De Novo nucleic acids: a review of synthetic alternatives to DNA and RNA that could act as bio-information storage molecules

Modern terran life uses several essential biopolymers like nucleic acids, proteins and polysaccharides. The nucleic acids, DNA and RNA are arguably life’s most important, acting as the stores and translators of genetic information contained in their base sequences, which ultimately manifest themselves in the amino acid sequences of proteins. But just what is it about their structures; an aromatic heterocyclic base appended to a (five-atom ring) sugar-phosphate backbone that enables them to carry out these functions with such high fidelity? In the past three decades, leading chemists have created in their laboratories synthetic analogues of nucleic acids which differ from their natural counterparts in three key areas as follows: (a) replacement of the phosphate moiety with an uncharged analogue, (b) replacement of the pentose sugars ribose and deoxyribose with alternative acyclic, pentose and hexose derivatives and, finally, (c) replacement of the two heterocyclic base pairs adenine/thymine and guanine/cytosine with non-standard analogues that obey the Watson-Crick pairing rules. This manuscript will examine in detail the physical and chemical properties of these synthetic nucleic acid analogues, in particular on their abilities to serve as conveyors of genetic information. If life exists elsewhere in the universe, will it also use DNA and RNA

The way forward for the origin of life: prions and prion-like molecules first hypothesis

In this paper the hypothesis that prions and prion-like molecules could have initiated the chemical evolutionary process which led to the eventual emergence of life is reappraised. The prions first hypothesis is a specific application of the protein-first hypothesis which asserts that protein-based chemical evolution preceded the evolution of genetic encoding processes. This genetics-first hypothesis asserts that an “RNA-world era” came before protein-based chemical evolution and rests on a singular premise that molecules such as RNA, acetyl-CoA, and NAD are relics of a long line of chemical evolutionary processes preceding the Last Universal Common Ancestor (LUCA). Nevertheless, we assert that prions and prion-like molecules may also be relics of chemical evolutionary processes preceding LUCA. To support this assertion is the observation that prions and prion-like molecules are involved in a plethora of activities in contemporary biology in both complex (eukaryotes) and primitive life forms. Furthermore, a literature survey reveals that small RNA virus genomes harbor information about prions (and amyloids). If, as has been presumed by proponents of the genetics-first hypotheses, small viruses were present during an RNA world era and were involved in some of the earliest evolutionary processes, this places prions and prion-like molecules potentially at the heart of the chemical evolutionary process whose eventual outcome was life. We deliberate on the case for prions and prion-like molecules as the frontier molecules at the dawn of evolution of living systems

Self-similar patterns from abiotic decarboxylation metabolism through chemically oscillating reactions: a prebiotic model for the origin of life

The origin of life must have included an abiotic stage of carbon redox reactions that involved electron transport chains and the production of lifelike patterns. Chemically oscillating reactions (COR) are abiotic, spontaneous, out-of-equilibrium, and redox reactions that involve the decarboxylation of carboxylic acids with strong oxidants and strong acids to produce CO2 and characteristic self-similar patterns. Those patterns have circular concentricity, radial geometries, characteristic circular twins, colour gradients, cavity structures, and branching to parallel alignment. We propose that COR played a role during the prebiotic cycling of carboxylic acids, furthering the new model for geology where COR can also explain the patterns of diagenetic spheroids in sediments. The patterns of COR in Petri dishes are first considered and compared to those observed in some eukaryotic lifeforms. The molecular structures and functions of reactants in COR are then compared to key biological metabolic processes. We conclude that the newly recognised similarities in compositions and patterns warrant future research to better investigate the role of halogens in biochemistry; COR in life-forms, including in humans; and the COR-stage of prebiotic carbon cycling on other planets, such as Mars

Chemically oscillating reactions during the diagenetic formation of Ediacaran Siliceous and Carbonate Botryoids

Chemically oscillating reactions are abiotic reactions that produce characteristic, periodic patterns during the oxidation of carboxylic acids. They have been proposed to occur during the early diagenesis of sediments that contain organic matter and to partly explain the patterns of some enigmatic spheroids in malachite, phosphorite, jasper chert, and stromatolitic chert from the rock record. In this work, circularly concentric self-similar patterns are shown to form in new chemically oscillating reaction experiments with variable mixtures of carboxylic acids and colloidal silica. This is carried out to best simulate in vitro the diagenetic formation of botryoidal quartz and carbonate in two Ediacaran-age geological formations deposited after the Marinoan–Nantuo snowball Earth event in South China. Experiments performed with alkaline colloidal silica (pH of 12) show that this compound directly participates in pattern formation, whereas those with humic acid particles did not. These experiments are particularly noteworthy since they show that pattern formation is not inhibited by strong pH gradients, since the classical Belousov–Zhabotinsky reaction occurs in solution with a pH around 2. Our documentation of hundreds of classical Belousov–Zhabotinsky experiments yields a number of self-similar patterns akin to those in concretionary structures after the Marinoan–Nantuo snowball Earth event. Morphological, compositional, and size dimensional comparisons are thus established between patterns from these experiments and in botryoidal quartz and carbonate from the Doushantuo and Denying formations. Selected specimens exhibit circularly concentric layers and disseminations of organic matter in quartz and carbonate, which also occurs in association with sub-micron-size pyrite and sub-millimetre iron oxides within these patterns. X-ray absorption near edge structure (XANES) analyses of organic matter extracted from dolomite concretions in slightly younger, early Cambrian Niutitang Formation reveal the presence of carboxylic and N-bearing molecular functional groups. Such mineral assemblages, patterns, and compositions collectively suggest that diagenetic redox reactions take place during the abiotic decay of biomass, and that they involve Fe, sulphate, and organic matter, similarly to the pattern-forming experiments. It is concluded that chemically oscillating reactions are at least partly responsible for the formation of diagenetic siliceous spheroids and concretionary carbonate, which can relate to various other persistent problems in Earth and planetary sciences

