The coronavirus pandemic was declared by the World Health Organization (WHO) in 2020, and a global genetic vaccination program has been rapidly implemented as a fundamental solution. However, many countries around the world have reported that so-called genetic vaccines, such as those using modified mRNA encoding the spike protein and lipid nanoparticles as the drug delivery system, have resulted in post-vaccination thrombosis and subsequent cardiovascular damage, as well as a wide variety of diseases involving all organs and systems, including the nervous system. In this article, based on these circumstances and the volume of evidence that has recently come to light, we call the attention of medical professionals to the various risks associated with blood transfusions using blood products derived from people who have suffered from long COVID and from genetic vaccine recipients, including those who have received mRNA vaccines, and we make proposals regarding specific tests, testing methods, and regulations to deal with these risks. We expect that this proposal will serve as a basis for discussion on how to address post-vaccination syndrome and its consequences following these genetic vaccination programs.

Background: COVID-19 vaccines have been linked to myocarditis which in some circumstances can be fatal. This systematic review aims to investigate potential causal links between COVID-19 vaccines and death from myocarditis using post-mortem analysis. Methods: We performed a systematic review of all published autopsy reports involving COVID-19 vaccination-related myocarditis through July 3^rd, 2023. All autopsy studies that include COVID-19 vaccine-induced myocarditis as a possible cause of death were included, without imposing any additional restrictions. Causality in each case was determined by three independent reviewers with cardiac pathology experience and expertise. Results: We initially identified 1,691 studies and, after screening for our inclusion criteria, included 14 papers that contained 28 autopsy cases. The cardiovascular system was the only organ system affected in 26 cases. In 2 cases, myocarditis was characterized as a consequence from multisystem inflammatory syndrome (MIS). The mean and median number of days from last COVID-19 vaccination until death was 6.2 and 3 days, respectively. Most of the deaths occurred within a week from the last injection. We established that all 28 deaths were causally linked to COVID-19 vaccination by independent adjudication. Conclusions: The temporal relationship, internal and external consistency seen among cases in this review with known COVID-19 vaccine-induced myocarditis, its pathobiological mechanisms and related excess death, complemented with autopsy confirmation, independent adjudication, and application of the Bradford Hill criteria to the overall epidemiology of vaccine myocarditis, suggests there is a high likelihood of a causal link between COVID-19 vaccines and death from suspected myocarditis in cases where sudden, unexpected death has occurred in a vaccinated person. Urgent investigation is required for the purpose of risk stratification and mitigation in order to reduce the population occurrence of fatal COVID-19 vaccine-induced myocarditis.

Background: A significant proportion of SARS-CoV-2-infected patients develops respiratory failure. Thromboembolism is also prevalent in coronavirus disease 2019 (Covid-19). Vitamin K plays a role in coagulation and possibly also in lung diseases. We therefore hypothesized that vitamin K is implicated in Covid-19 pathogenesis. Methods: 134 Covid-19 patients and 184 controls were included. Inactive vitamin K-dependent matrix Gla protein (i.e.dp-ucMGP) and prothrombin (i.e. PIVKA-II) were measured, which are inversely related to respectively extrahepatic and hepatic vitamin K status. Desmosine was measured to quantify elastic fiber degradation. Lung involvement and arterial calcifications severity were assessed by computed tomography. Results Dp-ucMGP was elevated in Covid-19 patients compared to controls (P=0.001). Higher dp-ucMGP was found in Covid-19 patients with poor compared to better outcomes (P=0.002). PIVKA-II was normal in 81.8%, mildly elevated in 14.0% and moderately elevated in 4.1% of Covid-19 patients not using vitamin K antagonists. Dp-ucMGP in Covid-19 patients was correlated with desmosine (P<0.001), thoracic aortic calcification (P<0.001) but not with pneumonia severity. Conclusions: Extrahepatic vitamin K status was severely reduced in Covid-19 patients, as reflected by elevated inactive MGP, and related to poor outcome. Procoagulant prothrombin activity remained preserved in the majority of Covid-19 patients, which is compatible with the increased thrombogenicity that is frequently observed in severe Covid-19. Impaired MGP activation was linked to accelerated elastic fiber degradation and premorbid vascular calcifications. A trial should assess whether increasing MGP and protein S activity by vitamin K administration improves Covid-19 outcomes.

As a result of the spread of SARS-CoV-2, a global pandemic was declared. Indiscriminate COVID-19 vaccination has been extended to include age groups and naturally immune people with minimal danger of suffering serious complications due to COVID-19. Solid immuno-histopathological evidence demonstrates that the COVID-19 genetic vaccines can display an off-target distribution in tissues that are terminally differentiated, triggering autoimmune reactions. These include the heart and brain, which may incur in situ production of spike protein eliciting a strong autoimmunological inflammatory response. Due to the fact that every human cell which synthesizes non-self antigens becomes inevitably the target of the immune system, and since the human body is not a strictly compartmentalized system, accurate pharmacokinetic and pharmacodynamic studies are needed in order to determine precisely which tissues can be harmed. Therefore, our article aims to draw the attention of the scientific and regulatory communities on the critical need of bio-distribution studies for the genetic vaccines against COVID-19, as well as of rational harm-benefit assessments by age group.

We present a case of a 47-year-old male who died unexpectedly from acute pulmonary hemorrhage 555 days after completing the BNT162b2 (Pfizer) COVID-19 vaccination primary series. Before death, he exhibited symptoms of a mild respiratory infection. Despite a healthy medical history and no medication use, the patient’s condition rapidly deteriorated and he experienced severe respiratory distress, followed by cardiopulmonary arrest with evidence of profuse pulmonary bleeding. Autopsy findings revealed massive lung congestion without embolism, normal heart size, moderate coronary atherosclerosis without myocardial infarction, and no evidence of other hemorrhagic events. The patient tested negative for COVID-19 and other respiratory pathogens at autopsy. Despite these findings, the medical examiner determined the cause of death was attributed to atherosclerotic and hypertensive cardiovascular disease, without considering the recent pulmonary hemorrhage and unremarkable medical history. Investigation into the vaccine batch indicated a higher-than-average number of serious adverse events, including fatalities. The patient's BNT162b2 batch was among the top 2.8% for reported deaths. Moreover, the autopsy failed to investigate potential contributions from the vaccine, such as the presence of the Spike protein or related antibodies. The evidence suggests that the pulmonary hemorrhage, exacerbated by a viral infection, was the immediate cause of death, with the COVID-19 vaccine potentially playing a role in the development of cardiopulmonary pathology and hemorrhage. We propose autopsy protocols for COVID-19 vaccine recipients to better investigate vaccine-related pathologies among those with one or more prior injections.

Smoking is a risk factor for respiratory infections and there is reasonable concern that it may affect COVID-19 susceptibility and severity. Recent studies have focused on the interaction between smoking (and nicotine) and ACE2 expression, suggesting that ACE2 up-regulation could contribute to enhanced viral cell entry. However, case series have shown that there is an unexpectedly low prevalence of smoking among hospitalized COVID-19 cases. Since early April, we were the first to hypothesize that dysfunction of the nicotinic cholinergic system (NCS) may be implicated in the pathophysiology of severe COVID-19. We recently reported that many of the clinical manifestations of severe COVID-19 could be explained by dysregulation of the NCS. In this study, we present an amino acid sequence in the receptor binding domain of the SARS-CoV-2 Spike glycoprotein which is homologous to a sequence of a snake venom toxin. We present the 3D structural location of this “toxin-like” sequence on the Spike Glycoprotein. These findings suggest that SARS-CoV-2 could potentially interact with acetylcholine receptors causing dysregulation of the NCS and the cholinergic anti-inflammatory pathway.

Public health practices including handwashing and vaccinations help reduce the spread and impact of infections. Nevertheless, the global burden of infection is high, and additional measures are necessary. Acute respiratory tract infections, for example, are responsible for approximately 2.65 million deaths per year. The role nutrition plays in supporting the immune system is well-established. A wealth of mechanistic and clinical data show that vitamins, including vitamins A, B6, B12, C, D, E, and folate; trace elements, including zinc, iron, selenium, magnesium, and copper; and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid play important and complementary roles in supporting the immune system. Inadequate intake and status of these nutrients are widespread, leading to a decrease in resistance to infections and as a consequence an increase in disease burden. Against this background the following conclusions are made: 1) Supplementation with the above micronutrients and omega-3 fatty acids is a safe, effective, and low-cost strategy to help support optimal immune function; 2) Supplementation above the RDA, but within recommended upper safety limits, for specific nutrients such as vitamins C and D is warranted; and 3) Public health officials are encouraged to include nutritional strategies in their recommendations to improve public health.

Spike (S) protein of Coronaviruses help in receptor attachment and virus entry into the host cells. While S protein is required for virus entry, it is also important as an immunogen as it is the most accessible part of the virus architecture. S protein form knob like structures (viral spikes) protruding outwards in the form of homotrimers containing an S1 and S2 as monomers. Mutations in structural proteins of virus play crucial role in determining virulence and also in many instances influencing emergence of antibody escape variants and cellular tropism. In this paper we have performed in depth analyses of spike protein sequences from various parts of the world and tried to correlate the data with possible functional relevance of such mutations.

Few data are available on the health impact of tobacco heating products (THPs) at the population level. We used systems dynamics modelling to estimate effects in the established THP market in Japan. We projected effects of THP use in overall mortality up to 2100 and compare those projections against a baseline scenario based on smoking rates pre-THP launch, i.e., smoking only. The model was informed using data from publicly available sources and the literature, including population size, yearly deaths and smoking prevalence with initialisation year (2004) and, births and migration from 2004 to 2065. Transitions between products were estimated from cross-sectional population surveys in Japan. Potential life-years saved with the introduction of THPs was 13 million by 2100 compared with smoking only. In worst-case scenario, population health gains would be seen with THPs risk 10–50% lower risk than smoking. Assuming equal risk for dual use and smoking, THP risk would need to be at least 10% lower than smoking to achieve a population health benefit by 2100. In credible scenarios, substantial population health gains will follow the introduction of THPs in Japan in a relatively short time frame.

Complex systems exhibit critical thresholds at which they transition among alternative phases. Complex systems theory has been applied to analyze disease progression, distinguishing three stages along progression: (i) a normal non-infected state, (ii) a pre-disease state in which the host is infected and responds; therapeutic interventions could still be effective, (iii) an irreversible state, where the system is seriously threatened. The Dynamical Network Biomarker (DNB) theory sought for early-warnings of the transition from health to disease. Such DNBs might range from individual genes to complex structures in transcriptional regulatory or protein-protein interaction networks. Here we revisit transcriptomic data obtained during infection of tobacco plants with tobacco etch potyvirus to identify DNBs signaling the transition from mild/reversible to severe/irreversible disease. We identified genes showing a sudden transition in expression along disease. Some of these genes cluster in modules that show the properties of DNBs. These modules contain both genes known to be involved in response to pathogens (e.g., ADH2, CYP19, ERF1, KAB1, LAP1, MBF1C, PR1, or TPS5) and other genes not previously related to biotic stress responses (e.g., ABCI6, BBX21, NAP1, OSM34, or ZPN1).

Humanity’s social and economic development has been challenged by a range of adversities over the millennia that have caused widespread and unimaginable suffering. At the same time, these challenges have forced humans to evolve more wisely, overcoming adversity through creativity and leading to advancements in science and technology, medicine, ethics and legal systems, and socio-political systems. The dynamics of risks and opportunities caused by COVID-19, in the built, cyber, social and economic environments, present opportunities for deepening our understanding of resilient and sustainable development and infrastructure. This article reflects on five lessons that COVID-19 is teaching us about what it means to develop sustainably through the lens of transportation: (1) sustainable development planning and analytical frameworks must be comprehensive, for long-term sustainability; (2) multi-modal transportation is a superior vision for sustainable development than any one particular mode; (3) tele-activities are part of an effective infrastructure sustainability strategy; (4) economic capital is critically important to sustainable development even when it is not a critical existential threat, and, (5) effective social capital is essential in global disaster resistance and recovery, and can and must be leveraged between fast-moving and slow-moving disasters. Resilient and sustainable infrastructure will continue to be critical to addressing evolving natural and man-made hazards in the 21^st Century.

Exploring the biological significance of mutations in SARS-CoV-2 coronavirus, causing the COVID–19 pandemic, has recently become an area of paramount interest for many researchers, who are pouring their tremendous efforts, in cracking the COVID–19 pandemic code. One of many such mutations that have occurred in the viral genome is V483A mutation, which is a part of the receptor-binding motif (RBM), present in the S1 domain of the spike protein. V483A mutant virus is becoming popular in North America with 36 cases so far, due to its frequent occurrences in recent days. In this review, we have assembled all information, currently available on V483A mutation, and have made a critical analysis based on the perspectives of many researchers all around the world. Comparison is made between the wild type and the V483A mutants to analyze certain factors like the type of interaction between the virus and host cell interface, binding affinity, stability, partition energy, hydrophobicity, occurrence rate, and transmissibility. Insilico dynamic analysis shows minimal alteration in the receptor-binding domain (RBD) of V483A mutant protein in free-state and no significant change of mutant tertiary structure of RBM upon binding to the ACE2 receptor. Comprehensive details about infectivity and evasion of the immune system by the virus are discussed. This information can in turn be of monumental importance in the field of vaccine and drug development because the mutants are becoming resistant to the vaccines and monoclonal antibodies.

