Toll-Like Receptors Mediate Opposing Dendritic Cell Effects on Treg/Th17 Balance in Mice With Intracerebral Hemorrhage.

BACKGROUND: Dendritic cells (DCs) regulate the immune response associated with T lymphocytes, but their role in stroke remains unclear. In this study, we investigated the causal relationship between DCs and T-cell response in intracerebral hemorrhage (ICH) by focusing on TLRs (toll-like receptors) that may modulate the function of DCs. METHODS: We studied the effects of TLR4, TLR2, and TLR9 on DC-mediated T-cell response and the outcomes of ICH using male C57BL/6 and CD11c-DTx (diphtheria toxin) receptor mice. We administered specific agents intraperitoneally or orally and evaluated the results using flow cytometry, real-time polymerase chain reaction, Western blotting, immunofluorescence staining, histopathology, and behavioral tests. RESULTS: TLR4 and TLR2 activation induces DC maturation and reduces the ratio of regulatory T to T-helper 17 cells in the brain and periphery after ICH. When either of these receptors is activated, it can worsen neuroinflammation and exacerbate ICH outcomes. TLR9 also promotes DC maturation, stabilizing the number of DCs, particularly conventional DCs. TLR9 has the opposite effects on regulatory T/T-helper 17 balance, neuroinflammation, and ICH outcomes compared with TLR4 and TLR2. Upon stimulation, TLR4 and TLR9 may achieve these effects through the p38-MAPK (p38-mitogen-activated protein kinase)/MyD88 (myeloid differentiation primary response gene 88) and indoleamine 2,3-dioxygenase 1 (IDO1)/GCN2 (general control nonderepressible 2) signaling pathways, respectively. DCs act as intermediaries for TLR-mediated T-cell response. CONCLUSIONS: TLR-mediated opposing effects of DCs on T-cell response may provide novel strategies to treat ICH.

Melanin concentrating hormone regulates the JNK/ERK signaling pathway to alleviate influenza A virus infection-induced neuroinflammation.

Melanin concentrating hormone (MCH) controls many brain functions, such as sleep/wake cycle and memory, and modulates the inflammation response. Previous studies have shown that influenza A virus (IAV) infection-induced neuroinflammation leads to central nervous damage. This study investigated the potential effects of MCH against neuroinflammation induced by IAV infection and its mechanism. MCH (1 and 2 mg/ml) was administrated for 5 consecutive days before IAV infection. Pentobarbital-induced sleep tests, an open-field test, and a Morris water maze were performed to measure sleep quality, spatial learning and memory ability. Neuronal loss and microglial activation were observed with Nissl staining and immunofluorescence assay. The levels of inflammatory cytokines and the expression of the JNK/ERK signaling pathway were examined by ELISA and western blot. IAV infection led to poor sleep quality, impaired the ability of spatial learning and memory, caused neuronal loss and microglial activation in mice's hippocampus and cortex. Meanwhile the level of inflammatory cytokines increased, and the JNK/ERK signaling pathway was activated after IAV infection. MCH administration significantly alleviated IAV-induced neuroinflammation, cognitive impairment, and sleep disorder, decreased the levels of inflammatory cytokines, and inhibited neuronal loss and microglial activation in the hippocampus and cortex by regulating the JNK/ERK signaling pathway. Therefore, MCH alleviated the neuroinflammation, spatial learning and memory impairment, and sleep disorder in IAV-infected mice by regulating the JNK/ERK signaling pathway.

The efficacy and safety of iGlarLixi versus IDegAsp in Chinese people with type 2 diabetes suboptimally controlled with oral antidiabetic drugs: The Soli-D randomized controlled trial.