Antivirals for broader coverage against human coronaviruses

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses with a genome that is 27–31 kbases in length. Critical genes include the spike (S), envelope (E), membrane (M), nucleocapsid (N) and nine accessory open reading frames encoding for non-structural proteins (NSPs) that have multiple roles in the replication cycle and immune evasion (1). There are seven known human CoVs that most likely appeared after zoonotic transfer, the most recent being SARS-CoV-2, responsible for the COVID-19 pandemic. Antivirals that have been approved by the FDA for use against COVID-19 such as Paxlovid can target and successfully inhibit the main protease (MPro) activity of multiple human CoVs; however, alternative proteomes encoded by CoV genomes have a closer genetic similarity to each other, suggesting that antivirals could be developed now that target future CoVs. New zoonotic introductions of CoVs to humans are inevitable and unpredictable. Therefore, new antivirals are required to control not only the next human CoV outbreak but also the four common human CoVs (229E, OC43, NL63, HKU1) that circulate frequently and to contain sporadic outbreaks of the severe human CoVs (SARS-CoV, MERS and SARS-CoV-2). The current study found that emerging antiviral drugs, such as Paxlovid, could target other CoVs, but only SARS-CoV-2 is known to be targeted in vivo. Other drugs which have the potential to target other human CoVs are still within clinical trials and are not yet available for public use. Monoclonal antibody (mAb) treatment and vaccines for SARS-CoV-2 can reduce mortality and hospitalisation rates; however, they target the Spike protein whose sequence mutates frequently and drifts. Spike is also not applicable for targeting other HCoVs as these are not well-conserved sequences among human CoVs. Thus, there is a need for readily available treatments globally that target all seven human CoVs and improve the preparedness for inevitable future outbreaks. Here, we discuss antiviral research, contributing to the control of common and severe CoV replication and transmission, including the current SARS-CoV-2 outbreak. The aim was to identify common features of CoVs for antivirals, biologics and vaccines that could reduce the scientific, political, economic and public health strain caused by CoV outbreaks now and in the future

Room temperature DBN initiated phospha‐Brook rearrangement of α‐hydroxyphosphonates to phosphates

A series of substituted aryl phosphate esters have been synthesized from their α‐hydroxyphosphonates substrates, using DBN (1,5 diazabicyclo(4.3.0)non‐5‐ene) at room temperature, via a phospha‐Brook rearrangement. The aryl‐substrate dependence of the rearrangement was explored, and excellent yields of the phosphate esters were achieved irrespective of whether the aryl moiety was activated or unactivated. A plausible mechanism for the rearrangement has been proposed. Based on the low temperature 31P‐NMR, the mechanism of the phospha‐Brook rearrangement is proposed to take place via an oxaphosphirane intermediate

Nitrate-rich vegetables do not lower blood pressure in individuals with mildly elevated blood pressure: A 4-wk randomized controlled crossover trial

Background - Emerging evidence suggests that increasing intakes of nitrate-rich vegetables may be an effective approach to reduce blood pressure. Objective - Our primary aim was to determine whether daily consumption of nitrate-rich vegetables over 4 wk would result in lower blood pressure. Design - Thirty participants with prehypertension or untreated grade 1 hypertension were recruited to a randomized controlled crossover trial with 4-wk treatment periods separated by 4-wk washout periods. Participants completed 3 treatments in random order: 1) increased intake (∼200 g/d) of nitrate-rich vegetables [high-nitrate (HN); ∼150 mg nitrate/d], 2) increased intake (∼200 g/d) of nitrate-poor vegetables [low-nitrate (LN); ∼22 mg nitrate/d], and 3) no increase in vegetables (control; ∼6 mg nitrate/d). Compliance was assessed with the use of food diaries and by measuring plasma nitrate and carotenoids. Nitrate metabolism was assessed with the use of plasma, salivary, and urinary nitrate and nitrite concentrations. The primary outcome was blood pressure assessed by using 24-h ambulatory, home, and clinic measurements. Secondary outcomes included measures of arterial stiffness. Results - Plasma nitrate and nitrite concentrations increased with the HN treatment in comparison to the LN and control treatments (P \u3c 0.001). Plasma carotenoids increased with the HN and LN treatments compared with the control (P \u3c 0.01). HN treatment did not reduce systolic blood pressure [24-h ambulatory—HN: 127.4 ± 1.1 mm Hg; LN: 128.6 ± 1.1 mm Hg; control: 126.2 ± 1.1 mm Hg (P = 0.20); home—HN: 127.4 ± 0.7 mm Hg; LN: 128.7 ± 0.7 mm Hg; control: 128.3 ± 0.7 mm Hg (P = 0.36); clinic—HN: 128.4 ± 1.3 mm Hg; LN: 130.3 ± 1.3 mm Hg; control: 129.8 ± 1.3 mm Hg (P = 0.49)] or diastolic blood pressure compared with LN and control treatments (P \u3e 0.05) after adjustment for pretreatment values, treatment period, and treatment order. Similarly, no differences were observed between treatments for arterial stiffness measures (P \u3e 0.05). Conclusion - Increased intake of nitrate-rich vegetables did not lower blood pressure in prehypertensive or untreated grade 1 hypertensive individuals when compared with increased intake of nitrate-poor vegetables and no increase in vegetables

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts