Aberrant concordance among dynamics of spontaneous brain activity in patients with migraine without aura: A multivariate pattern analysis study.

Background: Alterations in the static and dynamic characteristics of spontaneous brain activity have been extensively studied to investigate functional brain changes in migraine without aura (MwoA). However, alterations in concordance among the dynamics of spontaneous brain activity in MwoA remain largely unknown. This study aimed to determine the possibilities of diagnosis based on the concordance indices. Methods: Resting-state functional MRI scans were performed on 32 patients with MwoA and 33 matched healthy controls (HCs) in the first cohort, as well as 36 patients with MwoA and 32 HCs in the validation cohort. The dynamic indices including fractional amplitude of low-frequency fluctuation, regional homogeneity, voxel-mirrored homotopic connectivity, degree centrality and global signal connectivity were analyzed. We calculated the concordance of grey matter volume-wise (across voxels) and voxel-wise (across time windows) to quantify the degree of integration among different functional levels represented by these dynamic indices. Subsequently, the voxel-wise concordance alterations were analyzed as features for multi-voxel pattern analysis (MVPA) utilizing the support vector machine. Results: Compared with that of HCs, patients with MwoA had lower whole-grey matter volume-wise concordance, and the mean value of volume-wise concordance was negatively correlated with the frequency of migraine attacks. The MVPA results revealed that the most discriminative brain regions were the right thalamus, right cerebellar Crus II, left insula, left precentral gyrus, right cuneus, and left inferior occipital gyrus. Conclusions: Concordance alterations in the dynamics of spontaneous brain activity in brain regions could be an important feature in the identification of patients with MwoA.

Modulation of temporal and occipital cortex by acupuncture in non-menstrual MWoA patients: a rest BOLD fMRI study.

OBJECTIVE: To investigate the changes in amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) values before and after acupuncture in young women with non-menstrual migraine without aura (MWoA) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI). METHODS: Patients with non-menstrual MWoA (Group 1, n = 50) and healthy controls (Group 2, n = 50) were recruited. fMRI was performed in Group 1 at 2 time points: before acupuncture (time point 1, TP1); and after the end of all acupuncture sessions (time point 2, TP2), and performed in Group 2 as a one-time scan. Patients in Group 1 were assessed with the Migraine Disability Assessment Questionnaire (MIDAS) and the Short-Form McGill Pain Questionnaire (SF-MPQ) at TP1 and TP2 after fMRI was performed. The ALFF and DC values were compared within Group 1 at two time points and between Group 1 and Group2. The correlation between ALFF and DC values with the statistical differences and the clinical scales scores were analyzed. RESULTS: Brain activities increased in the left fusiform gyrus and right angular gyrus, left middle occipital gyrus, and bilateral prefrontal cortex and decreased in left inferior parietal lobule in Group 1, which had different ALFF values compared with Group 2 at TP1. The bilateral fusiform gyrus, bilateral inferior temporal gyrus and right middle temporal gyrus increased and right angular gyrus, right superior marginal gyrus, right inferior parietal lobule, right middle occipital gyrus, right superior frontal gyrus, right middle frontal gyrus, right anterior central gyrus, and right supplementary motor area decreased in activity in Group 1 had different DC values compared with Group 2 at TP1. ALFF and DC values of right inferior temporal gyrus, right fusiform gyrus and right middle temporal gyrus were decreased in Group1 at TP1 compared with TP2. ALFF values in the left middle occipital area were positively correlated with the pain degree at TP1 in Group1 (correlation coefficient r, r = 0.827, r = 0.343; P < 0.01, P = 0.015). The DC values of the right inferior temporal area were positively correlated with the pain degree at TP1 in Group 1 (r = 0.371; P = 0.008). CONCLUSION: Spontaneous brain activity and network changes in young women with non-menstrual MwoA were altered by acupuncture. The right temporal area may be an important target for acupuncture modulated brain function in young women with non-menstrual MwoA.

Altered effective connectivity from cerebellum to motor cortex in chronic low back pain: A multivariate pattern analysis and spectral dynamic causal modeling study.