AIM: To compare the efficacy and safety of a fixed-ratio combination of insulin glargine 100 U/mL plus lixisenatide (iGlarLixi) with premixed insulin, insulin degludec plus insulin aspart (IDegAsp), in Chinese people with type 2 diabetes (T2D) suboptimally controlled with oral antidiabetic drug(s) (OADs). METHODS: In Soli-D, a 24-week, multicentre, open-label, study, insulin-naïve adults were randomized 1:1 to once-daily injections of iGlarLixi (n = 291) or IDegAsp (n = 291), with continued metformin ± sodium-glucose co-transporter-2 inhibitors. The primary endpoint was non-inferiority in HbA1c change from baseline to week 24. Key secondary endpoints included superiority in HbA1c change and body weight (BW) change at week 24. Hypoglycaemia rates were also assessed. RESULTS: At week 24, iGlarLixi showed non-inferiority and superiority over IDegAsp in HbA1c reduction (least squares [LS] mean difference: -0.20 [95% confidence interval {CI}: -0.33, -0.07]; P < .001 for non-inferiority; [97.5% CI: -0.35, -0.05]; P = .003 for superiority). iGlarLixi decreased BW and IDegAsp increased BW from baseline to week 24, with a statistically significant LS mean difference of -1.49 kg in favour of iGlarLixi (97.5% CI: -2.32, -0.66; P < .001). Event rates (per person-year) for American Diabetes Association (ADA) Level 1, 2 or 3 hypoglycaemia were lower for iGlarLixi (1.90) versus IDegAsp (2.72) (relative risk: 0.71; 95% CI: 0.52, 0.98). No ADA Level 3 hypoglycaemia or unexpected safety findings were reported. CONCLUSIONS: In Chinese people with T2D suboptimally controlled with OADs, once-daily iGlarLixi provided better glycaemic control with BW benefit and lower hypoglycaemia event rates versus IDegAsp.

Two new cases with the UBQLN2 gene mutation in Han Chinese.

Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. 18F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.

Age-Related Effects on MSC Immunomodulation, Macrophage Polarization, Apoptosis, and Bone Regeneration Correlate with IL-38 Expression.

Mesenchymal stem cells (MSCs) are known to promote tissue regeneration and suppress excessive inflammation caused by infection or trauma. Reported evidence indicates that various factors influence the expression of MSCs' endogenous immunomodulatory properties. However, the detailed interactions of MSCs with macrophages, which are key cells involved in tissue repair, and their regulatory mechanisms are not completely understood. We herein investigated how age-related immunomodulatory impairment of MSCs alters the interaction of MSCs with macrophages during bone healing using young (5-week old) and aged (50-week old) mice. To clarify the relationship between inflammatory macrophages (M1) and MSCs, their spatiotemporal localization at the bone healing site was investigated by immunostaining, and possible regulatory mechanisms were analyzed in vitro co-cultures. Histomorphometric analysis revealed an accumulation of M1 and a decrease in MSC number at the healing site in aged mice, which showed a delayed bone healing. In in vitro co-cultures, MSCs induced M1 apoptosis through cell-to-cell contact but suppressed the gene expression of pro-inflammatory cytokines by soluble factors secreted in the culture supernatant. Interestingly, interleukin 38 (Il-38) expression was up-regulated in M1 after co-culture with MSCs. IL-38 suppressed the gene expression of inflammatory cytokines in M1 and promoted the expression of genes associated with M1 polarization to anti-inflammatory macrophages (M2). IL-38 also had an inhibitory effect on M1 apoptosis. These results suggest that MSCs may induce M1 apoptosis, suppress inflammatory cytokine production by M1, and induce their polarization toward M2. Nevertheless, in aged conditions, the decreased number and immunomodulatory function of MSCs could be associated with a delayed M1 clearance (i.e., apoptosis and/or polarization) and consequent delayed resolution of the inflammatory phase. Furthermore, M1-derived IL-38 may be associated with immunoregulation in the tissue regeneration site.

Predicting hostility towards women: incel-related factors in a general sample of men.

Hostility towards women is a type of prejudice that can have adverse effects on women and society, but research on predictors of men's hostility towards women is limited. The present study primarily introduced predictors associated with misogynist involuntary celibates (incels), and then investigated whether loneliness, rejection, attractiveness, number of romantic and sexual partners, right-wing authoritarianism, and gaming predicted hostility towards women among a more general sample of men. A total of 473 men (aged 18-35, single, heterosexual, UK residents) recruited via Prolific answered the hostile sexism subscale, the misogyny scale, the self-perceived sexual attractiveness scale, the right-wing authoritarianism scale, the game addiction scale for adolescents, the adult rejection-sensitivity scale, the UCLA loneliness scale, and self-developed questions regarding number of sexual and romantic partners, and time spent gaming. We found a strong positive relationship between right-wing authoritarianism and hostility towards women, as well as a strong convex curvilinear relationship between attractiveness and hostility towards women. The number of sexual partners showed a moderate concave relationship with hostility towards women. We did not find sufficient support for a relationship between gaming and hostility towards women, and there was no support that loneliness, rejection, or romantic partners predicted hostility towards women among a general sample of men. Our study supports right-wing authoritarianism and self-perceived attractiveness as potential strong predictors in understanding men's hostility towards women in the wider community. Pre-registration: https://osf.io/ms3a4.

