A novel splicing mutation DNAH5 c.13,338 + 5G > C is involved in the pathogenesis of primary ciliary dyskinesia in a family with primary familial brain calcification.

BACKGROUND: Primary ciliary dyskinesia (PCD) is an autosomal recessive hereditary disease characterized by recurrent respiratory infections. In clinical manifestations, DNAH5 (NM_001361.3) is one of the recessive pathogenic genes. Primary familial brain calcification (PFBC) is a neurodegenerative disease characterized by bilateral calcification in the basal ganglia and other brain regions. PFBC can be inherited in an autosomal dominant or recessive manner. A family with PCD caused by a DNAH5 compound heterozygous variant and PFBC caused by a MYORG homozygous variant was analyzed. METHODS: In this study, we recruited three generations of Han families with primary ciliary dyskinesia combined with primary familial brain calcification. Their clinical phenotype data were collected, next-generation sequencing was performed to screen suspected pathogenic mutations in the proband and segregation analysis of families was carried out by Sanger sequencing. The mutant and wild-type plasmids were constructed and transfected into HEK293T cells instantaneously, and splicing patterns were detected by Minigene splicing assay. The structure and function of mutations were analyzed by bioinformatics analysis. RESULTS: The clinical phenotypes of the proband (II10) and his sister (II8) were bronchiectasis, recurrent pulmonary infection, multiple symmetric calcifications of bilateral globus pallidus and cerebellar dentate nucleus, paranasal sinusitis in the whole group, and electron microscopy of bronchial mucosa showed that the ciliary axoneme was defective. There was also total visceral inversion in II10 but not in II8. A novel splice variant C.13,338 + 5G > C and a frameshift variant C.4314delT (p. Asn1438lysfs *10) were found in the DNAH5 gene in proband (II10) and II8. c.347_348dupCTGGCCTTCCGC homozygous insertion variation was found in the MYORG of the proband. The two pathogenic genes were co-segregated in the family. Minigene showed that DNAH5 c.13,338 + 5G > C has two abnormal splicing modes: One is that part of the intron bases where the mutation site located is translated, resulting in early translation termination of DNAH5; The other is the mutation resulting in the deletion of exon76. CONCLUSIONS: The newly identified DNAH5 splicing mutation c.13,338 + 5G > C is involved in the pathogenesis of PCD in the family, and forms a compound heterozygote with the pathogenic variant DNAH5 c.4314delT lead to the pathogenesis of PCD.

Pedigree Analysis of Nonclassical Cholesteryl Ester Storage Disease with Dominant Inheritance in a LIPA I378T Heterozygous Carrier.

BACKGROUND: Cholesterol ester storage disorder (CESD; OMIM: 278,000) was formerly assumed to be an autosomal recessive allelic genetic condition connected to diminished lysosomal acid lipase (LAL) activity due to LIPA gene abnormalities. CESD is characterized by abnormal liver function and lipid metabolism, and in severe cases, liver failure can occur leading to death. In this study, one Chinese nonclassical CESD pedigree with dominant inheritance was phenotyped and analyzed for the corresponding gene alterations. METHODS: Seven males and eight females from nonclassical CESD pedigree were recruited. Clinical features and LAL activities were documented. Whole genome Next-generation sequencing (NGS) was used to screen candidate genes and mutations, Sanger sequencing confirmed predicted mutations, and qPCR detected LIPA mRNA expression. RESULTS: Eight individuals of the pedigree were speculatively thought to have CESD. LAL activity was discovered to be lowered in four living members of the pedigree, but undetectable in the other four deceased members who died of probable hepatic failure. Three of the four living relatives had abnormal lipid metabolism and all four had liver dysfunctions. By liver biopsy, the proband exhibited diffuse vesicular fatty changes in noticeably enlarged hepatocytes and Kupffer cell hyperplasia. Surprisingly, only a newly discovered heterozygous mutation, c.1133T>C (p. Ile378Thr) on LIPA, was found by gene sequencing in the proband. All living family members who carried the p.I378T variant displayed reduced LAL activity. CONCLUSIONS: Phenotypic analyses indicate that this may be an autosomal dominant nonclassical CESD pedigree with a LIPA gene mutation.

