Cobalt Nitride Nanoparticles Encapsulated in N-Doped Carbon Nanotubes Modified Separator of Li-S Battery Achieving the Synergistic Effect of Restriction-Adsorption-Catalysis of Polysulfides.

Although lithium-sulfur (Li-S) batteries have broad market prospects due to their high theoretical energy density and potential cost-effectiveness, the practical applications still face serious shuttle effects of polysulfides (LiPSs) and slow redox reactions. Therefore, in this paper, cobalt nitride nanoparticles encapsulated in nitrogen-doped carbon nanotube (CoN@NCNT) are prepared as a functional layer for the separator of high-performance Li-S batteries. Carbon nanotubes with large specific surface areas not only promote the transport of ions and electrons but also weaken the migration of LiPSs and confine the dissolution of LiPSs in electrolytes. The lithiophilic heteroatom N adsorbs LiPSs by strong chemical adsorption, and the CoN particles with high catalytic activity greatly improve the kinetics of the conversion between LiPSs and Li2S2/Li2S during the charge-discharge process. Due to these advantages, the battery with CoN@NCNT modified separator has superior rate performance (initial discharge capacity of 834.7 mAh g-1 after activation at 1 C) and excellent cycle performance (capacity remains 729.7 mAh g-1 after 200 cycles at 0.2 C). This work proposes a strategy that can give the separator a strong ability to confinement-adsorption-catalysis of LiPSs in order to provide more possibilities for the development of Li-S batteries.

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.

Structure-controlled Interpenetrated MOF@COF via C-C Linkage for Enhanced Photocatalysis.

Diversifying the connecting junctions will be feasible for the controllable collaboration of metal organic frameworks (MOFs) and covalent organic frameworks (COFs) to rationally design multifunction-integrated heterostructures with enhanced performance, yet it is in the nascent stage. Herein, by intelligently exploiting the polymerization of vinyl group, C-C bond is innovatively introduced to construct the core-shell MOF@COF heterostructures with adjustable shell thickness and rare interpenetrated structure. The unique structure endows prepared C-C-linked MIL-68@COF-Vs with more superior visible-light harvesting and photogenerated carrier separation capability, leading to significantly higher photocatalytic activity and faster degradation rate than pristine MIL-68-C=Cs, COF-V, and imine-linked MIL-68-NH2@COF-V. Further, the customized MIL-68@COF-V is in-situ grown as reusable films with significantly boosted performance under ambient condition, which realize the highly efficient degradation of tetracycline within 15 min (96.5%), rhodamine 6G within 25 min (97.6%), and phenol within 40 min (95.3%) by solar drive. This work exhibits the distinctive advantages of C-C junction in the MOF@COF construction, and highlights the application prospect of rational-designed heterostructure in the treatment of persistent organic pollutants.

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.

PACAP/PAC1-R activation contributes to hyperalgesia in 6-OHDA-induced Parkinson's disease model rats via promoting excitatory synaptic transmission of spinal dorsal horn neurons.

Pain is a common annoying non-motor symptom in Parkinson's disease (PD) that causes distress to patients. Treatment for PD pain remains a big challenge, as its underlying mechanisms are elusive. Pituitary adenylate cyclase-activating polypeptide (PACAP) and its receptor PAC1-R play important roles in regulating a variety of pathophysiological processes. In this study, we investigated whether PACAP/PAC1-R signaling was involved in the mechanisms of PD pain. 6-hydroxydopamine (6-OHDA)-induced PD model was established in rats. Behavioral tests, electrophysiological and Western blotting analysis were conducted 3 weeks later. We found that 6-OHDA rats had significantly lower mechanical paw withdrawal 50% threshold in von Frey filament test and shorter tail flick latency, while mRNA levels of Pacap and Adcyap1r1 (gene encoding PAC1-R) in the spinal dorsal horn were significantly upregulated. Whole-cell recordings from coronal spinal cord slices at L4-L6 revealed that the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in dorsal horn neurons was significantly increased, which was reversed by application of a PAC1-R antagonist PACAP 6-38 (250 nM). Furthermore, we demonstrated that intrathecal microinjection of PACAP 6-38 (0.125, 0.5, 2 µg) dose-dependently ameliorated the mechanical and thermal hyperalgesia in 6-OHDA rats. Inhibition of PACAP/PAC1-R signaling significantly suppressed the activation of Ca2+/calmodulin-dependent protein kinase II and extracellular signal-regulated kinase (ERK) in spinal dorsal horn of 6-OHDA rats. Microinjection of pAAV-Adcyap1r1 into L4-L6 spinal dorsal horn alleviated hyperalgesia in 6-OHDA rats. Intrathecal microinjection of ERK antagonist PD98059 (10 µg) significantly alleviated hyperalgesia in 6-OHDA rats associated with the inhibition of sEPSCs in dorsal horn neurons. In addition, we found that serum PACAP-38 concentration was significantly increased in PD patients with pain, and positively correlated with numerical rating scale score. In conclusion, activation of PACAP/PAC1-R induces the development of PD pain and targeting PACAP/PAC1-R is an alternative strategy for treating PD pain.