Pirtobrutinib versus venetoclax in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia: a matching-adjusted indirect comparison.

Venetoclax is a standard treatment for patients with CLL following covalent BTK inhibitor (cBTKi) therapy, despite relatively limited prospective data in this setting. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that was designed to overcome the pharmacologic limitations of cBTKi and re-establish BTK inhibition. An unanchored matching-adjusted indirect comparison (MAIC) was conducted to estimate the treatment effect of pirtobrutinib versus venetoclax monotherapy in patients with cBTKi pre-treated CLL. Data from patients with CLL who were venetoclax-naïve and pre-treated with cBTKi received pirtobrutinib (n=146) in the phase 1/2 BRUIN study were compared with the only identified trial of patients with CLL receiving venetoclax after a cBTKi (n=91), as administered as monotherapy until progression. Outcomes included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). Both unweighted and weighted analyses were conducted. PFS and OS of pirtobrutinib and venetoclax were comparable in both unweighted and weighted analyses (weighted hazard ratios for PFS: 1.01, 95% CI: 0.58-1.73, p=0.98 and OS: 0.64, 95% CI: 0.25-1.67, p=0.34). ORR was significantly higher for pirtobrutinib (80.2% vs 64.8%, p=0.01). Grade ≥3 TEAEs were lower in weighted analyses for pirtobrutinib vs venetoclax (all p.

T-cell receptor signaling modulated by the co-receptors: Potential targets for stroke treatment.

Stroke is a severe and life-threatening disease, necessitating more research on new treatment strategies. Infiltrated T lymphocytes, an essential adaptive immune cell with extensive effector function, are crucially involved in post-stroke inflammation. Immediately after the initiation of the innate immune response triggered by microglia/macrophages, the adaptive immune response associated with T lymphocytes also participates in the complex pathophysiology of stroke and partially informs the outcome of stroke. Preclinical and clinical studies have revealed the conflicting roles of T cells in post-stroke inflammation and as potential therapeutic targets. Therefore, exploring the mechanisms that underlie the adaptive immune response associated with T lymphocytes in stroke is essential. The T-cell receptor (TCR) and its downstream signaling regulate T lymphocyte differentiation and activation. This review comprehensively summarizes the various molecules that regulate TCR signaling and the T-cell response. It covers both the co-stimulatory and co-inhibitory molecules and their roles in stroke. Because immunoregulatory therapies targeting TCR and its mediators have achieved great success in some proliferative diseases, this article also summarizes the advances in therapeutic strategies related to TCR signaling in lymphocytes after stroke, which can facilitate translation.

Efficacy and safety of basal-first titration order in individuals with type 2 diabetes receiving short-term intensive insulin therapy: An exploratory analysis of BEYOND V.

AIMS: To present the results of an exploratory analysis of the BEYOND V study in which Chinese individuals with uncontrolled type 2 diabetes (T2D) received short-term intensive insulin therapy (SIIT) during study run-in (prior to randomization) using a basal-first insulin titration method. MATERIALS AND METHODS: This was exclusively an exploratory analysis of the 7- to 10-day run-in period of BEYOND V. Participants were hospitalized and had oral therapies withdrawn (except metformin). They received SIIT with once-daily insulin glargine and three-times-daily premeal insulin glulisine, titrated daily from a total starting dose of 0.4 to 0.5 units/kg/d, first adjusting insulin glargine to achieve fasting blood glucose (FBG) of 4.4 to 6.1 mmol/L (79 to 119 mg/dL), then insulin glulisine to achieve pre-meal blood glucose of 4.4 to 6.1 mmol/L. Key outcomes were the proportions of participants achieving FBG and 2-hour postprandial blood glucose (PBG) targets. RESULTS: Overall, 397 entered the run-in (mean 54.2 years, 235 males [59.2%]). At the end of SIIT, 374/396 participants (94.4%) had both FBG <7.0 mmol/L (<126 mg/dL) and 2-hour PBG <10 mmol/L (<180 mg/dL) and 282/396 (71.2%) had both FBG <6.1 mmol/L (<100 mg/dL) and 2-hour PBG <10 mmol/L. The mean first time taken to achieve FBG <7 mmol/L, 2-hour PBG <10 mmol/L, and both, was 4.35, 3.88, and 5.04 days, respectively. Hypoglycaemia occurred in 99 participants (24.9%). There was no severe hypoglycaemia. CONCLUSIONS: Titrating basal insulin first is an effective and safe method of SIIT in individuals with T2D, rapidly achieving target glucose levels with a relatively low rate of hypoglycaemia.

