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This research assesses Herat City's urban ecological degradation in 2000, 2013, and 2021 using Landsat and MODIS data. A Mean Remote Sensing Ecological Index (MRESI) is developed by integrating Known Granulation Entropy (KGE) and COmprehensive Distance-Based RAnking (COBRA) algorithms. Five ecological elements are considered: humidity, greenness, heat, dryness, and AOD. MRESI declined from 0.4544 to 0.4100, indicating deteriorating urban ecological quality. Spatial degradation increased from six to nine districts. MRSEI identified as the most representative indicator, effectively reflecting the urban ecological quality of Herat city. This approach offers an effective and economical method for managing urban development and spatial control. [ABSTRACT FROM AUTHOR]

Development of next-generation influenza virus vaccines is crucial to improve protection against circulating and emerging viruses. Current vaccine formulations have to be updated annually due to mutations in seasonal strains and do not offer protection against strains with pandemic potential. Computationally optimized broadly reactive antigen (COBRA) methodology has been utilized by our group to generate broadly reactive immunogens for individual influenza subtypes, which elicit protective immune responses against a broad range of strains over numerous seasons. Octavalent mixtures of COBRA hemagglutinin (HA) (H1, H2, H3, H5, H7, and influenza B virus) plus neuraminidase (NA) (N1 and N2) recombinant proteins mixed with c-di-AMP adjuvant were administered intranasally to naive or pre-immune ferrets in prime-boost fashion. Four weeks after final vaccination, collected sera were analyzed for breadth of antibody response, and the animals were challenged with seasonal or pre-pandemic strains. The octavalent COBRA vaccine elicited antibodies that recognized a broad panel of strains representing different subtypes, and these vaccinated animals were protected against influenza virus challenges. Overall, this study demonstrated that the mixture of eight COBRA HA/NA proteins mixed with an intranasal adjuvant is a promising candidate for a universal influenza vaccine. IMPORTANCE Influenza is a respiratory virus which infects around a billion people globally every year, with millions experiencing severe illness. Commercial vaccine efficacy varies year to year and can be low due to mismatch of circulating virus strains. Thus, the formulation of current vaccines has to be adapted accordingly every year. The development of a broadly reactive influenza vaccine would lessen the global economic and public health burden caused by the different types of influenza viruses. The significance of our research is producing a promising universal vaccine candidate which provides protection against a wider range of virus strains over a wider range of time. [ABSTRACT FROM AUTHOR]

Determining the quantitative values of geosites, which constitute the primary supply sources of geotourism, has an important role in developing geotourism. For this reason, the number of studies determining the values of geosites according to various factors is increasing daily. Although these studies make significant contributions to the literature, the problem of objectivity in geosite evaluation stages is still seen as an important issue. In particular, the fact that hesitant, uncertain, and ambiguous information from evaluators prevents objectivity in geosite evaluations is still controversial. In this context, this study aims to adapt fuzzy set-based MCDM (Multi-Criteria Decision Making) methods to geosite evaluation. For this purpose, SFSs (Spherical Fuzzy Sets), the new version of fuzzy sets, were used in integration with SWARA (Step-wise Weight Assessment Ratio Analysis)-COBRA (Comprehensive Distance-Based Ranking) methods. This methodological approach allows for minimising uncertain and ambiguous judgments arising from decision-makers. This proposed methodology was tested as a case study on six geosites selected from two districts of Aksaray province (Güzelyurt and Gülağaç) in Türkiye. According to the findings, significant differences were detected between traditional geosite evaluation approaches and the approach proposed in this study, both in weighting the criteria and ranking geosites. These results show that the proposed methodological approach can be a useful tool in reducing the objectivity problem frequently encountered in evaluating geosites. In this context, the proposed method is expected to contribute to the level of theoretical knowledge that will form the basis of geosites. [ABSTRACT FROM AUTHOR]

Purpose of Review: Snakebite envenomation, classified as a neglected tropical disease, represents a significant global health threat, particularly in Asia and Africa, where it causes between 57,000 and 100,000 deaths annually. Envenomation by cobras, especially those of the genus Naja, contributes substantially to this burden. This review explores the complexities of cobra venom composition, its associated complications, and current treatment strategies, with a focus on venom-derived therapeutic prospects. Recent Findings: Cobra venom is a complex mixture primarily composed of proteins and peptides that exert various toxic effects, including neurotoxicity, tissue damage, and systemic complications. Antivenom therapy remains the primary treatment for envenomation, successfully mitigating critical effects such as bleeding and paralysis. Recent research, however, has revealed that certain venom-derived molecules possess therapeutic potential, opening up new possibilities for drug development. Summary: Despite the lethal nature of cobra envenomation, advances in antivenom therapy and emerging research into the medicinal properties of venom-derived molecules offer hope. This review highlights the dual nature of cobra venom—both as a source of severe pathology and as a potential reservoir for therapeutic agents—fostering the development of novel drugs. [ABSTRACT FROM AUTHOR]

Abstract Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH2) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH2-adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH2 adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH2 -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses.

Introduction: Snakebites present a significant health threat, particularly in regions where human and snake habitats overlap. In India, a high incidence of snakebites is observed in rural areas due to farming practices and urbanization displacing wildlife. Although only a fraction of snake species are venomous, they can cause severe medical emergencies requiring prompt treatment. This study aims to explore the sociodemographic profile of new snakebite cases in Gujarat. Materials and Methodology: This retrospective, observational study analyzed medical records of patients admitted to a Gujarat hospital between June 2021 and December 2021 with a confirmed snakebite. A structured data collection form was used to gather demographic and clinical details through personal interviews with patients and attendants. Descriptive statistics were applied using GraphPad version 8.0. Results: The study included 100 patients, predominantly male (72%) and aged 21-40 years (54%), with a mean age of 38.17 ± 11.65 years. A significant 63% of patients were from rural areas, and 81% were from lower socioeconomic backgrounds. The most commonly identified snakes were kraits (34%), followed by cobras (19%) and vipers (8%), with 39% of cases involving unidentified snakes. Conclusion: The findings indicate that snakebite patients in Gujarat are mostly male, aged 21- 40, and from rural and lower socioeconomic backgrounds. The high incidence among agricultural workers suggests a need for targeted preventive measures and interventions in rural and economically disadvantaged communities to address the elevated risk of snakebites. [ABSTRACT FROM AUTHOR]

Influenza outbreaks are a major burden worldwide annually. While seasonal vaccines do provide protection against infection, they are limited in that they need to be updated every year to account for the constantly mutating virus. Recently, lipid nanoparticles (LNPs) encapsulating mRNA have seen major success as a vaccine platform for SARS-CoV-2. Herein, we applied LNPs to deliver an mRNA encoding a computationally optimized broadly active (COBRA) influenza immunogen. These COBRA mRNA LNPs induced a broadly active neutralizing antibody response and protection after lethal influenza challenge. To further increase the immunogenicity of the COBRA mRNA LNPs, we combined them with acetalated dextran microparticles encapsulating a STING agonist. Contrary to recent findings, the STING agonist decreased the immunogenicity of the COBRA mRNA LNPs which was likely due to a decrease in mRNA translation as shown in vitro. Overall, this work aids in future selection of adjuvants to use with mRNA LNP vaccines. [Display omitted] [ABSTRACT FROM AUTHOR]

Snake venoms constitute a complex blend of proteins and peptides, with their toxicity and pharmacological effects varying depending on their geographic origin. Naja haje, a venomous snake of significant medical importance in regions like Morocco and North Africa, can inflict severe pain, swelling, and neurotoxic symptoms upon biting. Without prompt medical intervention, these symptoms can rapidly worsen, potentially leading to fatal outcomes. Understanding the venom’s components is crucial for developing effective antivenom therapies. Specific antibodies that target the venom’s toxic elements are essential for neutralising its activity. Therefore, we conducted a proteomic analysis of these elements within Naja haje venom using gel filtration, HPLC, and mass spectrometry. Our findings identified eight fractions, among which fractions 5 and 6 exhibited notable toxicity, with fraction 5 resulting in mortality. Furthermore, we observed a prevalence of 3FTx, a diverse component in Naja venom, alongside short-chain neurotoxins such as short neurotoxin, cytotoxin, and muscarinic toxin-like proteins. Recognising these harmful elements is crucial for developing precise antivenom treatments. This investigation represents the first proteomic analysis of toxic fractions from Naja haje venom in Morocco, providing valuable insights into venom composition and aiding in the development of targeted therapies. [ABSTRACT FROM AUTHOR]

Adjuvants enhance, prolong, and modulate immune responses by vaccine antigens to maximize protective immunity and enable more effective immunization in the young and elderly. Most adjuvants are formulated with injectable vaccines. However, an intranasal route of vaccination may induce mucosal and systemic immune responses for enhancing protective immunity in individuals and be easier to administer compared to injectable vaccines. In this study, a next generation of broadly-reactive influenza hemagglutinin (HA) vaccines were developed using the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology. These HA vaccines were formulated with Mastoparan 7 (M7-NH2) mast cell degranulating peptide adjuvant and administered intranasally to determine vaccine-induced seroconversion of antibodies against a panel of influenza viruses and protection following infection with H1N1 and H3N2 viruses in mice. Mice vaccinated intranasally with M7-NH2-adjuvanted COBRA HA vaccines had high HAIs against a panel of H1N1 and H3N2 influenza viruses and were protected against both morbidity and mortality, with reduced viral lung titers, following challenge with an H1N1 influenza virus. Additionally, M7-NH2 adjuvanted COBRA HA vaccines induced Th2 skewed immune responses with robust IgG and isotype antibodies in the serum and mucosal lung lavages. Overall, this intranasally delivered M7-NH2 -adjuvanted COBRA HA vaccine provides effective protection against drifted H1N1 and H3N2 viruses. [ABSTRACT FROM AUTHOR]

Influenza neuraminidase (NA) is a promising target for a broadly protective vaccine. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to develop N2 NA vaccine candidates. The unique wild type (WT) N2 sequences of human and swine influenza strains isolated between 1957 and 2019 were used to design the COBRA N2-A NA vaccine, while the unique WT N2 sequences of human influenza strains isolated between 2000 and 2019 were used to design the COBRA N2-B NA vaccine. Sera collected from COBRA N2 NA vaccinated mice showed more broadly reactive antibody responses against a broad panel of H×N2 influenza virus strains than sera collected from mice vaccinated with WT N2 NA vaccines. Antibodies elicited by COBRA or WT N2 NA antigens cross react with recent human H3N2 influenza viruses from different clades, while the antibodies elicited by A/Switzerland/9715293/2013 hemagglutinin (HA) reacted with viruses from the same clade. Furthermore, mice vaccinated with COBRA N2-B NA vaccine had lower viral lung titers compared to mock vaccinated mice when challenged with human H3N2 influenza viruses. Thus, the COBRA N2 NA vaccines elicit broadly protective murine anti-NA antibodies against multiple strains across subtypes and the viral loads were significantly decreased in the lungs of the mice in the COBRA N2 NA vaccine groups, compared to the mice in the mock vaccinated group, indicating that the COBRA-based N2 subtype NA vaccines have a potential to be a component in a universal influenza vaccine.

The influenza viruses cause seasonal respiratory illness that affect millions of people globally every year. Prophylactic vaccines are the recommended method to prevent the breakout of influenza epidemics. One of the current commercial influenza vaccines consists of inactivated viruses that are selected months prior to the start of a new influenza season. In many seasons, the vaccine effectiveness (VE) of these vaccines can be relatively low. Therefore, there is an urgent need to develop an improved, more universal influenza vaccine (UIV) that can provide broad protection against various drifted strains in all age groups. To meet this need, the computationally optimized broadly reactive antigen (COBRA) methodology was developed to design a hemagglutinin (HA) molecule as a new influenza vaccine. In this study, COBRA HA-based inactivated influenza viruses (IIV) expressing the COBRA HA from H1 or H3 influenza viruses were developed and characterized for the elicitation of immediate and long-term protective immunity in both immunologically naïve or influenza pre-immune animal models. These results were compared to animals vaccinated with IIV vaccines expressing wild-type H1 or H3 HA proteins (WT-IIV). The COBRA-IIV elicited long-lasting broadly reactive antibodies that had hemagglutination-inhibition (HAI) activity against drifted influenza variants.

Adjuvants enhance immune responses stimulated by vaccines. To date, many seasonal influenza vaccines are not formulated with an adjuvant. In the present study, the adjuvant Advax-SM™ was combined with next generation, broadly reactive influenza hemagglutinin (HA) vaccines that were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. Advax-SM™ is a novel adjuvant comprising inulin polysaccharide and CpG55.2, a TLR9 agonist. COBRA HA vaccines were combined with Advax-SM™ or a comparator squalene emulsion (SE) adjuvant and administered to mice intramuscularly. Mice vaccinated with Advax-SM™ adjuvanted COBRA HA vaccines had increased serum levels of anti-influenza IgG and IgA, high hemagglutination inhibition activity against a panel of H1N1 and H3N2 influenza viruses, and increased anti-influenza antibody secreting cells isolated from spleens. COBRA HA plus Advax-SM™ immunized mice were protected against both morbidity and mortality following viral challenge and, at postmortem, had no detectable lung viral titers or lung inflammation. Overall, the Advax-SM™-adjuvanted COBRA HA formulation provided effective protection against drifted H1N1 and H3N2 influenza viruses. [ABSTRACT FROM AUTHOR]

Maintaining interconnected infrastructures such as transportation, communication, power grids, and pipeline networks is paramount in emerging economies. One of the critical interruptions is the targeted attacks on the operating cyber-physical systems to disconnect operations, inspection, or monitoring of the system. Therefore, adopting a cybersecurity system (or platform) that provides holistic protection is vital for protecting the integrity of critical infrastructure networks. As such, this research aspires to provide a decision support system for cybersecurity managers or practitioners (in the Indian power sector) to select the best and appropriate platform for protection against cyber-attacks. A three-phase method is adopted. First, a literature search followed by an expert panel discussion identified alternatives (cybersecurity platforms) and selection criteria. Next, a questionnaire was developed. Thirdly, a hybrid Best-Worst Improved and COmprehensive distance-Based RAnking (BWM-I and COBRA) method was proposed and applied to evaluate the cybersecurity platform alternatives. Four alternatives (Cloud-Based Platforms, Web-Based Platforms, Application-Based Platforms, and AI-Based Platforms), six primary criteria, and fifteen unique sub-criteria were identified. Responses were collected from 80 power utility managers on a pan-India basis, ranking "End-to-End Coverage" criteria and the AI-Based platform as best. This approach identified the best cybersecurity platform that, if adopted, can be extended to other critical infrastructures, with an appropriate adjustment in the selection criteria. The study can be helpful to practitioners in evaluating cybersecurity platforms. Furthermore, it addresses a research gap in its application in a developing country like India. [ABSTRACT FROM AUTHOR]

