Regulation of ctla-4 and pd-l1 expression in relapsing-remitting multiple sclerosis patients after treatment with fingolimod, ifnβ-1α, glatiramer acetate, and dimethyl fumarate drugs

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system (CNS) that is characterized by inflammation which typically results in significant impairment in most patients. Immune checkpoints act as co-stimulatory and co-inhibitory molecules and play a fundamental role in keeping the equilibrium of the immune system. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) and Programmed death-ligand 1 (PD-L1), as inhibitory immune checkpoints, participate in terminating the development of numerous autoimmune diseases, including MS. We assessed the CTLA-4 and PD-L1 gene expression in the different cell types of peripheral blood mononuclear cells of MS patients using single-cell RNA-seq data. Additionally, this study outlines how CTLA-4 and PD-L1 expression was altered in the PBMC samples of relapsing-remitting multiple sclerosis (RRMS) patients compared to the healthy group. Finally, it investigates the impact of various MS-related treatments in the CTLA-4 and PD-L1 expression to restrain autoreactive T cells and stop the development of MS autoimmunity

Misinformation, Trust, and Use of Ivermectin and Hydroxychloroquine for COVID-19

Importance The COVID-19 pandemic has been notable for the widespread dissemination of misinformation regarding the virus and appropriate treatment. Objective To quantify the prevalence of non–evidence-based treatment for COVID-19 in the US and the association between such treatment and endorsement of misinformation as well as lack of trust in physicians and scientists. Design, Setting, and Participants This single-wave, population-based, nonprobability internet survey study was conducted between December 22, 2022, and January 16, 2023, in US residents 18 years or older who reported prior COVID-19 infection. Main Outcome and Measure Self-reported use of ivermectin or hydroxychloroquine, endorsing false statements related to COVID-19 vaccination, self-reported trust in various institutions, conspiratorial thinking measured by the American Conspiracy Thinking Scale, and news sources. Results A total of 13 438 individuals (mean [SD] age, 42.7 [16.1] years; 9150 [68.1%] female and 4288 [31.9%] male) who reported prior COVID-19 infection were included in this study. In this cohort, 799 (5.9%) reported prior use of hydroxychloroquine (527 [3.9%]) or ivermectin (440 [3.3%]). In regression models including sociodemographic features as well as political affiliation, those who endorsed at least 1 item of COVID-19 vaccine misinformation were more likely to receive non–evidence-based medication (adjusted odds ratio [OR], 2.86; 95% CI, 2.28-3.58). Those reporting trust in physicians and hospitals (adjusted OR, 0.74; 95% CI, 0.56-0.98) and in scientists (adjusted OR, 0.63; 95% CI, 0.51-0.79) were less likely to receive non–evidence-based medication. Respondents reporting trust in social media (adjusted OR, 2.39; 95% CI, 2.00-2.87) and in Donald Trump (adjusted OR, 2.97; 95% CI, 2.34-3.78) were more likely to have taken non–evidence-based medication. Individuals with greater scores on the American Conspiracy Thinking Scale were more likely to have received non–evidence-based medications (unadjusted OR, 1.09; 95% CI, 1.06-1.11; adjusted OR, 1.10; 95% CI, 1.07-1.13). Conclusions and Relevance In this survey study of US adults, endorsement of misinformation about the COVID-19 pandemic, lack of trust in physicians or scientists, conspiracy-mindedness, and the nature of news sources were associated with receiving non–evidence-based treatment for COVID-19. These results suggest that the potential harms of misinformation may extend to the use of ineffective and potentially toxic treatments in addition to avoidance of health-promoting behaviors

Expression and characterization of a novel recombinant cytotoxin II from Naja naja oxiana venom: A potential treatment for breast cancer

