The emergence of mRNA vaccines represents a significant advancement in public health by conferring protection against a variety of infectious diseases. However, concerns regarding the potential risk of inducing or exacerbating autoimmune disorders, particularly connective tissue diseases (CTDs), have arisen. This paper explores the mechanisms by which mRNA vaccines may lead to the onset or worsening of CTDs, focusing on the immune responses induced by Pathogen-Associated Molecular Patterns (PAMPs), the interactions between Toll-like receptors 7/8 and 9 (TLR7/8 and TLR9), and the activation of self-reactive B cells. Furthermore, guidelines are suggested for administering vaccines to individuals at elevated risk, such as those with a positive antinuclear antibody (ANA) test or specific rheumatic disease genes. Our findings underscore the necessity for targeted vaccination strategies that mitigate risks while maintaining public health efficacy.

This review highlights the potential and limitations of mRNA vaccines with a particular focus on mucosal delivery as an alternative to parenteral administration. The strengths of mRNA vaccines are: a) Versatility: they can be adapted to target a wide range of pathogens; b) Faster development: designed and produced more quickly than traditional vaccines; c) High efficacy: effective in preventing severe disease, as demonstrated during the COVID-19 pandemic. Current challenges: a) Delivery: current methods (mainly intramuscular injection) may not be optimal for inducing mucosal immunity; b) Stability: mRNA is fragile and needs to be protected from degradation; c) Safety: potential side effects, including myocarditis, blood clotting, allergic reactions need further investigation. Mucosal delivery could be more effective in preventing the transmission of pathogens and is generally better accepted by the population. Pros: offers the potential to induce local immunity at the site of pathogen entry, potentially providing broader protection; Cons: developing effective delivery systems and adjuvants for mucosal delivery is difficult. Extracellular vesicles as a mucosal delivery system are promising and offer a potentially safe, scalable, and needle-free approach. Future directions: a) Optimizing mRNA constructs: strategies like codon optimization and self-amplifying RNA can improve stability and translation efficiency; b) Rigorous pre-clinical studies are essential before human trials.

Each injection of any known vaccine results in a strong expression of pro-inflammatory cytokines. This is the result of the innate immune system activation, without which no adaptive response to the injection of vaccines is possible. COVID-19 mRNA vaccines would not escape this rule. Unfortunately, the degree of inflammation produced by these vaccines is variable, probably depending on the genetic background and previous immune experiences, which through epigenetic modifications, could have made the innate immune system of each individual tolerant or reactive to subsequent immune stimulations.We hypothesize that we can move from a limited pro-inflammatory condition to conditions of increasing expression of pro-inflammatory cytokines that can culminate in multisystem hyperinflammatory syndromes following COVID-19 mRNA vaccines (MIS-V). We have graphically represented this idea in a hypothetical inflammatory pyramid (IP) and we have correlated the time factor to the degree of inflammation produced after the injection of vaccines. Furthermore, we have placed the clinical manifestations within this hypothetical IP, correlating them to the degree of inflammation produced. Surprisingly, excluding the possible presence of an early MIS-V, the time factor and the complexity of clinical manifestations are correlated to the increasing degree of inflammation: symptoms, heart disease and syndromes (MIS-V).

The COVID-19 pandemic, caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), is in its 5th year and is being maintained by the inability of current spike-alone based COVID-19 vaccines to prevent transmission leading to the continuous emergence of variants and sub-variants of concern (VOCs). This underscores the critical need for next-generation broad-spectrum pan-Coronavirus vaccines (pan-CoV vaccine) to break this cycle and end the pandemic. The development of a pan-CoV vaccine offering protection against a wide array of VOCs requires two key elements: (1) identifying protective antigens that are highly conserved between passed, current and future VOCs; and (2) developing a safe and efficient antigens deliver system for induction of broad-based B- and T-cell immunity. This review will (1) present the current state of antigen delivery platforms involving a multifaceted approach, including bioinformatics, molecular and structural biology, immunology, and advanced computational methods; (2) discuss the challenges facing development of safe and effective antigen delivery platforms; and (3) highlight the potential of nucleoside-modified mRNA encapsulated in lipid nanoparticles (LNP) as the platform that is well suited to the needs of a next-generation pan-CoV vaccine, such as the ability to induce broad-based immunity and amenable to large-scale manufacturing to safely provide durable protective immunity against current and future Coronavirus threats.

In the recent days, lipid nanoparticles have been successfully emerged as one of the most advanced technology for highly efficient in vivo delivery of exogenous mRNA, especially for delivery of COVID-19 vaccines. For the vaccines to be successful or protective, they require highly efficient mRNA delivery systems. However, developing effective, translatable vaccines with better safety against some of the SARS‐CoV‐2 variants is still a challenge. Lipid nanoparticles (LNPs) are composed of four different types of lipids including ionizable lipids, helper or neutral lipids, cholesterol and polyethylene glycol (PEG) attached lipids. In this review, we present recent advancements and insights in designing the advanced LNPs and their composition and properties, with a subsequent discussion on the development of COVID-19 vaccines. In particular, as the ionizable lipids are most important drivers for complexing the mRNA and in vivo delivery, the role of ionizable lipids in mRNA vaccines discussed in detail. Furthermore, the use of LNPs as effective delivery vehicles for vaccination, genome editing, and protein replacement therapy were discussed. Finally, expert opinion of LNPs for mRNA vaccines were discussed which might address the future challenges in the development of mRNA vaccines employing highly efficient LNPs using novel set of ionizable lipids.

ABSTRACT. In this paper, we suggest a biomathematical numerical method for analysing mRNA nucleotides sequences based on UA/CG Fibonacci numbers proportions. This method is used to evaluate then compare the spike genes related to the main SARS-CoV2 VARIANTS currently circulating within the world population. The 10 main results proposed to be reproduced by peers are: 1/ SARS-CoV2 genome and spike evolution in one year 2020-2021. 2/ SARS-CoV2 Origins. 3/ Comparing 11 reference variants spikes. 4/ analysing 32 CAL.20C California variant patients spikes. 5/ Toward a meta mRNA Fibonacci gene end message code. 6/ Analysing S501 UK, S484 South Africa and « 2 mutations » INDIA variants. 7/ Suggesting a possible variants spike mRNA palindrome symmetry metastructure improving mRNA stability then infectiousness. 8/ Analysing Fibonacci Metastructures in the mRNA coding for the vaccines PFIZER and MODERNA. 9/ Does the CG-rich modification of the synonymous codons of the spikes of the 2 mRNA vaccines affect the expression and quantity of SARS-CoV2 antibodies? 10/ The exceptional case of the Brazilian variant P.1. Particularly, we suggest the following conjecture at mRNA folding level : CONJECTURE of SARS-CoV2 VARIANTS: The growth of long Fibonacci structures in the shape of "podiums" for almost all of the variants studied (UK, California, South Africa, India, etc.) suggests the probable folding of the Spike mRNA in the form of a "hairpin", which can strengthen the cohesion and the lifespan of this mRNA. Finally, we show that these kinds of Fibonacci matastructures disapear TOTALLY by analysing the published mRNA sequences of PFIZER and MODERNA vaccines. One fact is certain, the two mRNAs of the Moderna and Pfizer vaccines will result in a low functionality of the spike vaccine. This is because their designers by seeking greater stability, have doped to build CG rich sequences which, as soon as they are inserted into the human host, will, paradoxically, seek to mutate, like SARS-CoV2 variants, towards CG ==> UA forms in order to improve their STABILITY and LIFETIME. We conclude using new biomathematics theoretical methods (Master code and numerical standing waves), and comparing the Spikes of the two vaccines Moderna and Pfizer, that there will be very probable differences in stability and shelf life of the two respective mRNAs vaccines. However, “State of the Art” analyzes will disclose that their two protein sequences are strictly identical. By modified their synonymous codons using different strategies, no one can guarantee that the quantity of antibodies generated will be identical in the two cases. We wish to draw attention to the great ADAPTATION power - at the global scale of their genomes - of the most infectious VARIANTS, such as the BRAZIL 20J / 501Y.V3 variant (P.1). This is very worrying for the VACCINES <==> VARIANTS run: We demonstrate how the Brazilian variant P.1 which becomes uncontrollable in Brazil in April 2021 has a level of organization of long metastructures of 17,711 bases covering the genome which is 3.6 more important than that of the 2 reference genomes SARS-CoV2 and worldwide D614G. We suggest that this high level of overall structure of this variant contributes to the stability of this genome and, might explain its greater contagiousness.

