Toxicology profile of a novel GLP-1 receptor biased agonist-SAL0112 in nonhuman primates.

Oral small-molecule GLP-1 receptor biased agonists exhibit promising treatment efficacy of type 2 diabetes and obesity. SAL0112 is a novel compound that has demonstrated remarkable efficacy in preclinical animal models. Herein, both in vitro and in vivo preclinical toxicity investigations were conducted to explore the safety profile of SAL0112. The HTRF assay and TR-FRET assay were utilized for cAMP detection. Patch clamp assay was employed for hERG potassium ion channel determination. Cynomolgus monkeys were used in a cardiovascular safety pharmacology study and a 13-week repeated dose toxicity study. The telemetry system was employed to detect cardiovascular indicators such as ECG, HR, and BP. During the repeated dose toxicity study, body weight, food intake, hematology, coagulation function test, serum biochemistry tests, and urine analysis were measured. Macroscopic and microscopic observations were conducted at the end of the study. TK studies were conducted on Day 1 and Day 91. SAL0112 exhibited a high degree of potency in activating the monkey GLP-1 receptor whereas had no effect on the rodent GLP-1 receptor. In contrast to Danuglipron, which demonstrated high potency on hERG with an IC50 value of 6.9 µM, the IC50 of SAL0112 on hERG was greater than 100 µM. Compared to the Vehicle Control group, no significant changes in cardiovascular indicators were observed in the cardiovascular safety pharmacology study after a single dose of SAL0112 up to 250 mg/kg (P > 0.05). A repeated dose toxicity study revealed moderate anorexigenic effects and a reduction in body weight, effects that were found to be reversible and not associated with any pathological changes. The NOAEL of SAL0112 is 150 mg/kg, providing an approximate safety margin of threefold. SAL0112 demonstrated a favorable safety profile in cynomolgus monkeys, with a substantial therapeutic window that supports the progression of this compound into clinical studies.

Divergent sensory pathways of sneezing and coughing.

Sneezing and coughing are primary symptoms of many respiratory viral infections and allergies. It is generally assumed that sneezing and coughing involve common sensory receptors and molecular neurotransmission mechanisms. Here, we show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11+MrgprA3-) mediates sneezing responses to a multitude of nasal irritants, allergens, and viruses. Although this population also innervates the trachea, it does not mediate coughing, as revealed by our newly established cough model. Instead, a distinct sensory population (somatostatin [SST+]) mediates coughing but not sneezing, unraveling an unforeseen sensory difference between sneezing and coughing. At the circuit level, sneeze and cough signals are transmitted and modulated by divergent neuropathways. Together, our study reveals the difference in sensory receptors and neurotransmission/modulation mechanisms between sneezing and coughing, offering neuronal drug targets for symptom management in respiratory viral infections and allergies.

Prediction of freezing point and moisture distribution of beef with dual freeze-thaw cycles using hyperspectral imaging.

The freezing point (FP) is an important quality indicator of the superchilled meat. Currently, the potential of hyperspectral imaging (HSI) for predicting beef FP as affected by multiple freeze-thaw (F-T) cycles was explored. Correlation analysis revealed that the FP had a negative correlation with the proportion of bound water (P21) and a positive correlation with the proportion of immobilized water (P22). Moreover, the optimal wavelengths were selected by principal component analysis (PCA). Principal component regression (PCR) and partial least squares regression (PLSR) models were successfully developed based on the optimal wavelengths for predicting FP with determination coefficient in prediction (RP2) of 0.76, 0.76 and root mean square errors in prediction (RMSEP) of 0.12, 0.12, respectively. Additionally, PLSR based on full wavelengths was established for predicting P21 with RP2 of 0.80 and RMSEP of 0.67, and PLSR based on the optimal wavelengths was established for predicting P22 with RP2 of 0.87 and RMSEP of 0.66. The results show the potential of hyperspectral technology to predict the FP and moisture distribution of meat as a nondestructive method.