To explore the central processing mechanism of pain perception in chronic low back pain (cLBP) using multi-voxel pattern analysis (MVPA) based on the static and dynamic fractional amplitude of low-frequency fluctuations (fALFF) analysis, and spectral dynamic causal modeling (spDCM). Thirty-two patients with cLBP and 29 matched healthy controls (HCs) for the first cohort and 24 patients with cLBP and 22 HCs for the validation cohort underwent resting-state fMRI scan. The alterations in static and dynamic fALFF were as classification features to distinguish patients with cLBP from HCs. The brain regions gotten from the MVPA results were used for further spDCM analysis. We found that the most discriminative brain regions that contributed to the classification were the right supplementary motor area (SMA.R), left paracentral lobule (PCL.L), and bilateral cerebellar Crus II. The spDCM results displayed decreased excitatory influence from the bilateral cerebellar Crus II to PCL.L in patients with cLBP compared with HCs. Moreover, the conversion of effective connectivity from the bilateral cerebellar Crus II to SMA.R from excitatory influence to inhibitive influence, and the effective connectivity strength exhibited partially mediated effects on Chinese Short Form Oswestry Disability Index Questionnaire (C-SFODI) scores. Our findings suggest that the cerebellum and its weakened or inhibited connections to the motor cortex may be one of the underlying feedback pathways for pain perception in cLBP, and partially mediate the degree of dysfunction.

Association of vaccine-specific regulatory T cells with reduced antibody response to repeated influenza vaccination.

Repeated annual influenza vaccinations have been associated with reduced vaccine-induced antibody responses. This prospective study aimed to explore the role of vaccine antigen-specific regulatory T (Treg) cells in antibody response to repeated annual influenza vaccination. We analyzed pre- and postvaccination hemagglutination inhibition (HI) titers, seroconversion rates, seroprotection rates, vaccine antigen hemagglutinin (HA)-specific Treg cells, and conventional T (Tconv) cells. We compared these parameters between vaccinees with or without vaccine-induced seroconversion. Our multivariate logistic regression revealed that prior vaccination was significantly associated with a decreased likelihood of achieving seroconversion for both H1N1(adjusted OR, 0.03; 95% CI, 0.01-0.13) and H3N2 (adjusted OR, 0.09; 95% CI, 0.03-0.30). Furthermore, individuals who received repeated vaccinations had significantly higher levels of pre-existing HA-specific Treg cells than those who did not. We also found that vaccine-induced fold-increases in HI titers and seroconversion were negatively correlated with pre-existing HA-specific Treg cells and positively correlated with the ratio of Tconv to Treg cells. Overall, our findings suggest that repeated annual influenza vaccination is associated with a lower vaccine-induced antibody response and a higher frequency of vaccine-specific Treg cells. However, a lower frequency of pre-existing Treg cells correlates with a higher postvaccination antibody response.

Quantitative dynamic contrast-enhance MRI parameters for rectal carcinoma characterization: correlation with tumor tissue composition.

OBJECTIVE: To investigate the relationship between dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) measurements and the potential composition of rectal carcinoma. METHODS: Twenty-four patients provided informed consent for this study. DCE-MRI was performed before total mesorectal excision. Quantitative parameters were calculated based on a modified Tofts model. Whole-mount immunohistochemistry and Masson staining sections were generated and digitized at histological resolution. The percentage of tissue components area was measured. Pearson correlation analysis was used to evaluate the correlations between pathological parameters and DCE-MRI parameters. RESULTS: On the World Health Organization (WHO) grading scale, there were significant differences in extracellular extravascular space (Ktrans) (F = 9.890, P = 0.001), mean transit time (MTT) (F = 9.890, P = 0.038), CDX-2 (F = 4.935, P = 0.018), and Ki-67 (F = 4.131, P = 0.031) among G1, G2, and G3. ECV showed significant differences in extramural venous invasion (t = - 2.113, P = 0.046). Ktrans was strongly positively correlated with CD34 (r = 0.708, P = 0.000) and moderately positively correlated with vimentin (r = 0.450, P = 0.027). Interstitial volume (Ve) was moderately positively correlated with Masson's (r = 0.548, P = 0.006) and vimentin (r = 0.417, P = 0.043). There was a moderate negative correlation between Ve and CDX-2 (r = - 0.441, P = 0.031). The rate constant from extracellular extravascular space to blood plasma (Kep) showed a strong positive correlation with CD34 expression (r = 0.622, P = 0.001). ECV showed a moderate negative correlation with CDX-2 (r = - 0.472, P = 0.020) and a moderate positive correlation with collagen fibers (r = 0.558, P = 0.005). CONCLUSION: The dynamic contrast-enhanced MRI-derived parameters measured in rectal cancer were significantly correlated with the proportion of histological components. This may serve as an optimal imaging biomarker to identify tumor tissue components.