ABSTRACT In humans, seasonal influenza viruses cause epidemics. Avian influenza viruses are of particular concern because they can infect multiple species and lead to unpredictable and severe disease. Therefore, there is an urgent need for a universal influenza vaccine that provides protection against all influenza strains. The cyclic GMP-AMP (cGAMP) is a promising adjuvant for subunit vaccines, which promotes type I interferons’ production through the stimulator of interferon genes (STING) pathway. The encapsulation of cGAMP in acetalated dextran (Ace-DEX) microparticles (MPs) enhances its intracellular delivery. In this study, the Computationally Optimized Broadly Reactive Antigen (COBRA) methodology was used to generate H1, H3, and H5 vaccine candidates. Monovalent and multivalent COBRA HA vaccines formulated with cGAMP Ace-DEX MPs were evaluated in mice for protective antibody responses. cGAMP MPs adjuvanted COBRA HA vaccines elicited robust antigen-specific antibodies following vaccination. Compared with COBRA HA vaccine groups with no adjuvant or blank MPs, the cGAMP MPs enhanced HAI activity elicited by COBRA HA vaccines. The HAI activity was not significantly different between cGAMP MPs adjuvanted monovalent or multivalent COBRA HA vaccines. The cGAMP MPs adjuvanted COBRA vaccine groups had higher antigen-specific IgG2a-binding titers than the COBRA vaccine groups with no adjuvant or blank MPs. The COBRA vaccines formulated with cGAMP MPs mitigated diseases caused by influenza viral challenge and decreased pulmonary viral titers in mice. Therefore, the formulation of COBRA vaccines plus cGAMP MPs is a promising universal influenza vaccine that elicits protective immune responses against human seasonal and pre-pandemic strains.IMPORTANCEInfluenza viruses cause severe respiratory disease, particularly in the very young and the elderly. Next-generation influenza vaccines are needed to protect against new influenza variants. This report used a promising adjuvant, cyclic GMP-AMP (cGAMP), to enhance the elicited antibodies by an improved influenza hemagglutinin candidate and protect against influenza virus infection. Overall, adding adjuvants to influenza vaccines is an effective method to improve vaccines.

Snakebite is a neglected public health issue, with many scientific and medical issues to be solved. Cobras are among the most common venomous snakes in Myanmar and are responsible for a considerable number of severe snakebite envenoming. There are three species of cobra (Naja kaouthia, Naja mandalayensis and Ophiophagus hannah) in Myanmar. The study aims to characterize the N. kaouthia and N. mandalayensis venoms and to investigate the efficacy of anti-cobra antivenom (BPI) against the two venoms. Protein components and fibrinogenolytic activity were determined by SDS-PAGE. Enzymatic activities for PLA2, protease and acetylcholinesterase were determined by spectrophotometric method. Anticoagulant activity was determined by recalcification time of citrated human plasma. Myotoxicity, necrotizing activity, median lethal dose (LD50) and median effective dose (ED50) were determined by WHO recommended methods. The SDS-PAGE displayed the proteins and enzymes containing in two venoms were different. N. kaouthia venom exhibited more in PLA2, acetylcholinesterase, anticoagulant, fibrinogenolytic and necrotizing activities than N. mandalayensis venom. N. mandalayensis venom had more protease activity and myotoxicity than N. kaouthia venom. The median lethal dose (LD50) of N. kaouthia and N. mandalayensis venom was 4.33 μg/mouse and 5.04 μg/mouse respectively. Both venoms induced fibrinogen Aα chain degradation in 30 min (N. kaouthia) and in 6 h (N. mandalayensis). The same median effective dose (ED50) (19.56 μg/mouse) showed that anti-NK antivenom can neutralize against lethal effect of N. mandalayensis venom. It can also neutralize the protease activity, anticoagulant activity and fibrinogenolytic activity of both venoms. Immunodiffusion and immunoblotting studies showed that the antivenom recognized its homologous venom (N. kaouthia) and cross-reacted against the heterologous venom (N. mandalayensis). The anti-NK antivenom is suitable to use for N. mandalayensis bite if monospecific antivenom is not available.

A universal vaccine is in high demand to address the uncertainties of antigenic drift and the reduced effectiveness of current influenza vaccines. In this study, a strategy called computationally optimized broadly reactive antigen (COBRA) was used to generate a consensus sequence of the hemagglutinin globular head portion (HA1) of influenza virus samples collected from 1918 to 2021 to trace evolutionary changes and incorporate them into the designed constructs. Constructs carrying different HA1 regions were delivered into eukaryotic cells by Salmonella-mediated bactofection using a Semliki Forest virus RNA-dependent RNA polymerase (RdRp)-based eukaryotic expression system, pJHL204. Recombinant protein expression was confirmed by Western blot and immunofluorescence assays. Mice immunized with the designed constructs produced a humoral response, with a significant increase in immunoglobulin G (IgG) levels, and a cell-mediated immune response, including a 1.5-fold increase in CD4+ and CD8+ T cells. Specifically, constructs #1 and #5 increased the production of interferon-γ (IFN-γ) producing CD4+ and CD8+ T cells, skewing the response toward the T helper type 1 cell (Th1) pathway. Additionally, interleukin-4 (IL-4)-producing T cells were upregulated 4-fold. Protective efficacy was demonstrated, with up to 4-fold higher production of neutralizing antibodies and a hemagglutination inhibition titer > 40 against the selected viral strains. The designed constructs conferred a broadly protective immune response, resulting in a notable reduction in viral titer and minimal inflammation in the lungs of mice challenged with the influenza A/PR8/34, A/Brisbane/59/2007, A/California/07/2009, KBPV VR-92, and NCCP 43021 strains. This discovery revolutionizes influenza vaccine design and delivery; Salmonella-mediated COBRA-HA1 is a highly effective in vivo antigen presentation strategy. This approach can effectively combat seasonal H1N1 influenza strains and potential pandemic outbreaks.

Abstract Due to self-incompatibility (SI) prevents self-fertilization, natural or artificial cross-pollination has been conducted in many orchards to stabilize fruit yield. However, it is still puzzled which routes of self S-RNase arresting pollen tube growth. Herein, 17 COBRA genes were isolated from pear genome. Of these genes, the pollen-specifically expressed PbCOB.A.1 and PbCOB.A.2 positively mediates pollen tube growth. The promoters of PbCOB.A.1 and/or PbCOB.A.2 were bound and activated by PbABF.E.2 (an ABRE-binding factor) and PbC2H2.K16.2 (a C2H2-type zinc finger protein). Notably, the expressions of PbCOB.A.1, PbCOB.A.2, and PbC2H2.K16.2 were repressed by self S-RNase, suggesting that self S-RNase reduces the expression of PbCOB.A.1 and PbCOB.A.2 by decreasing the expression of their upstream factors, such as PbC2H2.K16.2, to arrest pollen tube growth. PbCOB.A.1 or PbCOB.A.2 accelerates the growth of pollen tubes treated by self S-RNase, but can hardly affect level of reactive oxygen species and deploymerization of actin cytoskeleton in pollen tubes and cannot physically interact with any reported proteins involved in SI. These results indicate that PbCOB.A.1 and PbCOB.A.2 may not relieve S-RNase toxicity in incompatible pollen tube. The information provides a new route to elucidate the arresting pollen tube growth during SI reaction. Graphical Abstract