An NIR-IIb emissive transmembrane voltage nano-indicator for the optical monitoring of electrophysiological activities in vivo.

In vivo transmembrane-voltage detection reflected the electrophysiological activities of the biological system, which is crucial for the diagnosis of neuronal disease. Traditional implanted electrodes can only monitor limited regions and induce relatively large tissue damage. Despite emerging monitoring methods based on optical imaging have access to signal recording in a larger area, the recording wavelength of less than 1000 nm seriously weakens the detection depth and resolution in vivo. Herein, a Förster resonance energy transfer (FRET)-based nano-indicator, NaYbF4:Er@NaYF4@Cy7.5@DPPC (Cy7.5-ErNP) with emission in the near-infrared IIb biological window (NIR-IIb, 1500-1700 nm) is developed for transmembrane-voltage detection. Cy7.5 dye is found to be voltage-sensitive and is employed as the energy donor for the energy transfer to the lanthanide nanoparticle, NaYbF4:Er@NaYF4 (ErNP), which works as the acceptor to achieve electrophysiological signal responsive NIR-IIb luminescence. Benefiting from the high penetration and low scattering of NIR-IIb luminescence, the Cy7.5-ErNP enables both the visualization of action potential in vitro and monitoring of Mesial Temporal lobe epilepsy (mTLE) disease in vivo. This work presents a concept for leveraging the lanthanide luminescent nanoprobes to visualize electrophysiological activity in vivo, which facilitates the development of an optical nano-indicator for the diagnosis of neurological disorders.

Clinical characteristics and outcome of COVID-19 patients with Parkinson's disease: a hospital-based case-control study in Shanghai, China.

Background: Clinical manifestations of Parkinson's disease (PD) after Corona Virus Disease 2019 (COVID-19) infection are poorly investigated. Objective: We aimed to explore the clinical features and outcomes of hospitalized PD patients with COVID-19. Methods: A total of 48 PD patients and 96 age-and sex-matched non-PD patients were included. Demographics, clinical characteristics and outcomes were compared between two groups. Results: PD patients with COVID-19 were elderly (76.69 ± 9.21 years) with advanced stage (H-Y stage 3-5 as 65.3%). They had less clinical symptoms (nasal obstruction, etc.), more proportions of severe/critical COVID-19 clinical classification (22.9 vs. 1.0%, p < 0.001), receiving oxygen (29.2 vs. 11.5%, p = 0.011), antibiotics (39.6 vs. 21.9%, p = 0.031) therapies, as well as longer hospitalization duration (11.39 vs. 8.32, p = 0.001) and higher mortality (8.3% vs. 1.0%, p = 0.001) relative to those without PD. Laboratory results showed that the PD group had higher white blood cell counts (6.29 vs. 5.16*109, p = 0.001), neutrophil-to-lymphocyte ratio (3.14 vs. 2.11, p < 0.001) and C-reactive protein level (12.34 vs. 3.19, p < 0.001). Conclusion: PD patients with COVID-19 have insidious clinical manifestation, elevated proinflammatory markers and are prone to the development of severe/critical condition, contributing to a relatively poor prognosis. Early identification and active treatment of COVID-19 are pivotal to advanced PD patients during the pandemic.

Dry eye disease in mice activates adaptive corneal epithelial regeneration distinct from constitutive renewal in homeostasis.

Many epithelial compartments undergo constitutive renewal in homeostasis but activate unique regenerative responses following injury. The clear corneal epithelium is crucial for vision and is renewed from limbal stem cells (LSCs). Using single-cell RNA sequencing, we profiled the mouse corneal epithelium in homeostasis, aging, diabetes, and dry eye disease (DED), where tear deficiency predisposes the cornea to recurrent injury. In homeostasis, we capture the transcriptional states that accomplish continuous tissue turnover. We leverage our dataset to identify candidate genes and gene networks that characterize key stages across homeostatic renewal, including markers for LSCs. In aging and diabetes, there were only mild changes with <15 dysregulated genes. The constitutive cell types that accomplish homeostatic renewal were conserved in DED but were associated with activation of cell states that comprise "adaptive regeneration." We provide global markers that distinguish cell types in homeostatic renewal vs. adaptive regeneration and markers that specifically define DED-elicited proliferating and differentiating cell types. We validate that expression of SPARC, a marker of adaptive regeneration, is also induced in corneal epithelial wound healing and accelerates wound closure in a corneal epithelial cell scratch assay. Finally, we propose a classification system for LSC markers based on their expression fidelity in homeostasis and disease. This transcriptional dissection uncovers the dramatically altered transcriptional landscape of the corneal epithelium in DED, providing a framework and atlas for future study of these ocular surface stem cells in health and disease.

Neurological Manifestations of hospitalized patients with mild to moderate infection with SARS-CoV-2 Omicron variant in Shanghai, China.

BACKGROUND: Accumulating studies demonstrated that patients with coronavirus disease 2019(COVID-19) could develop a variety of neurological manifestations and long-term neurological sequelae, which may be different from the strains. At the peak of the Omicron variant outbreak in Shanghai, China, no relevant epidemiological data about neurological manifestations associated with this strain was reported. OBJECTIVE: To investigate neurological manifestations and related clinical features in patients with mild to moderate COVID-19 patients with Omicron variant. METHODS: A self-designed clinical information registration form was used to gather the neurological manifestations of mild to moderate COVID-19 patients admitted to a designated hospital in Shanghai from April 18, 2022 to June 1, 2022. Demographics, clinical presentations, laboratory findings, treatments and clinical outcomes were compared between patients with and without neurological manifestations. RESULTS: One hundred sixty-nine(48.1 %) of 351 patients diagnosed with mild to moderate COVID-19 exhibited neurological manifestations, the most common of which were fatigue/weakness(25.1 %) and myalgia(20.7 %), whereas acute cerebrovascular disease(0.9 %), impaired consciousness(0.6 %) and seizure(0.6 %) were rare. Younger age(p = 0.001), female gender(p = 0.026) and without anticoagulant medication(p = 0.042) were associated with increasing proportions of neurological manifestations as revealed by multivariate logistic regressions. Patients with neurological manifestations had lower creatine kinase and myoglobin levels, as well as higher proportion of patchy shadowing on chest scan. Vaccination status, clinical classification of COVID-19 and clinical outcomes were similar between the two groups. CONCLUSIONS: Nearly half of the involved patients have neurological manifestations which were relatively subjective and closely associated with younger age, female gender and without anticoagulation. Patients with neurologic manifestations may be accompanied by increased lung patchy shadowing.

Clinical characteristics and short-term recovery of hyposmia in hospitalized non-severe COVID-19 patients with Omicron variant in Shanghai, China.