Long-term outcomes of COVID-19 convalescents: An 18.5-month longitudinal study in Wuhan.

OBJECTIVES: This study aimed to describe the full scope of long-term outcomes and the ongoing pathophysiological alterations among COVID-19 survivors. METHODS: We established a longitudinal cohort of 208 COVID-19 convalescents and followed them at 3.3 (interquartile range [IQR]: 1.3, 4.4, visit 1), 9.2 (IQR: 9.0, 9.6, visit 2), and 18.5 (IQR: 18.2, 19.1, visit 3) months after infection, respectively. Serial changes in multiple physical and psychological outcomes were comprehensively characterized. We, in addition, explored the potential risk factors of SARS-CoV-2 antibody response and sequelae symptoms. RESULTS: We observed continuous improvement of sequelae symptoms, lung function, chest computed tomography (CT), 6-minute walk test, and the Borg dyspnea scale, whereas sequelae symptoms (at least one) and abnormal chest CT patterns still existed in 45.2% and about 30% of participants at 18.5 months, respectively. Anxiety and depression disorders were alleviated for the convalescents, although depression status was sustained for a longer duration. CONCLUSIONS: Most COVID-19 convalescents had an overall improved physical and psychological health status, whereas sequelae symptoms, residual lesions on lung function, exercise impairment, and mental health disorders were still observed in a small proportion of participants at 18.5 months after infection. Implementing appropriate preventive and management strategies for the ever-growing COVID-19 population is warranted.

The Optimization of Assay Conditions and Characterization of the Succinic Semialdehyde Dehydrogenase Enzyme of Germinated Tartary Buckwheat.

In this study, the conditions for optimizing the determination of succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.79) activity in germinated Tartary buckwheat were investigated. Based on a single-factor test, the effects of temperature, pH, and succinic semialdehyde (SSA) concentration on the enzyme activity of germinated buckwheat SSADH were investigated by using the response surface method, and optimal conditions were used to study the enzymatic properties of germinated buckwheat SSADH. The results revealed that the optimum conditions for determining SSADH enzyme activity are as follows: temperature-30.8 °C, pH-8.7, and SSA concentration-0.3 mmol/L. Under these conditions, SSADH enzyme activity was measured as 346 ± 9.61 nmol/min. Furthermore, the thermal stability of SSADH was found to be superior at 25 °C, and its pH stability remained comparable at pH levels of 7.6, 8.1, and 8.6 in germinated Tartary buckwheat samples; however, a decline in stability was observed at pH 9.1. Cu2+, Co2+, and Ni2+ exhibited an activating effect on SSADH activity in germinating Tartary buckwheat, with Cu2+ having the greatest influence (p < 0.05), which was 1.21 times higher than that of the control group. Zn2+, Mn2+, and Na+ inhibited SSADH activity in germinating Tartary buckwheat, with Zn2+ showing the strongest inhibitory effect (p < 0.05). On the other hand, the Km and Vmax of SSADH for SSA in germinated Tartary buckwheat were 0.24 mmol/L and 583.24 nmol/min. The Km and Vmax of SSADH for NAD+ in germinated Tartary buckwheat were 0.64 mmol/L and 454.55 nmol/min.

Prostate-Specific Membrane Antigen-1-Mediated Au@SiO2@Au Core-Shell Nanoparticles: Targeting Prostate Cancer to Enhance Photothermal Therapy and Fluorescence Imaging.

