 1 (PD-L1) expression and no targetable driver mutations. The patient was treated with brain radiotherapy, multiple lines of chemotherapies, and PD-1 inhibitor and achieved a survival rate of 9 months. The patient finally died because of the progression of brain metastasis. The case report provides valuable information for the treatment strategy development of advanced HAL patients and reminds us of the therapeutic particularity of brain metastasis.

Diagnostic value of nerve conduction study in NOTCH2NLC-related neuronal intranuclear inclusion disease.

BACKGROUND AND AIMS: Neuronal intranuclear inclusion disease (NIID) is a rare progressive neurodegenerative disorder mainly caused by abnormally expanded GGC repeats within the NOTCH2NLC gene. Most patients with NIID show polyneuropathy. Here, we aim to investigate diagnostic electrophysiological markers of NIID. METHODS: In this retrospective dual-center study, we reviewed 96 patients with NOTCH2NLC-related NIID, 94 patients with genetically confirmed Charcot-Marie-Tooth (CMT) disease, and 62 control participants without history of peripheral neuropathy, who underwent nerve conduction studies between 2018 and 2022. RESULTS: Peripheral nerve symptoms were presented by 53.1% of patients with NIID, whereas 97.9% of them showed peripheral neuropathy according to electrophysiological examinations. Patients with NIID were characterized by slight demyelinating sensorimotor polyneuropathy; some patients also showed mild axonal lesions. Motor nerve conduction velocity (MCV) of the median nerve usually exceeded 35 m/s, and were found to be negatively correlated with the GGC repeat sizes. Regarding the electrophysiological differences between muscle weakness type (n = 27) and non-muscle weakness type (n = 69) of NIID, nerve conduction abnormalities were more severe in the muscle weakness type involving both demyelination and axonal impairment. Notably, specific DWI subcortical lace sign was presented in only 33.3% of muscle weakness type, thus it was difficult to differentiate them from CMT. Combining age of onset, distal motor latency, and compound muscle action potential of the median nerve showed the optimal diagnostic performance to distinguish NIID from major CMT (AUC = 0.989, sensitivity = 92.6%, specificity = 97.4%). INTERPRETATION: Peripheral polyneuropathy is common in NIID. Our study suggest that nerve conduction study is useful to discriminate NIID.

Tet2-mediated DNA demethylation regulates the proliferation and apoptosis of human leukemia K562 cells.

TET2 is a member of the TET protein family which is responsible for active DNA demethylation through catalyzing the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), and mutations of Tet2 frequently lead to hematological malignancies. However, the relationship between Tet2-mediated demethylation and hematological malignancies is unclear. The human leukemia K562 cell line is an immortalized leukemia line that serves as an in vitro model of erythroleukemia. In this study, we investigated the effect of Tet2-mediated demethylation on the apoptosis and proliferation of human leukemia K562 cells and found that knockdown of Tet2 promoted and inhibited K562 cell proliferation and apoptosis, respectively, while upregulation of TET2 enzymatic activity via alpha-ketoglutaric acid (α-KG) had the opposite effects. Therefore, the Tet2 gene acts as a potential target for the treatment of leukemia, and small molecules that target the Tet2 gene may be used to screen antitumor drugs for hematological malignancies.

The genetic and clinical spectrum in a cohort of 39 families with complex inherited peripheral neuropathies.

With complicated conditions and a large number of potentially causative genes, the diagnosis of a patient with complex inherited peripheral neuropathies (IPNs) is challenging. To provide an overview of the genetic and clinical features of 39 families with complex IPNs from central south China and to optimize the molecular diagnosis approach to this group of heterogeneous diseases, a total of 39 index patients from unrelated families were enrolled, and detailed clinical data were collected. TTR Sanger sequencing, hereditary spastic paraplegia (HSP) gene panel, and dynamic mutation detection in spinocerebellar ataxia (SCAs) were performed according to the respective additional clinical features. Whole-exome sequencing (WES) was used in patients with negative or unclear results. Dynamic mutation detection in NOTCH2NLC and RCF1 was applied as a supplement to WES. As a result, an overall molecular diagnosis rate of 89.7% was achieved. All 21 patients with predominant autonomic dysfunction and multiple organ system involvement carried pathogenic variants in TTR, among which nine had c.349G > T (p.A97S) hotspot variants. Five out of 7 patients (71.4%) with muscle involvement harbored biallelic pathogenic variants in GNE. Five out of 6 patients (83.3%) with spasticity reached definite genetic causes in SACS, KIF5A, BSCL2, and KIAA0196, respectively. NOTCH2NLC GGC repeat expansions were identified in all three cases accompanied by chronic coughing and in one patient accompanied by cognitive impairment. The pathogenic variants, p.F284S and p.G111R in GNE, and p.K4326E in SACS, were first reported. In conclusion, transthyretin amyloidosis with polyneuropathy (ATTR-PN), GNE myopathy, and neuronal intranuclear inclusion disease (NIID) were the most common genotypes in this cohort of complex IPNs. NOTCH2NLC dynamic mutation testing should be added to the molecular diagnostic workflow. We expanded the genetic and related clinical spectrum of GNE myopathy and ARSACS by reporting novel variants.

