In humans, coronaviruses can cause infections of the respiratory system, with damage of varying severity depending on the virus examined: ranging from mild or moderate upper respiratory tract diseases, such as the common cold, to pneumonia, severe acute respiratory syndrome, kidney failure and even death. Human coronaviruses known to date, common throughout the world, are seven. The most common - and least harmful - ones were discovered in the 1960s and cause a common cold. Others, more dangerous, were identified in the early 2000s and cause more severe respiratory tract infections. Among these the SARS-CoV, isolated in 2003 and responsible for the Severe Acute Respiratory Syndrome (the so-called SARS), which appeared in China in November 2002, the Coronavirus 2012 (2012-nCoV) cause of the Middle Eastern Respiratory Syndrome from Coronavirus (MERS), which exploded in June 2012 in Saudi Arabia, and actually SARS-CoV-2. On December 31, 2019, a new Coronavirus strain was reported in Wuhan, China, identified as a new Coronavirus beta strain ß-CoV from Group 2B, with a genetic similarity of approximately 70% to SARS-CoV, the virus responsible. of SARS. In the first half of February, the International Committee on Taxonomy of Viruses (ICTV), in charge of the designation and naming of the viruses (i.e., species, genus, family, etc.), thus definitively named the new coronavirus as SARS-CoV-2. This article highlights the main knowledge we have about the biomolecular and pathophysiologic mechanisms of SARS-CoV-2.

Accurate diagnosis at an early stage of infection is essential for the successful management of any contagious disease. The COVID-19, caused by the SARS-CoV-2 virus is a pandemic that has affected 214 countries affecting more than 30.8 million people causing 0.957 million deaths as of third week of September, 2020. The primary diagnosis of the infection is done either by the molecular technique of RT-qPCR by detecting portions of the RNA of the viral genome or through immunodiagnostic tests by detecting the viral proteins or the antibodies produced by the host. As the demand for the test increased rapidly many naive manufacturers entered the market with novel kits and more and more laboratories also entered the diagnostic arena making the test result more error-prone. There are serious debates globally and regionally on the sensitivity and specificity of these tests and about the overall accuracy and reliability of the tests for decision making on control strategies. The significance of the test is also complexed by the presence of asymptomatic carriers, re-occurrence of infection in cured patients as well as by the varied incubation periods of the infection and shifting of the viral location in the host tissues. In this paper, we review the techniques available for SARS-CoV-2 diagnosis and probable factors that can reduce the sensitivity and specificity of the different test methods currently in vogue. We also provide a check-list of factors to be taken care to avoid fallacious practices to reduce false positive and false negative results by the clinical laboratories

In regions lacking genomic data, analysis of sequences from the early stages of an outbreak can provide important insights into the diversity of pathogens present. Following the detection of the first imported case of COVID-19 in the Northern sector of Ghana on 13^th March 2020, we have now molecularly characterized and phylogenetically analysed sequences including three (3) complete genomes of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) isolated from nine (9) patients observed in Ghana. Eight (8) of these patients reported with a recent history of foreign travel and one (1) with no history of foreign travel. We performed high throughput sequencing for 9 samples following the determination of high concentration of viral RNA. In addition, we estimated the potential impact that long distance transportation of samples to testing centres may have on sequencing outcomes. Here, two samples that were closest in terms of viral RNA concentration but transported from sites which are over 400km apart were assessed. All sequences were compared to previous sequences from Ghana and representative sequences from regions where our patients had previously travelled. Complete genomes were obtained for three (3) sequences and with another near complete genome with a coverage of 95.6%. Sequences with coverage in excess of 80% were found to belong to three lineages namely A, B.1 and B.2. Our sequences clustered in two different clades with the majority falling within a clade composed of sequences from sub-Saharan Africa. Less RNA fragmentation was seen in sample KATH23 which was collected 9km compared with sample TTH6 which was collected and transported over a distance of 400km to the testing site. The clustering of several sequences from sub-Saharan Africa suggests regional circulation of the viruses in the subregion. Importantly, there may be the need to decentralize testing sites and build more capacity across Africa to boost the sequencing output of the subregion.

The novel coronavirus named by WHO and Coronavirus Study Group (CSG) as SARS-COV-2 is the etiological agent of the newly emerged Coronavirus disease (COVID-19). COVID-19 has become a pandemic threat as the WHO declared it a public health emergency of international concern. Early and precise detection of the virus is important for effective diagnosis and treatment. Various testing kits and assays, including real-time reverse Transcriptase PCR, thermal screening guns, ELISA-based immunoassays, and Point-of-Care (POC), have been implemented or are being explored to detect the virus and/or characterise cellular and antibody responses to the infection. However, these approaches have inherent limitations such as non-specificity, high cost, characterize by long turnaround times for test results, and can be labour intensive. Aptamers, which are single-stranded oligonucleotides, generated artificially by SELEX (Evolution of Ligands by Exponential Enrichment) may offer the capacity to generate high affinity bioprobes for monitoring relevant SARS-COV 2 and COVID-19 biomarkers. This article discusses the prospects of implementing aptasensing technologies for rapid point-of-care detection of SARS-COV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an RNA virus, is responsible for coronavirus disease 2019 (COVID-19) pandemic of 2020. Experimental evidence suggests that microRNA can mediate an intracellular defence mechanism against some RNA viruses. The purpose of this study was to identify microRNA with predicted binding sites in the SARS-CoV-2 genome, compare these to their microRNA expression profiles in lung epithelial tissue and make inference towards possible roles for microRNA in mitigating coronavirus infection. We hypothesize that high expression of specific coronavirus-targeting microRNA in lung epithelia may protect against infection and viral propagation, conversely low expression may confer susceptibility to infection. We have identified 128 human microRNA with potential to target the SARS-CoV-2 genome, most of which have very low expression in lung epithelia. Six of these 128 microRNA are differentially expressed upon in vitro infection of SARS-CoV-2. Twenty-eight and 23 microRNA also target the SARS-CoV and MERS-CoV, respectively. In addition, 48 and 32 microRNA are commonly identified in two other studies. Further research into identifying bona fide coronavirus targeting microRNA will be useful in understanding the importance of microRNA as cellular defence mechanism against pathogenic coronavirus infections.

Respiratory transmission is the primary route of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Angiotensin I converting enzyme 2 (ACE2) is the known receptor of SARS-CoV-2 surface spike glycoprotein for entry into human cells. A recent study reported absent to low expression of ACE2 in a variety of human lung epithelial cell samples. Three bioprojects (PRJEB4337, PRJNA270632 and PRJNA280600) invariably found abundant expression of ACE1 (a homolog of ACE2 and also known as ACE) in human lungs compared to very low expression of ACE2. In fact, ACE1 has a wider and more abundant tissue distribution compared to ACE2. Although it is not obvious from the primary sequence alignment of ACE1 and ACE2, comparison of X-ray crystallographic structures show striking similarities in the regions of the peptidase domains (PD) of these proteins, which is known (for ACE2) to interact with the receptor binding domain (RBD) of the SARS-CoV-2 spike protein. Critical amino acids in ACE2 that mediate interaction with the viral spike protein are present and organized in the same order in the PD of ACE1. In silico analysis predicts comparable interaction of SARS-CoV-2 spike protein with ACE1 and ACE2. In addition, this study predicts from a list of 1263 already approved drugs that may interact with ACE2 and/or ACE1, potentially interfere with the entry of SARS-CoV-2 inside the host cells and alleviate the symptoms of Coronavirus disease (COVID-19).

COVID-19 pandemic in first seven months has led to more than 15 million confirmed infected cases and 600,000 deaths. SARS-CoV-2, the causative agent for COVID-19 has proved a great challenge for its ability to spread in asymptomatic stages and a diverse disease spectrum it has generated. This has created a challenge of unimaginable magnitude not only affecting human health and life but also potentially generating a long-lasting socioeconomic impact. Both medical sciences and biomedical research have also been challenged consequently leading to a large number of clinical trials and vaccine initiatives. While known proteins of pathobiological importance are targets for these therapeutic approaches, it is imperative to explore other factors of viral significance. Accessory proteins are one such trait that have diverse roles in coronavirus pathobiology. Here we analyze certain genomic characteristics of SARS-CoV-2 accessory protein ORF8, predict upon its protein features and review current available literature regarding its function. We have also undertaken review of ORF8 homolog ORF8ab from SARS-CoV with a purpose of developing holistic understanding of these proteins for reason that coronaviruses have been infecting humans repeatedly and might continue to do so. Despite low nucleotide and protein identity and differentiating genome level characteristics, there appears to be significant structural integrity and functional proximity between these proteins pointing towards their high significance. There is further need for comprehensive genomics and structural-functional studies to lead towards definitive conclusions regarding their criticality and that can eventually define their relevance to therapeutics development.

Since there is no vaccine or regulatory approved therapy available for treatment of SARS-CoV-2 infection, the medical need to prevent the transition of a mild into the severe COVID-19 stage of infection is of outmost importance. Among several drug candidates, Chloroquine (CQN) and Hydroxy-Chloroquine (H-CQN) have been tested most intensively. However, the therapeutic effect of H-CQN and CQN has been discussed controversially in the light of severe side effects. Originally, H-CQN descended from the natural substance Quinine, a medicinal product used since the Middle Ages and is now regulatory approved for various indications. We hypothesized that Quinine also exerts anti-SARS-CoV-2 activity. First, virus production in Vero B4 cells was analyzed by Western blot, showing that Quinine exerts antiviral activity against SARS-CoV-2 that at 10 µM was even stronger than that of H-CQN or CQN. Second, fluorescence end-point and time lapse analysis of SARS-CoV-2-mNeonGreen-infected Caco-2 cells could confirm a similar antiviral effect of Quinine in a human-derived cell line. Thereby, our in vitro studies revealed, that the antiviral effect appears to be specific, since in Vero cells Quinine impacted cell viability at approximately 50-fold higher concentration, while the therapeutic window of H-CQN and CQN was approximately 10-fold lower. In Caco-2 cells no toxic effect was observed while complete block of infection occurred between 50 and 100 µM at high MOIs. In conclusion, our data indicate that Quinine would have the potential of a well tolerable and widely used treatment option for SARS-CoV-2 infections, with a predictable and significantly better toxicological profile when compared to H-CQN or CQN.

Motivated by the definition of the type 2 poly-Bernoulli polynomials introduced by Kim-Kim, in the present paper, we consider a class of new generating function for the Frobenius-Genocchi polynomials, called the type 2 poly-Frobenius-Genocchi polynomials, by means of the polyexponential function. Then, we derive some useful relations and properties. We show that the type 2 poly-Frobenius-Genocchi polynomias equal a linear combination of the classical Frobenius-Genocchi polynomials and Stirling numbers of the first kind. In a special case, we give a relation between the type 2 poly-Frobenius-Genocchi polynomials and Bernoulli polynomials of order k. Moreover, inspired by the definition of the unipoly-Bernoulli polynomials introduced by Kim-Kim, we introduce the unipoly-Frobenius-Genocchi polynomials by means of unipoly function and give multifarious properties including derivative and integral properties. Furthermore, we provide a correlation between the unipoly-Frobenius-Genocchi polynomials and the classical Frobenius-Genocchi polynomials.

Our first modern global pandemic is caused by a nanosized lipid vesicle, called SARS-CoV-2. Its molecular structure and biogenesis have remarkable similarities with Extracellular Vesicles (EVs, most notably exosomes) that are constantly shed by all cells during their life. Their resemblance may not be a coincidence. Growing body of evidence has shown that EVs have significant roles in various biological processes, including viral infection, transmission and anti-viral response. Drawing comparison with the virus might shed light on how we could fight the COVID-19 disease. This may include novel EV research and diagnostics technologies as well as novel EV-based treatments.

A new form of coronavirus called severe acute respiratory disease coronavirus type 2 (SARS-CoV-2) is currently causing a pandemic. A six-month evolutionary history of SARS-CoV-2 is witnessed by characterising the total genome of 821 samples using comparative phylogenomic approaches. Our analyses produced striking inclusive results that may guide scientists/professionals for the past/future of pandemic. Phylogenetic and time estimation analyses suggest the proximate origin of pandemic strain as Guangdong and the origin time as first half of September 2019, not Wuhan and December 2019, respectively. The viral genome experienced a substitution rate similar to other RNA viruses, but it is particularly high in some of the peptides encoding sequences such as leader protein, E gene, orf8, orf10, nsp10, N gene, S gene and M gene and nsp4, while low in nsp11, orf7a, 3C-like proteinase, nsp9, nsp8 and endoRNase. Most strikingly, the divergence rate of amino acid sequences is high proportional to nucleotide divergence. Additionally, specific non-synonymous mutations in nsp3 and nsp6 evolved under positive selection. The exponential growth rate (r), doubling time (Td) and R₀ were estimated to be 47.43 per year, 5.39 days and 2.72, respectively. Comparison of synapomorphies distinguishing the SARS-CoV-2 and the candidate ancestor bat coronavirus indicates that mutation pattern in nsp3 and S gene enabled the new strain to invade human and become a pandemic strain. We arrive at the following main conclusions: (i) six months evolution of viral genome is nearly neutral, (ii) origin of pandemic is not Wuhan and predates formal reports, (iii) although viral population is ongoing an exponential growth, the doubling time is evolving towards shortening, and (iv) divergence rate of total genome is similar to other RNA viruses, but it is prominently high in some genes while low in some others and evolution in these genes should be closely monitored as their protein products intervening to pathogenicity, virulence and immune response.

The outbreak across the globe due to coronavirus disease 2019 (COVID-19) has spread abruptly by infected humans worldwide. The continuous efforts by scientists is on way to understand how pandemic of COVID-19 resembles and differs from serve acute respiratory syndrome coronavirus (SARS-CoV) at transcriptomic and genomic level. The SARS-CoV and COVID-19 exploits the angiotensin converting enzyme 2 (ACE2) receptor to gain entry inside the cells.We analyzed the entry COVID-19 into host cell due to receptor binding domain (RBD) of spike glycoprotein. The proposed simulation data shows similar ternary structures from two viruses shares approximately 80 percent identity in amino acid sequences. Our molecular modeling investigation signifies that angiotensin converting enzyme 2 (ACE2) has stronger interaction with COVID -19 RBD. The Amino acid phenylaniline F486 LOOP plays vital role due to its penetration into hydrophobic pocket in ACE2.The said investigation of S-Glycoprotein RBD of COVID-19 or SARS-CoV-2 via ACE2 provides post genome analysis of protein-protein interaction for rapid assessing transmission of infected patients by deadly CoVID-19. The scientific data extracted implies early guidance to control and viral prevention of CoVID-19.