Pramipexole inhibits astrocytic NLRP3 inflammasome activation via Drd3-dependent autophagy in a mouse model of Parkinson's disease.

Inflammation is one of the pathogenic processes in Parkinson's disease (PD). Dopamine receptor agonist pramipexole (PPX) is extensively used for PD treatment in clinics. A number of studies show that PPX exerts neuroprotection on dopaminergic (DA) neurons, but the molecular mechanisms underlying the protective effects of PPX on DA neurons are not fully elucidated. In the present study, we investigated whether PPX modulated PD-related neuroinflammation and underlying mechanisms. PD model was established in mice by bilateral striatum injection of lipopolyssaccharide (LPS). The mice were administered PPX (0.5 mg·kg-1·d-1, i.p.) 3 days before LPS injection, and for 3 or 21 days after surgery, respectively, for biochemical and histological analyses. We showed that PPX administration significantly alleviated the loss of DA neurons, and suppressed the astrocyte activation and levels of proinflammatory cytokine IL-1ß in the substantia nigra of LPS-injected mice. Furthermore, PPX administration significantly decreased the expression of NLRP3 inflammasome-associated proteins, i.e., cleaved forms of caspase-1, IL-1ß, and apoptosis-associated speck-like protein containing a caspase recruit domain (ASC) in the striatum. These results were validated in LPS+ATP-stimulated primary mouse astrocytes in vitro. Remarkably, we showed that PPX (100-400 µM) dose-dependently enhanced the autophagy activity in the astrocytes evidenced by the elevations in LC3-II and BECN1 protein expression, as well as the increase of GFP-LC3 puncta formation. The opposite effects of PPX on astrocytic NLRP3 inflammasome and autophagy were eliminated by Drd3 depletion. Moreover, we demonstrated that both pretreatment of astrocytes with autophagy inhibitor chloroquine (40 µM) in vitro and astrocyte-specific Atg5 knockdown in vivo blocked PPX-caused inhibition on NLRP3 inflammasome and protection against DA neuron damage. Altogether, this study demonstrates an anti-neuroinflammatory activity of PPX via a Drd3-dependent enhancement of autophagy activity in astrocytes, and reveals a new mechanism for the beneficial effect of PPX in PD therapy.

Sarcopenia is associated with non-motor symptoms in Han Chinese patients with Parkinson's Disease: a cross-sectional study.

BACKGROUND: Sarcopenia is commonly seen in the older adults and increases in incidence with age, also in Parkinson's disease (PD). Although research has indicated that the development of sarcopenia in patients with PD may be related to both motor symptoms and non-motor symptoms (NMS), the precise relationship between the two conditions remains unclear. Therefore, we aimed to investigate the incidence of sarcopenia in patients with PD and its association with NMS. METHODS: The study included 123 patients with PD and 38 age- and sex-matched healthy controls (HC). All participants were evaluated for sarcopenia using the 2019 Asian Sarcopenia Diagnostic Criteria, and patients with PD underwent standard assessments of motor symptoms and NMS. Multiple logistic regression and receiver operating characteristic (ROC) curve analyses were used to examine the association between sarcopenia and NMS in patients with PD. RESULTS: The incidence of sarcopenia was significantly higher in patients with PD than in HC (26.8% vs. 10.4%, p = 0.046). Multiple logistic regression analysis revealed that poorer sleep quality (odds ratio [OR]: 1.245; 95% confidence interval [CI]: 1.011-1.533; p = 0.040) and fatigue (OR: 1.085, 95% CI: 1.006-1.170, p = 0.034) were independently associated with sarcopenia. ROC analysis indicated that the optimal cut-off value for Pittsburgh Sleep Quality Index (PSQI) scores was 10, with 72.7% sensitivity and 74.4% specificity (area under the curve [AUC] = 0.776, 95% CI: 0.683-0.868, p < 0.001). The optimal cut-off value for Fatigue Severity Scale (FSS) scores was 39, with 87% sensitivity and 50% specificity (AUC = 0.725, 95% CI: 0.629 -0.820, p < 0.001). Joint use of FSS and PSQI scores increased the predictive value for sarcopenia(AUC = 0.804, 95% CI: 0.724-0.885, p < 0.001). CONCLUSION: Patients with PD are more susceptible to sarcopenia than healthy older adults, and fatigue and poorer sleep are positively associated with sarcopenia. Further longitudinal studies are needed to clarify the causal relationships.

On-Chip Compressive Sensing with a Single-Photon Avalanche Diode Array.

Single-photon avalanche diodes (SPADs) are novel image sensors that record photons at extremely high sensitivity. To reduce both the required sensor area for readout circuits and the data throughput for SPAD array, in this paper, we propose a snapshot compressive sensing single-photon avalanche diode (CS-SPAD) sensor which can realize on-chip snapshot-type spatial compressive imaging in a compact form. Taking advantage of the digital counting nature of SPAD sensing, we propose to design the circuit connection between the sensing unit and the readout electronics for compressive sensing. To process the compressively sensed data, we propose a convolution neural-network-based algorithm dubbed CSSPAD-Net which could realize both high-fidelity scene reconstruction and classification. To demonstrate our method, we design and fabricate a CS-SPAD sensor chip, build a prototype imaging system, and demonstrate the proposed on-chip snapshot compressive sensing method on the MINIST dataset and real handwritten digital images, with both qualitative and quantitative results.

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.

NOTCH2NLC Intermediate-Length Repeat Expansions Are Associated with Parkinson Disease.

NOTCH2NLC GGC repeat expansions were recently identified in neuronal intranuclear inclusion disease (NIID); however, it remains unclear whether they occur in other neurodegenerative disorders. This study aimed to investigate the role of intermediate-length NOTCH2NLC GGC repeat expansions in Parkinson disease (PD). We screened for GGC repeat expansions in a cohort of 1,011 PD patients and identified 11 patients with intermediate-length repeat expansions ranging from 41 to 52 repeats, with no repeat expansions in 1,134 controls. Skin biopsy revealed phospho-alpha-synuclein deposition, confirming the PD diagnosis in 2 patients harboring intermediate-length repeat expansions instead of NIID or essential tremor. Fibroblasts from PD patients harboring intermediate-length repeat expansions revealed NOTCH2NLC upregulation and autophagic dysfunction. Our results suggest that intermediate-length repeat expansions in NOTCH2NLC are potentially associated with PD. ANN NEUROL 2021;89:182-187.

Dry eye symptoms in interferon regulatory factor 3-deficient mice due to herpes simplex virus infection in harderian gland and lacrimal gland.

PURPOSE: Dry eye syndrome (DES) is a multifactorial ocular disorder. The possible pathogens and pathogenic mechanisms for virus-related dry eye disease are largely unknown. The current study aimed to provide evidence for mechanisms contributing to DES induced by herpes simplex virus (HSV) infection in the harderian gland (HG) and lacrimal gland (LG). METHODS: We recorded the dry eye-like cornea pathology of irf3-/- mice infected with HSV-1 till 8 months of age. The slit-lamp and confocal microscopy was used to observe the corneal defects. TUNEL was used to detect the corneal apoptosis. Human corneas suffered from herpes stromal keratitis (HSK) were also analyzed as a comparison. Then, we measure the aqueous tear production with a phenol red thread test in irf3-/-mice, and recorded their tear film breakup time. HGs and LGs were sectioned and analyzed using HE and oil-red-O staining. For molecular signaling pathway analysis, we used mRNA sequencing to explore the related gene ontology. Western blotting (WB) and real-time reverse transcription-quantitative polymerase chain reaction were used to verify the level of the Akt signaling pathway and related inflammatory factors. RESULTS: Inoculated irf3-/- mice tended to develop dry eye-like symptoms, such as corneal keratinization, corneal cell apoptosis, and tear reduction. The HGs and LGs of irf3-/- mice showed increased level of HSV-1, and exhibited inflammatory pathological changes and impaired function, which explained the damaged tear film. WB and mRNA sequencing indicated that enhanced PI3K-Akt pathway in irf3-/- mice might account for the higher susceptibility to HSV infection. CONCLUSIONS: We observed evidence of DES in irf3-/- mice induced by HSV-1 infection in the HGs and LGs, which may introduce a potential novel target for DES treatment.

Fiber selectivity of peripheral neuropathy in patients with Parkinson's disease.

OBJECTIVE: To determine the function of each type of peripheral nerve fiber and investigate the possible role of levodopa (LD) in peripheral neuropathy (PN) in Parkinson's disease (PD) patients. METHODS: We enrolled 60 patients with idiopathic PD. All PD patients were divided into three groups: levodopa exposure >3 years (LELD), levodopa exposure ≤3 years (SELD) and de novo patients with PD (NOLD). The current perception threshold (CPT), which was measured by Neurometer at 2000, 250 and 5 Hz, the level of homocysteine, Vitamin B12 and folic acid in plasma, were compared with those of sex- and age-matched healthy controls (HCs). RESULTS: Current perception threshold was higher at 250 Hz (p < .05) and 5 Hz (p < .05) in the LELD group than the NOLD, SELD, and control group. CPT was lower at 5 Hz in the NOLD than in the HCs group (p < .05). The CPT of the more affected side of PD patients was positively correlated with H-Y stage at 5 Hz current stimulation (r = .42, p = .01). Multivariate logistic regression analysis showed that elevated homocysteine levels were the risk factor of sensory nerve injury in PD patients (p < .01). Serum homocysteine levels were positively correlated with levodopa (LD) daily dose, LD equivalent daily dose, and LD cumulative lifetime dose (p < .05). CONCLUSIONS: Peripheral neuropathy in PD patients can occur in the early stage of PD exhibiting as hyperesthesia and is fiber selectivity, especially for Aδ and C nerve fibers. PN in PD patients is related to PD itself and long-term LD exposure. Elevated plasma homocysteine is a risk factor for PN in PD patients.

Predictive and prognostic value of v-set and transmembrane domain-containing 1 expression in monocytes for coronary artery disease.

The aim of this study was to investigate the correlation between v-set and transmembrane domain-containing 1 (VSTM1) expression and incidence of major adverse cardiac events (MACE) in patients with coronary heart disease (CHD). A total of 310 patients were divided into a non-acute coronary syndrome (non-ACS) group (containing the stable angina group, and the asymptomatic coronary artery diseaseand other patients group) and an ACS group (containing unstable angina and acute myocardial infarction patients). Monocytic VSTM1 expression levels (assessed via average fluorescence intensity derived from antibody binding to VSTM1) in each group were detected and analyzed. The cut-off value of monocytic VSTM1 expression to predict the onset of ACS and MACE was confirmed. VSTM1 expression in monocytes from the ACS group was lower than that of the non-ACS group. The incidence of MACEs in the high VSTM1-expression group was much less than that of those in the low VSTM1 expression group at the 1 year follow-up stage. VSTM1 expression had an independent-inversed association with increased incidence of MACE and ACS. VSTM1 expression in monocytes may help to predict the occurrence of ACS in patients with CHD, and moreover it may provide the means to evaluate MACE prognosis during CHD patient follow-up.

Sex and onset-age-related features of excessive daytime sleepiness and night-time sleep in patients with Parkinson's disease.

BACKGROUND: The clinical characteristics of Parkinson's disease (PD) differ between men and women, and late- and early-onset patients, including motor symptoms and some nonmotor symptoms, such as cognition, anxiety, and depression. OBJECTIVE: To explore the features of excessive daytime sleepiness (EDS) and night-time sleep quality in PD patients of different sexes and age at onset (AAO). METHODS: Demographic data and clinical characteristics of 586 PD patients were collected. Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were used to investigate the daytime drowsiness and nocturnal sleep. Multivariate logistic regression analysis was used to explore the risk factors of EDS and poor night-time sleep quality. RESULTS: Sleep disorders were common in PD patients. EDS was more prominent in men than in women. There was no significant difference in ESS scores between late-onset PD (LOPD) and early-onset PD. LOPD patients had a higher probability of poor night-time sleep quality. Male sex, disease duration, and depression were risk factors for EDS. In all patients of both sexes and all AAO, depression was a risk factor for poor night-time sleep. CONCLUSION: More attention should be paid to sleep disorders of PD patients, especially male LOPD patients. Depression is a common risk factor for EDS and poor sleep quality in PD patients.

Shear wave elastography characteristics of upper limb muscle in rigidity-dominant Parkinson's disease.

BACKGROUND: Rigidity is one of the major manifestations of Parkinson's disease (PD), but no quantitative and objective imaging method has been developed to measure rigidity. Ultrasound shear wave elastography (SWE) can reflect the stiffness of tissue by providing a quantitative index. Thus, we conducted this study to evaluate the potential clinical value of SWE in assessing rigidity in PD. METHODS: A total of 63 subjects (44 patients with rigidity-dominant PD and 19 right-dominant-hand normal controls with matched age) were enrolled, and each underwent ultrasound SWE testing. The tests were conducted on the brachioradialis (BR) and biceps brachii (BB) on the more affected side in patients with PD and on the right side in normal controls. Differences in quantitative shear wave velocity (SWV) between patients with PD and normal controls were determined. The relationship of muscle SWV with joint rigidity, UPDRSIII, disease duration, sex, and age in patients with PD was analyzed. The intraclass correlation coefficient (ICC) was used to evaluate the reliability of SWE in assessing muscle stiffness in patients with PD. RESULTS: The mean SWVs of the BB and BR were higher in the PD group (3.65±0.46 and 4.62±0.89 m/s, respectively) than in normal controls (2.79±0.37 and 3.26±0.40 m/s, respectively). Stiffness in BR and BB was correlated with the upper-limb joint rigidity, UPDRSIII, and disease duration but not with sex or age in the PD group. The intraobserver correlation coefficients (ICCs) for interobserver and intraobserver variations in measuring SWV were 0.85 (95% confidence interval 0.56-0.95) and 0.85 (95% confidence interval 0.58-0.95), respectively, for BR and 0.90 (95% confidence interval 0.73-0.97) and 0.86 (95% confidence interval 0.61-0.95), respectively, for BB. CONCLUSIONS: SWV is associated with joint rigidity and disease duration, indicating that SWE can be potentially used as an objective and quantitative tool for evaluating rigidity.

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16.

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease.

Effect of Sleep-Disordered Breathing During Rapid Eye Movement Sleep and Non-Rapid Eye Movement sleep on Acute Ischemic Stroke.

OBJECTIVES: Sleep-disordered breathing adversely impacts stroke outcomes. We investigated whether sleep-disordered breathing during rapid eye movement sleep and non-rapid eye movement sleep differentially influenced stroke outcomes. MATERIALS AND METHODS: Acute ischemic stroke patients who finished polysomnography within 14 days of stroke onset from April 2010 to August 2018 were reviewed. Patients were divided into four groups according to apnea-hypopnea index during rapid eye movement sleep and non-rapid eye movement sleep. The modified Rankin Scale was used to evaluate short-term outcome. During January and April 2019, another follow-up was performed for long-term outcomes, including stroke-specific quality-of-life scale, modified Rankin Scale, stroke recurrence and death. RESULTS: Of 140 patients reviewed, 109 were finally recruited. Although patients with sleep-disordered breathing during non-rapid eye movement sleep only and with sleep-disordered breathing during both rapid eye movement sleep and non-rapid eye movement sleep had higher apnea-hypopnea indices and more disrupted sleep structures, short-term and long-term outcomes did not significantly different between four groups. In Logistic regression analysis, apnea-hypopnea index (p = 0.013, OR 1.023, 95%CI 1.005-1.042) was found independently associated with short-term outcome. Rapid eye movement sleep latency (p = 0.045, OR 0.994, 95%CI 0.987-1.000) was found independently associated with quality of life. Apnea-hypopnea indices during rapid eye movement sleep or non-rapid eye movement sleep were not significantly associated with short-term or long-term outcomes. CONCLUSIONS: Apnea-hypopnea index is an independent risk factor of short-term outcome of acute ischemic stroke while sleep-disordered breathing during rapid eye movement sleep and non-rapid eye movement sleep do not affect stroke outcomes differently.

The Evi5 oncogene promotes laryngeal cancer cells proliferation by stabilizing c-Myc protein.

