Evaluating the effects of circulating inflammatory proteins as drivers and therapeutic targets for severe COVID-19.

Objective: The relationships between circulating inflammatory proteins and COVID-19 have been observed in previous cohorts. However, it is not unclear which circulating inflammatory proteins may boost the risk of or protect against COVID-19. Methods: We performed Mendelian randomization (MR) analysis using GWAS summary result of 91 circulating inflammation-related proteins (N = 14,824) to assess their causal impact on severe COVID-19. The COVID-19 phenotypes encompassed both hospitalized (N = 2,095,324) and critical COVID-19 (N = 1,086,211). Moreover, sensitivity analyses were conducted to evaluate the robustness and reliability. Results: We found that seven circulating inflammatory proteins confer positive causal effects on severe COVID-19. Among them, serum levels of IL-10RB, FGF-19, and CCL-2 positively contributed to both hospitalized and critical COVID-19 conditions (OR: 1.10~1.16), while the other 4 proteins conferred risk on critical COVID-19 only (OR: 1.07~1.16), including EIF4EBP1, IL-7, NTF3, and LIF. Meanwhile, five proteins exert protective effects against hospitalization and progression to critical COVID-19 (OR: 0.85~0.95), including CXCL11, CDCP1, CCL4/MIP, IFNG, and LIFR. Sensitivity analyses did not support the presence of heterogeneity in the majority of MR analyses. Conclusions: Our study revealed risk and protective inflammatory proteins for severe COVID-19, which may have vital implications for the treatment of the disease.

Gut microbiota's causative relationship with peripheral artery disease: a Mendelian randomization study.

Introduction: The relationship between gut microbiota and peripheral artery disease (PAD) remains understudied. While traditional risk factors like smoking and hyperlipidemia are well-understood, our study aims to determine the potential causative association of gut microbiota with PAD using Mendelian Randomization. Methods: Data from the International MiBioGen Consortium and the FinnGen research project were used to study 211 bacterial taxa. Instrumental variables, comprising 2079 SNPs, were selected based on significance levels and linkage disequilibrium. Analyses were conducted utilizing the inverse-variance weighted (IVW) method and other statistical MR techniques to mitigate biases, processed in R (v4.3.1) with the TwosampleMR package. Results: Three bacterial taxa, namely genus Coprococcus2, RuminococcaceaeUCG004, and RuminococcaceaeUCG010, emerged as protective factors against PAD. In contrast, family. FamilyXI and the genus Lachnoclostridium and LachnospiraceaeUCG001 were identified as risk factors. Conclusion: Our findings hint at a causative association between certain gut microbiota and PAD, introducing new avenues for understanding PAD's etiology and developing effective treatments. The observed associations now warrant further validation in varied populations and detailed exploration at finer taxonomic levels.

Transcriptional patterns of the cortical Morphometric Inverse Divergence in first-episode, treatment-naïve early-onset schizophrenia.

Early-onset Schizophrenia (EOS) is a profoundly progressive psychiatric disorder characterized by both positive and negative symptoms, whose pathogenesis is influenced by genes, environment and brain structure development. In this study, the MIND (Morphometric Inverse Divergence) network was employed to explore the relationship between morphological similarity and specific transcriptional expression patterns in EOS patients. This study involved a cohort of 187 participants aged between 7 and 17 years, consisting of 97 EOS patients and 90 healthy controls (HC). Multiple morphological features were used to construct the MIND network for all participants. Furthermore, we explored the associations between MIND network and brain-wide gene expression in EOS patients through partial least squares (PLS) regression, shared genetic predispositions with other psychiatric disorders, functional enrichment of PLS weighted genes, as well as transcriptional signature assessment of cell types, cortical layers, and developmental stages. The MIND showed similarity differences in the orbitofrontal cortex, pericalcarine cortex, lingual gyrus, and multiple networks in EOS patients compared to HC. Moreover, our exploration revealed a significant overlap of PLS2 weighted genes linking to EOS-related MIND differences and the dysregulated genes reported in other psychiatric diseases. Interestingly, genes correlated with MIND changes (PLS2-) exhibited a significant enrichment not only in metabolism-related pathways, but also in specific astrocytes, cortical layers (specifically layer I and III), and posterior developmental stages (late infancy to young adulthood stages). However, PLS2+ genes were primarily enriched in synapses signaling-related pathways and early developmental stages (from early-mid fetal to neonatal early infancy) but not in special cell types or layers. These findings provide a novel perspective on the intricate relationship between macroscopic morphometric structural abnormalities and microscopic transcriptional patterns during the onset and progression of EOS.