A prognostic model for predicting progression-free survival in patients with advanced non-small cell lung cancer after image-guided microwave ablation plus chemotherapy.

OBJECTIVES: This study aimed to build and validate a prediction model that can predict progression-free survival (PFS) in patients with advanced non-small cell lung cancer (NSCLC) after image-guided microwave ablation (MWA) plus chemotherapy. METHODS: Data from a previous multi-center randomized controlled trial (RCT) was used and assigned to either the training data set or the external validation data set according to the location of the centers. Potential prognostic factors were identified by multivariable analysis in the training data set and used to construct a nomogram. After bootstraps internal and external validation, the predictive performance was evaluated by concordance index (C-index), Brier Score, and calibration curves. Risk group stratification was conducted using the score calculated by the nomogram. Then a simplified scoring system was built to make risk group stratification more convenient. RESULTS: In total, 148 patients (training data set: n = 112; external validation data set: n = 36) were enrolled for analysis. Six potential predictors were identified and entered into the nomogram, including weight loss, histology, clinical TNM stage, clinical N category, tumor location, and tumor size. The C-indexes were 0.77 (95% CI, 0.65-0.88, internal validation) and 0.64 (95% CI, 0.43-0.85, external validation). The survival curves of different risk groups also displayed significant distinction (p < 0.0001). CONCLUSIONS: We found weight loss, histology, clinical TNM stage, clinical N category, tumor location, and tumor size were prognostic factors of progression after receiving MWA plus chemotherapy and constructed a prediction model that can predict PFS. CLINICAL RELEVANCE STATEMENT: The nomogram and scoring system will assist physicians to predict the individualized PFS of their patients and decide whether to perform or terminate MWA and chemotherapy according to the expected benefits. KEY POINTS: • Build and validate a prognostic model using the data from a previous randomized controlled trial to predict progression-free survival after receiving MWA plus chemotherapy. • Weight loss, histology, clinical TNM stage, clinical N category, tumor location, and tumor size were prognostic factors. • The nomogram and scoring system published by the prediction model can be used to assist physicians to make clinical decisions.

Genome-Wide Characterization and Expression Profiling of ABA Biosynthesis Genes in a Desert Moss Syntrichia caninervis.

Syntrichia caninervis can survive under 80-90% protoplasmic water losses, and it is a model plant in desiccation tolerance research. A previous study has revealed that S. caninervis would accumulate ABA under dehydration stress, while the ABA biosynthesis genes in S. caninervis are still unknown. This study identified one ScABA1, two ScABA4s, five ScNCEDs, twenty-nine ScABA2s, one ScABA3, and four ScAAOs genes, indicating that the ABA biosynthesis genes were complete in S. caninervis. Gene location analysis showed that the ABA biosynthesis genes were evenly distributed in chromosomes but were not allocated to sex chromosomes. Collinear analysis revealed that ScABA1, ScNCED, and ScABA2 had homologous genes in Physcomitrella patens. RT-qPCR detection found that all of the ABA biosynthesis genes responded to abiotic stress; it further indicated that ABA plays an important role in S. caninervis. Moreover, the ABA biosynthesis genes in 19 representative plants were compared to study their phylogenetic and conserved motifs; the results suggested that the ABA biosynthesis genes were closely associated with plant taxa, but these genes had the same conserved domain in each plant. In contrast, there is a huge variation in the exon number between different plant taxa; it revealed that ABA biosynthesis gene structures are closely related to plant taxa. Above all, this study provides strong evidence demonstrating that ABA biosynthesis genes were conserved in the plant kingdom and deepens our understanding of the evolution of the phytohormone ABA.

Transcriptome Reveals the Molecular Mechanism of the ScALDH21 Gene from the Desert Moss Syntrichia caninervis Conferring Resistance to Salt Stress in Cotton.

The desert moss Syntrichia caninervis has proven to be an excellent plant material for mining resistance genes. The aldehyde dehydrogenase 21 (ScALDH21) gene from S. caninervis has been shown to confer tolerance to salt and drought, but it is unclear how the transgene ScALDH21 regulates tolerance to abiotic stresses in cotton. In the present work, we studied the physiological and transcriptome analyses of non-transgenic (NT) and transgenic ScALDH21 cotton (L96) at 0 day, 2 days, and 5 days after salt stress. Through intergroup comparisons and a weighted correlation network analysis (WGCNA), we found that there were significant differences between NT and L96 cotton in the plant hormone, Ca2+, and mitogen-activated protein kinase (MAPK) signaling pathways as well as for photosynthesis and carbohydrate metabolism. Overexpression of ScALDH21 significantly increased the expression of stress-related genes in L96 compared to NT cotton under both normal growth and salt stress conditions. These data suggest that the ScALDH21 transgene can scavenge more reactive oxygen species (ROS) in vivo relative to NT cotton and improve cotton resistance to salt stress by increasing the expression of stress-responsive genes, responding quickly to stress stimuli, enhancing photosynthesis and improving carbohydrate metabolism. Therefore, ScALDH21 is a promising candidate gene to improve resistance to salt stress, and the application of this gene in cotton provides new insights into molecular plant breeding.

Corrigendum: Case report: Potential predictive value of MMR/MSI status and PD-1 expression in immunotherapy for urothelial carcinoma.

[This corrects the article DOI: 10.3389/pore.2022.1610638.].

Case Report: Potential Predictive Value of MMR/MSI Status and PD-1 Expression in Immunotherapy for Urothelial Carcinoma.

Immune checkpoint inhibitors (ICIs) have shown encouraging outcomes against Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H). However, there is as yet no clarity on the safety and efficacy of immunotherapy combined with chemotherapy in LS-associated urothelial carcinoma (UC). Here, we report a patient with recurrent and metastatic LS-associated UC who achieved sustained response to programmed death protein 1 (PD-1) inhibitor combined with chemotherapy over 31 months, during which the side effects of immunotherapy could be controlled and managed. Our findings indicate that the dMMR/MSI status and PD-1 expression in UC may have potential predictive value for the response to PD-1-targeted immunotherapy. Our case supports the inclusion of such combination and/or monotherapy for UC in clinical studies and using dMMR/MSI status and PD-1 expression as potential predictive biomarkers for assessment of the therapeutic response.

[Retracted] MicroRNA­133a acts as a tumour suppressor in breast cancer through targeting LASP1.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting assay data shown in Figs. 5B, 5E, 6C and 7A were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 39: 473­482, 2018; DOI: 10.3892/or.2017.6114].

Genotype and phenotype distribution of 435 patients with Charcot-Marie-Tooth disease from central south China.

BACKGROUND AND PURPOSE: The purpose was to provide an overview of genotype and phenotype distribution in a cohort of patients with Charcot-Marie-Tooth disease (CMT) and related disorders from central south China. METHODS: In all, 435 patients were enrolled and detailed clinical data were collected. Multiplex ligation-dependent probe amplification for PMP22 duplication/deletion and CMT multi-gene panel sequencing were performed. Whole exome sequencing was further applied in the remaining patients who failed to achieve molecular diagnosis. RESULTS: Among the 435 patients, 216 had CMT1, 14 had hereditary neuropathy with pressure palsies (HNPP), 178 had CMT2, 24 had distal hereditary motor neuropathy (dHMN) and three had hereditary sensory and autonomic neuropathy (HSAN). The overall molecular diagnosis rate was 70%: 75.7% in CMT1, 100% in HNPP, 64.6% in CMT2, 41.7% in dHMN and 33.3% in HSAN. The most common four genotypes accounted for 68.9% of molecular diagnosed patients. Relatively frequent causes were missense changes in PMP22 (4.6%) and SH3TC2 (2.3%) in CMT1; and GDAP1 (5.1%), IGHMBP2 (4.5%) and MORC2 (3.9%) in CMT2. Twenty of 160 detected pathogenic variants and the associated phenotypes have not been previously reported. Broad phenotype spectra were observed in six genes, amongst which the pathogenic variants in BAG3 and SPTLC1 were detected in two sporadic patients presenting with the CMT2 phenotype. CONCLUSIONS: Our results provided a unique genotypic and phenotypic landscape of patients with CMT and related disorders from central south China, including a relatively high proportion of CMT2 and lower occurrence of PMP22 duplication. The broad phenotype spectra in certain genes have advanced our understanding of CMT.

