Background and Purpose
There is a need for effective anti‐COVID‐19 treatments, mainly for individuals at risk of severe disease such as the elderly and the immunosuppressed. Drug repositioning has ...proved effective in identifying drugs that can find a new application for the control of coronavirus disease, in particular COVID‐19. The purpose of the present study was to find synergistic antiviral combinations for COVID‐19 based on lethal mutagenesis.
Experimental Approach
The effect of combinations of remdesivir and ribavirin on the infectivity of SARS‐CoV‐2 in cell culture has been tested. Viral populations were monitored by ultra‐deep sequencing, and the decrease of infectivity as a result of the treatment was measured.
Key Results
Remdesivir and ribavirin exerted a synergistic inhibitory activity against SARS‐CoV‐2, quantified both by CompuSyn (Chou‐Talalay method) and Synergy Finder (ZIP‐score model). In serial passage experiments, virus extinction was readily achieved with remdesivir‐ribavirin combinations at concentrations well below their cytotoxic 50 value, but not with the drugs used individually. Deep sequencing of treated viral populations showed that remdesivir, ribavirin, and their combinations evoked significant increases of the number of viral mutations and haplotypes, as well as modification of diversity indices that characterize viral quasi‐species.
Conclusion and Implications
SARS‐CoV‐2 extinction can be achieved by synergistic combination treatments based on lethal mutagenesis. In addition, the results offer prospects of triple drug treatments for effective SARS‐CoV‐2 suppression.
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•Strawberry methanolic extract was rich in phenolic compounds and minerals.•Treatments significantly delayed amyloid β-protein induced paralysis in CL4176.•The extract reduced ...oxidative stress induced by AAPH in the wild strain.•Effects were mediated by DAF-16 and SKN-1 pathway signaling.•Strawberry could be an excellent ingredient to be used for functional food.
Bioactive compounds from strawberries have been associated with multiple healthy benefits. The present study aimed to assess chemical characterization of a methanolic extract of the Romina strawberry variety in terms of antioxidant capacity, polyphenols profile and chemical elements content. Additionally, potential toxicity, the effect on amyloid-β production and oxidative stress of the extract was in vivo evaluated in the experimental model Caenorhabditis elegans. Results revealed an important content in phenolic compounds (mainly ellagic acid and pelargonidin-3-glucoside) and minerals (K, Mg, P and Ca). The treatment with 100, 500 or 1000 μg/mL of strawberry extract did not show toxicity. On the contrary, the extract was able to delay amyloid β-protein induced paralysis, reduced amyloid-β aggregation and prevented oxidative stress. The potential molecular mechanisms present behind the observed results explored by RNAi technology revealed that DAF-16/FOXO and SKN-1/NRF2 signaling pathways were, at least partially, involved.
Zika virus (ZIKV), an emerging mosquito-borne flavivirus, has quickly spread in many regions around the world where dengue virus (DENV) is endemic. This represents a major health concern, given the ...high homology between these two viruses, which can result in cross-reactivity. The aim of this study was to determine the cross-reacting antibody response of the IgM and IgG classes against the recombinant envelope protein of ZIKV (rE-ZIKV) in sera from patients with acute-phase infection of different clinical forms of dengue, i.e., dengue fever (DF) and dengue hemorrhagic fever (DHF) (before the arrival of ZIKV in Mexico 2010), as well as acute-phase sera of ZIKV patients, together with the implications in neutralization and antibody-dependent enhancement. Differences in IgM responses were observed in a number of DF and DHF patients whose sera cross-reacted with the rE-ZIK antigen, with 42% recognition between acute-phase DHF and ZIKV but 27% recognition between DF and ZIKV. Regarding IgG antibodies, 71.5% from the DF group showed cross-reactivity to rE-ZIKV in contrast with 50% and only 25% of DHF and ZIKV serum samples, respectively, which specifically recognized the homologous antigen. The DHF group showed more enhancement of ZIKV infection of FCRγ-expressing cells compared to the DF group. Furthermore, the DHF group also showed a higher cross-neutralizing ability than that of DF. This is the first report where DF and DHF serum samples were evaluated for cross-reactivity against Zika protein and ZIKV. Furthermore, DENV serum samples cross-protect against ZIKV through neutralizing antibodies but at the same time mediate antibody-dependent enhancement in the sequential ZIKV infection.
The Dengue (DENV) and zika (ZIKV) virus infections are currently a public health concern. At present, there is no treatment or a safe and effective vaccine for these viruses. Hence, the development ...of new strategies as host-directed therapy is required. In this sense, Metformin (MET), an FDA-approved drug used for the treatment of type 2 diabetes, has shown an anti-DENV effect in vitro by activating AMPK and reducing HMGCR activity. In this study, MET treatment was evaluated during in vitro and in vivo ZIKV infection and compared to MET treatment during DENV infection. Our results demonstrated that MET has a broad in vitro antiviral spectrum. MET inhibited ZIKV infection in different cell lines, but it was most effective in inhibiting DENV and yellow fever virus (YFV) infection in Huh-7 cells. However, the drug failed to protect against ZIKV infection when AG129 immunodeficient mice were used as in vivo model. Interestingly, MET increased DENV-infected male mice's survival time, reducing the severe signs of the disease. Together, these findings indicate that, although MET was an effective antiviral agent to inhibit in vitro and in vivo DENV infection, it could only inhibit in vitro ZIKV infection.
The epidemic potential of Chikungunya virus (CHIKV) was recently made evident by its introduction and rapid expansion in the Caribbean and the Americas. We sought to gain a detailed understanding of ...the dynamics of the epidemic in Mexico, the country with the highest number of confirmed CHIKV cases in the Americas, and to characterise viral evolution at the population and intra-host level. Analysis of the spatiotemporal distribution of 2,739 diagnosed cases in Mexico from December 2014 to December 2015 showed a rapid nationwide expansion of the epidemic with focalisation in the South West of the country. We sequenced the envelope glycoprotein 1 gene (E1) from 25 patients using the Illumina MiSeq platform and report synonymous and non-synonymous consensus mutations. Bayesian phylogenetic analysis using 249 Asian lineage E1 sequences gave updated estimates of nucleotide substitution rates for E1 and time to most recent common ancestor of major lineages. The analysis indicates phylogenetically-related emergent Latin American clusters in South Western Mexico, Nicaragua and Honduras and transmission of American strains in the Pacific islands. Detailed analysis showed that intra-host changes in E1 mainly occurred in two variable regions (E1:189-220 and E1:349-358) in domains II and III, respectively, in residues involved in inter and intra-envelope spike interactions. At the population level, this study sheds light on the introduction and evolutionary dynamics of CHIKV in the Americas. At the intra-host level, this study identifies mutational hotspots of the E1 protein with implications for understanding the relationship between the CHIKV quasispecies, viral fitness and pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Experimental studies suggest that low-frequency (LF) (63 Hz) deep brain stimulation (DBS) of the substantia nigra pars reticulata (SNr) could be useful to regulate gait disorders refractory to ...medical treatment in Parkinson's disease (PD). The SNr neurons could act as high-frequency (HF) pacemakers within locomotor control systems. Currently, no specific therapies can treat gait disorders in PD with insufficient response to dopaminergic treatment.
To investigate whether LF-SNr-DBS combined with standard HF stimulation of the subthalamic nucleus (STN) is clinically relevant in improving gait disorders that no longer respond to levodopa in PD patients, compared with HF-STN or LF-SNr stimulation alone.
Patients received LF-SNr or HF-STN stimulation alone or combined (COMB) stimulation of both nuclei (crossover design). The nucleus to be stimulated was randomly assigned and clinical evaluations performed by a blinded examiner after three months follow-up for each. Clinical assessment included the Freezing of Gait questionnaire, Tinetti Balance and Walking Assessing tool, and Unified Parkinson's Disease Rating.
We included six patients (mean age 59.1 years, disease duration 16.1 years). All patients suffered motor fluctuations and dyskinesias. The best results were obtained with COMB in four patients (who preferred and remained with COMB over 3 years of follow-up) and with HF-STN in two patients. SNr stimulation alone did not produce better results than COMB or STN in any patient.
COMB and HF-STN stimulation improved PD-associated gait disorders in this preliminary case series, sustained over time. Further multicenter investigations are required to better explore this therapeutic option.
•Freezing during the “on” period in Parkinson's disease is very difficult to treat pharmacollogically or with conventional DBS.•Low frequency stimulation of the substantia nigra reticulata could regulate gait disorders in Parkinson's disease.•Simultaneous DBS in the subthalamus and SNr at different frequencies showed substained improvement of “on” freezing in PD.
Improved knowledge of the prediagnostic phase of progressive supranuclear palsy (PSP) might provide information on when and how the disease starts, along with the opportunity to test therapies in ...disease stages with lesser neurodegeneration.
To explore the symptoms in years preceding the PSP diagnosis.
This is a single-center retrospective case-control study based on clinical charts review and a structured interview to PSP patients and their caregivers. Prediagnostic symptoms were defined as those present more than one year before the diagnosis. We explored 35 symptoms in the following domains: visual, dizziness, motor, mood/apathy, cognitive, behavioral, sleep, gastrointestinal/urinary and miscellaneous. Non-parametric statistics were applied, with significance set at <0.05 (FDR-corrected).
We included 150 subjects: 50 PSP patients (38% females, age 75.8) and an age- and sex-matched control group of 50 Parkinson's disease (PD) and 50 subjects (CS) without neurodegenerative disease. The frequencies of visual, motor, cognitive, behaviour and dizziness domains were significantly higher in PSP vs. PD, and so were the motor, mood/apathy, cognitive, behaviour and dizziness ones in PSP vs. CS. Over 50% of prediagnostic falls, apathy and anxiety, depression and memory-attention-executive symptoms, and over 30% of gait disturbances started more than three and up to ten years before the diagnosis. PSP patients had more consultations to ENT and ophthalmologists than PD patients.
PSP patients present a broad variety of motor and non-motor symptoms several years before the diagnosis. The definition of a prediagnostic PSP phase might be helpful to identify patients in early disease stages.
•Motor and non-motor prediagnostic PSP symptoms have not been studied in depth.•We retrospectively assessed prediagnostic symptoms in PSP vs. PD and controls.•Prediagnostic falls but also gait, cognitive and mood disturbances were more frequent in PSP.•These symptoms might help define prediagnostic PSP.•These might assist selection of enriched populations in future PSP research.
Profile determination in field hockey is critical to determining athletes' physical strengths and weaknesses, and is key in planning, programming, and monitoring training. This study pursued two ...primary objectives: (i) to provide descriptive data on sprinting, deceleration, and change of direction (COD) abilities and (ii) to elucidate the mechanical variables that influence sprint and COD performance in elite female field hockey players. Using radar and time-gate technology, we assessed performance and mechanical data from 30 m sprinting, deceleration, and COD tests for 26 elite female hockey players. A machine learning approach identified mechanical variables related to sprint and COD performance. Our findings offer a framework for athlete categorization and the design of performance-enhancing training strategies at the international level. Two pivotal mechanical variables-relative maximum horizontal force (F0) and maximum velocity (Vmax)-predominantly influence the times across all tested distances. However, the force-velocity profile (FVP) and horizontal deceleration do not influence the variance in the COD test outcomes. These insights can guide the design, adjustment, and monitoring of training programs, assisting coaches in decision making to optimize performance and mitigate injury risks for female hockey players.
Abstract
Study Objectives
Patients with isolated rapid eye movement (REM) sleep behavior disorder (IRBD) develop Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy ...(MSA). Magnetic resonance imaging (MRI) is abnormal in MSA showing abnormalities in the putamen, cerebellum, and brainstem. Our objective was to evaluate the usefulness of MRI to detect MRI abnormalities in IRBD and predict development of MSA and not PD and DLB.
Methods
In IRBD patients that eventually developed PD, DLB, and MSA, we looked for the specific structural MRI abnormalities described in manifest MSA (e.g. hot cross-bun sign, putaminal rim, and cerebellar atrophy). We compared the frequency of these MRI changes among groups of converters (PD, DLB, and MSA) and analyzed their ability to predict development of MSA. The clinical and radiological features of the IRBD patients that eventually converted to MSA are described in detail.
Results
A total of 61 IRBD patients who underwent MRI phenoconverted to PD (n = 30), DLB (n = 26), and MSA (n = 5) after a median follow-up of 2.4 years from neuroimaging. MRI changes typical of MSA were found in four of the five (80%) patients who converted to MSA and in three of the 56 (5.4%) patients who developed PD or DLB. MRI changes of MSA had sensitivity of 80.0%, specificity of 94.6%, positive likelihood ratio of 14.9 (95% CI 4.6–48.8), and negative likelihood ratio of 0.2 (95% CI 0.04–1.2) to predict MSA.
Conclusions
In IRBD, conventional brain MRI is helpful to predict conversion to MSA. The specific MRI abnormalities of manifest MSA may be detected in its premotor stage.
•The effect of in vitro digestion-fermentation on green and roasted coffee was studied.•The fermented fraction was more antioxidant than regular and digested coffees.•Individual polyphenols and SCFAs ...production were different in green coffees.•The microbial community was different after fermenting green and roasted coffees.•Green and roasted coffees behave as different foods after digestion-fermentation.
Coffee is one of the most consumed beverages and has been linked to health in different studies. However, green and roasted coffees have different chemical composition and therefore their health properties might differ as well. Here, we study the effect of in vitro digestion-fermentation on the antioxidant capacity, phenolic profile, production of short-chain fatty acids (SCFAs), and gut microbiota community structure of green and roasted coffee brews. Roasted coffees showed higher antioxidant capacity than green coffees, with the highest level achieved in fermented samples. Polyphenol profile was similar between green and roasted coffees in regular coffee brews and the digested fraction, but very different after fermentation. Production of SCFAs was higher after fermentation of green coffee brews. Fermentation of coffee brews by human gut microbiota led to different community structure between green and roasted coffees. All these data suggest that green and roasted coffees behave as different types of food.
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