Fasting, a practice with historical roots in various cultures, has recently garnered significant interest in the field of medicine. In this article, we delve into the mechanisms underlying fasting-induced autophagy and its therapeutic applications for spike protein associated pathology. We explore the therapeutic potential of fasting on spike protein-related pathology. Additionally, we discuss factors that affect fasting, such as duration, type (dry vs. water), and the role of specific compounds like spermidine, resveratrol, rapamycin, and metformin. Furthermore, we analyse the interactions between fasting and other practices such as exercise, and highlight important considerations regarding participant characteristics, including pregnancy, breastfeeding, medication interactions, and metabolic disorders. In conclusion, fasting, coupled with an understanding of its nuances, holds promise as a therapeutic intervention with broad implications for human health.

The existence of a common ancestor to all living organisms in Earth is a necessary corollary of Darwin idea of common ancestry. The Last Universal Common Ancestor (LUCA) has been normally considered as the ancestor of cellular organisms that originated the three domains of life: Bacteria, Archaea and Eukarya. Recent studies about the nature of LUCA indicate that this first organism should present hundreds of genes and a complex metabolism. Trying to bring another of Darwin ideas into the origins of life discussion, we went back into the prebiotic chemistry trying to understand how LUCA could be originated under gradualist assumptions. Along this line of reasoning, it became clear to us that the definition of another ancestral should be of particular relevance to the understanding about the emergence of biological systems. Together with the view of biology as a language for chemical translation, on which proteins are encoded into nucleic acids polymers, we glimpse a point in the deep past on which this Translation mechanism could have taken place. Thus, we propose the emergence of this process shared by all biological systems as a point of interest and propose the existence of this pre-cellular entity named FUCA, as the First Universal Common Ancestor. FUCA was born in the very instant on which RNA-world replicators started to be capable to catalyze the bonding of amino acids into oligopeptides. FUCA has been considered mature when the translation system apparatus has been assembled together with the establishment of a primeval, possibly error-prone genetic code. This is FUCA, the earliest ancestor of LUCA’s lineage.

SARS-CoV-2 mRNA vaccination can entail chronic fatigue/dis-autonomy tentatively termed post-acute COVID-19 vaccination syndrome (PACVS). We explored receptor autoantibodies and interleukin-6 (IL-6) as somatic correlates of PACVS. Blood markers determined before and six months after first-time SARS-CoV-2-vaccination of healthy controls (N = 89, 71 females, mean/ median age 39/ 49 years) were compared with corresponding values of PACVS-affected persons (N= 191, 159 females, mean/median age: 40/39 years) exhibiting chronic fatigue/dis-autonomy (≥ three symptoms for ≥ five months after last SARS-CoV-2 mRNA vaccination) not due to SARS-CoV-2 infection and/or confounding diseases/medications. Normal vaccination response encompassed decreases of 11 receptor-antibodies (by 25 - 50 %, p < 0.0001), increases in two receptor-antibodies (by 15 - 25 %, p < 0.0001) and normal IL-6. In PACVS, serological vaccination-response appeared significantly (p < 0.0001) altered, allowing discrimination from normal post-vaccination state (sensitivity = 90%, p &lt; 0.0001) by increased angiotensin II type 1 receptor antibodies (cut-off ≤ 10.7 U/ml, ROC-AUC = 0.824 ± 0.027), decreased alpha-2B adrenergic receptor antibodies (cut-off ≥ 25.2 U/ml, ROC-AUC = 0.828 ± 0.025) and increased IL-6 (cut-off ≤ 2.3 pg/ml, ROC-AUC = 0.850 ± 0.022). PACVS is thus indicated as a somatic syndrome delineated/detectable by diagnostic blood markers

An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) occurred in China towards the end of 2019, and has spread rapidly ever since. Previous studies showed that some virus could affect the reproductive system and cause long-term complications. Recent studies exploring the source of SARS-CoV-2 using genomic sequencing have revealed that SARS-CoV-2 enters the host cells via the angiotensin-converting enzyme II (ACE2), the receptor that recognizes SARS-CoV. To investigate the expression of ACE2 and to explore the potential risk of infection in the reproductive system, we performed a thorough bioinformatic analysis on data from public databases involving RNA expression, protein expression, and single-cell RNA expression studies. The analyzed data showed high levels of ACE2 mRNA and protein expression in the testis and spermatids and equal levels of ACE2 expression in the uterus and lung. Comprehensive single-cell analysis identified ACE2 expression in the lung, testis, spermatids, and uterus. In conclusion, this study revealed the potential risk associated with the SARS-CoV-2 infection in the reproductive system and predicted that long-term complications might have a significant impact on the prevention and management of COVID-19, the disease caused upon infection with SARS-CoV-2.

This case study investigates the heart rate (HR) and heart rate variability (HRV) in a patient with coronavirus disease 2019 (COVID-19). We report the case of a 58-year old male who contracted COVID-19. During his disease, 24-hour Holter electrocardiography (ECG) was performed continuously. For comparison, his 24-hour Holter ECGs from the previous 10 years were available. In this patient, COVID-19 was associated with a decrease in HR and a paradoxical decline in HRV. An abrupt decline in HRV and a decrease in HR may signal the onset of COVID-19 before common symptoms such as dry cough or fever appear. In addition, HRV and HR measurements may help to evaluate the course of the disease.

New coronavirus (SARS-CoV-2) treatments and vaccines are under development to combat the COVID-19 disease. Several approaches are being used by scientists for investigation including 1) various small molecule approaches targeting RNA polymerase, 3C-like protease, and RNA endonuclease and 2) exploration of antibodies obtained from convalescent plasma from patients who have recovered from COVID-19. The coronavirus genome is highly prone to mutations that lead to genetic drift and escape from immune recognition; thus, it is imperative that sub-strains with different mutations are also accounted for during vaccine development. As the disease has grown to become a pandemic, new B-cell and T-cell epitopes predicted from SARS coronavirus have been reported. Using the epitope information along with variants of the virus, we have found several variants which might cause drifts. Among such variants, 23403A>G variant (p.D614G) in spike protein B-cell epitope is observed frequently in European countries such as the Netherlands, Switzerland and France.

Biomolecular structure drives function, and computational capabilities have progressed such that the prediction and computational design of biomolecular structures is increasingly feasible. Because computational biophysics attracts students from many different backgrounds and with different levels of resources, teaching the subject can be challenging. One strategy to teach diverse learners is with interactive multimedia material that promotes self-paced, active learning. We have created a hands-on education strategy with a set of fifteen modules that teach topics in biomolecular structure and design, from fundamentals of conformational sampling and energy evaluation to applications like protein docking, antibody design, and RNA structure prediction. Our modules are based on PyRosetta, a Python library that encapsulates all computational modules and methods in the Rosetta software package. The workshop-style modules are implemented as Jupyter Notebooks that can be executed in the Google Colaboratory, allowing learners access with just a web browser. The digital format of Jupyter Notebooks allows us to embed images, molecular visualization movies, and interactive coding exercises. This multimodal approach may better reach students from different disciplines and experience levels as well as attract more researchers from smaller labs and cognate backgrounds to leverage PyRosetta in their science and engineering research. All materials are freely available at https://github.com/RosettaCommons/PyRosetta.notebooks.

Acetylcholine (ACh) is the best one characterized neurotransmitter. Its central roles in the cholinergic areas and central nervous system (CNS) and peripheral (PNS) synapses are well known. It was the first molecule identified as a neurotransmitter and appears to be phylogenetically the oldest one signaling molecules. ACh was detected in bacteria, protozoa, fungi, algae and primitive plants, indicating that the cholinergic system was widely distributed in living organisms before its appearance in the nervous system. The autonomous nervous system (ANS) is an integral part animal kingdom history. It determines fight-escape reactions as well as outlining the vital and cognitive functions bio-organization rhythms. The virus (Covid-19) extraneous effects acting on it could help to better understand its functions. The Blast results show some factors like protein that can be implicated such as bungaro-toxins, phospholipase A2 and the similar prothrombin activator protein. A positive correlation with different toxins is obtained and the Covid-19 double pathogenic mechanism theory is proposed. The process allows us to outline the possibility about toxic-like factors presence.

Presence and identity of secondary metabolites are two of the main components of lichen taxonomy. Aromatic compounds formed via the acetyl-polymalonate pathway are the most studied lichen substances. In addition, compounds derived from the mevalonic acid pathway (e.g., terpenes and steroids) are sometimes detected in the medulla. However, their identity and value as diagnostic characters in the genus Usnea are yet poorly understood despite the fact that they were mentioned in several taxonomical papers. We conclude that i) aside from the previously recognized polyphenolic compounds, carbohydrates and steroids are also detected in the medulla of some Usnea species; ii) the use of sulfuric anisaldehyde reagent greatly improves the detection of terpenes, carbohydrates and steroids compared with the sulfuric acid reagent routinely used in thin layer chromatography; iii) among carbohydrates, we detected arabitol and sucrose in the medulla; iv) steroids and terpenes remain unidentified and deserve further investigations.

This paper presents ROSGPT, an innovative concept that harnesses the capabilities of large language models (LLMs) to significantly advance human-robot interaction. We develop ROSGPT as a ROS2 package that seamlessly integrates ChatGPT with ROS2-based robotic systems. The core idea is to leverage prompt engineering with LLMs, specifically ChatGPT, utilizing its unique properties such as ability eliciting, chain-of-thought, and instruction tuning. The concept employs ontology development to convert unstructured natural language commands into structured robotic instructions specific to the application context through prompt engineering. We capitalize on LLMs' zero-shots and few-shots learning capabilities by eliciting \textit{structured} robotic commands from \textit{unstructured} human language inputs. To demonstrate the feasibility of this concept, we implemented a proof-of-concept that integrates ChatGPT with ROS2, showcasing the transformation of human language instructions into spatial navigation commands for a ROS2-enabled robot. This versatile concept can be easily adapted to various other robotic missions. ROSGPT serves as a new stride towards Artificial General Intelligence (AGI) and paves the way for the robotics and natural language processing communities to collaborate in creating novel, intuitive human-robot interactions. The open-source implementation of ROSGPT on ROS 2 is available on GitHub.

The novel coronavirus (SARS-CoV-2) is a human pathogen recently emerged in China, causing a global pandemic of severe respiratory illness (COVID19). SARS-CoV-2 makes entry into human cells through its spike (S) protein that binds to cell surface receptors. Widespread of SARS-CoV-2 has been attributed to high affinity of S protein to its receptor. A homology model of the receptor binding domain of SARS-CoV-2 S protein (RBD) was built. RBD- receptor docking and published molecular dynamics data were used to map the key RBD-receptor interaction hotspot (RBDhp) on the RBD. Primary virtual screening was carried out against RBDhp using more than 3300 compounds approved by U.S Food and Drug Administration (FDA) and other authorities for human use. Compounds that bind to hpRBD with a binding energy ≤ - 6.5 kcal/mol were subjected to secondary screening using a recently published cryo EM (2.9 Å) structure of RBD. A cardiac glycoside (dgitoxin), two anthracyclines (zorubicin and aclarubicin), a tetracycline derivative (rolitetracycline), a cephalosporin (cefoperazone) and a food dye (E-155) were predicted to be most potent inhibitors of RBD – receptor interaction. An anti-asthmatic drug (zafirlukast) and several other drugs (itrazol, fazadinium, troglitazone, gliquidone, Idarubicin, Oxacillin) were found to be high affinity binders that may have a potential to inhibit RBD – receptor interaction.

The recent outbreak of the new virus in Wuhan city, China from the sea food market has led to the identification of a new strain called the corona virus and named as novel corona virus (2019-nCoV) belonging to Coronaviridae family. This has created major havoc and concern due to the mortality of 250 persons and affecting more than 10,000 people. This virus causes sudden fever, pneumonia and also kidney failure. In this study a computational approach is proposed for drug and vaccine design. The spike protein sequences were collected from a protein database and analysed with various bioinformatics tools to identify suitable natural inhibitors for the N-terminal receptor binding domain of spike protein. Also, it is attempted to identify suitable vaccine candidates by identifying B-Cell and T-cell epitopes. In the drug design, the tanshinone Iia and methyl Tanshinonate were identified as natural inhibitors based on the docking score. In the vaccine design, B-cell epitope VLLPLVSSQCVNLTTRTQLPPAYTN was found to have the highest antigenicity. FVFLVLLPL of MHC class-I allele and FVFLVLLPL of MHC class-II allele were identified as best peptides based on a number of alleles and antigencity scores. The present study identifies natural inhibitors and putative antigenic epitopes which may be useful as effective drug and vaccine candidates for the eradication of novel corona virus.

There is much discussion among clinicians, epidemiologists, and public health experts about why case fatality rate from COVID-19 in Italy (at 13.3% as of April 20, 2020, versus a global case fatality rate of 6.9%) is considerably higher than estimates from other countries (especially China, South Korea, and Germany). In this article, we propose several potential explanations for these differences. We suggest that Italy’s overall and relative case fatality rate, as reported by public health authorities, is likely to be inflated by such factors as heterogeneous reporting of coronavirus-related fatalities across countries and the iceberg effect of under-testing, yielding a distorted view of the global severity of the COVID-19 pandemic. We also acknowledge that deaths from COVID-19 in Italy are still likely to be higher than in other equally affected nations due to its unique demographic and socio-economic profile. Lastly, we discuss the important role of the stress imparted by the epidemic on the Italian healthcare system, which weakened its capacity to adequately respond to the sudden influx of COVID-19 patients in the most affected areas of the country, especially in the Lombardy region.