Due to self-incompatibility (SI) prevents self-fertilization, natural or artificial cross-pollination has been conducted in many orchards to stabilize fruit yield. However, it is still puzzled which routes of self S-RNase arresting pollen tube growth. Herein, 17 COBRA genes were isolated from pear genome. Of these genes, the pollen-specifically expressed PbCOB.A.1 and PbCOB.A.2 positively mediates pollen tube growth. The promoters of PbCOB.A.1 and/or PbCOB.A.2 were bound and activated by PbABF.E.2 (an ABRE-binding factor) and PbC2H2.K16.2 (a C2H2-type zinc finger protein). Notably, the expressions of PbCOB.A.1, PbCOB.A.2, and PbC2H2.K16.2 were repressed by self S-RNase, suggesting that self S-RNase reduces the expression of PbCOB.A.1 and PbCOB.A.2 by decreasing the expression of their upstream factors, such as PbC2H2.K16.2, to arrest pollen tube growth. PbCOB.A.1 or PbCOB.A.2 accelerates the growth of pollen tubes treated by self S-RNase, but can hardly affect level of reactive oxygen species and deploymerization of actin cytoskeleton in pollen tubes and cannot physically interact with any reported proteins involved in SI. These results indicate that PbCOB.A.1 and PbCOB.A.2 may not relieve S-RNase toxicity in incompatible pollen tube. The information provides a new route to elucidate the arresting pollen tube growth during SI reaction. [ABSTRACT FROM AUTHOR]

Software development effort estimation (SDEE) is a critical activity in developing software. Accurate effort estimation in the early phases of software design life cycle has important effects on the success of software projects. COCOMO (Constructive Cost Model) is a parametric data‐driven SDEE model whose parameters must be calibrated with an organization's local data for accurate estimation. Such data are scarce for most organizations. On the other hand, CoBRA (Cost estimation, Benchmarking, and Risk Assessment) is one of the powerful hybrid methods that need a small number of local historical data for effort estimation. However, data gathering in CoBRA is time‐consuming and costly. To ease the use of CoBRA, in this paper, we design a methodology that extracts CoBRA‐required data from COCOMO datasets. By the proposed method, data collected for COCOMO would be used in CoBRA. Using CoBRA, a more accurate estimation of the required effort would be achieved with fewer number of historical data than what is required to calibrate the COCOMO model. We apply the proposed method on six well‐known public COCOMO datasets and use them in CoBRA. Obtained results depict an increase in the accuracy of estimations in comparison with other existing methods. [ABSTRACT FROM AUTHOR]

Abstract Currently, there is an increasing amount of evidence indicating that exosomes and the miRNAs they contain are crucial players in various biological processes. However, the role of exosomes and miRNAs in snake venom during the envenomation process remains largely unknown. In this study, fresh venom from Naja atra of different ages (2-month-old, 1-year-old, and 5-year-old) was collected, and exosomes were isolated through ultracentrifugation. The study found that exosomes with inactivated proteins and enzymes can still cause symptoms similar to cobra envenomation, indicating that substances other than proteins and enzymes in exosomes may also play an essential role in cobra envenomation. Furthermore, the expression profiles of isolated exosome miRNAs were analyzed. The study showed that a large number of miRNAs were co-expressed and abundant in cobra venom exosomes (CV-exosomes) of different ages, including miR-2904, which had high expression abundance and specific sequences. The specific miR-2094 derived from CV-exosomes (CV-exo-miR-2904) was overexpressed both in vitro and in vivo. As a result, CV-exo-miR-2904 induced symptoms similar to cobra envenomation in mice and caused liver damage, demonstrating that it plays a crucial role in cobra envenomation. These results reveal that CV-exosomes and the miRNAs they contain play a significant regulatory role in cobra envenomation. Our findings provide new insights for the treatment of cobra bites and the development of snake venom-based medicines. Graphic abstract

When freedom and freedom from the simulation of reality became one of the most important characteristics of modern art and the artist's denial of reality became one of the most important manifestations of the subjectivity of art, the content in art no longer has the first value, but the artist's own human and artistic experiences became the goal of his artistic expression, but technically the artist moved to new aesthetic values that came to him by identifying the secrets of light and color and the visual content that lies behind them contributes to the influence of sensory perception and mental and on the effective effects of the line in the sense of movement within the void or around it and then finally through innovative expression and the method of implementation that is not bound by a rule or law. When art began to clearly express the idea of irrationality, absurdity and play, which became a starting point for overcoming reality, the art of "Cobra" emerged as an art that reflected the spirit of the twentieth century, the century of world civilization in which man raced all over the world to reveal the secrets of science and life, and thus art became new characteristics, characteristics that reflect form and this realization, and that beauty and ugliness are not qualities of the artwork but are qualities of the spirit that expressed itself intuitively in these works of art. Since the conflict between the self and the subject in modern art, which was the dominant self in most battles, appeared cobra using the method of combining what is realistic and what is virtual fiction, and the self re-visual re-evaluation of the things and events that man deals with. The art of "Cobra" has been chosen as a design entry point for the development of designs suspended from the road, combining form and form, between objectivity and subjectivity, and destroying the effect of empty and disturbing beauty by bringing the ocean into the artwork through the living things that surround the human being and furnish his place and memory.

Snakebite is one of the most common complaints related to wilderness medicine. Venomous snakebite manifestation is divided into local and systemic envenomation. For the Elapidae group, the most feared complication is respiratory muscle paralysis due to neurotransmitter malfunction at the neuromuscular junction level which leads to respiratory insufficiency. However, there is a lack of evidence or case report incidence to suggest that it can potentially associate with the development of stroke disorder. We present a rare case of massive posterior circulation infarct in a middle-aged gentleman following a cobra bite. He was brought to our center few hours later following the bite and antivenom was administered. He improved shortly after receiving it. However, he had an abrupt drop in his conscious level several hours later. Noncontrast-enhanced computed tomography (NCCT) brain was performed immediately, but stroke disorder was excluded prematurely. Repeated NCCT imaging which was done 12 h apart showed massive posterior circulation infarction with hydrocephalus. He succumbed to death 3 days later. Given its rarity, the evolution of his clinical condition warrants clinician's early suspicion of potential stroke-related complications that can occur following a cobra bite. [ABSTRACT FROM AUTHOR]

Currently, there is an increasing amount of evidence indicating that exosomes and the miRNAs they contain are crucial players in various biological processes. However, the role of exosomes and miRNAs in snake venom during the envenomation process remains largely unknown. In this study, fresh venom from Naja atra of different ages (2-month-old, 1-year-old, and 5-year-old) was collected, and exosomes were isolated through ultracentrifugation. The study found that exosomes with inactivated proteins and enzymes can still cause symptoms similar to cobra envenomation, indicating that substances other than proteins and enzymes in exosomes may also play an essential role in cobra envenomation. Furthermore, the expression profiles of isolated exosome miRNAs were analyzed. The study showed that a large number of miRNAs were co-expressed and abundant in cobra venom exosomes (CV-exosomes) of different ages, including miR-2904, which had high expression abundance and specific sequences. The specific miR-2094 derived from CV-exosomes (CV-exo-miR-2904) was overexpressed both in vitro and in vivo. As a result, CV-exo-miR-2904 induced symptoms similar to cobra envenomation in mice and caused liver damage, demonstrating that it plays a crucial role in cobra envenomation. These results reveal that CV-exosomes and the miRNAs they contain play a significant regulatory role in cobra envenomation. Our findings provide new insights for the treatment of cobra bites and the development of snake venom-based medicines. [ABSTRACT FROM AUTHOR]

Secondary metabolites are not essential for the growth of microorganisms, but they play a critical role in how microbes interact with their surroundings. In addition to this important ecological role, secondary metabolites also have a variety of agricultural, medicinal, and industrial uses, and thus the examination of secondary metabolism of plants and microbes is a growing scientific field. While the chemical production of certain secondary metabolites is possible, industrial-scale microbial production is a green and economically attractive alternative. This is even more true, given the advances in bioengineering that allow us to alter the workings of microbes in order to increase their production of compounds of interest. This type of engineering requires detailed knowledge of the "chassis" organism's metabolism. Since the resources and the catalytic capacity of enzymes in microbes is finite, it is important to examine the tradeoffs between various bioprocesses in an engineered system and alter its working in a manner that minimally perturbs the robustness of the system while allowing for the maximum production of a product of interest. The in silico multi-objective analysis of metabolism using genome-scale models is an ideal method for such examinations. [ABSTRACT FROM AUTHOR]