Background: Olfactory dysfunction is a common neurological symptom of Corona Virus Disease 2019(COVID-19). Little is known about hyposmia after COVID-19 infection with Omicron variant in Chinese population. Objective: To investigate the incidence, clinical characteristics and recovery of hyposmia in hospitalized non-severe COVID-19 patients with Omicron variant in Shanghai, China. Methods: Three hundred and forty-nine Chinese non-severe COVID-19 patients with Omicron variant were consecutively enrolled in a designated hospital to investigate the incidence of hyposmia in hospitalization and the recovery rate 1 month later. The visual assessment scale (VAS) was used to evaluate the severity of hyposmia. We compared the demographic, clinical features and treatment outcomes, as well as laboratory parameters between patients with and without hyposmia. Results: The cross-sectional survey showed that 22 (6.3%) hospitalized patients with non-severe COVID-19 had hyposmia. Patients with hyposmia were younger (61.5 vs. 72.0, p = 0.002), had more related clinical symptoms (sore throat, cough, poor appetite, diarrhea, myalgia and taste impairment, etc.), a higher proportion of moderate clinical type (31.8 vs. 13.5%, p = 0.028) and longer duration of hospitalization (11 vs. 8 days, p = 0.027) than those without hyposmia. Whereas, there were no significant differences regarding gender, comorbidity and nucleic acid conversion time between the two groups. Laboratory subgroup analyses demonstrated that patients with hyposmia had slightly low serum IL-6 and TNF-α levels. However, both of the levels were not associated with hyposmia occurrence in multivariate regression analyses. Further follow-up study disclosed that 16 of 22 (72.7%) hyposmia patients had recovered olfaction 1 month later. Serum IL-6 and TNF-α levels were similar between hyposmia recovered patients and those with persistent hyposmia. Conclusion: Although the incidence of hyposmia after Omicron variant infection is relatively low and the short-term recovery rate is quite high, patients with hyposmia are prone to have a higher proportion of both upper and lower respiratory tract involvements, gastrointestinal and neurological symptoms, contributing to a longer duration of hospitalization.

Psychological and sleep disturbances among first-line, second-line, and at home medical staff during the COVID-19 pandemic in Shanghai, China.

Objectives: Medical workers are prone to psychological and sleep disturbances during the coronavirus disease 2019 (COVID-19) pandemic. Little is known about the varying degrees of influence among vaccinated medical staff working in different positions. The current study is aimed to evaluate and compare depression, anxiety and sleep disturbances among first-line, second-line and at home vaccinated medical staff during the COVID-19 pandemic in Shanghai, China. Methods: A cross-sectional online survey was conducted in May 2022. In addition to demographic data, levels of depression, anxiety, sleep quality, and insomnia were measured using the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Pittsburgh Sleep Quality Index (PSQI), and Athens Insomnia Scale (AIS). Results: A total of 236 vaccinated medical workers completed the questionnaires, including 85 first-line medical staff (FMS), 82 second-line medical staff (SMS) and 69 at home medical staff (HMS). The proportions of depressive symptoms, anxiety symptoms, poor sleep quality, and insomnia were 52.1, 44.1, 55.9, and 49.2%, respectively. Compared with HMS, medical staff at work (FMS and SMS) got significantly higher frequency of poor sleep quality (both p < 0.001), insomnia (both p < 0.001), depressive (p < 0.001 and p = 0.003, respectively) and anxiety symptoms (p < 0.001 and p = 0.002, respectively). Compared with SMS, FMS were more likely to have poor sleep quality (p = 0.020). Besides, nurses got significantly higher percentage of poor sleep quality (OR = 1.352, p = 0.016) and insomnia (OR = 1.243, p = 0.041) than doctors. Whereas, the proportion of anxiety symptoms was increased in females than in males (OR = 2.772, p = 0.008). Conclusions: Psychological and sleep disturbances are common among medical staff at work during the COVID-19 pandemic. More psychological intervention should be administrated for FMS, especially for nurses.

A Fast Point Cloud Recognition Algorithm Based on Keypoint Pair Feature.

At present, PPF-based point cloud recognition algorithms can perform better matching than competitors and be verified in the case of severe occlusion and stacking. However, including certain superfluous feature point pairs in the global model description would significantly lower the algorithm's efficiency. As a result, this paper delves into the Point Pair Feature (PPF) algorithm and proposes a 6D pose estimation method based on Keypoint Pair Feature (K-PPF) voting. The K-PPF algorithm is based on the PPF algorithm and proposes an improved algorithm for the sampling point part. The sample points are retrieved using a combination of curvature-adaptive and grid ISS, and the angle-adaptive judgment is performed on the sampling points to extract the keypoints, therefore improving the point pair feature difference and matching accuracy. To verify the effectiveness of the method, we analyze the experimental results in scenes with different occlusion and complexity levels under the evaluation metrics of ADD-S, Recall, Precision, and Overlap rate. The results show that the algorithm in this paper reduces redundant point pairs and improves recognition efficiency and robustness compared with PPF. Compared with FPFH, CSHOT, SHOT and SI algorithms, this paper improves the recall rate by more than 12.5%.