The advantages of deep tissue penetration and the high spatial accuracy of photothermal therapy have been widely studied. Gold, as a photothermal material, has received particular attention. Different sizes and shapes of gold have been studied and characterized for their varying photothermal properties. The core-shell structure of gold nanoparticles and silica enhances the photothermal conversion through the coupling effect between gold clusters on the material's surface. With excellent photothermal conversion performance, the core-shell nanoparticles can quickly reach 40 °C in 200 s under the irradiation of 808 nm, 1.5 W·cm-2. The highest conversion temperature of these nanoparticles is 56 °C, and the photothermal conversion rate is 45%. In vitro cell experiments displayed that NPs with targeted function can efficiently aggregate in prostate cancer cells and effectively kill cells. In vitro experiments showed that the tumor cells of mice after photothermal treatment completely disappeared after 15 days, which fully demonstrated the potential of the nanoparticles for targeted photothermal therapy.

The Changes of Brain Function After Spinal Manipulation Therapy in Patients with Chronic Low Back Pain: A Rest BOLD fMRI Study.

OBJECTIVE: To investigate the changes of regional homogeneity (Reho) values before and after spinal manipulative therapy (SMT) in patients with chronic low back pain (CLBP) through rest blood-oxygen-level-dependent functional magnetic resonance imaging (BOLD fMRI). METHODS: Patients with CLBP (Group 1, n = 20) and healthy control subjects (Group 2, n = 20) were recruited. The fMRI was performed three times in Group 1 before SMT (time point 1, TP1), after the first SMT (time point 2, TP2), after the sixth SMT (time point 3, TP3), and for one time in Group 2, which received no intervention. The clinical scales were finished in Group 1 every time before fMRI was performed. The Reho values were compared among Group 1 at different time points, and between Group 1 and Group 2. The correlation between Reho values with the statistical differences and the clinical scale scores were calculated. RESULTS: The bilateral precuneus and right mid-frontal gyrus in Group 1 had different Reho values compared with Group 2 at TP1. The Reho values were increased in the left precuneus and decreased in the left superior frontal gyrus in Group 1 at TP2 compared with TP1. The Reho values were increased in the left postcentral gyrus and decreased in the left posterior cingulate cortex and the superior frontal gyrus in Group 1 at TP3 compared with TP1. The ReHo values of the left precuneus in Group 1 at TP1 were negatively correlated with the pain degree at TP1 and TP2 (r = -0.549, -0.453; p = 0.012, 0.045). The Reho values of the middle temporal gyrus in Group 1 at TP3 were negatively correlated with the changes of clinical scale scores between TP3 and TP1 (r = 0.454, 0.559; p = 0.044, 0.01). CONCLUSION: Patients with CLBP showed abnormal brain function activity, which was altered after SMT. The Reho values of the left precuneus could predict the immediate analgesic effect of SMT.

Autophagy Upregulates miR-449a Expression to Suppress Progression of Colorectal Cancer.

Many studies reported that microRNAs (miRNAs) target autophagy-related genes to affect carcinogenesis, however, autophagy-deficiency-related miRNA dysfunction in cancer development remains poorly explored. During autophagic progression, we identified miR-449a as the most up-regulated miRNA. MiR-449a expression was low in the tumor parts of CRC patient specimens and inversely correlated with tumor stage and metastasis with the AUC (area under the curve) of 0.899 and 0.736 as well as poor overall survival rate, indicating that miR-449a has the potential to be a prognostic biomarker. In the same group of CRC specimens, low autophagic activity (low Beclin 1 expression and high p62 accumulation) was detected, which was significantly associated with miR-449a expression. Mechanistic studies disclosed that autophagy upregulates miR-449a expression through degradation of the coactivator p300 protein which acetylates the transcription factor Forkhead Box O1 (FoxO1). Unacetylated FoxO1 translocated to the nucleus and bound to the miR-449a promoter to drive gene expression. Either activation of autophagy by the inducer or overexpression of exogenous miR-449a decreases the expression of target gene LEF-1 and cyclin D1, which lead to decreased proliferation, colony formation, migration, and invasion of CRC cells. Autophagy-miR-449a-tartet genes mediated suppression of tumor formation was further confirmed in the xenograft mouse model. In conclusion, this study reveals a novel mechanism wherein autophagy utilizes miR-449a-LEF1-cyclin D1 axis to suppress CRC tumorigenesis. Our findings open a new avenue toward prognosis and treatment of CRC patients by manipulating autophagy-miR-449a axis.