Adjuvants enhance immune responses stimulated by vaccines. To date, many seasonal influenza vaccines are not formulated with an adjuvant. In the present study, the adjuvant Advax-SM™ was combined with next generation, broadly reactive influenza hemagglutinin (HA) vaccines that were designed using a computationally optimized broadly reactive antigen (COBRA) methodology. Advax-SM™ is a novel adjuvant comprising inulin polysaccharide and CpG55.2, a TLR9 agonist. COBRA HA vaccines were combined with Advax-SM™ or a comparator squalene emulsion (SE) adjuvant and administered to mice intramuscularly. Mice vaccinated with Advax-SM™ adjuvanted COBRA HA vaccines had increased serum levels of anti-influenza IgG and IgA, high hemagglutination inhibition activity against a panel of H1N1 and H3N2 influenza viruses, and increased anti-influenza antibody secreting cells isolated from spleens. COBRA HA plus Advax-SM™ immunized mice were protected against both morbidity and mortality following viral challenge and, at postmortem, had no detectable lung viral titers or lung inflammation. Overall, the Advax-SM™-adjuvanted COBRA HA formulation provided effective protection against drifted H1N1 and H3N2 influenza viruses.

Background: Snake bite is an underestimated cause of accidental deaths in India. This hospital based post-mortem study has been carried out at Government Chengalpattu Medical college and Hospital during the year 2021 (1 year). Total of 1437 autopsies were conducted in the mortuary of Chengalpattu medical college and hospital during this period. Out of total 1437 cases of post mortem examinations, 229 poisoning cases noted and out of 229 poisoning cases, Snake bite was observed in 39 (2.71%) cases. Total 27 (69.23%) males and 12 (30.77%) females died due to snake bite. Maximum cases were observed in 11 – 30 years of age group and were 17 (43.59%). The male to female ratio was 2.25:1. Maximum number of deaths belong to rural area, comprising of 31 (79.49%) out of 39, while 8 (20.51%) deaths were belonged to urban area. Maximum deaths are occurred between 6 to 24 hours (46.15%) from bite. The need to educate the public about hazards of snake bite, early hospital referral and treatment. [ABSTRACT FROM AUTHOR]

Background: Snakebite envenoming is a global health problem, mostly in tropical and subtropical countries. Bangladesh is a subtropical country facing thousands of snakebite envenoming death every year. Knowledge of the distribution of venomous snakes is necessary to identify snakebite-prone areas, develop strategies for prevention and management, and reduce venom-induced mortalities and morbidities. Methods: An integrated effort of direct observations of snakes, qualitative analysis of museum specimen records, clinical records of snakebites, and scholarly literature records were used to understand the pattern of distribution of venomous snakes in Bangladesh. Results: We enlist 65 venomous snake species from Bangladesh and present detailed documentation on their distribution pattern. However, only nine species were considered medically relevant species because of their venom potentiality to kill humans and available clinical records of envenomation. The distribution pattern of those species divides the country into two major portions. A portion consists of northern, northwestern, and western parts of the country, which are habitats of Naja naja, Bungarus caeruleus, and B. lividus. Another portion comprised of the northeastern, southeastern, and southern parts of the country provides habitats for N. kaouthia, B. niger, and Trimeresurus erythrurus. However, Daboia. russelii had a different distribution pattern along the bank of the Padma and Meghna, and some coastal districts. Moreover, B. walli had a scattered distribution over the country. The knowledge of this ecological distribution of venomous snakes across the country bears a significant practical effect on clinical management of snakebite. Treating physicians can have a better understanding of possible offending snake species using this knowledge and the clinical syndromes produced by venoms. Conclusion: Pattern of distribution of medically relevant venomous snakes in Bangladesh approaches to initiate concise and specific bite management strategies for two distinct distributional regions of the country. Moreover, the distribution of D. russelii and B. walli demands specific strategies for bite management. [ABSTRACT FROM AUTHOR]

Snakebite is one of the most common complaints related to wilderness medicine. Venomous snakebite manifestation is divided into local and systemic envenomation. For the Elapidae group, the most feared complication is respiratory muscle paralysis due to neurotransmitter malfunction at the neuromuscular junction level which leads to respiratory insufficiency. However, there is a lack of evidence or case report incidence to suggest that it can potentially associate with the development of stroke disorder. We present a rare case of massive posterior circulation infarct in a middle-aged gentleman following a cobra bite. He was brought to our center few hours later following the bite and antivenom was administered. He improved shortly after receiving it. However, he had an abrupt drop in his conscious level several hours later. Noncontrast-enhanced computed tomography (NCCT) brain was performed immediately, but stroke disorder was excluded prematurely. Repeated NCCT imaging which was done 12 h apart showed massive posterior circulation infarction with hydrocephalus. He succumbed to death 3 days later. Given its rarity, the evolution of his clinical condition warrants clinician's early suspicion of potential stroke-related complications that can occur following a cobra bite.

Snake bites are an important cause of illness and deaths in the rural population in tropical, subtropical and southeast Asian countries. There are more than 3000 species of snakes found all over the world of which around 300 species are found in India. In India, most of snake bite deaths occur due to delayed arrival to treatment centers. The purpose of the present review article is to explore the various species of snakes, their toxicology, clinical manifestations, and management. In addition, various ways to avoid snake bites and early approaches to government centers rather than private centers for the availability of Anti-snake venom have been discussed in this article. Rapid diagnostic test for the identification of species is available in selective centers only and treatment mainly depends on the administration of anti-snake venom. In addition, proper community education and strong health-care policy will reduce the morbidity and mortality due to snake bites.

Snake bites are an important cause of illness and deaths in the rural population in tropical, subtropical and southeast Asian countries. There are more than 3000 species of snakes found all over the world of which around 300 species are found in India. In India, most of snake bite deaths occur due to delayed arrival to treatment centers. The purpose of the present review article is to explore the various species of snakes, their toxicology, clinical manifestations, and management. In addition, various ways to avoid snake bites and early approaches to government centers rather than private centers for the availability of Anti-snake venom have been discussed in this article. Rapid diagnostic test for the identification of species is available in selective centers only and treatment mainly depends on the administration of anti-snake venom. In addition, proper community education and strong health-care policy will reduce the morbidity and mortality due to snake bites. [ABSTRACT FROM AUTHOR]