In the last decades, technological advances related to RNA manipulation enabled and expanded its application in vaccine development. This approach comprises synthetic single-stranded mRNA molecules that direct the translation of the antigen responsible for activating the desired immune response. The success of RNA vaccines depends on the delivery vehicle employed. Among the systems, yeasts emerge as a new approach to a natural delivery platform. The presence of β-glucans and mannans in its wall is responsible for the adjuvant action of this system. Yeasts are already employed to deliver protein antigens, with success and efficacy demonstrated through pre-clinical and clinical trials. Yeast β-glucan capsules, microparticles, and nanoparticles are capable of modulating host immune responses and have a high capacity to carry RNA and small molecules, with bioavailability upon oral immunization and with targeting to receptors present in anti-gen-presenting cells (APCs). Besides, yeasts are interesting vehicles for the protection and specific delivery of therapeutic vaccines based on shRNA or dsRNA. In this review, we present an overview of the attributes of yeast or its derivatives for the delivery of RNA-based vaccines, discussing their current challenges and prospects for using this promising strategy.

Circular RNA (circRNA) vaccines are emerging as a revolutionary strategy in cancer immunotherapy, offering novel mechanisms for inducing robust and durable immune responses. Unlike traditional linear mRNA vaccines, circRNAs exhibit exceptional stability, enhanced translational efficiency, and resistance to exonuclease degradation, making them ideal candidates for vaccine development. This review delves into the fundamental principles underlying circRNA biology, highlighting their unique structural advantages and translational potential. We examine recent advancements in circRNA vaccine design, focusing on their application in oncology. As the circRNA-based cancer vaccine is a relatively novel approach, accounts of all the major studies describing the efficacy have been discussed. To maximize the anti-cancer effects of circRNA vaccines, we also investigate their combination with other immunotherapeutic modalities such as immune checkpoint inhibitors and adoptive cell therapies. Large-scale manufacturing, immunogenicity optimization, delivery systems, and other challenges and future directions in the sector are also discussed. This study aims to thoroughly analyse the state-of-the-art and potential future applications of circRNA vaccines in cancer immunotherapy, highlighting them as exciting possibilities for next-generation cancer therapies.

With its unique properties and potential applications, nanoparticle-based delivery platforms for vac-cines have gained significant attention in recent years. Nanoparticles have the advantages of enhancing immunogenicity, targeting delivery and improving stability, providing a new solution for drug and vaccine delivery. And in some clinical studies, a variety of nanoparticle delivery platforms have been gradually applied to a wide range of vaccine applications. Current research priorities are exploring various types of nanoparticles as vaccine delivery system to enhance vaccine stability and immunogen-icity. Lipid nanoparticles have shown promising potential in preclinical and clinical studies to efficiently deliver antigens to immune cells. Moreover, lipid nanoparticles (LNPs) and other nanoparticles as nu-cleic acids especially mRNA delivery system, have shown vast potential for vaccine development. In this review, we present various vaccine platforms with an emphasis on nanoparticles for mRNA nano-vaccine delivery vehicles. We introduce several novel nanoparticles delivery platforms for mRNA vac-cine such as lipid, polymer, protein-based nanoparticle and so on. In addition, we overview the an-ti-tumor immunity of nanovaccine against different tumors in cancer immunotherapy. Finally, we give an outlook future perspectives and remaining challenges for this promising technolo-gy-nanoparticle-based delivery platforms for vaccines.

Lipid nanoparticles (LNPs) have attracted extensive attention in tumor immunotherapy in recent years. The strategy of targeting immune cells in cancer therapy has become a research area of great interest. mRNA vaccines are a potential choice for tumor immunotherapy due to their ability to directly encode antigen proteins and stimulate a strong immune response. However, the mode of delivery and lack of stability of mRNA are key issues limiting its application. LNPs are an excellent mRNA delivery vector, and their structural stability and biocompatibility make them an effective means to deliver mRNA to specific targets. This study summarizes the research progress in LNP delivery vector-assisted targeted controlled release mRNA vaccines in tumor immunity. The role of LNPs in improving mRNA stability, immunogenicity and targeting is discussed. In addition, combined with the cutting-edge research results, the potential mechanisms and application prospects of LNP-mRNA vaccines in tumor immunotherapy were further analyzed. This review aims to systematically summarize the latest research progress in LNP delivery carrier-assisted targeted controlled-release mRNA vaccines in tumor immunity to provide new ideas and strategies for tumor immunotherapy and provide more effective treatment plans for patients.

The new class of mRNA vaccines is studied extensively, leading to many novel prospects based on the pivotal success of vaccines against the SARS-Cov-2 virus. Many novel mechanisms of immune response discovered have led to the possibility of mutation-resistant vaccines by combining multiple conserved epitopes as antigens to manipulate the T-cell and B-cell responses; these antigens can also come from different organisms, providing protection against numerous diseases and of most tremendous significance is the utility of mRNA vaccines in preventing and treating more than 100 autoimmune disorders. This is a significant humanitarian breakthrough given the ease and faster and low cost of mRNA vaccines, being a chemical entity. This paper provides a prospective analysis of mRNA vaccines with much broader applications than anticipated when these vaccines entered treating SARS-Cov-2 infections.

Pharmacovigilance databases are showing evidence of injury in the context of the COVID-19 modified mRNA shots. According to recent publications, adverse event reports linked to the mRNA COVID-19 products largely point to the spike protein as an aetiological agent of adverse events, but we propose that the platform itself may be culpable. To assess the safety of current and future mRNA vaccines, further analysis on the risks due to the platform itself, and not specifically the expressed antigen. If harm can be exclusively and conclusively attributed to the spike protein, then it is possible that future mRNA vaccines expressing other antigens will be safe. If harms are attributable to the platform itself, then regardless of the toxicity, or lack thereof, of the chosen payload therein, the platform may be inherently unsafe, pending modification. In this work, we examine previous studies of RNA-based delivery by a lipid nanoparticle and break down the possible etiological elements of harm.

Human rotavirus (HRV) is still a leading cause of severe dehydrating gastroenteritis globally, particularly in infants and children. Previously, we demonstrated immunogenicity of mRNA-based HRV vaccine candidates expressing the viral spike protein VP8* in rodent models. In the present study, we assessed the immunogenicity and protective efficacy of two mRNA-based HRV trivalent vaccine candidates, encoding VP8* of the genotypes P[8], P[6] or P[4], in the gnotobiotic (Gn) pig model of Wa (G1P[8]) HRV infection and diarrhea. Vaccines either encoded VP8* alone fused to the universal T cell epitope P2 (P2-VP8*) or expressed P2-VP8* as a fusion protein with lumazine synthase (LS-P2-VP8*) to allow the formation and secretion of protein particles that present VP8* on their surface. Gn pigs were randomly assigned into groups and immunized three times with either P2-VP8* (30 µg) or LS-P2-VP8* (30 µg or 12 µg). A trivalent alum-adjuvanted P2-VP8* protein vaccine or an LNP-formulated irrelevant mRNA vaccine served as positive and negative control, respectively. Upon challenge with virulent Wa HRV, significantly shortened duration and decreased severity of diarrhea and significant protection from virus shedding was induced by both mRNA vaccine candidates compared to the negative control. Both LS-P2-VP8* doses induced significantly higher VP8*-specific IgG antibody titers in the serum after immunizations than the negative as well as the protein control. The P[8] VP8*-specific IgG anti-body-secreting cells in ileum, spleen and blood seven days post-challenge as well as VP8*-specific IFN--producing T cell numbers increased in all three mRNA-vaccinated pig groups compared to the negative control. Overall, there was a clear tendency towards improved responses in LS-P2-VP8* compared to P2-VP8*mRNA vaccine. The demonstrated strong humoral immune responses, priming for effector T cells, and significant reduction of viral shedding and duration of diarrhea in Gn pigs provide a promising proof of concept and may provide guidance for further development of mRNA-based rotavirus vaccines.

Infection with Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) causes Coronavirus Disease 2019 (COVID-19), which has reached pandemic proportions. A number of effective vaccines have been produced, including mRNA vaccines and viral vector vaccines, which are now being implemented on a large scale in order to control the pandemic. The mRNA vaccines are composed of the Spike S1 protein encoding mRNA, incorporated in a lipid nanoparticle, stabilized by polyethylene glycol (PEG). mRNA vaccines are novel in many respects, including cellular uptake, the intracellular routing, processing, and secretion of the viral protein. Viral vector vaccines have incorporated DNA sequences encoding the SARS-CoV-2 Spike S1 protein into (attenuated) adenoviruses. The antigen presentation routes in MHC class I and class II, in relation to induction of virus neutralizing antibodies and cytotoxic T-lymphocytes will be reviewed. In rare cases, mRNA vaccines induce unwanted immune mediated side effects. mRNA based vaccines may lead to an anaphylactic reaction. This reaction may be triggered by PEG. The intracellular routing of PEG, and potential presentation in the context of CD1 will be discussed. Adenovirus vector based vaccines have been associated with thrombocytopenic thrombosis events. The anti-platelet factor 4 antibodies found in these patients could be generated due to conformational changes of relevant epitopes presented to the immune system.

Pancreatic cancer, one of the deadliest cancers worldwide, necessitates improved therapeutics due to its low survival rate (12% in 5 years) and typically late-stage diagnosis [1]. This malignancy tends to present asymptomatically until advanced stages, leading to high rates of metastasis and limiting surgical options [2]. Genetic mutations in key genes like KRAS, CDKN2A, TP53, and SMAD4 are central to pancreatic cancer pathogenesis, driving uncontrolled cell proliferation and making treatment difficult [3]. Current treatment modalities include surgery, chemotherapy, radiation, and emerging immunotherapies. Surgery, particularly the Whipple procedure, offers the only potential cure but is applicable in just 15-20% of cases due to the late diagnosis [4]. Chemotherapy, though commonly used, offers limited long-term survival benefits [5]. Radiation therapy has seen advancements with techniques like stereotactic body radiation therapy (SBRT), which shows promise in reducing toxicity and improving outcomes [6] . Immunotherapy, particularly mRNA vaccines, has demonstrated potential in prolonging recurrence-free survival (>18 months), especially when combined with traditional therapies (13.4 months with surgical resection alone) [7] . Combinations of different treatments have been found to be effective. The challenge of early pancreatic cancer diagnosis mirrors the difficulty of disease management. Prophylactic immunotherapies, like vaccines, could offer a crucial breakthrough for prevention and recurrence reduction. As pancreatic cancer remains difficult to treat effectively, continued research and development in preventative and therapeutic strategies are essential to improving outcomes.

The emergence of mRNA vaccines for SARS-CoV-2 has opened a new page in vaccine development; nevertheless, concerns of the experts have been expressed about unintentional side effects on the gut microbiota (GM). Previous studies showed that this virus acts as a bacteriophage, which infects and destroys specific bacterial strains in the GM. The present manuscript hypothesizes that the synthetic spike protein could create changes in the composition and the functioning of the GM by entering the intestinal cells after vaccination and impairing the symbiotic relationship between intestinal cells and the GM. An experimental protocol to test the hypothesis is suggested.

Due to the health crisis caused by SARS-CoV-2, the creation of a new vaccine platform based on mRNA was implemented. Globally, around 13.32 billion COVID-19 vaccine doses of diverse platforms have been given, and up to this date, 69.7% of the total population received at least one injection of a COVID-19 vaccine. Although these vaccines prevent hospitalization and severe forms of the disease, increasing evidence has shown they do not produce sterilizing immunity, allowing people to suffer frequent re-infections. Recent research has also raised concerns that mRNA vaccines could induce immune tolerance, which, added to that caused by the virus itself, could complicate the clinical course of a COVID-19 infection. Furthermore, recent investigations have found high IgG4 levels in people who were administered two or more injections of mRNA vaccines. It has been suggested that an increase in IgG4 levels could have a protecting role by preventing immune over-activation, similar to that occurring during successful allergen-specific immunotherapy by inhibiting IgE-induced effects. Altogether, evidence suggests that the reported increase in the IgG4 levels detected after repeated vaccination with the mRNA vaccines is not a protective mechanism; rather, it may be a part of the immune tolerance mechanism to the spike protein that could promote unopposed SARS-CoV2 infection and replication by suppressing natural antiviral responses. IgG4-induced suppression of the immune system due to repeated vaccination can also cause autoimmune diseases, promotes cancer growth, and autoimmune myocarditis in susceptible individuals.

This prospective cohort study aimed to evaluate the efficacy of COVID-19 vaccine schemes, ho-mologous versus heterologous vaccine strategies, and vaccine-induced anti-S-RBD-IgG antibody response in preventing COVID-19 among 942 healthcare workers one year after vaccination with the inactivated and/or mRNA vaccines. All participants received the first two primary doses of vaccines, 13.6% of them lacked the dose-3, 50.5% the dose-4, and 90.3% the dose-5. Antibody lev-els increased with the increase in number of vaccine doses and also in heterologous vaccine regi-mens. In both inactive and mRNA vaccines, infection rates were significantly higher in 2-dose-receivers, but lower in 4- or 5-dose receivers and increasing the total number of vaccine doses resulted in more protection against infection: the 3-dose regimen yielded 4.71 times more protection, the 4-dose 11.76 times and 5-dose 38.46 times more protection from COVID-19 infec-tion, compared to any 2-dose vaccination regimens. Antibody levels at the end of the first year of 4- or 5-dose-receivers were significantly higher than 2- or 3-dose-receivers. To conclude; increased number of total vaccine doses and anti-S-RBD antibody levels increased the protection from COVID-19 infection. Therefore, four or more doses are recommended in one year, for effective protection, especially in risk groups.

Since the beginning of the mass immunization with COVID-19 vaccines of patients with multiple sclerosis, many data on the efficacy and safety of these vaccines have been produced. Considering that MS is an autoimmune disease whose pathology can be explained by an altered immune system and that some DMTs seem to be able to decrease the antibody response against COVID-19 vaccines, we carried out this retrospective study with the aim to evaluate the safety in terms of AEFIs occurrence and the antibody response after the third dose of COVID-19 vaccines in people with MS. Third doses were administered from October 2021 to January 2022. Two hundred and ten patients (64.8% female; mean age: 46 years) received the third dose of the mRNA-based COVID-19 vaccine and were included in the study. The majority of patients (n=193) were diagnosed with RRMS and EDSS values were ≤3.0 in 72.4% of them. DMTs most commonly used by included patients were interferon Beta 1-a, dimethyl fumarate, natalizumab and fingolimod. Overall, 160 patients (68.8% female) experienced 294 AEFIs, of which about 90% were classified as short-term, while 9.2% were classified as long-term. The most commonly reported following the booster dose were pain at the injection site, flu-like symptoms, headache, fever and fatigue. Regarding the immune response, consistently with literature data, we found that patients receiving ocrelizumab and fingolimod had lower IgG titer than patients receiving other DMTs.

