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The D614G variant of SARS-CoV-2 S-protein emerged in early 2020 and quickly became the dominant circulating strain in Europe and its environs. The variant was characterized by the higher viral load, which is not associated with disease severity, higher incorporation into the virion, and high cell entry via ACE-2 and TMPRSS2. Previous strains of the coronavirus and the current SARS-CoV-2 have demonstrated the selection of mutations as a mechanism of escaping immune responses. In this study, we used molecular dynamics simulation and MM-PBSA binding energy analysis to provide insights into the behaviour of the D614G S-protein at the molecular level and describe the neutralization mechanism of this variant. Our results show that the D614G S-protein adopts distinct conformational dynamics which is skewed towards the open-state conformation more than the closed-state conformation of the wild-type S-protein. Residue-specific variation of amino acid flexibility and domain-specific RMSD suggest that the mutation causes an allosteric conformational change in the RBD. Evaluation of the interaction energies between the S-protein and neutralizing antibodies show that the mutation may enhance, reduce or not affect the neutralizing interactions depending on the neutralizing antibody, especially if it targets the RBD. The results of this study have shed insights into the behaviour of the D614G S-protein at the molecular level and provided a glimpse of the neutralization mechanism of this variant.

BackgroundFilarial pathologies such as lymphedema may be associated with complications such as chronic non-healing wounds. Nonetheless, the role of bacterial population colonizing the lymphedematous legs has been posited to worsen the conditions of those living with the infection. These bacteria are usually composed of staphylococcal species partly because they are commensals. Thus, this present study sought to type the methicillin-resistant Staphylococcus aureus (MRSA) prevalence among individuals presenting with filarial lymphedema, particularly as MRSA tends to affect treatments options.MethodsWe recruited individuals (n = 321) with stages I–VII of lymphedema in a cross-sectional study in the Ahanta West district of the Western Region of Ghana. Swabs from lymphedematous limb ulcers, pus, and cutaneous surfaces were cultured using standard culture-based techniques. The culture isolates were later identified using Matrix-assisted Laser Desorption/Ionization Time of Flight (MALDI-TOF) mass spectrometry.ResultsA total of 192 Staphylococci species were isolated, with an overall prevalence of 39.7% (95% CI: 35%–44%; N = 483). S. hominis was the most prevalent species (23.95%), followed by S. haemolyticus (20.83%), S. epidermidis (15.10%), S. aureus (10.41%), and S. saprophyticus (9.32%). The remaining 20.34% were distributed among S. wanneri, S. sciuri, S. pasteuri, S. xylosus, S. simulans, S. cohnii, S. caprae, S. lugdunensis, and S. capitis. MRSA, containing mecA gene, was detected in 21 out of 31 Staphylococci isolates tested, with an overall prevalence of 68% (95% CI: 51%–84%). In addition, a virulent gene, Panton–Valentine leukocidin (PVL), which is usually associated with S. aureus, was detected in 20/31 (64.5%) S. aureus in the study.ConclusionThese results suggest that MRSA species may pose a challenge to the treatment of filarial lymphedema with antibiotics particularly, as doxycycline is currently being piloted in some endemic areas to treat the infection. Thus, intensive antimicrobial resistance surveillance should be conducted in endemic areas by health authorities to forestall the dilemma of multidrug resistance not only against lymphatic filariasis (LF) infection but other diseases.

The transcription factor NF-κB promotes immunity by controlling the expression of genes involved in inflammation. Cytokines and pathogen-associated molecular patterns stimulate cell surface receptors, including toll-like receptors, to initiate a signalling cascade resulting in the activation of NF-κB. NF-κB drives the expression of target genes that mediate cell proliferation and release antimicrobial molecules and cytokines to activate an immune response. Filariasis is one of the most complex infections of humans. The actual causes of the heterogeneity in infection are not well understood. However, they have been attributed to differences in inflammatory processes that are immune-mediated, secondary bacterial infections, and host immune-genetics. Elevated production of angiogenic molecules (VEGFs, CEACAM and MMPs) in filarial pathology has been shown to be dependent on phosphorylation and intracellular activation of NF-κB. This review examines the role of NF-κB in filarial pathology and its potential therapeutic options for individuals with the disease.

Background: Lymphatic Filariasis (LF), a neglected tropical disease, has been speculated to be complicated by secondary bacteria, yet a systematic documentation of these bacterial populations is lacking. Thus, the primary focus of this study was to profile bacteria diversity in the progression of filarial lymphedema among LF individuals with or without wounds.Methods: A cross-sectional study design recruited 132 LF individuals presenting with lymphedema with or without wounds from eight communities in the Ahanta West District in the Western Region, Ghana. Swabs from the lymphedematous limbs, ulcers, pus, and cutaneous surfaces were cultured using standard culture-based techniques. The culture isolates were subsequently profiled using Matrix-assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry.Results: Of the 132 LF participants recruited, 65% (85) had filarial lymphedema with no wounds. In total, 84% (235) of the bacterial isolates were identified. The remaining 16% (46) could not be identified with the method employed. Additionally, 129(55%) of the strains belonged to the phylum Firmicutes, while 61 (26%) and 45 (19%) represented Proteobacteria and Actinobacteria, respectively. Generally, irrespective of the samples type (i.e., wound sample and non-wound samples), there was a sharp increase of bacteria diversity from Stages 1 to 3 and a drastic decrease in these numbers by Stage 4, followed by another surge and a gradual decline in the advanced stages of the disease. The Shannon Diversity Index and Equitability for participants with and without wounds were (3.482, 0.94) and (3.023, 0.75), respectively. Further, Staphylococcus haemolyticus and Escherichia coli showed resistance to tetracycline, chloramphenicol, and penicillin.

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Human gremlin-1 is a physiologically versatile signaling molecule that has been associated with several human diseases including cancer. The ability of gremlin-1 to induce fibrosis in organs and transduce angiogenesis makes it a target for cancer therapy. RNAi-based therapy has proven to be very efficient and specific in tumor growth inhibition. The efficacy and specificity of siRNA-mediated gene silencing depends on the designing approaches. Here, empirical guidelines for siRNA design and comprehensive target site availability analysis were used to select effective siRNA from a plethora of potential candidates designed using several computation algorithms. Then, the selected siRNA candidates were subjected to stringent similarity searches in order to obtain siRNA candidates with reduced off-target effects (high specificity). The best candidates were compared to experimentally successful gremlin-1 siRNAs in order to predict the silencing potency of the selected siRNAs. siRNA-6 (sense strand: 5'-CCAAGAAAUUCACUACCAU-3'), siRNA-7 (sense strand: 5'-CCAUGAUGGUCACACUCAA-3') and siRNA-47 (sense strand: 5'-GGCCCAGCACAAUGACUCA-3') were predicted to be highly effective siRNA candidates for gremlin-1 silencing. These siRNAs can be considered for RNAi-based therapy because off-target effects are predicted to be minimal.

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