Medium & long-chain acylcarnitine's relation to lipid metabolism as potential predictors for diabetic cardiomyopathy: a metabolomic study.

BACKGROUND: Acylcarnitine is an intermediate product of fatty acid oxidation. It is reported to be closely associated with the occurrence of diabetic cardiomyopathy (DCM). However, the mechanism of acylcarnitine affecting myocardial disorders is yet to be explored. This current research explores the different chain lengths of acylcarnitines as biomarkers for the early diagnosis of DCM and the mechanism of acylcarnitines for the development of DCM in-vitro. METHODS: In a retrospective non-interventional study, 50 simple type 2 diabetes mellitus patients and 50 DCM patients were recruited. Plasma samples from both groups were analyzed by high throughput metabolomics and cluster heat map using mass spectrometry. Principal component analysis was used to compare the changes occurring in the studied 25 acylcarnitines. Multivariable binary logistic regression was used to analyze the odds ratio of each group for factors and the 95% confidence interval in DCM. Myristoylcarnitine (C14) exogenous intervention was given to H9c2 cells to verify the expression of lipid metabolism-related protein, inflammation-related protein expression, apoptosis-related protein expression, and cardiomyocyte hypertrophy and fibrosis-related protein expression. RESULTS: Factor 1 (C14, lauroylcarnitine, tetradecanoyldiacylcarnitine, 3-hydroxyl-tetradecanoylcarnitine, arachidic carnitine, octadecanoylcarnitine, 3-hydroxypalmitoleylcarnitine) and factor 4 (octanoylcarnitine, hexanoylcarnitine, decanoylcarnitine) were positively correlated with the risk of DCM. Exogenous C14 supplementation to cardiomyocytes led to increased lipid deposition in cardiomyocytes along with the obstacles in adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathways and affecting fatty acid oxidation. This further caused myocardial lipotoxicity, ultimately leading to cardiomyocyte hypertrophy, fibrotic remodeling, and increased apoptosis. However, this effect was mitigated by the AMPK agonist acadesine. CONCLUSIONS: The increased plasma levels in medium and long-chain acylcarnitine extracted from factors 1 and 4 are closely related to the risk of DCM, indicating that these factors can be an important tool for DCM risk assessment. C14 supplementation associated lipid accumulation by inhibiting the AMPK/ACC/CPT1 signaling pathway, aggravated myocardial lipotoxicity, increased apoptosis apart from cardiomyocyte hypertrophy and fibrosis were alleviated by the acadesine.

Rice ubiquitin-conjugating enzyme OsUBC26 is essential for immunity to the blast fungus Magnaporthe oryzae.

The functions of ubiquitin-conjugating enzymes (E2) in plant immunity are not well understood. In this study, OsUBC26, a rice ubiquitin-conjugating enzyme, was characterized in the defence against Magnaporthe oryzae. The expression of OsUBC26 was induced by M. oryzae inoculation and methyl jasmonate treatment. Both RNA interference lines and CRISPR/Cas9 null mutants of OsUBC26 reduced rice resistance to M. oryzae. WRKY45 was down-regulated in OsUBC26 null mutants. In vitro E2 activity assay indicated that OsUBC26 is an active ubiquitin-conjugating enzyme. Yeast two-hybrid assays using OsUBC26 as bait identified the RING-type E3 ligase UCIP2 as an interacting protein. Coimmunoprecipitation assays confirmed the interaction between OsUBC26 and UCIP2. The CRISPR/Cas9 mutants of UCIP2 also showed compromised resistance to M. oryzae. Yeast two-hybrid screening using UCIP2 as bait revealed that APIP6 is a binding partner of UCIP2. Moreover, OsUBC26 working with APIP6 ubiquitinateds AvrPiz-t, an avirulence effector of M. oryzae, and OsUBC26 null mutation impaired the proteasome degradation of AvrPiz-t in rice cells. In summary, OsUBC26 plays important roles in rice disease resistance by regulating WRKY45 expression and working with E3 ligases such as APIP6 to counteract the effector protein AvrPiz-t from M. oryzae.