Cortical structural changes of morphometric similarity network in early-onset schizophrenia correlate with specific transcriptional expression patterns.

BACKGROUND: This study aimed to investigate the neuroanatomical subtypes among early-onset schizophrenia (EOS) patients by exploring the association between structural alterations and molecular mechanisms using a combined analysis of morphometric similarity network (MSN) changes and specific transcriptional expression patterns. METHODS: We recruited 206 subjects aged 7 to 17 years, including 100 EOS patients and 106 healthy controls (HC). Heterogeneity through discriminant analysis (HYDRA) was used to identify the EOS subtypes within the MSN strength. The differences in morphometric similarity between each EOS subtype and HC were compared. Furthermore, we examined the link between morphometric changes and brain-wide gene expression in different EOS subtypes using partial least squares regression (PLS) weight mapping, evaluated genetic commonalities with psychiatric disorders, identified functional enrichments of PLS-weighted genes, and assessed cellular transcriptional signatures. RESULTS: Two distinct MSN-based EOS subtypes were identified, each exhibiting different abnormal MSN strength and cognitive functions compared to HC. The PLS1 score mapping demonstrated anterior-posterior gradients of gene expression in EOS1, whereas inverse distributions were observed in EOS2 cohorts. Genetic commonalities were identified in autistic disorder and adult schizophrenia with EOS1 and inflammatory bowel diseases with EOS2 cohorts. The EOS1 PLS1- genes (Z < -5) were significantly enriched in synaptic signaling-related functions, whereas EOS2 demonstrated enrichments in virtual infection-related pathways. Furthermore, the majority of observed associations with EOS1-specific MSN strength differences contributed to specific transcriptional changes in astrocytes and neurons. CONCLUSIONS: The findings of this study provide a comprehensive analysis of neuroanatomical subtypes in EOS, shedding light on the intricate relationships between macrostructural and molecular aspects of the EOS disease.

Radiotherapy plus immune checkpoint inhibitor in prostate cancer.

The immune checkpoint inhibitor (ICI) is a promising strategy for treating cancer. However, the efficiency of ICI monotherapy is limited, which could be mainly attributed to the tumor microenvironment of the "cold" tumor. Prostate cancer, a type of "cold" cancer, is the most common cancer affecting men's health. Radiotherapy is regarded as one of the most effective prostate cancer treatments. In the era of immune therapy, the enhanced antigen presentation and immune cell infiltration caused by radiotherapy might boost the therapeutic efficacy of ICI. Here, the rationale of radiotherapy combined with ICI was reviewed. Also, the scheme of radiotherapy combined with immune checkpoint blockades was suggested as a potential option to improve the outcome of patients with prostate cancer.

Improving Depressive Symptoms of Post-stroke Depression Using the Shugan Jieyu Capsule: A Resting-State Functional Magnetic Resonance Imaging Study.

Regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuation (fALFF) were used to detect the neuroimaging mechanism of Shugan Jieyu Capsule (SG) in ameliorating depression of post-stroke depression (PSD) patients. Fifteen PSD patients took SG for 8 weeks, completed the 24-item Hamilton Depression Scale (HAMD) assessment at the baseline and 8 weeks later, and underwent functional magnetic resonance imaging (fMRI) scanning. Twenty-one healthy controls (HCs) underwent these assessments at the baseline. We found that SG improved depression of PSD patients, in which ReHo values decreased in the left calcarine sulcus (CAL.L) and increased in the left superior frontal gyrus (SFG.L) of PSD patients at the baseline. The fALFF values of the left inferior parietal cortex (IPL.L) decreased in PSD patients at the baseline. Abnormal functional activities in the brain regions were reversed to normal levels after the administration of SG for 8 weeks. Receiver operating characteristic (ROC) analysis found that the changes in three altered brain regions could be used to differentiate PSD patients at the baseline and HCs. Average signal values of altered regions were related to depression in all subjects at the baseline. Our results suggest that SG may ameliorate depression of PSD patients by affecting brain region activity and local synchronization.

