GGC repeat expansion in NOTCH2NLC induces dysfunction in ribosome biogenesis and translation.

GGC repeat expansion in the 5' untranslated region (UTR) of NOTCH2NLC is associated with a broad spectrum of neurological disorders, especially neuronal intranuclear inclusion disease (NIID). Studies have found that GGC repeat expansion in NOTCH2NLC induces the formation of polyglycine (polyG)-containing protein, which is involved in the formation of neuronal intranuclear inclusions. However, the mechanism of neurotoxicity induced by NOTCH2NLC GGC repeats is unclear. Here, we used NIID patient-specific induced pluripotent stem cell (iPSC)-derived 3D cerebral organoids (3DCOs) and cellular models to investigate the pathophysiological mechanisms of NOTCH2NLC GGC repeat expansion. IPSC-derived 3DCOs and cellular models showed the deposition of polyG-containing intranuclear inclusions. The NOTCH2NLC GGC repeats could induce the upregulation of autophagic flux, enhance integrated stress response and activate EIF2α phosphorylation. Bulk RNA sequencing for iPSC-derived neurons and single-cell RNA sequencing (scRNA-seq) for iPSC-derived 3DCOs revealed that NOTCH2NLC GGC repeats may be associated with dysfunctions in ribosome biogenesis and translation. Moreover, NOTCH2NLC GGC repeats could induce the NPM1 nucleoplasm translocation, increase nucleolar stress, impair ribosome biogenesis and induce ribosomal RNA sequestration, suggesting dysfunction of membraneless organelles in the NIID cellular model. Dysfunctions in ribosome biogenesis and phosphorylated EIF2α and the resulting increase in the formation of G3BP1-positive stress granules may together lead to whole-cell translational inhibition, which may eventually cause cell death. Interestingly, scRNA-seq revealed that NOTCH2NLC GGC repeats may be associated with a significantly decreased proportion of immature neurons while 3DCOs were developing. Together, our results underscore the value of patient-specific iPSC-derived 3DCOs in investigating the mechanisms of polyG diseases, especially those caused by repeats in human-specific genes.

Shared Genetic Architecture between Parkinson's Disease and Brain Structural Phenotypes.

BACKGROUND: Patients with Parkinson's disease (PD) have consistently demonstrated brain structure abnormalities, indicating the presence of shared etiological and pathological processes between PD and brain structures; however, the genetic relationship remains poorly understood. OBJECTIVE: The aim of this study was to investigate the extent of shared genetic architecture between PD and brain structural phenotypes (BSPs) and to identify shared genomic loci. METHODS: We used the summary statistics from genome-wide association studies to conduct MiXeR and conditional/conjunctional false discovery rate analyses to investigate the shared genetic signatures between PD and BSPs. Subsequent expression quantitative trait loci mapping in the human brain and enrichment analyses were also performed. RESULTS: MiXeR analysis identified genetic overlap between PD and various BSPs, including total cortical surface area, average cortical thickness, and specific brain volumetric structures. Further analysis using conditional false discovery rate (FDR) identified 21 novel PD risk loci on associations with BSPs at conditional FDR < 0.01, and the conjunctional FDR analysis demonstrated that PD shared several genomic loci with certain BSPs at conjunctional FDR < 0.05. Among the shared loci, 16 credible mapped genes showed high expression in the brain tissues and were primarily associated with immune function-related biological processes. CONCLUSIONS: We confirmed the polygenic overlap with mixed directions of allelic effects between PD and BSPs and identified multiple shared genomic loci and risk genes, which are likely related to immune-related biological processes. These findings provide insight into the complex genetic architecture associated with PD. © 2023 International Parkinson and Movement Disorder Society.

Robot versus video-assisted thoracoscopic thymectomy for large thymic epithelial tumors: a propensity-matched analysis.