Clinical, laboratory, and radiological features of cerebral amyloid angiopathy-related inflammation (CAA-ri): retrospective, observational experience of a single centre.

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a subtype of CAA with an inflammatory response to the vascular ß-amyloid deposits. Reliable and non-invasive clinical diagnostic methods may allow patients to avoid the side effects of brain biopsy. OBJECTIVE: In this observational study, we retrospectively analyzed the clinical, laboratory, radiological features, treatment, and outcome of patients diagnosed with CAA-ri. The main purpose is to enhance knowledge of CAA-ri and to avoid misdiagnosis. METHODS: We described 15 consecutive patients with probable or possible CAA-ri at Henan Provincial People's Hospital according to a validation study of proposed criteria for the diagnosis of CAA-ri. The clinical features, imaging, laboratory findings, and treatment which included the response to immunotherapy were revealed in the study. RESULTS: The median age of 15 patients was 67.0 years (range 48.0-90.0 years), and the male-to-female ratio was 7: 8. In our study, the most common clinical manifestations were cognitive decline (7/15, 46.7%), focal neurologic deficit (6/15, 40.0%), and headache (5/15, 33.3%). In terms of imaging results, white matter hyperintensity (WMH) lesions were rarely seen in the cerebellum and brainstem, while no hemorrhagic lesion was observed in the brainstem of all 15 patients. In addition, 12 patients (80.0%) showed improvement or stability for the clinical and radiological outcomes after immunotherapy. CONCLUSION: CAA-ri should be considered as a differential diagnosis when brain MRI shows typical features in the elderly. Once the diagnosis is established, immunotherapy should be initiated as early as possible to promote neurological function recovery and reduce recurrence.

[Clinical characteristics and genetic analysis of a case with adult neuronal ceroid lipofuscinosis type 7 due to variant of MFSD8 gene].

OBJECTIVE: To explore the clinical characteristics and genetic variants in a patient with adult ceroid lipofuscinosis neuronal type 7 (ACLN7). METHODS: A female patient diagnosed with ACLN7 in Henan Provincial People's Hospital in June 2021 was selected as the study subject. Clinical data, auxiliary examination and result of genetic testing were retrospectively analyzed. RESULTS: The patient, a 39-year-old female, has mainly presented progressive visual loss, epilepsy, cerebellar ataxia and mild cognitive decline. Neuroimaging analysis has revealed generalized brain atrophy, prominently cerebellum. Fundus photography has revealed retinitis pigmentosa. Ultrastructural skin examination has revealed granular lipofuscin deposits in the periglandular interstitial cells. Whole exome sequencing revealed that she has harbored compound heterozygous variants of the MSFD8 gene, namely c.1444C>T (p.R482*) and c.104G>A (p.R35Q). Among these, c.1444C>T (p.R482*) was a well established pathogenic variant, while c.104G>A (p.R35Q) was a missense variant unreported previously. Sanger sequencing confirmed that the daughter, son and elder brother of the proband have respectively carried heterozygous c.1444C>T (p.R482*), c.104G>A (p.R35Q), and c.104G>A (p.R35Q) variants of the same gene. The family has therefore fit with the autosomal recessive inheritance pattern of the CLN7. CONCLUSION: Compared with previously reported cases, this patient has the latest onset of the disease with a non-lethal phenotype. Her clinical features have involved multiple systems. Cerebellar atrophy and fundus photography may be indicative of the diagnosis. The c.1444C>T (p.R482*) and c.104G>A (p.R35Q) compound heterozygous variants of the MFSD8 gene probably underlay the pathogenesis in this patient.

Dietary intake of thiamine and riboflavin in relation to severe headache or migraine: A cross-sectional survey.

