In this work, kinetics of the reaction between 5,10,15,20-tetrakis(N-methylpyridium-4-yl)porphyrin and Ni2+ species were investigated in aqueous solution at 25 ±1 ºC in I = 0.10 M (NaNO3). Speciation of Ni2+ was carried out in I = 0.10 M (NaNO3) in order to provide the distribution of the Ni2+ species with different solution pH. The experimental data have been compared with the speciation diagram constructed from the values of hydrolysis constants of Ni2+ ion. Speciation data showed that the hexaaquanickel(II), [Ni(H2O)6]2+, ions take place in hydrolysis reactions through formation of [Ni(OH2)6-n(OH)n]2-n species with solution pH. Based on the speciation of Ni2+ and pH dependent rate constants, rate expression can be written as: d[Ni(TMPyP)4+]/dt = (k1[Ni2+(aq)] + k2[Ni(OH)+(aq)] + k3[Ni(OH)2o(aq)] + k4[Ni(OH)3-(aq)])[H2TMPyP4+], where k1, k2, k3 and k4 were found to be k1 = (0.62 ± 0.22) × 10-2; k2 = (3.60 ± 0.40) × 10-2; k3 = (2.09 ± 0.52) × 10-2, k4 = (0.53 ± 0.04) × 10-2 M-1s-1 at 25 ±1 °C, respectively. Kinetic results showed that monohydroxo, [Ni(H2O)5(OH)]+, is the most reactive among the [Ni(OH2)6-n(OH)n]2-n species. The enhanced reactivity has been ascribed to the formation of hydrogen bonding between oxygen atom of hydroxyl group of the [Ni(H2O)5(OH)]+ species and the pyrrolic hydrogen atom of the [H2TMPyP]4+. The rate of formation of [Ni(II)TMPyP]4+ complex was to be 3.99 × 10-2 M-1s-1 in I = 0.10 M, NaNO3 (25 ± 1 ºC). Ionic strength effect on the reaction rate is suggested that the net charge of the tetracationic porphyrin is to be +3.6 on the basis of Brønsted-Bjerrum equation. The UV-Vis and fluorescence data revealed that [Ni(II)TMPyP]4+ and H2(TMPyP)4+ interact with DNA, and UV-Vis results suggest that Ni(II)-porphyrin and free base porphyrin interact with DNA via outside binding with self-stacking and intercalation, respectively. Mechanism of kinetics of formation of the [Ni(II)TMPyP]4+ complex in aqueous medium is discussed. An investigation of application of the [Ni(II)TMPyP]4+ complex along with other metalloporphyrins such as Zn2+-, Ru2+-, Pt2+-, [Au(III)TMPyP]5+ as anti-COVID-19 agents is now in progress under international collaboration.

Jingmen viruses are newly described segmented flavi-like viruses that have a worldwide distribution in ticks and have been associated with febrile illnesses in humans. Computational analyses were used to predict that Jingmen flavi-like virus glycoproteins have structural features of class II viral fusion proteins, including an ectodomain consisting of beta-sheets and short alpha-helices, a fusion peptide with interfacial hydrophobicity and a three domain architecture. Jingmen flavi-like virus glycoproteins have a sequence enriched in serine, threonine and proline at the amino terminus, which is a feature of mucin-like domains. Several of the serines and threonines are predicted be modified by the addition of O-linked glycans. Some of the glycoproteins are predicted to have an additional mucin-like domain located prior to the transmembrane anchor, whereas others are predicted to have a stem consisting of two alpha-helices. The flavivirus envelope protein and Jingmen flavi-virus glycoproteins may have diverged from a common class II precursor glycoprotein with a mucin-like domain or domains acquired after divergence.

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2/2019-nCoV) infection is an emerging pandemic. The virus binds to angiotensin converting enzyme 2 (ACE2) and TMPRSS2 which are abundantly expressed on various human cells including lung epithelial cells and intestinal cells and the virus can infect these cells. Currently no specific treatments or vaccines are available for this disease. A per oral live attenuated vaccine can be beneficial in SARS-Cov-2 infection because the attenuated virus initially infects the gut, stimulates the mucosa associated immune system sparing the respiratory system during the initial immune response. The live virus can also spread in the community boosting herd immunity.