Mitochondria are dynamic organelles that can adjust and respond to different stimuli within a cell. This plastic ability allows them to effectively coordinate several cellular functions in cells and becomes particularly relevant in highly complex cells such as neurons. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular function and ultimately to a range of diseases, including neurodegenerative disorders. Regulation of mRNA transport and local translation inside neurons is crucial for maintaining the proteome of distal mitochondria, which is vital for energy production and synaptic function. A significant portion of the axonal transcriptome is dedicated to mRNAs for mitochondrial proteins, emphasizing the importance of local translation in sustaining mitochondrial function in areas far from the cell body. In neurons, local translation and the regulation of mRNAs encoding mitochondrial-shaping proteins could be essential for synaptic plasticity and neuronal health. The dynamics of these mRNAs, including their transport and local translation, may influence the morphology and function of mitochondria, thereby affecting the overall energy status and responsiveness of synapses. Comprehending the mitochondria-related mRNAs regulation and local translation, as well as its influence on mitochondrial morphology near the synapses will help to better understand neuronal physiology and neurological diseases where mitochondrial dysfunction and impaired synaptic plasticity play a central role.

The cellular stress response corresponds to the molecular changes that cell undergoes in response to various environmental stimuli. It induces drastic changes in the regulation of gene expression, at transcriptional and post-transcriptional levels. Actually, translation is strongly affected with a blockade of the classical cap-dependent mechanism, whereas alternative mechanisms are activated to support translation of specific mRNAs. One of the major mechanisms involved in stress-activated translation is the internal ribosome entry site (IRES)-driven initiation. IRESs, first discovered in viral mRNAs, are present in cellular mRNAs coding for master regulators of cell responses, whose expression must be tightly controlled. IRESs allow translation of these mRNAs in response to different stresses, including DNA damage, amino-acid starvation, hypoxia or endoplasmic reticulum stress, as well as to physiological stimuli such as cell differentiation or synapse network formation. Importantly, cellular mRNA IRESs are regulated by IRES trans-acting factor (ITAFs), exerting their action by at least nine different mechanisms. This review presents an update of the reported ITAFs regulating cellular mRNA translation and of the different mechanisms allowing them to control translation initiation in specific conditions. The impact of ITAFs on coordinated expression of mRNA families and consequences in cell physiology and diseases are also highlighted.

High rates of phosphorus (P) currently being applied to soils for the production of vegetables in the Mekong Delta, Vietnam has led to the concern of its negative effect on the economics and the environment. This research presents a comprehensive study on the determination of P supplying capacity in this region of Vietnam to examine the possibility of reducing P fertilizer input. One hundred twenty (120) soil samples were collected to evaluate total P and Bray 1 available P in the soils. Phosphorus maximum sorption, degree of P saturation, P release, and the effect of P fertilizer on corn (Zea mays L.) yield in greenhouse and fields were also determined. Total P concentrations of 56.7% soil samples evaluated yielded high P concentrations (>560 mg P/kg), while 74.2% of the samples had high Bray 1 available P concentrations (>20 mg P/kg soil). Maximum P sorption ranged from 149 to 555 mg P/kg soil, respectively and has negative correlation to available P (r = - 0.63*), degrees of P saturation ranged from 0.63 to 5.46% correlated to available P (r = 0.98**) and maximum P release ranged from 1.2 to 61.9 mg P/kg soil, respectively correlated to available P (r = 0.96**). Corn grown in soils with available P concentrations >15 mg P/kg did not respond to P fertilizer in greenhouse or field experiments. We conclude that many farmers in this region can reduce P fertilizer input, thus increasing their profits and reducing negative environmental impacts associated with excess soil P for sustainable agriculture.

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

This is a case study of a 55-year-old patient who died four months after receiving the mRNA-vaccine BNT162b2 (Pfizer-BioNTech) against COVID-19 as a second dose, following an initial vaccination with the ChAdOx1 nCov-19 vector vaccine (AstraZeneca) two months earlier. The autopsy diagnosis revealed general atherosclerosis. The histopathologic analyses of cardiac tissue demonstrated the presence of a thrombus occluding the right coronary artery (RCA) without evidence of plaque rupture. As a substitute trigger of clotting, the RCA presented with characteristics of acute lymphocytic vasculitis that extended to vasa vasorum in the adventitia and vessels in adjacent adipose tissue. Microthrombi were occasionally detected in these small vessels. It was obvious that lymphocytic myocarditis had been a chronic ongoing process temporally distinct from acute myocardial infarction. The myocardium contained patchworks of fibrotic areas alongside foci of displaying acute inflammation and fresh myocyte damage. SARS-CoV-2 Spike protein, but not nucleocapsid protein was sporadically detected in vessel walls by immunohistochemical assay. The cause of death was determined to be acute myocardial infarction and lymphocytic myocarditis. These findings indicate that myocarditis, as well as thrombo-embolic events following injection of spike-inducing gene-based vaccines, are causally associated with a injurious immunological response to the encoded agent. Because of the fact that the immune response to a first gene-based vaccination is very low in comparison with the immune response to the second vaccination, the found adverse events has rather to be attributed to the mRNA-based second vaccination as to the initial vector-based one.

The current report represents a case of a 77-year-old man with Parkinson’s disease who died three weeks after receiving his third COVID-19 vaccination in January 2022. The patient was first vaccinated in May 2021 with the ChAdOx1 nCov- 19 vector vaccine, followed by two more doses with the BNT162b2 mRNA vaccine in July and December 2021. The family of the deceased requested an autopsy due to the ambivalent clinical features noted before death. The underlying illness (Parkinson’s disease) was confirmed by autopsy. However, no sign of a florid COVID-19 was discovered. Meanwhile, the immunohistochemical staining of the brain and heart revealed previously undiagnosed conditions. The brain, in distinctive, revealed multifocal necrotizing encephalitis with massive inflammatory lymphocyte infiltrates. In addition, the heart showed signs of serious myocarditis. Finally, immunohistochemical staining revealed that the SARS-CoV-2 spike protein was evident in the tissues investigated. Based on these immunohistochemical findings, it appears that the inflammatory changes in the patient's brain tissues are most likely the result of immunological processes. Concurrently, the absence of SARS-CoV-2 nucleocapsid-protein was evidenced, indicating that the detected spike-protein is unrelated to a SARS-CoV-2 infection. If such an infection was the cause of the spike protein, the SARS-CoV-2 nucleocapsid protein would also be detectable. As a consequence, the confirmed presence of the spike protein had to be attributed to the previous vaccination with the BNT162b2 mRNA vaccine that the deceased patient had received.

Orthostatic hypotension (OH) is a condition marked by a significant drop in blood pressure upon standing, resulting from impaired autonomic regulation of vascular tone and blood volume. This study investigates the prevalence, physiological mechanisms, and occupational risk factors for OH among high-risk professions in Nepal, such as traffic police, security guards, and shopkeepers. Using a cross-sectional design, participants were evaluated for blood pressure variability, autonomic function, and fluid balance. The findings reveal a high incidence of OH, linked to reduced baroreceptor sensitivity and impaired sympathetic activation due to prolonged standing and inadequate hydration. This study highlights the need for tailored clinical interventions and workplace modifications to mitigate OH in vulnerable occupational groups.