BACKGROUND: Both video-assisted thoracoscopic surgery (VATS) thymectomy and robot-assisted thoracoscopic surgery (RATS) thymectomy have been suggested as technically sound approaches for early-stage thymic epithelial tumors. However, the choice of VATS or RATS thymectomy for large and advanced thymic epithelial tumors remains controversial. In this study, the perioperative outcomes of VATS and RATS thymectomy were compared in patients with large thymic epithelial tumors (size ≥5.0 cm). METHODS: A total of 113 patients with large thymic epithelial tumors who underwent minimally invasive surgery were included. Sixty-three patients underwent RATS, and 50 patients underwent VATS. Patient characteristics and perioperative variables were compared. RESULTS: Compared with the VATS group, the RATS group experienced a shorter operation time (median: 110 min vs.130 min; P < 0.001) and less blood loss (30.00 ml vs. 100.00 ml, P < 0.001). No patients in the RATS group needed conversion to open surgery, but in the VATS series, five patients required conversion to open procedures (0% vs. 14.29%, P = 0.054). The rate of concomitant resection in the RATS group was similar to that in the VATS group (11.43% vs. 5.71%; P = 0.673). There was no significant difference between the two groups in the duration of chest tube (P = 0.587), postoperative complications (P = 1.000), and the duration of postoperative hospital stay (P = 0.141). CONCLUSION: For large thymic epithelial tumors, RATS thymectomy can be performed safely and effectively in a radical fashion. Due to the advanced optics and precise instrument control, concomitant resections can be easily achieved in larger thymic epithelial tumors using the robotic approach.

A Non-Invasive Method for Monitoring Osteogenesis and Osseointegration Using Near-Infrared Fluorescent Imaging: A Model of Maxilla Implantation in Rats.

Currently, computed tomography and conventional X-ray radiography usually generate a micro-artifact around metal implants. This metal artifact frequently causes false positive or negative diagnoses of bone maturation or pathological peri-implantitis around implants. In an attempt to repair the artifacts, a highly specific nanoprobe, an osteogenic biomarker, and nano-Au-Pamidronate were designed to monitor the osteogenesis. In total, 12 Sprague Dawley rats were included in the study and could be chategorized in 3 groups: 4 rats in the X-ray and CT group, 4 rats in the NIRF group, and 4 rats in the sham group. A titanium alloy screw was implanted in the anterior hard palate. The X-ray, CT, and NIRF images were taken 28 days after implantation. The X-ray showed that the tissue surrounded the implant tightly; however, a gap of metal artifacts was noted around the interface between dental implants and palatal bone. Compared to the CT image, a fluorescence image was noted around the implant site in the NIRF group. Furthermore, the histological implant-bone tissue also exhibited a significant NIRF signal. In conclusion, this novel NIRF molecular imaging system precisely identifies the image loss caused by metal artifacts and can be applied to monitoring bone maturation around orthopedic implants. In addition, by observing the new bone formation, a new principle and timetable for an implant osseointegrated with bone can be established and a new type of implant fixture or surface treatment can be evaluated using this system.

Identifying causal genes for migraine by integrating the proteome and transcriptome.

BACKGROUND: While previous genome-wide association studies (GWAS) have identified multiple risk variants for migraine, there is a lack of evidence about how these variants contribute to the development of migraine. We employed an integrative pipeline to efficiently transform genetic associations to identify causal genes for migraine. METHODS: We conducted a proteome-wide association study (PWAS) by combining data from the migraine GWAS data with proteomic data from the human brain and plasma to identify proteins that may play a role in the risk of developing migraine. We also combined data from GWAS of migraine with a novel joint-tissue imputation (JTI) prediction model of 17 migraine-related human tissues to conduct transcriptome-wide association studies (TWAS) together with the fine mapping method FOCUS to identify disease-associated genes. RESULTS: We identified 13 genes in the human brain and plasma proteome that modulate migraine risk by regulating protein abundance. In addition, 62 associated genes not reported in previous migraine TWAS studies were identified by our analysis of migraine using TWAS and fine mapping. Five genes including ICA1L, TREX1, STAT6, UFL1, and B3GNT8 showed significant associations with migraine at both the proteome and transcriptome, these genes are mainly expressed in ependymal cells, neurons, and glial cells, and are potential target genes for prevention of neuronal signaling and inflammatory responses in the pathogenesis of migraine. CONCLUSIONS: Our proteomic and transcriptome findings have identified disease-associated genes that may give new insights into the pathogenesis and potential therapeutic targets for migraine.