The role of iron-rich hydrosaline liquids in the formation of Kiruna-type iron oxide-apatite deposits.

Kiruna-type iron oxide-apatite (IOA) deposits, an important source of iron, show close associations with andesitic subvolcanic intrusions. However, the processes of ore formation and the mechanism controlling iron concentration remain uncertain. Here, we report the widespread presence of high-temperature (>800°C) water-poor multisolid hydrosaline liquid inclusions in pre- and syn-ore minerals from IOA deposits of eastern China. These inclusions consistently homogenize to a liquid phase by vapor disappearance and mostly contain 3 to 10 wt % Fe, signifying a substantial capacity for iron transportation by such hydrosaline liquids. We propose that the hydrosaline liquids were likely immiscible from the dioritic magmas with high Cl/H2O in subvolcanic settings. Subsequent reaction with host rocks and/or decompression and cooling of the hydrosaline liquids is deemed responsible for the simultaneous formation of high-temperature alteration and magnetite ores, thereby providing important insights into the distinctive characteristics of IOA deposits in shallow magmatic-hydrothermal systems.

Exploring the possible relationship between skin microbiome and brain cognitive functions: a pilot EEG study.

Human microbiota mainly resides on the skin and in the gut. Human gut microbiota can produce a variety of short chain fatty acids (SCFAs) that affect many physiological functions and most importantly modulate brain functions through the bidirectional gut-brain axis. Similarly, skin microorganisms also have identical metabolites of SCFAs reported to be involved in maintaining skin homeostasis. However, it remains unclear whether these SCFAs produced by skin bacteria can affect brain cognitive functions. In this study, we hypothesize that the brain's functional activities are associated with the skin bacterial population and examine the influence of local skin-bacterial growth on event-related potentials (ERPs) during an oddball task using EEG. Additionally, five machine learning (ML) methods were employed to discern the relationship between skin microbiota and cognitive functions. Twenty healthy subjects underwent three rounds of tests under different conditions-alcohol, glycerol, and water. Statistical tests confirmed a significant increase in bacterial population under water and glycerol conditions when compared to the alcohol condition. The metabolites of bacteria can turn phenol red from red-orange to yellow, confirming an increase in acidity. P3 amplitudes were significantly enhanced in response to only oddball stimulus at four channels (Fz, FCz, and Cz) and were observed after the removal of bacteria when compared with that under the water and glycerol manipulations. By using machine learning methods, we demonstrated that EEG features could be separated with a good accuracy (> 88%) after experimental manipulations. Our results suggest a relationship between skin microbiota and brain functions. We hope our findings motivate further study into the underlying mechanism. Ultimately, an understanding of the relationship between skin microbiota and brain functions can contribute to the treatment and intervention of diseases that link with this pathway.

Clinical phenotype and genetic function analysis of a family with hypomyelinating leukodystrophy-7 caused by POLR3A mutation.

Hypomyelinating leukodystrophy (HLD) is a rare genetic heterogeneous disease that can affect myelin development in the central nervous system. This study aims to analyze the clinical phenotype and genetic function of a family with HLD-7 caused by POLR3A mutation. The proband (IV6) in this family mainly showed progressive cognitive decline, dentin dysplasia, and hypogonadotropic hypogonadism. Her three old brothers (IV1, IV2, and IV4) also had different degrees of ataxia, dystonia, or dysarthria besides the aforementioned manifestations. Their brain magnetic resonance imaging showed bilateral periventricular white matter atrophy, brain atrophy, and corpus callosum atrophy and thinning. The proband and her two living brothers (IV2 and IV4) were detected to carry a homozygous mutation of the POLR3A (NM_007055.4) gene c. 2300G > T (p.Cys767Phe), and her consanguineous married parents (III1 and III2) were p.Cys767Phe heterozygous carriers. In the constructed POLR3A wild-type and p.Cys767Phe mutant cells, it was seen that overexpression of wild-type POLR3A protein significantly enhanced Pol III transcription of 5S rRNA and tRNA Leu-CAA. However, although the mutant POLR3A protein overexpression was increased compared to the wild-type protein overexpression, it did not show the expected further enhancement of Pol III function. On the contrary, Pol III transcription function was frustrated (POLR3A, BC200, and tRNA Leu-CAA expression decreased), and MBP and 18S rRNA expressions were decreased. This study indicates that the POLR3A p.Cys767Phe variant caused increased expression of mutated POLR3A protein and abnormal expression of Pol III transcripts, and the mutant POLR3A protein function was abnormal.