BACKGROUND: The Ecotropic viral integration site 5 (Evi5) is recognized as a potential oncogene and a cell cycle regulator. Evi5 regulates the abundance of Emi1, an inhibitor of the anaphase-promoting complex/cyclosome, to govern mitotic fidelity. Evi5 has been shown to be dysregulated in several cancer types. However, the expression and biological function of Evi5 in human laryngeal squamous cell carcinoma (LSCC) are still unknown. METHODS: Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate Evi5 knockout (KO) LSCC cells. The proliferation and cell cycle distribution of LSCC cells was determined. The effect of Evi5 on LSCC tumor growth in vivo was studied in a tumor xenograft model in mice. The interaction between Evi5 and c-Myc was detected by immunoprecipitation (IP) assay. Luciferase assay was used to determine the transcriptional activity of c-Myc. RESULTS: Here, we show that Evi5 controls LSCC tumorigenesis via the stabilization of c-MYC oncogene. CRISPR-mediated knockout (KO) of Evi5 decreased the proliferation and decreased colony formation ability of LSCC cells. Knockout of Evi5 caused increased G1 phase and decreased S phase cells. In the tumor-bearing nude mice, The transplanted tumors originated from Evi5-KO TU212 cells were significantly decreased when compared with control TU212 cells. At the molecular level, we found that Evi5 interacted with c-MYC and Evi5 antagonized E3 ligase FBXW7-mediated ubiquitination and degradation of c-Myc protein, and promoted c-Myc-dependent transactivation. CONCLUSION: Given the critical role of c-Myc in tumorigenesis, our data suggest that Evi5 is a potential therapeutic target in LSCC, and inhibition of Evi5 should be a prospective strategy for LSCC therapy.

Propionate enhances the expression of key genes involved in the gluconeogenic pathway in bovine intestinal epithelial cells.

Approximately 15 to 50% of short-chain fatty acids (SCFA) reach the ruminant small intestine. Previous research suggests that activation of small intestinal gluconeogenesis induced by propionate has beneficial effects on energy homeostasis. However, the regulatory effect of propionate on key gluconeogenic genes in enterocytes of the bovine small intestine remains less known. Therefore, the purpose of this study was to establish the long-term cultures of bovine intestinal epithelial cells (BIEC) from bovine jejunum tissue using SV40T (1:200; Santa Cruz, Shanghai, China) and investigate the regulatory effect of propionate on the key gluconeogenic genes in BIEC. Our study showed that long-term BIEC cultures were established by SV40T-induced immortalization. Immortal BIEC were distinguished by the expression of cytokeratin 18, villin, fatty acid binding protein 2, and small intestine peptidase. The mRNA expression of genes involved in the SCFA transporters, monocarboxylate transporter 4, and Na+/H+ exchanger isoforms 1 were significantly elevated with 20 mM SCFA compared with untreated controls. In addition, BIEC exhibited significant uptake of propionate and butyrate from the culture medium. Remarkably, 3 mM propionate induced profound changes in mRNA level of key genes involved in gluconeogenesis, including phosphoenolpyruvate carboxykinase 2, pyruvate carboxylase, fructose-1,6-bisphosphatase 1, and peroxisome proliferator-activated receptor-γ coactivator 1α. Additionally, 3 mM propionate enhanced the expression of PGC1A mRNA at 3, 6, 12, and 24 h of incubation. These findings suggest that propionate controls the mRNA expression of genes involved in key enzymes for gluconeogenesis in the enterocytes of bovines.

SVM-Enabled Intelligent Genetic Algorithmic Model for Realizing Efficient Universal Feature Selection in Breast Cyst Image Acquired via Ultrasound Sensing Systems.

In recent years, there are several cost-effective intelligent sensing systems such as ultrasound imaging systems for visualizing the internal body structures of the body. Further, such intelligent sensing systems such as ultrasound systems have been deployed by medical doctors around the globe for efficient detection of several diseases and disorders in the human body. Even though the ultrasound sensing system is a useful tool for obtaining the imagery of various body parts, there is always a possibility of inconsistencies in these images due to the variation in the settings of the system parameters. Therefore, in order to overcome such issues, this research devises an SVM-enabled intelligent genetic algorithmic model for choosing the universal features with four distinct settings of the parameters. Subsequently, the distinguishing characteristics of these features are assessed utilizing the Sorensen-Dice coefficient, T-test, and Pearson's R measure. It is apparent from the results of the SVM-enabled intelligent genetic algorithmic model that this approach aids in the effectual selection of universal features for the breast cyst images. In addition, this approach also accomplishes superior accuracy in the classification of the ultrasound image for four distinct settings of the parameters.