Construction of an Integrated Device of a Self-Powered Biosensor and Matching Capacitor Based on Graphdiyne and Multiple Signal Amplification: Ultrasensitive Method for MicroRNA Detection.

The detection of microRNA (miRNA) in human serum has great significance for cancer prevention. Herein, a novel self-powered biosensing platform is developed, which effectively integrates an enzymatic biofuel cell (EBFC)-based self-powered biosensor with a matching capacitor for miRNA detection. A catalytic hairpin assembly and hybrid chain reaction are used to improve the analytical performance of EBFC. Furthermore, the matching capacitor is selected as an auxiliary signal amplifying device, and graphdiyne is applied as substrate material for EBFC. The results confirm that the developed method obviously increases the output current of EBFC, and the sensitivity can reach 2.75 µA/pM, which is 786% of pure EBFC. MiRNA can be detected in an expanded linear range of 0.1-100000 fM with a detection limit of 0.034 fM (S/N = 3). It can offer a selective and sensitive platform for nucleotide sequence detection with great potential in clinical diagnostics.

Repeatability and reliability of GABA measurements with magnetic resonance spectroscopy in healthy young adults.

PURPOSE: Gamma-aminobutyric acid (GABA) abnormalities have been implicated in a range of neuropsychiatric disorders. Despite substantial interest in probing GABA in vivo, human imaging studies relying on magnetic resonance spectroscopy (MRS) have generally been hindered by technical challenges, including GABA's relatively low concentration and spectral overlap with other metabolites. Although past studies have shown moderate-to-strong test-retest repeatability and reliability of GABA within certain brain regions, many of these studies have been limited by small sample sizes. METHODS: GABA+ (macromolecular-contaminated) test-retest reliability and repeatability were assessed via a Meshcher-Garwood point resolved spectroscopy (MEGA-PRESS) MRS sequence in the rostral anterior cingulate cortex (rACC; n = 21) and dorsolateral prefrontal cortex (dlPFC; n = 20) in healthy young adults. Data were collected on a 3T scanner (Siemens Prisma, Siemens Healthcare, Erlangen, Germany) and GABA+ results were reported in reference to both total creatine (GABA+/tCr) and water (GABA+/water). RESULTS: Results showed strong test-retest repeatability (mean GABA+/tCr coefficient of variation [CV] = 4.6%; mean GABA+/water CV = 4.0%) and reliability (GABA+/tCr intraclass correlation coefficient [ICC] = 0.77; GABA+/water ICC = 0.87) in the dlPFC. The rACC showed acceptable (but comparatively lower) repeatability (mean GABA+/tCr CV = 8.0%; mean GABA+/water CV = 7.5%), yet low-moderate reliability (GABA+/tCr ICC = 0.40; GABA+/water ICC = 0.44). CONCLUSION: The present study found excellent GABA+ MRS repeatability and reliability in the dlPFC. The rACC showed inferior results, possibly because of a combination of shimming impedance and measurement error. These data suggest that MEGA-PRESS can be utilized to reliably distinguish participants based on dlPFC GABA+ levels, whereas the mixed results in the rACC merit further investigation.

Regional GABA Concentrations Modulate Inter-network Resting-state Functional Connectivity.