Adult type I Gaucher disease with splenectomy caused by a compound heterozygous GBA1 mutation in a Chinese patient: a case report.

Gaucher disease (GD) is an autosomal recessive ailment resulting from glucocerebrosidase deficiency caused by a mutation in the GBA1 gene, leading to multi-organ problems in the liver, spleen, and bone marrow. In China, GD is extremely uncommon and has a lower incidence rate than worldwide. In this study, we report the case of an adult male with an enlarged spleen for 13 years who presented with abdominal distension, severe loss of appetite and weight, reduction of the three-line due to hypersplenism, frequent nosebleeds, and bloody stools. Regrettably, the unexpected discovery of splenic pathology suggestive of splenic Gaucher disease was only made after a splenectomy due to a lack of knowledge about rare disorders. Our patient's delayed diagnosis may have been due to the department where he was originally treated, but it highlights the need for multidisciplinary consultation in splenomegaly of unknown etiology. We then investigated the patient's clinical phenotypes and gene mutation features using genetically phenotypical analysis. The analysis of the GBA1 gene sequence indicated that the patient carried a compound heterozygous mutation consisting of two potentially disease-causing mutations: c.907C > A (p. Leu303Ile) and c.1448 T > C (p. Leu483Pro). While previous research has linked the p. Leu483Pro mutation site to neurologic GD phenotypes (GD2 and GD3), the patients in this investigation were identified as having non-neuronopathic GD1. The other mutation, p. Leu303Ile, is a new GD-related mutation not indexed in PubMed that enriches the GBA1 gene mutation spectrum. Biosignature analysis has shown that both mutations alter the protein's three-dimensional structure, which may be a pathogenic mechanism for GD1 in this patient.

Vof16-miR-185-5p-GAP43 network improves the outcomes following spinal cord injury via enhancing self-repair and promoting axonal growth.

INTRODUCTION: Self-repair of spinal cord injury (SCI) has been found in humans and experimental animals with partial recovery of neurological functions. However, the regulatory mechanisms underlying the spontaneous locomotion recovery after SCI are elusive. AIMS: This study was aimed at evaluating the pathological changes in injured spinal cord and exploring the possible mechanism related to the spontaneous recovery. RESULTS: Immunofluorescence staining was performed to detect GAP43 expression in lesion site after spinal cord transection (SCT) in rats. Then RNA sequencing and gene ontology (GO) analysis were employed to predict lncRNA that correlates with GAP43. LncRNA smart-silencing was applied to verify the function of lncRNA vof16 in vitro, and knockout rats were used to evaluate its role in neurobehavioral functions after SCT. MicroRNA sequencing, target scan, and RNA22 prediction were performed to further explore the underlying regulatory mechanisms, and miR-185-5p stands out. A miR-185-5p site-regulated relationship with GAP43 and vof16 was determined by luciferase activity analysis. GAP43-silencing, miR-185-5p-mimic/inhibitor, and miR-185-5p knockout rats were also applied to elucidate their effects on spinal cord neurite growth and neurobehavioral function after SCT. We found that a time-dependent increase of GAP43 corresponded with the limited neurological recovery in rats with SCT. CRNA chip and GO analysis revealed lncRNA vof16 was the most functional in targeting GAP43 in SCT rats. Additionally, silencing vof16 suppressed neurite growth and attenuated the motor dysfunction in SCT rats. Luciferase reporter assay showed that miR-185-5p competitively bound the same regulatory region of vof16 and GAP43. CONCLUSIONS: Our data indicated miR-185-5p could be a detrimental factor in SCT, and vof16 may function as a ceRNA by competitively binding miR-185-5p to modulate GAP43 in the process of self-recovery after SCT. Our study revealed a novel vof16-miR-185-5p-GAP43 regulatory network in neurological self-repair after SCT and may underlie the potential treatment target for SCI.