The Coronavirus Disease 2019 (COVID-19) is a new viral infection caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2). Genomic analyses have revealed that SARS-CoV-2 is related to Pangolin and Bat coronaviruses. In this report, a structural comparison between the Sars-CoV-2 Envelope and Membrane proteins from different human isolates with homologous proteins from closely related viruses is described. The analyses here reported show the high structural similarity of Envelope and Membrane proteins to the counterparts from Pangolin and Bat coronavirus isolates. However, the comparisons have also highlighted structural differences specific of Sars-CoV-2 proteins which may be correlated to the cross-species transmission and/or to the properties of the virus. Structural modelling has been applied to map the variant sites onto the predicted three-dimensional structure of the Envelope and Membrane proteins.

A short review of the important studies was conducted to evaluate the potential of aerosol transmission of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). The minimum size of droplets potentially carrying the SARS-CoV-2 was newly estimated and discussed in this review.

Recently, the outbreak of coronavirus disease 2019 (COVID-19) is threatening human health globally. There is a dire need to find potential therapeutic agents. Angiotensin converting enzyme 2 (ACE2), as an entry receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered as potential therapeutic target in COVID-19 pandemic. Here, our bioinformatics analysis revealed that the biological function of ACE2 was correlated with regulation of blood pressure and mediation of SARS-CoV-2 entry into host cells. Ten ACE2 cooperative proteins were identified by using STRING with a high score. ACE2 expressed highly in the small intestine, testis, and kidney. The level of ACE2 expression in tumor tissues varies in different types of cancers compared with that in normal tissues. It was worth noting that the expression level of ACE2 in the tumor has no effect on patient survival. MiRNA hsa-miR-942-5p, and three transcription factors (TFs) including Signal transducer and activator of transcription 4 (STAT4), Estrogen related receptor α (ESRRA), and Signal transducer and activator of transcription 3 (STAT3) were selected as novel ACE2 regulators. Moreover, nine potential therapeutic drugs were predicted by two online databases. Thus, our research may expand the overall view of ACE2 in COVID-19 treatment.

This review chronicles the indirect transmission method which seems to be overlooked by most people and makes attempts to clearly document the various transmission ways with a hope that such information may strengthen the knowledge base of researchers towards methods of eradicating the pandemic. Current knowledge of transmission and exposure of SARS-CoV-2 has been explained. Various researchers have put forward different ways of exposure and transmission. Literature does not reveal whether the indirect transmission route is the dominant one. However total lockdown could be a veritable means to reduce both direct and indirect transmission routes. In many countries where the indirect transmission has been reduced, the scourge of the virus is less. The work creates awareness on the need to watch out for those routes of transmissions that may not be popular and suggested key knowledge gaps that needs to filled.

The coronavirus disease 2019 (COVID-19) has spread over the world for more than one year. COVID-19 often develops life-threatening hypoxemia. Endothelial injury caused by the viral infection leads to intravascular coagulation and ventilation-perfusion mismatch. However, besides above pathogenic mechanisms, the role of alveolar edema in the disease progression has not been discussed comprehensively. Since the exudation of pulmonary edema fluid was extremely serious in COVID-19 patients, we bring out a hypothesis that severity of alveolar edema may determine the size of poorly-ventilated area and the blood oxygen content. Treatments to pulmonary edema (alcohol-oxygen vapor therapy and fluid management) may be great helpful for reducing occurrence of severe cases. Given that late mechanical ventilation may cause mucus (edema fluid) to be blown to the deep of the small airways, oxygen therapy should be given at the early stages. The optimal time and SpO₂ threshold for oxygen therapy are also discussed.

We propose a Gauss model (GM), a map from time to the bell-shaped Gauss function to model the deaths per day and country, as a quick and simple model to make predictions on the coronavirus epidemic. Justified by the sigmoidal nature of a pandemic, i.e. initial exponential spread to eventual saturation, we apply the GM to existing data, as of April 2, 2020, from 25 countries during first corona pandemic wave and study the model's predictions. We find that logarithmic daily fatalities caused by Covid-19 are well described by a quadratic function in time. By fitting the data to second order polynomials from a statistical chi2-fit with 95\% confidence, we are able to obtain the characteristic parameters of the GM, i.e. a width, peak height and time of peak, for each country separately, with which we extrapolate to future times to make predictions. We provide evidence that this supposedly oversimplifying model might still have predictive power and use it to forecast the further course of the fatalities caused by Covid-19 per country, including peak number of deaths per day, date of peak, and duration within most deaths occur. While our main goal is to present the general idea of the simple modeling process using GMs, we also describe possible estimates for the number of required respiratory machines and the duration left until the number of infected will be significantly reduced.

The 2019 novel coronavirus (previously 2019-nCoV) or coronavirus infectious disease 2019 (COVID-19) outbreak has been summarized as on March 29, 2020. COVID-19 is a highly transmittable and pathogenic viral infection caused by severe acute respiratory syndrome coronavirus 2 (SERS-CoV-2). The disease was first seen during an outbreak in Wuhan, China and continuous spreading from human to human around the sphere. The disease is uncontrolled and increasing the death toll through. The world is facing a global challenge to protect human lives caused by coronavirus outbreak. The number of infected patients is increasing day by day due to COVID-19 as a pandemic. The world health organization (WHO) has declared global public health emergency on January 30, 2020. The disease has been spread around 201 countries with total confirmed cases 634835 and death cases 29891 as on March 29, 2020. The goal of this review to summaries and update the clinical/medical features and suggestions for diagnosis of the COVID-19 as a pandemic. The discussion of the various therapeutic algorithms, risk, prevention and control based on the latest reports has been provided.

At a time when the world faces an emotional breakdown, crushing our dreams if not taking our lives, we realize that together we must fight the war against the COVID-19 outbreak even if almost the majority of the scientific community finds itself confined to home. Every day, like everyone else, we, scientists, listen to the latest news with its promises and announcements. Across the world, a surge of clinical trials trying to cure or slow down the coronavirus pandemic has been launched to bring hope instead of fear and despair. One first proposed clinical trial has drawn worldwide hype to the benefit of chloroquine (CQ), a well-known and broadly used anti-malarial drug, in the treatment of patients infected by the recently emerged deadly coronavirus (SARS-CoV-2). We should consider this information in the light of the long-standing anti-inflammatory and anti-viral properties of CQ-related drugs. Yet, none of the articles promoting the use of CQ in the current pandemic evoked a possible molecular or cellular mechanism of action that could account for any efficacy. Here, given the interaction of viruses with macroautophagy (hereafter referred to as autophagy), a CQ-sensitive anti-viral safeguard pathway, we would like to discuss the pros, but also the cons concerning the current therapeutic options targeting this process.

Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China and has subsequently spread worldwide. In the absence of any antiviral or immunomodulatory therapies, the disease is spreading at an alarming rate. 5 to 10% of recovered patients in Wuhan test positive again; this suggest that for controlling COVID-19, vaccines may be better option than drugs. A clinical trial to evaluate an anti-COVID-19 vaccine has started recently. However, its efficacy and potency have to be evaluated and validated. As an alternative, we are presenting a first-of-its-kind, designed multi-peptide subunit based epitope vaccine against COVID-19. The vaccine construct comprise an adjuvant, CTL, HTL, and B-cell epitopes joined by linkers. The vaccine is non-toxic, non-allergenic, thermostable and immunogenic with the capability to elicit a humoral and cell-mediated immune response. The findings are validated with high-end computation-based methods. This unique vaccine is made up of 33 highly antigenic epitopes from three proteins that have a prominent role in host receptor recognition, viral entry, and pathogenicity. We advocate this vaccine must be synthesized and tested urgently as public health priority.

The recent outbreak of coronavirus disease 2019 caused by the new coronavirus, SARS-CoV-2, has become an international emergency. Since there is no effective therapy for the treatment of this disease, drugs or vaccine that can prevent or cure the SARS-CoV-2 infection are urgently needed. The viral 3-chymotrypsin-like cysteine protease (3CLpro), which plays a key role in the replication of coronavirus, is a potential drug target for the development of anti-SARS-CoV-2 drugs. With the crystal structure of 3CLpro, we performed virtual screening from a small chemical library of a Traditional Chinese Medicine recipe- FuFang Zhenzhu Tiaozhi (FTZ). Five compounds with the best scores were screened and could be considered as potential hit compounds to be investigated further with bioassays for their anti-virus effects.

A novel coronavirus (SARS-CoV-2) that is initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has killed 2,718 people in China by February 26, 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 38 countries around the world. However, the drug has not yet been officially licensed or approved to treat SARS-Cov-2 infection. NSP12-NSP7-NSP8 complex of SARS-CoV-2, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12-NSP7-NSP8 complex (PDB ID: 6NUR) structure of SARS, two homologous models were established for virtual screening in the present study, namely NSP12-NSP7 interface model and NSP12-NSP8 interface model. Seven compounds (Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All seven compounds can combine well with NSP12-NSP7-NSP8 in the homologous model, providing drug candidates for the treatment and prevention of SARS-CoV-2.

Curcumin and trans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell death via redox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide 1512 showed a moderate antiproliferative potency (HCT-116 cell line inhibition of 32.0 µM), good selectivity profile (no inhibition of normal cell lines), and proven cellular activities leading to apoptosis. SAR studies led to more than 10-fold increase in activity. Our most promising compound, [(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] 4112 killed colon cancer cells at IC50 = 0.89 µM (Caco-2), 2.85 µM (HCT-116) and 1.65 µM (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50 = 71 µM and 77.6 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part as a result of oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of covalently-acting Michael addition compounds that potently kill cancer cells by a defined mechanism, with minimal effect on normal noncancerous cell.

The structures of recently discovered primarolides A and B suggest their non-enzymatic formation from a common 2-formylbenzophenone precursor. This hypothesis is based on the experimentally proven facile conversion of pestalone (also a 2-formyl-benzophenone) either into the isomeric lactone pestalalactone or the structurally related isoindolinone pestalachloride A. In a related fashion, the racemic isoindolinone natural product mariline A is supposed to biosynthetically originate from the corresponding keto-aldehyde and an aniline, as experimentally supported by model studies. Due to the close structural relationship with known systems, it appears highly probable that primarolides A and B were generated under the fermentation conditions from a massarinin-related 2-formylbenzophenone (proprimarolide) by reaction either with aniline or a nucleophilic catalyst, respectively. Suberoylanilide hydroxamic acid (SAHA), used as an additive during the fermentation, is supposed to act both as a source of aniline and as a nucleophilic catalyst.

We derive time evolution equations, namely the Schrodinger-like equations and the Klein-Gordon equations for coherent fields and the Kadanoff-Baym (KB) equations for quantum fluctuations, in Quantum Electrodynamics (QED) with electric dipoles in 2 + 1 dimensions. Next we introduce a kinetic entropy current based on the KB equations in the 1st order of the gradient expansion. We show the H-theorem for the Leading-Order self-energy in the coupling expansion (the Hartree-Fock approximation). We show a conserved energy in the spatially homogeneous systems in the time evolution. We derive aspects of the super-radiance and the equilibration in our single Lagrangian. Our analysis can be applied to Quantum Brain Dynamics, that is QED with water electric dipoles. The total energy consumption to maintain super-radiant states in microtubules seems to be within the energy consumption to maintain the ordered systems in a brain.

Aim: To perform a descriptive analysis of eating patterns and biophysical conditions of previously diagnosed and currently under treatment individuals from a semi-urban Mayan community of Yucatan, and to contrast them with T2DM therapeutic guidelines. Methods: The present study is derived from a randomized clinical trial conducted at Komchen, Yucatan. Participants’ diagnosed with T2DM were included. A 24-hour dietary recall, anthropometric parameters (weight, visceral fat, height, and waist circumference), biochemical (HbA1c) and clinical (blood pressure) variables were evaluated and compared via hypothesis test with T2DM treatment cut-off points (based on World Health Organization criteria). Results: Anthropometric characteristics differ significantly from the ideal criteria. Obesity prevalence within women with T2DM was 92.9%. Only 21% of the participants were under T2DM control (≤7%). Energy and carbohydrates consumption, significantly exceed therapeutic guidelines, whereas protein, fat, and fiber intake were lower than the recommendations. Conclusions: Komchen’s diet, concomitantly with food characteristics, could be related to glycemic decontrol. There is a disproportion in macronutrients consumption in favor of carbohydrates, probably associated with socioeconomic limitations, food availability, and price. Developing nutritional assistance programs which contemplate cultural and economic factors in this Mayan population must be taken into consideration.

This paper reports design of a 2 × 4 hybrid multimode interferometer-Mach-zehnder interferometer (MMI-MZI) configuration and compact thermo-optical switch consisting of slab waveguides on the silicon-on-insulator (SOI), platform. The device consisted of two identical MMIs as power splitters and couplers that are connected with two identical MMI-based phase shifters, and linear tapers at both ends of the MMIs to minimize the power coupling loss. A thin Al pad is used as a heating element, and a trench is created around this pad to prevent heat from spreading and to minimize loss. The calculated average thermo-optical switching power consumption, excess loss, and power imbalance are 1.4 mW, 0.9 dB, and 0.1 dB, respectively. The overall footprint of the device is 6 × 304 μm². The new heating method has advantages of compact size, ease of fabrication on SOI platform with the current CMOS technology, and offers low excess loss and power consumption as demanded by devices based on SOI technology. The device can act as two independent optical switches in one structure.