Coordinated activity within and differential activity between large-scale neuronal networks such as the default mode network (DMN) and the control network (CN) is a critical feature of brain organization. The CN usually exhibits activations in response to cognitive tasks while the DMN shows deactivations; in addition, activity between the two networks is anti-correlated at rest. To address this issue, we used functional MRI to measure whole-brain BOLD signal during resting-state and task-evoked conditions, and MR spectroscopy (MRS) to quantify GABA and glutamate concentrations, in nodes within the DMN and CN (MPFC and DLPFC, respectively) in 19 healthy individuals at 3 Tesla. We found that GABA concentrations in the MPFC were significantly associated with DMN deactivation during a working memory task and with anti-correlation between DMN and CN at rest and during task performance, while GABA concentrations in the DLPFC weakly modulated DMN-CN anti-correlation in the opposite direction. Highlighting specificity, glutamate played a less significant role related to brain activity. These findings indicate that GABA in the MPFC is potentially involved in orchestrating between-network brain activity at rest and during task performance.

Potential role of IL-37 signaling pathway in feedback regulation of autoimmune Hashimoto thyroiditis.

IL-37, the anti-inflammatory cytokine of the IL-1 family, plays several key roles in the regulation of autoimmune diseases. Yet, its role in Hashimoto's thyroiditis (HT) is not clear. In the present study, we found that, in tissues from HT patients, most of the follicular epithelial cells were positive for both IL-37 and single Ig IL-1-related receptor (SIGIRR) by immunohistochemical staining, while the infiltrating lymphocytes and other inflammatory cells hardly expressed any. Meanwhile, mRNA expression levels of IL-37 in peripheral blood mononuclear cells (PBMC) of HT patients were significantly higher than those in normal controls measured by quantitative real-time PCR. Finally, we studied the possible role of IL-37 in IFN-γ-stimulated rat FRTL-5 cells. The results showed that IL-1ß, TNF-α, and MCP-1 mRNA levels were significantly decreased, while the expression of IL-4 mRNA was dramatically up-regulated in IFN-γ-stimulated rat thyroid cell line FRTL-5 pre-treated with IL-37. The current study, for the first time, demonstrated that the IL-37 network is involved in Hashimoto's thyroiditis, and IL-37 signaling pathway may ameliorate the excessive autoimmune responses in this chronic lymphocytic thyroiditis.

Cerebral bioenergetic differences measured by phosphorus-31 magnetic resonance spectroscopy between bipolar disorder and healthy subjects living in two different regions suggesting possible effects of altitude.

AIM: Increased oxidative stress in cerebral mitochondria may follow exposure to the systemic hypobaric hypoxia associated with residing at higher altitudes. Because mitochondrial dysfunction is implicated in bipolar disorder (BD) pathophysiology, this may impact the cerebral bioenergetics in BD. In this study, we evaluated the cerebral bioenergetics of BD and healthy control (HC) subjects at two sites, located at sea level and at moderate altitude. METHODS: Forty-three veterans with BD and 33 HC veterans were recruited in Boston (n = 22) and Salt Lake City (SLC; n = 54). Levels of phosphocreatine, ß nucleoside triphosphate (ßNTP), inorganic phosphate, and pH over total phosphate (TP) were measured using phosphorus-31 magnetic resonance spectroscopy in the following brain regions: anterior cingulate cortex and posterior occipital cortex, as well as bilateral prefrontal and occipitoparietal (OP) white matter (WM). RESULTS: A significant main effect of site was found in ßNTP/TP (Boston > SLC) and phosphocreatine/TP (Boston < SLC) in most cortical and WM regions, and inorganic phosphate/TP (Boston < SLC) in OP regions. A main effect analysis of BD diagnosis demonstrated a lower pH in posterior occipital cortex and right OP WM and a lower ßNTP/TP in right prefrontal WM in BD subjects, compared to HC subjects. CONCLUSION: The study showed that there were cerebral bioenergetic differences in both BD and HC veteran participants at two different sites, which may be partly explained by altitude difference. Future studies are needed to replicate these results in order to elucidate the dysfunctional mitochondrial changes that occur in response to hypobaric hypoxia.

Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations.

Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, BMI, dyslipidemia, risk of atrial fibrillation and atherosclerosis. Most of the variance in TSH levels is thought to be genetically influenced. We conducted a genome-wide association study of TSH levels in 1346 Chinese Han individuals. In the replication study, we genotyped four candidate SNPs with the top association signals in an independent isolated Chinese She cohort (n = 3235). We identified a novel serum TSH susceptibility locus within XKR4 at 8q12.1 (rs2622590, Pcombined = 2.21 × 10(-10)), and we confirmed two previously reported TSH susceptibility loci near FOXE1 at 9q22.33 and near CAPZB at 1p36.13, respectively. The rs2622590_T allele at XKR4 and the rs925489_C allele near FOXE1 were correlated with low TSH levels and were found to be nominally associated to patients with papillary thyroid carcinoma (PTC) (OR = 1.41, P= 0.014 for rs2622590_T, and OR = 1.61, P= 0.030 for rs925489_C). The rs2622590 and rs925489 genotypes were also correlated with the expression levels of FOXE1 and XKR4, respectively, in PTC tissues (P = 2.41 × 10(-4) and P= 0.02). Our findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels.

Characterization of the life cycle of the tick Haemaphysalis tibetensis under field conditions in Qinghai-Tibet plateau.

The tick Haemaphysalis tibetensis Hoogstraal is found uniquely in the Qinghai-Tibet plateau of Tibet and Gansu of China. Not much is known of this tick. Therefore, in this study we investigated the life cycle of H. tibetensis under field conditions from March 2014 to March 2015 in Damxung County, north Lhasa City in Tibet (Autonomous Region in China). The results of the study demonstrated that the tick H. tibetensis requires an average of 177.8 days (range 129-202 days) to complete a life cycle, with rabbits supplied as hosts in the field plot. Under natural lighting and climate conditions, the feeding period of females was an average of 7.7 days, and the pre-oviposition period was 9.4 days, followed by 28.2 days for oviposition. The premolting period of nymphs lasted 52.7 days, which was the longest life cycle phase. The average weight ratio of engorged to unfed females was 58.2. Additionally, there was a highly positive correlation between the weight of engorged and the number of the eggs that were laid (r = 0.83, P < 0.05). The reproductive efficiency index and reproductive fitness index in females were 5.1 and 4.7, respectively.

Decreased brain PME/PDE ratio in bipolar disorder: a preliminary (31) P magnetic resonance spectroscopy study.

OBJECTIVES: The aim of the present study was to measure brain phosphorus-31 magnetic resonance spectroscopy ((31) P MRS) metabolite levels and the creatine kinase reaction forward rate constant (kf ) in subjects with bipolar disorder (BD). METHODS: Subjects with bipolar euthymia (n = 14) or depression (n = 11) were recruited. Healthy comparison subjects (HC) (n = 23) were recruited and matched to subjects with BD on age, gender, and educational level. All studies were performed on a 3-Tesla clinical magnetic resonance imaging system using a (31) P/(1) H double-tuned volume head coil. (31) P spectra were acquired without (1) H-decoupling using magnetization-transfer image-selected in vivo spectroscopy. Metabolite ratios from a brain region that includes the frontal lobe, corpus callosum, thalamus, and occipital lobe are expressed as a percentage of the total phosphorus (TP) signal. Brain pH was also investigated. RESULTS: Beta-nucleoside-triphosphate (ß-NTP/TP) in subjects with bipolar depression was positively correlated with kf (p = 0.039, r(2) = 0.39); similar correlations were not observed in bipolar euthymia or HC. In addition, no differences in kf and brain pH were observed among the three diagnostic groups. A decrease in the ratio of phosphomonoesters to phosphodiesters (PME/PDE) was observed in subjects with bipolar depression relative to HC (p = 0.032). We also observed a trend toward an inverse correlation in bipolar depression characterized by decreased phosphocreatine and increased depression severity. CONCLUSIONS: In our sample, kf was not altered in the euthymic or depressed mood state in BD. However, decreased PME/PDE in subjects with bipolar depression was consistent with differences in membrane turnover. These data provide preliminary support for alterations in phospholipid metabolism and mitochondrial function in bipolar depression.

Brucella infection combined with Nocardia infection: A case report and literature review.

