Coordinated Spine Pruning and Maturation Mediated by Inter-Spine Competition for Cadherin/Catenin Complexes.

Dendritic spines are postsynaptic compartments of excitatory synapses that undergo dynamic changes during development, including rapid spinogenesis in early postnatal life and significant pruning during adolescence. Spine pruning defects have been implicated in developmental neurological disorders such as autism, yet much remains to be uncovered regarding its molecular mechanism. Here, we show that spine pruning and maturation in the mouse somatosensory cortex are coordinated via the cadherin/catenin cell adhesion complex and bidrectionally regulated by sensory experience. We further demonstrate that locally enhancing cadherin/catenin-dependent adhesion or photo-stimulating a contacting channelrhodopsin-expressing axon stabilized the manipulated spine and eliminated its neighbors, an effect requiring cadherin/catenin-dependent adhesion. Importantly, we show that differential cadherin/catenin-dependent adhesion between neighboring spines biased spine fate in vivo. These results suggest that activity-induced inter-spine competition for ß-catenin provides specificity for concurrent spine maturation and elimination and thus is critical for the molecular control of spine pruning during neural circuit refinement.

Metabolic and Microbial Dysregulation in Preterm Infants with Neonatal Respiratory Distress Syndrome: An Early Developmental Perspective.

Neonatal respiratory distress syndrome (NRDS) is one of the most severe respiratory disorders in preterm infants (PTIs) due to immature lung development. To delineate the serum metabolic alterations and gut microbiota variations in NRDS and assess their implications on neonatal development, we enrolled 13 NRDS neonates and 12 PTIs and collected fecal and serum specimens after birth. Longitudinal fecal sampling was conducted weekly for a month in NRDS neonates. NRDS neonates were characterized by notably reduced gestational ages and birth weights and a higher rate of asphyxia at birth relative to PTIs. Early postnatal disturbances in tryptophan metabolism were evident in the NRDS group, concomitant with elevated relative abundance of Haemophilus, Fusicatenibacter, and Vibrio. Integrative multiomics analyses revealed an inverse relationship between tryptophan concentrations and Blautia abundance. At one-week old, NRDS neonates exhibited cortisol regulation anomalies and augmented hepatic catabolism. Sequential microbial profiling revealed distinct gut microbiota evolution in NRDS subjects, characterized by a general reduction in potentially pathogenic bacteria. The acute perinatal stress of NRDS leads to mitochondrial compromise, hormonal imbalance, and delayed gut microbiota evolution. Despite the short duration of NRDS, its impact on neonatal development is significant and requires extended attention.

Performance of the 2019 ACR/EULAR Classification Criteria for IgG4-Related Disease in a Large Chinese Cohort.

OBJECTIVE: The purpose of this research was to ascertain the effectiveness of the newly established criteria for classifying IgG4-related disease (IgG4-RD), as applied to a large Chinese cohort in real-world clinical settings. METHODS: Patient data were procured from the digital health records of 4 prominent academic hospitals. The criterion standard for identifying IgG4-RD patients was from a seasoned rheumatologist. The control group consisted of individuals with other ailments such as cancer, other forms of pancreatitis, infectious diseases, and illnesses that mimic IgG4-RD. RESULTS: A total of 605 IgG4-RD patients and 760 mimickers were available for analysis. The 2019 EULAR/ACR criteria have a sensitivity of 69.1% and a specificity of 90.9% in this large Chinese cohort. IgG4-RD had a greater proportion of males (55.89% vs 36.25%, p < 0.001), an older average age at diagnosis (54.91 ± 13.44 vs 48.91 ± 15.71, p < 0.001), more pancreatic (29.59% vs 6.12%, p < 0.001) and salivary gland (63.30% vs 27.50%, p < 0.001) involvement, and a larger number of organ involvement (3.431 ± 2.054 vs 2.062 ± 1.748, p < 0.001) compared with mimickers. CONCLUSIONS: The 2019 EULAR/ACR criteria are effective in classifying IgG4-RD in Chinese patients, demonstrating high specificity and moderate sensitivity.