Angiogenesis mediated by proteins such as Fibroblast Growth Factor – 2 (FGF-2) is a vital component of normal physiological processes and has also been implicated in contributing to disease state associated with various microbial infections. Previous studies by our group and others have shown that Candida albicans, a common agent of candidiasis, induces FGF-2 expression in vitro, and angiogenesis in brains and kidneys during systemic infections. However, the underlying mechanism(s) via which the fungus increases FGF-2 expression and the role(s) that FGF-2/angiogenesis plays in C. albicans disease remain unknown. Here we show, for the first time, that C. albicans hyphae (and not yeast cells) increase the FGF-2 response in human endothelial cells. Moreover, candidalysin, a toxin secreted exclusively by C. albicans in the hyphal state is required to induce this response. Our in vivo studies show that, in the systemic C. albicans infection model, mice treated with FGF-2 exhibit significantly higher mortality rates when compared to untreated mice not given the angiogenic growth factor. Even treatment with fluconazole could not fully rescue infected animals that were administered FGF-2. Our data suggest that the increase of FGF-2 production/angiogenesis induced by candidalysin contributes to the pathogenicity of C. albicans.

A simple procedure to obtain 1,5-disubstituted 1,2,3-triazoles, using the catalytic system erbium(III) trifluoromethanesulfonate, 1-methyl pyridinium trifluoromethanesulfonate and water is described. The reaction proceeds through an eliminative azide–olefin cycloaddition (EAOC) offering a highly regioselective approach and good yields (81–94%). The advantages of this method include simple operations of work-up and the ability of the catalytic system to be re-used five times without an evident loss in yield.

Prostanoids modulate the pathogenesis of vascular diseases such as atherosclerosis, in which inflammation has an important role. It is well known that inducible Ciclooxygenase-2 (COX-2) is responsible for prostanoid production associated with inflammation. Angiotensin II may be implicated through the expression of COX-2 in the vascular wall. The purpose of this study was to examine in angiotensin II-stimulated adventitial fibroblasts the anti-inflammatory activity of different food peptides by inhibiting COX-2 expression, and the production of pro-inflammatory prostanoids. Fibroblasts from aorta of Sprague-Dawley rats were incubated with different food derived peptides followed by incubation with Angiotensin II. COX-2 expression was determined by western blot, transcriptional activity by luciferase assays and prostaglandin E2 by enzyme immunoassay. COX-2 expression was inhibited in the presence of Val-Pro-Pro (bovine β-casein 84–86), Arg-Asp-Ile-Leu-Asn-Gln (ovalbumin 84–89) and Tyr-Arg-Gly-Gly-Leu-Glu-Pro-Ile-Asn-Phe (ovalbumin 125–134). Angiotensin II-induced prostaglandin E2 production was also reduced by all the above-mentioned sequences. The incubation with ovalbumin-derived peptides displayed a significant reduction of COX-2 promoter activity compared to the stimuli with Angiotensin II in transiently transfected cells. These three sequences could potentially be used as functional food ingredients to reduce inflammation related to cardiovascular diseases.

Rapid urbanization, increasing population and increased industrialization to cater to demands of the growing population has imposed upon us a huge environmental cost. The significantly deteriorated air quality across the globe is associated with a direct and indirect impact on public health. While associated disorders such as chronic obstructive pulmonary diseases, heart failures are well documented, less is known about the biological basis of the process. We hypothesize that the worsening air quality may likely impact common systemic inflammatory processes, thus driving communicable and non-communicable diseases alike.Receptor mediated entry of particulate matter (PM2.5) results in activation of signaling cascades which culminate in production of inflammatory chemokine and cytokine responses, traversing through the blood mediating impacting not only on other organs but also dysbiosis of microflora. For the purpose of the review we choose tuberculosis (TB) as a model for communicable infectious disease and type 2 diabetes mellitus (T2DM) as a marker for non-communicable disorder. The increasing prevalence of these co-morbidities and the burdening of public health systems justifies this example. However the hypothesis may be applicable to other inflammation driven disorders also.

A compact 2-DOF (two degrees of freedom) piezoelectric-driven platform for 3D cellular bio-assembly systems has been proposed based on “Z-shaped” flexure hinges. Multiple linear motions with high resolution both in x and y directions are achieved. The “Z-shaped” flexure hinges and the parallel-six-connecting-rods structure are utilized to obtain the lowest working stress while compared with other types of flexure hinges. In order to achieve the optimized structure, matrix-based compliance modeling (MCM) method and finite element method (FEM) are used to evaluate both the static and dynamic performances of the proposed 2-DOF piezoelectric-driven platform. Experimental results indicate that the maximum motion displacements for x stage and y stage are lx=17.65 μm and ly=15.45 μm, respectively. The step response time for x stage and y stage are tx=1.7 ms and ty =1.6 ms, respectively.

β-Lactams are pharmacologically important compounds because of their various biological uses, including antibiotic and so on. β-Lactams were synthesized from benzylidene-inden derivatives and acetoxyacetyl chloride. The inhibitory effect of these compounds was also examined for human carbonic anhydrase I and II (hCA I, and II) and acetylcholinesterase (AChE). The results reveal that β-lactams are inhibitors of hCA I, II and AChE. The K_i values of β-lactams (2a-k) were 0.44-6.29 nM against hCA I, 0.93-8.34 nM against hCA II, and 0.25-1.13 nM against AChE. Our findings indicate that β-lactams (2a-k) inhibit both CA isoenzymes and AChE at low nanomolar concentrations.

The problem of quantifying the vulnerability of graphs has received much attention nowadays, especially in the field of computer or communication networks. In a communication network, the vulnerability measures the resistance of the network to disruption of operation after the failure of certain stations or communication links. If we think of a graph as modeling a network, the average lower 2-domination number of a graph is a measure of the graph vulnerability and it is defined by ${\gamma }_{2av}\left(G\right)=\frac{1}{\left|V\left(G\right)\right|}{\sum }_{v\in V\left(G\right)}{\gamma }_{2v}\left(G\right)$, where the lower 2-domination number, denoted by ${\gamma }_{2v}\left(G\right)$, of the graph G relative to v is the minimum cardinality of 2-domination set in G that contains the vertex v. In this paper, the average lower 2-domination number of wheels and some related networks namely gear graph, friendship graph, helm graph and sun flower graph are calculated. Then, we offer an algorithm for computing the 2-domination number and the average lower 2-domination number of any graph G.

Background/Objectives: The global burden of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Cardiovascular disease (CVD) is the leading cause of mortality in MASLD patients, therefore, the therapeutic interventions for MASLD should improve coronary risk factors such as obesity, diabetes and dyslipidemia, in addition to improving liver function. The evidence on effect of sodium-glucose cotransporter 2 inhibitors (SGLT2is) which have beneficial pharmacological properties for MASLD, especially the long-term effects, on the progression of MASLD in Asian population is very limited. Methods: The retrospective longitudinal study was performed by using the medical records at the National Center for Global Health and Medicine, Kohnodai Hospital, Japan. We picked up patients with type 2 diabetes who had taken SGLT2is for at least 3 years or longer between April 1, 2014 and March 31, 2018. We collected the data on metabolic parameters, including blood tests and anthropometric parameters, and compared the data before and after the initiation of SGLT2is treatment. Results: During the observation period, 324 patients had taken SGLT2is for 3 years. The 3-year-SGLT2is treatment significantly reduced body weight, hemoglobin A1c, low-density lipoprotein-cholesterol, triglyceride and non-high-density lipoprotein-cholesterol (HDL-C) and significantly increased HDL-C. Furthermore, this treatment significantly improved liver function and the markers for hepatic steatosis and hepatic fibrosis. Conclusions: Considering that the development of CVD determines the prognosis of MASLD patients, the long-term SGLT2is treatment may be an ideal therapy for MASLD patients.

The rodent collecting duct (CD) expresses a 24p3/NGAL/lipocalin-2 (Lcn2) receptor (Slc22a17) apically to possibly mediate high-affinity reabsorption of filtered proteins by endocytosis, yet its functions remain uncertain. Recently, we showed that hyperosmolarity/-tonicity upregulates Slc22a17 in cultured mouse inner medullary CD cells, whereas activation of toll-like receptor 4 (TLR4) via bacterial lipopolysaccharides (LPS) downregulates Slc22a17. This is similar to the upregulation of Aqp2 by hyperosmolarity/-tonicity and arginine vasopressin (AVP) and downregulation by TLR4 signaling that occur via the transcription factors Nfat5 (TonEBP or OREBP), cAMP-responsive element binding protein (CREB), and nuclear factor-kappa B, respectively. The aim of the study was to determine the effects of osmolarity/tonicity via Nfat5, AVP via CREB and TLR4 signaling on the expression of Slc22a17 and its ligand Lcn2 in the mouse (m) cortical collecting duct cell line mCCD(cl.1). Normosmolarity/-tonicity was 300 mosmol/l whereas addition of 50-100 mmol/l NaCl for up to 72 h induced hyperosmolarity/-tonicity (400-500 mosmol/l). RT-PCR, qPCR, immunoblotting and immunofluorescence microscopy detected Slc22a17 and Lcn2 expression. RNAi silenced Nfat5, and the pharmacological agent 666-15 blocked CREB. Activation of TLR4 occurred with LPS. Similar to Aqp2, hyperosmotic/-tonic media and AVP upregulated Slc22a17 via activation of Nfat5 and CREB, respectively, and LPS/TLR4 signaling downregulated Slc22a17. Conversely, though Nfat5 mediated hyperosmolarity/-tonicity induced downregulation of Lcn2 expression, AVP reduced Lcn2 expression and predominantly apical Lcn2 secretion evoked by LPS, but through a posttranslational mode of action that was independent of cAMP signaling. In conclusion, the hyperosmotic/-tonic upregulation of Slc22a17 in mCCD(cl.1) cells via Nfat5 and by AVP via CREB suggests a contribution of Slc22a17 to adaptive osmotolerance, whereas Lcn2 downregulation could counteract increased proliferation and permanent damage of osmotically stressed cells.

RT-PCR tests have become the gold standard for detecting the SARS-CoV-2 virus in the context of the COVID-19 pandemic. Because of the extreme number of cases in periodic waves of infection, there is a severe financial and logistical strain on diagnostic laboratories. For this reason, alternative implementations, and validations of academic protocols, that employ the lowest cost and most widely available equipment and reagents found in different regions, is essential. In this study, we report an alternative implementation of the EUA 2019-nCoV CDC assay which uses a previously characterized duplex PCR reaction for the N1 and RNAse P target regions and an additional uniplex reaction for the N2 target region. Taking advantage of the Abbott m2000 Sample Preparation System and NEB Luna Universal Probe One-Step RT-qPCR kit, some of the most widely available and lowest cost nucleic acid extraction and amplification platforms, this modified test shows a state-of-the-art analytical and clinical sensitivities and specificities, when compared with the Seegene Allplex-SARS-CoV-2 assay. This implementation has the potential to be verified and implemented by diagnostic laboratories around the world to guarantee low-cost RT-PCR tests that can take advantage of widely available equipment and reagents.

Background and Objectives: Infections are the most common and potentially life-threatening complications of the treatment of children with acute lymphoblastic leukemia (ALL). The aim of this study was to determine epidemiological, clinical and microbiological characteristics of infections in pediatric patients with ALL. Materials and Methods:  Twenty-three children (16 male and 7 female, mean age 5.9 years [range 1.3 to 12.2 years]) with ALL, treated at the Division of Hematology, Oncology and Clinical Genetics, Department of Pediatrics, Clinical Hospital Center Rijeka, Croatia, from January 1, 2015 to December 31, 2020, were included in the study Results: One hundred and four infectious episodes (IEs) were reported (average 4.5 IE per patient). IEs were more frequent in the intensive phases of antileukemic treatment. Neutropenia was present in 48 IEs (46.2%) with a duration greater than 7 days in 28 IEs (58.3%). The respiratory tract was the most common infection site (48.1%). We documented 49 bacterial (47.1%), 4 viral (3.9%), 4 fungal (3.9%) and 10 mixed isolates (9.6%), while in 37 IEs (35.6%) pathogen was not isolated. The most common causes of bacteremia were coagulase-positive staphylococci. The most frequent empirical therapy was third- and fourth-generation cephalosporins, followed by piperacillin/tazobactam. Modification of the first-line antimicrobial therapy was performed in 56.9% of IEs. Granulocyte-colony stimulating factor was administered in 53.8% of IEs, and intravenous immunoglobulins in 62.5% of IEs. One patient required admission to the intensive care unit. No infection-related mortality was reported. Conclusions: ALL patients have frequent IEs. Close monitoring, identification of risk factors, rapid empirical use of antibiotics in febrile neutropenia, and timely modification of antimicrobial therapy play a key role in reducing infection-related morbidity and mortality in children with ALL.

Sepsis, characterized by a dysregulated systemic inflammatory response to infection, remains a significant global health burden, despite substantial advancements in its treatment. An understanding of the underlying mechanisms driving sepsis is crucial for the development of targeted therapeutic strategies. Silent information regulator 1 (SIRT1), a member of the class III histone deacetylases, plays a pivotal role in regulating gene expression by catalyzing the deacetylation of lysine residues on non-histone and histone proteins. With the advancement of sepsis research, SIRT1 has been shown to exert significant anti-inflammatory, anti-oxidative, anti-apoptotic, and metabolic regulatory effects, positioning it as a potential therapeutic target for sepsis. This article reviews the latest progress on research into the signaling pathways modulated by SIRT1 in sepsis and its associated regulatory mechanisms to further elucidate the pathogenesis of sepsis and assist in guiding clinical treatment.

Despite soccer popularity, comparatively little scientific information is available concerning the assessment of youth players’ physiological characteristics. The use of medical software integrating wearable sensors to provide accurate and objective data is necessary. In the present study, the objective assessment of physical performance of 128 adolescent soccer players at two timepoints (pre-season and end-season) has been performed. Participants completed a comprehensive test battery including stability, countermovement jumps (CMJ), plyometric jumps (PJ), agility, and quick feet tests. A single Inertial Measurement Unit (IMU) sensor provided quantitative data on various performance metrics. Principal Component Analysis (PCA) reduced the dataset to four principal components (PCs) explaining over 80% of the variance: power (PC1), balance (PC2), speed/agility (PC3), and stiffness (PC4). Paired samples t-test between the two timepoints showed no significant differences in the PCs between the two timepoints, indicating that the training program did not significantly alter the assessed physical attributes. However, subtle individual changes may still inform personalized training adjustments. The study highlights the importance of continuous monitoring and individualized training strategies to optimize athlete performance and reduce injury risk.

