Clinical features, disease progression, and nuclear imaging in ATXN2-related parkinsonism in a longitudinal cohort.

BACKGROUND: Spinocerebellar ataxia 2 (SCA2) with a low range of CAG repeat expansion of ATXN2 gene can present with predominant or isolated parkinsonism that closely resembles Parkinson's disease (PD). This study is aimed at comparing clinical features, disease progression, and nuclear imaging between ATXN2-related parkinsonism (ATXN2-P) and PD. METHODS: Three hundred and seventy-seven clinically diagnosed PD with family history were screened by multiplex ligation-dependent probe amplification, whole-exome sequencing or target sequencing, and dynamic mutation testing of 10 SCA subtypes. The baseline and longitudinal clinical features as well as the dual-tracer positron emission tomography (PET) imaging were compared between ATXN2-P and genetically undefined familial PD (GU-fPD). RESULTS: Fifteen ATXN2-P patients from 7 families and 50 randomly selected GU-fPD patients were evaluated. Significantly less resting tremor and more symmetric signs were observed in ATXN2-P than GU-fPD. No significant difference was found in motor progression and duration from onset to occurrence of fluctuation, dyskinesia, and recurrent falls between the two groups. Cognitive impairment and rapid-eye-movement sleep behavior disorder were more common in ATXN2-P. During follow-up, olfaction was relatively spared, and no obvious progression of cognition dysfunction evaluated by Mini-Mental State Examination scores was found in ATXN2-P. PET results of ATXN2-P demonstrated a symmetric, diffuse, and homogenous dopamine transporter loss of bilateral striatum and a glucose metabolism pattern inconsistent with that in PD. CONCLUSIONS: Symmetric motor signs and unique nuclear imaging might be the clues to distinguish ATXN2-P from GU-fPD.

Low-intensity pulsed ultrasound activated the anti-tumor immunity by irradiating the spleen of mice in 4 T-1 breast cancer.

Tumor immunotherapy is booming around the world. However, strategies to activate the immune system and alleviate the immunosuppression still need to be refined. Here, we demonstrate for the first time that low-intensity pulsed ultrasound (LIPUS, spatial average time average intensity (Isata) is 200 mW/cm2, frequency is 0.3 MHz, repetition frequency is 1 kHz, and duty cycle is 20%) triggers the immune system and further reverses the immunosuppressive state in the mouse models of breast cancer by irradiating the spleen of mice. LIPUS inhibited tumor growth and extended survival in mice with 4 T-1 tumors. Further studies had previously shown that LIPUS enhanced the activation of CD4+ and CD8+ T cells in the spleen and led to significant changes in cytokines, as well as induced upregulation of mRNA levels involved in multiple immune regulatory pathways in the spleen. In addition, LIPUS promoted tumor-infiltrating lymphocyte accumulation and CD8+ T cell activation and improved the dynamics of cytokines/chemokines in the tumor microenvironment, resulting in a reversal of the immunosuppressive state of the tumor microenvironment. These results suggest a novel approach to activate the immune response by irradiating the spleen with LIPUS.

Control priority based on source-specific DALYs of PM2.5-bound heavy metals by PMF-PSCF-IsoSource model in urban and suburban Beijing.

To determine the priority control sources, an approach was proposed to evaluate the source-specific contribution to health risks from inhaling PM2.5-bound heavy metals (PBHMs). A total of 482 daily PM2.5 samples were collected from urban and suburban areas of Beijing, China, between 2018 and 2019. In addition to the PMF-PSCF model, a Pb isotopic IsoSource model was built for more reliable source apportionment. By using the comprehensive indicator of disability-adjusted life years (DALYs), carcinogenic and noncarcinogenic health risks could be compared on a unified scale. The study found that the annual average concentrations of the total PBHMs were significantly higher in suburban areas than in urban areas, with significantly higher concentrations during the heating season than during the nonheating season. Comprehensive dust accounted for the largest contribution to the concentration of PBHMs, while coal combustion contributed the most to the DALYs associated with PBHMs. These results suggest that prioritizing the control of coal combustion could effectively reduce the disease burden associated with PBHMs, leading to notable public health benefits.