Relationship between clinical features and droplet digital PCR copy number in non-HIV patients with pneumocystis pneumonia.

OBJECTIVE: Droplet digital PCR (ddPCR) is a novel assay to detect pneumocystis jjrovecii (Pj) which has been defined to be more sensitive than qPCR in recent studies. We aimed to explore whether clinical features of pneumocystis pneumonia (PCP) were associated with ddPCR copy numbers of Pj. METHODS: A total of 48 PCP patients were retrospectively included. Pj detection was implemented by ddPCR assay within 4 h. Bronchoalveolar fluid (BALF) samples were collected from 48 patients with molecular diagnosis as PCP via metagenomic next generation sequencing (mNGS) or quantitative PCR detection. Univariate and multivariate logistic regression were performed to screen out possible indicators for the severity of PCP. The patients were divided into two groups according to ddPCR copy numbers, and their clinical features were further analyzed. RESULTS: Pj loading was a pro rata increase with serum (1,3)-beta-D glucan, D-dimmer, neutrophil percentage, procalcitonin and BALF polymorphonuclear leucocyte percentage, while negative correlation with albumin, PaO2/FiO2, BALF cell count, and BALF lymphocyte percentage. D-dimmer and ddPCR copy number of Pj were independent indicators for moderate/severe PCP patients with PaO2/FiO2 lower than 300. We made a ROC analysis of ddPCR copy number of Pj for PaO2/FiO2 index and grouped the patients according to the cut-off value (2.75). The high copy numbers group was characterized by higher level of inflammatory markers. Compared to low copy number group, there was lower level of the total cell count while higher level of polymorphonuclear leucocyte percentage in BALF in the high copy numbers group. Different from patients with high copy numbers, those with high copy numbers had a tendency to develop more severe complications and required advanced respiratory support. CONCLUSION: The scenarios of patients infected with high ddPCR copy numbers of Pj showed more adverse clinical conditions. Pj loading could reflect the severity of PCP to some extent.

Clinical characteristics of IgG4-related respiratory disease patients: a large Chinese cohort study.

OBJECTIVES: IgG4-related disease (IgG4-RD) is an autoimmune disorder and frequently involves multiple organs. The respiratory tract is one of the most frequently affected sites. In this study, we aimed to compare the demographic and clinical characteristics between IgG4 related respiratory disease (IgG4-RRD+) and extra-thoracic IgG4-related disease (IgG4-RRD-) in a large cohort. METHODS: A total of 448 cases of IgG4-RD (104 IgG4-RRD+ patients and 344 IgG4-RRD- patients) diagnosed at Peking University People's Hospital during 2003 to 2020 were included in our study. Patients' demographic data, clinical characteristics, laboratory parameters and imaging features were analysed. RESULTS: IgG4-RRD+ patients had an older age at disease onset and diagnosis. Multiorgan involvement and hypocomplementaemia were more common in IgG4-RRD+. Besides, the level of ESR, IgG and IgG4 were higher in IgG4-RRD+ patients. In IgG4-RRD+ group, salivary gland, lacrimal gland, lymph nodes, biliary system and kidney were more commonly involved than those in the IgG4-RRD- group. Also, more organ involvement eosinophilia and biliary involvement were independent risk factors for the development of IgG4-RRD+. CONCLUSIONS: Our study revealed demographic, clinical and laboratory differences between the two phenotypes, in addition to describing the imaging features of IgG4-RRD+, which will be helpful for understanding of the disease.

Autism-like behaviours and germline transmission in transgenic monkeys overexpressing MeCP2.