The unprecedented progress in Artificial Intelligence (AI), particularly in deep learning algorithms with ubiquitous internet connected smart devices, has created a high demand for AI computing on the edge devices. This review studied commercially available edge processors, and the processors that are still in industrial research stages. We categorized state-of-the-art edge processors based on the underlying architecture, such as dataflow, neuromorphic, and Processing in-Memory (PIM) architecture. The processors are analyzed based on their performance, chip area, energy efficiency, and application domains. The supported programming frameworks, model compression, data precision, and the CMOS fabrication process technology are discussed. Currently, most of the commercial edge processors utilize dataflow architectures. However, emerging non-von Neumann computing architectures have attracted the industry in recent years. Neuromorphic processors are highly efficient for performing computation with fewer synaptic operations, and several neuromorphic processors offer online training for secured and personalized AI applications. This review found that the PIM processors show significant energy efficiency and consume less power compared to dataflow and neuromorphic processors. The future direction of the industry would be to implement state-of-the-art deep learning algorithms in emerging non-Von Neumann computing paradigms for low power computing on the edge devices.

This study critically explores the legislative frameworks and national regulations of Serbia, Croatia, and Slovenia concerning the engagement, training, and responsibilities of search and rescue dogs and their handlers. The goal is to offer a thorough understanding of how these dogs and their handlers are engaged, trained, and managed in each country. By carefully analyzing the legal foundations, the study aims to clarify the rights, duties, and responsibilities of all parties involved, ensuring that search and rescue dog deployments are conducted within a structured and lawful framework. Such an understanding is crucial for improving disaster management and ensuring a coordinated response to various emergencies. The findings reveal that although each country has strong legal provisions for deploying search and rescue dogs, there are significant differences in the detail and scope of these regulations. Slovenia is notable for its detailed guidelines, regular evaluations, and licensing processes, setting a high standard. Croatia benefits from strong institutional support and active international collaboration, which greatly enhances its disaster response capabilities. On the other hand, Serbia, despite having a solid foundational framework, could improve by better coordinating with non-governmental organizations and aligning more closely with international standards. Key areas for improvement include harmonizing standards, enhancing training programs, increasing public awareness, better resource allocation, and adopting new technologies. By addressing these issues, Serbia, Croatia, and Slovenia can further strengthen their legal and institutional frameworks, ensuring their search and rescue teams are better prepared for disasters. This study emphasizes the need for continuous improvement through collaboration, standardization, and innovation to maximize the effectiveness of search and rescue operations involving dogs.

The Congo River Basin is the second-largest watershed globally, flowing through nine countries before reaching the Atlantic Ocean. The Kasai River Basin (KARB), containing about one-fourth of Congo’s freshwater resources, plays a strategic role in sustaining navigation, food production, and hydroelectricity generation in Central Africa. A multi-model framework suited for data scarce regions is applied for climate change impacts on water availability in the KARB to propose effective development plans in the future. This includes consideration of two conceptual hydrological models calibrated using four reanalysis datasets and fed with bias-corrected outputs of 19 climate models under two future Representative Climate Pathways (RCPs). Changes in mean annual discharge in the KARB from -18% to +3% are projected depending on the considered modeling configuration. This shows the sensitivity of impact assessment to the choice of models as well as input data. Moreover, about 9%, 18%, and 13% decline in streamflow signatures (Q10, Q50 and Q90) are projected based on the ensemble of models under RCP 8.5. A decrease of 14% and 5% in annual hydropower potential of the mainstream is estimated under RCPs 4.5 and 8.5, respectively. These changes in flows conditions should be considered in decision-making around constructing reservoirs and hydroelectricity generation.

COVID-19, caused by SARS-CoV-2, was first identified in China in 2019. The exact origin of the disease remains uncertain, with theories suggesting it may have emerged from animals or accidentally leaked from a research laboratory. If the hypothesis that COVID-19 originated from a research laboratory is accurate, it is crucial to investigate potential pathways for pathogens to escape from biocontainment research animal facilities (BRAFs). We examine key biosafety issues associated with BRAFs, including inadequate decontamination procedures for water and experimental samples, handling high biosafety level pathogens in lower level laboratories, risks of animal bites and sharps injuries, contamination of bedding and enrichment materials, and improper management and transportation of biohazard samples. Additionally, we discuss the role of veterinarians in African research animal facilities and the challenges they encounter in maintaining biocontainment standards. We emphasize the importance of routine monitoring of effluent water to detect possible disease outbreaks. We recommend a thorough investigation of the COVID-19 pandemic to identify potential sources of pathogen release from BRAFs, which could serve as hotspots for future disease outbreaks. Findings from such investigations will inform the development of policies aimed at safeguarding human populations from future pandemics and preventing BRAFs from becoming sources of infectious disease outbreaks.

Algeria, the main fire hotspot on the southern rim of the Mediterranean Basin, lacks complete fire dataset with official fire perimeters, and the existing one contains inconsistencies. Preprocessed global and regional burned area (BA) products provide valuable insights into fire patterns, characteristics and dynamics over time and space, and into their impact on climate change. Nevertheless, they exhibit certain limitations linked with their inherent spatio-temporal resolutions. To address the need for reliable BA information in Algeria, we systematically reconstructed, validated and analyzed a 40-year (1984–2023) BA product (NEALGEBA; North Eastern ALGeria Burned Area) at 30-m spatial resolution in the typical Mediterranean Ecosystems of this region, following international standards. We used Landsat data and the BA Mapping Tools (BAMTs) in the Google Earth Engine (GEE) to map BAs. The spatial validation of NEALGEBA, performed for 2017 and 2021 using independent 10-m spatial resolution Sentinel-2 reference data, showed overall accuracies > 98.10 %; commission and omission errors < 8.20 %; Dice coefficients > 91.90 %, and relative biases < 3.44 %. The temporal validation, however, using MODIS and VIIRS active fire hotspots, emphasized the limitation of Landsat-based BA products in temporal fire reporting accuracy terms. The intercomparison with five readily available BA products for 2017, by using the same validation process, demonstrated the overall outperformance of NEALGEBA. Furthermore, our BA product exhibited the highest correspondence with the ground-based BA estimates. NEALGEBA currently represents the most extensive and reliable time series of BA history at fine spatial resolution for NE Algeria, offering a significant contribution for further national and international fire hazard and impact assessments and acts as a reference dataset for contextualizing future weather extremes, such as the 2023 exceptional heat wave, which we show not to have led to the most extreme fire year over the last four decades.

The cortical motor system can be reorganized following a stroke, with an increasing recruitment of the contralesional hemisphere. However, it is unknown whether a similar hemispheric shift occurs in the somatosensory system to adapt to this motor change, and whether this is related to movement impairments.  This proof-of-concept study assessed somatosensory evoked potentials (SEPs), P50 and N100, in hemiparetic stroke participants and age-matched controls using high-density electroencephalograph (EEG) recordings during tactile finger stimulation. The laterality index was calculated to determine hemispheric dominance of the SEP and re-confirmed with source localization.  The study found that latencies of P50 and N100 were significantly delayed in stroke brains when stimulating the paretic hand. The amplitude of P50 was negatively correlated with Fügl-Meyer Upper Extremity Motor Score in stroke. Bilateral cortical responses were detected in stroke, while only contralateral cortical responses were shown in controls, resulting in a significant difference in the laterality index.  These results suggested that somatosensory reorganization after stroke involves increased recruitment of ipsilateral cortical regions. This reorganization delays the latency of somatosensory processing after a stroke.  This research provided new insights related to the somatosensory reorganization after stroke, which could enrich future hypothesis-driven therapeutic rehabilitation strategies from a sensory or sensory-motor perspective.

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.

The artificial solar saltwork fields of Hon Khoi are important industrial and biodiversity resources in southern Vietnam. Most hypersaline environments in this area are characterized by saturated salinity, nearly neutral pH, intense ultraviolet radiation, elevated temperatures and fast desiccation processes. However, the extreme halophilic prokaryotic communities associated with these stressful environments remain uninvestigated. To fill this gap, a metabarcoding approach was conducted to characterize these communities by comparing them with solar salterns in northern Vietnam as well as with Italian salterns. Sequencing analyses revealed that the multiple reuses of crystallization ponds apparently create significant perturbations and structural instability in prokaryotic consortia. However, some interesting features were noticed when we examined the diversity of ultra-small prokaryotes belonging to Patescibacteria and DPANN Archaea. Surprisingly, we found at least five deeply branched clades, two from Patescibacteria and three from DPANN Archaea, which seem to be quite specific to Hon Khoi saltwork fields ecosystem and can be considered as a part of biogeographical connotation. Further studies are needed to characterize these uncultivated taxa, to isolate and cultivate them, which will allow us to elucidate their ecological role in these hypersaline habitats and to explore their biotechnological and biomedical potential.

Segment Anything Model 2 (SAM 2) is a state-of-the-art development by Meta AI Research, designed to address the limitations of its predecessor, SAM, particularly in the realm of video segmentation. SAM 2 employs a transformer-based architecture enhanced with streaming memory, enabling real-time processing for both images and videos. This advancement is important given the exponential growth of multimedia content and the subsequent demand for efficient video analysis. Utilizing the SA-V dataset, SAM 2 excels in handling the intricate spatio-temporal dynamics inherent in video data, ensuring accurate and efficient segmentation. Key features of SAM 2 include its ability to provide real-time segmentation with minimal user interaction, maintaining robust performance even in dynamic and cluttered visual environments. This study provides a comprehensive overview of SAM 2, detailing its architecture, functionality, and diverse applications. It further explores the model's potential in improving practical implementations across various domains, emphasizing its significance in advancing real-time video analysis.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis caused by β-human papillomaviruses (HPV) in immunodeficient patients. EV is characterized by flat warts and pityriasis-like lesions and might be isolated or syndromic, associated with some other infectious manifestations. We report here three patients from 2 independent families with syndromic EV for 2 of them. By whole exome sequencing, we found that patients carry new homozygous variants in STK4, both leading to a premature stop codon. STK4 deficiency causes a combined immunodeficiency characterized by a broad infectious susceptibility to bacteria, viruses and fungi. Auto-immune manifestations were also reported. Deep immunophenotyping revealed multiple cytopenia in the three affected patients, in particular deep CD4+ T cells deficiency. We report here the fourth and the fifth cases of syndromic EV due to STK4 deficiency.

This study investigates the energy profile of a regional hospital in North America using an ASHRAE Level 2 Energy Audit. The audit aimed to assess the efficiency of existing systems, identify areas for improvement, and recommend cost-effective measures to reduce energy consumption and environmental impact. The analysis revealed a well-maintained heating system with efficient boilers. However, a critical concern emerged regarding operational risks due to the lack of redundancy in the cooling system. To address this vulnerability, the study recommends installing an air-cooled chiller for increased operational resilience. The economic feasibility of proposed improvements was evaluated, highlighting the balance between initial investment and long-term savings in energy costs and reduced greenhouse gas emissions. The findings contribute to the discourse on sustainable healthcare practices, emphasizing the importance of energy audits, strategic planning, and redundancy measures for optimized performance and environmental responsibility in hospitals.

Rat H9c2 cardiomyocytes overexpressing the abscisic acid (ABA) hormone receptors LANCL1 and LANCL2 have an increased mitochondrial proton gradient, respiration and vitality after hypoxia/reoxygenation. Our aim was to investigate the role of the ABA/LANCL1-2 system in ROS turnover in H9c2. H9c2 cells were retrovirally infected to induce overexpression or silencing of LANCL1 and LANCL2, without or with the concomitant silencing of the transcription factor ERRα. Enzymes involved in radical production or scavenging were studied by qPCR and Western blot. Mitochondrial proton gradient and ROS were measured with specific fluorescent probes. ROS generating enzymes decreased, ROS-scavenging enzymes increased, and mitochondrial ROS were reduced in LANCL1/2-overexpressing vs. control cells infected with the empty vector, while the opposite occurred in LANCL1/2-silenced cells. Knock-down of ERRα abrogated all beneficial effects on ROS turnover in LANCL1/2 overexpressing cells. Taken together, these results indicate that the ABA/LANCL1-2 system controls ROS turnover in H9c2 via ERRα. The ABA/LANCL system emerges as a promising target to improve cardiomyocyte mitochondrial function and resilience to oxidative stress.

Addressing escalating energy demands and greenhouse gas emissions in the oil and gas industry has driven extensive efforts in carbon capture and utilization (CCU), focusing on power plants and industrial facilities. Utilizing CO2 as a primary feedstock for industrial fuels and petrochemical materials offers a favorable alternative to sequestration, with byproducts substituting traditional chemical feedstocks. This comprehensive review explores the current landscape of CO2 capture technologies, examining opportunities, economic viability, and efficiency challenges. It provides a detailed analysis of various CO2 utilization methods and the combined process of capture and utilization. The review highlights primary obstacles in planning, production, and widespread implementation, emphasizing the need for strategic integration of materials research, process performance, and cost-effectiveness to advance new technologies.

Introduction: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection may cause acute respiratory failure but also remains responsible for many other pathologies, including electrolyte disorders. SARS-CoV-2 infection can cause dysfunction of the renin-angiotensin-aldosterone system and disrupt water hemostasis with thirst and appetite abnormalities. Dysnatremia affects prognosis and may be associated with mortality in patients admitted to SARS-CoV2 intensive care. Patients and Methods: The study included 209 patients admitted to the Intensive Care Unit between April 12, 2021, and March 1, 2022 who were over 18 years old and diagnosed with SARS-CoV-2 infection by clinical and thoracic tomography findings or with a positive reverse transcription polymerase chain reaction (RT-PCR) test result. The laboratory markers, treatment modalities, nutritional, and respiratory support also for outcome evaluation, length of stay in the ICU, total hospitalization duration, and mortality in ICU were recorded.The laboratory marker comparison was made admission with the final assessment performed before the time of mortality in ICU or discharge. Results: Inotropic requirements among patients were high which was reflected in the first-month mortality. Hypernatremia presence was associated with an increase in enteral support and inotropic support requirement and mortality. Hypernatremia was correlated with diabetes mellitus, chronic renal failure, and a longer duration under mechanical ventilation. Discussion: Hypernatremia was an important risk factor in ICU patients hospitalized for SARS-CoV-2 infection, which was also affected by the treatment regimens given itself. This complex relationship underlies the importance of proper electrolyte management, especially in patients who were under severe stress and organ failure.