Pneumonia caused by a new coronavirus SARS-CoV-2 has caused serious harm to people's lives and health in Wuhan, China. By February 26, 2020, over 80,000 people were infected and 2,814 died from the infection. The initial route of infection is the binding of the spike protein (S protein) of the virus to the angiotensin-converting enzyme 2 (ACE2). From bioinformatics analysis, we found that the S protein of SARS-CoV-2 produced an evolutionary mutation of K403R compared with the S protein of SARS-CoV, forming an adjacent RGD motif at the interaction surface. As the RGD motif is considered as a ligand for many cell surface integrins, we proposed that the binding of S protein of SARS-CoV-2 with integrins may facilitate the infection process of the virus. Therefore, high-throughput virtual screening was performed by choosing the key residues of S protein interface of SARS-CoV-2 and the adjacent RGD motif as potential binding site, to search for the potential agents targeting interaction of S protein of SARS-CoV-2 with both ACE2 and integrins as potential therapeutic drugs. Various libraries including the FDA-approved drugs etc. were screened, and Nadide, Losartan, 9'''-Methyllithospermate B and Leonurine etc. were identified as representative potential drugs candidate for COVID-19.

The relative force strengths of the Coulomb forces, gravitational forces, dark matter forces, weak forces and strong forces are compared for the dark matters, leptons, quarks, and normal matters (p and n baryons) in terms of the 3-D quantized space model. The quark confinement and asymptotic freedom are explained by the CC merging to the A(CC=-5)₃ state. The proton with the (EC,LC,CC) charge configuration of p(1,0,-5) is p(1,0) + A(CC=-5)₃. The A(CC=-5)₃ state has the 99.6% of the proton mass. The three quarks in p(1,0,-5) are asymptotically free in the EC and LC space of p(1,0) and are strongly confined in the CC space of A(CC=-5)₃. This means that the lepton beams in the deep inelastic scattering interact with three quarks in p(1,0) by the EC interaction and weak interaction. Then, the observed spin is the partial spin of p(1,0) which is 32.6 % of the total spin (1/2) of the proton. The A(CC=-5)₃ state has the 67.4 % of the proton spin. This explains the proton spin crisis. The EC charge distribution of the proton is the same to the EC charge distribution of p(1,0) which indicates that three quarks in p(1,0) are mostly near the proton surface. From the EC charge distribution of neutron, the 2 lepton system (called as the koron) of the koron is, for the first time, reported in the present work.

The process of modelling energy systems is accompanied by challenges inherently connected with mathematical modelling. However, due to modern realities in the 21st century, existing challenges are gaining in magnitude and are supplemented with new ones. Modellers are confronted with a rising complexity of energy systems and high uncertainties on different levels. In addition, interdisciplinary modelling is necessary for getting insight in mechanisms of an integrated world. At the same time models need to meet scientific standards as public acceptance becomes increasingly important. In this intricate environment model application as well as result communication and interpretation is also getting more difficult. In this paper we present the open energy modelling framework (oemof) as a novel approach for energy system modelling and derive its contribution to existing challenges. Therefore, based on literature review, we outline challenges for energy system modelling as well as existing and emerging approaches. Based on a description of the philosophy and elementary structural elements of oemof, a qualitative analysis of the framework with regard to the challenges is undertaken. Inherent features of oemof such as the open source, open data, non-proprietary and collaborative modelling approach are preconditions to meet modern realities of energy modelling. Additionally, a generic basis with an object-oriented implementation allows to tackle challenges related to complexity of highly integrated future energy systems and sets the foundation to address uncertainty in the future. Experiences from the collaborative modelling approach can enrich interdisciplinary modelling activities. Our analysis concludes that there are remaining challenges that can neither be tackled by a model nor a modelling framework. Among these are problems connected to result communication and interpretation.

Many of the wide-ranging symptoms of COVID-19 have not been associated previously with a respiratory illness. A similarity between these atypical symptoms and the symptoms of malnutrition was observed. To investigate, a comparison of COVID-19 symptomatology with recognised states of malnutrition showed a significant relationship that was further explored in a review of the literature. This hypothesis links the atypical symptoms to the effects of increasing protein malnutrition. The rapid appearance of malnutrition symptoms at the beginning of the COVID-19 infection is concurrent with the rapid cell proliferation of the immune system. Although previous work has, in general, assumed that the body is capable of providing for the needs of the immune system during infection, heightened immune activity from the commencement of COVID-19 could require an early increase in energy yielding sources. Should insufficient availability of protein resources occur, this could quickly lead to malnutrition. Any continuing insufficiency, during the active phase of the virus, might result in widespread depletions in the tissues and the consequential malfunctioning of many organs. A new appraisal of the immune system requirements needed to counteract the impact of the novel virus, COVID-19, could show the potential benefit for earlier protein intervention in the disease process. This hypothesis could also have relevance for other life situations where a rapid cell proliferation might occur.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

Pneumonia is a severe lower respiratory tract infection that is a common complication and a major cause of mortality of the vitamin C-deficiency disease scurvy. This suggests an important link between vitamin C status and lower respiratory tract infections. Due to the paucity of information on the vitamin C status of patients with pneumonia, we assessed the vitamin C status of 50 patients with community-acquired pneumonia and compared these with 50 healthy community controls. The pneumonia cohort comprised 44 patients recruited through the Acute Medical Assessment Unit (AMAU) and 6 patients recruited through the intensive care unit (ICU); mean age 68 ± 17 years, 54% male. Clinical, microbiological and haematological parameters were recorded. Blood samples were tested for vitamin C status using HPLC with electrochemical detection and protein carbonyl concentrations, a marker of oxidative stress, using ELISA. Patients with pneumonia had depleted vitamin C status compared with healthy controls (23 ± 14 µmol/L vs 56 ± 24 µmol/L, P <0.001). The more severe patients in the ICU had significantly lower vitamin C status than those recruited through AMAU (11 ± 3 µmol/L vs 24 ± 14 µmol/L, P = 0.02). The total pneumonia cohort comprised 62% with hypovitaminosis C and 22% with deficiency, compared with only 8% hypovitaminosis C and no cases of deficiency in the healthy controls. The pneumonia cohort also exhibited significantly elevated protein carbonyl concentrations compared with the healthy controls (P < 0.001), indicating enhanced oxidative stress in the patients. We were able to collect subsequent samples form 28% of the cohort (mean 2.7 ± 1.7 days; range 1-7 days). These showed no significant differences in vitamin C status or protein carbonyl concentrations compared with baseline values (P = 0.6). Overall, the depleted vitamin C status and elevated oxidative stress observed in the patients with pneumonia indicates an enhanced requirement for the vitamin during their illness. Due to the important roles that vitamin C plays in the immune system, low vitamin C status is possibly both a cause and a consequence of the disease. Therefore, these patients would likely benefit from additional vitamin C supplementation to restore their blood and tissue levels to optimal. This may decrease oxidative stress and aid in their recovery.

COVID-19 is a novel severe acute respiratory syndrome coronavirus. Presently, there is no effective treatment for COVID-19. As part of the worldwide efforts to find efficient therapies and preventions, it has been reported the crystalline structure of the SARS-CoV-2 main protease Mpro (also called 3CL^pro) bound to a synthetic inhibitor which represents a major druggable target. The druggability of Mpro could be used for discovering drugs to treat coronavirus disease 2019. It was carried out a multi-level computational study to evaluate the potential anti-viral properties of the components of the medicinal herb Uncaria tomentosa (Cat´s claw) focusing on the inhibition of M^pro. The in-silico approach starts with protein-ligand docking of 26 Cat’s claw key components followed by ligand pathway calculations, molecular dynamics simulations and MM-GBSA calculation of the free energy of binding for the best docked candidates. The structural bioinformatics approaches led to the identification of three bioactive compounds of Uncaria tomentosa (Speciophylline, Cadambine and Proanthocyanidin B2) with potential therapeutic effects by strong interaction with 3CLpro. Additionally, in silico drug-likeness indices for these components were calculated and show good predicted therapeutic profiles of these phytochemicals. Our findings suggest the potential effectiveness of Cat's claw as complementary and/or alternative medicine for COVID-19 treatment.

We analyzed the SARS-CoV-2 spike (S) protein amino acid sequence extracted from 11,542 viral genomic sequences submitted to the Global Initiative on Sharing All Influenza Data (GISAID) database through April 27, 2020. Consistent with prior reports, we found a major S protein mutation, D614 to G614, that was represented in 56% of all the analyzed sequences. All other mutations combined were less than 10%. After parsing the data geographically, we found most of the Chinese patient samples showed D614 (97%). By contrast, most patient samples in many European countries showed G614 (51 to 88%). In the United States, the genotypic distribution in California and Washington was similar to Asian countries, while the distribution in other US states was comparable to Europe. We observed a dramatic increase in the frequency of G614 over time in multiple regions, surpassing D614 when both were present, suggesting G614 S protein virus outcompetes D614 S protein virus. To gain insight into the consequences of the D614G mutation, homology modeling using a multi-template threading mechanism with ab initio structural refinement was performed for a region of the S protein (S591 to N710) spanning the D614G mutation and the S1 furin cleavage site. Molecular models of this region containing D614 or G614 revealed a major difference in secondary structure at the furin domain (RRARS, R682 to S686). The D614 model predicted a random coil structure in the furin domain whereas the G614 model predicted an alpha helix. Critical residues in the cleavage domain of G614 model were found to better align with the PDB structure of a furin inhibitor. Thus, homology modeling studies suggest a potential mechanism whereby the D614G mutation may confer a competitive advantage at the furin binding domain that may contribute to the rise of the D614G SARS-CoV-2 mutant.

The outbreak of 2019-novel coronavirus (SARS-CoV-2) that causes severe respiratory infection (COVID-19) has spread in China, and the world health organization declared it pandemic. However, no approved drug or vaccines are available, and treatment is mainly supportive and through a few repurposed drugs. In this urgency situation, development of SARS-CoV-2 based vaccines is immediately required. Immunoinformatic and molecular modelling are generally used time-efficient methods to accelerate the discovery and design of the candidate peptides for vaccine development. In recent years, the use of multiepitope vaccines is proved to be a promising immunization strategy against viruses and pathogens, which induce more comprehensive protective immunity. The current study demonstrated a comprehensive in-silico strategy to design stable multiepitope vaccine construct (MVC) from B-cell and T-cell epitopes of essential SARS-CoV-2 proteins with the help of adjuvants and linkers. The integrated molecular dynamics simulations analysis revealed the stability of MVC and its interaction with human Toll-like receptors (TLRs), which trigger an innate and adaptive immune response. Later, the in-silico cloning in a known pET28a vector system also estimated the possibility of MVC expression in E. Coli. Despite this study lacks validation of this vaccine construct in terms of its efficacy, the current integrated strategy encompasses the initial multiple epitope vaccine design concepts. After validation, this MVC can present to be a better prophylactic solution against COVID-19.

The Rosetta software suite for macromolecular modeling, docking, and design is widely used in pharmaceutical, industrial, academic, non-profit, and government laboratories. Considering its broad modeling capabilities, Rosetta consistently ranks highly when compared to other leading methods created for highly specialized protein modeling and design tasks. Developed for over two decades by a global community of scientists at more than 60 institutions, Rosetta has undergone multiple refactorings, and now comprises over three million lines of code. Here we discuss the methods developed in the last five years, involving the latest protocols for structure prediction, protein–protein and protein–small molecule docking, protein structure and interface design, loop modeling, the incorporation of various types of experimental data, and modeling of peptides, antibodies and other proteins in the immune system, nucleic acids, non-standard amino acids, carbohydrates, and membrane proteins. We briefly discuss improvements to the energy function, user interfaces, and usability of the ­­software. Rosetta is available at www.rosettacommons.org.

Causative agent of the viral pneumonia outbreak in the World identified as SARS-CoV2 leads to a severe respiratory illness like SARS and MERS. The pathogen spreading has turned into a pandemic dissemination and increased the mortality rate. Therefore, useful information is urgently necessary for effective control of the disease. Our study shows the existence of unvarying sequence with no mutation, including ORF1ab regions in 134 high-quality filtered genome sequences of SARS-CoV2 downloaded from the GISAID database. We have detected this sequence stability by using MAUVE analysis and pairwise alignment with Global Needleman Wunsch algorithm for each two different sequences, reciprocally. They also confirmed all these results were also with the Clustal W analysis. The first 6500 bp including ORF1ab region is an unvarying sequence. According to the highest TM-score of predicted protein structure analysis, the results showed it is very similar to spike protein of feline infectious peritonitis virus strain UU4 (PDB 6JX7) depending on amino acid sequences encoded by this unvarying region, and N-acetyl-D-glucosamine is the ligand of this protein. These results have confirmed that N-acetyl-D-glucosamine could play an important role in controlling of SARS-CoV-2. Also, our molecular docking analysis data supports a strong protein-ligand interaction of N-acetyl-D-glucosamine with spike receptor-binding domain bound with ACE2 (PDB 6M0J) and RNA-binding domain of nucleocapsid phosphoprotein (PDB 6WKP) from SARS CoV-2. Therefore, binding of N-acetyl-D-glucosamine to these proteins could inhibit SARS CoV-2’s replication. In the present work, we have suggested providing a repurposing compound for further in vitro and in vivo studies and new insights for ongoing clinical treatments as a new strategy to control of SARS-CoV-2 infections.