Determining rib fracture age from CT scans with a radiomics-based combined model: a multicenter retrospective study.

OBJECTIVES: We aimed to develop a combined model based on clinical and radiomic features to classify fracture age. METHODS: We included 1219 rib fractures from 239 patients from our center between March 2016 and September 2022. We created an external dataset using 120 rib fractures from 32 patients from another center between October 2019 and August 2023. According to tasks (fracture age between < 3 and ≥ 3 weeks, 3-12, and > 12 weeks), the internal dataset was randomly divided into training and internal test sets. A radiomic model was built using radiomic features. A combined model was constructed using clinical features and radiomic signatures by multivariate logistic regression, visualized as a nomogram. Internal and external test sets were used to validate model performance. RESULTS: For classifying fracture age between < 3 and ≥ 3 weeks, the combined model had higher areas under the curve (AUCs) than the radiomic model in the training set (0.915 vs 0.900, p = 0.009), internal test (0.897 vs 0.854, p < 0.001), and external test sets (0.881 vs 0.811, p = 0.003). For classifying fracture age between 3-12 and > 12 weeks, the combined model had higher AUCs than the radiomic model in the training model (0.848 vs 0.837, p = 0.12) and internal test sets (0.818 vs 0.793, p < 0.003). In the external test set, the AUC of the nomogram-assisted radiologist was 0.966. CONCLUSION: The combined radiomic and clinical model showed good performance and has the potential to assist in the classification of rib fracture age. This will be beneficial for clinical practice and forensic decision-making. CRITICAL RELEVANCE STATEMENT: This study describes the development of a combined radiomic and clinical model with good performance in the classification of the age of rib fractures, with potential clinical and forensic applications. KEY POINTS: • Complex factors make it difficult to determine the age of a fracture. • Our model based on radiomic features performed well in classifying fracture age. • Associating the radiomic features with clinical features improved the model's performance.

Traumatic rib fracture patterns associated with bone mineral density statuses derived from CT images.

Background: The impact of decreased bone mineral density (BMD) on traumatic rib fractures remains unknown. We combined computed tomography (CT) and artificial intelligence (AI) to measure BMD and explore its impact on traumatic rib fractures and their patterns. Methods: The retrospective cohort comprised patients who visited our hospital from 2017-2018; the prospective cohort (control group) was consecutively recruited from the same hospital from February-June 2023. All patients had blunt chest trauma and underwent CT. Volumetric BMD of L1 vertebra was measured by using an AI software. Analyses were done by using BMD categorized as osteoporosis (<80 mg/cm3), osteopenia (80-120 mg/cm3), or normal (>120 mg/cm3). Pearson's χ2, Fisher's exact, or Kruskal-Wallis tests and Bonferroni correction were used for comparisons. Negative binomial, and logistic regression analyses were used to assess the associations and impacts of BMD status. Sensitivity analyses were also performed. Findings: The retrospective cohort included 2,076 eligible patients, of whom 954 (46%) had normal BMD, 806 (38.8%) had osteopenia, and 316 (15.2%) had osteoporosis. After sex- and age-adjustment, osteoporosis was significantly associated with higher rib fracture rates, and a higher likelihood of fractures in ribs 4-7. Furthermore, both the osteopenia and osteoporosis groups demonstrated a significantly higher number of fractured ribs and fracture sites on ribs, with a higher likelihood of fractures in ribs 1-3, as well as flail chest. The prospective cohort included 205 eligible patients, of whom 92 (44.9%) had normal BMD, 74 (36.1%) had osteopenia, and 39 (19.0%) had osteoporosis. The findings observed within this cohort were in concurrence with those in the retrospective cohort. Interpretation: Traumatic rib fractures are associated with decreased BMD. CT-AI can help to identify individuals who have decreased BMD and a greater rib fracture rate, along with their fracture patterns.

