“Dividing and Conquering” and “Caching” in Molecular Modeling

Molecular modeling is widely utilized in subjects including but not limited to physics, chemistry, biology, materials science and engineering. Impressive progress has been made in development of theories, algorithms and software packages. To divide and conquer, and to cache intermediate results have been long standing principles in development of algorithms. Not surprisingly, most important methodological advancements in more than half century of molecular modeling are various implementations of these two fundamental principles. In the mainstream classical computational molecular science, tremendous efforts have been invested on two lines of algorithm development. The first is coarse graining, which is to represent multiple basic particles in higher resolution modeling as a single larger and softer particle in lower resolution counterpart, with resulting force fields of partial transferability at the expense of some information loss. The second is enhanced sampling, which realizes “dividing and conquering” and/or “caching” in configurational space with focus either on reaction coordinates and collective variables as in metadynamics and related algorithms, or on the transition matrix and state discretization as in Markov state models. For this line of algorithms, spatial resolution is maintained but results are not transferable. Deep learning has been utilized to realize more efficient and accurate ways of “dividing and conquering” and “caching” along these two lines of algorithmic research. We proposed and demonstrated the local free energy landscape approach, a new framework for classical computational molecular science. This framework is based on a third class of algorithm that facilitates molecular modeling through partially transferable in resolution “caching” of distributions for local clusters of molecular degrees of freedom. Differences, connections and potential interactions among these three algorithmic directions are discussed, with the hope to stimulate development of more elegant, efficient and reliable formulations and algorithms for “dividing and conquering” and “caching” in complex molecular systems.     

Insight on Solution Plasma in Aqueous Solution and Their Application in Modification of Chitin and Chitosan

Sustainability and environmental concerns have persuaded researchers to explore renewable materials, such as nature-derived polysaccharides, and add value by changing chemical structures with the aim to possess specific properties, like biological properties. Meanwhile, finding methods and strategies that can lower hazardous chemicals, simplify production steps, reduce time consumption, and acquire high-purified products is an important task that requires attention. To break through these issues, electrical discharging in aqueous solutions at atmospheric pressure and room temperature, referred to as the “solution plasma process”, has been introduced as a novel process for modification of nature-derived polysaccharides like chitin and chitosan. This review reveals insight into the electrical discharge in aqueous solutions and scientific progress on their application in a modification of chitin and chitosan, including degradation and deacetylation. The influencing parameters in the plasma process are intensively explained in order to provide a guideline for the modification of not only chitin and chitosan but also other nature-derived polysaccharides, aiming to address economic aspects and environmental concerns.     

In-Silico Drug Toxicity and Interaction Prediction for Plant Complexes Based on Virtual Screening and Text Mining

Potential drug toxicities and drug interactions of redundant compounds of plant complexes may cause unexpected clinical responses or even severe adverse events. On the other hand, super-additivity of drug interactions between natural products and synthetic drugs may be utilized to gain better performance in disease management. Although without enough datasets for prediction model training, based on the SwissSimilarity and PubChem platforms, for the first time, a feasible workflow of prediction of both toxicity and drug interaction of plant complexes was built in this study. The optimal similarity score threshold for toxicity prediction of this system is 0.6171, based on an analysis of 20 different herbal medicines. From the PubChem database, 31 different sections of toxicity information such as “Acute Effects”, “NIOSH Toxicity Data”, “Interactions”, “Hepatotoxicity”, “Carcinogenicity”, “Symptoms”, and “Human Toxicity Values” sections have been retrieved, with dozens of active compounds predicted to exert potential toxicities. In Spatholobus suberectus Dunn (SSD), there are 9 out of 24 active compounds predicted to play synergistic effects on cancer management with various drugs or factors. The synergism between SSD, luteolin and docetaxel in the management of triple-negative breast cancer was proved by the combination index assay, synergy score detection assay, and xenograft model.     

Editorial: Biodegradable Materials

This Special Issue “Biodegradable Materials” features research and review papers concerning recent advances on the development, synthesis, testing and characterisation of biomaterials. These biomaterials, derived from natural and renewable sources, offer a potential alternative to existing non-biodegradable materials with application to the food and biomedical industries amongst many others. In this Special Issue, the work is expanded to include the combined use of fillers that can enhance the properties of biomaterials prepared as films. The future application of these biomaterials could have an impact not only at the economic level, but also for the improvement of the environment.     

Symbiotic Nitrogen Fixation in Legume Nodules: Metabolism and Regulatory Mechanisms

The special issue “Symbiotic Nitrogen Fixation in Legume Nodules: Metabolism and Regulatory Mechanisms” aims to investigate the physiological and biochemical advances in the symbiotic process with an emphasis on nodule establishment, development and functioning. The original research articles included in this issue provide important information regarding novel aspects of nodule metabolism and various regulatory pathways, which could have important future implications. This issue also included one review article that highlights the importance of using legume trees in the production of renewable biofuels.     

Theoretical Study of Charge Mobility in Crystal Porphine and a Computer Design of a Porphine-Based Semiconductive Discotic Liquid Mesophase

Organic semiconductors are the focus of numerous studies; they are used in electronic devices. Modern research involves the production of neuromorphic organic materials, including those based on liquid crystal materials. The purpose of this work involves the theoretical modeling of molecules (the “core with branches” type) to construct a discotic mesophase capable of performing the functions of a neuromorphic material. For this purpose, the conductivity of crystal porphine, which can act as the nucleus of a molecule of the “core with branches” type, was investigated. The Marcus theory charge mobility values for the hole and electron were 0.148 and 0.088 cm²/V·s, respectively (the MOO method for calculating transfer integrals), and 0.561 and 0.160 cm²/V·s (DIPRO method). Based on TD-HF (HF-3c level of theory) calculations, possible structures of molecules for the formation of a discotic mesophase are proposed.     

DAMPs and RAGE Pathophysiology at the Acute Phase of Brain Injury: An Overview

Early or primary injury due to brain aggression, such as mechanical trauma, hemorrhage or is-chemia, triggers the release of damage-associated molecular patterns (DAMPs) in the extracellular space. Some DAMPs, such as S100B, participate in the regulation of cell growth and survival but may also trigger cellular damage as their concentration increases in the extracellular space. When DAMPs bind to pattern-recognition receptors, such as the receptor of advanced glycation end-products (RAGE), they lead to non-infectious inflammation that will contribute to necrotic cell clearance but may also worsen brain injury. In this narrative review, we describe the role and ki-netics of DAMPs and RAGE at the acute phase of brain injury. We searched the MEDLINE database for “DAMPs” or “RAGE” or “S100B” and “traumatic brain injury” or “subarachnoid hemorrhage” or “stroke”. We selected original articles reporting data on acute brain injury pathophysiology, from which we describe DAMPs release and clearance upon acute brain injury, and the implication of RAGE in the development of brain injury. We will also discuss the clinical strategies that emerge from this overview in terms of biomarkers and therapeutic perspectives     

Identification of a Plastid-Localized Bifunctional Nerolidol/Linalool Synthase in Relation to Linalool Biosynthesis in Young Grape Berries

Monoterpenoids are a diverse class of natural products and contribute to the important varietal aroma of certain Vitis vinifera grape cultivars. Among the typical monoterpenoids, linalool exists in almost all grape varieties. A gene coding for a nerolidol/linalool (NES/LINS) synthase was evaluated in the role of linalool biosynthesis in grape berries. Enzyme activity assay of this recombinant protein revealed that it could convert geranyl diphosphate and farnesyl diphosphate into linalool and nerolidol in vitro, respectively, and thus it was named VvRILinNer. However, localization experiment showed that this enzyme was only localized to chloroplasts, which indicates that VvRILinNer functions in the linalool production in vivo. The patterns of gene expression and linalool accumulation were analyzed in the berries of three grape cultivars (“Riesling”, “Cabernet Sauvignon”, “Gewurztraminer”) with significantly different levels of monoterpenoids. The VvRILinNer was considered to be mainly responsible for the synthesis of linalool at the early developmental stage. This finding has provided us with new knowledge to uncover the complex monoterpene biosynthesis in grapes.     

Biosurfactants: Multifunctional Biomolecules of the 21st Century

In the era of global industrialisation, the exploration of natural resources has served as a source of experimentation for science and advanced technologies, giving rise to the manufacturing of products with high aggregate value in the world market, such as biosurfactants. Biosurfactants are amphiphilic microbial molecules with hydrophilic and hydrophobic moieties that partition at liquid/liquid, liquid/gas or liquid/solid interfaces. Such characteristics allow these biomolecules to play a key role in emulsification, foam formation, detergency and dispersal, which are desirable qualities in different industries. Biosurfactant production is considered one of the key technologies for development in the 21st century. Besides exerting a strong positive impact on the main global problems, biosurfactant production has considerable importance to the implantation of sustainable industrial processes, such as the use of renewable resources and “green” products. Biodegradability and low toxicity have led to the intensification of scientific studies on a wide range of industrial applications for biosurfactants in the field of bioremediation as well as the petroleum, food processing, health, chemical, agricultural and cosmetic industries. In this paper, we offer an extensive review regarding knowledge accumulated over the years and advances achieved in the incorporation of biomolecules in different industries.     

Childhood B-Cell Preleukemia Mouse Modeling

Leukemia is the most usual childhood cancer, and B-cell acute lymphoblastic leukemia (B-ALL) is its most common presentation. It has been proposed that pediatric leukemogenesis occurs through a “multi-step” or “multi-hit” mechanism that includes both in utero and postnatal steps. Many childhood leukemia-initiating events, such as chromosomal translocations, originate in utero, and studies so far suggest that these “first-hits” occur at a far higher frequency than the incidence of childhood leukemia itself. The reason why only a small percentage of the children born with such preleukemic “hits” will develop full-blown leukemia is still a mystery. In order to better understand childhood leukemia, mouse modeling is essential, but only if the multistage process of leukemia can be recapitulated in the model. Therefore, mouse models naturally reproducing the “multi-step” process of childhood B-ALL will be essential to identify environmental or other factors that are directly linked to increased risk of disease.     

Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to “self” nucleic acids, LL37 acts as “danger signal,” leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while “fully-citrullinated” LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated “adjuvant-like” properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to “fully citrullinated-LL37,” “fully carbamylated-LL37” maintains both innate and adaptive immune-cells’ stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.     

Identification and Expression Analysis of Candidate Genes Associated with Defense Responses to Phytophthora capsici in Pepper Line “PI 201234”

Phytophthora capsici (Leonian), classified as an oomycete, seriously threatens the production of pepper (Capsicum annuum). Current understanding of the defense responses in pepper to P. capsici is limited. In this study, RNA-sequencing analysis was utilized to identify differentially expressed genes in the resistant line “PI 201234”, with 1220 differentially expressed genes detected. Of those genes, 480 were up-regulated and 740 were down-regulated, with 211 candidate genes found to be involved in defense responses based on the gene annotations. Furthermore, the expression patterns of 12 candidate genes were further validated via quantitative real-time PCR (qPCR). These genes were found to be significantly up-regulated at different time points post-inoculation (6 hpi, 24 hpi, and 5 dpi) in the resistant line “PI 201234” and susceptible line “Qiemen”. Seven genes were found to be involved in cell wall modification, phytoalexin biosynthesis, symptom development, and phytohormone signaling pathways, thus possibly playing important roles in combating exogenous pathogens. The genes identified herein will provide a basis for further gene cloning and functional verification studies and will aid in an understanding of the regulatory mechanism of pepper resistance to P. capsici.     

Impact of Four Ovine TMEM154 Haplotypes on Ewes during Multiyear Lentivirus Exposure

Polypeptide variation encoded by the ovine transmembrane protein 154 gene (TMEM154) is associated with susceptibility to ovine lentivirus, the causative agent of Ovine Progressive Pneumonia (OPP) and Visna/Maedi. Our aim was to compare the four most prevalent TMEM154 haplotypes on the incidence of infection and ewe productivity during natural multiyear virus exposure. Prospective cohort studies were designed to test gene action and estimate effects of TMEM154 haplotypes encoding distinctive variant residues: K35 (“1”), I70 (“2”), ancestral (“3”), and A4del/M44 (“4”). Exposure consisted of co-mingling infected ewes at a rate greater than 30% with serological status evaluated every four months. For ewes with one or two copies of the highly susceptible haplotypes “2” and ”3”, the infection prevalence steadily increased to nearly 100% at 55 months. Haplotypes “2” and “3” were equally susceptible and dominant to haplotype “1”. A difference was not detected (p < 0.53) in the magnitude of effect with haplotype combinations of “1” and ”4”. The ewe infection prevalence with “1,1”; “1,4”; and “4,4” was 10% to 40% at 55 months. The latter suggested that two copies of the K35 amino acid substitution (“1”) were as effective as a homozygous TMEM154 “knockout” with the frame-shift deletion mutation (“4”) in reducing infection susceptibility. When considering ewe reproductive performance, a difference was not detected when comparing haplotypes “2”, and “3” to each other, or “1” and “4” to each other. Our study indicated that ewes with two copies of the severely truncated versions of TMEM154 (“4,4”) had normal lamb productivity. Without complete understanding of the natural function of TMEM154 our recommendations to producers interested in using TMEM154 selection to reduce their flock’s genetic predisposition to OPP are encouraged to increase the frequency of TMEM154 haplotype K35 (“1”) since it encodes a full-length protein with minimal difference to the ancestral polypeptide.     