Protective Effects of Zinc on Spinal Cord Injury.

Spinal cord injury is a serious disease of the central nervous system, but there is no effective treatment. And zinc is an essential nutrient for human body and participates in many physiological processes, such as immune response, homeostasis, oxidative stress, cell cycle progression, DNA replication, DNA damage repair, apoptosis, and aging. This article mainly summarizes that zinc could predict the prognosis and treat the spinal cord injury. Especially, zinc could help to inhibit inflammation, regulate autophagy, and reduce oxidative stress. However, excessive zinc will damage neurons.

Sneezing reflex is mediated by a peptidergic pathway from nose to brainstem.

Sneezing is a vital respiratory reflex frequently associated with allergic rhinitis and viral respiratory infections. However, its neural circuit remains largely unknown. A sneeze-evoking region was discovered in both cat and human brainstems, corresponding anatomically to the central recipient zone of nasal sensory neurons. Therefore, we hypothesized that a neuronal population postsynaptic to nasal sensory neurons mediates sneezing in this region. By screening major presynaptic neurotransmitters/neuropeptides released by nasal sensory neurons, we found that neuromedin B (NMB) peptide is essential for signaling sneezing. Ablation of NMB-sensitive postsynaptic neurons in the sneeze-evoking region or deficiency in NMB receptor abolished the sneezing reflex. Remarkably, NMB-sensitive neurons further project to the caudal ventral respiratory group (cVRG). Chemical activation of NMB-sensitive neurons elicits action potentials in cVRG neurons and leads to sneezing behavior. Our study delineates a peptidergic pathway mediating sneezing, providing molecular insights into the sneezing reflex arc.

Mechanisms of transformation of nicotinamide mononucleotides to cerebral infarction hemorrhage based on MCAO model.

OBJECTIVE: The study aims at discussing the effect of nicotinamide mononucleotides on protecting hemorrhagic transformation of cerebral infarction in the middle cerebral artery occlusion (MCAO) model. METHOD: Male mice aged 4-5 weeks and weighing about 22-35 g in Shanghai Ninth People's Hospital are divided into three groups: sham group, collagenase intracerebral hemorrhage model (cICH + Vehicle) group and collagenase nicotinamide mononucleotide (cICH + NMN) group. Then, the intervention therapy research is carried out. After 24 h, the neurological function, brain edema, hematoma volume, body weight, hemorrhage volume, RNA expression level, apoptosis, inflammatory factors and reactive oxygen species (ROS) content in surrounding tissues of mice are analyzed comprehensively. RESULTS: Compared with the other two groups, nicotinamide mononucleotides in MCAO model have significant effects on improving neurological function, brain edema, inflammatory factors, body weight and cell apoptosis in mice, but have no significant effect on hemorrhage volume and hematoma volume in mice. CONCLUSION: Nicotinamide mononucleotides can significantly improve the collagenase-induced intracerebral hemorrhage (ICH) model in mice under MCAO model, and they can protect the brain tissue of mice from RNA level to tissue cell level or mouse body weight and volume level.

Altered Spontaneous Activity and Functional Connectivity in the Posterior Pons of Patients With Migraine Without Aura.

The brainstem has been discussed as the main player in the pathogenesis of migraine. Dysfunctional brainstem nuclei and their abnormal connections to other key brain centers may contribute to headache and other symptoms of migraine. In the present study, 32 patients with migraine without aura (MWoA) and 32 age- and sex-matched healthy controls (HCs) underwent resting-state fMRI scans. We used masked independent analysis (mICA) to investigate whether patients with MWoA exhibited abnormal brainstem nuclei-cortical functional connectivity (FC). The mICA can suppress adjacent physiological noise and prevent results from being driven by the much stronger signals of the surrounding structures. Regional homogeneity (ReHo) was used to investigate whether the brainstem regions with abnormal FC to other brain areas exhibited abnormal regional neuronal activity. Patients with MWoA showed significantly weaker FC between the posterior pons and the left superior parietal lobule, the left middle temporal gyrus, and the left middle frontal gyrus. Furthermore, patients with MWoA exhibited significantly decreased ReHo values in the posterior pons compared with HCs, and the posterior pons ReHo value was significantly negatively correlated with HIT-6 scores in the MWoA group. Patients with MWoA exhibited functional abnormalities in the posterior pons and weakened connections between the posterior pons and several key cortical brain areas involved in pain processing during the resting state. PERSPECTIVE: This study provided increased evidence that the pons is involved in the pathophysiological mechanism of migraine, and weakened connections suggest that the touch and pain sensation of migraine sufferers may not be properly relayed to cortical processing areas, which may be associated with the pathogenesis of MWoA.

Structural changes of cerebellum and brainstem in migraine without aura.

BACKGROUND: Increasing evidence has suggested that the cerebellum is associated with pain and migraine. In addition, the descending pain system of the brainstem is the major site of trigeminal pain processing and modulation and has been discussed as a main player in the pathophysiology of migraine. Cerebellar and brainstem structural changes associated with migraineurs remain to be further investigated. METHODS: Voxel-based morphometry (VBM) (50 controls, 50 migraineurs without aura (MWoAs)) and diffusion tensor imaging (DTI) (46 controls, 46 MWoAs) were used to assess cerebellum and brainstem anatomical alterations associated with MWoAs. We utilized a spatially unbiased infratentorial template toolbox (SUIT) to perform cerebellum and brainstem optimized VBM and DTI analysis. We extracted the average diffusion values from a probabilistic cerebellar white matter atlas to investigate whether MWoAs exhibited microstructure alterations in the cerebellar peduncle tracts. RESULTS: MWoAs showed decreased fractional anisotropy (FA) in the vermis VI extending to the bilateral lobules V and VI of the cerebellum. We also found higher axial diffusivity (AD), mean diffusivity (MD), and radial diffusivity (RD) in the right inferior cerebellum peduncle tract in MWoAs. MWoAs exhibited both reduced gray matter volume and increased AD, MD and RD in the spinal trigeminal nucleus (SpV). CONCLUSION: MWoAs exhibited microstructural changes in the cerebellum and the local brainstem. These structural differences might contribute to dysfunction of the transmission and modulation of noxious information, trigeminal nociception, and conduction and integration of multimodal information in MWoAs. These findings further suggest involvement of the cerebellum and the brainstem in the pathology of migraine without aura.

Cerebellar functional abnormalities in early stage drug-naïve and medicated Parkinson's disease.

