Correlation of gestational age and age at death in sudden infant death syndrome: another pointer to the role of critical developmental period?

BACKGROUND: Filiano and Kinney proposed a triple-risk model for the sudden infant death syndrome (SIDS) that involves the intersection of three risks: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). The primary evidence for the role of a critical developmental period in SIDS etiology is the peak of cases around the third month of life. Independently, several studies pointed to correlation between gestational age and age at death in SIDS, but used that to assess the SIDS risk for preterm infants, ignoring further ramifications. METHODS: We did a detailed analysis of CDC data spanning over two decades (1983-2011). We focused not only on the correlation between two age variables (gestational and age at death), but also on the possibility of misdiagnosis. Also, we attempted to account for potential biases in the data induced by the ICD-9/ICD-190 transition or the "Back to Sleep" campaign. RESULTS: The peak of deaths in the third month of life, that was the main argument for the role of the critical development period, wasn't unique to SIDS. However, we confirmed an almost linear and negative correlation between gestational age and the week of death due to SIDS. This pattern (slope of correlation < 0 and significance of correlation p < 0.05) is characteristic of SIDS among all diseases analyzed in the study. CONCLUSIONS: We interpret the results as the evidence of the role of the critical development period in SIDS etiology. Possibly more attention in the future research should be put to theories that are based on homeostatic control.

The relationship between EMG high frequency and low frequency band amplitude changes correlates with tissue inorganic phosphate levels.

Assessing inorganic phosphate levels seems crucial in deciphering the biochemical state of organisms or tissues. The concentration of inorganic phosphate in blood is an order of magnitude smaller than in tissues and, on top of that, it is dynamically used to fill temporary gaps in tissues. This is the reason blood inorganic phosphate level is considered a poor proxy for tissue levels. Therefore, tissue biopsy seems to be the dominant method when assessing inorganic phosphate levels for instance in muscles. In this study, we attempted to derive a non-invasive biomarker for phosphate tissue levels. We analyzed surface electromyography signals taken during 31P spectroscopy of leg muscles in five adult pigs. We induced hypophosphatemia via 20 minutes-long hyperventilation. It turned out that the proportion of the amplitude of the low frequency band and the high frequency band is significantly (p=0.002) correlated with the relative phosphate levels. The electromyographic signal did not correlate significantly with pCO2 levels in the blood, suggesting that the changes in the signal are a result of inorganic phosphate levels, not hyperventilation. The results might lead to the development of a real-time phosphate fluctuations measurement procedure.

Interactions of piRNAs with the mRNA of Candidate Genes in Esophageal Squamous Cell Carcinoma.

Recently, a database of human piRNAs (piwi-interacting RNAs) was created, which allows the study of the binding of many piRNAs to the mRNAs of genes involved in many diseases, including cancer. In the present work, we identified the piRNAs that can interact with candidate esophageal squamous cell carcinoma (ESCC) genes. The binding of 480 thousand piRNAs with the mRNAs of 66 candidate ESCC genes was studied. Bioinformatic studies found that piRNAs bind only to the mRNAs of nine candidate genes: AURKA, BMP7, GCOM1, ERCC1, MTHFR, SASH1, SIX4, SULT1A1, and TP53. It has been shown that piRNAs can bind to mRNA by overlapping nucleotide sequences in limited 3'UTR and 5'UTR regions called clusters of binding sites (BSs). The existence of clusters of piRNA BSs significantly reduces the proportion of the nucleotide sequences of these sites in the mRNA of target genes. Competition between piRNAs occurs for binding to the mRNA of target genes. Individual piRNAs and groups of piRNAs that have separate BSs and clusters of BSs in the mRNAs of two or more candidate genes have been identified in the mRNAs of these genes. This organization of piRNAs BSs indicates the interdependence of the expression of candidate genes through piRNAs. Significant differences in the ability of genes to interact with piRNAs prevent the side effects of piRNAs on genes with a lack of the ability to bind such piRNAs. Individual piRNAs and sets of piRNAs are proposed and recommended for the diagnosis and therapy of ESCC.