Methyl-CpG binding protein 2 (MeCP2) has crucial roles in transcriptional regulation and microRNA processing. Mutations in the MECP2 gene are found in 90% of patients with Rett syndrome, a severe developmental disorder with autistic phenotypes. Duplications of MECP2-containing genomic segments cause the MECP2 duplication syndrome, which shares core symptoms with autism spectrum disorders. Although Mecp2-null mice recapitulate most developmental and behavioural defects seen in patients with Rett syndrome, it has been difficult to identify autism-like behaviours in the mouse model of MeCP2 overexpression. Here we report that lentivirus-based transgenic cynomolgus monkeys (Macaca fascicularis) expressing human MeCP2 in the brain exhibit autism-like behaviours and show germline transmission of the transgene. Expression of the MECP2 transgene was confirmed by western blotting and immunostaining of brain tissues of transgenic monkeys. Genomic integration sites of the transgenes were characterized by a deep-sequencing-based method. As compared to wild-type monkeys, MECP2 transgenic monkeys exhibited a higher frequency of repetitive circular locomotion and increased stress responses, as measured by the threat-related anxiety and defensive test. The transgenic monkeys showed less interaction with wild-type monkeys within the same group, and also a reduced interaction time when paired with other transgenic monkeys in social interaction tests. The cognitive functions of the transgenic monkeys were largely normal in the Wisconsin general test apparatus, although some showed signs of stereotypic cognitive behaviours. Notably, we succeeded in generating five F1 offspring of MECP2 transgenic monkeys by intracytoplasmic sperm injection with sperm from one F0 transgenic monkey, showing germline transmission and Mendelian segregation of several MECP2 transgenes in the F1 progeny. Moreover, F1 transgenic monkeys also showed reduced social interactions when tested in pairs, as compared to wild-type monkeys of similar age. Together, these results indicate the feasibility and reliability of using genetically engineered non-human primates to study brain disorders.

Development of a 3D Printed Lung Model Made of Synthetic Materials for Simulation.

BACKGROUND: Considering the complexity of lung structures and the difficulty of thoracoscopic surgery, simulation-based training is of paramount importance for junior surgeons. Here, we aim to design a high-fidelity lung model through utilizing the three-dimensional (3D) printing technology combined with synthetic materials to mimic the real human lung. METHODS: The 3D printed lung model was manufactured based on the computed tomography images of a randomly selected male patient. Synthetic materials were used for the construction of lung parenchyma, blood vessels, and bronchi. Then, the model was assessed in terms of its visual, tactile, and operational features by participants (the senior surgeons, junior surgeons, and medical students), who were asked to complete the specially designed survey-questionnaires. RESULTS: A 3D printed model of the right lung made of synthetic materials was successfully fabricated. Thirty subjects participated in our study (10 senior surgeons, 10 junior surgeons, and 10 medical students). The average visual evaluation scores for senior surgeons, junior surgeons, and medical students were 3.97 ± 0.61, 4.56 ± 0.58, 4.76 ± 0.49, respectively. The average tactile evaluation scores were 3.40 ± 0.50, 4.13 ± 0.68, 4.00 ± 0.64, respectively. The average operation evaluation scores were 3.33 ± 0.83, 3.93 ± 0.66, 4.03 ± 0.66, respectively. Significant lower scores were obtained in the group of the senior surgeons compared with the other two groups. CONCLUSION: A high level of fidelity was exhibited in our 3D printed lung model and it could be applied as a promising simulator for the surgical training in the future.

Bacterial Skin Infections in Hospitalized Patients with Bullous Pemphigoid.

OBJECTIVE: To explore the features and risk factors of bacterial skin infections (BSIs) in hospitalized patients with bullous pemphigoid (BP). METHODS: Records were retrospectively reviewed for 110 hospitalized patients with BP admitted to Peking University First Hospital between 2013 and 2019. Bacterial species and drug resistance were assessed, and then the underlying risk factors for BSIs were evaluated. RESULTS: Infections were present in 40% (44/110) of the patients. Staphylococcus aureus (72.7%, 32/44) was the most common bacterium, and it was highly resistant to penicillin (81.3%, 26/32), erythromycin (62.5%, 20/32), and clindamycin (56.3%, 18/32), but 100.0% sensitive to vancomycin and tigecycline. Coronary heart disease (P = .02; odds ratio [OR], 12.68), multisystem comorbidities (P = .02; OR, 3.67), hypoalbuminemia (P = .04; OR, 3.70), high levels of anti-BP180 antibodies (>112.4 U/mL; P = .003; OR, 6.43), and season (spring: reference; summer: P = .002; OR, 23.58; autumn: P = .02; OR, 12.19; winter: P = .02; OR, 13.19) were significantly associated with BSIs. CONCLUSIONS: Hospitalized patients with BP had a high incidence of BSIs, and those patients with underlying risk factors require careful management to prevent and control BSIs.

Features and associated factors of bacterial skin infections in hospitalized patients with pemphigus: a single-center retrospective study.

BACKGROUND: Infections were the primary cause of death (34.3-55.5%) in patients with pemphigus. Skin was usually the origin of infections. The study aimed to explore features and associated factors of bacterial skin infections (BSIs) in inpatients with pemphigus. METHODS: One hundred and seventy-seven inpatients with pemphigus hospitalizing from November 2014 to April 2019 were continuously recruited through Peking University First Hospital's inpatient records inpatients with pemphigus hospitalizing from November 2014 to April 2019 were continuously recruited through Peking University First Hospital's inpatient records. Then, we retrieved the clinical and laboratory data to explore the characteristics and associated factors of BSIs. RESULTS: Of patients enrolled, pemphigus vulgaris (PV, n = 142) and pemphigus foliaceus (PF, n = 9) were most common, followed by pemphigus erythematosus (PE, n = 25) and pemphigus vegetans (Pveg, n = 1). Eighty-seven of 177 (49.2%) inpatients developed BSIs, and they had a longer length of stay compared with inpatients without BSIs (median: 18.9 vs. 14.1 days, p = 0.008). Staphylococcus aureus was the most common bacteria (71.3%, 62/87) and highly resistant to penicillin (91.9%, 57/62). Higher levels of anti-Dsg1 autoantibodies (> 124.2 U/mL) (p < 0.001, odds ratio [OR] = 3.564, 95% confidence interval [CI]: 1.784-7.123) and anti-Dsg3 autoantibodies (> 169.5 U/mL) (p = 0.03, OR = 2.074, 95% CI: 1.084-3.969) were underlying risk factors of BSIs when analyzed by binary regression analysis. As for Gram's stain of bacteria, females had a lower rate of Gram-positive infections (p = 0.03). Patients using oral antibiotics (p = 0.05) had a higher rate of Gram-negative infections. Inpatients who were hospitalized in other hospitals within 2 weeks before the current admission had a higher rate of Gram-negative and co-infections (p = 0.03). CONCLUSIONS: Inpatients with pemphigus had a high incidence of BSIs. Some factors were associated with the susceptibility of BSIs and bacterial species.

Plasma proteome analysis and validation of patients with community-acquired pneumonia: A cohort study.

PURPOSE: This study aimed to investigate the diagnostic potential of plasma biomarkers of community-acquired pneumonia (CAP) and their severity grading. EXPERIMENTAL DESIGN: Plasma proteomes from cohort I (n = 32) with CAP were analyzed by data-independent acquisition mass spectrometry (MS). MetaboAnalyst 5.0 was used to statistically evaluate significant differences in proteins from different samples, and demographic and clinical data were recorded for all enrolled patients. Cohort II (n = 80) was used to validate candidate biomarkers. Plasma protein levels were determined using quantitative enzyme-linked immunosorbent assay (ELISA). Correlations were assessed using Pearson's correlation coefficient. A receiver operating characteristic curve was used to verify the association between the variables, CAP diagnosis, and prognosis. RESULTS: 121 differentially expressed proteins (DEPs) were obtained between CAP and controls. These DEPs were mainly aggregated in pathways of phagosome(hsa04145) and complement and coagulation cascades (hsa04610). No significant differential proteins were detected in bacterial, viral, and mixed infection groups. The plasma levels of fetuin-A, alpha-1-antichymotrypsin (AACT), α1-acid glycoprotein (A1AG), and S100A8/S100A9 heterodimers detected by ELISA were consistent with those of MS. AACT, A1AG, S100A8/S100A9 heterodimer, and fetuin-A can potentially be used as diagnostic predictors, and fetuin-A and AACT are potential predictors of SCAP. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma protein profiling can successfully identify potential biomarkers for CAP diagnosis and disease severity assessment. These biomarkers should be further studied for their clinical application.

