The Diagnostic Value of the Modified STdmax/MET Criterion in Treadmill Exercise Electrocardiographic Test for Coronary Artery Disease in an Aged Population.

Objective: The primary objective of this study is to assess the diagnostic value of treadmill exercise electrocardiographic test (EET) for coronary artery disease (CAD) in the aged population, emphasizing the need for improved diagnostic criteria due to the limitations of traditional EET in accurately diagnosing CAD among elderly patients. This focus is critical as the aged population has a higher prevalence of CAD, and early and accurate diagnosis is essential for effective management and treatment. Methods: This study comprised two stages. Initially, we retrospectively analyzed data from patients aged > 60 years who underwent treadmill EET within two weeks of coronary angiography (CAG) during hospitalization from June 1, 2014, to May 31, 2017. We evaluated the diagnostic value of treadmill EET using both the standard criterion (ST depression > 0.1 mV) and a modified criterion (the ratio of ST depression to metabolic equivalent [STdmax/MET]), explaining our choice of the modified criterion as it potentially offers a more nuanced assessment by considering the patient's exercise capacity. A subgroup analysis was also conducted. Subsequently, a prospective study to further investigate the modified criterion was carried out. Results: In the retrospective analysis, 190 patients were enrolled, with 71.5% confirmed to have CAD. The sensitivity, specificity, and accuracy of the standard criterion were 66.2%, 42.6%, and 59.5%, respectively. With a cut-off value for STdmax/MET set at 0.255 mV·W/m2, these metrics improved to 79.4%, 55.7%, and 72.4%, respectively, for the modified criterion. The prospective study, involving 47 patients, confirmed significant improvements in sensitivity (85.7% vs. 64.3%, P = .041) and specificity (68.4% vs. 31.6%, P = .046) when applying the modified criterion. Conclusions: The introduction of the novel modified diagnostic criterion, STdmax/MET, significantly enhances the diagnostic value of treadmill EET for detecting CAD in elderly patients. The adoption of this modified criterion could potentially improve clinical outcomes by facilitating more accurate and timely diagnosis of CAD in this high-risk group.

HiFi long-read amplicon sequencing for full-spectrum variants of human mtDNA.

BACKGROUND: Mitochondrial diseases (MDs) can be caused by single nucleotide variants (SNVs) and structural variants (SVs) in the mitochondrial genome (mtDNA). Presently, identifying deletions in small to medium-sized fragments and accurately detecting low-percentage variants remains challenging due to the limitations of next-generation sequencing (NGS). METHODS: In this study, we integrated targeted long-range polymerase chain reaction (LR-PCR) and PacBio HiFi sequencing to analyze 34 participants, including 28 patients and 6 controls. Of these, 17 samples were subjected to both targeted LR-PCR and to compare the mtDNA variant detection efficacy. RESULTS: Among the 28 patients tested by long-read sequencing (LRS), 2 patients were found positive for the m.3243 A > G hotspot variant, and 20 patients exhibited single or multiple deletion variants with a proportion exceeding 4%. Comparison between the results of LRS and NGS revealed that both methods exhibited similar efficacy in detecting SNVs exceeding 5%. However, LRS outperformed NGS in detecting SNVs with a ratio below 5%. As for SVs, LRS identified single or multiple deletions in 13 out of 17 cases, whereas NGS only detected single deletions in 8 cases. Furthermore, deletions identified by LRS were validated by Sanger sequencing and quantified in single muscle fibers using real-time PCR. Notably, LRS also effectively and accurately identified secondary mtDNA deletions in idiopathic inflammatory myopathies (IIMs). CONCLUSIONS: LRS outperforms NGS in detecting various types of SNVs and SVs in mtDNA, including those with low frequencies. Our research is a significant advancement in medical comprehension and will provide profound insights into genetics.

Clinical and genetic study of ABCB4 gene-related cholestatic liver disease in China: children and adults.

BACKGROUND: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. The correlation between genotype and clinical phenotype still unclear. This study retrospectively analyzed the clinical and pathological characteristics of 23 patients with ABCB4 gene-related cholestatic liver diseases. Next-generation sequencing was used to identify the genetic causes. RESULTS: The 23 included patients (15 children and 8 adults) were diagnosed as progressive familial intrahepatic cholestasis type 3 (PFIC3), drug-induced liver injury (DILI), cirrhosis cholestasis, cirrhosis, and mild liver fibrosis. Nineteen patients underwent liver pathological examination of the liver, exhibiting fibrosis, small bile duct hyperplasia, CK7(+), Cu(+), bile duct deletion, and cirrhosis. Thirty ABCB4 variants were identified, including 18 novel variants. CONCLUSION: ABCB4 gene-related cholestatic liver diseases have a wide spectrum of clinical and genetic variations. Biallelic ABCB4 mutation carriers tended to severe PFIC3, which mostly occurs in children; while ABCB4 non-biallelic variants can lead to milder ICP, LACP, DILI or overlapping, mostly in adults. Thus, the ABCB4 genotype has a specific correlation with the phenotype, but there are exceptions. Non-biallelic null mutations can cause severe diseases. The mechanisms underlying this genetic phenotype require further investigation.

Diagnostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography imaging in pediatric opsoclonus myoclonus ataxia syndrome presenting with neuroblastoma.

BACKGROUND: Early precision diagnosis and effective treatment of opsoclonus myoclonus ataxia syndrome (OMAS) patients presenting with neuroblastoma can prevent serious neurological outcomes. OBJECTIVE: To assess the diagnostic value of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) imaging in pediatric OMAS with neuroblastoma. MATERIALS AND METHODS: A retrospective evaluation of 45 patients diagnosed with OMAS who underwent 18F-FDG PET/CT was performed. A univariate analysis was performed to compare clinical characteristics between OMAS with and without neuroblastoma. Univariate and multivariate logistic regression analyses were applied to identify independent risk factors for OMAS with neuroblastoma and to develop the clinical model. Finally, independent risk factors and PET/CT were fitted to build the combined model for the diagnosis of OMAS with neuroblastoma and presented as a nomogram. Receiver operating characteristic curve, decision curve, and calibration curve analyses were conducted to evaluate the performance of the models. RESULTS: Among 45 patients, 27 were PET/CT-positive, 23/27 lesions were neuroblastoma, and four were false positives. One of the false positive patients was confirmed to be adrenal reactive hyperplasia by postoperative pathology, and the symptoms of OMAS disappeared in the remaining three cases during clinical follow-up. The average maximal standardized uptake value of PET/CT-positive lesions was 2.6. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PET/CT were 100%, 81.8%, 85.2%, 100%, and 91.1%, respectively. Age at diagnosis, lactate dehydrogenase, and neuron-specific enolase showed statistically significant differences between OMAS with and without neuroblastoma. Lactate dehydrogenase was identified as the independent risk factor to develop the clinical model, and the clinical model demonstrated an area under the curve (AUC) of 0.82 for the diagnosis of OMAS with neuroblastoma, with an AUC as high as 0.91 when combined with PET/CT. The decision curve analysis and calibration curve demonstrated that the nomogram had good consistency and clinical usefulness. CONCLUSION: In patients with OMAS, 18F-FDG PET/CT has a high diagnostic accuracy in detecting tumors of the neuroblastoma, especially when combined with the independent risk factor serum lactate dehydrogenase.

Simultaneous improvement of martensitic phase transition and ductility in Cu-doped and/or alloyed all-d-metal Ni2MnTa Heusler compounds.

Ductile all-d-metal Heusler compounds with tunable martensitic phase transition are desirable for solid-state refrigeration applications. The theoretical investigations on martensitic phase transition and ductile characteristics of novel all-d-metal Ni2MnTa were conducted in this study. By introducing Cu atoms into Ni2MnTa, the improvement of martensitic phase transition and ductility was simultaneously realized. It was found that the substitution of Cu with more valence electrons for Ni, Mn, and Ta atoms resulted in an increase in metallic bonding. Owing to the enhanced metallic bonding, elastic moduli were softened, which improved shear deformation ability and contributed to tailoring the austenite phase stability. Hopefully, the anticipated martensitic phase transition can be tailored to an optimal temperature range. Moreover, the increased metallicity accounted for the simultaneously enhanced ductility. The enhanced metallic characteristics also resulted in contracting lattice sizes of Cu-doped and/or alloyed Ni2MnTa compounds due to the volume effect. Metallic bonding may be described as the mechanism for simultaneously controlling the phase stability and enhancing ductile properties in Cu-doped and/or alloyed Ni2MnTa compounds. The calculated energy, electronic structure, and elastic parameters further verified the occurrence of martensitic phase transition in Cu-doped and/or alloyed Ni2MnTa compounds. Current results suggest that chemical bonding could be employed as a significant tuning factor in the exploration of multipurpose Heusler compounds.