Synthesis, crystal structures, DNA interactions, and antitumor activity of two new dinuclear copper(ii) complexes with thiazole ligand.

Two new dinuclear copper(ii) complexes, [Cu(ambt)2(cnba)4] (1) and [Cu(ambt)2(clba)4] (2) were synthesized with 2-amino-6-methoxybenzothiazole (ambt) as the main ligand. The structures of the two complexes were characterized by single-crystal XRD. The binding between CT-DNA (calf thymus DNA) and the complexes was evaluated by viscometry, electronic absorption, and fluorescence spectroscopy, and the binding constants were calculated using the Stern-Volmer equation. The complexes were intercalatively bound to CT-DNA, and [Cu(ambt)2(clba)4] having a greater binding constant than [Cu(ambt)2(cnba)4]. The two complexes had better antitumor properties against HepG2 (human hepatocellular carcinoma), A549 (human lung carcinoma), and HeLa (human cervical carcinoma) tumor cell lines than their respective ligands and cisplatin. Furthermore, [Cu(ambt)2(clba)4] had a stronger inhibitory ability on the three types of tumor cells than [Cu(ambt)2(cnba)4], which is congruent with the binding power of the complexes with DNA. Flow cytometry revealed that [Cu(ambt)2(cnba)4] and [Cu(ambt)2(clba)4] could trigger apoptosis or necrosis, arrest the HepG2 cell cycles, and cause G0/G1-phase cells to accumulate.

Assessment of the association between NUS1 variants and essential tremor.

BACKGROUND: A recent study on early onset Parkinson's disease (PD) revealed that NUS1 is a risk gene for PD. Clinically, essential tremor (ET) is closely related to PD. In this study, we aimed to detect NUS1 variants and assess the effect of those variants on patients with ET. METHODS: The 5 coding regions and the exon-intron boundaries of NUS1 were directly sequenced in 395 patients with ET and an equal number of healthy controls, matched for age and sex. The function of variants was assessed by pathogenic predictive software programs. Genetic analysis of variants was used to evaluate susceptibility to ET. RESULTS: A total of 6 exonic variants were identified, including 3 synonymous and 3 missense variants. The non-synonymous variants were predicted to be tolerable. No variants had significant association with ET (none of the p-values were less than 0.05, using Fisher's exact test). CONCLUSION: Our study suggested that NUS1 variants may not contribute to the risk of ET.

lncRNA TINCR facilities bladder cancer progression via regulating miR­7 and mTOR.

Long non­coding RNAs (lncRNAs) have been implicated in various human malignancies, but the molecular mechanism of lncRNA TINCR ubiquitin domain containing (TINCR) in bladder cancer remains unclear. The present study found that the expression of TINCR was significantly increased in bladder cancer tissues and cell lines, when compared with that in adjacent normal tissues and normal urinary tract epithelial cell line SV­HUC­1, respectively. Moreover, the high expression of TINCR was associated with tumor metastasis and advanced tumor, node, metastasis stage, as well as reduced overall survival rates of patients with bladder cancer. Further investigation revealed that microRNA (miR)­7 was negatively mediated by TINCR in bladder cancer cells. Silencing of TINCR expression significantly increased miR­7 expression and reduced bladder cancer cell proliferation, migration and invasion, while knockdown of miR­7 expression reversed the inhibitory effects of TINCR downregulation on bladder cancer cells. mTOR was then identified as a target gene of miR­7 in bladder cancer, and it was demonstrated that overexpression of mTOR reversed the inhibitory effects of miR­7 on bladder cancer cells. In conclusion, this study suggests that TINCR/miR­7/mTOR signaling may be a potential therapeutic target for bladder cancer.

The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.