Parkinson's disease (PD) is a progressive neurological degenerative disorder characterized by impaired motor function and non-motor dysfunctions. While recent studies have highlighted the role of the cerebellum in PD, our understanding of its role in PD remains limited. In the present study, we used resting-state fMRI to evaluate dysfunctions within the cerebellum in PD patients treated with medication and drug-naïve PD patients. We applied amplitude of low-frequency fluctuation (ALFF) and degree centrality (DC) analysis methods. Thirty-one patients with early stage PD (22 drug-naïve and 9 medicated patients) and 31 gender- and age-matched healthy controls were recruited in this study. ALFFs increased in the left cerebellar areas (lobules VI/VIIb/CruI/CruII and the dentate gyrus) and right cerebellar areas (lobules VI/VIIb/VIIIa/CruI/CruII and the dentate gyrus) of all PD patients and in the left and right cerebellar areas (lobules VI/VIIb/CruI and the dentate gyrus) of drug-naive PD patients but were not significantly changed in medicated PD patients. DC increased in the right cerebellar areas of all PD patients and medicated PD patients. All PD patients and all drug-naive PD patients showed significantly weaker functional connectivity (FC) between the left cerebellum and the left medial frontal gyrus. However, FC was significantly stronger between the right cerebellum and the left precentral and right middle occipital gyri in the medicated PD patients than in controls. Furthermore, a correlation analyses revealed that ALFF z scores in the left cerebellum (lobule VI) and right cerebellum (lobule VI/CruI and dentate gyrus) were negatively correlated with Mini-Mental State Examination (MMSE) scores in all PD patients and drug-naive patients. These results indicate that the cerebellum plays an important role in PD, mainly by exerting a compensatory effect in early stage PD. Additionally, antiparkinsonian medication would modified PD-induced changes in local neural activity and FC in PD patients. The results of this study offer novel insights into the roles of the cerebellum in early stage drug-naïve PD.

Brain functional changes in patients with botulism after illegal cosmetic injections of botulinum toxin: A resting-state fMRI study.

BACKGROUND: Botulinum toxin type A (BoNT-A) is generally considered safe and is widely used to treat a variety of clinical conditions involving muscle hyperactivity and for cosmetic purposes. However, the effects of BoNT-A poisoning (botulism) on brain function are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: Herein, we investigated brain functions in 9 patients who received illegal cosmetic injections of botulinum and 18 matched controls by combining the analysis methods of regional homogeneity (ReHo) and amplitude of low-frequency fluctuation (ALFF) based on resting-state fMRI. Compared with the controls, the patients with botulism exhibited significantly reduced ReHo values in the left posterior lobe of the cerebellum extending to the right anterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum extending to the parahippocampal gyrus and right posterior lobe of the cerebellum. The patients with botulism also showed weakened ALFF values in the right anterior lobe of the cerebellum extending to the left anterior lobe of the cerebellum and right posterior lobe of the cerebellum, as well as in the right anterior lobe of the cerebellum. CONCLUSIONS/SIGNIFICANCE: The results indicate that BoNT-A may modulate cerebral activation in specific areas, which may play roles in both the adverse effects of botulism and the mechanism underlying clinical treatment with BoNT-A.

Rivaroxaban does not influence hemorrhagic transformation in a diabetes ischemic stroke and endovascular thrombectomy model.

Managing endovascular thrombectomy (ET) in diabetic ischemic stroke (IS) with novel anticoagulants is challenging due to putative risk of intracerebral hemorrhage. The study evaluates increased hemorrhagic transformation (HT) risk in Rivaroxaban-treated diabetic rats post ET. Diabetes was induced in male Sprague-Dawley rats by intraperitoneal injection of 60 mg/kg streptozotocin. After 4-weeks, rats were pretreated orally with 30 mg/kg Rivaroxaban/saline; prothrombin time was monitored. IS and ET was induced after 1 h, by thread-induced transient middle cerebral artery occlusion (tMCAO) that mimicked mechanical ET for proximal MCA occlusion at 60 min. After 24 h reperfusion, infarct volumes, HT, blood-brain barrier (BBB) permeability, tight junction at peri-ischemic lesion and matrix metalloproteinase-9 (MMP-9) activity was measured. Diabetic rats seemed to exhibit increased infarct volume and HT at 24 h after ET than normal rats. Infarct volumes and functional outcomes did not differ between Rivaroxaban and diabetic control groups. A significant increase in HT volumes and BBB permeability under Rivaroxaban treatment was not detected. Compared to diabetic control group, neither the occludin expression was remarkably lower in the Rivaroxaban group nor the MMP-9 activity was higher. Together, Rivaroxaban does not increase HT after ET in diabetic rats with proximal MCA occlusion, since Rivaroxaban has fewer effects on post-ischemic BBB permeability.