Human brucellosis is an infectious disease caused by Brucella and is often misdiagnosed for atypical manifestations including fever of unknown origin, headache, weakness, among else. Nocardiosis is a zoonotic disease caused by the genus Nocardia, which usually spreads through the respiratory tract, skin, and digestive tract. Limited research has documented cases of co-infection involving both Brucella and Nocardia pathogens in patients. A 55-year-old male was admitted to our hospital with intermittent high-grade fever. Following sputum and blood cultures, as well as other laboratory examinations, the patient was diagnosed with concurrent brucellosis and nocardiosis. According to recommendations of previous studies and reports, the patient was successively treated with levofloxacin, doxycycline, piperacillin sodium and sulbactam sodium, trimethoprim-sulfamethoxazole, rifampicin, and tigecycline, after which the patient recovered and was discharged. Brucella and Nocardia are both opportunistic pathogens and simultaneous infection of Brucella and Nocardia is relatively rare. If patients continue to experience persistent fever despite receiving empirical antibiotic therapy, it becomes necessary to conduct examinations to identify potential atypical pathogens, including Brucella and Nocardia. Sputum staining, sputum culture, and blood culture are critical auxiliary examinations during clinical practice. The treatment plan should be selected based on guidelines and the individual patient's condition. Regular reevaluation should be conducted, and antimicrobial agents should be adjusted accordingly.

Case report: Lateral medullary syndrome with eight-and-a-half syndromes.

RATIONALE: Lateral medullary syndrome is caused by atherosclerosis or embolism of the vertebral artery and its branches or the posterior inferior cerebellar artery (PICA).The eight-and-a-half syndrome is a rare pontocerebellar nerve-ocular syndrome presenting as a one-and-a-half syndrome plus ipsilateral seventh cerebral nerve palsy. The dorsolateral medullary syndrome combined with the eight-and-a-half syndromes is even rarer, so it is important to recognize the features of the classical brainstem syndrome and the eight-and-a-half syndromes. PATIENT CONCERNS: Most patients with dorsolateral medullary syndrome combined with eight-and-a-half syndromes have a good prognosis, with recovery occurring within a few weeks to a few months, although a few patients may take longer to recover. DIAGNOSIS INTERVENTIONS: In the course of disease development, the patient developed dysarthria, dysphagia, hypothermia, ipsilateral Horner sign and ataxia. Computed tomography was performed which showed cerebral infarction in the left brainstem. Cranial diffusion-weighted imaging + magnetic resonance angiography showed acute infarction in the left cerebellar hemisphere, with a high probability of severe stenosis or occlusion in the intracranial and proximal segments of the basilar arteries. This supports the diagnosis of dorsolateral medullary syndrome. The patient's limited adduction and abduction of the left eye and limited adduction of the right eye, combined with peripheral paralysis of the affected lateral nerve, supported the diagnosis of eight-and-a-half syndromes. The administration of antiplatelet and anti-ester fixation treatment can effectively improve the symptoms and shorten the course of the disease. OUTCOMES: After antiplatelet and anti-ester fixation treatment, the symptoms improved and the patient was discharged. LESSONS: Dorsolateral medullary syndrome combined with eight-and-a-half syndromes is a rare clinical condition, and therefore more attention should be paid to the early diagnosis and treatment of such patients.

The potential protective role of peripheral immunophenotypes in Alzheimer's disease: a Mendelian randomization study.

Introduction: Alzheimer's disease (AD) is the most widespread neurodegenerative disease in the world. Previous studies have shown that peripheral immune dysregulation plays a paramount role in AD, but whether there is a protective causal relationship between peripheral immunophenotypes and AD risk remains ambiguous. Methods: Two-sample Mendelian randomization (MR) was performed using large genome-wide association study (GWAS) genetic data to assess causal effects between peripheral immunophenotypes and AD risk. Utilizing the genetic associations of 731 immune cell traits as exposures. We adopted the inverse variance weighted method as the primary approach. The Weighted median and MR-Egger regression methods were employed as supplements. Various sensitivity analyses were performed to assess the robustness of the outcomes. Results: Based on the IVW method, we identified 14 immune cell traits that significantly reduced the risk of AD, of which six demonstrated statistical significance in both IVW and Weighted median methods. Among the seven immune traits, four were related to regulatory T (Treg) cells : (1) CD25++ CD45RA- CD4 not regulatory T cell % T cell (odds ratio (OR) [95% confidence interval (CI)] = 0.96 [0.95, 0.98], adjusted P = 1.17E-02), (2) CD25++ CD45RA- CD4 not regulatory T cell % CD4+ T cell (OR [95% CI] = 0.97 [0.96, 0.99], adjusted P = 3.77E-02), (3) Secreting CD4 regulatory T cell % CD4 regulatory T cell (OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03), (4) Activated & secreting CD4 regulatory T cell % CD4 regulatory T cell(OR [95% CI] = 0.98 [0.97, 0.99], adjusted P = 7.10E-03). In addition, HLA DR++ monocyte % monocyte (OR [95% CI] = 0.93 [0.89, 0.98], adjusted P = 4.87E-02) was associated with monocytes, and HLA DR on myeloid Dendritic Cell (OR [95% CI] = 0.93 [0.89, 0.97], adjusted P = 1.17E-02) was related to dendritic cells (DCs). Conclusion: These findings enhance the comprehension of the protective role of peripheral immunity in AD and provide further support for Treg and monocyte as potential targets for immunotherapy in AD.

Oxidative stress mediated decrement of spinal endomorphin-2 contributes to lumbar disc herniation sciatica in rats.

Increasing evidence supported that oxidative stress induced by herniated lumbar disc played important role in the formation of lumbar disc herniation sciatica (LDHS), however, the neural mechanisms underlying LDHS need further clarification. Endomorphin-2 (EM2) is the endogenous ligand for mu-opioid receptor (MOR), and there is increasing evidence implicating the involvement of spinal EM2 in neuropathic pain. In this study, using an nucleus pulposus implantation induced LDHS rat model that displayed obvious mechanical allodynia, it was found that the expression of EM2 in dorsal root ganglion (DRG) and spinal cord was significantly decreased. It was further found that oxidative stress in DRG and spinal cord was significantly increased in LDHS rats, and the reduction of EM2 in DRG and spinal cord was determined by oxidative stress dominated increment of dipeptidylpeptidase IV activity. A systemic treatment with antioxidant could prevent the forming of mechanical allodynia in LDHS rats. In addition, MOR expression in DRG and spinal cord remained unchanged in LDHS rats. Intrathecal injection of MOR antagonist promoted pain behavior in LDHS rats, and the analgesic effect of intrathecal injection of EM2 was stronger than that of endomorphin-1 and morphine. Taken together, our findings suggest that oxidative stress mediated decrement of EM2 in DRG and spinal cord causes the loss of endogenous analgesic effects and enhances the pain sensation of LDHS.

Association of Lower Rostral Anterior Cingulate GABA+ and Dysregulated Cortisol Stress Response With Altered Functional Connectivity in Young Adults With Lifetime Depression: A Multimodal Imaging Investigation of Trait and State Effects.