This study aimed to determine the mutational spectrum of familial Parkinson's disease and sporadic early-onset Parkinson's disease (sEOPD) in a mainland Chinese population and the clinical features of mutation carriers. We performed multiplex ligation-dependent probe amplification assays and whole-exome sequencing for 1676 unrelated patients with Parkinson's disease in a mainland Chinese population, including 192 probands from families with autosomal-recessive Parkinson's disease, 242 probands from families with autosomal-dominant Parkinson's disease, and 1242 sEOPD patients (age at onset ≤ 50). According to standards and guidelines from the American College of Medical Genetics and Genomics, pathogenic/likely pathogenic variants in 23 known Parkinson's disease-associated genes occurred more frequently in the autosomal-recessive Parkinson's disease cohort (65 of 192, 33.85%) than in the autosomal-dominant Parkinson's disease cohort (10 of 242, 4.13%) and the sEOPD cohort (57 of 1242, 4.59%), which leads to an overall molecular diagnostic yield of 7.88% (132 of 1676). We found that PRKN was the most frequently mutated gene (n = 83, 4.95%) and present the first evidence of an SNCA duplication and LRRK2 p.N1437D variant in mainland China. In addition, several novel pathogenic/likely pathogenic variants including LRRK2 (p.V1447M and p.Y1645S), ATP13A2 (p.R735X and p.A819D), FBXO7 (p.G67E), LRP10 (c.322dupC/p.G109Rfs*51) and TMEM230 (c.429delT/p.P144Qfs*2) were identified in our cohort. Furthermore, the age at onset of the 132 probands with genetic diagnoses (median, 31.5 years) was about 14.5 years earlier than that of patients without molecular diagnoses (i.e. non-carriers, median 46.0 years). Specifically, the age at onset of Parkinson's disease patients with pathogenic/likely pathogenic variants in ATP13A2, PLA2G6, PRKN, or PINK1 was significantly lower than that of non-carriers, while the age at onset of carriers with other gene pathogenic/likely pathogenic variants was similar to that of non-carriers. The clinical spectrum of Parkinson's disease-associated gene carriers in this mainland Chinese population was similar to that of other populations. We also detected 61 probands with GBA possibly pathogenic variants (3.64%) and 59 probands with GBA p.L444P (3.52%). These results shed insight into the genetic spectrum and clinical manifestations of Parkinson's disease in mainland China and expand the existing repertoire of pathogenic or likely pathogenic variants involved in known Parkinson's disease-associated genes. Our data highlight the importance of genetic testing in Parkinson's disease patients with age at onset < 40 years, especially in those from families with a recessive inheritance pattern, who may benefit from early diagnosis and treatment.

Thermal tolerance of dried shoots of the moss Bryum argenteum.

We conducted laboratory experiments to determine the lethal temperatures of the shoots of dried Bryum argenteum and to determine how this restoration species responds to extreme environments. We specifically assessed changes in gene expression levels in the shoots of dried B. argenteum plants that were subjected to sudden heat shock (control (20 ± 2°C), 80°C, 100°C, 110°C or 120°C) followed by exposure to heat for an additional 10, 20, 30 or 60 min. After they were exposed to heat, the samples were placed in wet sand medium, and their survival and regeneration abilities were evaluated daily for 56 days. The results showed that lethal temperatures significantly reduced the shoot regeneration potential, delayed both shoot and protonemal emergence times and reduced the protonemal emergence area. In addition, the expression of nine genes (HSF3, HSP70, ERF, LEA, ELIP, LHCA, LHCB, Tr288 and DHN) was induced by temperature stress, as assessed after 30 min of exposure. Additionally, a new thermal tolerance level for dried B. argenteum - 120°C for 20 min - was determined, which was the highest temperature recorded for this moss; this tolerance exceeded the previous record of 110°C for 10 min. These findings help elucidate the survival mechanism of this species under heat shock stress and facilitate the recovery and restoration of destroyed ecosystems.

Functional Aspects of Early Light-Induced Protein (ELIP) Genes from the Desiccation-Tolerant Moss Syntrichia caninervis.

The early light-induced proteins (ELIPs) are postulated to act as transient pigment-binding proteins that protect the chloroplast from photodamage caused by excessive light energy. Desert mosses such as Syntrichia caninervis, that are desiccation-tolerant and homoiochlorophyllous, are often exposed to high-light conditions when both hydrated and dry ELIP transcripts are accumulated in response to dehydration. To gain further insights into ELIP gene function in the moss S. caninervis, two ELIP cDNAs cloned from S. caninervis, ScELIP1 and ScELIP2 and both sequences were used as the basis of a transcript abundance assessment in plants exposed to high-light, UV-A, UV-B, red-light, and blue-light. ScELIPs were expressed separately in an Arabidopsis ELIP mutant Atelip. Transcript abundance for ScELIPs in gametophytes respond to each of the light treatments, in similar but not in identical ways. Ectopic expression of either ScELIPs protected PSII against photoinhibition and stabilized leaf chlorophyll content and thus partially complementing the loss of AtELIP2. Ectopic expression of ScELIPs also complements the germination phenotype of the mutant and improves protection of the photosynthetic apparatus of transgenic Arabidopsis from high-light stress. Our study extends knowledge of bryophyte photoprotection and provides further insight into the molecular mechanisms related to the function of ELIPs.