Estimating the geographical patterns and health risks associated with PM2.5-bound heavy metals to guide PM2.5 control targets in China based on machine-learning algorithms.

PM2.5 is the main component of haze, and PM2.5-bound heavy metals (PBHMs) can induce various toxic effects via inhalation. However, comprehensive macroanalyses on large scales are still lacking. In this study, we compiled a substantial dataset consisting of the concentrations of eight PBHMs, including As, Cd, Cr, Cu, Mn, Ni, Pb and Zn, across different cities in China. To improve prediction accuracy, we enhanced the traditional land-use regression (LUR) model by incorporating emission source-related variables and employing the best-fitted machine-learning algorithm, which was applied to predict PBHM concentrations, analyze geographical patterns and assess the health risks associated with metals under different PM2.5 control targets. Our model exhibited excellent performance in predicting the concentrations of PBHMs, with predicted values closely matching measured values. Noncarcinogenic risks exist in 99.4% of the estimated regions, and the carcinogenic risks in all studied regions of the country are within an acceptable range (1 × 10-5-1 × 10-6). In densely populated areas such as Henan, Shandong, and Sichuan, it is imperative to control the concentration of PBHMs to reduce the number of patients with cancer. Controlling PM2.5 effectively decreases both carcinogenic and noncarcinogenic health risks associated with PBHMs, but still exceed acceptable risk level, suggesting that other important emission sources should be given attention.

Atrial giant cell myocarditis with preserved left ventricular function: a case report and literature review.

Giant cell myocarditis (GCM) is a rare and fatal inflammatory disorder induced by T-lymphocytes, typically affecting young adults. Generally, this disease presents with a rapidly progressive course and a very poor prognosis. In recent years, atrial GCM (aGCM) has been recognized as a clinicopathological entity distinct from classical GCM. As described by retrievable case reports, although its histopathological manifestations are highly similar to those of classical GCM, this entity is characterized by preserved left ventricular function and atrial arrhythmias, without ventricular arrhythmias. aGCM tends to show benign disease progression with a better clinical prognosis compared with the rapid course and poor prognosis of vGCM. We report a patient with aGCM with a history of renal abscess whose persistent myocardial injury considered to be associated with a history of renal abscess. Infection could be a potential trigger for the development of aGCM in this patient. An extensive literature review was also performed and the following three aspects were summarized: (1) Epidemiology and histopathological characteristics of aGCM; (2) The role of imaging in the evaluation of aGCM; (3) Diagnostic points and therapeutic decisions in aGCM.

The genetic spectrum of a cohort of patients clinically diagnosed as Parkinson's disease in mainland China.

So far, over 20 causative genes of monogenic Parkinson's disease (PD) have been identified. Some causative genes of non-parkinsonian entities may also manifest with parkinsonism mimicking PD. This study aimed to investigate the genetic characteristics of clinically diagnosed PD with early onset age or family history. A total of 832 patients initially diagnosed with PD were enrolled, of which, 636 were classified into the early-onset group and 196 were classified into the familial late-onset group. The genetic testing included the multiplex ligation-dependent probe amplification and next generation sequencing (target sequencing or whole-exome sequencing). The dynamic variants of spinocerebellar ataxia were tested in probands with family history. In the early-onset group, 30.03% of patients (191/636) harbored pathogenic/likely pathogenic (P/LP) variants in known PD-related genes (CHCHD2, DJ-1, GBA (heterozygous), LRRK2, PINK1, PRKN, PLA2G6, SNCA and VPS35). Variants in PRKN were the most prevalent, accounting for 15.72% of the early-onset patients, followed by GBA (10.22%), and PLA2G6 (1.89%). And 2.52% (16/636) had P/LP variants in causative genes of other diseases (ATXN3, ATXN2, GCH1, TH, MAPT, GBA (homozygous)). In the familial late-onset group, 8.67% of patients (17/196) carried P/LP variants in known PD-related genes (GBA (heterozygous), HTRA2, SNCA) and 2.04% (4/196) had P/LP variants in other genes (ATXN2, PSEN1, DCTN1). Heterozygous GBA variants (7.14%) were the most common genetic cause found in familial late-onset patients. Genetic testing is of vital importance in differential diagnosis especially in early-onset and familial PD. Our findings may also provide some clues to the nomenclature of genetic movement disorders.