Breast cancer (BC) is among the leading causes of mortality from cancer in women. Many of the available anticancer drugs have various side effects. Therefore, researchers are seeking novel anticancer agents particularly from natural compounds and in this regard, snake venom is still one of the main sources of drug discovery. Previous studies showed potential anticancer effects of Cytotoxin II (CTII) from Naja naja oxiana against the different types of cancers. In this study, a pET-SUMO-CTII vector was transformed into SHuffle® T7 Express, an Escherichia coli strain, for recombinant protein expression (rCTII) and the cytotoxic effects of this protein was assessed in MCF-7 cells. The flow cytometry assay was applied to measure the apoptosis and cell cycle. Also, mRNA levels of the Bax, Bcl2, P53, caspase-3, caspase-8, caspase-9, caspase-10, matrix metalloproteinases (MMP)-3, and MMP-9 were analyzed by quantitative real-time PCR to determine the underlying cellular pathways affected by rCTII. The results of this study showed that treatment with 4 μg mL−1 of rCTII enhanced apoptosis through the intrinsic and extrinsic pathways. Also, the increase of the cells' proportion in the sub-G1 phase as well as a reduction in S phase was observed. In addition, the expression of MMP-3 and MMP-9 was decreased in the treated group in comparison to the control group that may contribute to the reduced migratory ability of tumor cells. These experimental results indicate that rCTII has anti-proliferative potential, and so this protein could be a potential drug for BC therapy in combination with other drugs

Community Mobility and Depressive Symptoms During the COVID-19 Pandemic in the United States

Importance Marked elevation in levels of depressive symptoms compared with historical norms have been described during the COVID-19 pandemic, and understanding the extent to which these are associated with diminished in-person social interaction could inform public health planning for future pandemics or other disasters. Objective To describe the association between living in a US county with diminished mobility during the COVID-19 pandemic and self-reported depressive symptoms, while accounting for potential local and state-level confounding factors. Design, Setting, and Participants This survey study used 18 waves of a nonprobability internet survey conducted in the United States between May 2020 and April 2022. Participants included respondents who were 18 years and older and lived in 1 of the 50 US states or Washington DC. Main Outcome and Measure Depressive symptoms measured by the Patient Health Questionnaire-9 (PHQ-9); county-level community mobility estimates from mobile apps; COVID-19 policies at the US state level from the Oxford stringency index. Results The 192 271 survey respondents had a mean (SD) of age 43.1 (16.5) years, and 768 (0.4%) were American Indian or Alaska Native individuals, 11 448 (6.0%) were Asian individuals, 20 277 (10.5%) were Black individuals, 15 036 (7.8%) were Hispanic individuals, 1975 (1.0%) were Pacific Islander individuals, 138 702 (72.1%) were White individuals, and 4065 (2.1%) were individuals of another race. Additionally, 126 381 respondents (65.7%) identified as female and 65 890 (34.3%) as male. Mean (SD) depression severity by PHQ-9 was 7.2 (6.8). In a mixed-effects linear regression model, the mean county-level proportion of individuals not leaving home was associated with a greater level of depression symptoms (β, 2.58; 95% CI, 1.57-3.58) after adjustment for individual sociodemographic features. Results were similar after the inclusion in regression models of local COVID-19 activity, weather, and county-level economic features, and persisted after widespread availability of COVID-19 vaccination. They were attenuated by the inclusion of state-level pandemic restrictions. Two restrictions, mandatory mask-wearing in public (β, 0.23; 95% CI, 0.15-0.30) and policies cancelling public events (β, 0.37; 95% CI, 0.22-0.51), demonstrated modest independent associations with depressive symptom severity. Conclusions and Relevance In this study, depressive symptoms were greater in locales and times with diminished community mobility. Strategies to understand the potential public health consequences of pandemic responses are needed

The expression pattern of VISTA in the PBMCs of relapsing-remitting multiple sclerosis patients: A single-cell RNA sequencing-based study

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS). Dysregulated immune responses have been implicated in MS development. Growing evidence has indicated that inhibitory immune checkpoint molecules can substantially regulate immune responses and maintain immune tolerance. V-domain Ig suppressor of T cell activation (VISTA) is a novel inhibitory immune checkpoint molecule that can suppress immune responses; however, its expression pattern in the peripheral blood mononuclear cells (PBMCs) of relapsing-remitting multiple sclerosis (RRMS) has not thoroughly been studied. Herein, we evaluated Vsir expression in PBMCs of RRMS patients and characterized the expression pattern of the Vsir in the PBMCs of MS patients. Besides, we investigated the effect of fingolimod, IFNβ-1α, glatiramer acetate (GA), and dimethyl fumarate (DMF) on Vsir expression in PBMCs of RRMS patients. Our results have shown that Vsir expression is significantly downregulated in the PBMCs of patients with RRMS. Besides, the single-cell RNA sequencing results have demonstrated that Vsir expression is downregulated in classical monocyte, intermediate monocytes, non-classical monocytes, myeloid DCs (mDC), Plasmacytoid dendritic cells (pDCs), and naive B-cells of PBMCs of MS patients compared to the control. In addition, DMF, IFNβ-1α, and GA have significantly upregulated Vsir expression in the PBMCs of RRMS patients. Collectively, the current study has shed light on Vsir expression in the PBMCs of MS patients; however, further studies are needed to elucidate the significance of VISTA in the mentioned immune cells