Endogenous piRNAs Can Interact with the Omicron Variant of the SARS-CoV-2 Genome.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which caused the COVID-19 pandemic, can still infect populations in many countries around the globe. The Omicron strain is the most mutated variant of SARS-CoV-2. The high transmissibility of the strain and its ability to evade immunity necessitate a priority study of its properties in order to quickly create effective means of preventing its spread. The current research aimed to examine the in silico interaction between PIWI-interacting RNAs (piRNAs) and the SARS-CoV-2 genome (gRNA) to identify endogenous piRNAs and propose synthetic piRNAs with strong antiviral activity for drug development. This study used validated bioinformatic approaches regarding the interaction of more than eight million piRNAs with the SARS-CoV-2 genome. The piRNAs' binding sites (BSs) in the 5'UTR were located with overlapping nucleotide sequences termed clusters of BSs. Several BSs clusters have been found in the nsp3, nsp7, RNA-dependent RNA polymerase, endoRNAse, S surface glycoprotein, ORF7a, and nucleocapsid. Sixteen synthetic piRNAs that interact with gRNA have been proposed with free binding energy ranging from -170 kJ/mol to -175 kJ/mol, which can be used to create drugs that suppress the reproduction of SARS-CoV-2.

Antioxidant Activity and Photosynthesis Efficiency in Melissa officinalis Subjected to Heavy Metals Stress.

The aim of this study was to assess influence of cadmium and zinc treatments on antioxidant activity combined with the photosynthesis efficiency in a popular herb lemon balm (Melissa officinalis L.). Plants were grown under greenhouse conditions by the pot method. The Mn, Cu, Cd, and Zn contents in soil and plants were measured by HR-CS FAAS. The activity of net photosynthesis, stomatal conductance, transpiration rate, intercellular CO2, and index of chlorophyll in leaves were determined for all investigated species. Reduction of the net photosynthesis was observed for cultivations subjected to either Zn or Cd treatments. Phenolic contents were determined by the chemical Folin-Ciocalteu method, while enhanced voltammetric analysis was applied to assess the antioxidant properties of plant extracts. Both of these approaches yielded similar results. Herbal extracts had exceptional antioxidant capacities and were good scavengers of free radicals and reactive oxygen species. Structural similarity of cadmium and zinc facilitated their mutual structural exchange and prompted substantial expansion of phenolics under the mixed Zn and Cd treatments.

Design of Crotoxin-Based Peptides with Potentiator Activity Targeting the ΔF508NBD1 Cystic Fibrosis Transmembrane Conductance Regulator.

We have previously shown that the CBb subunit of crotoxin, a ß-neurotoxin with phospholipase A2 (PLA2) activity, targets the human ΔF508CFTR chloride channel implicated in cystic fibrosis (CF). By direct binding to the nucleotide binding domain 1 (NBD1) of ΔF508CFTR, this neurotoxic PLA2 acts as a potentiator increasing chloride channel current and corrects the trafficking defect of misfolded ΔF508CFTR inside the cell. Here, for a therapeutics development of new anti-cystic fibrosis agents, we use a structure-based in silico approach to design peptides mimicking the CBb-ΔF508NBD1 interface. Combining biophysical and electrophysiological methods, we identify several peptides that interact with the ΔF508NBD1 domain and reveal their effects as potentiators on phosphorylated ΔF508CFTR. Moreover, protein-peptide interactions and electrophysiological studies allowed us to identify key residues of ΔF508NBD1 governing the interactions with the novel potentiators. The designed peptides bind to the same region as CBb phospholipase A2 on ΔF508NBD1 and potentiate chloride channel activity. Certain peptides also show an additive effect towards the clinically approved VX-770 potentiator. The identified CF therapeutics peptides represent a novel class of CFTR potentiators and illustrate a strategy leading to reproducing the effect of specific protein-protein interactions.

Improvement of native structure-based peptides as efficient inhibitors of protein-protein interactions of SARS-CoV-2 spike protein and human ACE2.