Single-neuron projectomes of mouse paraventricular hypothalamic nucleus oxytocin neurons reveal mutually exclusive projection patterns.

Oxytocin (OXT) plays important roles in autonomic control and behavioral modulation. However, it is unknown how the projection patterns of OXT neurons align with underlying physiological functions. Here, we present the reconstructed single-neuron, whole-brain projectomes of 264 OXT neurons of the mouse paraventricular hypothalamic nucleus (PVH) at submicron resolution. These neurons hierarchically clustered into two groups, with distinct morphological and transcriptional characteristics and mutually exclusive projection patterns. Cluster 1 (177 neurons) axons terminated exclusively in the median eminence (ME) and have few collaterals terminating within hypothalamic regions. By contrast, cluster 2 (87 neurons) sent wide-spread axons to multiple brain regions, but excluding ME. Dendritic arbors of OXT neurons also extended outside of the PVH, suggesting capability to sense signals and modulate target regions. These single-neuron resolution observations reveal distinct OXT subpopulations, provide comprehensive analysis of their morphology, and lay the structural foundation for better understanding the functional heterogeneity of OXT neurons.

Clinical performance of BALF droplet digital PCR for differential diagnosis of Pneumocystis jirovecii pneumonia and Pneumocystis jirovecii colonization.

BACKGROUND: Accurate differentiation between Pneumocystis jirovecii (Pj) infection and colonization is crucial for effective treatment. METHODS: From September 2016 to June 2022, 89 immunocompromised patients with unexplained lung infiltrates and clinical suspicion of Pj pneumonia were enrolled at Peking University People's Hospital. Bronchoalveolar lavage fluid (BALF) of these patients were detected by quantitative PCR (qPCR) and droplet digital PCR (ddPCR). RESULTS: The performance of ddPCR was superior to qPCR in detecting Pj infection. Area under the curve was 0.97 (95 %CI: 0.94-1) for ddPCR of the BALF in all patients. The optimal threshold value for discriminating Pj infection from colonization by ddPCR was 13.98 copies/test, with a sensitivity of 97.96 %, specificity of 85.71 %. No obvious correlation between ddPCR copy number and disease severity was observed. CONCLUSION: BALF ddPCR exhibits robust potential in detecting Pj and effectively discriminating colonization and infection.

Automated Sleep Deprivation Setup Using a Shaking Platform in Mice.

The functions of sleep remain largely unclear, and even less is known about its role in development. A general strategy to tackle these questions is to disrupt sleep and measure the outcomes. However, some existing sleep deprivation methods may not be suitable for studying the effects of chronic sleep disruption, due to their lack of effectiveness and/or robustness, substantial stress caused by the deprivation method, or consuming a large quantity of time and manpower. More problems may be encountered when applying these existing protocols to young, developing animals, because of their likely heightened vulnerability to stressors, and difficulties in precisely monitoring sleep at young ages. Here, we report a protocol of automated sleep disruption in mice using a commercially available, shaking platform-based deprivation system. We show that this protocol effectively and robustly deprives both non-rapid-eye-movement (NREM) sleep and rapid-eye-movement (REM) sleep without causing a significant stress response, and does not require human supervision. This protocol uses adolescent mice, but the method also works with adult mice. Graphical abstract Automated sleep deprivation system. The platform of the deprivation chamber was programmed to shake in a given frequency and intensity to keep the animal awake while its brain and muscle activities were continuously monitored by electroencephalography and electromyography.

Adolescent sleep defects and dopaminergic hyperactivity in mice with a schizophrenia-linked Shank3 mutation.

Shank3 is a shared risk gene for autism spectrum disorders and schizophrenia. Sleep defects have been characterized for autism models with Shank3 mutations; however, evidence has been lacking for the potential sleep defects caused by Shank3 mutation associated with schizophrenia and how early in development these defects may occur. Here we characterized the sleep architecture of adolescent mice carrying a schizophrenia-linked, R1117X mutation in Shank3. We further employed GRABDA dopamine sensor and fiber photometry to record dopamine release in the nucleus accumbens during sleep/wake states. Our results show that homozygous mutant R1117X mice have significantly reduced sleep in the dark phase during adolescence, altered electroencephalogram power, especially during the rapid-eye-movement sleep, and dopamine hyperactivity during sleep but not during wakefulness. Further analyses suggest that these adolescent defects in sleep architecture and dopaminergic neuromodulation tightly correlate with the social novelty preference later in adulthood and predict adult social performance during same-sex social interactions. Our results provide novel insights into the sleep phenotypes in mouse models of schizophrenia and the potential use of developmental sleep as a predictive metric for adult social symptoms. Together with recent studies in other Shank3 models, our work underscores the idea that Shank3-involved circuit disruptions may be one of the shared pathologies in certain types of schizophrenia and autism. Future research is needed to establish the causal relationship among adolescent sleep defects, dopaminergic dysregulation, and adult behavioral changes in Shank3 mutation animals and other models.

Immune phenotype changes in IgG4-related disease: CD161 + Treg and Foxp3 + Treg.

OBJECTIVE: We aimed to characterize the alterations in the immune phenotypes and explore the potential relevance to pathogenesis in IgG4-RD. METHODS: Forty-two IgG4-RD patients and thirty-eight healthy controls were recruited in this study. Peripheral immunocompetent cells including T cells, CD4 + T cells, CD8 + T cells, B cells, NK cells CD4 + CD45RA + T cells (naïve T cells), CD4 + CD25 - / + Foxp3 - T cells (Teff), CD4 + CD25hiCD127lowCD161 + T cells (CD161 + Treg), CD4 + CD25hiFoxp3 + T cells (Foxp3 + Treg), CD4 + CD4RA-CXCR5 + PD1 + CCR7low T cells (pTfh), T helper (Th) 1, Th2, and Th17 before and after treatment were immunophenotyped by flow cytometry. RESULTS: Compared with healthy controls, IgG4-RD patients showed higher proportions of NK (20.1% vs 13.6%, p < 0.01), Th1 (CD4 + IFN-γ + : 17.9% vs 14.2%, p = 0.061; TNF-α: 43.7% vs 36.7%, p < 0.05), Th2 (CD4 + IL-4 + : 2.4% vs 1.3%, p < 0.0001), CD161 + Treg (14.9% vs 11.6%, p < 0.01), pTfh (3.2% vs 2.4%, p < 0.05), and Foxp3 + Treg (8.3% vs 7.0%, p < 0.01) and lower proportions of B lymphocytes (8.4% vs 13.1%, p < 0.001), Teff (91.6% vs 92.6%, p < 0.01), and naïve Th cells (19.9% vs 32.1%, p < 0.01) before treatment. Foxp3 + Treg percentage decreased significantly after treatment (8.6% vs 6.9%, p < 0.05). Both serum C3 (r = - 0.6374, p < 0.01) and C4 (r = - 0.6174, p < 0.01) levels were in negative correlation with CD161 + Treg. The eosinophil percentage was positively correlated with Foxp3 + Treg (r = 0.5435, p < 0.05). Serum IgE level was positively correlated with Th2 (r = 0.5545, p < 0.05). There was a positive correlation between CD161 + Treg and pTfh (r = 0.4974, p < 0.05) while a negative correlation between Th2 and B cells (r = - 0.4925, p < 0.05). CONCLUSION: Immune phenotypes were altered in IgG4-RD. Treg/Teff balance was shifted toward Treg in IgG4-RD. CD161 + Treg was likely to be involved in the pathogenesis of IgG4-RD. Key Points •Immune phenotypes were altered in B cells, T cells, and NK cells in IgG4-RD. •Treg/Teff balance was shifted toward Treg in IgG4-RD. •CD161+ Treg maybe play a proinflammatory role in IgG4-RD.

T2T-YAO: A Telomere-to-telomere Assembled Diploid Reference Genome for Han Chinese.

Since its initial release in 2001, the human reference genome has undergone continuous improvement in quality, and the recently released telomere-to-telomere (T2T) version - T2T-CHM13 - reaches its highest level of continuity and accuracy after 20 years of effort by working on a simplified, nearly homozygous genome of a hydatidiform mole cell line. Here, to provide an authentic complete diploid human genome reference for the Han Chinese, the largest population in the world, we assembled the genome of a male Han Chinese individual, T2T-YAO, which includes T2T assemblies of all the 22 + X + M and 22 + Y chromosomes in both haploid. The quality of T2T-YAO is much better than all currently available diploid assemblies, and its haploid version, T2T-YAO-hp, generated by selecting the better assembly for each autosome, reaches the top quality of fewer than one error per 29.5 Mb, even higher than that of T2T-CHM13. Derived from an individual living in the aboriginal region of the Han population, T2T-YAO shows clear ancestry and potential genetic continuity from the ancient ancestors. Each haplotype of T2T-YAO possesses ∼ 330-Mb exclusive sequences, ∼ 3100 unique genes, and tens of thousands of nucleotide and structural variations as compared with CHM13, highlighting the necessity of a population-stratified reference genome. The construction of T2T-YAO, a truly accurate and authentic representative of the Chinese population, would enable precise delineation of genomic variations and advance our understandings in the hereditability of diseases and phenotypes, especially within the context of the unique variations of the Chinese population.

Adolescent sleep shapes social novelty preference in mice.

Sleep disturbances frequently occur in neurodevelopmental disorders such as autism, but the developmental role of sleep is largely unexplored, and a causal relationship between developmental sleep defects and behavioral consequences in adulthood remains elusive. Here, we show that in mice, sleep disruption (SD) in adolescence, but not in adulthood, causes long-lasting impairment in social novelty preference. Furthermore, adolescent SD alters the activation and release patterns of dopaminergic neurons in the ventral tegmental area (VTA) in response to social novelty. This developmental sleep function is mediated by balanced VTA activity during adolescence; chemogenetic excitation mimics, whereas silencing rescues, the social deficits of adolescent SD. Finally, we show that in Shank3-mutant mice, improving sleep or rectifying VTA activity during adolescence ameliorates adult social deficits. Together, our results identify a critical role of sleep and dopaminergic activity in the development of social interaction behavior.

Characteristics of IgG4-related disease complicated with allergic rhinitis or chronic rhinosinusitis: a large cross-sectional cohort study.

In clinical practice, we found that IgG4-related disease (IgG4-RD) patients complicated with allergic rhinitis (AR)/chronic rhinosinusitis (CRS) seemed to have unique characteristics different from patients with IgG4-RD alone. In this study, demographic, clinical and laboratory characteristics of IgG4-RD patients complicated with AR/CRS were investigated. We retrospectively analyzed 756 IgG4-RD patients who were recruited in four medical centers from 2009 to 2021. We divided 756 IgG4-RD patients into 2 groups: the case group included IgG4-RD patients complicated with AR/CRS, and the control group included IgG4-RD patients without AR/CRS. 411 patients were complicated with AR/CRS among 756 IgG4-RD patients. Multiple organs involvement (≥ 3, p < 0.0001, OR 3.585 (95% CI 2.655-4.839)) and other types of allergic disease (p < 0.0001, OR 2.007 (95% CI 1.490-2.693)) were more common in the case group. Patients in the case group had a higher level of serum IgG4 (650 mg/dL vs 385 mg/dL, p < 0.0001), IgE (347 mg/dL vs 98 mg/dL, p < 0.0001) and ESR (14 mm/h vs 12 mm/h, p < 0.05). High IgE level (p < 0.01, OR 1.003 (95% CI 1.001-1.005)) and other types of allergic disease (p < 0.05, OR 3.196 (95% CI 1.146-8.908)) were risk factors for patients in the case group, in which most patients had nasal manifestations before the diagnosis of IgG4-RD. The median time interval from nasal symptoms appearance to IgG4-RD diagnosis was - 120 and - 90 months for patients complicated with AR and CRS, respectively. IgG4-RD patients are often complicated with AR/CRS and have distinct characteristics, which appear to be a subgroup of IgG4-RD. The data suggests a pathogenic association of IgG4-RD and AR/CRS.

Hyperexcitable arousal circuits drive sleep instability during aging.

Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness. Aged Hcrt neurons showed hyperexcitability with lower KCNQ2 expression and impaired M-current, mediated by KCNQ2/3 channels. Single-nucleus RNA-sequencing revealed adaptive changes to Hcrt neuron loss in the aging brain. Disruption of Kcnq2/3 genes in Hcrt neurons of young mice destabilized sleep, mimicking aging-associated sleep fragmentation, whereas the KCNQ-selective activator flupirtine hyperpolarized Hcrt neurons and rejuvenated sleep architecture in aged mice. Our findings demonstrate a mechanism underlying sleep instability during aging and a strategy to improve sleep continuity.

Malignancy Risk of Immunoglobin G4-Related Disease: Evidence from a Large Cohort Multicenter Retrospective Study.

INTRODUCTION: The aim of this work was to evaluate the prevalence of malignancies in a multicenter cohort of Chinese patients with immunoglobulin G4-related disease (IgG4-RD) and to identify the related risk factors of malignancy in IgG4-RD patients. METHODS: We retrospectively analyzed 602 IgG4-RD patients who were recruited in five medical centers from 2009 to 2020. Standardized prevalence ratios (SPRs) against the general Chinese population were calculated along with 95% confidence intervals (CIs). We identified the risk factors of malignancy in IgG4-RD and calculated the odds ratios (ORs) of different factors. We then developed and validated a prediction model for malignancy risk of IgG4-RD based on our cohort. RESULTS: We observed a significantly increased prevalence of total malignancies in this cohort compared to the general Chinese population (SPR 8.66 [95% CI 5.84, 12.31]). Logistic regression analysis indicated that eosinophil percentage (OR 1.096 [95% CI 1.019-1.179], P = 0.016), serum albumin-to-globulin ratio (AGR) (OR 0.185 [95% CI 0.061-0.567], P = 0.002) and autoimmune pancreatitis (OR 2.400 [95% CI 1.038-5.549], P = 0.041) were three potential risk factors of malignancy in IgG4-RD patients. Four predictors were included in our final prediction model: age at IgG4-RD diagnosis, eosinophil percentage, AGR and autoimmune pancreatitis. The nomogram performed well in the internal validation cohort, with a concordance index (C-index) of 0.738. CONCLUSIONS: A significantly increased prevalence of total malignancies was observed in our multicenter cohort. Eosinophil percentage and autoimmune pancreatitis are risk factors, whereas AGR is negatively associated with malignancy in IgG4-RD. A prediction model for malignancy risk of IgG4-RD was first developed and validated in our study.