Upregulation of proBDNF/p75NTR signaling in immune cells and its correlation with inflammatory markers in patients with major depression.

ProBDNF is the precursor protein of brain-derived neurotrophic factor (BDNF) expressed in the central nervous system and peripheral tissues. Previous studies showed that the blood levels of both proBDNF and p75 neurotrophic receptors (p75NTR) in major depressive disorder (MDD) were increased, but which blood cell types express proBDNF and its receptors is not known. Furthermore, the relationship between proBDNF/p75NTR and inflammatory cytokines in peripheral blood of MDD is unclear. Peripheral blood mononuclear cells (PBMCs) and serum were obtained from depressive patients (n = 32) and normal donors (n = 20). We examined the expression of proBDNF and inflammatory markers and their correlative relationship in patients with major depression. Using flow cytometry analysis, we examined which blood cells express proBDNF and its receptors. Finally, the role of proBDNF/p75NTR signal in inflammatory immune activity of PBMCs was verified in vitro experiments. Inflammatory cytokines in PBMC from MDD patients were increased and correlated with the major depression scores. The levels of IL-1ß and IL-10 were also positively correlated with the major depression scores, while the levels of TNF-α and IL-6 were negatively correlated with the major depression scores. Intriguingly, the levels of sortilin were positively correlated with IL-1ß. Q-PCR and Western blots showed proBDNF, p75NTR, and sortilin levels were significantly increased in PBMCs from MDD patients compared with that from the normal donors. Flow cytometry studies showed that proBDNF and p75NTR were present mainly in CD4+ and CD8+ T cells. The number of proBDNF and p75NTR positive CD4+ and CD8+ T cells from MDD patients was increased and subsequently reversed after therapeutic management. Exogenous proBDNF protein or p75ECD-Fc treatment of cultured PBMC affected the release of inflammatory cytokines in vitro. ProBDNF promoted the expression of inflammatory cytokines, while p75ECD-Fc inhibited the expression of inflammatory cytokines. Given there was an inflammatory response of lymphocytes to proBDNF, it is suggested that proBDNF/p75NTR signaling may upstream inflammatory cytokines in MDD. Our data suggest that proBDNF/p75NTR signaling may not only serve as biomarkers but also may be a potential therapeutic target for MDD.

Effects of bilateral repetitive transcranial magnetic stimulation on prospective memory in patients with schizophrenia: A double-blind randomized controlled clinical trial.

AIMS: To investigate effects of repetitive transcranial magnetic stimulation (rTMS) on the prospective memory (PM) in patients with schizophrenia (SCZ). METHODS: Fifty of 71 patients completed this double-blind placebo-controlled randomized trial and compared with 18 healthy controls' (HCs) PM outcomes. Bilateral 20 Hz rTMS to the dorsolateral prefrontal cortex at 90% RMT administered 5 weekdays for 4 weeks for a total of 20 treatments. The Positive and Negative Symptom Scale (PANSS), the Scale for the Assessment of Negative Symptoms (SANS), and PM test were assessed before and after treatment. RESULTS: Both Event-based PM (EBPM) and Time-based PM (TBPM) scores at baseline were significantly lower in patients with SCZ than that in HCs. After rTMS treatments, the scores of EBPM in patients with SCZ was significantly improved and had no differences from that in HCs, while the scores of TBPM did not improved. The negative symptom scores on PANSS and the scores of almost all subscales and total scores of SANS were significantly improved in both groups. CONCLUSIONS: Our findings indicated that bilateral high-frequency rTMS treatment can alleviate EBPM but not TBPM in patients with SCZ, as well as improve the negative symptoms. SIGNIFICANCE: Our results provide one therapeutic option for PM in patients with SCZ.

Epigenetic-based combination therapy and liposomal codelivery overcomes osimertinib-resistant NSCLC via repolarizing tumor-associated macrophages.

Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.