The optimization of animal feeds and cell culture media are problems of interest to a wide range of industries and scientific disciplines. Both problems are dictated by the properties of an organism's metabolism. However, due to the tremendous complexity of metabolic systems, it can be difficult to predict how metabolism will respond to changes in nutrient availability. A common tool used to capture the complexity of metabolism in a computational framework is a genome-scale metabolic model (GEM). GEMs are useful for predicting the fluxes of reactions within an organism's metabolism. To optimize feed or media, in silico experiments can be performed with GEMs by systematically varying nutritional constraints and predicting metabolic activity. In this way, the influence of various nutritional changes on metabolic outcomes can be evaluated. However, this methodology does not guarantee an optimal solution. Here, we develop a nutrition algorithm that utilizes linear programming to search the entire flux solution space of possible dietary intervention strategies to identify the most efficient changes to nutrition for a desirable metabolic outcome. We illustrate the utility of the nutrition algorithm on GEMs of Atlantic salmon (Salmo salar) and Chinese hamster ovary (CHO) cell metabolism and find that the nutrition algorithm makes predictions that not only align with experimental findings but reveal new insights into promising feeding strategies. We show that the nutrition algorithm is highly versatile and customizable to meet the user's needs. For instance, we demonstrate that the nutrition algorithm can be used to predict feed/media compositions that maximize profit margins. While the nutrition algorithm can be used to define an optimal feed/medium ab initio , it can also identify minimal changes to be made to an existing feed/medium to drive the largest metabolic shift. Moreover, the nutrition algorithm can target multiple metabolic pathways simultaneously with only a marginal increase in computational expense. While the nutrition algorithm has its limitations, we believe that this tool can be leveraged in a broad range of biotechnological applications to enhance the feed/medium optimization process. • The nutrition algorithm is a flexible and robust tool for optimizing feed and media using GEMs. • The nutrition algorithm can target multiple reactions of interest simultaneously at marginal cost to computational time. • Fish meal may be more reliable than soybean meal for minimizing nitrogen excretion in Atlantic salmon. • The nutrition algorithm identified synergetic combinations of nutrients to improve CHO cell antibody and biomass yield. [ABSTRACT FROM AUTHOR]

In this study, calcium carbonate (CaCO3) was considered as nanoparticle. In the first part of the study, half-value layer (HVL) and mean free path (MFP) values, which are radiation shielding parameters, were investigated in determined energy ranges by Phy-X open access software. At increasing energy levels, the HVL value reached approximately 10 cm, while the MFP value reached approximately 17 cm. In the second part of the study, the reactor core geometry was modeled with the MCNP code and then the relative power distribution values were determined. COBRA code input was prepared with the determined relative power distribution values and thermal analyzes were made. These analyzes were performed for three different nanoparticle ratios. As a result of the analysis, the temperature value at the end of the channel was 613 K when only water was used as a coolant, while the temperature value at the end of the channel was 611.19 K when 0.03% nanoparticles were used. Although the coolant temperature increased with the nanoparticle ratio, it was observed that the temperature decreased when only water was used. [ABSTRACT FROM AUTHOR]

This paper discusses three mummy wrappings, stored in the Cairo Egyptian Museum with the inventory numbers SR 2201, 2202, 2203 (JE 96813), which are as yet unpublished. No information about their provenance, date and owner is recorded. The mummy wrapping SR 2201 is probably unique as it presents a cryptographic writing of the name of king Ramesses II with a representation of Cobra as Amun. The two other bandages present different abridged versions of BD Spell 101 for a woman named Nesikhonsu. Although no titles or family affiliations are included, she may have belonged to a Theban family of the Twenty-first Dynasty. This paper interprets these illustrations, and presents a transliteration, translation, and commentary of Spell 101.

For decades, studies of snake venoms focused on the venom-ome-specific toxins (VSTs). VSTs are dominant soluble proteins believed to contribute to the main venomous effects and emerged into gene clusters for fast adaptation and diversification of snake venoms. However, the conserved minor venom components, such as snake venom phosphodiesterase (svPDE), remain largely unexplored. Here, we focus on svPDE by genomic and transcriptomic analysis across snake clades and demonstrate that soluble svPDE is co-opted from the ancestral membrane-attached ENPP3 (ectonucleotide pyrophosphatase/phosphodiesterase 3) gene by replacing the original 5′ exon with the exon encoding a signal peptide. Notably, the exons, promoters, and transcription/translation starts have been replaced multiple times during snake evolution, suggesting the evolutionary necessity of svPDE. The structural and biochemical analyses also show that svPDE shares the similar functions with ENPP family, suggesting its perturbation to the purinergic signaling and insulin transduction in venomous effects.

Computationally optimized broadly reactive antigens (COBRAs) are a next-generation universal influenza vaccine candidate. However, how these COBRAs induce antibody responses when combined with different adjuvants has not previously been well-characterized. Therefore, we performed in vivo studies with an HA-based H1 COBRA, Y2, and an NA-based N1 COBRA, N1-I, to assess this effect for the H1N1 subtype. We tested the adjuvants AddaVax, AddaS03, CpG, and Alhydrogel. AddaS03 performed the best, eliciting high IgG titers and hemagglutination inhibition (HAI) activity for Y2 immunizations. Interestingly, serum antibody epitopes were relatively similar across adjuvant groups. Moreover, following N1-I immunization with these adjuvants, AddaS03 also elicited the highest IgG and neuraminidase inhibition (NAI) titers against the 2009 pandemic virus, A/California/07/2009 (A/CA/09). These results inform adjuvant selection efforts for H1 and N1 COBRA HA and NA antigens in a mouse model. [ABSTRACT FROM AUTHOR]

Initial exposure to influenza virus(es) during early childhood produces protective antibodies that may be recalled following future exposure to subsequent viral infections or vaccinations. Most influenza vaccine research studies use immunologically naïve animal models to assess vaccine effectiveness. However, most people have an extensive influenza immune history, with memory cells produced by viruses or vaccines representing multiple influenza viruses. In this study, we explored the effect influenza seasonal virus-induced immunity has on pre-pandemic influenza virus vaccination. The mice that were pre-immune to historical H1N1 and H3N2 seasonal influenza viruses were vaccinated with adjuvanted pre-pandemic (H2, H5, and H7) HA-based computationally optimized broadly reactive antigen (COBRA) vaccines, and were fully protected from lethal challenge, whereas the mock-vaccinated mice, with or without pre-immunity, were not protected from morbidity or mortality. Detectable antibody titers were present in the pre-immune mice vaccinated with a single dose of vaccine, but not in the immunologically naïve mice. The mice vaccinated twice with the trivalent COBRA HA vaccine had similar antibody titers regardless of their pre-immune status. Overall, seasonal pre-immunity did not interfere with the immune responses elicited by pre-pandemic COBRA HA vaccines or the protection against pre-pandemic viruses. [ABSTRACT FROM AUTHOR]

The influenza neuraminidase (NA) is a promising target for next-generation vaccines. Protection induced by vaccination with the computationally optimized broadly reactive NA antigen (N1-I COBRA NA) was characterized in both influenza serologically naive and pre-immune ferret models following H1N1 (A/California/07/2009, CA/09) or H5N1 (A/Vietnam/1203/2004, Viet/04) influenza challenges. The N1-I COBRA NA vaccine elicited antibodies with neutralizing ELLA activity against both seasonal and pandemic H1N1 influenza, as well as the H5N1 influenza virus. In both models, N1-I COBRA NA-vaccinated ferrets that were challenged with CA/09 virus had similar morbidity (weight loss and clinical symptoms) as ferrets vaccinated with the CA/09 HA control vaccine. There were significantly reduced viral titers compared to the mock-vaccinated control animals. Ferrets vaccinated with N1-I COBRA NA or Viet/04 NA vaccines were protected against the H5N1 virus infection with minimal clinical symptoms and negligible weight loss. In contrast, ferrets vaccinated with the CA/09 NA vaccine lost ~10% of their original body weight with 25% mortality. Vaccination with either HA or NA vaccines did not inhibit contact transmission of CA/09 virus to naïve cage mates. Overall, the N1-I COBRA vaccine elicited protective immune responses against both H1N1 and H5N1 infections and partially mitigated disease in contact-transmission receiving ferrets. These results indicate that the N1-I COBRA NA performed similarly to the CA/09 HA and NA positive controls. Therefore, the N1-I COBRA NA alone induces protection against viruses from both H5N1 and H1N1 subtypes, indicating its value as a vaccine component in broadly protective influenza vaccines. [ABSTRACT FROM AUTHOR]

The purpose of this quantitative-deductive paper is to explore the link amongst customer satisfaction and engagement on social media on repurchase intention in the hospitality industry. The study was conducted on social media because, it is the fastest growing media in history. Data was collected from hotels in the three major business hub cities (Accra, Tamale and Kumasi) in Ghana. A total of 504 valid responses were obtained from respondents in the selected cities. SmartPLS software was used to analyze the data using (PLS-SEM) method. The results show that customer satisfaction has a positive and significant relationship on the dimensions of customer engagement. The three dimensions of customer engagement (contribution, consumption and creation) were found to significantly influence repurchase intention. Finally, two dimensions of engagement (contribution and consumption) were found to mediate the relationship between customer satisfactions and repurchase intention. The study is among the few to combine the COBRA model and Social Exchange Theory to assess the nexus between customers’ engagement in an online environment and its linkages with satisfaction and repurchase intentions. Marketers should consider creating posts with photos, videos, and animation that consumers find entertaining and enjoyable, as this stimulates their desire to consume, contribute, and create content on social media pages for hotel brands.