Type 2 Diabetes Mellitus and Alzheimer's disease are two diseases with a high incidence today that share similar pathophysiological mechanisms suggesting a potential causal relationship between them. In fact, Alzheimer-associated Mellitus Diabetes is also known as Type 3 Diabetes Mellitus and constitutes a diabetes intricately linked to Alzheimer's disease. Central to this association is insulin resistance, a key factor leading to decreased insulin sensitivity, hyperglycemia, and impaired glucose uptake. Because of this, the brain is altered resulting in energy deficits and neuronal damage associated with neurodegenerative disorder characteristic of Alzheimer's disease. Both diseases exhibit common biochemical and physiological characteristics such as inflammation, mitochondrial dysfunction, oxidative stress, and the formation of advanced glycation end products. Understanding the complex pathophysiology of Type 3 Mellitus Diabetes and identifying common features shared with Diabetes and Alzheimer's disease are essential steps towards potential therapeutic interventions targeting the insulin resistance pathway. The authors of this review on the relationships between type 2 diabetes and Alzheimer's disease have developed two works. In the first (Relationships between Type 2 Diabetes Mellitus and Alzheimer's Disease. I. Common pathogenic mechanisms), authors explore the shared (physiological, genetics and molecular) pathological changes occurring in Type 2 Mellitus Diabetes and Alzheimer's disease as well as pathways such as AMPK, PPARγ, cAMP, and PI3K/Akt as potential targets for managing Type 3 Diabetes Mellitus. By exploring these intricate mechanisms, the goal is to uncover their interdependencies and facilitate the discovery of innovative pharmacological and nutritional (epigenetics) strategies. In the second paper (Relationships between Type 2 Diabetes Mellitus and Alzheimer's Disease. II Potential therapies) we describe possible nutritional intervention, particularly dietary patterns and phytochemicals that can enhance the effects of pharmaceutical drugs designed against pathological mechanisms involved in the complex dual disease Type 2 Diabetes Mellitus and Alzheimer's disease (or in Type 3 Diabetes Mellitus as other authors consider).

Retroviruses perpetuate their survival by incorporating a copy of their genome into the host cell, a critical step catalyzed by the virally encoded integrase. The viral capsid plays an important role during the viral life-cycle, including nuclear importation in case of lentiviruses and integration targeting events, hence, targeting the integrase and the viral capsid is a favorable therapeutic strategy. While integrase strand transfer inhibitors (INSTIs) are recommended as first-line regimens given their high efficacy and tolerability, lenacapavir is the first capsid inhibitor and the newest addition to the HIV treatment arsenal. These inhibitors are however designed for treatment of HIV-1 infection, and their efficacy against HIV-2 remains widely understudied and inconclusive, supported only by few limited phenotypic susceptibility studies. We therefore carried out inhibition profiling of a panel of second-generation INSTIs and lenacapavir against HIV-2 in cell culture, utilizing pseudovirion inhibition profiling assays. Our results show that the tested INSTIs and lenacapavir exerted excellent efficacy against ROD-based HIV-2 integrase, and interestingly, raltegravir also showed modest antiviral activity against the SARS-CoV-2 Omicron variant in antiviral assays carried out in Vero E6 cells.

COVID-19, caused by the SARS-CoV-2 virus, has spread around the world and killed around 6.9 million people. Rapid and accurate diagnosis is essential for preventing and controlling the disease, reducing transmission and consequently saving lives. RT-PCR is the gold standard test used to detect the disease. However, the test is expensive and the result is time-consuming, which makes mass testing difficult, especially in countries with limited resources. In addition, the test has high analytical specificity and low diagnostic sensitivity, which leads to false-negative results. Several studies in the literature report the presence of hematological and biochemical alterations in infected patients and use these alterations with machine learning algorithms to help diagnose the disease. Therefore, this article presents the results obtained by different neural network architectures based on Adaptive Resonance Theory (ART) for the diagnosis of COVID-19. The study was conducted in two distinct stages: the first consisted of selecting the best ART network among several, using three open-access datasets and comparing the results with the literature. In the second stage, the chosen model was tested on a dataset containing patients from various hospitals in four countries. In addition, the model was subjected to external validation, including data from a country not present during the training and adjustment of the model, in order to validate the robustness and generalization capacity of the model. The results obtained by the ART networks in this study are promising, outperforming not only classical models, but also the deep learning models often used in the literature. Validation on data from different countries strengthens the model’s reliability and effectiveness.

Dengue is one the most significant mosquito-borne viral diseases globally, with its prevalence extending across tropical and subtropical regions, exerting a considerable financial strain on health systems. Despite decades of research leading to the development of a vaccine implemented in endemic countries, its usage remains restricted to a fraction of the population at risk of contracting dengue. Due to these limitations, there is a growing focus on research aimed at unraveling the cellular mechanisms crucial for Dengue virus (DENV) infection to pinpoint potential host targets. Multiple studies propose a pivotal role of cytoskeletal remodeling in DENV infection. Specifically, DENV alters the organization of actin to facilitate viral entry, replication, and release. In this study, we investigated the involvement of the protein c-Abl, a kinase crucial in actin dynamics, in the context of DENV infection. Our findings suggest that either silencing or pharmacological inhibition of the kinase c-Abl leads to accumulation of dengue ENV protein in vitro, associated with actin remodeling. These results illuminate cellular mechanisms that could serve as potential therapeutic alternatives for dengue management.

Background: The COVID-19 pandemic has affected Madagascar, Cameroon, and the Central African Republic (CAR), with each experiencing multiple waves by mid-2022. This study aimed to evaluate immunity against SARS-CoV-2 strains Wuhan (W) and BA.2 (BA.2) among healthcare workers (HCWs) in these countries, focusing on vaccination and natural infection effects. Methods: HCWs' serum samples were analyzed for neutralizing antibodies (nAbs) against W and BA.2 variants, with statistical analyses comparing responses between countries and vaccination statuses. Results: Madagascar showed significantly higher nAb titers against both strains compared to CAR and Cameroon. Vaccination notably increased nAb levels against W by 2.6-fold in CAR and 1.8-fold in Madagascar, and against BA.2 by 1.6-fold in Madagascar and 1.5-fold in CAR. However, in Cameroon, there was no significant difference in nAb levels between vaccinated and unvaccinated groups. Conclusion: The study highlights the complex relationship between natural and vaccine-induced immunity, emphasizing the importance of assessing immunity in regions with varied epidemic experiences and low vaccination rates.

This is a SARS-CoV-2 seroepidemiological study in pediatric population(0-16 years) during BA.5 Omicron predominance period in Athens metropolitan area. Serum samples were tested for SARS-CoV-2 nucleocapsid antibodies(Abs-N), representing natural infection during three sub-periods of BA.5 predominance: 01/05/2022-31/08/2022(period A), 01/09/2022-31/12/2022(period B) and July 2023(period C) and epidemiological data were collected. Additionally in period C Abs-N seronegative samples were tested for SARS-CoV-2 spike antibodies(Abs-S). A total of 878 children were tested (males:51.3%) with median age(IQR): 108(36-156) months and seropositivity during the 3 subperiods was: A:292/417(70%), B:288/356(80.9%), C:89/105(84.8%), P-value<0.001. SARS-CoV-2 seropositivity increased for from period A to C for 0-1-year (P-value: 0.044), 1-4 years (P-value: 0.028) and 6-12 years children (P-value: 0.003). Children 6-12y had the highest seroposi-tivity rates in all subperiods (A: 77.3%, B: 91.4% and C: 95.8%). A significant correlation of monthly SARS-CoV-2 median antibody titers with monthly seropositivity rates was detected (rs:0.812, P-value:0.008). During period C, an additional 12/105 (11.4%) Abs-S seropositive and Abs-N ser-onegative samples were detected and total seropositivity was estimated at 96.2% (101/105). The increased SARS-CoV-2 seropositivity detected in current seroepidemiology study illustrates a high exposure rate during BA.5 predominance period. These data could guide public health decisions regarding immunization strategies and protection measures.

Viruses continue to provide vital insights into the field of control of gene expression. Viral transactivators, in concert with other viral and cellular proteins, regulate expression of self, other viruses, and host genes with profound effects on infected cells, underlying inflammation, control of immune responses, and pathogenesis. The multifunctional Tat proteins of lentiviruses (HIV-1, HIV-2, and SIV) transactivate gene expression by recruiting host proteins and binding to trans-acting responsive regions (TARs) in viral and host RNAs. SARS-CoV-2 nucleocapsid participates in early viral transcription, recruits similar cellular proteins, and shares intracellular, surface, and extracellular distribution with Tat. SARS-CoV-2 nucleocapsid interacting with the Replication-Transcription complex might, therefore, transactivate viral and cellular RNAs in transcription and reactivation of self and other viruses, acute and chronic pathogenesis, immune evasion, and viral evolution, constituting a potential pan-coronaviral therapeutic target. Here, we show by using primary and secondary structural comparisons that the leaders of SARS-CoV-2 and other coronaviruses contain TAR-like sequences in stem-loops 2 and 3, the coronaviral nucleocapsid C-terminal domains (N-CTDs) harbor a region of similarity to TAR-binding regions of lentiviral Tat proteins, and the coronaviral nonstructural protein 12 has a cysteine-rich metal binding, dimerization domain similar to that in lentiviral Tat proteins.

The C-C motif chemokine receptor 8 (CCR8) is highly and selectively expressed in regulatory T (Treg) cells and is associated with tumor progression. The massive accumulation of Treg cells into tumors suppresses the effector function of CD8⁺ cells against tumor cells. Therefore, selective depletion of Treg cells using anti-CCR8 monoclonal antibodies (mAbs) reinvigorates antitumor immune responses and improves responses to cancer immunotherapy. Previously, we developed an anti-mouse CCR8 (mCCR8) mAb, C₈Mab-2, using the Cell-Based Immunization and Screening (CBIS) method. In this study, the binding epitope of C₈Mab-2 was investigated using flow cytometry. The mCCR8 extracellular domain-substituted mutant analysis showed that C₈Mab-2 recognizes the N-terminal region (1–33 amino acids) of mCCR8. Next, 1×alanine (or glycine) scanning and 2×alanine (or glycine) scanning were conducted in the N-terminal region. The results revealed that the _17-DFFTAP_-22 sequence is important for the recognition by C₈Mab-2, and Thr20 is a central amino acid of the epitope. These results revealed the involvement of the N-terminus of mCCR8 in the recognition by C₈Mab-2.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality of type 2 diabetes mellitus (T2DM). Aim of this study was to investigate whether albumin structural alterations correlate with DKD severity and evaluate whether native and reduced albumin concentrations could complement the diagnosis of DKD. To this aim, one hundred and seventeen T2DM patients without (n=42) and with (n=75) DKD (DKD I-III upon KDIGO classification) were evaluated; total albumin concentration (tHA) was quantified by bromocresol green assay, while structural alterations were profiled assessed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). The concentrations of albumin in native (eHA, effective albumin) and reduced (rHA) forms were then assessed. HRMS analyses showed a reduced relative amount of native albumin in DKD patients along with an increased abundance of altered forms, especially those bearing oxidative modifications. Accordingly, both eHA and rHA values varied along the stages of progressive renal failure, and alterations dose-dependently correlated with renal dysfunction. ROC curves analysis showed a significantly higher sensitivity and specificity of eHA and rHA with respect to tHA for the diagnosis of DKD. Importantly, at multivariable logistic regression analysis, eHA was identified as independent predictor of DKD.

The COVID-19 pandemic has raised concerns about its impact on maternal and neonatal health. This study aimed to investigate the influence of maternal COVID-19 infection during pregnancy on neonatal inflammatory parameters. A retrospective cohort study was conducted at Premiere Hospital in Timisoara between May 2021 and January 2022. Participants were categorized into two groups: the COVID-19 positive group, consisting of patients with confirmed SARS-CoV-2 in-fection during pregnancy, and the control group, which comprised COVID-19-free pregnant women. The primary outcome was the assessment of inflammatory markers (NLR, dNLR, PLR, and SII) in neonates born to mothers with COVID-19. The results suggest that maternal COVID-19 infection during pregnancy significantly impacts certain neonatal inflammatory parameters. Spe-cifically, newborns exposed to maternal COVID-19 exhibited elevated white blood cell counts, particularly when infection occurred during the first trimester. Lymphocyte counts were dimin-ished in neonates born to COVID-19-positive mothers, irrespective of infection trimester. Gesta-tional age played a role in altering neonatal immune profiles, with correlations observed between GA and parameters in the Control Group (COVID-19 negative during pregnancy). However, the influence of neonatal immunoreactivity on laboratory parameters remained generally non-significant after adjusting for GA and infection trimester. In conclusion, maternal COVID-19 infection during pregnancy has a discernible impact on neonatal inflammatory parameters, in-cluding WBC and lymphocyte counts, which may have clinical implications.