New pathogens responsible for novel human disease outbreaks in the last two decades are mainly the respiratory system viruses. Not different was the last pandemic episode, caused by infection of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). One of the extensively explored targets, in the recent scientific literature, as a possible way for rapid development of COVID-19 specific drug(s) is the interaction between the receptor-binding domain of the virus' spike (S) glycoprotein and human receptor angiotensin-converting enzyme 2 (hACE2). This protein-protein recognition process is involved in the early stages of the SARS-CoV-2 life cycle leading to the host cell membrane penetration. Thus, disrupting this interaction may block or significantly reduce the infection caused by the novel pathogen. Previously we have designed (by in silico structure-based analysis) three very short peptides having sequences inspirited by hACE2 native fragments, which effectively bind to the SARS-CoV-2 S protein and block its interaction with the human receptor. In continuation of the above mentioned studies, here we presented an application of molecular modeling approach resulting in improved binding affinity of the previously proposed ligand and its enhanced ability to inhibit meaningful host-virus protein-protein interaction. The new optimized hexapeptide binds to the virus protein with affinity one magnitude higher than the initial ligand and, as a very short peptide, has also great potential for further drug development. The peptide-based strategy is rapid and cost-effective for developing and optimizing efficient protein-protein interactions disruptors and may be successfully applied to discover antiviral candidates against other future emerging human viral infections.

New Advances in Short Peptides: Looking Forward.

It is beyond doubt that short peptides hold significant promise in bio-medicine, as the most versatile molecules, both structurally and functionally [...].

The Anti-Inflammatory Effect of Cabbage Leaves Explained by the Influence of bol-miRNA172a on FAN Expression.

Recently, the possibility of cross-kingdom gene expression regulation by miRNAs from other species ("xenomiRs"), specifically from plants, has acquired scientific meaning. Based on the one of oldest methods for dealing with inflammation via the use of cabbage leaf compresses, we investigated the effects of Brassica oleracea derived miR172a on the potential human target gene encoding FAN (Factor Associated with Neutral Sphingomyelinase Activation) protein. In vitro experiments showed a decrease in FAN protein levels in both human and mouse cells transfected with bol-miRNA172a. As the FAN protein mediates inflammatory responses, the potential of miR172a to mitigate the inflammatory process was tested in a mouse model of rheumatoid arthritis. Animal studies showed the decreased oedema of inflamed paws in mouse with rheumatoid arthritis model induced after treatment with miR172a.

Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice.

Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th amino-acid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway's epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftrtm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl-) conductance in F508del Cftrtm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis.

Atherosclerosis Pathways are Activated in Pericoronary Adipose Tissue of Patients with Coronary Artery Disease.

PURPOSE: Perivascular release of inflammatory mediators may accelerate coronary lesion formation and contribute to plaque instability. Accordingly, we compared gene expression in pericoronary adipose tissue (PCAT) in patients with advanced coronary artery disease (CAD) and non-CAD controls. PATIENTS AND METHODS: PCAT samples were collected during coronary bypass grafting from CAD patients (n = 21) and controls undergoing valve replacement surgery, with CAD excluded by coronary angiography (n = 19). Gene expression was measured by GeneChip™ Human Transcriptome Array 2.0. Obtained list of 1348 transcripts (2.0%) that passed the filter criteria was further analyzed by Ingenuity Pathway Analysis software, identifying 735 unique differentially expressed genes (DEGs). RESULTS: Among the CAD patients, 416 (30.9%) transcripts were upregulated, and 932 (69.1%) were downregulated, compared to controls. The top upregulated genes were involved in inflammation and atherosclerosis (chemokines, interleukin-6, selectin E and low-density lipoprotein cholesterol (LDL-C) receptor), whereas the downregulated genes were involved in cardiac ischaemia and remodelling, platelet function and mitochondrial function (miR-3671, miR-4524a, multimerin, biglycan, tissue factor pathway inhibitor (TFPI), glucuronidases, miR-548, collagen type I, III, IV). Among the top upstream regulators, we identified molecules that have proinflammatory and atherosclerotic features (High Mobility Group Box 2 (HMGB2), platelet-derived growth platelet (PDGF) and evolutionarily conserved signaling intermediate in Toll pathways (ESCIT)). The activated pathway related to DEGs consisted of molecules with well-established role in the pathogenesis of atherosclerosis (TFPI, plasminogen activator, plasminogen activator, urokinase receptor (PLAUR), thrombomodulin). Moreover, we showed that 22 of the altered genes form a pro-atherogenic network. CONCLUSION: Altered gene expression in PCAT of CAD patients, with genes upregulation and activation of pathway involved in inflammation and atherosclerosis, may be involved in CAD development and progression.