Multiple preventive vaccines are being developed to counter the COVID-19 pandemic. The leading candidates have now been evaluated in non-human primates (NHPs) and human Phase 1 and/or Phase 2 clinical trials. Several vaccines have already advanced into Phase 3 efficacy trials, while others will do so before the end of 2020. Here, we summarize what is known of the antibody and T-cell immunogenicity of these vaccines in NHPs and humans. To the extent possible, we compare how the vaccines have performed, taking into account the use of different assays to assess immunogenicity and inconsistencies in how the resulting data are presented. We also summarize the outcome of SARS-CoV-2 challenge experiments in immunized macaques, while noting variations in the protocols used, including but not limited to the virus challenge doses.

The sustainability of ecotourism is the backbone of tourism development of a country. Ecotourism can contribute to both conservation and development in which involves dynamic relationship between tourism, biodiversity and communities, facilitate by great management. The purpose of this study is to analyze the dimensions of the socio-economic and environmental impacts of ecotourism in communities surrounding the Tasik Kenyir in Terengganu, Malaysia. This study provides a framework for the development and evaluation of ecotourism. The framework will determine if the relationships between indicators are positively correlated which will result in positive contribution to the other by using System Dynamic. Socio-cultural and economic data will be collected through interviews and group discussions in selected communities in Tasik Kenyir. Data on wildlife will be extracted from secondary data from Kenyir Research Institute, Universiti Malaysia Terengganu. The data analysis will explore the socio-cultural and economic differences between and within different communities due to ecotourism development, the contribution of ecotourism to conservation activities, local support for conservation and ecotourism as well as the influence of tourist activities on the distribution of wildlife species in Tasik Kenyir. This study aims to contribute toward understanding the natural resource community-ecotourism inter-relationship and help to bridge the knowledge gap that hinders biodiversity conservation initiatives. The findings will be used as a base for further development of ecotourism and will recommend alternative management options where necessary for the study area.

Amyloids are fibrillar protein aggregates that are associated with diseases such as Alzheimer’s disease, Parkinson’s disease, type II diabetes and Creutzfeldt–Jakob disease. The process of amyloid aggregation involves three pathological protein transformations; from natively-folded conformation to the cross-β conformation, from biophysically soluble to insoluble, and from biologically functional to non-functional. While amyloids share a similar cross-β conformation, the biophysical transformation can either take place spontaneously via a homogeneous nucleation mechanism (HON) or catalytically on an exogenous surface via a heterogeneous nucleation mechanism (HEN). Here, we postulate that the different nucleation pathways can serve as a mechanistic basis for an etiological classification of amyloidopathies, where hereditary forms generally follow the HON pathway, while sporadic forms follow surface-induced (including microbially-induced) HEN pathways. Furthermore, the conformational and biophysical amyloid transformation results in loss-of-function (LOF) of the original natively-folded and soluble protein. This LOF can, at least initially, be the mechanism of amyloid toxicity even before amyloid accumulation reaches toxic levels. By highlighting the important role of non-protein species in amyloid formation and LOF mechanisms of toxicity, we propose a generalized mechanistic framework that could help better understand the diverse etiology of amyloid diseases and offer new opportunities for therapeutic interventions including replacement therapies.

The present grievous situation of the tuberculosis disease can be improved by efficient case management and timely follow-up evaluations. With the advent of digital technology this can be achieved by quick summarization of the patient-centric data. The aim of our study was to assess the effectiveness of the ODK Scan paper-to-digital system during testing period of three months. A sequential, explanatory mixed-method research approach was employed to elucidate technology use. Training, smartphones, application and 3G enabled SIMs were provided to the four field workers. At the beginning, baseline measures of the data management aspects were recorded and compared with endline measures to see the impact of ODK Scan. Additionally, at the end, users’ feedback was collected regarding app usability, user interface design and workflow changes. 122 patients’ records were retrieved from the server and analysed for quality. It was found that ODK Scan recognized 99.2% of multiple choice bubble responses and 79.4% of numerical digit responses correctly. However, the overall quality of the digital data was decreased in comparison to manually entered data. Using ODK Scan, a significant time reduction is observed in data aggregation and data transfer activities, however, data verification and form filling activities took more time. Interviews revealed that field workers saw value in using ODK Scan, however, they were more concerned about the time consuming aspects of the use of ODK Scan. Therefore, it is concluded that minimal disturbance in the existing workflow, continuous feedback and value additions are the important considerations for the implementing organization to ensure technology adoption and workflow improvements.

The storage of biochemical information, which is a prerequisite for the development of the first cell, is an unsolved problem affecting all concepts of the origin of life. However, if the protected environment in the continental crust is taken into account, completely new possibilities emerge for identifying processes that may have been crucial for the formation of the first cell. Under this background, we can hypothesize that, before cellular life began, a self-sustaining cycle of molecular reaction steps with information storage in RNA existed outside of a cell. This cycle was made possible in an open system bound to gas-permeable tectonic fracture zones with a high proportion of CO2 and N2. The formation of peptides and vesicles in supercritical CO2 and the chemical evolution of peptides have already been proven for the upper continental crust. Further considerations include the interactions of vesicles with catalytic peptides and the emergence of proto-tRNA. In combination with the formation of proto-tRNA synthetases, which consist of only two amino acid species and associated proto-tRNAs, the first RNA as an information storage system could have been formed with the information of proto-enzymes.

While SARS-CoV-2 uses angiotensin converting enzyme 2 (ACE2) as the receptor for cell entry, it is important to examine for other potential interactions between the virus and other cell receptors. Based on the clinical observation of low smoking prevalence among hospitalized COVID-19 patients, we recently identified a “toxin-like” amino acid (aa) sequence on the receptor binding domain of the spike glycoprotein of SARS-CoV-2 (aa 375-390) with homology to a sequence of a snake venom toxin, which could interact with nicotinic acetylcholine receptors (nAChRs). We now present computational molecular modelling and docking experiments using 3D structures of the SARS-CoV-2 spike glycoprotein and the extracellular domain of the nAChR alpha9 subunit. We identified an interaction between the aa381-386 of the SARS-CoV-2 spike glycoprotein and the aa189-192 of the extracellular domain of the nAChR alpha9 subunit, a region which forms the core of the “toxin-binding site” of the nAChRs. The mode of interaction is very similar to the interaction between the alpha9 nAChR and alpha-bungarotoxin. A similar interaction was observed between the pentameric alpha7 AChR and the SARS-CoV-2 spike glycoprotein. Our findings support the hypothesis that severe COVID-19 may be associated with disruption of the nicotinic cholinergic system which could be caused by an interaction between SARS-CoV-2 and nAChRs.

What is the function of cognition? On one influential account, cognition evolved to co-ordinate behaviour with environmental change or complexity (Godfrey-Smith 1996). Liberal interpretations of this view ascribe cognition to an extraordinarily broad set of biological systems – even bacteria, which modulate their activity in response to salient external cues, would seem to qualify as cognitive agents. However, equating cognition with adaptive flexibility per se glosses over important distinctions in the way biological organisms deal with environmental complexity. Drawing on contemporary advances in theoretical biology and computational neuroscience, we cash these distinctions out in terms of different kinds of generative models, and the representational and uncertainty-resolving capacities they afford. This analysis leads us to propose a formal criterion for delineating cognition from other, more pervasive forms of adaptive plasticity. On this view, biological cognition is rooted in a particular kind of functional organisation; namely, that which enables the agent to detach from the present and engage in counterfactual (active) inference.

The underlying molecular basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is not well understood. Characterized by chronic, unexplained fatigue, a disabling payback following exertion (“post-exertional malaise”) and variably presenting, multi-system symptoms, ME/CFS is a complex disease which demands concerted biomedical investigation from disparate fields of expertise. ME/CFS research and patient treatment have been challenged by the lack of diagnostic biomarkers and finding these is a prominent direction of current work. Despite these challenges, modern research demonstrates a tangible biomedical basis for the disorder across many body systems. This evidence is largely comprised of disturbances to immunological and inflammatory pathways, autonomic and neurologic systems, abnormalities in muscle and mitochondrial function, shifts in metabolism, and gut physiology or gut microbiome disturbances. It is possible that these threads are together entangled as parts of an underlying molecular pathology reflecting a far-reaching homeostatic shift affecting each of these systems. Due to the variability of non-overlapping symptom presentation or precipitating events such as infection or other bodily stresses, the initiation of body-wide pathological cascades with similar outcomes stemming from different causes may be implicated in the condition. Patient stratification to account for this heterogeneity is therefore one important consideration during exploration of potential diagnostic developments.

The role of the Renin-Angiotensin-Aldosterone System (RAAS) in Corona Virus Disease 2019 (COVID-19) infection has become a controversial topic of discussion. RAAS inhibitors, such as Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin II receptor blockers (ARBs), which are used to treat cardiovascular diseases, have been implicated in potentially increasing cell surface levels of ACE2. ACE2 is the host receptor for COVID-19 that was discovered in Wuhan, China in December 2019. Since December, COVID-19 has transmitted rapidly across the world and has become a global pandemic. COVID-19 is similar to the Middle East respiratory syndrome coronavirus (MERS-CoV) with the first case reported in Saudi Arabia in September 2012. COVID-19, also known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is also similar to SARS-CoV, which first infected humans in the Guangdong province of southern China in 2002, and caused an epidemic between November 2002 and July 2003. Both SARS-CoV and COVID-19 use ACE2 to enter host cells. ACE2 is primarily expressed in the mouth, lung, heart, esophagus, kidney, bladder, and intestines, and is a component of RAAS, which serves to maintain vascular tone and blood volume. Inhibition or activation of other components of RAAS has been shown to directly increase or decrease the expression and/or activity of ACE2. Furthermore, RAAS-targeting therapeutics, such as ACE inhibitors and ARBs, have also been shown to regulate the expression and/or activity of ACE2, albeit in animal models. Although these changes in ACE2 have been demonstrated only in animal models, there is no evidence that administration of RAAS-targeting therapeutics to humans for the treatment of hypertension, diabetes, and other cardiovascular diseases (e.g., myocardial infarction and heart failure) causes changes in ACE2 expression. Nor is there clinical evidence that RAAS-targeting therapeutics augment COVID-19 infection, morbidity, or mortality. However, clinical evidence does suggest that ACE2 expression may protect against respiratory distress caused by a variety of noxious agents. This review attempts to provide a balanced overview of the potential role of RAAS in regulating ACE2, and the role of ACE2 during COVID-19 infection. Evidence is provided to show that the expression of ACE2 may mediate both positive and negative outcomes, depending on the timing of ACE2 expression.

Fusion protein therapeutics engineering is advancing to meet the need for novel medicine. Herein, we further characterize the development of novel RTA & PAP-S1 antiviral fusion proteins. In brief, RTA/PAP-S1 and PAP-S1/RTA fusion proteins were produced in both cell free and E. coli in vivo expression systems, purified by His-tag affinity chromatography, and protein synthesis inhibitory activity assayed by comparison to the production of a control protein, CalmL3. Results showed that the RTA/PAP-S1 fusion protein is amenable to standardized production and purification and has both increased potency and less toxicity compared to either RTA or PAP-S1 alone. Thus, this research highlights the developmental potential of novel fusion proteins with reduced cytotoxic risk and increased potency.

The function of sleep in mammal and other vertebrates is one of the great mysteries of biology. Many hypotheses have been proposed, but few of these have made even the slightest attempt to explain the essence of sleep - the uncompromising need for reversible unconsciousness. During sleep, epiphenomena - often of a somatic character - occur, but these cannot explain the core function of sleep. One answer could be hidden in the observations made for long periods of time of the function of the central nervous system (CNS). The CNS is faced with conflicting requirements on stability and excitability. A high level of excitability is desirable, and is also a prerequisite for sensitivity and quick reaction times; however, it can also lead to instability and the risk of feedback, with life-threatening epileptic seizures. Activity-dependent negative feedback in neuronal excitability improves stability in the short term, but not to the degree that is required. A hypothesis is presented here demonstrating how calibration of individual neurons - an activity which occurs only during sleep - can establish the balanced and highest possible excitability while also preserving stability in the CNS. One example of a possible mechanism is the observation of slow oscillations in EEGs made on birds and mammals during slow wave sleep. Calibration to a genetically determined level of excitability could take place in individual neurons during the slow oscillation, so that action potentials are generated during the oscillations “up-phase”. This can only take place offline, which explains the need for sleep. The hypothesis can explain phenomena such as the need for unconsciousness during sleep, with the disconnection of sensory stimuli, slow EEG oscillations, the relationship of sleep and epilepsy, age, the effects of sleep on neuronal firing rate and the effects of sleep deprivation and sleep homeostasis. This is with regard primarily to mammals, including humans, but also all other vertebrates.

Polyunsaturated fatty acids (PUFAs) and antioxidants are important mediators in the central nervous system (CNS). Lipid derivatives may be used to generate endocannabinoids or prostanoids derived from arachidonic acid, which attenuates excitotoxicity in quadripartite synapses with a focus in astrocytes and microglia; on the other hand, antioxidants, such as glutathione (GSH) and ascorbate, have been shown to signal through transmitter receptors and protect against acute and chronic oxidative stress, modulating the activity of different signaling pathways. Several authors have investigated the role of these nutrients in young and senescent brain, as well as in degenerative conditions such as Alzheimer’s and Parkinson's diseases. Through literature review, we aimed to highlight recent data on the role of fatty acids, antioxidants and physical activity in physiology and in molecular mechanisms of brain senescence. Data indicate the complexity and essentiality of endogenous/dietary antioxidants for maintenance of the redox status and control of neuroglial signaling under stress. Recent studies also indicate that omega-3 and -6 fatty acids act in a competitive manner to generate mediators for energy metabolism, feeding behavior, plasticity and memory mechanisms throughout aging. Finding pharmacological or dietary resources that mitigate or prevent neurodegenerative affections continues to be a great challenge and require additional efforts from researchers, clinicians and nutritionists in the field.

From June 18 to 19, 2013, the Ésera river in the Pyrenees, Northern Spain, caused widespread damage due to flooding as a result of torrential rains and sustained snowmelt. We estimate the contribution of snow melt to total discharge applying a snow energy balance to the catchment. Precipitation is derived from sparse local measurements and the WRF-ARW model over three nested domains, down to a grid cell size of 2 km. Temperature profiles, precipitation and precipitation gradient are well simulated, although with a possible displacement regarding the observations. Snowpack melting was correctly reproduced and verified in three instrumented sites, and according to satellite images. We found that the hydrological simulations agree well with measured discharge. Snowmelt represented 33% of total runoff during the main flood event and 23% at peak flow. The snow energy balance model indicates that most of the energy for snow melt during the day of maximum precipitation came from turbulent fluxes. This approach forecast correctly peak flow and discharge during normal conditions at least 24h in advance and could give an early warning of the extreme event 2.5 days before.

Adeno-associated viruses (AAVs, genus dependoparvovirus) are promising gene therapy vectors. In strains AAV1-12, the capsid gene VP1 encodes a recently discovered protein, MAAP, in an overlapping frame. MAAP binds the cell membrane by an unknown mechanism. We discovered that MAAP is also encoded in bovine AAV and in porcine AAVs (which have shown promise for gene transfer into muscle tissues), in which it is probably translated from a non-canonical start codon. MAAP is predicted to be mostly disordered except for a predicted C-terminal, membrane-binding amphipathic α-helix. MAAP has a highly unusual composition. In particular, it lacks internal methionines, and is devoid of tyrosines in most strains. Unexpectedly, we discovered that the N-terminus of VP1 also lacks several amino acids. In all AAVs that encode MAAP, the first 200 aas of VP1 are devoid of internal methionines, probably owing to a selection against ATG codons that could prevent translation of MAAP and of capsid isoforms (VP2, VP3). The N-terminus of VP1 also lacks cysteines, likely to avoid the formation of disulfide bridges when it becomes exposed outside of the capsid during post-endocytic trafficking. Finally, the region common to VP1 and VP2 lacks tyrosine in the vast majority of AAVs that encode MAAP. Avoiding these "forbidden" aas in MAAP and VP1 when creating recombinant AAV capsids might increase the efficiency of capsid design. Conversely, the presence of "forbidden" aas in some rare strains probably indicates that they have unusual properties that could help us understand the viral cycle.

The state of community lock-down due to COVID-19 pandemic caused restricted movements of people. There are existing evidence of the negative impact of quarantine and isolation to the mental health of a person in different contexts. A scoping review of literature using Google Scholar was conducted to discover records about the public mental health while in a community quarantine due to COVID-19 pandemic. A methodological approach suggested by Arksey and O’Malley was utilized. It comprised (a) identifying the research questions, (b) identifying relevant literatures, (c) selecting literature, (d) charting the extracted data, and (e) summarizing, analyzing, and reporting the results. As of April 17, 2020, there were only 4 original articles found that discuss psychosocial aspect of the COVID-19 crisis. After an online survey, they present evidence that (1) there is an outward change in the people’s behavior toward self-care during the pandemic and (2) trusting the community governing bodies can minimize the level of anxiety and stress. Other literatures found are original articles in preprint (n=8), letters, commentaries, editorial (n=6), review paper (n=4), and WHO guideline (n=1). It is evident that the psychosocial aspect of COVID-19 crisis needs more attention from the scholars and a large research gap can be lessened trough expansion of online platforms.

Till date there are three full length COVID 19 virus genome sequences available from India. The earlier two were reported from Kerala, Southern India and the more recent one has been reported from Gujarat, western part of India. In this paper we report two novel mutations in the Spike protein sequence of Gujarat’s isolate. These mutations are based on comparison with the original Wuhan sequence. The two mutations have been found to be located just upstream and downstream of the receptor binding domain (RBD). Out of these two one has also been found to affect the secondary structure of the S1 domain. Since both of these mutations lie near the receptor binding domain, they might influence the spike receptor interactions by changing the conformation of the spike protein S1 domain. These mutations are uniquely placed and might be important in the context of vaccine engineering and therapeutic interventions.

Soy protein isolate (SPI) based materials are abundant, biocompatible, renewable, and biodegradable. In order to improve the tensile strength (TS) of SPI films, we prepared a novel composite film modified with microcrystalline cellulose (MCC) and metal nanoclusters (NCs) in this research. The effects of the modification of MCC on the properties of SPI-Cu NCs and Zn NCs films were investigated. Attenuated total reflectance-Fourier transformed infrared spectroscopy analyses and X-ray diffraction patterns characterized the strong interactions and reduction of the crystalline structure of the composite films. Scanning electron microscope showed the enhanced cross-linked and entangled structure of modified films. Compared with untreated SPI film, the tensile strength of the SPI-MCC-Cu and SPI-MCC-Zn films increased from 2.91 MPa to 13.95 and 6.52 MPa, respectively. Moreover, the results also indicated their favorable water resistance with higher water contact angle. Meanwhile, the composite films exhibited increased initial degradation temperatures, demonstrating their higher thermostability. The results suggested that MCC could effectively improve the performance of SPI-NCs films, which would provide a novel preparation method for environmentally friendly SPI-based films in the applications of packaging materials.

Georgia is ranked fifth highest among states for rates of HIV diagnosis. About 4% of persons living with HIV infection in the United States reside in Georgia, and almost 19% of these people do not know their HIV status. The present study examined the trends and associated factors of HIV testing among adults in Georgia between 2010 and 2014 by analyzing data of the Behavioral Risk Factor Surveillance System (BRFSS). A total of 30,791 persons aged ≥18 years were identified who responded to the question “Have you ever been tested for HIV?” Overall, there were 11,543 respondents who had been tested for HIV, with a decrease in percentage from 49.4% in 2010 to 43.7% in 2014 (p<0.001). Factors associated with HIV testing were being black (p<0.001), being younger than 55 years (p<0.001), single (p=0.02), attaining education level above high school (P<0.001), engaging in HIV high-risk behaviors (p<0.001), and not having healthcare coverage (p=0.03). Overall in Georgia, there has been a decline in the temporal trend of HIV testing, and more than half of adults have never been tested for HIV. For reducing HIV transmission in Georgia, enhancing access and utilization of HIV testing should be a public health priority.

Proteins possess complex three-dimensional structures, and these structures are stable only within specific ranges of temperature which mostly correspond to the temperature ranges of the host organisms. However, few exceptional proteins, called heat-stable proteins, are stable at temperatures that are substantially higher than those tolerated by the host organisms themselves. Most of the heat-stable proteins possess heat stability to perform their functions at high temperatures, but some of them are intrinsically heat-stable due to their structure. Heat-stable proteins are usually divided into three or four groups depending upon the intricacies of their structures and thermal behaviors. Their peculiar property, i.e. heat-stability, makes them very valuable in applications such as polymerase chain reaction, industrial processes requiring high temperature, and protein engineering. Heat-stability also makes it feasible to purify such proteins, from the rest of the heat-labile proteins, using a simple heat-treatment method. Moreover, heat treatment can be used as a combined cell-lysis and protein purification step which, as compared to conventional methods, can result in a higher yield of heat-stable proteins. Furthermore, some special heat-stable proteins, i.e. intrinsically disordered proteins (which include the proteins involved in important neurodegenerative diseases), need heat-treatment step, in some cases, as the only way for their successful purification and study. Hence, this paper provides a first-ever comprehensive review of all major aspects of heat-stable proteins, i.e., their structure, evolution, classification, significance, and heat-treatment mediated purification.

This study presents an exact solution to the free vibration analysis of a uniform Timoshenko beam, with a harmonic vibration being assumed. The Timoshenko beam theory covers cases associated with small deflections based on shear deformation and rotary inertia considerations. In this paper, a moment-shear force-circular frequency-curvature relationship was presented. The complete study was based on this relationship and closed-form expressions of efforts and deformations were derived. The free vibration response of single-span systems and spring-mass systems was analyzed; closed-form formulations of matrices expressing the boundary conditions were presented and the natural frequencies were determined by solving the eigenvalue problem. Systems with intermediate mass, spring, or spring-mass system were also analyzed. Furthermore, first-order dynamic stiffness matrices in local coordinates were derived. Finally, a second-order analysis of beams resting on an elastic Winkler foundation was conducted. The results obtained in this paper were in good agreement with those of other studies.

Human number understanding is thought to rely on the analogue number system (ANS), working according to Weber’s law. We propose an alternative account, suggesting that symbolic mathematical knowledge is based on a discrete semantic system (DSS), a representation that stores values in a semantic network, similar to the mental lexicon or to a conceptual network. Here, focusing on the phenomena of numerical distance and size effects in comparison tasks, first we discuss how a DSS model could explain these numerical effects. Second, we demonstrate that DSS model can give quantitatively as appropriate a description of the effects as the ANS model. Finally, we show that symbolic numerical size effect is mainly influenced by the frequency of the symbols, and not by the ratios of their values. This last result suggests that numerical distance and size effects cannot be caused by the ANS, while the DSS model might be the alternative approach that can explain the frequency-based size effect.

All life on Earth uses three integrated molecular systems in which genetic information contained in DNA base sequences is transmitted to ribosomes by RNA and a genetic code, then translated into the amino acid sequences of structural and catalytic proteins. Therefore, the most important point for understanding the origin of life is to determine how such systems could emerge from random processes on the early Earth. In this review, two alternatives are compared: the RNA world hypothesis and the [GADV]-protein world hypothesis. [GADV] refers to four amino acids, Gly [G], Ala [A], Asp [D] and Val [V] that are conserved in the amino acid sequences of many common proteins. Here I will argue that the origins of the three primary processes required for life to begin can be better explained by the GADV hypothesis than the RNA world hypothesis. The GADV hypothesis also incorporates a conversion process by which random polymers can evolve into proteins with ordered sequences.

Fasting, a practice with historical roots in various cultures, has recently garnered significant interest in the field of medicine. In this article, we delve into the mechanisms underlying fasting-induced autophagy and its therapeutic applications for spike protein associated pathology. We explore the therapeutic potential of fasting on spike protein-related pathology and the role of interventions to upregulate autophagy, including compounds like spermidine, resveratrol, rapamycin, and metformin. In conclusion, fasting, coupled with an understanding of its nuances, holds promise as a therapeutic intervention for spike protein related diseases; with broad implications for human health. This review presents the therapeutic possibility of using autophagy to treat spike protein related diseases, and details the interventions to deploy this therapeutic modality.

It is known that knockdown of the mitochondrial 18 kDa translocator protein (TSPO) as well as TSPO ligands modulate various functions, including functions related to cancer. To study the ability of TSPO to regulate gene expression regarding such functions, we applied microarray analysis of gene expression to U118MG glioblastoma cells. Within 15 minutes, the classical TSPO ligand PK 11195 induced changes in expression of immediate early genes and transcription factors. These changes also included gene products that are part of the canonical pathway serving to modulate general gene expression. These changes are in accord with reverse transcriptase (RT) real-time -PCR. At the time points of 15, 30, 45, and 60 minutes, as well as 3 and 24 hours of PK 11195 exposure, the functions associated with the changes in gene expression in these glioblastoma cells covered well known TSPO functions. These functions included cell viability, proliferation, differentiation, adhesion, migration, tumorigenesis, and angiogenesis. This was corroborated microscopically for cell migration, cell accumulation, adhesion, and neuronal differentiation. Changes in gene expression at 24 hours of PK 11195 exposure were related to downregulation of tumorigenesis and upregulation of programmed cell death. In the vehicle treated as well as PK 11195 exposed cell cultures, our triple labeling showed intense TSPO labeling in the mitochondria but no TSPO signal in the cell nuclei. Thus, mitochondrial TSPO appears to be part of the mitochondria-to-nucleus signaling pathway for modulation of nuclear gene expression. The novel TSPO ligand 2-Cl-MGV-1 appeared to be very specific regarding modulation of gene expression of immediate early genes and transcription factors.

Both SARS-CoV-2 (COVID-19) and SARS coronaviruses (CoVs) are members of the subgenus Sarbecovirus. To understand the origin of SARS-CoV-2 and its relation to other viruses, protein sequences from sarbecoviruses were analyzed to identify conserved inserts or deletions (termed CSIs) demarcating either particular clusters/lineages of sarbecoviruses or those shared by specific lineages shedding light on their interrelationships. We report several clade-specific CSIs in the spike (S) and nucleocapsid (N) proteins that reliably demarcate distinct sarbecoviruses clades providing important insights into the origin and evolution of SARS-CoV-2. Two CSIs in the N-terminal domain (NTD) of S-protein are uniquely shared by SARS-CoV-2, BatCoV-RaTG13 and most pangolin CoVs (SARS-CoV-2r cluster); another CSI supports a closer relationship of SARS-CoV-2 to BatCov-RaTG13. Three additional CSIs in the NTD are specific for two Bat-SARS-like CoVs (viz. CoVZXC21 and CoVZC45; CoVZC cluster) which form an outgroup of the SARS-CoV-2r cluster. Interestingly, one of the pangolin-CoV-MP789 also shares these CSIs but lack the CSIs specific for the SARS-CoV-2r cluster. The N-terminal sequence (aa 1-320) of the S-protein for pangolin-CoV-MP789 shows highest similarity (85.94%) to the CoVZC cluster, while its C-terminal region including the receptor binding domain (RBD) is most similar (97-98% identity) to the SARS-CoV-2 virus. These observations indicate that the spike protein sequence for the strain MP789 is of chimeric origin. Multiple CSIs described here also distinguish two bat SARS-CoVs strains (BM48-31/BGR/2008 and SARS_BtKY72) from all others. Our work also clarifies that two large CSIs (5 aa and 13 aa) found in the RBD of S-protein are mainly specific for the SARS and SARS-CoV-2r clusters of CoVs. The surface loops formed by these CSIs are predicted to be important in the binding of S-protein with the human ACE-2 receptor. Lastly, we have mapped the locations of different CSIs in the structure of the S-protein. These studies reveal that the three CSIs specific for the SARS-CoV-2r cluster form distinct surface-exposed loops/patches on the S-protein. As the surface-exposed loops play important roles in mediating novel interactions, the novel lobes/patches formed by the SARS-CoV-2-specific CSIs in the spike protein are predicted to play important roles in the interaction of this protein with other surface-exposed components in the host cells thereby enhancing the binding/infectivity of this virus to humans.