OBJECTIVE: Preclinical work suggests that excess glucocorticoids and reduced cortical γ-aminobutyric acid (GABA) may affect sex-dependent differences in brain regions implicated in stress regulation and depressive phenotypes. The authors sought to address a critical gap in knowledge, namely, how stress circuitry is functionally affected by glucocorticoids and GABA in current or remitted major depressive disorder (MDD). METHODS: Multimodal imaging data were collected from 130 young adults (ages 18-25), of whom 44 had current MDD, 42 had remitted MDD, and 44 were healthy comparison subjects. GABA+ (γ-aminobutyric acid and macromolecules) was assessed using magnetic resonance spectroscopy, and task-related functional MRI data were collected under acute stress and analyzed using data-driven network modeling. RESULTS: Across modalities, trait-related abnormalities emerged. Relative to healthy comparison subjects, both clinical groups were characterized by lower rostral anterior cingulate cortex (rACC) GABA+ and frontoparietal network amplitude but higher amplitude in salience and stress-related networks. For the remitted MDD group, differences from the healthy comparison group emerged in the context of elevated cortisol levels, whereas the MDD group had lower cortisol levels than the healthy comparison group. In the comparison group, frontoparietal and stress-related network connectivity was positively associated with cortisol level (highlighting putative top-down regulation of stress), but the opposite relationship emerged in the MDD and remitted MDD groups. Finally, rACC GABA+ was associated with stress-induced changes in connectivity between overlapping default mode and salience networks. CONCLUSIONS: Lifetime MDD was characterized by reduced rACC GABA+ as well as dysregulated cortisol-related interactions between top-down control (frontoparietal) and threat (task-related) networks. These findings warrant further investigation of the role of GABA in the vulnerability to and treatment of MDD.

Joint analysis of proteome, transcriptome, and multi-trait analysis to identify novel Parkinson's disease risk genes.

Genome-wide association studies (GWAS) have identified multiple risk variants for Parkinson's disease (PD). Nevertheless, how the risk variants confer the risk of PD remains largely unknown. We conducted a proteome-wide association study (PWAS) and summary-data-based mendelian randomization (SMR) analysis by integrating PD GWAS with proteome and protein quantitative trait loci (pQTL) data from human brain, plasma and CSF. We also performed a large transcriptome-wide association study (TWAS) and Fine-mapping of causal gene sets (FOCUS), leveraging joint-tissue imputation (JTI) prediction models of 22 tissues to identify and prioritize putatively causal genes. We further conducted PWAS, SMR, TWAS, and FOCUS using a multi-trait analysis of GWAS (MTAG) to identify additional PD risk genes to boost statistical power. In this large-scale study, we identified 16 genes whose genetically regulated protein abundance levels were associated with Parkinson's disease risk. We undertook a large-scale analysis of PD and correlated traits, through TWAS and FOCUS studies, and discovered 26 casual genes related to PD that had not been reported in previous TWAS. 5 genes (CD38, GPNMB, RAB29, TMEM175, TTC19) showed significant associations with PD at both the proteome-wide and transcriptome-wide levels. Our study provides new insights into the etiology and underlying genetic architecture of PD.

Effects of GABA, Sex, and Stress on Reward Learning in Current and Remitted Major Depression.

BACKGROUND: Neurocognitive factors including aberrant reward learning, blunted GABA (gamma-aminobutyric acid), and potentiated stress sensitivity have been linked to anhedonia, a hallmark depressive symptom, possibly in a sex-dependent manner. However, previous research has not investigated the putative associations among these factors or the extent to which they represent trait- or state-based vulnerabilities for depression. METHODS: Young adults with current major depressive disorder (MDD) (n = 44), remitted MDD (n = 42), and healthy control participants (HCs) (n = 44), stratified by sex assigned at birth, underwent magnetic resonance spectroscopy to assess macromolecular contaminated GABA (GABA+) and then a reward learning task before and after acute stress. We assessed changes in reward learning after stress and associations with GABA+. RESULTS: Results revealed blunted baseline reward learning in participants with remitted MDD versus participants with current MDD and HCs but, surprisingly, no differences between participants with current MDD and HCs. Reward learning was reduced following acute stress regardless of depressive history. GABA+ in the rostral anterior cingulate cortex, but not the dorsolateral prefrontal cortex, was associated with reduced baseline reward learning only in female participants. GABA+ did not predict stress-related changes in reward learning. CONCLUSIONS: To our knowledge, this is the first study to investigate associations among GABA, reward learning, and stress reactivity in current versus past depression. Hypothesized depression-related differences in reward learning did not emerge, precluding claims about state versus trait vulnerabilities. However, our finding that blunted GABA was associated with greater reward learning in female participants provides novel insights into sex-selective associations between the frontal GABAergic inhibitory system and reward processing.