Genome-wide association study reveals HSF2, GJA1 and TRIM36 as susceptibility genes for preeclampsia: a community-based population study in Tianjin, China.

BACKGROUND: Preeclampsia (PE) mainly occurs in pregnant women and is hereditary. Several genome-wide association studies (GWAS) on Caucasian samples have reported some gene loci that are associated with preeclampsia. However, these studies have not reached consistent conclusions. No previous GWAS has examined preeclampsia in the Chinese Han population. METHOD: This study aimed to identify common genetic variations associated with preeclampsia in the Chinese Han population through two-stage case‒control studies. The discovery cohort included 92 patients with severe preeclampsia and 187 healthy controls. The validation cohort included 52 patients with preeclampsia and 104 controls. A genome-wide association study was performed to identify putative preeclampsia genes in the discovery cohort, with validation in the validation cohort. RESULTS: In the discovery cohort, GWAS demonstrated that 19 single-nucleotide polymorphisms (SNPs) were associated with preeclampsia (P < 10-5). The pathway analysis revealed that these 19 SNP representative genes were mainly enriched in the adenylyl cyclase-inhibiting G-protein coupled receptor signaling pathway. After validation in the validation cohort, rs13176432 and rs13210237 remained closely related to preeclampsia (P<0.05). In the combined data set, the frequency of the G allele in rs13176432 was significantly higher in cases with preeclampsia than in controls (P = 5 × 10-6). The frequency of the A allele in rs13210237 was higher in the preeclampsia group (P = 8 × 10-6). The rs13210237 representative genes include HSF2 and GJA1, while the rs13176432 representative gene is TRIM36. There were no differences in genotype distribution between the early-onset and late-onset preeclampsia groups (P > 0.05). Furthermore, rs13210237 and rs13176432 were related to preeclampsia in the adjusted regression model (P < 0.000). CONCLUSION: In this study of two independent cohorts, we found that rs13210237 and rs13176432 might be novel preeclampsia-susceptible genetic factors in the Han population in China. However, there was no association between the onset of preeclampsia and these genotypes.

Somatic ARAF mutations in pediatric Langerhans cell histiocytosis: clinicopathologic, genetic and functional profiling.

ARAF mutations have been identified in a limited subset of patients with Langerhans cell histiocytosis (LCH), a rare disorder characterized by abnormal proliferation of Langerhans cells. LCH is primarily instigated by mutations in the mitogen-activated protein kinase (MAPK) signaling pathway, with BRAFV600E and MAP2K1 mutations constituting most cases. ARAF mutations in LCH highlight the heterogeneity of the disease and provide insights into its underlying molecular mechanisms. However, the occurrence of ARAF-positive LCH cases is extremely rare, with only two reported globally. Although they may be linked to a more aggressive form of LCH and a more severe clinical progression, the clinical significance and functional consequences of these mutations remain uncertain. We performed next-generation sequencing (NGS) to explore driver mutations in 148 pediatric LCH patients and recognized a series of mutations, including an identical novel somatic ARAF mutation, c.1046_1051delAGGCTT (p.Q349_F351delinsL), in four pediatric LCH patients. It was considered an ARAF hotspot mutation. All reported ARAF-positive patients worldwide exhibited characteristic pathological features of LCH, albeit with involvement across multiple systems. In vitro functional studies showed that this mutation could trigger the MAPKinase pathway and phosphorylate its downstream effectors MEK1/2 and ERK1/2 (relatively weaker than BRAFV600E). Over-activation of mutant A-Raf kinase could be inhibited by the BRAF inhibitor vemurafenib. LCH is uncommon, and ARAF mutation is even rarer. In our study, we have identified a novel hotspot somatic ARAF mutation, which has been verified through functional analysis to be an activating mutation. LCH patients with ARAF mutation typically have an unfavorable prognosis due to limited treatment experiences, although they do not exhibit a high relapse rate. To aid in the development of personalized treatment approaches and prognostic markers for LCH patients, it is recommended to conduct typical pathological and immunohistochemical examinations, as well as genetic tests utilizing a targeted gene panel or whole exome sequencing (WES), for LCH diagnosis, thereby promoting the use of inhibitor treatment strategies.

Investigation of CuCoFe-LDH as an efficient and stable catalyst for the degradation of acetaminophen in heterogeneous electro-Fenton system: Key operating parameters, mechanisms and pathways.

Pharmaceuticals, as anthropogenic pollutants in a wide range of water sources, generally require specific treatment methods for degradation. A trimetallic layered double hydroxide (CuCoFe-LDH) was successfully fabricated by coprecipitation and applied as a novel heterogeneous electro-Fenton (EF) catalyst for the degradation of acetaminophen (ACT) from aqueous environments. The EF experiments showed that the CuCoFe-LDH/EF process achieved 100% of ACT degradation efficiency within 60 min at pH = 5, catalyst dosage of 0.50 g/L, current density of 10 mA/cm2 and initial ACT concentration of 20 mg/L. An impressive (>80%) mineralization of ACT was obtained over a wide pH range (pH 3-9) after 180 min. Meanwhile, the role of ·OH and O2.- were certified by radical quenching experiments and electron paramagnetic resonance (EPR) analysis. Through mechanism exploration, the coexistence of Cu and Co on Fe-based LDHs can accelerate the interfacial electron transfer and promote the formation of the reactive oxygen species (ROS), thus facilitating the EF process. Furthermore, the degradation by-products and possible degradation pathways of ACT in the CuCoFe-LDH/EF process were proposed. The reusability test and the treatment of various typical organic pollutants experiments indicated that the CuCoFe-LDH/EF process has excellent stability and broad application prospects. This work provides a valuable reference for the treatment of pharmaceuticals by the heterogeneous EF process in a wide range of pH.

ANXA11 mutations are associated with amyotrophic lateral sclerosis-frontotemporal dementia.

Background: The Annexin A11 (ANXA11) gene has been newly identified as a causative gene of amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). The current study aimed to investigate the ANXA11 mutations in a Chinese ALS-FTD or FTD cohort. Methods: We included ten probands/patients with suspected ALS-FTD or FTD. Mutational analysis of ANXA11 was performed through Next Generation Sequencing (NGS) and Sanger sequencing. We collected and reviewed clinical presentation, neuropsychology test results, brain-imaging findings, and electrophysiological examination findings. Results: In total, six probands presented with ALS-FTD, and four with behavior variant FTD (bv-FTD). We identified a non-synonymous heterozygous mutation (c.119A>G, p.D40G) of ANXA11 in proband 1, which is associated with ALS. However, this is the first report of the mutation causing ALS-FTD. Proband 1 started with abnormal behavior and progressed to classic upper motor nervous disease. Magnetic resonance imaging (MRI) showed significant bilateral temporal lobe atrophy and bilateral hyperintensities along the corticospinal tracts.18F-AV45-PET imaging showed negative amyloid deposits. Conclusion: ANXA11-related diseases have high clinical and genetic heterogeneity. Our study confirmed the contribution of ANXA11 mutations to ALS-FTD. The ANXA11 mutations established a complex genotype-phenotype correlation in ALS-FTD. Our research further elucidated the genetic mechanism of ALS-FTD and contributed to setting the foundation of future targeted therapy.

Microalgae simultaneously promote antibiotic removal and antibiotic resistance genes/bacteria attenuation in algal-bacterial granular sludge system.