Abnormal Cortical Activation Patterns Among Chinese-Speaking Schizophrenia Patients During Category and Letter Verbal Fluency Tasks Revealed by Multi-Channel Functional Near-Infrared Spectroscopy.

Background: Functional near-infrared spectroscopy (fNIRS) has many advantages over other neuroimaging modalities for routine measurement of task-dependent cortical activation, but most fNIRS studies of schizophrenia have used letter fluency tasks (LFTs). Further, performances on category fluency tasks (CFTs) and LFTs may be distinct in Chinese patients due to the unique semantic features of Chinese written characters. To identify unique disease biomarkers measurable by fNIRS in Chinese schizophrenia patients, this study compared cortical oxygenated hemoglobin changes ([oxy-Hb]) during a Chinese LFT and CFT between patients and healthy controls. Methods: Inpatients of the Second Affiliated Hospital of Xinxiang Medical University were recruited from Match 2020 to July 2021. The Positive and Negative Symptom Scale (PANSS) was used to evaluate psychiatric symptoms. Dynamic changes in [oxy-Hb], an indicator of neural activity, were measured during CFT and LFT performance by 52-channel fNIRS. Results: Forty-seven schizophrenia inpatients and 29 healthy controls completed all tests. Schizophrenia patients showed significant cortical activation at 15 channels covering the left hemisphere and 17 channels over the right hemisphere during the CFT. During the LFT, activity was significantly increased at only six channels, all over the left hemisphere (FDR P < 0.05). In healthy controls, significant [oxy-Hb] increases were found at 24 channels over the left hemisphere and 19 channels over the right hemisphere during CFT. While during the LFT, the significant increases were found at 7 channels all over the left hemisphere (FDR P < 0.05). When years of education was included as a covariate, the schizophrenia group demonstrated no significant hypoactivation relative to healthy controls at any channel after FDR correction (FDR P < 0.05) during CFT while demonstrated significant hypoactivation at channel 11 during LFT (FDR P < 0.05). There were no significant associations between PANSS scores and [oxy-Hb] changes after FDR correction (FDR P < 0.05). Conclusions: Left lateralization during CFT was reduced among schizophrenia patients and may be related to the semantic deficit. The Chinese-CFT could be a more sensitive indicator of frontal-temporal dysfunction in schizophrenia.

Prefrontal cortex alterations in major depressive disorder, generalized anxiety disorder and their comorbidity during a verbal fluency task assessed by multi-channel near-infrared spectroscopy.

Major depressive disorder (MDD) and generalized anxiety disorder (GAD) are frequently comorbid with each other, and both associated with substantial cognitive impairments; however, it is still unclear whether their impairments are neurobiologically similar or distinct. This study aims to investigate the cognitive functions of the prefrontal cortex (PFC) in patients with MDD and GAD during the verbal fluency task (VFT) using functional near-infrared spectroscopy (fNIRS). Fifty-two patients with MDD, fifty-one patients with GAD, fifty-two patients with the comorbidity of MDD and GAD (CMG), and forty-seven healthy controls (HC) participated in the study. Significant hypoactivation in the left ventrolateral and the left dorsolateral PFC was common in all patient groups when compared to HCs, suggesting a shared etiology. Furthermore,  MDD patients showed significant hypoactivation at the right frontal pole cortex (FPoC) when compared to HCs and significant hypoactivation at the middle FPoC when compared to the CMG patients. Our work is the first fNIRS study to reveal the shared and unique neurobiological profiles of MDD, GAD and their comorbidity under the same standard experimentation condition, suggesting fNIRS holds promise as an adjutant to assist clinical diagnosis.