Gas and power networks are tightly coupled and interact with each other due to physically interconnected facilities. In an integrated gas and power network, a contingency observed in one system may cause iterative cascading failures, resulting in network wide disruptions. Therefore, understanding the impacts of the interactions in both systems is crucial for governments, system operators, regulators and operational planners, particularly, to ensure security of supply for the overall energy system. Although simulation has been widely used in the assessment of gas systems as well as power systems, there is a significant gap in simulation models that are able to address the coupling of both systems. In this paper, a simulation framework that models and simulates the gas and power network in an integrated manner is proposed. The framework consist of a transient model for the gas system and a steady state model for the power system based on AC-Optimal Power Flow. The gas and power system model are coupled through an interface which uses the coupling equations to establish the data exchange and coordination between the individual models. The bidirectional interlink between both systems considered in this studies are the fuel gas offtake of gas fired power plants for power generation and the power supply to LNG terminals and electric drivers installed in gas compressor stations and underground gas storage facilities. The simulation framework is implemented into an innovative simulation tool named SAInt (Scenario Analysis Interface for Energy Systems) and the capabilities of the tool are demonstrated by performing a contingency analysis for a real world example. Results indicate how a disruption triggered in one system propagates to the other system and affects the operation of critical facilities. In addition, the studies show the importance of using transient gas models for security of supply studies instead of successions of steady state models, where the time evolution of the line pack is not captured correctly.

More people around the world now have obesity than suffer from starvation thanks to our modern food system. Agriculture was transformed over the 20^th century by a variety of technological advancements that relied heavily on fossil fuels. In the United States of America, government policies and economic incentives led to surplus production of cheap inputs to processed food industries that produced a wide variety of heavily marketed, convenient, rewarding, timesaving, and relatively inexpensive ultra-processed foods. The energy available in the United States food supply increased much more than population needs, albeit with large inequities in food distribution and nutrition security. While most of the rise in per capita food availability during the late 20^th and early 21^st centuries in the United States resulted in increased food waste, a variety of mechanisms have been proposed by which changes in the increasingly ultra-processed food environment resulted in excess energy intake disproportionately in people genetically susceptible to obesity. As populations continue to grow, substantial investments in coordinated nutrition and agricultural research are needed to transform our current food system to one that relies less on fossil fuels, preserves biodiversity, ensures environmental health, and provides equitable access to affordable, safe, and nutritious food that reduces the prevalence of chronic diseases like obesity.

In graduate programs such as social work, field education is the signature pedagogy of education. As such, student placement with an appropriate field education agency is critical to ensure academic success and career readiness. A variety of Learning Management System (LMS) and Integrated Planning and Advising Service (IPAS) technologies have been developed to fully integrate technology into the educational system and streamline and improve the learning experience for students, educators, and administrators. Few (if any) of the existing solutions have capabilities to match students with field educators on the basis of an individual student’s completed coursework and area of specialization, as well as field educator needs and opportunities. This paper describes our experience developing a custom LMS/IPAS system—the School of Social Work information System (SSWiS)—that was designed specifically for student learning, faculty advising, and academic administration within our social work graduate program. We present the challenges that motivated the design of the SSWiS before describing the architecture and functionality of our solution. We then discuss our preliminary evaluation results. We conclude with a discussion of the benefits and limitations of our system in the context of today’s technical needs in graduate education in social work and other fields.

Cell-penetrating peptides (CPPs), a group of small peptides capable of promoting the transport of molecular cargo across the plasma membrane, have become important tools in promoting the cellular uptake of exogenously delivered macromolecules. GV1001, a peptide derived from a reverse-transcriptase subunit of telomerase (hTERT) and developed as a vaccine against various cancers, reportedly has unexpected CPP properties. Unlike typical CPPs, such as the HIV-1 TAT peptide, GV1001 enabled the cytosolic delivery of macromolecules such as proteins, DNA and siRNA via extracellular heat shock protein 90 (eHSP90) and 70 (eHSP70) complexes. The eHSP-GV1001 interaction may have biological effects in addition to its cytosolic delivery function. GV1001 was originally designed as a MHC class II-binding cancer epitope, but its CPP properties may contribute to its strong anti-cancer immune response relative to other telomerase peptide-based vaccines. Cell signaling via eHSP-GV1001 binding may lead to unexpected biological effects, such as direct anticancer or antiviral effects. In this review, we focus on the CPP effects of GV1001 bound to eHSP90 and ehsp70.

Neurotrophins play a principal role in neuronal survival and differentiation during development, but also in the maintenance of appropriate adult neuronal circuits and phenotypes. In the oculomotor system, we have demonstrated that neurotrophins are key regulators of developing and adult neuronal properties, but with peculiarities depending on each neurotrophin. For instance, the administration of NGF, BDNF or NT-3 protects neonatal extraocular motoneurons from cell death after axotomy, but only NGF and BDNF prevent the downregulation in ChAT. In the adult, in vivo recordings of axotomized extraocular motoneurons have demonstrated that the delivery of NGF, BDNF or NT-3 recovers different components of the firing discharge activity of these cells, with some particularities in the case of NGF. All neurotrophins have also synaptotrophic activity, although to different degrees. Accordingly, neurotrophins can restore the axotomy-induced alterations acting selectively on different properties of the motoneuron. In this review we summarize these evidences and discuss them in the context of other motor systems.

An existing power grid is going through a massive transformation. Smart grid technology is a radical approach for improvisation in prevailing power grid. Integration of electrical and communication infrastructure is inevitable for the deployment of Smart grid network. Smart grid technology is characterized by full duplex communication, automatic metering infrastructure, renewable energy integration, distribution automation and complete monitoring and control of entire power grid. Wireless sensor networks (WSNs) are small micro electrical mechanical systems which are accomplished to collect and communicate the data from surroundings. WSNs can be used for monitoring and control of smart grid assets. Security of wireless sensor based communication network is a major concern for researchers and developers. The limited processing capabilities of wireless sensor networks make them more vulnerable to cyber-attacks. The countermeasures against cyber-attacks must be less complex with an ability to offer confidentiality, data readiness and integrity. The address oriented design and development approach for usual communication network requires a paradigm shift to design data oriented WSN architecture. WSN security is an inevitable part of smart grid cyber security. This paper is expected to serve as a comprehensive assessment and analysis of communication standards, cyber security issues and solutions for WSN based smart grid infrastructure.

The SARS (severe acute respiratory syndrome)-CoV (Coronavirus)-2 S(spike)-protein mRNA/cDNA currently being used as vaccines are antigenic but not antigens against SARS-CoV-2, that causes COVID (Coronavirus Disease) -19. Furthermore, the mRNA and cDNA antigenic vaccines also have potentials for homologous as well as heterologous recombination, primarily into the somatic cell DNA of the vaccine recipients. On the contrary, a SARS-CoV-2 RBD-protein antigen, a part of the S-protein, will directly stimulate antibody production against SARS-CoV-2. Hence, a vaccine composed of SARS-CoV-2 RBD-protein as a safer, fast acting, and effective vaccine against SARS-CoV-2 and thus against COVID-19. This is also useful for some immune compromised individuals.

After decades of research, oncolytic virotherapy has recently advanced to clinical application, and currently a multitude of novel agents and combination treatments are being evaluated for cancer therapy. Oncolytic agents preferentially replicate in tumor cells, inducing tumor cell lysis and complex anti-tumor effects, such as innate and adaptive immune responses and the destruction of tumor vasculature. With the availability of different vector platforms and the potential of both genetic engineering and combination regimens to enhance particular aspects of safety and efficacy, the identification of optimal treatments for patient subpopulations or even individual patients becomes a top priority. Mathematical modeling can provide support in this arena by making use of experimental and clinical data to generate hypotheses about the mechanisms underlying complex biology and, ultimately, predict optimal treatment protocols. Increasingly complex models can be applied to account for therapeutically relevant parameters such as components of the immune system. In this review, we describe current developments in oncolytic virotherapy and mathematical modeling to discuss the benefit of integrating different modeling approaches into biological and clinical experimentation. Conclusively, we propose a mutual combination of these fields of research for more efficient development and effective treatments.

Extracorporeal shock wave therapy (ESWT) is a well investigated and widely used treatment modality for a number of musculoskeletal disorders. A limitation of ESWT is its potential painfulness at higher, clinically relevant energy flux density (EFD), which may limit its applicability and, thus, effectiveness. Various studies in the literature demonstrated that neither application of a higher number of extracorporeal shock waves with lower EFD nor use of local anesthesia may solve this problem. Based on the results of several other studies in the literature it is hypothesized here that in patients suffering from musculoskeletal disorders that can be treated with ESWT, pretreatment with a pulsed, high power laser with a wavelength of 904 or 905 nanometers (hereafter: "laser pretreatment") does not only allow to apply higher EFDs in subsequent ESWT but actually results in faster and/or better treatment outcome than ESWT without laser pretreatment. Accordingly, it is hypothesized here that combining ESWT with laser pretreatment leads to synergistic effects and, thus, is superior to either treatment modality alone. Confirming this hypothesis in preclinical and clinical research may raise significance and increase the use of ESWT in physical and rehabilitation medicine, with immediate benefit for patients.

Recently emerging data-driven citizen sciences need to harness increasing amount of massive data with varying quality. This paper develops essential theoretical frameworks and example models and examine its computational complexity for interactive data-driven citizen science within the context of guided self-organization. We first define a conceptual model that incorporates quality of observation in terms of accuracy and reproducibility, ranging between subjectivity, inter-subjectivity, and objectivity. Next, we examine the database's algebraic and topological structure in relation to informational complexity measures, and evaluate its computational complexities with respect to exhaustive optimization. Conjectures of criticality are obtained on self-organizing processes of observation and dynamical model development. Example analysis is demonstrated with the use of biodiversity assessment database, the process that inevitably involves human subjectivity for the management in open complex systems.

Noni juice is a globally popular health beverage that originates from the tropics. Traditional Tahitian healers believe the noni plant to be useful for a wide range of maladies, and noni juice consumers throughout the world have similar perceptions. Nevertheless, human clinical trials are necessary for an understanding of what the health benefits of noni juice truly are. A review of published human intervention studies suggest that noni juice may provide protection against tobacco smoke-induced DNA damage, blood lipid and homocysteine elevation, and systemic inflammation. Human interventions studies also suggest that noni juice may improve joint health, increase physical endurance, increase immune activity, inhibit glycation of proteins, aid weight management, help maintain bone health in women, help maintain normal blood pressure, and improve gum health. Further, these studies point to noni juice possessing notable antioxidant activity, more so than the other fruit juices that served as placebos. It is this antioxidant effect, and its interaction with the immune system and inflammation pathways, that may account for many of the observed health benefits of noni juice. However, the existing evidence does have some limitations in its application to noni juice products in general as all the peer-reviewed human interventions studies to-date have involved only one source of French Polynesian noni juice. Geographical factors and variations in processing methods are known to produce commercial noni juice products with divergent phytochemical and nutrient compositions. Therefore, other sources of noni products may have different toxicological and pharmacological profiles.

The present study was performed to examine that transforming growth factor beta (TGF-β) in root-surrounding tissues on deciduous teeth during the physiological root resorption regulates the differentiation induction into odontoclast. We prepared root-surrounding tissues with (R) or without (N) physiological root resorption scraped off at three regions (R1-R3 or N1-N3) from the cervical area to the apical area of the tooth and measured both TGF-β and the tartrate-resistant acid phosphatase (TRAP) activities. The TGF-β activity level was increased in N1-N3, whereas the TRAP activity was increased in R2 and R3. In vitro experiments for RANKL-mediated osteoclast differentiation revealed that TGF-β in N1-N3 and R1-R3 enhanced the TRAP activity in RAW264 cells. A genetic study indicated that the mRNA level of TGF-β1 in N1 and N2 was significantly increased, and corresponded with that of osteoprotegerin (OPG). In contrast, the expression level of receptor activator of NF-κB ligand (RANKL) was increased in R2 and R3. Our findings suggest that TGF-β is closely related to the regulation of OPG induction and RANKL-mediated odontoclast differentiation depending on the timing of RANKL and OPG mRNA expression in the root-surrounding tissues of deciduous teeth during physiological root resorption.