Autosomal dominant Parkinson's disease caused by the recently identified LRRK2 N1437D mutation in a Chinese family: Clinical features, imaging findings, and functional impact.

INTRODUCTION: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of autosomal dominantly inherited Parkinson's disease (PD). Recently, a novel pathogenic variant (N1437D; c.4309A > G; NM_98578) in the LRRK2 gene has been identified in three Chinese families with PD. In this study, we describe a Chinese family with autosomal dominant PD that segregated with the N1437D mutation. A detailed clinical and neuroimaging characterization of the affected family members is reported. We also sought to investigate the functional mechanisms by which the detected mutation could cause PD. METHODS: We characterized the clinical and imaging phenotype of a Chinese pedigree with autosomal dominant PD. We searched for a disease-causing mutation by targeted sequencing and multiple ligation-dependent probe amplification. The functional impact of the mutation was investigated in terms of LRRK2 kinase activity, guanosine triphosphate (GTP) binding, and guanosine triphosphatase (GTPase) activity. RESULTS: The disease was found to co-segregate with the LRRK2 N1437D mutation. Patients in the pedigree exhibited typical parkinsonism (age at onset: 54.0 ± 5.9 years). One affected family member - who had evidence of abnormal tau accumulation in the occipital lobe on tau PET imaging - developed PD dementia at follow-up. The mutation markedly increased LRRK2 kinase activity and promoted GTP binding, without affecting GTPase activity. CONCLUSIONS: This study describes the functional impact of a recently identified LRRK2 mutation, N1437D, that causes autosomal dominant PD in the Chinese population. Further research is necessary to investigate the contribution of this mutation to PD in multiple Asian populations.

Anti-inflammatory Effect of Low-Intensity Ultrasound in Septic Rats.

OBJECTIVE: Sepsis is a severe systemic inflammatory response caused by infection. Here, the spleen region of Sprague-Dawley (SD) rats with sepsis was irradiated with low-intensity ultrasound (LIUS) to explore the regulation of inflammation and its mechanism by LIUS. METHODS: In this study, 30 rats used for survival analysis were randomly divided into the sham-operated group (Sham, n = 10), the group in which sepsis was induced by cecal ligation and puncture (CLP, n = 10) and the group treated with LIUS immediately after CLP (LIUS, n = 10). The other 120 rats were randomly divided into the aforementioned three groups for detection at each time point. The parameters used in the LIUS group were 200 mW/cm2, 0.37 MHz, 20% duty cycle and 20 min, and no ultrasonic energy was produced in the Sham and CLP groups. Seven-day survival rate, histopathology and expression of inflammatory factors and proteins were evaluated in the three groups. RESULTS: LIUS was able to improve the survival rate of septic SD rats (p < 0.05), significantly inhibit the expression of tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6) and nuclear factor-κB p65 (NF-κB p65) (p < 0.05) and restore the ultrastructure of the spleen. CONCLUSION: Our study determined that LIUS can relieve spleen damage and alleviate severe cytokine storm to improve survival outcomes in septic SD rats, and its mechanism may be related to the inhibition of the NF-κB signaling pathway by downregulation of IL-1ß.

Association between Respiratory Function and Motor Function in Different Stages of Parkinson's Disease.