A Perspective on Studies of Phage DNA Packaging Dynamics

The Special Issue “DNA Packaging Dynamics of Bacteriophages” is focused on an event that is among the physically simplest known events with biological character. Thus, phage DNA (and RNA) packaging is used as a relatively accessible model for physical analysis of all biological events. A similar perspective motivated early phage-directed work, which was a major contributor to early molecular biology. However, analysis of DNA packaging encounters the limitation that phages vary in difficulty of observing various aspects of their packaging. If a difficult-to-access aspect arises while using a well-studied phage, a counterstrategy is to (1) look for and use phages that provide a better access “window” and (2) integrate multi-phage-accessed information with the help of chemistry and physics. The assumption is that all phages are characterized by the same evolution-derived themes, although with variations. Universal principles will emerge from the themes. A spin-off of using this strategy is the isolation and characterization of the diverse phages needed for biomedicine. Below, I give examples in the areas of infectious disease, cancer, and neurodegenerative disease.     

Complex Analysis of Antioxidant Activity,Abscisic Acid Level,and Accumulation of Osmotica in Apple and Cherry In Vitro Cultures under Osmotic Stress

Plant response to osmotic stress is a complex issue and includes a wide range of physiological and biochemical processes. Extensive studies of known cultivars and their reaction to drought or salinity stress are very important for future breeding of new and tolerant cultivars. Our study focused on the antioxidant activity, accumulations of osmotica, and the content of abscisic acid in apple (cv. “Malinové holovouské”, “Fragrance”, “Rubinstep”, “Idared”, “Car Alexander”) and cherry (cv. “Regina”, “Napoleonova”, “Kaštánka”, “Sunburst”, “P-HL-C”) cultivated in vitro on media containing different levels of polyethylene glycol PEG-6000. Our results indicated that the studied genotypes responded differently to osmotic stress manifested as reduction in the leaf relative water content (RWC) and increment in the activities of antioxidant enzymes, proline, sugars, and abscisic acid content. Overall, cherry cultivars showed a smaller decrease in percentage RWC and enzymatic activities, but enhanced proline content compared to the apple plants cultivars. Cultivars “Rubinstep”, “Napoleonova”, and “Kaštánka” exhibited higher antioxidant capacity and accumulation of osmoprotectants like proline and sorbitol that can be associated with the drought-tolerance system.     

Controlled Synthesis of Polyions of Heavy Main-Group Elements in Ionic Liquids

Ionic liquids (ILs) have been proven to be valuable reaction media for the synthesis of inorganic materials among an abundance of other applications in different fields of chemistry. Up to now, the syntheses have remained mostly “black boxes”; and researchers have to resort to trial-and-error in order to establish a new synthetic route to a specific compound. This review comprises decisive reaction parameters and techniques for the directed synthesis of polyions of heavy main-group elements (fourth period and beyond) in ILs. Several families of compounds are presented ranging from polyhalides over carbonyl complexes and selenidostannates to homo and heteropolycations.     

State-of-the-Art on Wound Vitality Evaluation: A Systematic Review

The vitality demonstration refers to determining if an injury has been caused ante- or post-mortem, while wound age means to evaluate how long a subject has survived after the infliction of an injury. Histology alone is not enough to prove the vitality of a lesion. Recently, immunohistochemistry, biochemistry, and molecular biology have been introduced in the field of lesions vitality and age demonstration. The study was conducted according to the preferred reporting items for systematic review (PRISMA) protocol. The search terms were “wound”, “lesion”, “vitality”, “evaluation”, “immunohistochemistry”, “proteins”, “electrolytes”, “mRNAs”, and “miRNAs” in the title, abstract, and keywords. This evaluation left 137 scientific papers. This review aimed to collect all the knowledge on vital wound demonstration and provide a temporal distribution of the methods currently available, in order to determine the age of lesions, thus helping forensic pathologists in finding a way through the tangled jungle of wound vitality evaluation.