Humans are often exposed to various environmental contaminants, among which phthalates are prevalent due to their extensive use as plasticizers in various consumer goods. Di(2-ethylhexyl) phthalate (DEHP), a widely used phthalate, is recognized as an endocrine disruptor chemical (EDC). DEHP is reported to affect various organs. Few studies have addressed the effects of phthalates on bone. However, the effects of DEHP on the bone forming cells (osteoblasts) are obscure. The present study was peformed to determine the cytotoxic effects of DEHP on human osteoblasts in vitro and to delineate the mechansims. In this study, we exposed the human osteo-blastic cell line MG-63 to various concentrations of DEHP (1, 25, 50 and 100 µM) for 24, 48 and 72 h. Cell viability was assessed by MTT assay. Total RNA and protein were collected after 48 h treatment with 1 and 100 µM DEHP and determined for the mRNA and/or protein expression of alkaline phosphatase (ALP), sex steroid receptors (androgen and estrogen receptors), receptor activator of nuclear factor kappa-Β ligand (RANKL), runt-related transcription factor 2 (RUNX2) and peroxisome proliferator-activated receptor alpha (PPARα). The mRNA expression was stud-ied by real-time RT-PCR analysis and the protein expression was determined by western blot analysis. Statistical analyses were done by one-way analysis of variance (ANOVA) followed by the Students–Newman–Keuls (SNK) test. The exposure of MG-63 cells to DEHP caused a signifi-cant decrease in osteoblast viability in all the treatment groups and at all the time points stud-ied. Interestingly, DEHP exposure decreased the mRNA expression of ALP, a bone formation marker. DEHP had differential effects on estrogen receptor alpha (ERα) mRNA and protein ex-pression. However, DEHP treatment downregulated the mRNA and protein expression of ERβ, and androgen receptor (AR). Surprisingly, DEHP downregulated the RANKL mRNA expression. DEHP decreased the protein expression of RUNX2, the key transcription factor and master regu-lator of bone formation. Furthermore, DEHP increased the PPARα protein expression in the os-teoblasts. Importantly, DEHP increased the reactive oxygen species (ROS) molecules and thus oxidative stress in osteoblasts, as observed by increased hydrogen peroxide, hydroxyl radical levels and lipid peroxidation. On the other hand, it decreased the enzymatic and non-enzymatic antioxidant levels namely catalase, superoxide dismutase, glutathione peroxidase activity and reduced glutathione. Our study demonstrated that in vitro exposure to DEHP reduces the osteo-blast viability possibly through alterations in the oxidant-antioxidant system and modulation of the key genes involved in bone formation, highlighting the cytotoxic effects of DEHP on bone forming cells.

Dementia, characterized by cognitive decline beyond age-related expectations, poses a formidable global health challenge. With an estimated 55 million individuals affected worldwide and 10 million new cases annually, dementia profoundly impacts memory, comprehension, language, and behavior. Then, the global diabetes population increased from 108 million in 1980 to 422 million in 2014, with a more rapid rise in prevalence observed in low- and middle-income countries compared to high-income countries. Individuals with diabetes have an increased risk of cognitive problems, including a higher likelihood of developing dementia, Alzheimer's disease, and vascular dementia, especially in older age. Managing diabetes through diet, physical activity, medication, and consistent screening and treatment for complications can prevent or delay its consequences.Globally ranking as the seventh leading cause of death, dementia's societal implications are substantial. The chapter delves into Mild Cognitive Impairment (MCI), a precursor to dementia, emphasizing its global epidemiological trends. Neuroimaging, particularly Functional Near-Infrared Spectroscopy (fNIRS), emerges as a non-invasive diagnostic tool, surpassing traditional imaging methods' portability. The chapter investigates the effects of non-invasive electrical stimulation on neurovascular tissues, shedding light on its impact including potential to address metaboreflex related reduced exercise tolerance. Furthermore, the chapter presents a clinical trial (ClinicalTrials.gov NCT04626453 and NCT04812288) examining the effects of a 2-month exercise program on cognitive function and muscular oxidative capacity in older adults with type 2 diabetes. The study's design, individualized exercise regimens to address muscle mechanoreflex and metaboreflex responses, and their physiological changes during exercise are discussed, offering insights into the interplay between exercise tolerance, cognition, and vascular health. The findings contribute to tailored and effective interventions for cognitive well-being. Here, our exploration extends to the application of transcranial electrical stimulation (tES) in optimizing exercise performance, with a focus on its various forms, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS). A physiological modeling approach based on the neurovascular unit (NVU) is employed, revealing potential avenues for also treating vascular dementia (often noted to have a strong association with type 2 diabetes) through tACS, guided by human-in-the-loop approaches. Here, modal analysis for control is applied to assess the NVU model's characteristic dynamics under tACS, providing a comprehensive understanding of neurovascular coupling modes.In summary, this chapter synthesizes diverse facets in type 2 diabetes comorbidity and cognitive decline, ranging from global impact and diagnostic criteria to innovative interventions like exercise and transcranial electrical stimulation. The multidisciplinary approach integrates epidemiology, clinical trials, and physiological modeling, contributing valuable insights into the holistic management of cognitive health and neurovascular function.

Human epidermal growth factor receptor 2 (HER2) belongs to the ErbB family, a group of four transmembrane glycoproteins with tyrosine kinase activity, all structurally related to the epidermal growth factor receptor (EGFR). These tyrosine kinases are involved in the transmission of cellular signals controlling normal cell growth and differentiation. If this transmission goes awry, it can lead to dysregulated growth of the cell. HER2 specifically can be implicated in the pathogenesis of at least eight malignancies. HER2 positivity quickly became a well characterized indicator of aggressiveness and poor prognosis, with high rates of disease progression and mortality. After realizing the implication of HER2, it first became investigated as a target for treatment in breast cancer, and later expanded to areas of research in other cancers types. To this day, the most therapeutic advancements of anti-HER2 therapy have been in breast cancer, however, there have been strong advancements made in the incorporation of anti HER2 therapy in other cancer types as well. This comprehensive review dissects HER2 to its core incorporating the most up to date information. The topics touched upon are discussed in detail and up to 200 published sources from the most highly recognized journals have been integrated. The importance of knowing about HER2 is exemplified by the groundbreaking advancements that have been made, and the change in treatment plans it has brought to the oncological world in the last twenty years. Since, its ground breaking discovery there has been significant breakthroughs in knowledge regarding the actual receptor, the receptors biology, its mechanism of action, advancements in tests to detect HER2 and significant strides on how to best incorporate targeted treatment. Due to the success of this field thus far, the review concludes by discussing the future of novel anti-HER2 therapy currently in development that everyone should be aware of.

Background: SARS-CoV-2 continues to impact human health globally, with airborne transmission being a significant mode for transmission. In addition to tools like vaccination and testing, counter-measures that reduce viral spread in indoor settings are critical. This study aims to assess the efficacy of UV-C light, utilizing the Violett sterilization device, as a countermeasure against airborne transmission of SARS-CoV-2 in the highly susceptible Golden Syrian hamster model. Methods: Two cohorts of naïve hamsters were subjected to airborne transmission from experimentally infected hamsters; one cohort was exposed to air treated with UV-C sterilization, while the other cohort was exposed to un-treated air. Results: Treatment of air with UV-C light prevented the airborne transmission of SARS-CoV-2 from experimentally exposed hamster to naïve hamsters. Notably, this protection was sustained over a muti-day exposure period during peak viral shedding from hamsters. Conclusion: These findings demonstrate the efficacy of the UV-C light to mitigate airborne SARS-CoV-2 transmission. As variants continue to emerge, UV-C light holds promise as a tool to reduce infections in diverse indoor settings, ranging from healthcare facilities to households. This study reinforces the urgency of implementing innovative methods to reduce airborne disease transmission and safeguard public health against emerging biological threats.

This paper aims to search for lump waves in a spatial symmetric (2+1)-dimensional dispersive wave model. Through an ansatz on positive quadratic functions, we conduct symbolic computations with Maple to generate lump waves for the proposed nonlinear model. A line of critical points of the lump waves is computed, whose two spatial coordinates travel at constant speeds. The corresponding maximum and minimum values are evaluated in terms of the wave numbers, and interestingly, all those extreme values do not change with time, either. The last section is the conclusion.

Background. Waning of neutralizing and cell-mediated immune response after the primary vac-cine cycle (PVC) and the first booster dose (BD) is of concern, especially for PLWH with a CD4 count ≤200 cells/ mm3.Methods.Neutralizing antibodies (nAbs) titers by microneutralization assay against WD614G /Omicron BA.1 and IFNγ production by ELISA assay were measured in samples of PLWH at 4 time points [2 and 4 months post-PVC (T1 and T2), 2 weeks and 5 months after the BD (T3 and T4)]. Participants were stratified by CD4 count after PVC (LCD4, <200/mm3; ICD4, 201-500/mm3 and HCD4, >500/mm3). Mixed models were used to compare mean responses over T1-T4 across CD4 groups. Results. 314 PLWH on ART (LCD4=56; ICD4=120; HCD4=138) were enrolled. At T2, levels of nAbs were significantly lower in LCD4 vs ICD4/HCD4 (p=0.04). BD was crucial for increasing nAbs titres above 1:40 at T3 and up to T4 for WD614G. A positive T cell response after PVC was observed in all groups, regardless of CD4 (p=0.31). Conclusions. Waning of nAbs after PVC was more important in LCD4 group. BD managed to re-establish higher levels of nAbs against WD614G which were retained for 5 months. The level of T-cellular response was significantly higher in HCD4 and ICD4 compared to the LCD4 group although it remained above detectable levels over the entire study period regardless of CD4 count. Keywords: HIV-1 infection; SARS-CoV-2 infection;

This paper presents a new method for the design of separable denominators 2-D IIR filters with nearly linear phase in the passband. The design method is based on a balanced-realization model reduction technique. The nearly linear-phase 2-D IIR filter is designed using 2-D model reduction from a linear-phase 2-D FIR filter, which serves as the initial filter. The structured controllability and observability Gramians $P^s$ and $Q^s$ serve as the foundation for this technique. These Gramians are block diagonal positive-definite matrices that satisfy 2-D Lyapunov equations. An efficient method is used to compute these Gramians by minimizing the traces of $P^s$ and $Q^s$ under linear matrix inequalities (LMI) constraints. The use of these Gramians ensures that the resulting 2-D IIR filter preserves stability and can be implemented using a separable denominator 2-D filter with fewer coefficients than the original 2-D FIR filter. Numerical examples show that the proposed method compares favorably with existing techniques.

Sepsis is a life-threatening condition caused by the body's overwhelming response to an infection, such as pneumonia or urinary tract infection. It occurs when the immune system releases cytokines into the bloodstream, triggering widespread inflammation. If not treated, it can lead to organ failure and death. Unfortunately, sepsis has a high mortality rate, with studies reporting rates ranging from 20% to over 50%, depending on the severity and promptness of treatment. According to the World Health Organization (WHO), the annual death toll in the world is about 11 million. One of the main toxins responsible for inflammation induction are lipopolysaccharides (LPS, endotoxin) from Gram-negative bacteria, which ranks among the most potent immunostimulants found in nature. Antibiotics are consistently prescribed as a part of anti-sepsis-therapy. However, antibiotic therapy (i) is increasingly ineffective due to resistance development and (ii) most antibiotics are unable to bind and neutralize LPS, a prerequisite to inhibit the interaction of endotoxin with its cellular receptor complex, namely Toll-like receptor 4 (TLR4)/MD-2, responsible for the intracellular cascade leading to pro-inflammatory cytokine secretion. The pandemic virus SARS-CoV-2 has infected hundreds of millions of humans worldwide since its emergence in 2019. The COVID-19 (Coronavirus disease-19) caused by this virus is associated with high lethality, particularly for elderly and immunocompromised people. As of August 2023, nearly 7 million deaths were reported worldwide due to this disease. According to some reported studies, upregulation of TLR4 and the subsequent inflammatory signaling detected in COVID-19 patients “mimics bacterial sepsis”. Furthermore, the immune response to SARS-CoV-2 was described by others as “mirror image of sepsis”. Similarly, the cytokine profile in sera from severe COVID-19 patients was very similar to those suffering from the acute respiratory distress syndrome (ARDS) and sepsis. Finally, the severe COVID-19 infection was frequently accompanied by bacterial co-infections, as well as by the presence of significant LPS concentrations. These data indicate similarity and interdependences of both syndromes, but also significant differences which will be discussed in the present review.

By slowly evaporating 4-bromo-2-methylbenzonitrile at room temperature, it was possible to make a single organic nonlinear optical crystal. The grown crystal's crystalline nature was verified, and the unit cell characteristics are provided as a = 4.08Å, b = 6.61 Å, c = 28.93Å, α = 90º, β = 90º, γ = 90º. The functional groups of the crystal produced were identified using the FTIR and FT-Raman spectra. The UV cutoff wavelength is found at 221.6 nm, and the transparency nature of the crystal was analyzed in the optical studies.  The band gap of the grown crystal was estimated using the Taucs’ plot. The violet and red emissions of photoluminescence are discussed. A high dielectric constant was received at a low frequency. The TG/DTA curve shows that the grown crystal was stable up to 125.59 ºC.  The Kurtz-Perry powder technique was applied to confirm the Second Harmonic Generation's (SHG) nature. By using the agar diffusion method, the antibacterial property of the grown 4B2MBN crystal was determined.

Worldwide, the COVID-19 pandemic, which was brought on by the brand-new coronavirus SARS-CoV-2, has claimed a sizable number of lives. Despite the urgency, COVID-19 does not have any particular antiviral treatments at this time. As a result, scientists are concentrating on repurposing already existing antiviral medications or creating brand-new ones. The SARS-CoV-2 main protease, which is necessary for viral replication, has been identified as a possible target for a family of medicines called main protease inhibitors (MPIs). Studies of the major proteases from SARS-CoV and MERS-CoV, which have remarkably similar structures and functions to SARS-CoV-2, have provided insight for the creation of MPIs. By analyzing the MPI trials for SARS-CoV and MERS-CoV, this review sheds light on the possible therapeutic uses of MPIs for COVID-19. The review talks about how MPIs work, how effective they are against SARS-CoV and MERS-CoV, and how safe they are. The paper also emphasizes current developments in the creation of MPIs for SARS-CoV-2, including as computational studies, in vitro and in vivo research, and clinical trials. According to the review, there is a lot of hope for MPIs in the treatment of COVID-19, and numerous medications are in the works. Although more research is needed to assess their safety and effectiveness in clinical settings, these medications may offer patients with COVID-19 a much-needed therapeutic option. The review also emphasizes the importance of ongoing research into the structure and function of the SARS-CoV-2 main protease, as this information will be critical for the development of effective MPIs and other antiviral drugs in the future.

Covid-19 is one of humanity’s biggest threat in the 21st century with WHO figures reporting 636 million cases and up to 6.6 million deaths globally. SARS-CoV-2, the virus that causes the Covid-19 disease, is characterized by high mutation which contributes to its rapid spread. While several vaccines have been produced to minimize the severity of the coronavirus and diverse treatment regimens have been approved by the US FDA under Emergency Use Authorization (EUA), SARS-CoV-2 viral mutations continue to derail the efforts of scientists as the emerging variants evade the recommended therapies. Nonetheless, diverse computational models exist that offer an opportunity to overcome the barriers involved in developing new drugs. In this review, the focus is on the use of various virtual screening techniques like molecular docking, molecular dynamics simulations, QSAR, pharmacophore modeling, and homology modeling in repurposing SARS-CoV-2 therapeutics. The results have been promising from the computer-aided drug design (CADD) studies in suggesting potential compounds for treatment of Covid-19 and helping in bringing the pandemic under control.

The SARS-CoV-2 virus, causative agent of COVID-19, is known for its genetic diversity. Virus variants of concern (VOCs) as well as variants of interest (VOIs) are classified by the World Health Organization (WHO) according to their potential risk to global health. This study seeks to enhance the identification and classification of such variants by developing a novel bioinformatics criterion centered on the virus's spike protein (SP1), a key player in host cell entry, immune response, and a mutational hotspot. To achieve this, we pioneered a unique phylogenetic algorithm which calculates EIIP-entropy as a distance measure based on the distribution of the Electron-Ion Interaction Potential (EIIP) of amino acids in SP1. This method offers a comprehensive, scalable, and rapid approach to analyze large genomic data sets and predict the impact of specific mutations. This innovative approach provides a robust tool for classifying emergent SARS-CoV-2 variants into potential VOCs or VOIs. It could significantly augment surveillance efforts and understanding of variant characteristics, while also offering potential applicability to the analysis and classification of other emerging viral pathogens and enhancing global readiness against emerging and re-emerging viral pathogens.

Despite successful vaccination efforts, the emergence of new SARS-CoV-2 variants poses ongoing challenges to control COVID-19. Understanding humoral responses concerning SARS-CoV-2 infections and their impact is crucial for developing future vaccines that are effective worldwide. Here, we identified 41 immunodominant linear IgG B-cell epitopes in its Spike glycoprotein with a SPOT synthesis peptide array probed with a pool of serum from hospitalized COVID-19 patients. Bioinformatics showed a restricted set of epitopes unique to SARS-CoV-2 compared to other coronavirus family members. Potential crosstalk was also detected with Dengue virus (DENV), confirmed by screening individuals infected with DENV before the COVID-19 pandemic in a commercial ELISA assay for anti-SARS-CoV-2 antibodies. Higher reactivity indices were often measured in individuals with a pre-pandemic dengue infection than those with COVID-19. A high-resolution evaluation of antibody reactivity against peptides representing epitopes in the spike protein identified ten sequences in the NTD, RBD, and S2 domains. Functionally, antibody-dependent enhancement (ADE) in SARS-CoV-2 infection of monocytes was observed with pre-pandemic dengue-positive sera. A significant increase in viral load was measured compared to controls, with no detectable neutralization or considerable cell death, suggesting its role in viral entry. This study highlights the importance of identifying the epitopes generated during the humoral response to a pathogenic infection to understand the potential interplay of previous and future conditions on disease. Vaccine development and optimization strategies should be mindful of the potential for A.D.E. that could differ geographically due to endemic biological risks.

One of the hallmarks of microgravity-induced effects in several cellular models is represented by the alteration of oxidative balance with the consequent accumulation of Reactive Oxygen Species (ROS). It is well known that male germ cells are sensitive to oxidative stress and to changes of gravitational force even if published data on germ cell models are scarce. To gain more insights into the mechanisms of male germ cell response to altered gravity, a 3D cell culture model has been established from TCam-2 cells, a seminoma-derived cell line considered the only human cell line available to study in vitro mitotically active human male germ cells. TCam-2 cell spheroids were cultured for 24 hours under unitary gravity (Ctr) or simulated microgravity (s-microgravity) conditions, these last ones were obtained using the Random Positioning Machine (RPM). A significant increase in intracellular ROS and mitochondria superoxide anion levels has been observed after RPM exposure. In line with these results a trend of protein and lipid oxidation increase, and increased pCAMKII expression levels were observed after RPM exposure. The ultrastructural analysis by Transmission Electron Microscopy revealed that RPM-exposed mitochondria appeared enlarged and, even if seldom, disrupted. Notably, even the expression of the main enzymes involved in the redox homeostasis appears modulated by RPM exposure in a compensatory way, being GPX1, NCF1, and CYBB downregulated, whereas NOX4 and HMOX1 upregulated. Interestingly, HMOX1 is involved in the heme catabolism of mitochondria cytochromes, and therefore the positive modulation of this marker can be associated to the observed mitochondria alteration. All together, these data demonstrate TCam-2 spheroid sensitivity to acute SM exposure and indicate the capability of these cells to trigger compensatory mechanisms that allow to overcome the exposure to altered gravitational force.

The uneven immunogenicity of the attenuated tetravalent dengue vaccine has created the diffi-culty to achieve a balanced protection against all four serotypes of dengue virus (DENV). To overcome this problem, non-replicative-based vaccines have come into focus as their immuno-genicity is adjustable. This approach is excellent for multivalent vaccines but commonly faces the issue of low immunogenicity. In this present study, we developed a non-replicating dengue vaccine composing of UV-inactivated dengue-2 virus (UV-DENV2) and DENV-2 NS1-279 protein encapsidated within nanoparticles. This vaccine candidate was administered in the presence of BCG cell wall cytoskeleton (BCG-CWS) as an adjuvant. We revealed, here, that encapsidated immunogens with BCG-CWS exerted potent activities on both B and T cells and elicited Th-1/Th-2 responses in mice. This was evidenced by strong neutralizing antibody activity with an unde-tectable antibody enhancing activity in a group of mice receiving encapsidated immunogens with BCG-CWS. Importantly, BCG-CWS significantly augmented antibody-mediated comple-ment-fixing activity, strongly stimulated the antigen-specific polyfunctional T cell responses as well as activated mixed Th-1/Th-2 responses specific to DENV2- and NS1-279 antigens. In conclu-sion, BCG-CWS potently adjuvanted the inactivated DENV-2 and subunit DENV immunogens. The mechanism of adjuvanticity remains unclear. This study revealed the potential use of BCG-CWS in vaccine development.

In order to solve the interference of narrowband in the ultra-wideband (UWB) system, a high isolation of multiple-input multiple-output (MIMO) antenna is investigated in this paper. The MIMO antenna consists of 2 or 4 UWB elements; and each UWB antenna element is a monopole reconstructed with 2-notched slots, a U-shaped and inverted U-shaped slots etched on the monopole patch to achieve notch characteristics in WIMAX and ITU bands. The property of a 2-element MIMO antenna is analyzed firstly, which is put into a same substrate in parallel. Two rectangular branches are located in the middle to reduce the coupling. Then a 4-element MIMO antenna is studied to meet big size space and more application scenarios. Each element is placed orthogonally on the same substrate; and the isolation is implemented by a cross-shaped branch located in the middle of elements. Both MIMO antenna samples have been tested to verify the design. Measured results show that the working bandwidth is 2.45-14.88 GHz and 2.14-14.95 GHz, the isolation is greater than 17 dB and 20 dB, the peak gain is 5.7 dB and 5.9 dB, the max-imum radiation efficiency can reach 96% and 95%, the envelope correlation coefficient is less than 0.02 and 0.05 for the 2- and 4-element UWB MIMO antenna, respectively. They both are with very good omnidirectional characteristic with notched bands such as the WIMAX and ITU, and meet the requirements of the UWB application in most cases.

There is an international concern for reducing energy consumption and protecting the environment in the construction industry. The energy efficiency of a building depends on the thermal resistance of concrete, and utilizing concrete products with elevated thermal resistance can enhance this aspect. This study analyzes the impact of perlite, as an addition, on the physico-mechanical properties of concrete, with the aim of identifying perlite concrete products that will respond to the improvement of the heat transfer resistance of the building envelope. The study examines the effect of replacing different amounts of concrete aggregates with perlite in percentages of 10%, 20%, 30%, and 100%. The results show that substituting sand with perlite improves the thermal performance of concrete, but its mechanical properties are negatively affected. The research carried out highlighted that perlite can be successfully introduced in the production of concrete blocks used for external non-bearing wall panels, the outstanding feature being the reduction of energy consumption in buildings. Overall, the paper identifies an efficient and environmentally friendly way of using perlite in the construction industry, enhancing the energy efficiency of buildings while minimizing the environmental footprint caused by the construction industry.

Evaluating the performance of water indices and mapping the spatial distribution of water-related ecosystems are important for monitoring surface water resources. This is particularly the case for Ethiopia since there is limited information available on water resources development over time despite its relevance for the people and ecosystems. To address this problem, this paper evaluates the performance of seven water indices for country-scale surface water detection based on high spatial and multi-temporal resolution Sentinel-2 data, processed using the Google Earth Engine cloud computing system. Results show that the water index (WI) and automatic water extraction index with shadow (AWEIsh) are the most accurate ones to extract surface water. Comparisons are based on qualitative visual inspections and quantitative accuracy indicators. For the latter, WI and AWEIsh obtained kappa coefficients of 0.96 and 0.95, respectively, and an overall accuracy of 0.98 each. Both indices accounted for similar spatial coverages of surface waters with 82,650 km2 (WI) and 86,530 km2 (AWEIsh) for the whole of Ethiopia.

The main problem in creating anti-coronavirus vaccines that target mainly proteins of the outer membrane of the virus remains the rapid variability of the RNA genome of the pathogen that encodes these proteins. In addition, the introduction of technologies that can provide affordable and fast production of flexible vaccine formulas that easily adapt to the emergence of new subtypes of SARS-CoV-2 is required. Universal oligonucleotide vaccine can take into account the dynamics of rapid changes in the virus genome, as well as be synthesized on automatic DNA synthesizers in large quantities in a short time. In this brief report, the effectiveness of four phosphorothioate constructs of the La-S-so type oligonucleotide vaccine will be evaluated for the first time on transgenic mice [B6.Cg-Tg (K18-ACE2)2]. In our primary trials, the oligonucleotide vaccine increased the survival rate of animals infected with SARS-CoV-2 and also reduced the destructive effects of the virus on the lung tissue of mice. The obtained results show the perspective of the development of vaccine constructs of the La-S-so type for the prevention of coronavirus infections, including those caused by SARS-СoV-2.

Background & aims. The fourth dose of anti-SARS-CoV-2 vaccine slightly improved the humoral response among previously seronegative liver transplant (LT) recipients. Mycophenolate (MMF) treatment worsens the vaccination response. This study aimed to evaluate whether temporary MMF interruption might improve immunogenicity of the fourth anti-SARS-CoV-2 BNT16b2 vaccine dose in nonresponsive LT recipients. Methods. LT recipients negative for anti-spike glycoprotein-specific immunoglobulin G receptor-binding domain (s-RBD) antibodies after the third vaccine dose were enrolled. Anti-SARS-CoV-2 spike-specific T cell responses were measured before and two months following the fourth vaccine dose, and anti-SARS-CoV-2-s-RBD antibodies also 6 months thereafter. MMF was suspended two weeks before and after vaccination. Results. Five LT recipients were enrolled. After a mean of 78 days after vaccination, all patients tested positive for anti-SARS-CoV-2-s-RBD antibodies. The mean antibody titer was 8944 UI/ml. The positive antibody response was maintained during a mean of 193 days of follow-up. Three patients developed a positive T cell response. Two patients (one positive for T cell response) developed a self-limited SARS-CoV-2 infection. Conclusions. Suspending MMF prior to the fourth dose of anti-SARS-CoV-2 mRNA vaccine seems feasible and safe. This procedure could restore vaccine-induced immunogenicity in a large portion of previously nonresponsive LT recipients.

Several studies suggest that children infected with SARS-CoV-2 have fewer clinical manifestations than adults; when they develop symptoms, they rarely progress to severe disease. Different immunological theories have been proposed to explain this phenomenon. In September 2020, 16% of the active COVID-19 cases in Venezuela were children under 19 years. We conducted a cross-sectional study of pediatric patients' immune response and clinical conditions with SARS-CoV-2 infection. The patients were admitted to the COVID-19 area of the emergency department of Dr José Manuel de los Ríos Children's Hospital (2021-2022). The lymphocyte subpopulations were analysed by flow cytometry, and IFNγ, IL-6 and IL-10 serum concentrations were quantified using commercial ELISA assays. The analysis was conducted on 72 patients aged one month and 18 years. The majority, 52.8%, had mild disease, and 30.6 % were diagnosed with MIS-C. The main symptoms reported were fever, cough and diarrhoea. A correlation was found between IL-10 and IL-6 concentrations and age group; lymphocyte subpopulations and nutritional status and steroid use; IL-6 concentrations and clinical severity. The results suggest a different immune response depending on age and nutritional status that should be considered for treating pediatric COVID-19 patients.

The first diastereoselective synthesis of (–)-1-epi-lentiginosine stars from a common chiral trans-epoxyamide derived from 2-pyridincarbaldehyde is reported. This methodology involves a sequential oxirane ring opening and intramolecular 5-exo-tet cyclization of tosylate tras-epoxyalcohol to afford a diastereomeric mixture of indolizinium salts in a one-pot fashion, followed by regio- and diastereospecific pyridinium ring reduction.

Background: The SARS-CoV-2 laboratory PCR tests were generally reported only as binary positive or negative outcomes. Instead test positivity, these results contain a great deal of epidemiological information related to viral transmission patterns in populations. These transmission patterns during India’s SARS-CoV-2 viral waves remain largely undocumented. Methods: We analysed 2.7 million real-time polymerase chain reaction (PCR) testing records collected in Mumbai, a bellwether for other Indian cities. We used the inverse of cycle threshold (Ct) values to determine community-level viral load. We quantified wave-specific differences by age, sex and slum population density. Results: Overall PCR positivity was 3.4% during non-outbreak periods, rising to 23.2% and 42.8% during the Aleph (June-November 2020) and Omicron waves (January 2022), respectively, but only 9.9% during the Delta wave (March-June 2021). The community-level median Ct values fell and rose ~7-14 days prior to PCR positivity rates. Viral loads were 4-fold higher during the Delta and Omicron waves than during non-outbreak months. The Delta wave had high viral loads at older ages, in women and in areas of higher slum density. During the Omicron wave, differences in viral load by sex and for slum density had disappeared, but older adults continued to show higher viral load. Conclusions: Mumbai’s viral waves had markedly high viral loads representing an early signal of pandemic trajectory. Continue the vaccination in elderly Indians could reduce viral load in subsequent waves. Ct values are practicable monitoring tools.