INTRODUCTION: Respiratory dysfunction in patients with Parkinson's disease (PD) could present in the early stage and worsen in the late stages. These changes could be a factor affecting the ability of daily living and quality of life of patients with PD. The primary objective of this study was to assess the respiratory function and its association with motor function in patients with different stages of PD. METHODS: This was a cross-sectional study conducted at the Huashan Hospital of Fudan University in Shanghai, China. The study included 65 patients diagnosed with PD (the Hoehn and Yahr scale between 1 and 4) and 20 healthy individuals of similar age, gender, weight, and height. The ventilatory function was assessed using the spirometry. Motor function was evaluated using subscale III of the United Parkinson's disease rating scale (UPDRS-III). After confirming the normality of data distribution, we performed one-way ANOVA with a Tukey's post hoc test. RESULTS: Compared with the healthy individuals, there was no statistical significance in forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) in the H&Y 1 group and H&Y 2 group (p > 0.05) but reduced peak expiratory flow (PEF) in the H&Y 2 group (p = 0.002). Reduced FVC, FEV1, and PEF was seen in the H&Y 3 group (p = 0.002, p = 0.001, and p = 0.0001, respectively). Reduced FVC, FEV1, PEF, and FEF25-75% was seen in the H&Y 4 group (p = 0.001, p = 0.0001, p = 0.0001, and p = 0.025, respectively). The correlation analysis revealed that there was a significant negative correlation between FVC and UPDRS-III scores (r = -0.248, p = 0.046), disease duration (r = -0.276, p = 0.026), H&Y scale (r = -0.415, p = 0.001). FEV1 was negatively correlated with UPDRS-III scores (r = -0.277, p = 0.025), disease duration (r = -0.291, p = 0.019), H&Y scale (r = -0.434, p = 0.0001). FEF25-75% was negatively correlated with disease duration (r = -0.247, p = 0.047), H&Y scale (r = -0.278, p = 0.025). CONCLUSION: Our findings revealed that respiratory impairment is present in moderate and advanced PD patients, and directly related to the severity of the disease. It is important to conduct respiratory function test in the clinical practice.

Diagnosis of Acute Aortic Syndromes on Non-Contrast CT Images with Radiomics-Based Machine Learning.

We aimed to detect acute aortic syndromes (AAS) on non-contrast computed tomography (NCCT) images using a radiomics-based machine learning model. A total of 325 patients who underwent aortic CT angiography (CTA) were enrolled retrospectively from 2 medical centers in China to form the internal cohort (230 patients, 60 patients with AAS) and the external testing cohort (95 patients with AAS). The internal cohort was divided into the training cohort (n = 135), validation cohort (n = 49), and internal testing cohort (n = 46). The aortic mask was manually delineated on NCCT by a radiologist. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used to filter out nine feature parameters; the Support Vector Machine (SVM) model showed the best performance. In the training and validation cohorts, the SVM model had an area under the curve (AUC) of 0.993 (95% CI, 0.965-1); accuracy (ACC), 0.946 (95% CI, 0.877-1); sensitivity, 0.9 (95% CI, 0.696-1); and specificity, 0.964 (95% CI, 0.903-1). In the internal testing cohort, the SVM model had an AUC of 0.997 (95% CI, 0.992-1); ACC, 0.957 (95% CI, 0.945-0.988); sensitivity, 0.889 (95% CI, 0.888-0.889); and specificity, 0.973 (95% CI, 0.959-1). In the external testing cohort, the ACC was 0.991 (95% CI, 0.937-1). This model can detect AAS on NCCT, reducing misdiagnosis and improving examinations and prognosis.

Heath management app use in Parkinson's disease and quality of life during the COVID-19 pandemic.