Clarity on the blazing trail: clearing the way for amyloid-removing therapies for Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with a complex pathogenesis. Senile plaques composed of the amyloid-ß (Aß) peptide in the brain are the core hallmarks of AD and a promising target for the development of disease-modifying therapies. However, over the past 20 years, the failures of clinical trials directed at Aß clearance have fueled a debate as to whether Aß is the principal pathogenic factor in AD and a valid therapeutic target. The success of the recent phase 3 trials of lecanemab (Clarity AD) and donanemab (Trailblazer Alz2), and lessons from previous Aß clearance trials provide critical evidence to support the role of Aß in AD pathogenesis and suggest that targeting Aß clearance is heading in the right direction for AD treatment. Here, we analyze key questions relating to the efficacy of Aß targeting therapies, and provide perspectives on early intervention, adequate Aß removal, sufficient treatment period, and combinatory therapeutics, which may be required to achieve the best cognitive benefits in future trials in the real world.

Potential regulatory role of the Nrf2/HMGB1/TLR4/NF-κB signaling pathway in lupus nephritis.

OBJECTIVES: Systemic lupus erythematosus is an autoimmune disease that involves multiple organ systems. One of its major complications, lupus nephritis (LN), is associated with a high mortality rate, and children-onset LN have a more severe course and worse prognosis than adults. Oxidative stress and inflammatory responses are involved in LN development and pathogenesis. Thus, this study aimed to explore the role of signaling regulation of the Nrf2/HMGB1/TLR/NF-κB pathway in LN pathogenesis and unravel the expression of TLR4+CXCR4+ plasma cells subset (PCs) in LN. METHODS: C57BL/6 and MRL/lpr mice were divided into four groups: control, model, vector control, and Nrf2 overexpression groups. The vector control and Nrf2 overexpression groups were injected with adenoviral vectors into the kidney in situ. Pathological changes in kidney tissues were observed by hematoxylin-eosin staining. The expression of Nrf2, HMGB1, TLR4, NF-κB, and downstream inflammatory factors in kidney samples was analyzed by quantitative polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. The ratios of TLR4+CXCR4+ PC subsets in the blood and kidneys of mice were determined by flow cytometry. RESULTS: In MRL/lpr mice, Nrf2 was downregulated while HMGB1/TLR4/NF-κB pathway proteins were upregulated. Nrf2 overexpression decreased the expression of HMGB1, TLR4, NF-κB, and its downstream inflammatory cytokines (IL-1ß and TNFα). These cytokines were negatively correlated with an increase in Nrf2 content. PC and TLR4 + CXCR4 + PCs in the blood and kidney samples were significantly increased in MRL/lpr mice; however, they were decreased upon Nrf2 overexpression. CONCLUSION: This study showed severe kidney injury in an LN mouse model and an increased ratio of TLR4 + CXCR4 + PCs. Furthermore, we observed that Nrf2 regulates LN immune response through the Nrf2/HMGB1/TLR4/NF-κB pathway, which can be considered an important target for LN treatment. The clinical value of the findings of our study requires further investigation.

The Characteristic of {101¯2}<101¯1¯> Twin of Ti-10V-2Fe-3Al under Planar Wave Detonation.

The microstructure evolution of the twin of TB6 (Ti-10V-2Fe-3Al) under planar wave detonation was studied. The initial microstructure of the alloy consists of an α and ß phase. It is found that twin deformation is operated in only the α phase due to the limited slip system in this phase. α grains are mainly rotated from {101¯0} to {0002} during the deformation due to the {101¯2}<101¯1¯> twin. Twin variant selection is found in this study, and the orientation of all {101¯2} twins is oriented at {0002} in different α grains with different deformation degrees. The twin variant selection is well explained based on the strain relaxation along the loading axis and the Schmid factor for twinning shear.

Clinical phenotype and genetic function analysis of a rare family with hereditary leiomyomatosis and renal cell carcinoma complicated with Birt-Hogg-Dubé syndrome.