Native Structure-Based Peptides as Potential Protein-Protein Interaction Inhibitors of SARS-CoV-2 Spike Protein and Human ACE2 Receptor.

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) is a positive-strand RNA virus that causes severe respiratory syndrome in humans, which is now referred to as coronavirus disease 2019 (COVID-19). Since December 2019, the new pathogen has rapidly spread globally, with over 65 million cases reported to the beginning of December 2020, including over 1.5 million deaths. Unfortunately, currently, there is no specific and effective treatment for COVID-19. As SARS-CoV-2 relies on its spike proteins (S) to bind to a host cell-surface receptor angiotensin-converting enzyme-2(ACE2), and this interaction is proved to be responsible for entering a virus into host cells, it makes an ideal target for antiviral drug development. In this work, we design three very short peptides based on the ACE2 sequence/structure fragments, which may effectively bind to the receptor-binding domain (RBD) of S protein and may, in turn, disrupt the important virus-host protein-protein interactions, blocking early steps of SARS-CoV-2 infection. Two of our peptides bind to virus protein with affinity in nanomolar range, and as very short peptides have great potential for drug development.

A Global Review on Short Peptides: Frontiers and Perspectives.

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.

Stress-Induced Phosphaturia in Weaned Piglets.

The weaning period in piglets draws significant attention from researchers, veterinarians, and breeders. A substantial change in diet accompanied by enormous stress has health and welfare implications (abnormal feeding intake, infections, umbilical lesions, etc.). While the parameters like optimal age or weight for the weaning have been studied extensively, relatively less attention has been devoted to the study of stress effects in the piglets' biochemistry. As one of the effects of stress is hyperventilation, a gasometric analysis supported by measurements of hypoxia biomarkers was conducted. Piglets blood and urine, one day and seven days before and one day and seven days after the weaning, were tested. There was no evidence of hyperventilation, but phosphaturia and hypophosphatemia were observed one and seven days postweaning, respectively. A statistical analysis across the population also pointed to minor tissue hypoxia. Our work contributes to an understanding of biochemical dynamics and helps in the interpretation of physiological changes observed in piglets in this critical period.

Improving detection of protein-ligand binding sites with 3D segmentation.

In recent years machine learning (ML) took bio- and cheminformatics fields by storm, providing new solutions for a vast repertoire of problems related to protein sequence, structure, and interactions analysis. ML techniques, deep neural networks especially, were proven more effective than classical models for tasks like predicting binding affinity for molecular complex. In this work we investigated the earlier stage of drug discovery process - finding druggable pockets on protein surface, that can be later used to design active molecules. For this purpose we developed a 3D fully convolutional neural network capable of binding site segmentation. Our solution has high prediction accuracy and provides intuitive representations of the results, which makes it easy to incorporate into drug discovery projects. The model's source code, together with scripts for most common use-cases is freely available at http://gitlab.com/cheminfIBB/kalasanty.

Copper Does Not Induce Tenogenic Differentiation but Promotes Migration and Increases Lysyl Oxidase Activity in Adipose-Derived Mesenchymal Stromal Cells.