: Seasonal influenza (a.k.a flu) is responsible for considerable morbidity and mortality across the globe. The three recognized pathogens that cause epidemics during the winter season are influenza A, B and C. The influenza virus is particularly dangerous due to its mutability. Vaccines are an effective tool in preventing seasonal influenza, and their formulas are updated yearly according to WHO recommendations. However, in order to facilitate decision-making in the planning of the intervention, policymakers need information on the projected costs and quantities related to introducing the influenza vaccine, in order to help governments obtain an optimal allocation of the vaccine each year. In this paper, an approach based on a Controlled Elitism Non-Dominated Sorting Genetic Algorithm (CENSGA) model is introduced to optimize the allocation of influenza vaccination. A bi-objective model is formulated to control the infection volume, and reduce the unit cost of the vaccination campaign. An SIR (Susceptible–Infected–Recovered) model is employed for representing a potential epidemic. The model constraints are based on the epidemiological model, time management, and vaccine quantity. A two-phase optimization process is proposed: guardian control followed by contingent controls. The proposed approach is an evolutionary metaheuristic multi-objective optimization algorithm with a local search procedure based on a hash table. Moreover, in order to optimize the scheduling of a set of policies over a predetermined time to form a complete campaign, an extended CENSGA is introduced with a variable-length chromosome (VLC) along with mutation and crossover operations. To validate the applicability of the proposed CENSGA, it is compared with the classical Non-Dominated Sorting Genetic Algorithm (NSGA-II). The results are analyzed using graphical and statistical comparisons in terms of cardinality, convergence, distribution and spread quality metrics, illustrating that the proposed CENSGA is effective and useful for determining the optimal vaccination allocation campaigns.

Nonalcoholic fatty liver disease (NAFLD) is becoming the leading cause of hepatocellular carcinoma (HCC), liver-related mortality, and liver transplantation. There is reasonable epidemiological cohort data to recommend surveillance of patients with NAFLD based upon the incidence of HCC. The American Gastroenterology Association (AGA) expert review published in 2020 recommend that NAFLD patients with cirrhosis or advanced fibrosis estimated by non-invasive tests (NITs) should consider HCC surveillance. NITs include fibrosis-4 (FIB-4) index, the enhanced liver fibrosis (ELF) test, FibroScan, and MR elastography. The recommended surveillance modality is abdominal ultrasound (US) given that it is cost effective and noninvasive with good sensitivity. However, US is limited in obese patients and those with NAFLD. In NAFLD patients with a high likelihood of having an inadequate US or if US is attempted but inadequate, CT or MRI may be utilized. The GALAD score, consisting of age, gender, AFP, lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), and protein induced by vitamin K absence or antagonist-II (PIVKA-II), can help to identify high risk of incident HCC in NAFLD patients. Innovative parameters including Mac-2 binding protein glycated isomer , type IV collagen 7S, free apoptosis inhibitor of macrophage, combination of single nucleoside polymorphisms are expected to be established. Considering a large number of NAFLD population, optimal screening tests must meet several criteria including high sensitivity, cost effectiveness and availability.

Plants offer a simpler and cheaper alternative to mammalian animal models for the study of Endoplasmic Reticulum glycoprotein folding Quality Control (ERQC). In particular, the Arabidopsis thaliana (At) innate immune response to bacterial peptides provides an easy means of assaying ERQC function in vivo. A number of mutants that are useful to study ERQC in planta have been described in the literature, but only for a subset of these mutants the innate immune response to bacterial elicitors has been measured beyond monitoring plant weight and some physio-pathological parameters related to the plant immune response. In order to probe deeper into the role of ERQC in the plant immune response, we monitored expression levels of the PHI-1 and RET-OX genes in the At ER α-Glu II rsw3 and the At UGGT uggt1-1 mutant plants, in response to bacterial peptides elf18 and flg22. The elf18 response was impaired in the rsw3 but not completely abrogated in the uggt1-1 mutant plants, raising the possibility that the latter enzyme is partly dispensable for ERF signalling. In the rsw3 mutant, seedling growth was impaired only by concomitant application of the At ER α-Glu II NB-DNJ inhibitor at concentrations above 500 nM, suggesting residual activity in this mutant. The study highlights the need for extending plant innate immune response studies to assays sampling EFR signalling at the molecular level.

The limited information available on the structure of complexes involving transcription factors and cognate DNA response elements represents a major obstacle in the quest to understand their mechanism of action at the molecular level. We implemented a concerted structural proteomics approach, which combined hydrogen-deuterium exchange (HDX), quantitative protein-protein and protein-nucleic acid cross-linking (XL), and homology analysis, to model the structure of the complex between the full-length DNA binding domain (DBD) of FOXO4 and its DNA binding element (DBE). The results confirmed that FOXO4-DBD assumes the characteristic forkhead topology shared by these types of transcription factors, but its binding mode differs significantly from those of other members of the family. The results showed that the binding interaction stabilized regions that were rather flexible and disordered in the unbound form. Surprisingly, the conformational effects were not limited only to the interface between bound components but extended also to distal regions that may be essential to recruiting additional factors to the transcription machinery. In addition to providing valuable new insights into the binding mechanism, this project provided an excellent evaluation of the merits of structural proteomics approaches in the investigation of systems that arematerial not directly amenable to traditional high-resolution techniques.

RLF-100 (Aviptadil), a synthetic form of Vasoactive Intestinal Peptide (VIP) is shown to block replication of the SARS-CoV-2 virus and has been granted Fast Track Designation by the US FDA for the treatment of Critical COVID-19 with Respiratory Failure. We describe the clinical course of the first patient treated with this investigational medication in an open label manner -- a 54 year old patient suffering antibody-mediated rejection of his double lung transplant who contracted COVID-19 with respiratory failure refractory to all currently available therapies. He received three infusions of RLF-100 under an FDA-approved emergency use IND. Within 24 hours of the third infusion, substantial improvement in oxygen saturation and radiographic improvement in characteristic COVID-19 pneumonitis was noted. He was discharged from intensive care at that point and scheduled for discharge to home at 1 week on room air. Despite an intervening hospitalization for trauma, he remains alive and free of respiratory failure at 28 days post treatment.

Although congenital sensorineural hearing loss (SHL) in the bilateral cochleae mainly results from genetic abnormalities, chronic SHL progressing in later life is often influenced by systemic immune disturbances, including autoimmunity, chronic inflammation, and immunosenescence. We have investigated the relationship between the inner ear and systemic immunity and reviewed the possibilities to prevent SHL, including autoimmune SHL and age-related SHL. We also demonstrated two lymphocyte populations, interleukin 1 receptor type II (IL-1R2)-positive T cells (T1R2) and naturally occurring regulatory T cells (nTregs) in CD4⁺ T cells, which increase with aging, suppress host immune function and promote organ degeneration. Alterations in systemic immunity by fewer microbial antigen challenges in the living environment, elimination of immune suppressive lymphocytes, or immune rejuvenation with a reconstituted thymus may contribute not only to renew the cochlear function in SHL, but also to extend the healthy life of functional organs in a vigorous and youthful body, one of humanity’s greatest dreams.

Although most cases of COVID-19 are paucisymptomatic, severe disease is characterized by immune dysregulation, with a decreased type I interferon response, increased inflammatory indicators, surging IL-6, IL-10 and TNFα suggestive of cytokine storm, progressive lymphopenia, and abnormal blood clotting. Factors determining susceptibility to severe disease are poorly understood, although mortality correlates with increasing age and co-morbidities including diabetes and cardiovascular disease (CVD). Pyridoxal 5'-phosphate (PLP) tends to be insufficient in populations particularly vulnerable to COVID-19, including the elderly, the institutionalized, and people with diabetes and CVD, and PLP becomes further depleted during infection and inflammation. In turn, low PLP results in immune imbalance, as PLP is an essential cofactor in pathways regulating cytokine production, in particular type I interferons and IL-6, and in lymphocyte trafficking and endothelial integrity. Furthermore, normalizing PLP levels attenuates abnormalities in platelet aggregation and clot formation. Finally, PLP insufficiency induces excess secretion of renin and angiotensin, and hypertension. In inflammatory disease, pharmacological doses of PLP decrease circulating TNFα, IL-6 and D-dimer, and animal studies demonstrate that supplemental PLP shortens the duration and severity of viral pneumonia. Severe COVID-19 manifests as an imbalance in the immune response and the clotting system. Pharmacological PLP supplementation may therefore mitigate COVID-19 symptoms by alleviating both the immune suppression underlying viral spread and the pathological hypersecretion of inflammatory cytokines, as well as directly bolstering endothelial integrity and preventing hypercoagulability.

There are no theorems (proven theories) in the biological sciences. We propose that the 3 31 nt minihelix tRNA evolution theorem be universally accepted as one. The 3 31 nt minihelix theorem completely describes evolution of type I and type II tRNAs from ordered precursors (RNA repeats and inverted repeats). Despite diversification of tRNAome sequences, statistical tests overwhelmingly support the theorem. Furthermore, the theorem relates the dominant pathway for the origin of life on Earth, specifically, how tRNAomes and the genetic code may have coevolved. Alternate models for tRNA evolution (i.e., 2 minihelix, convergent and accretion models) are falsified. In the context of the pre-life world, tRNA was a molecule that via mutation could modify anticodon sequences and teach itself to code. We relate the clearest history to date of the chemical evolution of life on Earth. From analysis of tRNA evolution, ribozyme-mediated RNA ligation was a primary driving force in evolution of complexity during the pre-life to life transition on Earth.

Coronavirus Disease-19 (COVID-19) is caused by the infection of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The virus enters host cells through receptor-mediated endocytosis of angiotensin-converting enzyme-2 (ACE2), leading to systemic inflammation, also known as a “cytokine storm,” and neuroinflammation. COVID-19’s upstream regulator, interferon-gamma (IFNG), is downregulated upon the infection of SARS-CoV-2, which leads to the downregulation of ACE2. The neuroinflammation signaling pathway (NISP) can lead to neurodegenerative diseases, such as Parkinson's disease (PD), which is characterized by the formation of Lewy Bodies made of α-Synuclein protein encoded by synuclein alpha (SNCA). This study presents the pathways involved in the downregulation of ACE2 following SARS-CoV-2 infection and its effect on PD progression. Through QIAGEN’s Ingenuity Pathway Analysis, the study identifies the NISP as a top-five canonical pathway/signaling pathway and SNCA as a top-five upstream regulator. Core Analysis was also conducted on the associated molecules between COVID-19 and SNCA to construct a network connectivity map. The Molecule Activity Predictor tool was used to simulate the infection of SARS-CoV-2 by downregulating IFNG, which leads to the predicted activation of SNCA, and subsequently PD, through a dataset of intermediary molecules. Downstream Effect analysis was further used to quantify the downregulation of ACE2 on SNCA activation.

SARS-CoV-2 Omicron variant spike RBD epitopes in complex with spike (S) -protein D614G mutations now predominate globally and increase infectivity by assembling more functional S proteins into the virion. On average, homeopathic medicine contains less than one molecule per dose on average. Single variable SphericalHarmonicY, LaguerreL, WhittakerM, SphericalBesselJ, LegendreP, LegendreQ, LaguerreL, ChebyshevT, and Hypergeometric1F1 Functions pFqarise in connection with the power series solution of the Schrodinger equation or in the summation of perturbation expansions in quantum mechanics. A quantum interpretation of the homeopathic method is presented here through a novel algebraic topology approach to supersymmetry and symmetry breaking in quantum fields and quantum gravity theory with the aim of developing a wide range of physical-based drug design applications in a Small Molecule Quantized Water Memory Network suggesting that the Hidden Black Hole Paradox of Information Loss might be solved under suitable conditions.