Functionalized metallic 2D transition metal dichalcogenide-based solid-state electrolyte for flexible all-solid-state supercapacitors

Highly efficient and durable flexible solid-state supercapacitors (FSSSCs) are emerging as low-cost devices for portable and wearable electronics due to the elimination of leakage of toxic/corrosive liquid electrolytes and their capability to withstand elevated mechanical stresses. Nevertheless, the spread of FSSSCs requires the development of durable and highly conductive solid-state electrolytes, whose electrochemical characteristics must be competitive with those of traditional liquid electrolytes. Here, we propose an innovative composite solid-state electrolyte prepared by incorporating metallic two-dimensional group-5 transition metal dichalcogenides, namely, liquid-phase exfoliated functionalized niobium disulfide (f-NbS2) nanoflakes, into a sulfonated poly(ether ether ketone) (SPEEK) polymeric matrix. The terminal sulfonate groups in f-NbS2 nanoflakes interact with the sulfonic acid groups of SPEEK by forming a robust hydrogen bonding network. Consequently, the composite solid-state electrolyte is mechanically/dimensionally stable even at a degree of sulfonation of SPEEK as high as 70.2%. At this degree of sulfonation, the mechanical strength is 38.3 MPa, and thanks to an efficient proton transport through the Grotthuss mechanism, the proton conductivity is as high as 94.4 mS cm–1 at room temperature. To elucidate the importance of the interaction between the electrode materials (including active materials and binders) and the solid-state electrolyte, solid-state supercapacitors were produced using SPEEK and poly(vinylidene fluoride) as proton conducting and nonconducting binders, respectively. The use of our solid-state electrolyte in combination with proton-conducting SPEEK binder and carbonaceous electrode materials (mixture of activated carbon, single/few-layer graphene, and carbon black) results in a solid-state supercapacitor with a specific capacitance of 116 F g–1 at 0.02 A g–1, optimal rate capability (76 F g–1 at 10 A g–1), and electrochemical stability during galvanostatic charge/discharge cycling and folding/bending stresses

Cytotoxic t-lymphocyte antigen-4 in colorectal cancer: Another therapeutic side of capecitabine

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an inhibitory immune checkpoint that can be expressed in tumor-infiltrating lymphocytes and colorectal cancer (CRC) cells. This immune checkpoint can attenuate anti-tumoral immune responses and facilitate tumor growth and metastasis. Although capecitabine is an effective chemotherapeutic agent for treating CRC, its effect on the tumoral CTLA-4 expression remains unclear. In the current research, we applied the GSE110224 and GSE25070 datasets to characterize CTLA-4 expression in CRC patients. Then, we analyzed CTLA-4 expression in CRC samples, HT-29, HCT-166, and SW480 cell lines using real-time PCR. Our bioinformatic results have highlighted the overexpression of CTLA-4 in the CRC tissues compared to the adjacent non-tumoral tissues. Our in vitro studies have indicated that SW480 cells can sub-stantially overexpress CTLA-4 compared to HT-29 and HCT 116 cells. In addition, capecitabine can remarkably downregulate the expression of CTLA-4 in SW480 cells. Collectively, capecitabine can inhibit the expression of CTLA-4 in CRC cells and might bridge the immunotherapy approaches with chemotherapy

Efficient RT-QuIC seeding activity for \u3b1-synuclein in olfactory mucosa samples of patients with Parkinson's disease and multiple system atrophy

Background: Parkinson's disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal \u3b1-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either \u3b1-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of \u3b1-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM). Methods: We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant \u3b1-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce \u3b1-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP. Results: Our results showed that a significant percentage of MSA and PD samples induced \u3b1-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination. Conclusions: Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for \u3b1-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages