COVID-19 hospitalization increases the risk of developing glioblastoma: a bidirectional Mendelian-randomization study.

Background: As a result of the COVID-19 pandemic, patients with glioblastoma (GBM) are considered a highly vulnerable population. Despite this, the extent of the causative relationship between GBM and COVID-19 infection is uncertain. Methods: Genetic instruments for SARS-CoV-2 infection (38,984 cases and 1,644,784 control individuals), COVID-19 hospitalization (8,316 cases and 1,549,095 control individuals), and COVID-19 severity (4,792 cases and 1,054,664 control individuals) were obtained from a genome-wide association study (GWAS) from European populations. A total of 6,183 GBM cases and 18,169 controls from GWAS were enrolled in our study. Their associations were evaluated by applying Mendelian randomization (MR) including IVW meta-analysis, MR-Egger regression, and weighted-median analysis. To make the conclusions more robust and reliable, sensitivity analyses were performed. Results: Our results showed that genetically predicted COVID-19 hospitalization increases the risk of GBM (OR = 1.202, 95% CI = 1.035-1.395, p = 0.016). In addition, no increased risk of SARS-CoV-2 infection, COVID-19 hospitalization and severity were observed in patients with any type of genetically predicted GBM. Conclusion: Our MR study indicated for the first time that genetically predicted COVID-19 hospitalization was demonstrated as a risk factor for the development of GBM.

Cerebrospinal fluid protein levels are elevated 100 times in a Leptomeningeal metastasis patient: a case report and literature review.

Leptomeningeal metastasis (LM) has a high degree of malignancy and high mortality. We describe a patient admitted to hospital with acute lower extremity weakness, dysuria, and high intracranial pressure. Enhanced magnetic resonance imaging (MRI) showed extensive enhancement of the leptomeningeal and spinal meninges with multiple nodular changes and extensive fusion. His cerebrospinal fluid (CSF) was yellow and cloudy, the Pandy test was strongly positive (++++), the protein was 46 g/L (normal range 0.15-0.45 g/L), which attracted our attention. Initially, miliary TB with associated tuberculous meningitis (TBM) was diagnosed, and neurosarcoidosis cannot be ruled out. After poor therapeutic effect of standard antituberculosis (anti-TB) therapy, further inspection found that malignant cells were detected by cerebrospinal fluid (CSF) cytology. PET/CT suggested the diagnosis of LM. The purpose of this paper is to describe the characteristics of atypical diffuse LM. In conclusion, when patient with unexplained high levels of CSF protein, it is necessary to be alert to the diagnosis of LM. Multiple examinations of fresh CSF are helpful to increase the positive detection rate of tumor cells. Early diagnosis and active treatment are conducive to improving survival rate.

A PARP1-related prognostic signature constructing and PARP-1 inhibitors screening for glioma.

The current standard treatments of glioma include surgical resection, supplemented with radiotherapy and chemotherapy, but the prognosis is poor. PARP-1 (Poly ADP-ribose polymerase 1) is a hot spot for cancer-targeted therapy and was reported to be significantly elevated in glioma. In this study, we analyzed the role of PARP-1 in DNA damage repair, constructed a PARP1-related DNA-repair prognostic signature (DPS), and screened targeted drugs for glioma. RNA-seq data of 639 glioma samples were downloaded from the GEO (Gene Expression Omnibus) database and divided into PARP1_H and PARP1_L according to the front and rear thirds of the expression level of PARP-1. First, we systematically analyzed the influence of PARP-1 on DNA damage repair, prognosis, and chemoradiotherapy sensitization of glioma. All glioma patients and patients with radiotherapy or chemotherapy had a better prognosis in PARP1_L than in PARP1_H. Next, differentially expressed DNA-repair related genes (DEGs) were identified between PARP1_H and PARP1_L by LASSO (Least Absolute Shrinkage and Selection Operator) Cox analysis and applied for constructing DPS. Based on the four-gene DPS, we then developed a new nomogram to assess overall survival in glioma patients. Additionally, PARP-1 was proved an effective target for glioma therapy. So, a series of computer-aided techniques, including Discovery Studio 4.5, Schrodinger, and PyMol, were applied for the virtual screening of favorable PARP-1 inhibitors. In conclusion, this study investigated the effect of PARP-1 on glioma prognosis and the sensitization effect of radiotherapy and chemotherapy, established a novel nomogram to evaluate the overall survival of glioma patients, and further explored targeted therapy for glioma.

Case Report: A Case of Adult Methylmalonic Acidemia With Bilateral Cerebellar Lesions Caused by a New Mutation in MMACHC Gene.

Methylmalonic acidemia is a severe heterogeneous disorder of methylmalonate and cobalamin (Cbl; vitamin B12) metabolism with poor prognosis. Around 90% of reported patients with methylmalonic acidemia (MMA) are severe infantile early onset, while cases with late-onset MMA have been rarely reported. Few reported late-onset MMA patients presented with atypical clinical symptoms, therefore, often misdiagnosed if without family history. Herein, we report a 29-year-old female who was admitted to our hospital due to symptoms manifested as encephalitis. The brain MRI showed symmetrical bilateral cerebellar lesions with Gd enhancement. Laboratory tests showed significantly elevated levels of homocysteine and methylmalonic acid. A genetic analysis identified a novel homozygous mutation (c.484G>A; p.Gly162 Arg) in the MMACHC gene. The patient was diagnosed with MMA, and her symptoms improved dramatically with intramuscular adenosine cobalamin treatment. In conclusion, for patients with symmetrical lesions in the brain, the possibility of metabolic diseases should be considered, detailed medical and family history should be collected, and metabolic screening tests as well as gene tests are necessary for correct diagnosis. The mutation diversity in MMACHC gene is an important factor leading to the heterogeneity of clinical manifestations of patients with MMA.

Computational research of Belnacasan and new Caspase-1 inhibitor on cerebral ischemia reperfusion injury.

Cerebral ischemia-reperfusion injury is one of the most severe diseases in terms of mortality and disability, which seriously threatens human life and health. In clinical treatment, drug thrombolysis or mechanical interventional thrombolysis are used to quickly restore the blood supply of ischemic brain tissue. But with the rapid recovery of blood flow, complex pathophysiological processes such as oxidative stress and inflammation will further aggravate brain tissue damage, namely cerebral ischemia-reperfusion injury, for which there is no effective treatment. Recent studies have shown that the medical community has paid the role of inflammation and pyroptosis in cerebral ischemia-reperfusion injury more and more attention. And Caspase-1 was found to play a vital role in regulating inflammation pathways and pyroptosis in many inflammation-associated diseases, especially in cerebral ischemia-reperfusion injury. Not only that, Caspase-1 inhibitors have been shown to reduce the damage of cerebral ischemia-reperfusion injury by inhibiting inflammation and pyroptosis. And the Caspase-1 inhibitor, Belnacasan, has been proved to modify the active site of Caspase-1 and lead to the blocking of Caspase-1, thus correlating with tissue protection of inflammatory diseases in animal models. Therefore, it's essential to screen and design potential Caspase-1 inhibitors to reduce cerebral ischemia-reperfusion injury and protect brain function by reducing inflammation and pyroptosis, which provides a new idea for clinical treatment of the cerebral ischemia-reperfusion injury. This study applied a group of computer-aided technology, such as Discovery Studio 4.5, Schrodinger, and PyMol, to screen and assess potential Caspase-1 inhibitors. Moreover, the ADME (absorption, distribution, metabolism, excretion) and TOPKAT (Toxicity Prediction by Computer Assisted Technology) molecules of Discovery Studio 4.5 were conducted to evaluate molecules' pharmacological and toxicological features. Then, precise molecular docking was applied to assess the binding mechanism and affinity between Caspase-1 and selected compounds. Besides, molecular dynamics simulations were performed to determine the stability of ligand-receptor complexes in the natural environment. In summary, this study lists promising drug candidates and their pharmacological properties, promoting the development of Caspase-1 inhibitors and deepening the understanding of the interaction between inhibitors and Caspase-1.

Computational research of mTORC1 inhibitor on cerebral ischemia-reperfusion injury.

Ischemic stroke contributes to more than 80% of all strokes and has the four characteristics of high prevalence, high disability, high mortality, and high recurrence. Stroke is a preventable and controllable disease. In addition to controlling the primary disease, effective prevention and control measures need to be given to the occurrence and development of stroke. With the development and progress of modern treatment methods for ischemic stroke, the mortality and disability rate have decreased significantly. At present, the main treatment methods for ischemic stroke include thrombolysis, thrombus removal at the ultra-early stage, and treatment of improving collateral circulation in the acute phase. However, the ultra-early and early blood reperfusion involves reperfusion injury, which will cause secondary nerve damage, which is called cerebral ischemia/reperfusion injury (CIRI). Studies have found that autophagy is involved in the entire process of CIRI and can reduce the damage of CIRI. The mammalian target of Rapamycin (mTORC1) is the primary signal pathway regulating autophagy. And the mTORC1 inhibitor, Rapamycin, has been proved to exert neuroprotective effects in the ultra-early and early cerebral ischemia-reperfusion. Therefore, screening and designing mTORC1 inhibitors is very important to control reperfusion injury and reduce neuronal death and apoptosis. In this research, plenty of computer-assisted was applied to virtually screen and select potential mTORC1's inhibitors. We used Libdock to screen the structure and performed toxicity predictions, ADME (absorption, distribution, metabolism, excretion) to predict small molecules' pharmacological and toxicological properties. To assess the binding mechanism and affinity between the mTORC1 dimer and the ligand, molecular docking was performed. Then, the pharmacophore of small molecules in the docking conformation with the protein was supplemented by Schrodinger. Additionally, molecular dynamics simulations were conducted to assess if the ligand-receptor complex was stable in a natural environment. Furthermore, an experiment was performed to verify the inhibitory effect of compound 1 and compound 2 on mTOR protein. All in all, the study provides a hand of candidate drugs as well as pharmacological properties, which can play an essential role in mTORC1 inhibitors.

Computational study on new natural compound agonists of dopamine receptor.

Dopamine receptor, a polypeptide chain composed of 7 hydrophobic transmembrane regions, is a new and vital drug target, especially Dopamine receptor 2(D2). Targeting dopamine receptors, Dopamine receptor agonists are a class of drugs similar in function and structure to dopamine and can directly act on dopamine receptors and activate it. Clinically, Dopamine receptor agonist drugs have achieved significant therapeutic effects on prolactinoma and Parkinson's Disease. In the study, we virtually screened a series of potential effective agonists of Dopamine receptor by computer techniques. Firstly, we used the Molecular Docking (LibDock) step to screen out some molecules that can dock well with the protein. Then, analysis of toxicity prediction and ADME (adsorption, distribution, metabolism and excretion) were carried out. More precise molecular docking (CDOCKER) and 3-Dimensional Quantitative Structure-Activity Relationship Modeling Study(3D-QSAR) pharmacophore generation were implemented to research and explore these compounds' binding mechanism with Dopamine receptor. Last but not least, to assess compound's binding stabilities, we carried out a molecular dynamic analysis. As the results show, two compounds (ZINC000008860530 and ZINC000004096987) from the small molecule database (ZINC database) were potential effective agonists of Dopamine receptor. These two compounds can combine with Dopamine receptor with higher affinity and proved to be no toxic. The cell experiment showed that two compounds could inhibit the proliferation and PRL secretion of MMQ cells (pituitary tumor cells). Thus, this study provided valuable information about Dopamine receptor agonist-based drug discovery. So, this study will benefit patients with prolactinoma and Parkinson's disease a lot.

Broadband Spin-Dependent Directional Coupler via Single Optimized Metallic Catenary Antenna.

With the rapid development of on-chip optics, integrated optical devices with better performance are desirable. Waveguide couplers are the typical integrated optical devices, allowing for the fast transmission and conversion of optical signals in a broad working band. However, traditional waveguide couplers are limited by the narrow operation band to couple the spatial light into the chip and the fixed unidirectional transmission of light flow. Furthermore, most of the couplers only realize unidirectional transmission under the illumination of the linear polarized light. In this work, a broadband polarization directional coupler based on a metallic catenary antenna integrated on a silicon-on-insulator (SOI) waveguide has been designed and demonstrated under the illumination of the circularly polarized light. By applying the genetic algorithm to optimize the multiple widths of the metallic catenary antenna, the numerical simulation results show that the extinction ratio of the coupler can be maintained larger than 18 dB in a wide operation band of 300 nm (from 1400 to 1700 nm). Moreover, the coupler can couple the spatial beam into the plane and transmit in the opposite direction by modulating the rotation direction of the incident light. The broadband polarization directional coupler might have great potential in integrated optoelectronic devices and on-chip optical devices.

Efficient planar plasmonic directional launching of linearly polarized light in a catenary metasurface.

Efficient directional excitation of planar surface plasmon polaritons (SPPs) has important and wide applications in micro-nano photonic technology. Recently, by using the geometric phase and spin-orbit interaction, catenary structures have been applied to the directional control of SPPs and showed excellent performance. However, due to the need to use the chirality of the subwavelength catenary apertures, the previously studied systems were only suitable for circularly polarized light. Here, based on a catenary metasurface we theoretically design and experimentally demonstrate a SPP directional launcher used for linearly polarized light. The numerical calculation results show that the directional extinction ratio reaches up to 35 dB under the normal incidence of p-polarized light at 750 nm which is 5 dB higher than the maximum extinction ratio in the existing results as we know. The experimental results show that the resonant wavelength position, bandwidth and extinction ratio change trend well match the theoretical results. The physical mechanism is analyzed and it is found that the asymmetric quadrupole mode is the key factor leading to the directional SPPs which is completely different from the geometric phase modulation mechanism to excite the directional SPPs of circularly polarized light in the catenary metasurface. These principles and methods could open new doors for future chip-level photonic device or system design such as multi-directional beam splitters and polarization detectors.