This study investigated the effects of microalgae growth on antibiotic removal and the attenuation of antibiotic resistance genes (ARGs)/ARGs host bacteria in algal-bacterial granular sludge (ABGS) system. In the presence of tetracycline (TC) and sulfadiazine (SDZ) mixture (2-4 mg/L), microalgae could grow on bacterial granular sludge (BGS) to form ABGS, with a chlorophyll-a content of 7.68-8.13 mg/g-VSS being achieved. The removal efficiencies of TC and SDZ by ABGS were as high as 79.0 % and 94.0 %, which were 4.3-5.0 % higher than those by BGS. Metagenomic analysis indicated that the relative abundances of TC/SDZ- related ARGs and mobile genetic elements (MGEs) in BGS were 56.1 % and 22.1 % higher than those in ABGS. A total of 26 ARGs were detected from the granules, and they were identified to associate with 46 host bacteria. 13 out of 26 ARGs and 13 out of 46 hosts were shared ARGs and hosts, respectively. The total relative abundance of host bacteria in BGS was 30.8 % higher than that in ABGS. Scenedesmus and Chlorella were the dominant microalgae that may reduce the diversity of ARGs hosts. Overall, ABGS is a promising biotechnology for antibiotic-containing wastewater treatment.

The prokaryotic community, physicochemical properties and flavors dynamics and their correlations in fermented grains for Chinese strong-flavor Baijiu production.

Fermented grain (FG), a complex and unique ecosystem, is the main microbial habitats, biochemical reaction system and direct source of flavor compounds for the Chinese strong-flavor Baijiu (CSFB) production. However, the dynamics of physicochemical properties, prokaryotic community and flavor compounds of FGs during the long-term fermentation process are still not completely clear. Here, the above topics on FGs in the actual production process were comprehensively studied by using a combination of physicochemical analysis, GC-MS detection and Illumina HiSeq sequencing methods. The whole fermentation process could be divided into two stages including early (0-25d) and the later stage (25-60d) based on the dynamics of FG physicochemical properties and the changes of prokaryotic community diversity. A total of 41phyla and 364 genera were detected, and 9 of them were dominant genera in FG complex ecosystem, including Lactobacillus, Pediococcus, Ochrobactrum, Bacillus etc. Among them, the dynamics of 29 top10 genera in FGs were mainly influenced by the starch and total acid, followed by NH4+ and ethanol, and 7 genera (hubs, e.g., Clostridium, Methanosaeta, Bacillus, etc.) of them may play important roles in FG ecosystem stability. A total of 71 volatiles including 33 esters, 14 alcohols, 9 fatty acids, 5 phenols, and 10 other compounds were detected in the FGs, and most of them formed in the early stage. Some important flavor substances (e.g., ethyl octanoate, 3-methylbutanol, hexanoate, etc.) increased in the later stage. Moreover, the formation of some flavor compound might require multiple microbes involved. For instance, ten of the top10 genera, including Lactobacillus, Clostridium, Methanosarcina, Sedimentibacter, Bacillus, etc., were significantly and positively correlated with four important esters. This study may help to clarify the complex correlations among prokaryotic community, physicochemical properties and flavors, allow the improvement of CSFB quality by using bioaugmentation and/or controlling environmental factors, and shed more light on the ecological rules guiding community assembly in FGs.

Frequency detection of BRAF V600E mutation in a cohort of pediatric langerhans cell histiocytosis patients by next-generation sequencing.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare neoplastic disease that occurs in both children and adults, and BRAF V600E is detected in up to 64% of the patients. Several studies have discussed the associations between BRAF V600E mutation and clinicopathological manifestations, but no clear conclusions have been drawn regarding the clinical significance of the mutation in pediatric patients. RESULTS: We retrieved the clinical information for 148 pediatric LCH patients and investigated the BRAF V600E mutation using next-generation sequencing alone or with droplet digital PCR. The overall positive rate of BRAF V600E was 60/148 (41%). The type of sample (peripheral blood and formalin-fixed paraffin-embedded tissue) used for testing was significantly associated with the BRAF V600E mutation status (p-value = 0.000 and 0.000). The risk of recurrence declined in patients who received targeted therapy (p-value = 0.006; hazard ratio 0.164, 95%CI: 0.046 to 0.583). However, no correlation was found between the BRAF V600E status and gender, age, stage, specific organ affected, TP53 mutation status, masses close to the lesion or recurrence. CONCLUSIONS: This is the largest pediatric LCH study conducted with a Chinese population to date. BRAF V600E in LCH may occur less in East Asian populations than in other ethnic groups, regardless of age. Biopsy tissue is a more sensitive sample for BRAF mutation screening because not all of circulating DNA is tumoral. Approaches with low limit of detection or high sensitivity are recommended for mutation screening to avoid type I and II errors.