Recent Progress and Future Prospective in HBV Cure by CRISPR/Cas.

Hepatitis B virus (HBV) infection remains an important issue of global public health. Although current antiviral therapy has dramatically reduced the mortality and morbidity of chronic hepatitis B (CHB), it fails to cure it. Rebound viremia often occurs after stopping antiviral therapy. Persistent HBV covalently closed circular DNA (cccDNA) and integrated DNA under antiviral therapy form the major barrier to eradication of HBV infection. CRISPR-mediated genome editing has emerged as a promising therapeutic approach to specifically destroy persistent HBV genomes, both cccDNA and integrated DNA, for HBV cure. However, the cleavage of integrated HBV DNA by CRISPR-Cas9 will cause double-strand break (DSB) of host genome, raising a serious safety concern about genome instability and carcinogenesis. The newly developed CRISPR-derived base editors (BEs), which fuse a catalytically disabled nuclease with a nucleobase deaminase enzyme, can be used to permanently inactivate HBV genome by introducing irreversible point mutations for generation of premature stop codons without DSBs of host genome. Although promising, CRISPR-mediated base editing still faces daunting challenges before its clinical application, including the base-editing efficacy, the off-target effect, the difficulty in finding conserved target HBV sequences, and in vivo delivery efficiency. Several strategies have been adopted to optimize the efficiency and specificity of CRISPR-BEs and to improve in vivo delivery efficacy through novel viral and non-viral delivery approaches. Particularly, the non-viral delivery of Cas9 mRNA and ribonucleoprotein by lipid nanoparticles exhibits attractive potential for liver-targeted delivery in clinical. Along with all progress above, the CRISPR-mediated gene therapy will ultimately achieve HBV cure.

Spinal Manipulative Therapy Alters Brain Activity in Patients With Chronic Low Back Pain: A Longitudinal Brain fMRI Study.

Background: Spinal manipulative therapy (SMT) helps to reduce chronic low back pain (cLBP). However, the underlying mechanism of pain relief and the neurological response to SMT remains unclear. We utilized brain functional magnetic resonance imaging (fMRI) upon the application of a real-time spot pressure mechanical stimulus to assess the effects of SMT on patients with cLBP. Methods: Patients with cLBP (Group 1, n = 14) and age-matched healthy controls without cLBP (Group 2, n = 20) were prospectively enrolled. Brain fMRI was performed for Group 1 at three time points: before SMT (TP1), after the first SMT session (TP2), and after the sixth SMT session (TP3). The healthy controls (Group 2) did not receive SMT and underwent only one fMRI scan. During fMRI scanning, a real-time spot pressure mechanical stimulus was applied to the low back area of all participants. Participants in Group 1 completed clinical questionnaires assessing pain and quality of life using a visual analog scale (VAS) and the Chinese Short Form Oswestry Disability Index (C-SFODI), respectively. Results: Before SMT (TP1), there were no significant differences in brain activity between Group 1 and Group 2. After the first SMT session (TP2), Group 1 showed significantly greater brain activity in the right parahippocampal gyrus, right dorsolateral prefrontal cortex, and left precuneus compared to Group 2 (P < 0.05). After the sixth SMT session (TP3), Group 1 showed significantly greater brain activity in the posterior cingulate gyrus and right inferior frontal gyrus compared to Group 2 (P < 0.05). After both the first and sixth SMT sessions (TP2 and TP3), Group 1 had significantly lower VAS pain scores and C-SFODI scores than at TP1 (P < 0.001). Conclusion: We observed alterations in brain activity in regions of the default mode network in patients with cLBP after SMT. These findings suggest the potential utility of the default mode network as a neuroimaging biomarker for pain management in patients with cLBP. Clinical Trial Registration: Chinese Clinical Trial Registry, identifier ChiCTR1800015620.