The worldwide prevalence of type 2 diabetes (T2D) and prediabetes is rapidly increasing, particularly in children, adolescents, and young adults. Oxidative stress (OxS) has emerged as a likely initiating factor in T2D. The role of natural antioxidant products in combating T2D is best evaluated in the context of the complex physiological processes that modulate T2D-OxS such as glycemic control and exercise. The role of natural antioxidant compounds such as vitamin E in T2D must likewise be considered beyond their roles as inhibitors of OxS. In addition to antioxidant properties, vitamin E vitamers (tocopherols and tocotrienols) also exhibit distinct abilities to regulate cellular signal transduction pathways important to T2D progression. Most research on the role of vitamin E in T2D or prediabetes has been limited to tocopherols (Ts) but emerging trials with tocotrienols (T3s) show promise. Minimizing factors that induce chronic damaging OxS and maximizing natural antioxidant protective factors may provide a means of preventing or slowing T2D progression. This “optimal redox” (OptRedox) approach also provides a framework in which to discuss the potential benefits of natural antioxidant factors such as antioxidant products. Since early, effective intervention is critical, the OptRedox strategy would be optimally effective if implemented in the pediatric population.

In French Polynesia, Wuhan, Delta and Omicron SARS-CoV-2 variants-of-concern (VOCs) caused epidemics with variable severities. We assessed the prevalence and titers of anti-SARS-CoV-2 antibodies related to natural infection and/or vaccination, from a representative sample (N=673) of the adult population of Tahiti recruited during November-December 2021 (after the Delta outbreak and just before the Omicron epidemic). Of the 673 participants tested, 644 (95.7%) had detectable antibodies against SARS-CoV-2-S and/or -N proteins resulting from natural infection and/or vaccination, and 388 (57.7%) were positive only for the detection of anti-N antibodies indicating natural infection. SARS-CoV-2 seroprevalence extrapolated to the adult population of Tahiti was estimated at 95.9%. Concentrations of anti-SARS-CoV-2-S antibodies significantly increased with age, number of self-reported SARS-CoV-2 infections (0 or ≥1), and number of COVID-19 vaccine doses (0, 1, 2, or 3) received by the participants. Elderly people, who are at higher risk of severe outcomes, had received more vaccine doses than younger individuals both in our sample and in the general population. The high level of antibody responses related to past infections and vaccination, especially booster doses, has likely contributed to reducing the severity of the Omicron outbreak in French Polynesia.

(Background) the aim was to determine related factors to recurrent vitreous hemorrhage (RVH) in a sample of proliferative diabetic retinopathy (PDR) patients. (Methods) A retrospective, review-based study. We studied 183 eyes from 121 type 2 diabetes patients with PDR. We recorded diabetes duration, history of hypertension, retinal photocoagulation status, the posterior vitreous status, the mean HbA1c, mean hemoglobin, the renal function, and the systemic complications related to diabetes. We also recorded the use of ranibizumab prior to vitrectomy and the following surgical variables: the application of segmentation and diathermy on fibrovascular proliferative tissue, the use of silicone oil, and the occurrence of surgical complications, to study which independent variables were significantly related to the presence of RVH. (Results) Duration of diabetes (P= 0.028), hemoglobin (P=0.02), status of the posterior vitreous (P=0.03), retinal photocoagulation (P=0.002) and use of segmentation surgery technique (P=0.003) have significant link to the presence of RVH. In addition, patients with diabetic polyneuropathy, myocardial infarction and ischemia in lower limbs had more vitreous hemorrhage events (p&lt;0.001). (Conclusions) Patients with PDR and with longer diabetes duration, anemia, attached posterior vitreous, deficient retinal photocoagulation, and previously cardiovascular events, were more prone to RVH.

Background and Objectives: Most individuals infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are asymptomatic or have mild symptoms of COVID-19, which usually resolve after few days. Regardless of symptoms, infected people can transmit the virus to others especially on the first days of infection. Quantitative reverse transcription-polymerase chain reaction (RT-qPCR) is used to confirm SARS-CoV-2 infection; some individuals show persistent PCR-positivity after recovering from COVID-19. In this study, 12 individuals who showed persistence of COVID-19 symptoms and of SARS-CoV-2 PCR-positivity were followed-up. Methods: nasopharyngeal samples were collected for SARS-CoV-2 detection by RT-qPCR; clinical and epidemiological data were analyzed. Results: that persistence of SARS-CoV-2 PCR positivity was associated with duration of symptoms (r_s 0.81338), which varied between one and 49 days, with 75% of the individuals reporting symptoms for more than two weeks; 83.33% of cases remained positive after two weeks of onset of symptoms, despite decreases in viral load. Conclusion: neither RT-qPCR test nor a symptom-based approach alone are sufficient to evaluate discontinuation of patient isolation; other factors such as viral loads and symptom severity should also be considered. Additional studies are needed to understand how RT-PCR-positivity is related to symptoms and the risk of viral transmission, and to better support isolation guidelines.

Cervical cancer is the fourth most common type of cancer in the world that causes death in women. It is mainly caused by persistent infection by human papillomavirus (HPV) that triggers a chronic inflammatory process. Therefore, the use of anti-inflammatory drugs is a potential treatment option. The effects of piperine, an amino alkaloid derived from Piper nigrum, are poorly understood in cervical cancer inflammation, making it a target of research. This work aimed to investigate the antitumor effect of piperine on cervical cancer and to determine whether this effect is modulated by the cyclooxygenase 2 (PTGS2) pathway using in vitro model of cervical cancer (HeLa, SiHa, CaSki), and non-tumoral (HaCaT) cell lines. The results showed that, piperine reduces in vitro parameters associated with neoplastic evolution such proliferation, viability and migration by cell cycle arrest in the G1/G0 and G2/M phases, with subsequent induction of apoptosis. This action was modulated by downregulated of cyclooxygenase 2 (PTGS2) pathway, which in turn regulates the secretion of cytokines and the expression of mitogen activated protein kinases (MAPKs), metalloproteinases (MMPs), and their antagonists (TIMPs). These findings indicate the phytotherapeutic potential of piperine as complementary treatment in cervical cancer.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chemical phenotypes are frequently discovered in natural goods. In the current study, we used a fluorogenic assay to test a variety of natural products for their ability to inhibit SARS-CoV-2 Mpro. Several compounds were discovered to inhibit the Mpro at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 Mpro, and the X-ray structure revealed covalent interaction with the protease's catalytic Cys145 site. Selected potent molecules also exhibited antiviral properties without cytotoxicity. Some of these powerful inhibitors might be utilized as lead compounds for COVID-19 research.

The global threat of COVID-19 has led to the increasing use of metabolomics to study SARS-CoV-2 infection in humans and animals. Despite this, understanding SARS-CoV-2's metabolome during infection remains difficult and incomplete. Here, metabolic responses were characterized from sampled nasal washes collected from an asymptomatic ferret model (n = 20) at different time points before and after the SARS-CoV-2 challenge using an LC-MS-based metabolomics approach. Multivariate analysis of the nasal wash metabolome data resulted in several statistically significant features being observed. Despite no effects of gender or interaction between gender and time on the time course of SARS-CoV-2 infection, 16 metabolites were significantly different at every time point post-infection. Among these altered metabolites, the relative abundance of taurine was elevated post infection which could be an indication of hepatotoxicity, while the accumulation of sialic acids could indicate SARS-CoV-2 invasion. The pathway analysis identified several pathways influenced by SARS-CoV-2 infection. Of these, sugar, glycan, and amino acid metabolisms were the key altered pathways in the upper respiratory channel during infection. These findings provide some new insights into the progression of SARS-CoV-2 infection in ferrets at the metabolic level which could be useful for the development of early clinical diagnosis tools and new or repurposed drug therapies.

The COVID-19 pandemic has highlighted the importance and urgent need of rapid and accurate diagnostic tests for detection and screening of this infection. In our proposal, a biosensor based on the ELISA immunoassay was developed for monitoring antibodies against SARS-CoV-2 in human serum samples. The SARS-CoV-2 nucleocapsid protein (N-protein) was selected as a specific receptor for the detection of SARS-CoV-2 nucleocapsid immunoglobulin G. Thus, the N-protein was immobilized on surface of screen-printed carbon electrode (SPCE) modified with carboxylated graphene (CG). The IgG-SARS-CoV-2 nucleocapsid concentration was quantified using a secondary antibody labelled with horseradish peroxidase (HRP) (anti-IgG-HRP) catalyzed by 3,3’,5,5’-tetramethylbenzidine (TMB) mediator by chronoamperometry. A linear response was obtained in the range of 1:1000-1:200 v/v in phosphate buffer solution (PBS) and the limit of detection calculated was of 1:4947 v/v. The chronoamperometric method showed electrical signals directly proportional to antibody concentrations due to Ag-Ab specific and stable binding reaction.

Since the discovery of mitochondrial-derived peptides (MDP), their participation in cellular metabolism is no longer considered as the sole function of the mitochondria, but importance was also attached to its role as a source of protective factors of metabolic stress. These peptides are encoded in the mitochondrial genome and translated into the mitochondria or cytoplasm, to signal within the cell or be released and bind to membrane receptors. The objective of this work was explored and compare the frequency of MT-RNR1 and MT-RNR2 variants in sequences obtained from T2D individuals and control population. 213 different mitochondrial polymorphisms previously reported in the literature associated with T2D and cardiovascular diseases were analyzed. We can found three variants in the MT-RNR1 not related with MOTS-c coding sequence: m.1189T>C (rs28358571), m.1420T>C (rs111033356), and m.1438A>G (rs2001030); and secondly, three polymorphisms associated to MT-RNR2 m.2667T>C (rs878870626) related to humanin, m.1811A>G (rs28358576) in SHPL3 and m.3027T>C (rs199838004) in SHPL6 associated with statistical differences between the T2D and control group. All these findings were previously related to cardiovascular complications in literature and, as far as we know, relating for the first time in diabetic patients.

Numerous proteomic and transcriptomic studies have been carried out to better understand the current multi-variant SARS-CoV-2 virus mechanisms of action and effects. However, they are mostly centered on mRNAs and proteins. The effect of the virus on human post-transcriptional regulatory agents such as microRNAs (miRNAs) involved in the regulation of 60% of human gene activity remains poorly explored. Similar to what we have previously done with other viruses such as Ebola and HIV, in this study we investigated the miRNA profile of lung epithelial cells following infection with SARS-CoV-2. At the 24 and 72 hours post-infection, SARS-CoV-2 did not drastically alter the miRNome. About 90% of the miRNAs remained non-differentially expressed. The results revealed that miR-1246, miR-1290 and miR-4728-5p were the most upregulated over time. miR-196b-5p and miR-196a-5p were the most downregulated at 24 h while at 72 h, miR-3924, miR-30e-5p and miR-145-3p showed the highest level of downregulation. In the top significantly enriched KEGG pathways of genes targeted by differentially expressed miRNAs we found, among others, MAPK, RAS, P13K-Akt and renin secretion signaling pathways. By RT-qPCR, we also showed that SARS-CoV-2 may regulate several predicted host mRNA targets involved in the entry of the virus into host cells (ACE2, TMPRSS2, ADAM17 and FURIN), in renin–angiotensin system (RAS) (Renin, Angiotensinogen, ACE), innate immune response (IL-6, IFN1β, CXCL10, SOCS4) and fundamental cellular processes (AKT, NOTCH, WNT). Finally, we demonstrated by dual luciferase assay a direct interaction between miR-1246 and ACE-2 mRNA. This study highlights the modulatory role of miRNAs in the pathogenesis of SARS-CoV-2.

The main functions of the automated systems rely on the advanced sensors for detection and perception of the environment around the vehicle. Radars and cameras are commonly utilized to detect the potential obstacles and vehicles ahead on the road. Nevertheless, cameras can generate spurious detections in the extreme weather conditions such as fog, rain, dust, snow, dark, and heavy sunlight in the sky. Due to limitations in vertical field view of the radars, single radars are not reliable to detect the height of the targets precisely. In this paper, a triple radar arrangement (long-range, medium-range, and short-range radars) based on sensor fusion technique is proposed to detect objects with different size in level 2 Advanced Driver-Assistance (ADAS) system. The typical objects including truck, pedestrians, and animals are detected in different scenarios. The developed model considered ISO 26262 and ISO/PAS 21448 to reasonably address insufficient robustness and inability of the sensors. The models of sensor and level 2 ADAS systems are developed using MATLAB toolbox and Simulink. Sensor detection performance is determined by running simulations with triple radar setup. Obtained results demonstrate that the proposed approach generates accurate detections of targets in all tested scenarios.

Rapid SARS-CoV-2 self-tests have the potential to expand access to COVID-19 testing and improve community-level case detection, particularly in resource-constrained countries such as Kenya. However, prior to their introduction, their acceptability must be assessed. This qualitative study explored key decision-takers’ values towards SARS-CoV-2 self-testing in Kenya. Healthcare workers, representatives of civil society, and potential implementors from Mombasa and Taita-Taveta were selected as decision-takers. Semi-structured interviews and focus group discussions were used to collect data on their values towards self-testing. A thematic analysis approach was applied. Most informants considered that the Kenyan public is equipped to accept and use self-testing safely as an approach to help to reduce workload at public healthcare facilities, and know one’s COVID-19 status in a private manner. The informants emphasized the need to provide counselling to end-users, to support those needing to self-isolate, and to engage different civil society stakeholders in information provision on self-testing. Fear of stigma and of forced isolation were noted as potential deterrents to self-testing uptake for some individuals. In conclusion, there is high acceptability of self-testing in Kenya among decision-takers. However, enhanced education, counselling, and addressing deterrents to testing would be helpful to ensure effective use of SARS-CoV-2 self-testing in Kenya.