Sewage sludge is an organic waste generated in waste-water treatment plants with certain content of nutrients, what may potentially be used as a source of slow release fertilizer, especially as phosphorus (P) source, but it demands some pre-treatment and the content of P is much lower compared to soluble mineral fertilizers. For these reasons, composted sewage sludge was used to manufacture pelletized organomineral fertilizers, mixing it with the inorganic sources monoammonium phosphate (MAP) and AshDec® (ASD) (thermochemically incinerated sewage sludge). The fertilizers were physiochemically characterized and evaluated as to the dynamics of soil P solubilization, and the forms of P remaining according to its lability. The sources evaluated were: organic compost of sewage sludge powder (SSC), pelletized SSC (SCP), pelletized organominerals SSC+MAP (S+MAP) and SSC+ASD (S+ASD), ASD alone, all compared to a soluble mineral fertilizer (MAP), and a control without P fertilizer. A test was conducted in leaching columns with 50 g of soil (Oxisol), where the fertilizers were applied at a dose of 100 mg P/column, and 30 mL of water or 2% citric acid were added daily for 30 consecutive days. The collected leachates had pH measured and P content determined. Pelletizing process resulted in denser products and promoted more gradual P release. The organomineral S+MAP was the most water-soluble recycled source, solubilizing about 70% of the total P, while the others presented much lower solubilization (&lt;20%). In contrast, all fertilizers showed high solubility in 2% citric acid (except for S+ASD). After leaching, the greatest amount of P remaining in the soil as labile and moderately labile. Composting and the AshDec process produced materials with slow P solubilization, which would be favoured to solubilize in acidic soils and acidic rhizosphere conditions. In turn, the organomineral mixture of SSC with a highly soluble mineral fertilizer (MAP) resulted in a promising product with intermediate nutrient solubility, better synchronized with crop demand, thus increasing efficiency in P use.

A seroepidemiological study conducted from 2020 to 2022 in Guangzhou, China, aimed to evaluate varicella antibody levels. We measured varicella antibody concentrations using an enzyme-linked immunosorbent assay (ELISA) in a cohort of 3,300 subjects. The mean varicella IgG-specific antibody level was 171.2 mIU/mL (95% CI: 158.9, 184.4), with an overall positivity rate of 67.00% (95% CI: 65.37, 68.60). Varicella antibody levels were found to be influenced by age, vaccination dosage, and history of varicella infection. Notably, antibody concentrations increased with age and the number of vaccinations. Subjects with a vaccination history maintained positive antibody levels six years post-vaccination. We recommend two doses of the varicella vaccine for both children and adults. Before incorporating the varicella vaccine into Guangzhou's routine immunization programs, a comprehensive assessment of disease burden and the economic viability of vaccination strategies is essential.

mRNA vaccines have attracted widespread research attention with clear advantages in terms of molecular flexibility, rapid development, and potential for personalization. However, current mRNA vaccine platforms have not been optimized for induction of CD4/CD8 T cell responses. In addition, mucosal administration of mRNA based on lipid nanoparticle technology faces challenges in clinical translation. In contrast, adenovirus-based vaccines induce strong T-cell responses and have been approved for intranasal delivery. To leverage the inherent strengths of both the mRNA and adenovirus platforms, we developed a novel modular adenoviral mRNA delivery platform based on Tag/Catcher bioconjugation. Specifically, we engineered adenoviral vectors integrating Tag/Catcher proteins at specific locales on the Ad capsid proteins, allowing us to anchor mRNA to the surface of engineered Ad viruses. In proof-of-concept studies, the Ad-mRNA platform successfully mediated mRNA delivery and could be optimized via the highly flexible modular design of both the Ad-mRNA and protein bioconjugation systems.

Hospital-based programs democratize mRNA therapeutics by facilitating the processes to translate a novel RNA idea from the bench to the clinic. Because mRNA is essentially biological software, therapeutic RNA constructs can be rapidly developed. The generation of small batches of clinical grade mRNA to support IND applications and first-in-man clinical trials, as well as personalized mRNA therapeutics delivered at the point-of-care, is feasible at a modest scale of cGMP manufacturing. Advances in mRNA manufacturing science and innovations in mRNA biology, are increasing the scope of mRNA clinical applications.

In this paper, we introduce the (ρ,q)-analogue of the p-adic factorial function. By utilizing some properties of (ρ,q)-numbers, we obtain several new and interesting identities and formulas. We then construct the p-adic (ρ,q)-gamma function by means of the mentioned factorial function. We investigate several properties and relationships belonging to the foregoing gamma function, some of which are given for the case p = 2. We also derive more representations of the p-adic (ρ,q)-gamma function in general case. Moreover, we consider the p-adic (ρ,q)-Euler constant derived from the derivation of p-adic (ρ,q)-gamma function at x = 1. Furthermore, we provide a limit representation of aforementioned Euler constant based on (ρ,q)-numbers. Finally, we consider (ρ,q)-extension of the p-adic beta function via the p-adic (ρ,q)-gamma function and we then investigate various formulas and identities.

Introduction: Early childhood caries is a significant public health problem among preschool children. The COVID-19 pandemic, which restricted dental services, altered family dynamics, affected child development, and created new demands on caregivers, may have exacerbated this issue. Objective: Analyze the occurrence and severity of caries and identify associated factors in preschool children attending public municipal daycare centers in Salvador, Bahia, Brazil, Methodology: A cross-sectional epidemiological study was conducted to investigate caries in children aged 2 to 5 years in 2022 and 2023. Caries was assessed using the decayed, extracted, filled, and missing teeth (DEFT) index, and prevalence was calculated. Sociodemographic, family dynamic, dietary, and healthcare utilization data were obtained through a questionnaire. After descriptive and exploratory analyses, robust Poisson multivariable regression was conducted at a 5% significance level, considering socioeconomic, psychosocial, and behavioral aspects. Results: A total of 440 preschoolers participated, with a mean age of 55 months. The majority were Black or mixed race (88.86%) and female (52.73%). The prevalence of caries was 30.91% and the mean DEFT score was 1.1. In the multivariable analysis, low family income (up to one minimum wage) and not playing outdoors during the pandemic were associated with a higher prevalence of caries. Conclusion: The prevalence and severity of caries remain high, and the pandemic has contributed to the maintenance of this epidemiological scenario. Public health measures and policies promoting social justice should be planned to improve oral health conditions in childhood.

In this study, we propose a conservative and compact finite difference scheme designed to preserve both the mass change rate and energy for solving the sixth-order Boussinesq equation with the surface tension. Theoretical analysis confirms that the proposed scheme achieves second-order accuracy in temporal discretization and fourth-order accuracy in spatial discretization. The solvability, convergence, and stability of the difference scheme are rigorously established through the application of the discrete energy method. Additionally, a series of numerical experiments are conducted to illustrate the effectiveness and reliability of the conservative scheme for long-time simulations.

In this paper, we introduce a new class of $(p,q)$-analogue type of Fubini numbers and polynomials and investigate some properties of these polynomials. We establish summation formulas of these polynomials by summation techniques series. Furthermore, we consider some relationships for $(p,q)$-Fubini polynomials associated with $(p,q)$-Bernoulli polynomials, $(p,q)$-Euler polynomials and $(p,q)$-Genocchi polynomials and $(p,q)$-Stirling numbers of the second kind.