BACKGROUND: Social distancing during the COVID-19 pandemic affected follow-up visits and medication availability for patients with Parkinson's disease (PD). As a promising strategy to deal with these challenges, the implementation of health management smartphone apps was accelerated. However, whether more intense use of such apps could improve the quality of life (QoL) for PD patients during the COVID-19 pandemic was unknown. METHODS: Using a PD management app, this observational study assessed changes in QoL, as determined by PD Questionnaire 8 (PDQ-8), among PD patients before (Jan 20, 2019 to Oct 6, 2019) and after the beginning of the COVID-19 lockdown (Jan 20, 2020 to Oct 6, 2020). According to adherence to use of the app, participants were divided into low adherence, moderate adherence, and high adherence groups. A total of 4979 PD patients registered in the app, and 226 PD patients were enrolled, including 57 patients with low adherence, 112 with moderate adherence and 57 with high adherence. A generalized linear model was used to evaluate the change of PDQ-8 scores across these three different adherence groups. RESULTS: After the COVID-19 lockdown (1-year follow-up), the PDQ-8 scores are reduced by 0.8 (95% CI, 0.3-1.4) in all participants (P = 0.004). After adjustment for age, gender, education, disease duration and levodopa equivalent dose, PDQ-8 scores significantly less reduced in the high adherence group (0.3; 95% CI, 0.6-1.2) compared to the low adherence (1.9; 95% CI, 0.7-3.1) (P = 0.040) and moderate adherence groups (0.6; 95% CI, 0.2-1.3) (P = 0.012). CONCLUSIONS: A health management smartphone-based app might be a way to both measure and improve QoL among PD patients, provided that sufficient adherence is achieved.

The COVID-19 pandemic had an enormous impact on the lives of people living with Parkinson's disease (PD), given social distancing measures, and reduced access to healthcare. As a way to mitigate this, the use of health management apps was accelerated. However, there is a lack of studies on whether the use of such apps could over time affect the quality of life of people living with PD. Here, we analyzed changes in the quality of life of people living with PD using a health management app, before and after social distancing. We found that patients with high adherence to use of the app experienced a lower reduction of their quality of life. Using a health management smartphone app represents a novel approach that might help patients with PD improve their quality of life.

Plasma GFAP in Parkinson's disease with cognitive impairment and its potential to predict conversion to dementia.

Glial fibrillary acidic protein (GFAP) has been suggested as a biomarker for reactive astrogliosis. We measured the levels of plasma GFAP by Simoa in 60 patients with PD with normal cognition, 63 with mild cognitive impairment (PD-MCI), 24 with dementia (PDD) and 15 healthy controls. A subgroup of patients with PD-MCI (n = 31) was followed up for 4.1 ± 2.3 years. Compared with healthy controls, plasma GFAP levels were elevated in patients with PDD (adjusted P < 0.001) and PD-MCI (adjusted P = 0.013) and were negatively correlated with the Mini Mental State Examination (MMSE) score in PD participants. Plasma GFAP predicted MCI-to-dementia conversion with an AUC of 0.90, higher than NfL, Tau and pTau181. Our results support that plasma GFAP has potential value for distinguishing patients with PDD, and predicting MCI-to-dementia conversion in PD.

Conformational change of α-synuclein fibrils in cerebrospinal fluid from different clinical phases of Parkinson's disease.

α-Synuclein (α-syn) has been shown to form various conformational fibrils associated with different synucleinopathies. But whether the conformation of α-syn fibrils changes during disease progression is unclear. Here, we amplified α-syn aggregates from the cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) staged in preclinical PD (pre-PD), middle- to late-stage PD (mid-PD), and late-stage PD (late-PD). Our results show that α-syn fibrils derived from the late-PD patient are most potent in inducing endogenous α-syn aggregation in primary neurons, followed by the mid-PD and pre-PD fibrils. By using cryo-electron microscopy, we further determined the high-resolution structures of the CSF-amplified fibrils. The structures exhibit remarkable differences in a minor but significant population of conformational species in different staged samples. Our work demonstrates structural and pathological differences between α-syn fibrils derived from PD patients at a spectrum of clinical stages, which suggests potential conformational transition of α-syn fibrils during the progression of PD.

In Vivo 18 F-Florzolotau Tau Positron Emission Tomography Imaging in Parkinson's Disease Dementia.