Inhibitory compounds generated from biomass hydrolysis affect the production of biofuels. HMF is a furan derivative inhibitor and influences the ethanol yield by inhibiting enzymes such as alcohol dehydrogenase, aldehyde dehydrogenase and glycolysis. The most striking effect of HMF on the organisms is that it interferes with the microbial growth and is considered as the most potent inhibitor in bioethanol production. In this study, HMF inhibition within yeast cells is investigated by both computational (COBRA) and experimental approaches. The active subsystems in the medium with and without HMF and the coupling types of the reactions are determined to get an insight on how to improve bioethanol production by strain engineering techniques. While extracellular transport subsystem is prominent in term of flexibility, post transcriptional regulation is outstanding among transcriptional to metabolic regulation types. The strategies to increase biomass and ethanol simultaneously with gene/reaction deletion methods are discussed, and ethanol production can be increased by 17% up to 33.35 mmol gDW−1hr−1 with several reaction deletions. The genome scale metabolic model and the complementary experiment given here shed light on the biofuel management in the bio-based industry for future. [Display omitted] • HMF decreased the biomass generation and ethanol production rate • Biomass generation and ethanol production have highest flexibility in extracellular transport and sterol metabolisms • Post transcriptional regulation is the most dominant type of regulation in GSM model • Ethanol production is increased from 28.43 mmol gDW−1h−1 to 33.35 mmol gDW−1h−1 by various gene/reaction deletions • Metabolic network regulated can eliminate toxic by-products and overproduce chemical compounds of interest [ABSTRACT FROM AUTHOR]

In recent years, renewable portfolio standards (RPS), which require a certain percentage of electricity sold to consumers to come from renewable resources, have been established by many state governments to mitigate emissions of greenhouse gases and air pollutants in the United States. Nevada's RPS set a target of 50% of electricity to come from renewable sources by 2030. By coupling the U.S. Environmental Protection Agency's AVoided Emissions and geneRation Tool (AVERT) and CO–Benefits Risk Assessment (COBRA) model, this study assesses potential emission reductions from fossil fuels owing to this requirement and regional health benefits via improved air quality, as well as how these benefits vary spatially under high and low projected electricity demands in 2030. Successful implementation of the RPS could produce health benefits equivalent to USD 3–8 million per year for Nevada residents and up to USD 164 million per year for the entire U.S. Nevada is ranked only 6th among states benefiting from the policy, while California and Washington obtain the most health benefits. There is also inequity among Nevada counties, partly caused by the county population and proximity to major fossil fuel power plants. Lowering electricity demands by 5% in Nevada would lead to a ~10% increase in health benefits. These findings should empower public support of RPS policies and energy conservation to reduce air pollution and public health inequity for the region. [ABSTRACT FROM AUTHOR]

Development of next-generation influenza virus vaccines is crucial to improve protection against circulating and emerging viruses. Current vaccine formulations have to be updated annually due to mutations in seasonal strains and do not offer protection against strains with pandemic potential. Computationally optimized broadly reactive antigen (COBRA) methodology has been utilized by our group to generate broadly reactive immunogens for individual influenza subtypes, which elicit protective immune responses against a broad range of strains over numerous seasons. Octavalent mixtures of COBRA hemagglutinin (HA) (H1, H2, H3, H5, H7, and influenza B virus) plus neuraminidase (NA) (N1 and N2) recombinant proteins mixed with c-di-AMP adjuvant were administered intranasally to naive or pre-immune ferrets in prime-boost fashion. Four weeks after final vaccination, collected sera were analyzed for breadth of antibody response, and the animals were challenged with seasonal or pre-pandemic strains. The octavalent COBRA vaccine elicited antibodies that recognized a broad panel of strains representing different subtypes, and these vaccinated animals were protected against influenza virus challenges. Overall, this study demonstrated that the mixture of eight COBRA HA/NA proteins mixed with an intranasal adjuvant is a promising candidate for a universal influenza vaccine., Importance: Influenza is a respiratory virus which infects around a billion people globally every year, with millions experiencing severe illness. Commercial vaccine efficacy varies year to year and can be low due to mismatch of circulating virus strains. Thus, the formulation of current vaccines has to be adapted accordingly every year. The development of a broadly reactive influenza vaccine would lessen the global economic and public health burden caused by the different types of influenza viruses. The significance of our research is producing a promising universal vaccine candidate which provides protection against a wider range of virus strains over a wider range of time., Competing Interests: C.A.G. and T.E. are named as inventors in patents covering the use of bis-(3,5)-cyclic dimeric adenosine monophosphate as vaccine adjuvant (PCT/EP 2006010693) and neonatal adjuvant (EP 19193982). C.A.G., T.E., N.U., and T.M.R. are named as inventors on the patent covering vaccine plus adjuvant (U.S. provisional application number 63/556,916).

Secondary metabolites are not essential for the growth of microorganisms, but they play a critical role in how microbes interact with their surroundings. In addition to this important ecological role, secondary metabolites also have a variety of agricultural, medicinal, and industrial uses, and thus the examination of secondary metabolism of plants and microbes is a growing scientific field. While the chemical production of certain secondary metabolites is possible, industrial-scale microbial production is a green and economically attractive alternative. This is even more true, given the advances in bioengineering that allow us to alter the workings of microbes in order to increase their production of compounds of interest. This type of engineering requires detailed knowledge of the “chassis” organism’s metabolism. Since the resources and the catalytic capacity of enzymes in microbes is finite, it is important to examine the tradeoffs between various bioprocesses in an engineered system and alter its working in a manner that minimally perturbs the robustness of the system while allowing for the maximum production of a product of interest. The in silico multi-objective analysis of metabolism using genome-scale models is an ideal method for such examinations.