Previous studies had shown that mRNA, miRNA and lncRNA were associated with cardiovascular diseases. The study was aimed to explore the differential expressions of mRNA, lncRNA and miRNA between coronary artery disease (CAD) and healthy control, and their interaction in CAD. We investigated the differential expression of ceRNA between CAD and healthy control through data collected from Gene Expression Omnibus (GEO) microarrays. Furthermore, we investigated the biological function of these differential expressions of ceRNAs by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Protein-protein interaction (PPI) network was created to identify the hub genes. Biosystems and literature search were performed for signaling pathways and their function of the included differential expression ceRNAs. A total of 456 miRNA expression profiles, 16,325 mRNA expression profiles, and 2,869 lncRNA expression profiles were obtained. Eleven Go and KEGG pathways (count ≥9), top 15 of PPI network node connectivity rank, and top 15 of ceRNA network node degree centrality rank were achieved at the statistical significance level (P<0.05). We further identified that several differential expressions of ceRNAs and their signaling pathways were associated with CAD through biosystems and literature search. Based on eleven Go and KEGG pathways, top 15 of PPI network node connectivity rank, and top 15 of ceRNA network node degree centrality rank in CAD population, our findings would contribute to further exploration for the molecular mechanism of CAD.

Studies over the past three years have substantially expanded the involvements of eIF3 in mRNA translation. It now appears that this multi-subunit complex is involved in every possible form of mRNA translation, controlling every step of protein synthesis from initiation to elongation, termination and quality control in positive as well as negative fashion. Through the study of eIF3, we are beginning to appreciate protein synthesis as a highly integrated process coordinating protein production with protein folding, subcellular targeting, and degradation. At the same time, eIF3 subunits appear to have specific functions that probably vary between different tissues and individual cells. Considering the broad functions of eIF3 in protein homeostasis, it comes as little surprise that eIF3 is increasingly implicated in major human diseases and first attempts at therapeutically targeting eIF3 have been undertaken. Much remains to be learned, however, about subunit- and tissue-specific functions of eIF3 in protein synthesis and disease and their regulation by environmental conditions and posttranslational modifications.

Software Engineering education has grown during the past couple of decades as a specialized branch of computer science education to address employment demands. Software Engineering education is constantly evolving because of its dynamic nature. However, there are still some gaps between the skills being taught in the universities and skills required for employment. In this paper, we present our experience of designing and delivering a new module to enhance skills for employment. We have taken a structured approach to analyze the gap through literature review and our personal experiences of engaging with employers of our students. Based on the analysis, we arrived at a set of gaps between what we teach and what the employers of our students need. We prioritized the gaps and envisaged a new module ‘Contemporary Software Engineering’ to address the gaps and subsequently help our students for an easy transition to job. As part of our experience, we present the background, design and delivery of the module and reflect on our journey of delivering the module for a few years.

Polluting discharges are produced at a rate that is inexorably rising in tandem with human activity development. Eutrophication and other matters, such as offensive aquatic life, require wastewater to be treated before being discharged into the environment. Prior releasing into water bodies, the treated waters must to undertake laboratory analysis. For this purpose, an analysis using standard methods was carried out at the Laboratory Waterworks in Debrecen on various samples taken from various wastewater treatment plants (sewage treatment plants) in Hungary. The overall objective of this study was to assess the quality of the effluents from the fourteen (14) wastewater treatment plants and investigate their efficiency by measuring various physicochemical parameters and microbiological parameters as excellent indicators to evaluate the performance of the studied wastewater treatment plants. The microbiological indicator monitored was the heterotrophic count (HPC) by estimating its total number, which provides useful information for the assessment and monitoring of water samples. The determination of physicochemical parameters included biological oxygen demand (BOD5), chemical oxygen demand (COD) and nitrite -N (NO2), ammonia-N (NH3-N), nitrate-N (NO3) total phosphorus (TP), Kjeldahl- Nitrogen (organic N+ammonia-N) (TKN), total inorganic N (TI), total suspended solids (TSS) and total nitrogen (TN). The performance of the wastewater treatment plants examined was checked and the results were conclusive. In the future, solutions should be applied to these wastewater treatment plants and some recommendations are suggested.

Formaldehyde is generated via the biochemical and chemical pathways, and it widely exists in foods. Its chronic exposure causes carcinogenic, neurotoxic, reproductive, allergic, immunological, genetic and respiratory toxicities. However, food-sourced formaldehyde is usually neglected due to its rapid metabolism after intake. Compared with its residual level in processed foods, a large proportion of formaldehyde disappears because of its high reactivity. Nevertheless, its elimination reaction mechanism and the potential consequences remain unclear. In this review, the disappearing pathway of formaldehyde from two aspects, the formation of formaldehyde-derived toxins and aromas, was reviewed. This review article may help food scientists take appropriate strategies to use the beneficial reactions of formaldehyde or divert its harmful effects to beneficial ones.

Employee turnover is a significant issue for financial institutions, impacting productivity, increasing recruitment costs, and disrupting critical operations. In this project, this study aimed to predict employee turnover using a dataset containing attributes such as employee satisfaction, performance, and tenure. By framing the task as a binary classification problem, this study employed CatBoost and XGBoost, two advanced regression-based algorithms, to develop predictive models. This paper's analysis demonstrated that CatBoost outperformed XGBoost across all evaluation metrics, including MAE, MSE, RMSE, and R², making it the more effective model for predicting turnover in the financial sector. The study highlights key factors contributing to employee attrition, such as job satisfaction, tenure, and promotion opportunities, offering actionable insights for retention strategies. Additionally, by predicting probabilities rather than binary outcomes, this study aims to make more detailed decisions about employee retention. This research provides valuable tools for financial institutions to mitigate the risk of turnover, retain critical talent, and ensure operational continuity.

Granular material is one of the most common in nature. Recently, there has been a significant amount of interest in the granular materials, such as powders or sand. It is challenging to describe the motion of such kind of macroscopic size matter, because it behaves like solid, fluid or gas. Size division, pattern formation, avalanches, packing and convection - these are just a few examples from a wide range of observed phenomena that occur during the motion process of granular matter. Most of these processes are based by flow and no wonder that much effort has been devoted to obtain a hydrodynamic description in which granular materials are treated as a continuous medium. During the research of vertically shaken granular medium motion in an opened container it was found that experimental and numerical results are explained by hydrodynamic theory. This paper investigates the motion of a granular matter for a shallow, vertically shaken bed. We assume the Leidenfrost state as initial and the matter resembles a fluid heated up from below.A one-dimensional isothermal and a non-isothermal problem of granular material motion,simulatedby a hydrodynamic model are considered, and the material is assumed to be a continuous medium. The local temporal solvability of isothermal and non-isothermal initial boundary-value problem in Sobolev’s spaces is proved. This work presents a numerical study of the one-dimensional model of granular medium flow. The feature of this model is consideration of the Navier-Stokes equations accounting an interpolation form of VanderWaals constitutive equation for pressure. A finite-difference approximation for numerical solution is proposed.

This bibliometric study analysed breast cancer research trends and outputs from 2014 to 1 2023, utilising data from the Scopus database. The primary objectives include analysing publication 2 growth, citation metrics, document type distribution, leading countries, preferred journals and 3 authorship patterns. The study reveals a significant increase in breast cancer research publications, 4 with a total of 12,073 documents and 216,769 citations over the ten-year period. The United States 5 leads in publication output and citation impact, followed by China and Japan. Articles are the 6 predominant document type for total 73.4% of publications, while reviews and book chapters also 7 contribute notably. The most preferred journals for publishing breast cancer research include Breast 8 Cancer Research and Treatment, Clinical Breast Cancer, and Breast Cancer Research. Authorship 9 patterns show a trend towards multi-authored papers, with a substantial number of papers having 10 more than five authors. The study underscores the global collaborative effort in advancing breast 11 cancer research and highlights key areas for future exploration.

Background Our aim was to assess the expression profiles of the messenger RNA (mRNA) expression profiles of stem cell genes (OCT4, NANOG) and pancreatic progenitor genes (CK19, HES1, INS, PDX1) in peripheral blood mononuclear cells (PBMNCs) in selected neoplastic pancreatic diseases, such as cancer and neuroendocrine tumors, to identify neoplastic disease markers in the pancreas. Methods In this study, 49 patients diagnosed with pancreatic neoplastic diseases (37 with cancer and 12 with neuroendocrine tumors) and 34 control patients, all of whom were hospitalized at a tertiary center, were enrolled. Venous blood samples were collected from the participants, and RNA was extracted from peripheral blood mononuclear cells (PBMNCs). The mRNA expression levels of six stem cell and pancreatic progenitor markers—OCT4 (POU class 5 homeobox 1), NANOG, CK19 (keratin 19), HES1 (hes family bHLH transcription factor 1), INS (insulin), and PDX1 (pancreatic and duodenal homeobox 1)—were quantified via real-time quantitative PCR. The data were statistically analysed to explore associations between gene expression levels and various clinical, biochemical, and morphological parameters (including full blood count, Ca 19.9, weight, height, and BMI) via the Kruskal‒Wallis test, Mann‒Whitney U test, and Spearman rank correlation coefficient. Results The results revealed that the expression of the gene associated with early stem cells, NANOG (median= 0.002, p=0.03), as well as the genes encoding insulin INS (median = 0,004, p=0.02) and cytokeratin 19 CK19(median 0.0003, p=0.005), was significantly elevated in patients with pancreatic cancer. However, these gene expression levels were not significantly different from those of controls in patients with neuroendocrine tumors. Additionally, no significant differences in gene expression were observed among patients at different stages of pancreatic cancer. Furthermore, CK19 overexpression was found to be positively correlated with inflammatory markers, specifically CRP and WBC, in patients with pancreatic cancer. Conclusions Elevated PBMNC mRNA expression of selected stem and progenitor genes (NANOG, INS, CK19) may serve as a marker of pancreatic cancer and is correlated with coexisting inflammation.

mRNA-lipid nanoparticle (LNP) medicinal products can be considered a platform technology because the development process is similar for different diseases and conditions, with similar noncoding mRNA sequences and lipid nanoparticles and essentially unchanged manufacturing and analytical methods utilised often for different products. It is critical not to lose the momentum built using the platform approach during the development, regulatory approval and rollout of vaccines for SARS-CoV-2 and its variants. This Review proposes a set of modifications to existing regulatory requirements for mRNA products, based on a platform perspective for quality, manufacturing, preclinical and clinical data. For the first time, we address development and potential regulatory requirements when the mRNA sequences and LNP composition vary in different products as well. In addition, we propose considerations for self-amplifying mRNA, individualised oncology mRNA products and mRNA therapeutics. Providing a predictable development pathway for academic and commercial groups, so they can know in detail what product characterisation and data are required to develop a dossier for regulatory submission, has many potential benefits. These include reduced development and regulatory costs; faster consumer/patient access and more agile development of products in the face of pandemics; and for rare diseases where alternatives may not exist or to increase survival and the quality of life in cancer patients. Therefore, achieving consensus around platform approaches is both urgent and important. This approach with mRNA can be a template for similar platform frameworks for other therapeutics and vaccines to enable more efficient development and regulatory review.

Background: Respiratory syncytial virus[ RSV] is a lethal overwhelming defectiveness that influences people all over the world. The infection gets down in the lower respiratory tract and does not disperse to the remainder of the body. The objective of the study: Bioinformatics was used to create an mRNA vaccine against the Respiratory syncytial virus( RSV). Methodology: Lipid nanoparticle vaccines containing the Respiratory syncytial virus's surface fusion protein's mRNA were created for the current screening experimental investigation. Lipid nanoparticles[ LNP] with a particle size of around 90 nanometres that were created using the hot micro-emulsion process comprise the current vaccine delivery system. In stages 1 and 2 of clinical trials, the immunogenicity of the current mRNA RSV vaccine was evaluated. Results: The current vaccine demonstrated 81% immunogenicity in animal testing, but only 69% in stages 1 and 2 of clinical trials. Its side effects were manageable. The results persisted for a while. In the current trial, the vaccination proved effective as a preventative measure against RSV infection. The current immunization lacks antibody-dependent enhancement, which causes non-protective antibodies to develop. These non-neutralizing antibodies worsen infection by enhancing viral entrance and replication in the host cells, activating cytokines and the complement cascade through the production of immunological complexes, or both. However, the current LPN-RSV mRNA vaccine of the surface fusion protein resulted in the formation of potent neutralizing antibodies with persistent protection, especially for newborns and elderly individuals who get the ideal dose regimen. Conclusion: The invention of the LNP-mRNA RSV vaccine, which might prevent RSV-caused bronchiolitis and fatal pneumonia, made the current study promising

Background: RSV, or respiratory syncytial virus, is a deadly condition that is present all over the world today. The infection is initially contained in the lower respiratory tract without systemic transmission. The objective of the study: Bioinformatics was used in Egypt to create an mRNA vaccine against the Respiratory syncytial virus (RSV). Methodology: In the present screening experimental study, a lipid nanoparticles vaccine of mRNA of the surface fusion protein of Respiratory syncytial virus was manufactured. The present vaccine delivery system was lipid nanoparticles with a particle size of approximately 90 nanometres, manufactured by the hot micro-emulsion method. In stages 1 and 2 of clinical trials, the immunogenicity of the current mRNA RSV vaccine was evaluated. Results: The current vaccine demonstrated 81% immunogenicity in animal testing, but only 69% in stages 1 and 2 of clinical trials. Its side effects were manageable. The results persisted for a while. In the current trial, the vaccination proved effective as a preventative measure against RSV infection. The current vaccination lacked antibody-dependent enhancement, which causes non-protective antibodies to develop. These non-neutralizing antibodies exacerbate infection by activating cytokines and complement cascade through the formation of immune complexes or enhancement of the virus entry and replication in the host cells. On the other hand, the current RSV mRNA vaccine of the surface fusion protein consequent on the production of powerful neutralizing antibodies with prolonged immunity especially to infants and elderly candidates who received the optimal dosage regimen.

Currently available COVID-19 mRNA vaccines have demonstrated high efficacy in clinical trials.1-3 However, cancer patients, including those with hematological malignancies, were largely excluded from these trials. In this prospective, observational study we measured anti-S protein IgG titers as well as avidity in lymphoma patients (n=67) vaccinated with a COVID-19 mRNA vaccine. Serological response rates in lymphoma patients who were treatment naïve (100% in CLL, 88.9% in other, non-CLL non-Hodgkin lymphoma patients), or who were last treated more than 24 months prior to vaccination (100% in CLL, 90% in other-NHL), were similar to healthy controls (100%). Patients on active therapy, however, had a diminished response rate (40% in CLL, 21.0% in other-NHL). No patient who received anti-CD20 monoclonal antibodies (mAb) within six months of vaccination responded. Thus, the utility of testing anti-S titers should be explored in patients on active therapy or with recent anti-CD20 mAb exposure, to assess their response to vaccination. We also propose studying passive protection with S-protein mAbs as an alternative prophylactic strategy for patients who respond poorly to vaccination.

Dupilumab is an interleukin 4 (IL-4) receptor α-antagonist that inhibits IL-4 and IL-13 signaling through blockade of the shared IL-4αR subunit. Blockade of IL-4/13 is effective in reducing Th2-oriented response including the release of proinflammatory cytokines, chemokines, and IgE. These mechanisms are known as mediators in the pathogenesis of atopic dermatitis, food allergy, allergic rhinitis with and without polyposis, and asthma. We report the clinical case of a patient in which the Th2-mediated inflammatory substrate is evident in comorbid allergic manifestations who show a good response after treatment with Dupilumab for moderate atopic dermatitis.