To date, over 200 families with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) and over 600 families with Birt-Hogg-Dubé (BHD) syndrome have been reported, with low incidence. Here, we describe a patient with suspected rare HLRCC complicated by BHD syndrome. The proband (II1) had characteristic cutaneous leiomyoma-like protrusions on the neck and back, a left renal mass and multiple right renal, liver and bilateral lung cysts. Three family members (I1, II2, II3) had a history of renal cancer and several of the aforementioned clinical features. Two family members (II1, II3) diagnosed with fumarate hydratase (FH)-deficient papillary RCC via pathological biopsy carried two heterozygous variants: FH (NM_000143.3) missense mutation c.1189G>A (p.Gly397Arg) and FLCN (NM_144997.5) frameshift mutation c.1579_1580insA (p.Arg527Glnfs*75). No family member carrying a single variant had renal tumours. In HEK293T cells transfected with mutant vectors, mRNA and protein expression after FLCN p.Arg527Glnfs*75 and FH p.Gly397Arg mutations were significantly lower than those in wild-type (WT) cells. Cell immunofluorescence showed altered protein localisation and reduced protein expression after FLCN p.Arg527Glnfs*75 mutation. The FH WT was uniformly distributed in the cytoplasm, whereas FH protein expression was reduced after the p.Gly397Arg mutation and scattered sporadically with altered cell localisation. Patients with two variants may have a significantly increased penetrance of RCC.

An Imbalance in the Pro/mature BDNF Ratio Occurs in Multiple Brain Regions During Normal Ageing in Wild-Type Mice.

The early transition to Alzheimer's disease is characterized by a period of accelerated brain atrophy that exceeds normal ageing. Identifying the molecular basis of this atrophy could facilitate the discovery of novel drug targets. The precursor of brain-derived neurotrophic factor, a well characterized neurotrophin, is increased in the hippocampus of aged rodents, while its mature isoform is relatively stable. This imbalance could increase the risk of Alzheimer's disease by precipitating its pathological hallmarks. However, less is known about how relative levels of these isoforms change in middle-aged mice. In addition, the underlying mechanisms that might cause an imbalance are unknown. The main aim of this study was to determine how precursor brain-derived neurotrophic factor changes relative to its mature isoform with normal brain ageing in wild type mice. A secondary aim was to determine if signaling through the neurotrophin receptor, p75 influences this ratio. An increasing ratio was identified in several brain regions, except the hippocampus, suggesting a neurotrophic imbalance occurs as early as middle age. Some changes in receptors that mediate the isoforms effects were also identified, but these did not correspond with trends in the isoforms. Relative amounts of precursor brain-derived neurotrophic factor were mostly unchanged in mutant p75 mice. The lack of changes suggested that signaling through the receptor had no influence on the ratio.

Sex-Dependent Effects of Chronic Restraint Stress on Mood-Related Behaviours and Neurochemistry in Mice.

Anxiety and depressive disorders are closely associated; however, the pathophysiology of these disorders remains poorly understood. Further exploration of the mechanisms involved in anxiety and depression such as the stress response may provide new knowledge that will contribute to our understanding of these disorders. Fifty-eight 8-12-week-old C57BL6 mice were separated into experimental groups by sex as follows: male controls (n = 14), male restraint stress (n = 14), female controls (n = 15) and female restraint stress (n = 15). These mice were taken through a 4-week randomised chronic restraint stress protocol, and their behaviour, as well as tryptophan metabolism and synaptic proteins, were measured in the prefrontal cortex and hippocampus. Adrenal catecholamine regulation was also measured. The female mice showed greater anxiety-like behaviour than their male counterparts. Tryptophan metabolism was unaffected by stress, but some basal sex characteristics were noted. Synaptic proteins were reduced in the hippocampus in stressed females but increased in the prefrontal cortex of all female mice. These changes were not found in any males. Finally, the stressed female mice showed increased catecholamine biosynthesis capability, but this effect was not found in males. Future studies in animal models should consider these sex differences when evaluating mechanisms related to chronic stress and depression.

A retrospective case-control study of facial emotion recognition in male veterans with chronic schizophrenia and its correlation with interpersonal communication.