Characterization of genotype-phenotype correlation with MORC2 mutated Axonal Charcot-Marie-Tooth disease in a cohort of Chinese patients.

BACKGROUND: Charcot-Marie-Tooth (CMT) disease is an exciting field of study, with a growing number of causal genes and an expanding phenotypic spectrum. The microrchidia family CW-type zinc finger 2 gene (MORC2) was newly identified as a causative gene of CMT2Z in 2016. We aimed to describe the phenotypic-genetic spectrum of MORC2-related diseases in the Chinese population. METHODS: With the use of Sanger sequencing and Next Generation Sequencing (NGS) technologies, we screened a cohort of 284 unrelated Chinese CMT2 families. Pathogenicity assessments of MORC2 variants were interpreted according to the ACMG guidelines. Potential pathogenic variants were confirmed by Sanger sequencing. RESULTS: We identified 4 different heterozygous MORC2 mutations in four unrelated families, accounting for 1.4% (4/284). A novel mutation c.1397A>G p. D466G was detected in family 1 and all affected patients presented with later onset axonal CMT with hyperCKemia. The patient in family 2 showed a spinal muscular atrophy (SMA)-like disease with cerebellar hypoplasia and mental retardation, with a hot spot de novo mutation c.260C>T p. S87L. The twin sisters in family 3 were identified as having the most common mutation c.754C>T p. R252W and suffered from axonal motor neuropathy with high variability in disease severity and duration. The patient in family 4 developed an early onset axonal motor and sensory neuropathy, with a reported mutation c.1220G>A p.C407Y. All identified mutations associated with MORC2-related neuropathies are localized in the N-terminal ATPase module. CONCLUSIONS: Our study confirmed that MORC2-related neuropathies exist in the Chinese population at a relatively high mutation rate. We revealed a complex genotype-phenotype correlation with MORC2 mutations. This report adds a new piece to the puzzle of the genetics of CMT and contributes to a better understanding of the disease mechanisms.

Novel truncating mutations in ASXL1 identified in two boys with Bohring-Opitz syndrome.

Bohring-Opitz syndrome (BOS, or BOPS) is a rare congenital genetic disorder with multisystem abnormalities characterized by significant craniofacial dysmorphism, feeding difficulties, severe developmental delay, profound intellectual disability, flexion of elbows with ulnar deviation, and flexion of the wrists and metacarpophalangeal joints. Here, we report two Chinese BOS patients with distinctive phenotypes caused by novel truncating mutations. One was a boy aged 5 years 9 months who had a novel c.1049G>A/p.Trp350* mutation in ASXL1 and displayed relatively mild BOS symptoms with autism features. The other was a 16-month-old boy who carried a novel c.2689delC/p.His897Ilefs*11 mutation and displayed typical BOS symptoms. New cases with novel mutations, along with a detailed clinical and molecular analysis are important for a better diagnosis and understanding of BOS.

Autosomal Recessive Cerebellar Ataxia Type 1: Phenotypic and Genetic Correlation in a Cohort of Chinese Patients with SYNE1 Variants.

Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene have been reported to cause autosomal recessive cerebellar ataxia (ARCA) type 1 with highly variable clinical phenotypes. The aim of this study was to describe the phenotypic-genetic spectrum of SYNE1-related ARCA1 patients in the Chinese population. We screened 158 unrelated patients with autosomal recessive or sporadic ataxia for variants in SYNE1 using next-generation sequencing. Pathogenicity assessment of SYNE1 variants was interpreted according to the American College of Medical Genetics standards and guidelines. We identified eight truncating variants and two missense variants spreading throughout the SYNE1 gene from six unrelated families, including nine novel variants and one reported variant. Of the six index patients, two patients showed the classical pure cerebellar ataxia, while four patients exhibited non-cerebellar phenotypes, including motor neuron symptoms, cognitive impairment, or mental retardation. The variants associated with motor neuron or cognition involvement tend to be located in the C-terminal region of SYNE1 protein, compared with the variants related to pure cerebellar ataxia. Our data indicating SYNE1 mutation is one of the more common causes of recessive ataxia in the Chinese population. The use of next-generation sequencing has enabled the rapid analysis of recessive ataxia and further expanded our understanding of genotype-phenotype correlation.

Mutant BCL11B in a Patient With a Neurodevelopmental Disorder and T-Cell Abnormalities.

Background: BCL11B encodes B-cell lymphoma/leukemia 11B, a transcription factor that participates in the differentiation and migration of neurons and lymphocyte cells. De novo mutations of BCL11B have been associated with neurodevelopmental disorder and immunodeficiency, such as immunodeficiency 49 (IMD49) and intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities (IDDSFTA). However, the pathogenesis of the neurodevelopmental disorder and T-cell deficiency is still mysterious. The strategy to distinguish these two diseases in detail is also unclear. Methods: A patient with unique clinical features was identified. Multiple examinations were applied for evaluation. Whole-exome sequencing (WES) and Sanger sequencing were also performed for the identification of the disease-causing mutation. Results: We reported a 17-month-old girl with intellectual disability, speech impairment, and delay in motor development. She presented with mild dysmorphic facial features and weak functional movement. MRI indicated the abnormal myelination of the white matter. Immunological analysis showed normal levels of RTEs and γδT cells but a deficiency of naive T cells. Genetic sequencing identified a de novo heterozygous frameshift mutation c.1192_1196delAGCCC in BCL11B. Conclusions: An IDDSFTA patient of East Asian origin was reported. The unreported neurological display, immunophenotype, and a novel disease-causing mutation of the patient extended the spectrum of clinical features and genotypes of IDDSFTA.

Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report.

BACKGROUND: PPP3CA gene encodes the catalytic subunit A of a calcium-dependent protein phosphatase called calcineurin. However, two distinct mechanisms in PPP3CA deficiency would cause two clinically different diseases. Gain-of-function mutations in the autoinhibitory domain at the C-terminus would cause ACCIID that stands for arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development. While loss-of-function mutations in PPP3CA would cause infantile or early childhood onset epileptic encephalopathy1, named as IECEE1. IECEE1 is a severe epileptic neurodevelopmental disorder and mainly characterized by psychomotor delay. Here, we report a Chinese patient who was clinically and genetically diagnosed as IECEE1. We also extensively analyzed electroencephalogram (EEG) features of the patient in this study. CASE PRESENTATION: A 2-year-old Chinese patient who had recurrent polymorphic seizures was clinically and genetically diagnosed as IECEE1. A frameshift variant c.1283insC (p.T429NfsX22) was identified in this case. Multiple types of abnormal features were observed in the EEG, comparing with the previous reports. CONCLUSIONS: These findings could expand the spectrum of PPP3CA mutations and might also support the diagnosis and further study of IECEE1.

A micro-CT study of different regions of the atlas / Un estudio de micro-CT de diferentes regiones del atlas

This study aimed to examine the differences in bone microarchitecture between different regions of the atlas in 28 dry atlas specimens using micro-CT, in order to explain the mechanism of the predilection sites of atlas fractures from the morphological point of view. A total of 28 dry specimens of intact adult atlas were randomly selected, scanned by micro-CT, and divided into a region from the anterior arch midpoint (AAM) to the lateral masses (LM), a LM region, and a region from the LM to the posterior arch midpoint (PAM). Trabecular thickness, separation, number, connectivity, and structure model index were measured for each of the three regions using the built-in software of the CT scanner. Trabecular thickness was all measured to be 0.11 ± 0.00 mm for AAM to LM, LM, and LM to PAM. Trabecular separation: AAM to LM > LM to PAM > LM. Trabecular number: LM > LM to PAM > AAM to LM. Connectivity: LM > LM to PAM > AAM to LM. Structure model index: LM > LM to PAM > AAM to LM. A lower trabecular number and connectivity and higher trabecular separation were seen in the anterior and posterior arches of the atlas, in which higher fracture rates were reported. By contrast, a higher trabecular number and connectivity and lower trabecular separation were seen in the lateral masses, in which lower fracture rates were reported.