Viral infections are linked to a variety of human diseases. Despite the achievements made in drug and vaccine development, several viruses still lack preventive vaccines and efficient antiviral compounds. Thus, developing novel antiviral agents is of great concern, particularly the natural products that are promising candidates for such discoveries. In this study, we have purified an approximately 15 kDa basic phospholipase A2 (PLA2) enzyme from the Egyptian cobra Naja haje haje venom. The purified N. haje PLA2 showed a specific activity of 22 units/mg protein against 6 units/mg protein for the whole crude venom with 3.67-fold purification. The antiviral activity of purified N. haje PLA2 has been investigated in vitro against bovine coronavirus (BCoV) and simian rotavirus (RV SA-11). Our results showed that the CC50 of PLA2 were 33.6 and 29 µg/ml against MDBK and MA104 cell lines, respectively. Antiviral analysis of N. haje PLA2 showed an inhibition of BCoV and RV SA-11 infections with a therapeutic index equal to 33.6 and 16, respectively. Moreover, N. haje PLA2 decreased the BCoV and RV SA-11 titers by 4.25 log10 TCID50 and 2.5 log10 TCID50, respectively. Thus, this research suggests the potential antiviral activity of purified N. haje PLA2 against BCoV and RV SA-11 infections in vitro. [ABSTRACT FROM AUTHOR]

COBRA-Like (COBL) genes encode a glycosylphosphatidylinositol (GPI) anchoring protein unique to plants. In current study, 87 COBRA genes were identified in 6 Rosaceae species, including Pyrus bretschneideri (16 genes), Malus domestica (22 genes), Fragaria vesca (13 genes), Prunus mume (11 genes), Rubus occidentalis (13 genes) and Prunus avium (12 genes). We revealed the evolution of the COBRA gene in six Rosaceae species by phylogeny, gene structure, conservative sequence, hydrophobicity analysis, gene replication events and sliding window analysis. In addition, based on the analysis of expression patterns in pear fruit combined with bioinformatics, we identified PbCOBL12 and PbCOBL13 as potential genes regulating secondary cell wall (SCW) formation during pear stone cell development. This study aimed to understand the evolutionary relationship of the COBRA gene in Rosaceae species, clarify the potential function of COBRA in pear fruit development, and provide essential theoretical basis and gene resources for improving pear fruit quality through genetical modification mechanism. [ABSTRACT FROM AUTHOR]

Background:Neurotoxic Snake bite is an important health hazard that may lead to fatality in Bangladesh, particularly in rural areas. Epidemiological data point to 700000 incidences of snake bite resulting in 6000 deaths in a year. Despite the criticality of this issue, limited studies are available in the pertinent literature. Consequently, to bridge the gap and offer fresh insights into this domain, the present study was an effort to observe the clinical and demographic profile of neurotoxic snake bite in tertiary care hospital of Bangladesh. Methods:This research was a hospital based observational study which was conducted at the inpatient department of Medicine in Dhaka Medical College Hospital (DMCH). Thirty five patients admitted in DMCH for neurotoxic snake bite were examined according to the inclusion and exclusion criteria. Ethical issues were ensured properly throughout the study. After obtaining a written informed consent, patents’ history was taken and physical examination was done and data were recorded in structured case record form. In the end, the collected data was analysed by computer via SPSS 22. Results: Neurotoxic snake bite was most frequent (34.3%) in age group 21-30 years. The mean age of the subjects was 32.31 ±14.33 SD. Total 11 Neurotoxic snake was identified and 7 were Cobras and 4 were Kraits. Difficulty in swallowing, difficulty in speech, double vision, and difficulty in breathing were found in 11.4%, 28.6%, 5.7%, and 37.1% of the cases, respectively. Moreover, all the subjects had Ptosis (100%), 14.3% had external ophthalmoplegia, 57.1% had broken neck sign. Furthermore 60% of the cases recovered completely, 17.1% recovered with complications, but unfortunately 22.9% of the patients died. Conclusion: Ptosis and broken neck signs are the most frequent neurotoxic signs. However, a larger study is needed to validate and approve this finding.

Abstract Background Ogataea polymorpha is a thermotolerant, methylotrophic yeast with significant industrial applications. While previously mainly used for protein synthesis, it also holds promise for producing platform chemicals. O. polymorpha has the distinct advantage of using methanol as a substrate, which could be potentially derived from carbon capture and utilization streams. Full development of the organism into a production strain and estimation of the metabolic capabilities require additional strain design, guided by metabolic modeling with a genome-scale metabolic model. However, to date, no genome-scale metabolic model is available for O. polymorpha. Results To overcome this limitation, we used a published reconstruction of the closely related yeast Komagataella phaffii as a reference and corrected reactions based on KEGG and MGOB annotation. Additionally, we conducted phenotype microarray experiments to test the suitability of 190 substrates as carbon sources. Over three-quarter of the substrate use was correctly reproduced by the model and 27 new substrates were added, that were not present in the K. phaffii reference model. Conclusion The developed genome-scale metabolic model of O. polymorpha will support the engineering of synthetic metabolic capabilities and enable the optimization of production processes, thereby supporting a sustainable future methanol economy.

Influenza causes significant morbidity and mortality. As an alternative approach to current seasonal vaccines, the computationally optimized broadly reactive antigen (COBRA) platform has been previously applied to hemagglutinin (HA). This approach integrates wild-type HA sequences into a single immunogen to expand the breadth of accessible antibody epitopes. Adding to previous studies of H1, H3, and H5 COBRA HAs, we define the structural features of another H1 subtype COBRA, X6, that incorporates HA sequences from before and after the 2009 H1N1 influenza pandemic. We determined structures of this antigen alone and in complex with COBRA-specific as well as broadly reactive and functional antibodies, analyzing its antigenicity. We found that X6 possesses features representing both historic and recent H1 HA strains, enabling binding to both head- and stem-reactive antibodies. Overall, these data confirm the integrity of broadly reactive antibody epitopes of X6 and contribute to design efforts for a next-generation vaccine. [Display omitted] • X6 captures glycosylation and antigenic features of pre-2009 and post-2009 H1 HAs • Vaccine-induced COBRA-reactive mAbs can have broad H1 reactivity and neutralization • X6 possesses intact head and stem epitopes characteristic of several H1 viruses Current influenza vaccines confer narrow, relatively strain-specific protection. Through analyses of a next-generation vaccine, X6, Nagashima et al. describe the characteristics responsible for enhanced antibody-dependent breadth. Glycans and antibody-binding sites of the major surface protein, hemagglutinin (HA), were conserved from circulating strains from before and after the 2009 H1N1 pandemic. [ABSTRACT FROM AUTHOR]

Ustilago maydis is an important plant pathogen that causes corn smut disease and serves as an effective biotechnological production host. The lack of a comprehensive metabolic overview hinders a full understanding of the organism's environmental adaptation and a full use of its metabolic potential. Here, we report the first genome-scale metabolic model (GSMM) of Ustilago maydis (iUma22) for the simulation of metabolic activities. iUma22 was reconstructed from sequencing and annotation using PathwayTools, and the biomass equation was derived from literature values and from the codon composition. The final model contains over 25% annotated genes (6909) in the sequenced genome. Substrate utilization was corrected by BIOLOG phenotype arrays, and exponential batch cultivations were used to test growth predictions. The growth data revealed a decrease in glucose uptake rate with rising glucose concentration. A pangenome of four different U. maydis strains highlighted missing metabolic pathways in iUma22. The new model allows for studies of metabolic adaptations to different environmental niches as well as for biotechnological applications. [ABSTRACT FROM AUTHOR]

The logistics sector plays one of the most important roles in the supply chain with the aim of providing a fast, flexible, safe, economical, efficient, and environmentally acceptable performance of freight transport flows. In addition, the popularization of the concept of a circular economy (CE) used to retain goods, components, and materials at their highest usability and value at all times, illustrates the importance of the adequate performance of reverse logistics (RL) processes. However, traditional RL is unable to cope with the requirements of modern supply chains and requires the application of Industry 4.0 technologies, which would make it more efficient. The main aim of this study was to evaluate the applicability of various Industry 4.0 technologies in the RL sector in order to point out the most applicable ones. To solve the defined problem, a novel multi-criteria decision making (MCDM) model was defined by combining the best—worst method (BWM) to obtain the criteria weights, and the newly developed comprehensive distance-based ranking (COBRA) method to rank the technologies. Another aim of the study was to validate the newly established method. The results indicated that the most applicable technologies were the Internet of Things, cloud computing, and electronic—mobile marketplaces. These technologies will have a significant impact on the development of RL and the establishment of CE systems, thus bringing about all the related positive effects. [ABSTRACT FROM AUTHOR]