OBJECTIVE: To understand the facial emotion recognition of male veterans with chronic schizophrenia and the relationship between facial emotion recognition and interpersonal communication to provide a reference for designing social skills training programmes. METHOD: Fifty-six eligible male patients with chronic schizophrenia who were admitted to our hospital from October 2020 to April 2021 were selected, and 24 healthy people were selected as controls. Facial emotion recognition, social communication skills and self-perceived interpersonal disturbance were assessed using a facial emotion recognition stimulus manual, the Social Skills Checklist (SSC) and the Interpersonal Relationship Integrative Diagnostic Scale (IRIDS). Disease status was assessed using the Positive and Negative Syndrome Scale. RESULTS: Both the control group and the patient group had the highest recognition accuracy for neutral faces. The recognition rate for neutral expression was higher in the control group than in the patient group (p = 0.008). The rate of neutral expressions identified as happiness was higher in the patient group than in the control group (p = 0.001). The identification of anger as happiness was higher in the control group than in the patient group (p = 0.026), and the pattern of misidentification was similar between the control group and the patient group. The accuracy of facial emotion recognition was negatively associated with the age of onset (p < 0.05). The recognition accuracy for happiness was negatively associated with negative symptoms, general pathological symptoms and total scale scores (p < 0.05). The total score for expression recognition was negatively associated with the negative symptom subscale scores (p < 0.05), and there was no correlation between expression recognition and positive symptoms (p > 0.05). The recognition accuracy for happiness was negatively correlated with the IRIDS conversation factor (p < 0.05). The recognition accuracy for happiness and anger and the total scores for facial emotion recognition were negatively correlated with the SSC subscale score and the total score (p < 0.05 and p < 0.01, respectively). The main influencing factors on facial emotion recognition were the SSC total score (p < 0.001) and the positive factor score (p = 0.039). CONCLUSION: Veterans with chronic schizophrenia have facial emotion recognition impairments affected by negative symptoms. There is a correlation between facial emotion recognition and interpersonal communication. HIGHLIGHTS: 1. There are extensive facial expression recognition disorders in schizophrenia. 2. The pattern of misidentification was similar in both the control group and the patient group, with the tendency for happiness to be identified as a neutral emotion, anger as happiness, and fear as neutral emotion and anger. 3. Based on the comprehensive assessment of social cognitive impairment in patients with schizophrenia, prospective studies of standardised interventions are designed to provide support for clinical practice.

Han family with essential tremor caused by the P421L variant of the TENM4 gene in China.

BACKGROUND: Essential tremor (ET) is an autosomal dominant inheritance disorder. Mutations in fusion sarcoma (FUS), mitochondrial serine peptidase 2 (HTRA2), teneurin transmembrane protein 4 (TENM4), sortilin1 (SORT1), SCN11A, and notch2N-terminal-like (NOTCH2NLC) genes are associated with familial ET. METHODS: A proband with ET was tested using whole-exome sequencing and repeat-primed polymerase chain reaction. Subsequently, the family members were screened for the suspected mutation, and the results were verified using Sanger sequencing. The relationship between pedigree and phenotype was also analyzed, and structural and functional changes in the variants were predicted using bioinformatics analysis. RESULTS: In a family with ET, the proband (III4) and the proband's father (II1), grandfather (I1), uncle (II2), and cousin (III5) all presented with involuntary tremors of both upper limbs. The responsible mutation was identified as TENM4 c.1262C > T (p.P421L), which showed genetic co-segregation in the family survey. AlphaFold predicted a change in the spatial position of TENM4 after the P421L mutation, which may have affected its stability. AlphaFold also predicted P421L to be a deleterious variation, which would lead to lower degrees of freedom of the TENM4 protein, thereby affecting the protein's structure and stability. According to the bioinformatics analysis, TENM4 (p.P421L) may reduce the signal reaching the nucleus by affecting the expression of TENM4 messenger RNA (mRNA), thereby impairing the normal oligodendrocyte differentiation process and leading to impaired myelination. CONCLUSION: This study revealed that the TENM4 (p.P421L) pathogenic missense variation was responsible for ET in the proband.

Effect of thermal process on the key aroma components of green tea with chestnut-like aroma.

BACKGROUND: Chestnut-like aroma is one of the unique qualities of Chinese green tea and has become an important factor influencing consumer decisions. However, the chemical formation mechanism of chestnut-like aroma during green tea processing remains unclear. In this study, the dynamic changes of key components contributing to chestnut-like aroma and their precursors were analyzed in fresh leaves, fixation leaves, first baking tea leaves, and green tea. RESULTS: The thermal process had an important effect on volatile components in tea leaves, causing a significant decrease of alcohols and esters and a significant increase of ketones, acids, phenols, and sulfur compounds. Furthermore, 31 volatiles were identified as the key odorants responsible for chestnut-like aroma of green tea, including dimethyl sulfide, methyl isobutenyl ketone, 2-methylbutanal, 2,4-dimethylstyrene, d-limonene, methyl 2-methylvalerate, linalool, decanal, longifolene, phenylethyl alcohol, l-α-terpineol, jasmone, and so on. And the majority of these odorants were only formed in the drying stage. Additionally, isoleucine, theanine, methionine, and glucose were found to be involved in the formation of chestnut-like aroma of green tea. CONCLUSION: The drying process played a vital important role in the formation of chestnut-like aroma of green tea. © 2022 Society of Chemical Industry.

Clinical study on the level of neutrophil extracellular trap in the bile of patients with choledocholithiasis / 中华消化杂志

Objective:To investigate the activation level of neutrophil extracellular trap (NET) in the bile of patients with choledocholithiasis and its clinical significance.Methods:From May 2021 to October 2022, 130 patients underwent endoscopic retrograde cholangiopancreatography (ERCP) at the Department of Gastroenterology, the First Affiliated Hospital of Anhui Medical University were enrolled. The patients were divided into choledocholithiasis group (90 cases) and non-choledocholithiasis group (40 cases), and the choledocholithiasis group was further divided into large stone group (maximum diameter >1 cm, 36 cases) and small stone group (maximum diameter≤1 cm, 54 cases). The bile samples were collected from 130 patients during operation and 16 choledocholithiasis patients with nasobiliary drainage at 24 h after operation.The levels of myeloperoxidase(MPO), neutrophilelastase(NE), and citrullinated histone H3(CitH3) in bile were detected by enzyme-linked immunosorbent assay.The levels of MPO, NE, and CitH3 were compared between choledocholithiasis group and non-choledocholithiasis group, between large stone group and small stone group, as well as between choledocholithiasis patients before ERCP and after ERCP. Mann-Whitney U test and Wilcoxon signed rank test were used for statistical analysis. Results:The levels of MPO, NE and CitH3 in the bile of choledocholithiasis group were 32.6 U/L(28.5 U/L), 30.6 ng/L(35.2 ng/L) and 0.37 μg/L(0.73 μg/L), respectively, which were all higher than those of non-choledocholithiasis group (19.9 U/L(36.4 U/L), 18.2 ng/L(27.4 ng/L), and 0.10 μg/L(0.25 μg/L)), and the differences were statistically significant ( Z=2.91, 3.20 and 3.34; P=0.004, 0.001 and 0.001). The levels of MPO, NE and CitH3 of large stone group were 47.0 U/L(49.4 U/L), 48.4 ng/L(39.5 ng/L) and 0.83 μg/L(1.08 μg/L), respectively, which were all higher than those of small stone group (29.3 U/L(17.5 U/L), 24.0 ng/L(25.8 ng/L), and 0.27 μg/L(0.45 μg/L)), and the differences were statistically significant ( Z=2.01, 3.58 and 3.63; P=0.044, <0.001 and <0.001). The levels of MPO, NE and CitH3 in the bile of choledocholithiasis patients after ERCP significantly decreased compare with those before ERCP (19.4 U/L(19.8 U/L) vs. 33.6 U/L(36.7 U/L), 12.7 ng/L(15.1 ng/L) vs. 22.7 ng/L(25.9 ng/L), 0.05 μg/L(0.12 μg/L) vs. 0.14 μg/L(0.27 μg/L)), and the differences were statistically significant ( Z=3.52, 3.30 and 3.18; all P<0.001). Conclusion:The activation level of NET in the bile of patients with choledocholithiasis increase, while the activation level of NET decrease after ERCP, which indicate that NET may be involved in the formation of choledocholithiasis.