Dysregulation of cartilage homeostasis and the changes in the density and the architecture of the subchondral bone were postulated as a potent mechanically pathological activity contributing to osteoarthritis (OA) pathogenesis. Extracorporeal shockwave therapy (ESWT) is a new, none invasive and effective method in the treatment of animal OA model. In the current study, we demonstrated that shockwave induced the expression of protein-disulfide isomerase-associated 3 (Pdia-3) which is a multifunctional protein hypothesized to be a significant mediator for 1α,25-Dihydroxyvitamin D3 (1α,25(OH)₂D₃) signaling pathway using two-dimensional electrophoresis. Histological analysis and quantitative polymerase chain reaction (qPCR) were verified and observed that the expression of Pdia-3 at 2 weeks was significantly higher than that of any other group at 4 weeks, 8 weeks, and 12 weeks post-shockwave treatment in early OA knee of rat. The other factors of the 1α,25(OH)₂D₃ rapid membrane signaling pathway including extracellular signal-regulated protein kinases 1 (ERK1), osteopontin (OPG), alkaline phosphatase (ALP), and matrix metallopeptidase 13 (MMP13) were measured and significantly increased by qPCR at 2 weeks post-shockwave treatment in early OA knee. Our proteomic data revealed significant Pdia-3 expression in microenvironments of joint tissue that could be actively responded to ESWT, which may potentially regulate biological function of chondrocytes and osteoblasts in the treatment of OA knee.

Elevated carbon dioxide (eCO₂) stimulates wheat grain yield, but simultaneously reduces protein (N) concentration. Also other essential nutrients are subject to change. This study is a comprehensive synthesis of wheat experiments with eCO₂, estimating effects on N, minerals (B, Ca, Cd, Fe, K, Mg, Mn, Na, P, S, Zn), and starch. Analysis was made by i) deriving response functions for the relative effect on element concentration in relation to CO₂ concentration, ii) meta-analysis to test the magnitude and significance of observed effects, and iii) relating CO₂ effects on minerals to effects on N and grain yield. Responses range from zero to strong negative effects of eCO₂ on mineral concentration, with largest reductions for the nutritionally important elements N, Fe, S, Zn and Mg. Together with the positive but small and non-significant effect on starch concentration, the large variation in effects suggests that CO₂-induced responses cannot be explained by a simple dilution model. To explain the observed pattern, uptake and transport mechanisms may have to be considered, along with the link of different elements to N uptake. Our study shows that eCO₂ has a significant effect on wheat grain stoichiometry, with implications for human nutrition in a world of rising CO₂.

Recently, design of electric scooters (ESs) has commonly adopted brushless DC motors (BLDCMs) in place of brushed DC motors. This invention develops a new anti-lock braking system (ABS), based on a slip-ratio estimator, for ES utilizing the braking force generated by the BLDCM when electrical energy releases to the load yielding an analogous effect of ABS control in gas-engine vehicles. Comparing to mechanical ABS, the design possesses the advantages of rapid torque responses due to fast actuating response. The electrical ABS is realized by associating with kinematic and Short-circuit braking. A current controller is used to adjust the braking force, while the sliding mode control strategy is adopted to regulate the slip ratio for best road adhesion while braking. Real-world experiments have been conducted for functional and performance verification.

COVID-19 is now a major global health crisis, can lead to severe food crisis unless proper measures are not taken. Though a number of scientific studies have addressed the possible impacts of COVID-19 in Bangladesh on variety of issues, problems and food crises associated with aquatic resources and communities are missing. Therefore, this study aimed at bridging the gap in the existing situation and challenges of COVID-19 by linking its impact on aquatic food sector and small-scale fisheries with dependent population. The study was conducted based on secondary data analysis and primary fieldwork. Secondary data focused on COVID-19 overview and number of confirmed, recovered and death cases in Bangladesh; at the same time its connection with small-scale fisheries, aquatic food production, demand and supply was analyzed. Community perceptions were elicited to present how the changes felt and how they affected aquatic food system and small-scale fisheries and found devastating impact. Sudden illness, reduced income, complication to start production and input collection, labor crisis, transportation abstraction, complexity in food supply, weak value chain, low consumer demand, rising commodity prices, creditor’s pressure were identified as the primary affecting drivers. Dependent people felt the measures taken by the Government should be based on protecting the health and food security, although it could be detrimental to economic growth in the short term. The study provides insight into policies adopted by the policy makers to mitigate the effects of the pandemic on aquatic food sector and small-scale fisheries.

During its first month, the recently emerged 2019 Wuhan novel coronavirus (SARS-CoV-2) has already infected many thousands of people in mainland China and worldwide and took hundreds of lives. However, the swiftly spreading virus also caused an unprecedentedly rapid response from the research community facing the unknown health challenge of potentially enormous proportions. Unfortunately, the experimental research to understand the molecular mechanisms behind the viral infection and to design a vaccine or antivirals is costly and takes months to develop. To expedite the advancement of our knowledge we leverage the data about the related coronaviruses that is readily available in public databases, and integrate these data into a single computational pipeline. As a result, we provide a comprehensive structural genomics and interactomics road-maps of SARS-CoV-2 and use these information to infer the possible functional differences and similarities with the related SARS coronavirus. All data are made publicly available to the research community at http://korkinlab.org/wuhan .

We are witnessing the severe third outbreak mediated by coronaviruses affecting global public health with unprecedented economic consequences. A better understanding of its phylogenetics, exploration of sequence features and mutational changes could unveil its genealogy to gain insights into the mechanism of transmission and development of possible interventions. Our comparative genomic analyses of >160 isolates of SARS-CoV-2 reveal phylogenetic kinship with other coronaviruses and emergence of evolutionary divergence in clinical isolates. t-SNE-based clustering revealed different clades but no continent specific clusters. Amino acid substitutions at RBD of spike protein provide possible reasons for rapid transmission. Few proteins specific to SARS-CoV-2 were identified which could have implications as therapeutic targets and diagnostic biomarkers. Virtual screening identified repurposed drugs, known nutraceuticals, for specific interventions. These phylogenetic observations reveal the ancestry and computational studies reveal the emergency measures to interject this emerging pathogen that pose threat to whole of mankind.

In contrast to lytic phages, filamentous phages are assembled in the inner membrane and secreted across the bacterial envelope without killing the host. For assembly and extrusion of the phage across the host cell wall, filamentous phages code for membrane-embedded morphogenesis proteins. In the outer membrane of E. coli, the protein gp4 forms a pore-like complex, while gp1 and gp11 form a complex in the inner membrane of the host. By comparing sequences with other filamentous phages, we identified putative Walker A and B motifs in gp1 with a conserved lysine in the Walker A motif (K14), and a glutamic and aspartic acid in the Walker B motif (D88, E89). In this work we demonstrate that both, Walker A and Walker B, are essential for phage production. The crucial role of these key residues suggest that gp1 is likely to be a molecular motor driving phage assembly. We further identified essential residues for the function of the assembly complex. Mutations in three out of six cysteine residues abolish phage production. Similarly, two out of six conserved glycine residues are crucial for gp1 function. We hypothesise that the residues represent molecular hinges allowing domain movement for nucleotide binding and phage assembly.

Enveloped viruses represent a significant category of pathogens that cause serious diseases in animals. These viruses express envelope glycoproteins that are singularly important during infection of host cells by mediating fusion between the viral envelope and host cell membranes. Despite low homology at protein levels, three classes of viral fusion proteins have, as of yet, been identified based on structural similarities. Their incorporation into viral particles is dependent upon their proper sub-cellular localization after being expressed and folded properly in the endoplasmic reticulum (ER). However, viral protein expression can cause stress in the ER, and host cells respond to alleviate the ER stress in the form of the unfolded protein response (UPR); the effects of which have been observed potentiating or inhibiting viral infection. One important arm of UPR is to elevate the capacity of the ER-associated protein degradation (ERAD) pathway, which is comprised of host quality control machinery that ensures proper protein folding. In this review, we provide relevant details regarding viral envelope glycoproteins, UPR, ERAD, and their interactions in host cells.

Graph coloring is a manifestation of graph partitioning, wherein, a graph is partitioned based on the adjacency of its elements. Partitioning serves potentially as a compartmentalization for any structural problem. Vertex coloring is the heart of the problem which is to find the chromatic number of a graph. The fact that there is no general efficient solution to this problem that may work unequivocally for all graphs opens up the realistic scope for combinatorial optimization algorithms to be invoked. The algorithmic complexity of graph coloring is non-deterministic in polynomial time (NP) and hard. To the best of our knowledge, there is no algorithm as yet that procures an exact solution of the chromatic number comprehensively for any and all graphs within the polynomial (P) time domain. However, several heuristics as well as some approximation algorithms have been attempted to obtain an approximate solution for the same. Here, we present a novel heuristic, namely, the 'trailing path', which returns an approximate solution of the chromatic number within polynomial time, and, with a better accuracy than most existing algorithms. The ‘trailing path’ algorithm is effectively a subtle combination of the search patterns of two existing heuristics (DSATUR and Largest First), and, operates along a trailing path of consecutively connected nodes (and thereby effectively maps to the problem of finding spanning tree(s) of the graph) during the entire course of coloring, where essentially lies both the novelty and the apt of the current approach. The study also suggests that the judicious implementation of randomness is one of the keys towards rendering an improved accuracy in such combinatorial optimization algorithms. Apart from the algorithmic attributes, essential properties of graph partitioning in random and different structured networks have also been surveyed, followed by a comparative study. The study reveals the remarkable stability and absorptive property of chromatic number across a wide array of graphs. Finally, a case study is presented to demonstrate the potential use of graph coloring in protein design – yet another hard problem in structural and evolutionary biology.

The foot-mounted inertial navigation system is an important application of pedestrian navigation as it in principle does not rely any external assistance. A real-time range decomposition constraint method is proposed in this paper to combine the information of dual foot-mounted inertial navigation systems. It is well known that low-cost inertial sensors with ZUPT (zero-velocity update) and range decomposition constraint perform better than in either single way. This paper recommends that the distance of separation between the position estimates of feet-mounted inertial navigation systems be restricted in the ellipsoidal constraint which relates to the maximum step and leg height. The performance of the proposed method is studied utilizing experimental data. The results indicate that the method can effectively correct the dual navigation systems’ position over the existing spherical constraint.

In tissue engineering scaffolds take the place of the natural extra cellular matrix (ECM). The natural ECM is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The design aspect along with the choice of the material for the artificial scaffold is very crucial to cell differentiation, adhesion, proliferation, and the transport of the growth factors or other bio molecular signals. In addition to the material and design of the scaffolds, it is necessary to replicate the normal physiological situation if the scaffold has to function as an implant. The cells have to be located in the porous scaffold to form a three dimensional assembly. The article discusses the important factors to be considered while designing a scaffold for tissue engineering and regenerative medicine.

We tested the hypothesis that concatemers of ancestral tRNAs gave rise to the 16S ribosomal RNA. We built an ancestral sequence of proto-tRNAs that showed a significant identity of 51.69% and a percentage of structural identity of 0.941 with the 16S ribosomal molecule. We also propose a hypothesis for the emergence of translation.

It is proposed that the primary living cells (“probionts”) cannot emerge of organic substance simply by continuous chemical complication of prebiotic macromolecules and microsystems. The complication must be accompanied by the radical thermodynamic transformation (“jump”) of prebiotic microsystems that resulted in the acquired ability to extract free energy from the environment and export entropy. This transformation is called “the thermodynamic inversion” The inversion may occur by means of the efficient (intensified) response of the microsystems on the oscillations of physic-chemical parameters in hydrothermal environment. In this case the surplus available free energy within a microsystem, when combined with the informational modality, facilitates its conversion into a new microsystem—a living probiont. It is shown the schematic representation of an oscillating prebiotic microsystem that is transforming into a living probiont. A new kind of laboratory and computational experiments on prebiotic chemistry under oscillating conditions is offered to verify the inversion concept.

Glioblastoma multiforme (GBM) is the most frequent and aggressive primary brain tumor. GBM is formed by a very heterogeneous astrocyte population, neurons, neovascularization and infiltrating myeloid cells (microglia and monocyte derived macrophages). The IQGAP1 scaffold protein interacts with components of the cytoskeleton, cell adhesion molecules, and several signaling molecules to regulate cell morphology and motility, cell cycle and other cellular functions. IQGAP1 overexpression and delocalization has been observed in several tumors, suggesting a role for this protein in cell proliferation, transformation and invasion. IQGAP1 has been identified as a marker of amplifying cancer cells in GBMs. To determine the involvement of IQGAP1 in the onco-biology of GBM, we performed immunohistochemical confocal microscopic analysis of the IQGAP1 protein in human GBM tissue samples using cell type-specific markers. IQGAP1 immunostaining and subcellular localization was heterogeneous; the protein was located in the plasma membrane and, at variable levels, in nucleus and/or cytosol. Moreover, IQGAP1 positive staining was found in podosome/invadopodia-like structures. IQGAP1⁺ staining was observed in neurons (Map2⁺ cells), in cancer stem cells (CSC; nestin⁺) and in several macrophages (CD31⁺ or Iba1⁺). Our results indicate that the IQGAP1 protein is involved in normal cell physiology as well as oncologic processes.