BACKGROUND: Tau pathology is observed during autopsy in many patients with Parkinson's disease dementia (PDD). Positron emission tomography (PET) imaging using the tracer 18 F-florzolotau has the potential to capture tau accumulation in the living brain. OBJECTIVE: The aim was to describe the results of 18 F-florzolotau PET/CT (computed tomography) imaging in patients with PDD. METHODS: Ten patients with PDD, 9 with Parkinson's disease with normal cognition (PD-NC), and 9 age-matched healthy controls (HCs) were enrolled. Clinical assessments and 18 F-florzolotau PET/CT imaging were performed. RESULTS: 18 F-Florzolotau uptake was significantly higher in the cortical regions of patients with PDD compared with both PD-NC and HCs, especially in the temporal lobe. Notably, 18 F-florzolotau uptake in the occipital lobe of patients with PDD showed a significant correlation with cognitive impairment as reflected by Mini-Mental State Examination (MMSE) scores. CONCLUSIONS: 18 F-Florzolotau PET imaging can effectively capture the occurrence of tau pathology in patients with PDD, which was also linked to MMSE scores. © 2022 International Parkinson and Movement Disorder Society.

Deficiency of miR-29a/b1 leads to premature aging and dopaminergic neuroprotection in mice.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive degeneration of midbrain dopaminergic neurons. The miR-29s family, including miR-29a and miR-29b1 as well as miR-29b2 and miR-29c, are implicated in aging, metabolism, neuronal survival, and neurological disorders. In this study, the roles of miR-29a/b1 in aging and PD were investigated. miR-29a/b1 knockout mice (named as 29a KO hereafter) and their wild-type (WT) controls were used to analyze aging-related phenotypes. After challenged with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), dopaminergic injuries, glial activation, and mouse behaviors were evaluated. Primary glial cells were further cultured to explore the underlying mechanisms. Additionally, the levels of miR-29s in the cerebrospinal fluid (CSF) of PD patients (n = 18) and healthy subjects (n = 17) were quantified. 29a KO mice showed dramatic weight loss, kyphosis, and along with increased and deepened wrinkles in skins, when compared with WT mice. Moreover, both abdominal and brown adipose tissues reduced in 29a KO mice, compared to their WT counterpart. However, in MPTP-induced PD mouse model, the deficiency of miR-29a/b1 led to less severe damages of dopaminergic system and mitigated glial activation in the nigrostriatal pathway, and subsequently alleviated the motor impairments in 3-month-old mice. Eight-month-old mutant mice maintained such a resistance to MPTP intoxication. Mechanistically, the deficiency of miR-29a/b-1 promoted the expression of neurotrophic factors in 1-Methyl-4-phenylpyridinium (MPP+)-treated primary mixed glia and primary astrocytes. In lipopolysaccharide (LPS)-treated primary microglia, knockout of miR-29a/b-1 inhibited the expression of inflammatory factors, and promoted the expression of anti-inflammatory factors and neurotrophic factors. Knockout of miR-29a/b1 increased the activity of AMP-activated protein kinase (AMPK) and repressed NF-κB/p65 signaling in glial cells. Moreover, we found miR-29a level was increased in the CSF of patients with PD. Our results suggest that 29a KO mice display the peripheral premature senility. The combined effects of less activated glial cells might contribute to the mitigated inflammatory responses and elicit resistance to MPTP intoxication in miR-29a/b1 KO mice.

Enhanced interactions of interlayer excitons in free-standing heterobilayers.

