Alpha-synuclein (αSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons αSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following αSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic αSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against αSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.Parkinson's disease (PD) is the second most common neurodegenerative disorder (1,2). Accruing evidence points to a causative role for the presynaptic protein alpha-synuclein (αSyn) in PD pathogenesis. αSyn is a major constituent of Lewy Bodies-cellular inclusions that are the hallmark pathological feature of PD and other neurodegenerative disorders collectively

Neurotransmitter released from neurons is known to signal to neighbouring neurons and glia. Here we demonstrate an additional signalling pathway in which glutamate is released from astrocytes and causes an NMDA (N-methyl-D-aspartate) receptor-mediated increase in neuronal calcium. Internal calcium was elevated and glutamate release stimulated by application of the neuroligand bradykinin to cultured astrocytes. Elevation of astrocyte internal calcium was also sufficient to induce glutamate release. To determine whether this released glutamate signals to neurons, we studied astrocyte-neuron co-cultures. Bradykinin significantly increased calcium levels in neurons co-cultured with astrocytes, but not in solitary neurons. The glutamate receptor antagonists D-2-amino-5-phosphonopentanoic acid and D-glutamylglycine prevented bradykinin-induced neuronal calcium elevation. When single astrocytes were directly stimulated to increase internal calcium and release glutamate, calcium levels of adjacent neurons were increased; this increase could be blocked by D-glutamylglycine. Thus, astrocytes regulate neuronal calcium levels through the calcium-dependent release of glutamate.

AbstractBackgroundAs the number of patients increases, there is a growing understanding of the form of pneumonia sustained by the 2019 novel coronavirus (SARS-CoV-2), which has caused an outbreak in China. Up to now, clinical features and treatment of patients infected with SARS-CoV-2 have been reported in detail. However, the relationship between SARS-CoV-2 and coagulation has been scarcely addressed. Our aim is to investigate the blood coagulation function of patients with SARS-CoV-2 infection.MethodsIn our study, 94 patients with confirmed SARS-CoV-2 infection were admitted in Renmin Hospital of Wuhan University. We prospectively collect blood coagulation data in these patients and in 40 healthy controls during the same period.ResultsAntithrombin values in patients were lower than that in the control group (p < 0.001). The values of D-dimer, fibrin/fibrinogen degradation products (FDP), and fibrinogen (FIB) in all SARS-CoV-2 cases were substantially higher than those in healthy controls. Moreover, D-dimer and FDP values in patients with severe SARS-CoV-2 infection were higher than those in patients with milder forms. Compared with healthy controls, prothrombin time activity (PT-act) was lower in SARS-CoV-2 patients. Thrombin time in critical SARS-CoV-2 patients was also shorter than that in controls.ConclusionsThe coagulation function in patients with SARS-CoV-2 is significantly deranged compared with healthy people, but monitoring D-dimer and FDP values may be helpful for the early identification of severe cases.

No abstract

Since the outbreak of coronavirus disease 2019 (COVID-19) in Wuhan, China, it has rapidly spread across many other countries. While the majority of patients were considered mild, critically ill patients involving respiratory failure and multiple organ dysfunction syndrome are not uncommon, which could result death. We hypothesized that cytokine storm is associated with severe outcome. We enrolled 102 COVID-19 patients who were admitted to Renmin Hospital (Wuhan, China). All patients were classified into moderate, severe and critical groups according to their symptoms. 45 control samples of healthy volunteers were also included. Inflammatory cytokines and C-Reactive Protein (CRP) profiles of serum samples were analyzed by specific immunoassays. Results showed that COVID-19 patients have higher serum level of cytokines (TNF-α, IFN-γ, IL-2, IL-4, IL-6 and IL-10) and CRP than control individuals. Within COVID-19 patients, serum IL-6 and IL-10 levels are significantly higher in critical group (n = 17) than in moderate (n = 42) and severe (n = 43) group. The levels of IL-10 is positively correlated with CRP amount (r = 0.41, P < 0.01). Using univariate logistic regression analysis, IL-6 and IL-10 are found to be predictive of disease severity and receiver operating curve analysis could further confirm this result (AUC = 0.841, 0.822 respectively). Our result indicated higher levels of cytokine storm is associated with more severe disease development. Among them, IL-6 and IL-10 can be used as predictors for fast diagnosis of patients with higher risk of disease deterioration. Given the high levels of cytokines induced by SARS-CoV-2, treatment to reduce inflammation-related lung damage is critical.

Graphene-based sp 2-carbon nanostructures such as carbon nanotubes and nanofibers can fail near their ideal strengths due to their exceedingly small dimensions. We have calculated the phonon spectra of graphene as a function of uniaxial tension by density functional perturbation theory to assess the first occurrence of phonon instability on the strain path, which controls the strength of a defect-free crystal at 0 K. Uniaxial tensile strain is applied in the x ͑nearest-neighbor͒ and y ͑second nearest-neighbor͒ directions, related to tensile deformation of zigzag and armchair nanotubes, respectively. The Young's modulus E = 1050 GPa and Poisson's ratio = 0.186 from our small-strain results are in good agreement with previous calculations. We find that in both x and y uniaxial tensions, phonon instabilities occur near the center of the Brillouin zone, at ͑ xx = 0.194, xx = 110 GPa, yy = −0.016͒ and ͑ yy = 0.266, yy = 121 GPa, xx = −0.027͒, respectively. Both soft phonons are longitudinal elastic waves in the pulling direction, suggesting that brittle cleavage fracture may be an inherent behavior of graphene and carbon nanotubes at low temperatures. We also predict that a phonon band gap will appear in highly stretched graphene, which could be a useful spectroscopic signature for highly stressed carbon nanotubes.

Background: The inflammatory response plays a critical role in coronavirus disease 2019 , and inflammatory cytokine storm increases the severity of COVID-19. Objective: To investigate the ability of interleukin-6 (IL-6), C-reactive protein (CRP), and procalcitonin (PCT) to predict mild and severe cases of COVID-19. Study design: This retrospective cohort study included 140 patients diagnosed with COVID-19 from January 18, 2020, to March 12, 2020. The study population was divided into two groups according to disease severity: a mild group (MG) (n = 107) and a severe group (SG) (n = 33). Data on demographic characteristics, baseline clinical characteristics, and the levels of IL-6, CRP, and PCT on admission were collected. Results: Among the 140 patients, the levels of IL-6, CRP, and PCT increased in 95 (67.9 %), 91 (65.0 %), and 8 (5.7 %) patients on admission, respectively. The proportion of patients with increased IL-6, CRP, and PCT levels was significantly higher in the SG than in the MG. Cox proportional hazard model showed that IL-6 and CRP could be used as independent factors to predict the severity of COVID-19. Furthermore, patients with IL-6 > 32.1 pg/mL or CRP > 41.8 mg/L were more likely to have severe complications. Conclusion:The serum levels of IL-6 and CRP can effectively assess disease severity and predict outcome in patients with COVID-19. BackgroundCoronavirus disease 2019 (COVID-19) is highly infectious and contagious. The first COVID-19 epidemic occurred in Wuhan, China, in December 2019 [1,2]. The epidemic was declared to be a public health emergency of international concern by the World Health Organization on January 30, 2020. The clinical manifestations change rapidly, and severe cases can lead to hypoxia, multiple organ dysfunction, and death. However, no reliable indicators are yet available to predict disease severity and progression. The objective of this study is to identify specific serological indicators that can be used for diagnosis and guidance of treatment decisions. ObjectiveTo investigate the ability of IL-6, CRP, and PCT to predict mild and severe cases of COVID-19. Study design Methods and definitionsThe General Hospital of Central Theater Command of People's Liberation Army was designated to treat COVID-19 patients. This single-center, retrospective observational study was approved by the institutional Research Ethics Committee (Process No. 2020-008-1). A total of 141 cases of COVID-19 were confirmed in this hospital between January 18, 2020, and March 12, 2020. All patients were confirmed positively by SARS-CoV-2 nucleic acid RT-PCR (Ct value≤38.0, BGI, Shenzhen, China) using specimens derived from oropharyngeal swabs or sputum, prior to or during the hospitalization. All patients were monitored via the electronic health information system, and clinical data were collected until March 12, 2020, the last follow-up date. Patients with severe disease were categorized based on the seventh edition of the Chinese National Health Commission [3] and should meet any of the following c...

No abstract