Este estudio tuvo como objetivo examinar las diferencias en la microarquitectura ósea entre diferentes regiones del atlas en 28 muestras de atlas secas utilizando micro-CT, con el fin de informar el área de mayor frecuencia en las fracturas de atlas, desde el punto de vista morfológico. Se seleccionaron al azar un total de 28 muestras secas de atlas adultos intactas las que se escanearon por micro-CT y se dividieron en una región desde el punto medio del arco anterior (MAA) hasta las masas laterales (ML), una región ML y una región desde el ML hasta el punto medio del arco posterior (MAP). Se midió el grosor trabecular, la separación, el número, la conectividad y el índice del modelo de estructura para cada una de las tres regiones utilizando el software incorporado del escáner CT. El grosor trabecular se midió en 0,11 ± 0,00 mm para MAA a ML, ML y ML a MAP. Separación trabecular: MAA a ML> ML a MAP> ML. Número trabecular: ML> ML a MAP> MAA a ML. Conectividad: ML> ML a MAP> MAA a ML. Índice del modelo de estructura: ML> ML a MAP> MAA a ML. Se observó un menor número de estructuras trabeculares y conectividad y una mayor separación trabecular en los arcos anterior y posterior del atlas, en los que se informaron tasas de fracturas más altas. Por el contrario, se observó un mayor número de estructuras trabeculares y conectividad, y una menor separación trabecular en las masas laterales, en las que se observó un número menor de fracturas.

Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1.

Hereditary spastic paraplegias (HSP) are a group of rare neurodegenerative diseases characterized by progressive spastic paraparesis. UBAP1 was recently found to induce a rare type of HSP (SPG80). We identified a family with eight inherited spastic paraplegic patients carrying a novel heterozygous mutation c.279delG (p.S94Vfs*9) of UBAP1. We demonstrated a lack of functional UBAP1 in these patients, resulting in the neurological disorder caused by interceptions of the ESCRT pathway. Extending from the older onset-age identified from this family, we found that comparing with the European and other populations, Asian patients displayed less proportion of severe patients and an older average age at onset. The origins of SPG80 patients associated with both their onset age and their disease severity, while the age at onset was not correlated with the disease severity.

Occurrence of super antibiotic resistance genes in the downstream of the Yangtze River in China: Prevalence and antibiotic resistance profiles.

The super antibiotic resistance genes (SARGs) demonstrate more severe threats than other antibiotic resistance genes while have not received enough attention in the environment. The study explored the prevalence and the antibiotic tolerance profiles of two typical SARGs, MCR-1 and NDM-1, and their hosting bacteria in the downstream of the Yangtze River and the nearby wastewater treatment plant (WWTP) and drinking water treatment plant (DWTP). Results indicated that MCR-1 and NDM-1 were prevalent in the influent and biological units of the WWTP. Their hosting bacteria were effectively removed, but 2.49 × 108 copies/L MCR-1 and 7.00 × 106 copies/L NDM-1 were still persistent in the effluent. In the Yangtze River, MCR-1 and NDM-1 were detected with higher abundance and antibiotic tolerance than the WWTP effluent and were significantly affected by nearby water contamination and human activities. In the DWTP, MCR-1 and NDM-1 were detected with average values 5.56 × 107 copies/L and 2.14 × 105 copies/L in the influent. Their hosting bacteria were undetectable in the effluent, but the two SARGs were still persistent with 1.39 × 107 copies/L and 6.29 × 104 copies/L, and were greatly enriched in the sludge. Molecular ecological networks demonstrated wide hosting relationships between MCR-1/NDM-1 and bacteria community in the DWTP. Redundancy analysis found that MCR-1 positively correlated with COD and NH3-N, while negatively correlated with turbidity. Additionally, MCR-1 hosting bacteria positively correlated with NO3--N and negatively correlated with COD and NH3-N. NDM-1 positively correlated with turbidity and NDM-1 hosting bacteria positively correlated with COD and NO2--N. The study demonstrated that the WWTP could not effectively remove SARGs with high amount of them being discharged into the Yangtze River. Then they were transported into the DWTP and the persistent SARGs in the effluent would probably be transferred into human, thus imposing great threats on public health.