Acquirement of HRP conjunct IgG anti-IgMs from most widely cultured freshwater fishes in China and its immunoreactivity.

Until now, custom-made or commercial polyclonal antibody against only one kind of fish IgM limited application of the antibody. During our research on development of vaccine against infection of Clonorchis sinensis (C. sinensis) in several kinds of fish, we were conscious of the urgency of secondary antibody to evaluate immune effect and screen C. sinensis infection with immunological technology instead of labor-intensive and time-consuming squash or artificial digestion of fish flesh. So that, we purified IgM of grass carp, bighead carp, crucian carp, common carp and tilapia which were widely cultured freshwater fishes in most areas of China. On this basis, we generated HRP-conjunct rabbit IgG anti-fish IgMs with high titers. IgM of other freshwater fishes including oshima, yellow catfish, bream, silver carp and so on could be recognized by the IgG sensitively. Additionally, The ELISA detection displayed that the IgG could be more specific and sensitive than custom-made rabbit IgG anti-grass carp IgM. The acquirement of HRP-conjunct rabbit IgG anti-fish IgMs was the cornerstone for studying the immune system of teleost fish, developing immunoassay methods and evaluation of fish vaccine with more convenience.

Abnormality of subcortical volume and resting functional connectivity in adolescents with early-onset and prodromal schizophrenia.

OBJECTIVE: Studies have found that there may be qualitative changes in brain structure and function in adolescents with early-onset schizophrenia (EOS) and prodromal schizophrenia (PDS). However, the abnormal brain structure and function of adolescents with EOS and PDS have received little attention, and their underlying neural mechanisms are still unknown. METHODS: In this study, structural and resting-state functional magnetic resonance imaging (fMRI) were used to compare the subcortical volume and functional connectivity (FC) among EOS, PDS, and a control group. The Positive and Negative Symptom Scale (PNASS) questionnaire was used for clinical evaluation. Structural MRI was used to calculate cortical-based morphological volume and subcortical volume, and resting-state fMRI was used to analyze seed-based FC. RESULTS: Structural MRI analyses showed that the gray matter volume of the hippocampus in EOS was significantly smaller than that in the control group, and the gray matter volume of the hippocampus, amygdala, and caudate nucleus in PDS was significantly smaller than that in the control group. Additionally, correlation analysis showed that the gray matter volume of the hippocampus was significantly negatively correlated with the negative symptom score of PANSS in EOS. When the hippocampus was used as the seed, fMRI analysis found that the FC between the hippocampus and the posterior cingulate gyrus and precuneus in EOS was significantly weaker than that in the control group. CONCLUSION: Our results indicate that the brain structure and function are abnormal in EOS and PDS, with abnormalities mainly concentrated in the limbic system, including the hippocampus, amygdala, caudate nucleus, cingulate gyrus, and precuneus. These findings provide a new direction for early intervention and improvement of the prognosis of schizophrenic patients.

Mechanisms of the Effects of Parental Emotional Warmth on Extraversion in Children and Adolescents.

The purpose of this study is to probe into the influence mechanism of parental emotional warmth (PEW) on extraversion for children and adolescents, as well as the moderating and mediating role of brain functional activity. Thirty-two children and adolescents underwent functional magnetic resonance imaging (fMRI) scans and completed Egna Minnen av Barndoms Uppfostran (EMBU) and Eysenck Personality Questionnaire (EPQ). Small-worldness (SW) of brain networks, fractional amplitude of low-frequency fluctuations (fALFF), and region-of-interest to region-of-interest (ROI-ROI) functional connectivity were calculated to study intrinsic neuronal activity. We found that PEW had a positive direct effect on extraversion, and all participants in the current study showed an efficient small-world structure. The positive association between PEW and extraversion was mediated by SW. Furthermore, the fALFF and extraversion were significantly and negatively correlated in the right precuneus and dorsolateral superior frontal gyrus. The mediating effect of SW was moderated by the functional connectivity between the right precuneus and the right dorsolateral superior frontal gyrus. The indirect effect was significant with lower level of the functional connectivity between the right precuneus and the right dorsolateral superior frontal gyrus. These findings indicate that SW of brain networks may be a key factor that accounts for the positive association between PEW and extraversion in children and adolescents and the level of the functional connectivity between the right precuneus and the right dorsolateral superior frontal gyrus could moderate the relationship.