Permanent Inactivation of HBV Genomes by CRISPR/Cas9-Mediated Non-cleavage Base Editing.

Current antiviral therapy fails to cure chronic hepatitis B virus (HBV) infection because of persistent covalently closed circular DNA (cccDNA). CRISPR/Cas9-mediated specific cleavage of cccDNA is a potentially curative strategy for chronic hepatitis B (CHB). However, the CRISPR/Cas system inevitably targets integrated HBV DNA and induces double-strand breaks (DSBs) of host genome, bearing the risk of genomic rearrangement and damage. Herein, we examined the utility of recently developed CRISPR/Cas-mediated "base editors" (BEs) in inactivating HBV gene expression without cleavage of DNA. Candidate target sites of the SpCas9-derived BE and its variants in HBV genomes were screened for generating nonsense mutations of viral genes with individual guide RNAs (gRNAs). SpCas9-BE with certain gRNAs effectively base-edited polymerase and surface genes and reduced HBV gene expression in cells harboring integrated HBV genomes, but induced very few insertions or deletions (indels). Interestingly, some point mutations introduced by base editing resulted in simultaneous suppression of both polymerase and surface genes. Finally, the episomal cccDNA was successfully edited by SpCas9-BE for suppression of viral gene expression in an in vitro HBV infection system. In conclusion, Cas9-mediated base editing is a potential strategy to cure CHB by permanent inactivation of integrated HBV DNA and cccDNA without DSBs of the host genome.

Hydrothermal conversion of N-acetyl-d-glucosamine to 5-hydroxymethylfurfural using ionic liquid as a recycled catalyst in a water-dimethyl sulfoxide mixture.

Here, N-acetyl-d-glucosamine (GlcNAc), the monomer composing the second most abundant biopolymer, chitin, was efficiently converted into 5-hydroxymethylfurfural (5-HMF) using ionic liquid (IL) catalysts in a water/dimethyl sulfoxide (DMSO) mixture solvent. Various reaction parameters, including reaction temperature and time, DMSO/water mass ratios and catalyst dosage were optimized. A series of ILs with different structures were analyzed to explore their impact on GlcNAc conversion. The substrate scope was expanded from GlcNAc to d-glucosamine, chitin, chitosan and monosaccharides, although 5-HMF yields obtained from polymers and other monosaccharides were generally lower than those from GlcNAc. Moreover, the IL N-methylimidazolium hydrogen sulfate ([Hmim][HSO4]) exhibited the best catalyst performance (64.6% yield) when GlcNAc was dehydrated in a DMSO/water mixture at 180 °C for 6 h without the addition of extra catalysts. To summarize, these results could provide knowledge essential to the production of valuable chemicals that are derived from renewable marine resources and benefit biofuel-related applications.

Combined preconditioning with hypoxia and GYKI-52466 protects rats from cerebral ischemic injury by HIF-1α/eNOS pathway.

Cerebral ischemic injury has been the leading cause of death and long term disability in the world because of the lack of successful therapies to it, leading to neurological and behavioral deficits. The present study aims to investigate the effects of combined preconditioning (PC) with hypoxia and GYKI-52466 (GYKI) on cerebral ischemic injury and to explore the mechanism. The results showed that combined preconditioning with hypoxia and GYKI-52466 increased the survival rate of cerebral ischemia rats, alleviated the neurological deficit, increased the object recognition and social recognition memory of rats and suppressed the inflammatory reaction induced by cerebral ischemia. Further experiments found that preconditioning with hypoxia and GYKI-52466 significantly increased the HIF-1α and eNOS expression as well as eNOS activity, while inhibitors of HIF-1α and eNOS abolished the protective effects of hypoxia+GYKI PC on neurological deficit. Taken together, these results indicate that combined preconditioning with hypoxia and GYKI-52466 is effective to prevent cerebral ischemia injury, while HIF-1α and eNOS may be involved in the mechanism.