BACKGROUND: Copper belongs to the essential trace metals that play a key role in the course of cellular processes maintaining the whole body's homeostasis. As there is a growing interest in transplanting mesenchymal stromal cells (MSCs) into the site of injury to improve the regeneration of damaged tendons, the purpose of the study was to verify whether copper supplementation may have a positive effect on the properties of human adipose tissue-derived MSCs (hASCs) which potentially can contribute to improvement of tendon healing. RESULTS: Cellular respiration of hASCs decreased with increasing cupric sulfate concentrations after 5 days of incubation. The treatment with CuSO4 did not positively affect the expression of genes associated with tenogenesis (COL1α1, COL3α1, MKX, and SCX). However, the level of COL1α1 protein, whose transcript was decreased in comparison to a control, was elevated after a 5-day exposition to 25 µM CuSO4. The content of the MKX and SCX protein in hASCs exposed to cupric sulfate was reduced compared to that of untreated control cells, and the level of the COL3α1 protein, whose transcript was decreased in comparison to a control, was elevated after a 5-day exposition to 25 µM CuSO4. The content of the MKX and SCX protein in hASCs exposed to cupric sulfate was reduced compared to that of untreated control cells, and the level of the COL3. CONCLUSION: Copper sulfate supplementation can have a beneficial effect on tendon regeneration not by inducing tenogenic differentiation, but by improving the recruitment of MSCs to the site of injury, where they can secrete growth factors, cytokines and chemokines, and prevent the effects of oxidative stress at the site of inflammation, as well as improve the stabilization of collagen fibers, thereby accelerating the process of tendon healing.

An Overview of miRNA and miRNA Target Analysis Tools.

microRNA molecules have been shown to play various significant roles in many physiological and pathophysiological processes in living organisms. The tremendous interest in these molecules has led to the significant development and constant release of a number of computational tools useful for basic as well as advanced miRNA-related analyses. These approaches have various constantly evolving utilities, such as detection, target prediction, functional annotation, and many others. In this chapter, we provide an overview of several computational tools useful for broadly defined plant miRNA analysis.

EU-OPENSCREEN: A Novel Collaborative Approach to Facilitate Chemical Biology.

Compound screening in biological assays and subsequent optimization of hits is indispensable for the development of new molecular research tools and drug candidates. To facilitate such discoveries, the European Research Infrastructure EU-OPENSCREEN was founded recently with the support of its member countries and the European Commission. Its distributed character harnesses complementary knowledge, expertise, and instrumentation in the discipline of chemical biology from 20 European partners, and its open working model ensures that academia and industry can readily access EU-OPENSCREEN's compound collection, equipment, and generated data. To demonstrate the power of this collaborative approach, this perspective article highlights recent projects from EU-OPENSCREEN partner institutions. These studies yielded (1) 2-aminoquinazolin-4(3 H)-ones as potential lead structures for new antimalarial drugs, (2) a novel lipodepsipeptide specifically inducing apoptosis in cells deficient for the pVHL tumor suppressor, (3) small-molecule-based ROCK inhibitors that induce definitive endoderm formation and can potentially be used for regenerative medicine, (4) potential pharmacological chaperones for inborn errors of metabolism and a familiar form of acute myeloid leukemia (AML), and (5) novel tankyrase inhibitors that entered a lead-to-candidate program. Collectively, these findings highlight the benefits of small-molecule screening, the plethora of assay designs, and the close connection between screening and medicinal chemistry within EU-OPENSCREEN.

Host microRNA analysis in cyprinid Herpesvirus-3 (CyHV-3) infected common carp.

BACKGROUND: The mechanism of latency and the ability of the cyprinid herpesvirus 3 (CyHV-3) to establish life-long infections in carp remains poorly understood. To explain the role of miRNAs in this process we applied a range of molecular tools including high-throughput sequencing of RNA libraries constructed from the blood samples of infected fish followed by bioinformatic and functional analyses which show that CyHV-3 profoundly influences the expression of host miRNAs in vivo. RESULTS: We demonstrated the changed expression of 27 miRNAs in the clinical phase and 5 in the latent phase of infection. We also identified 23 novel, not previously reported sequences, from which 8 showed altered expressions in control phase, 10 in clinical phase and 5 in latent phase of infection. CONCLUSIONS: The results of our analysis expand the knowledge of common carp microRNAs engaged during CyHV-3 infection and provide a useful basis for the further study of the mechanism of CyHV-3 induced pathology.