Alterations of Functional Connectivity in Stroke Patients With Basal Ganglia Damage and Cognitive Impairment.

Background: Stroke with basal ganglia damage (SBG) is a neurological disorder characterized by cognitive impairment. The neurobiological mechanism of cognitive impairment in stroke patients with basal ganglia damage (SBG patients) remains unclear. This study aimed to explore the underlying neurobiological mechanism of cognitive impairment in SBG patients using resting-state functional magnetic resonance imaging (rs-fMRI). Methods: The differences in functional connectivity (FC) between 14 SBG patients (average age: 61.00 ± 7.45 years) and 21 healthy controls (HC) (average age: 60.67 ± 6.95 years) were examined using voxel-mirrored homotopic connectivity (VMHC) and degree centrality (DC). Moreover, we compared the cognitive functions of SBG patients with HC using the Chinese Revised Wechsler Adult Intelligence Scale (WAIS-RC) and Wechsler Memory Scale (WMS). Results: Full-scale intelligence quotient (FIQ) (t = 2.810, p < 0.010) and memory quotient (MQ) (t = 2.920, p < 0.010) scores of SBG patients were significantly lower than those of HC. Compared with HC, significantly decreased VMHC values in the bilateral angular gyrus, supramarginal gyrus, inferior frontal gyrus, middle temporal gyrus, hippocampus, precuneus, precentral gyrus, and middle occipital gyrus and decreased DC values in the right supramarginal gyrus, bilateral angular gyrus, and right postcentral gyrus were observed in SBG patients. Moreover, the VMHC values in the angular gyrus, inferior frontal gyrus, supramarginal gyrus, and middle temporal gyrus and the DC values in the right supramarginal gyrus were significantly correlated with cognitive functions in all participants. Conclusion: Our findings may provide a neural basis for cognitive impairments in SBG patients. Furthermore, local abnormalities of functional networks and interhemispheric interaction deficits may provide new ideas and insights for understanding and treating SBG patients' cognitive impairments.

Improved Resting-State Functional Dynamics in Post-stroke Depressive Patients After Shugan Jieyu Capsule Treatment.

Shugan Jieyu Capsule (SG), a Chinese herbal medicine mainly composed of Acanthopanax and Hypericum perforatum, has been used to ameliorate cognitive impairments and emotional problems induced by post-stroke depression (PSD), while the altered brain dynamics underlying the ameliorative effects of SG have remained unclear. Our study focused on investigating the potential neurobiological mechanisms of SG in improving the cognitive function of PSD patients via resting-state functional magnetic resonance imaging (fMRI). Fifteen PSD patients (mean ages: 64.13 ± 6.01 years) were instructed to take 0.72 g of SG twice a day for 8 weeks. PSD patients underwent fMRIs, the 24-item Hamilton Depression Scale (HAMD-24) and the Montreal Cognitive Assessment (MoCA) at baseline and the end of intervention, and these assessments were also performed on twenty-one healthy controls (HC) (mean ages: 60.67 ± 6.95 years). Additionally, the dynamic amplitude of low-frequency fluctuations (dALFF) and functional connectivity (dFC) were determined to reveal changes in dynamic functional patterns. We found that taking SG significantly reduced the depressive symptoms assessed by HAMD-24 and improved cognitive functions assessed by MoCA in PSD patients. Furthermore, at baseline, PSD patients showed decreased dALFF in the right precuneus and increased dFC between the right precuneus and left angular gyrus, compared with HC. After intervention, the dALFF and dFC variances of the abnormal patterns were reversed. Additionally, the dALFF variance in the right precuneus was positively correlated with MoCA scores in PSD patients after SG treatment. Collectively, our results indicate that SG may improve the cognitive function of PSD patients through alteration of brain dynamics. Our findings lay a foundation for the exploration of the neurobiological mechanisms of SG in ameliorating symptoms of PSD patients.