Strong, long-range dipole-dipole interactions between interlayer excitons (IXs) can lead to new multiparticle correlation regimes1,2, which drive the system into distinct quantum and classical phases2-5, including dipolar liquids, crystals and superfluids. Both repulsive and attractive dipole-dipole interactions have been theoretically predicted between IXs in a semiconductor bilayer2,6-8, but only repulsive interactions have been reported experimentally so far3,9-16. This study investigated free-standing, twisted (51°, 53°, 45°) tungsten diselenide/tungsten disulfide (WSe2/WS2) heterobilayers, in which we observed a transition in the nature of dipolar interactions among IXs, from repulsive to attractive. This was caused by quantum-exchange-correlation effects, leading to the appearance of a robust interlayer biexciton phase (formed by two IXs), which has been theoretically predicted6-8 but never observed before in experiments. The reduced dielectric screening in a free-standing heterobilayer not only resulted in a much higher formation efficiency of IXs, but also led to strongly enhanced dipole-dipole interactions, which enabled us to observe the many-body correlations of pristine IXs at the two-dimensional quantum limit. In addition, we firstly observed several emission peaks from moiré-trapped IXs at room temperature in a well-aligned, free-standing WSe2/WS2 heterobilayer. Our findings open avenues for exploring new quantum phases with potential for applications in non-linear optics.

Direct observation of contact resistivity for monolayer TMD based junctions via PL spectroscopy.

Monolayer transition metal dichalcogenides (mTMDs) possess a direct band gap and strong PL emission that is highly sensitive to doping level and interfaces, laying the foundation for investigating the contact between mTMD and metal via PL spectroscopy. Currently, electrical methods have been utilized to measure the contact resistance (RC), but they are complicated, time-consuming, high-cost and suffer from inevitable chemical disorders and Fermi level pinning. In addition, previously reported contact resistances comprise both Schottky barrier and tunnel barrier components. Here, we report a simple, rapid and low-cost method to study the tunnel barrier dominated contact resistance of mTMD based junctions through PL spectroscopy. These junctions are free from chemical disorders and Fermi level pinning. Excluding the Schottky barrier component, solely tunnel barrier dominated contact resistances of 1 L MoSe2/Au and 1 L MoSe2/graphene junctions were estimated to be 147.8 Ω µm and 54.9 Ω µm, respectively. Density functional theory (DFT) simulations revealed that the larger RC of the former was possibly due to the existence of intrinsic effective potential difference (Φbarrier) between mTMD and metal. Both junctions exhibit an increasing tendency of RC as temperature decreases, which is probably attributed to the thermal expansion coefficient (TEC) mismatch-triggered interlayer spacing (d) increase and temperature-induced doping. Remarkably, a significant change of RC was observed in 1 L MoSe2/Au junctions, which is possibly ascribed to the changes of their orbital overlaps. Our results open new avenues for exploring fundamental metal-semiconductor contact principles and constructing high-performance devices.

Prediction of Quality of Life in Patients With Parkinson's Disease With and Without Excessive Daytime Sleepiness: A Longitudinal Study.

Objective: There is a lack of longitudinal studies that directly compare the quality of life (QoL) and investigate the impact of clinical factors on QoL across different excessive daytime sleepiness (EDS) statuses in Parkinson's disease (PD); therefore, we aimed to compare QoL and reveal the potential heterogeneous predictors of QoL between patients with PD with and without EDS. Methods: We collected clinical data among 306 patients with PD over 2 years. EDS was assessed by the Epworth Sleepiness Scale and QoL was measured with the 39-item Parkinson's Disease Questionnaire. Results: We found that at both baseline and follow-up, patients with PD with EDS had poorer QoL and suffered more non-motor symptoms including depression and clinical probable rapid eye movement sleep behavior disorder (cpRBD). The generalized linear mixed model analysis indicated that the major predictors of QoL in PD with EDS were the akinetic-rigid type, disease duration, and total levodopa equivalent dose, while in PD without EDS, the primary determinants of QoL were Hoehn and Yahr, Mini-Mental State Examination (MMSE), and cpRBD. Conclusion: Patients with PD with EDS presented with poorer QoL. Besides, the baseline predictors of future QoL differed between patients with PD with and without EDS. These findings remind clinicians to target specific clinical factors when attempting to improve QoL among patients with PD.