For the first time in the world, we provided a phenomenologically verifiable proof for the validation of origin of universe and perceivable reality from the unperceivable information based on Ayurveda. We also provided the axiomatic definitions for the terminologies used to deliver the theoretical framework for the same based on Bharatheeya Knowledge Systems. The presented manuscript provides a corelation between quantum information transport and emergence of gunam “Laghu” and gunam “Guru”. We identified that this point of emergence can be considered as the origin point in the continuous process of generation of Perceivable Reality “Vyaktham” from Unperceivable Information “Avyaktham”. In this context we can consider the unperceivable information in “Avyaktham” as dark matter. So, we must develop methods like gunascopy or informationscopy to understand the types of information imbibed in the quantum matter of a dravyam to understand its original physico-chemical-biological and information state of the constituent matter. This is possible through the assessment of Dravya Guna aspects and panchabhootha tatwas of the dravyas. For the first time in the world, we have developed the method to derive all the gunas from “guru” and “Laghu” and calculated the mass of the finitie components of Nava Dravyas including Mann, Aatma, Kaal, Disha, Aakash, Vaayu, Agni, Jal and Prithvi from the quantum information emergence equation. We strongly believe that this work will open up new avenues to explore the frontiers of reality and universe through natural cognition. The solutions to the Yang-Mill conjecture is achieved by our team using the Quantum Information Emergence and Transport Equations. We proved that the information bounded in the quantum states of the constituent quantum matter of quantum particles will provide them positive masses, even though they travel at the speed of light. Based on the phenomenologically verifiable axioms proposed in this work, we proved that the space on the topologically invarient 2D Poincare Sphere which is equivalent to a 2D space without boundaries can facilitate the never-ending loop of continuous quantum information transport between “Avyaktham” and “Vyaktham”. So the information availabe in the constituent quantum states of “Avyaktham” is equal to the postiive mass of quantum systems travelling at the speed of light. In such condition all the mass of the quantum particles will be converted in to information bounded in the corresponding quantum states of the quantum matter. This complete conversion of mass of the quantumparticles into information will happen only at maximum entropy. Thus at maximum entropy the information which is self information entangled with its own quantum states in “Avyaktham” will have a positive mass equal to the mass gap proposed in the Yang-Mill conjecture.

Conditions under which compositions of component systems form a well-defined system-of-systems here are formulated at a fundamental level. Statement of what defines a well-defined composition and sufficient conditions guaranteeing such a result offers insight into exemplars that can be found in special cases such as differential equation and discrete event systems. For any given global state of a composition, two requirements can be stated informally as: 1) the system can leave this state, i.e., there is at least one trajectory defined that starts from the state, and 2) the trajectory evolves over time without getting stuck at a point in time. Considered for every global state, these conditions determine whether the resultant is a well-defined system and if so, whether it is non-deterministic or deterministic. We formulate these questions within the framework of iterative specifications for mathematical system models that are shown to be behaviorally equivalent to the Discrete Event System Specification (DEVS) formalism. This formalization supports definitions and proofs of the afore-mentioned conditions. Implications are drawn at the fundamental level of existence where the emergence of a system from an assemblage of components can be characterized. We focus on systems with feedback coupling where existence and uniqueness of solutions is problematic.

In this study, the olive pomace was considered because of its importance in the environment. So, this study carried out to estimate the total nitrogen content and the fatty acids profile of olive pomace. The olive pomace samples were collected from Irbid, Jarash, Ajloun and Mafraq during the harvesting season 2014 to study the biochemical characteristics of fatty acid composition and the total nitrogen (TN) content. The total nitrogen content was determined by standard Kjeldahl method and the fatty acid profile was detected by gas chromatography (GC). The results show that the total nitrogen content ranged from (0.39 ± 0.0) to (0.62 ± 0.02) with statistically significant difference suggesting that the composition of matrices and their percentage may be responsible for composition of amendments. The calculated total protein percentage ranged between (2.43 ± 0.00) to (3.87 ± 0.17). Also, 13 different fatty acids were quantitatively profiled and quantitated. Oleic acid (C 18:1) was found to be the highest percentage of all other fatty acids and ranged between (59.03%) and (63.81%), moreover the C 18:1/C 18:2 (oil quality) was calculated and C.V% showed variation meaning that nutritional implication could affect the oxidative stability of oils. In conclusion, OP by-product could give a sustainable and alternative-cheap source for fertilizers, pharmaceutical industries, cosmetics and other industries.

Energy system models have become indispensable to shape future energy systems by providing insights into different trajectories. However, sustainable systems with high shares of renewable energy are characterized by growing cross-sectoral interdependencies and decentralized structures. To capture important properties of increasingly complex energy systems, sophisticated and flexible modelling tools are needed. At the same time open science becomes increasingly important in energy system modelling. This paper presents the Open Energy Modelling Framework (oemof) as a novel approach in energy system modelling, representation and analysis. The framework forms a toolbox to construct comprehensive energy system models and has been published open source under a free license. With a collaborative development based on open processes the framework seeks for a maximum level of participation and transparency to facilitate open science principles in energy system modelling. Based on a generic graph based description of energy systems it is well suited to flexibly model complex cross-sectoral systems and incorporate various modelling approaches. This makes the framework a multi-purpose modelling environment for modelling and analyzing different systems ranging from an urban to a transnational scale.

The spread of the infection caused by the new coronavirus SARS-CoV-2 (COVID-19) became pandemic on March 11, 2020. From the time of the first cases (in November 2019, Wuhan, China), to date, a large number of COVID-19 observations have been accumulated in different age groups of patients both in China and abroad. Published scientific data allows us to conclude that children suffer from COVID-19 much less often than adults and tolerate the disease in a milder form, often appear to be asymptomatic. There is currently no final answer why children are less susceptible to this virus; however, scientists are increasingly inclined to consider a complex effect of the immune response and components of the renin-angiotensin system (RAS), which according to recent studies affects not only the cardiovascular system, but is also responsible for the activation of inflammatory reactions. A hypothesis of genetic predisposition to the development of severe forms of COVID-19 has recently been made. We conducted a search for publications in the databases and showed current scientific ideas about COVID-19 pathogenesis and factors influencing the disease development in childhood. Childhood immunity may have several protective features against SARS-CoV-2: immaturity of particular elements of the innate immune response, constitutional lymphocytosis with a shift towards anti-inflammatory Th2-response, as well as "trained" immunity. The influence of renin-angiotensin system reactions in this review is shown from two perspectives: expression of ACE2 receptors and polymorphisms of certain genes of this system. It was established that ACE2 transmembrane protein is not only the entry point for the virus but also plays a regulatory role, turning the pro-inflammatory vasoconstrictor angiotensin II into anti-inflammatory angiotensin (1-7), which has vasodilating properties. Higher ACE2 content in children compared with adults helps maintain balance in the renin-angiotensin system and prevents the development of complications. It was also shown that the presence of certain genetic polymorphisms (AGTR1, AGTR2, ACE2, ACE) could determine the imbalance inside the RAS, leading to more pronounced reactions of alveolocytes, vascular endothelium and smooth muscle fibers in response to SARS-CoV-2 infection due to a shift towards vasoconstrictor, proliferative and profibrotic mechanisms.

A novel and highly pathogenic coronavirus (2019-nCoV)-induced pneumonia spread worldwide in a short time. However, studies on the effects of 2019-nCoV on the male reproductive system are limited. The aim of this study is to describe the clinical characteristics of the male reproductive system of COVID-19 patients and to explore the presence of 2019-nCoV in semen. Retrospective, single-center case series of 112 male patients with confirmed COVID-19 who were admitted to Renmin Hospital of Wuhan University from January 2 to March 7, 2020. Demographic data, symptoms and signs related to the male reproductive system, throat swabs and semen samples were collected and analyzed. 2019-nCoV RNA measured in throat swab and semen samples. The organ distribution of ACE2 mRNA and protein in human tissue on The Human Protein Atlas portal and investigated immunohistochemistry (IHC) images of the testis. The HPA dataset revealed relatively high levels of ACE2 protein and RNA expression in the testis. A total of 3 severe COVID-19 patients (2.7%) presented with orchidoptosis, while no patients experienced other symptoms or signs related to the male reproductive system. The analysis of 2019-nCoV RNA in semen included 17 patients with fertility needs. Among these patients, 9 (52.9%) remained positive for 2019-nCoV according to throat swab analysis, and 8 (47.1%) became negative. In the semen 2019-nCoV analysis, all 17 patients were negative for the N gene and ORF1ab gene. In view of the potential impairment, long-term follow-up for male COVID-19 patients with fertility needs is of great significance.

Study of RNA-protein interactions and identification of RNA targets are among the key aspects of understanding the RNA biology. Currently, various methods are available to investigate these interactions, in particular, RNA pulldown assay. In the present paper, a method based on the HaloTag technology is presented that is called Halo-RPD (HaloTag RNA PullDown). The proposed protocol uses plants with stable fusion protein expression and the MagneBeads magnetic beads to capture RNA-protein complexes directly from the cytoplasmic lysate of transgenic A. thaliana plants. The key stages described in the paper are as follows: 1) preparation of the magnetic beads 2) tissue homogenization and collection of control samples 3) precipitation and wash of RNA-protein complexes; 4) evaluation of protein binding efficacy; 5) RNA isolation; 6) analysis of the obtained RNA. Recommendations for better NGS assay designs are provided.

Wheat is the essential constituent of cereal-based diets and one of the most significant sources of calories. However, there is an inherently low bioavailability of proteins, mineral, and vitamins in modern wheat grains. Biofortification has earned recognition as an outstanding approach, at the same time as a cure for world hunger. The developments in the identifications of quantitative trait loci (QTL) analysis and understanding of the physiological and molecular basis of QTLs controlling the biofortification traits in wheat has revealed new horizons for the improvement of modern wheat varieties. Within this review, we have compiled the information from the studies carried out in wheat using QTL mapping methodologies that is among the best methods for biofortification traits. We hope this review will serve as an essential reference for the QTLs identified for the several important biofortification traits in wheat.

Nanoparticles have been used as a novel drug delivery system. Drug-incorporated nanoparticles for local delivery might optimize the efficacy and minimize the side effects of drugs. The efficacy and safety of intratracheal administration of prostacyclin analog (beraprost)-incorporated nanoparticles and imatinib, a PDGF-receptor tyrosine kinase inhibitor, -incorporated nanoparticles in Sugen-hypoxia-normoxia or monocrotaline rat models of PAH and in human PAH-pulmonary arterial smooth muscle cells have been reported. The use of inhaled drug-incorporated nanoparticles might be a novel approach for treatment of PAH.

Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) has claimed nearly 180,000 lives and continues to spread. There are currently no approved medications or vaccines for this new coronavirus. Studies have shown that the positive RNA genome of SARS-CoV-2 contains unique features, including a 12-base sequence inserted between the two subunits of viral receptor protein Spike. This inserted sequence facilitates the cleavage of Spike by the cellular proteases Furin and TMPRSS2, leading to the fusion of virus and host cell membranes. Current studies are mostly focused on the SARS-CoV-2 Spike protein and its interacting cellular proteins ACE2, Furin, and TMPRSS2. RNA structural studies are limited and little is known about the potential impact of the 12-base sequence insert on the secondary structure of SARS-CoV-2 genomic RNA and/or its transcripts. Here, by using local and global RNA secondary structure predictions, we show that the novel 12-base insert of SARS-CoV-2 genome likely induces a major RNA secondary structure change.

The Wind Energy Conversion System (WECS) plays an inevitable role across the world. In particular, the attention for Permanent Magnet Synchronous Generators (PMSGs) connected with wind farm is popular. This paper deals with the literature review that describes the recent advances, progresses and innovatory trends on PMSGs for WECS. Comparison between geared and direct-driven conversion systems and the classification of electrical machines used in WECS are discussed. A detailed analysis on the design aspects considering various topologies of PMSGs are encompassed in the literature. The PMSG design and optimization problems are solved by field computation techniques and optimized by using Soft Computing (SC) techniques .The three-dimensional, finite element software platform for the analysis and design of PMSGs is discussed. This paper also deals with the interdisciplinary modeling, analysis, and optimization of PMSG using Finite Element Analysis (FEM) and SC techniques. Finally, PMSGs are reviewed and compared for further exploration.

Directed evolution methods are becoming increasingly popular, as they are extremely powerful toward developing new biomolecules with altered/novel activities, e.g., proteins with new catalytic functions or substrate specificities, and nucleic acids that recognize an intended target. Especially useful are systems that have incorporated continuous evolution, where the protein to be evolved undergoes continuous mutagenesis to evolve a desired trait with little to no input from the researcher once the system is started. However, continuous evolution methods can be challenging to implement in the lab and daunting for researchers to invest time and resources. Our intent is to provide basic information and helpful suggestions that we have gained from our experience with bacterial phage-assisted continuous evolution (PACE). Specifically, we review factors to consider before adopting PACE for a given evolution scheme, different types of selection circuits that can be utilized with particular focus on the PACE-B1H selection system, what optimization of a PACE selection circuit may look like using directed evolution of ME47 as a case study, and additional techniques that may be incorporated into a PACE experiment. With this information, researchers will be better equipped to determine if PACE is a valid strategy to use to evolve their proteins and how to set up a valid selection circuit.

Copper demand for a country's copper industry has a greater pull effect. China's copper consumption in 2015 has accounted for 50% of the world. The scientific forecast of China's copper demands trend is also an important basis for analyzing its future environmental impact. This paper assumes that China's economy will be developing high, medium and low scenarios, and forecasts economic and social indicators such as total GDP, population and per capita GDP in China from 2016 to 2030. Then, predicted the demand of copper resources in China from 2016 to 2030 by the combination of system dynamics model, vector autoregressive moving average model and inverted U-type empirical model. The results show that: (1) in 2020, 2025 and 2030, China's refined copper demand will be 13 Mt, 15 Mt and 15.5 Mt. (2) China's copper demand growth slowed down significantly from 2016-2030. (3) 2025-2030, China's copper resource demand is stable, into the platform of demand growth, the highest peak value in 2027 will be 15.5 Mt. (4) 2030 years later, China's copper resource demand will enter a slow decline.