OBJECTIVE: The purpose of this study was to identify the prevalence of severe headache or migraine and the association between dietary thiamine and riboflavin intake with headache history using a large, nationally representative population sample. BACKGROUND: Severe headache and migraine are common and disabling neurological disorders worldwide. Previous studies revealed that the B vitamin group, as an important nutrient of diet, can reduce migraine disability. METHODS: We performed a cross-sectional study of American adults surveyed in the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Information on headache history was collected in the Miscellaneous Pain section of the Questionnaire Data. Dietary intake data of thiamine and riboflavin were obtained by 24-h dietary recall interview. RESULTS: The present study included 13,439 participants and indicated that 2745/13,439 (21.6%) adults (aged ≥20 years) experienced severe headache or migraine in the past 3 months. Dietary thiamine intake was significantly inversely associated with severe headache or migraine (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.88-1.00, p = 0.046). In the stratified analysis, the relationship was maintained in the female group (OR = 0.90, 95% CI = 0.82-0.98, p = 0.022), and the sex interaction term was significant (p = 0.020). However, no significant interaction was found between the age groups (p = 0.352). For dietary riboflavin, no significant negative association was observed between dietary riboflavin intake and headache history (OR = 0.98, 95% CI = 0.94-1.02, p = 0.367). After stratifying by sex or age, there remained no significant relationship between dietary riboflavin and migraine. CONCLUSIONS: We found that high intake of thiamine was significantly associated with lower odds of migraine, especially in females. In the future, more clinical studies are needed to confirm our conclusions, and additional experiments are needed to explore the possible mechanisms of prevention and treatment for migraine.

Prediction of Alzheimer's disease using multi-variants from a Chinese genome-wide association study.

Previous genome-wide association studies have identified dozens of susceptibility loci for sporadic Alzheimer's disease, but few of these loci have been validated in longitudinal cohorts. Establishing predictive models of Alzheimer's disease based on these novel variants is clinically important for verifying whether they have pathological functions and provide a useful tool for screening of disease risk. In the current study, we performed a two-stage genome-wide association study of 3913 patients with Alzheimer's disease and 7593 controls and identified four novel variants (rs3777215, rs6859823, rs234434, and rs2255835; Pcombined = 3.07 × 10-19, 2.49 × 10-23, 1.35 × 10-67, and 4.81 × 10-9, respectively) as well as nine variants in the apolipoprotein E region with genome-wide significance (P < 5.0 × 10-8). Literature mining suggested that these novel single nucleotide polymorphisms are related to amyloid precursor protein transport and metabolism, antioxidation, and neurogenesis. Based on their possible roles in the development of Alzheimer's disease, we used different combinations of these variants and the apolipoprotein E status and successively built 11 predictive models. The predictive models include relatively few single nucleotide polymorphisms useful for clinical practice, in which the maximum number was 13 and the minimum was only four. These predictive models were all significant and their peak of area under the curve reached 0.73 both in the first and second stages. Finally, these models were validated using a separate longitudinal cohort of 5474 individuals. The results showed that individuals carrying risk variants included in the models had a shorter latency and higher incidence of Alzheimer's disease, suggesting that our models can predict Alzheimer's disease onset in a population with genetic susceptibility. The effectiveness of the models for predicting Alzheimer's disease onset confirmed the contributions of these identified variants to disease pathogenesis. In conclusion, this is the first study to validate genome-wide association study-based predictive models for evaluating the risk of Alzheimer's disease onset in a large Chinese population. The clinical application of these models will be beneficial for individuals harbouring these risk variants, and particularly for young individuals seeking genetic consultation.

Encephalitis in Kikuchi-Fujimoto disease being immune-mediated.

INTRODUCTION: Histiocytic necrotizing lymphadenitis, also known as Kikuchi-Fujimoto disease, is a rare benign self-limiting inflammatory disease often seen in young adults. The main clinical features are fever with cervical lymphadenopathy. Neurological complications of Kikuchi-Fujimoto disease were occasionally reported although the specific pathogenesis was not clear. The condition could be severe when encephalitis coexists. METHODS: Here we reported a young case of Kikuchi-Fujimoto disease with subsequent severe autoimmune encephalitis. RESULTS: The symmetric striatal and limbic MRI lesions combined with psycho-cognitive, epileptic symptoms supported encephalitis. Tissue-based immunofluorescence revealed widely cytoplasmic fluorescence in rat cerebellar and hippocampal neurons, which provide evidence for immune-mediated encephalitis. The clinical outcome was satisfactory after immunosuppressive therapy with MRI lesions largely disappeared. CONCLUSION: The encephalitis complication of Kikuchi disease may be autoimmune and mediated by cytotoxic T cells.

Adult-onset autosomal dominant leukodystrophy and neuronal intranuclear inclusion disease: lessons from two new Chinese families.

INTRODUCTION: Adult-onset autosomal dominant leukodystrophy (ADLD) is a rare genetic leukoencephalopathy caused by duplication of the lamin B1 gene (LMNB1) or LMNB1 upstream deletions. Neuronal intranuclear inclusion disease (NIID) is another leukoencephalopathy due to GGC repeat expansion in the 5'-untranslated region of the NOTCH2NLC gene. Here, we report two Chinese ADLD families with neuroimaging and clinical features mimicking NIID. METHODS: We conducted detailed medical history inquiry, neurological examinations, and magnetic resonance imaging in the two families. Candidate gene sequencing and whole exome sequencing (WES) with copy number variation analysis were used to screen the genetic variations. The special points on the clinical and neuroimaging findings in the current families and differential diagnosis of ADLD with NIID are discussed. RESULTS: The two families presented with slowly progressive, multiple central nervous system symptoms, including spastic paraplegia, autonomic dysfunction, ataxia, deep sensory loss, and tremor. Clinical phenotypes were consistent within the family. Transient hypoglycemia and transient dilated pupils indicating autonomic dysfunctions were recorded for the first time in ADLD. Brain MRI showed band-like hyperintensities at the cortico-medullary junction on DWI, typical for NIID. Skin biopsy and genetic sequencing of the NOTCH2NCL gene did not support the diagnosis of NIID. Further whole exome sequencing (WES) identified the duplication mutation spanning the entire LMNB1 gene. CONCLUSIONS: The novel feature of transient hypoglycemia and dilated pupils broadens the spectrum of autonomic dysfunction in ADLD. Clinical manifestations and neuroimaging of ADLD can mimic NIID. Although ADLD is even rarer than NIID, the differential diagnosis of these two diseases should not be confused.

Identification of BcARR Genes and CTK Effects on Stalk Development of Flowering Chinese Cabbage.

Flowering Chinese cabbage (Brassica campestris L. ssp. Chinensis var. utilis Tsen et Lee) is an important and extensively cultivated vegetable in south China, whose major food product is the stalk. In the process of stalk formation, its initiation and development are regulated by a series of hormonal signals, such as cytokinin and gibberellin. In this study, we analyzed the effects of zeatin (ZT) and gibberellin A3 (GA3), and their interaction, on the bolting of flowering Chinese cabbage. The results indicated that the three-true-leaf spraying of ZT and GA synthesis inhibitor (PAC) inhibited plant height but increased stem diameter. Cytokinin (CTK) synthesis inhibitor (YZJ) and GA3 treatment increased plant height and decreased stem diameter. In addition, ZT and GA3 co-treated plants displayed antagonistic effect. Further, 19 type-B authentic response regulators (ARR-Bs), the positive regulators of cytokinin signal transduction were identified from flowering Chinese cabbage. Comprehensive analysis of phylogeny showed BcARR-Bs clustered into three subfamilies with 10 conserved motifs. Analysis of their expression patterns in different tissues and at various growth stage, and their response to hormone treatment suggest that ARR1-b localized in the nucleus displayed unique highest expression patterns in stem tips, are responsive both to ZT and GA, suggesting a significant role in mediating the crosstalk of ZT and GA in the bolting of flowering Chinese cabbage.

[Analysis of a pedigree with distal hereditary motor neuropathy type 2A caused by mutation in HSPB8 gene].

OBJECTIVE: To explore phenotypic and mutational characteristics of a pedigree with distal hereditary motor neuropathy (dHMN). METHODS: Clinical data of the proband and her family members was collected. Electrophysiology, muscle biopsy and whole exome sequencing were carried out for the proband. RESULTS: Patients of the family mainly presented with distal lower limb weakness. Electrophysiological test of the proband revealed distal motor neuropathy and sensory nerves were normal. Muscle biopsy suggested neurogenic atrophy of muscle fibers. Genetic analysis revealed a heterozygous c.421A>G (p.K141E) mutation in exon 2 of the HSPB8 gene, which was a hot spot mutation. CONCLUSION: This family was the first reported HSPB8 related dHMN2A in Chinese population, and p.K141E was the causative mutation, which enriched the mutational spectrum of dHMN in China.

A Novel Human Acute Encephalitis Caused by Pseudorabies Virus Variant Strain.

BACKGROUND: Pseudorabies virus (PRV) is a common pathogen in multiple animal species, particularly in pigs. However, PRV infection in humans is rare and, to the best of our knowledge, PRV has never been isolated from human cases before. METHODS: Four acute encephalitis cases in humans were confirmed as PRV infection based on clinical symptoms, laboratory diagnosis, and metagenomic next-generation sequencing (mNGS). Cerebrospinal fluid (CSF) samples were collected and applied for virus isolation. Etiological and genetic characteristics of this PRV human isolate were further determined. RESULTS: The patients manifested respiratory dysfunction and acute neurological symptoms. The mNGS revealed PRV-specific nucleotide sequences in patients' CSF samples (7-6198 reads and 0.2446%-80.58% coverage). The PRV envelope glycoprotein B antibody, glycoprotein E antibody, and neutralizing antibody were positively detected. For the first time, a PRV strain, designated hSD-1/2019, was isolated and identified from a CSF sample, and transmission electron microscopy revealed that hSD-1/2019 had typical morphology similar to that of swine PRV. Phylogenetic analysis illustrated that hSD-1/2019 was genetically closest to those PRV variant strains currently circulating in pigs in China, and this strain showed similar etiological characteristics to Chinese PRV variant strains, while different from Chinese classical strain. Moreover, hSD-1/2019 showed high pathogenicity and induced acute neurological symptoms in pigs. CONCLUSIONS: A PRV strain was isolated from an acute human encephalitis case. This isolate showed close phylogenetic relationships and similar etiological characteristics to Chinese PRV variant strains, implying the great risk of PRV transmission from pigs to humans.

Genotype-phenotype correlations of heterozygous HTRA1-related cerebral small vessel disease: case report and systematic review.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is caused by biallelic HTRA1 pathogenic variants. Recent studies have shown that heterozygous HTRA1 mutations are associated with autosomal dominant cerebral small vessel disease (CSVD). However, large studies evaluating heterozygous HTRA1 carriers are lacking and the genotype-phenotype correlation is unknown. This study aimed to describe these mutations to clarify factors playing a role in the clinical phenotype amongst these patients. We reported two unrelated families and performed a systematic review of all published cases of heterozygous HTRA1-related CSVD. The clinical phenotype severity was independently related to the pathogenicity score (CADD score; p < 0.05) and mutation in the loop 3/loop D domains (p = 0.05); the pathogenicity score was also associated with exon distribution. More importantly, patients with mutations in exon 4 (p = 0.0001) or vascular risk factors (p < 0.05) presented with more severe clinical symptoms. Thus, clinical phenotype severity is influenced by the mutation domain and vascular risk factors. Applying the pathogenicity score to predict clinical outcomes and adopting preventive measures against cerebral vascular risk factors is advantageous.

Immune changes in peripheral blood and hematoma of patients with intracerebral hemorrhage.

Immunologic changes in the hematoma of patients with intracerebral hemorrhage (ICH) and the contribution of these changes to prognosis are unknown. We collected the blood samples and hematoma fluid from 35 patients with acute ICH (<30 hours from symptom onset) and 55 age-matched healthy controls. Using flow cytometry and ELISA, we found that the percentages of granulocytes, regulatory T cells, helper T (Th) 17 cells, and dendritic cells were higher in the peripheral blood of patients with ICH than in healthy controls, whereas the percentages of lymphocytes, M1-like macrophages, and M2-like macrophages were lower. Levels of IL-6, IL-17, IL-23, TNF-α, IL-4, IL-10, and TGF-ß were higher in the peripheral blood of patients with ICH. The absolute counts of white blood cells, lymphocytes, monocytes, and granulocytes in the hematoma tended to be greater at 12-30 hours than they were within 12 hours after ICH, but the percentage of Th cells decreased in peripheral blood. Increased levels of IL-10 in the serum and hematoma, and a reduction in M1-like macrophages in hematoma were independently associated with favorable outcome on day 90. These results indicate that immunocytes present in the hematoma may participate in the acute-phase inflammatory response after ICH.