Breast cancer is among the most prevalent cancers in Indonesia. One of the methods for early detection of breast cancer is utilizing ultrasound images to classify breast conditions into normal, benign tumors, or cancer. The advent of deep learning technology facilitates the image analysis process, such as the use of Transfer Learning Convolutional Neural Networks (CNNs). Generally, CNN models require large and balanced datasets to perform well in classification tasks. However, medical datasets like breast ultrasound images tend to be limited and imbalanced. The Wasserstein GAN (WGAN) is a generative data augmentation method capable of producing synthetic images by learning the pattern of the distribution of real image data. The implementation of the Wasserstein distance results in the training process of WGAN demonstrating stability from epochs 3000, 2500, and 3000 out of a total of 5000 epochs. The quality of the synthetic images improves with an increasing number of training iterations. By using WGAN, all of the evaluation metrics of each classifier are increasing, with the best accuracy score is achieved by VGG16 model with 83.33% accuracy.

Background: Nanotechnology has emerged as a promising field of study, aiming to revolutionize healthcare through the innovative development of drugs, diagnostic tools, and medical devices. As a result, healthcare professionals in training are constantly faced with the challenge of understanding and applying these emerging technologies. The objective of this study is to determine the factors to consider for including the teaching of nanotechnological tools in medical specialty postgraduate programs. Methods: A study based on the Nominal Group Technique (NGT) was conducted to identify the factors that promote and hinder the implementation of nanotechnology in certain postgraduate programs where nanotechnology is employed, such as Internal Medicine, Critical Care Medicine, Family Medicine, and Clinical Pharmacology at the School of Medicine of Universidad de La Sabana. A framework analysis was used to analyze the collected data. Results: Based on the two research questions, several aspects were identified for the inclusion of nanotechnology in the medical practice of specialties. Key challenges include lack of knowledge and resource availability, misinformation, and lack of knowledge, as well as paradigmatic analysis as the main obstacles to the use of nanotechnology. Conclusions: The findings provide a first-time study on nanotechnology curricula within medical specialty programs in Colombia, with potential extrapolation to similar situations in other medical schools.

The species and bio-availability of phosphorus (P) in primary, secondary and digested sludge were fractionated and further analyzed in this study. Results showed that inorganic P (IP) was the primary P fraction in the secondary sludge and digested sludge, in which non-apatite IP (NAIP) amounted to 91.6% and 69.3% of IP, respectively. Organic P (OP), accounting for about 71.7% of total P (TP), was the dominant P composition in primary sludge. The content of bio-available P was about 9.7, 43.4, 29.8 mg-P/g-TS in primary sludge, secondary sludge and digested sludge, respectively, suggesting secondary sludge is the optimal choice when land application of sewage sludge is taken into consideration, followed by digested sludge and primary sludge. Polyphosphate and orthophosphate, comprising approximately 54.3% and 89.2% of TP, was the dominant P species in the secondary sludge and digested sludge, respectively. Monoester-P (54.6% of TP in extract) and diester- P (24.1%) were identified as OP species in primary sludge by Phosphorus-31 nuclear magnetic resonance (31PNMR). The present results would be helpful for P recovery and recycle from sewage sludge in wastewater treatment plant.

We conducted a comparative study on the development of two synthetic methods. The solvent-free synthesis is a green chemistry method developed in a bid to ameliorate environmental adverse effects of the conventional solvent-based synthesis. The synthesis of novel dichloro and polymethoxy p-nitrophenylhydrazones through solvent free technique gave moderate to high yields which were however lower than those of the solvent-based method. The established solvent-free approach has several benefits, including universality and simplicity of the approach, catalyst-free conditions, non-use of an organic solvent, quick reaction time, fast and efficient workup, and un-solvated pure products in moderate to high yields.

The aim of the study was to evaluate two widely studied biomarkers: MMP-9 and S100B in blood serum in healthy people after physical exercise mimicking physical activity during bi-lateral tonic-clonic seizures. Both biomarkers have been shown to increase after seizures, and their serum levels tend to be higher in epilepsy patients compared to individuals without epi-lepsy. To achieve this goal, we have developed two sets of exercises, each consisting of a tonic contrac-tion phase and a phase of alternating muscle work, lasting a total of approximately 5 minutes. Both sets of motor exercises were performed in the same group of healthy volunteers 6 months apart. Serum samples were collected before exercise, 3 hours after exercise, and the next day (time points 0, 3 hours, and 24 hours). Our results demonstrated that both sets of motor exercises led to a similar increase in MMP-9 levels, while neither while neither affected S100B levels. No significant differences in MMP-9 levels were observed due to muscle failure. We propose that the increase in MMP-9 is primarily induced by muscle contraction and additional mechanisms observed during exercise, such as neutrophil degranulation. S100B appears to be a promising biomarker in epilepsy, as it is not induced by physical activity but does increase following seizures.

Recent research has demonstrated that endophytes, or non-pathogenic fungi found in plant bi-omes, can dramatically alter the expression of host plants. Our natural ecology is burdened by an increasing amount of chemicals owing to the rapid modernization of agricultural sector. This study examined the use of natural pesticides in place of chemical pesticides to eradicate patho-genic fungi that destroy cabbage crops every year. Agrochemicals-, or pesticides-, are used in ag-ricultural land and crops to protect plants from various diseases. The cabbage crop was treated using the appropriate methodology. In an effort to identify endophytic fungi that can stop the growth of pathogenic fungi, samples are gathered from markets and farms to find solutions at the source of the issue. The outcome revealed a number of fungal endophytes that have the ability to suppress fungal infections and act as a defense against crops. Because plants have endophytic fungi, which act as a barrier to protect plants, in addition to harmful fungi, fungi play a critical role in the discussion of natural pesticides. These findings also indicate that market samples were more contaminated with microorganisms. These endophytes can be the main source of materials for producing natural insecticides for crops;-, thus, further research on them can be conducted. Furthermore, farmers may be able to overcome obstacles and find a potential solution with the use of numerous more potent strategies in the field of microorganism development.

Reaction of the phosphonated hydrazone (2-hydrazineylidenepropyl) diphenylphosphine oxide 1 with p-fluorophenyl-isothiocyanate yields as major product the thiosemicarbazone Ph2P(=O)CH2{C=N-NH(C=S)-N(H)C6H4F}CH3 (2-(1-(diphenylphosphoryl)propan-2-ylidene)-N-(4-fluorophenyl)hydrazine-1-carbothioamide) 2 along with bis(N-p-fluorophenylthiourea) 3 as minor product. This latter product 3 was isolated as main product by direct treatment of p-FC6H4N=C=S with hydrazine in a 2:1 ratio. Both 2 and 3 were characterized by NMR. Furthermore, the molecular structure of 3 was elucidated by an X-ray diffraction study. A conformational DFT study, at the B3LYP/6311 G++ (d, p) level of theo-ry, confirmed a good match between the calculated structure and the experimental one.

The design and control of lower limb rehabilitation robots for patients after a stroke has gained significant attention. This paper presents the dynamic analysis and control of a 3-degree-of-freedom lower limb rehabilitation robot using combined position-force control based on the force feed-forward and compensate gravity proportional derivative method. In the lower limb rehabilitation robot, the interaction force between the patient with the joints and links of the robot is uncertain and nonlinear due to the disturbance effect of Coriolis force, centrifugal force, gravitational force, and friction force. During recovery stages, forces exerted by the patient's lower limb are considered disturbances. Therefore, to meet the quality requirements in using the rehabilitation robot with different recovery stages of patient training, combining position control and force control is essential. In this paper, we proposed a combinations of proportional-derivative gravity compensation motion control and force feed-forward control to form an advanced combined controller (Position-Force Feedforward Control - PFFC) for a 3 DOF lower limb functional rehabilitation robot. The forces can be sensed using a 3-axis force sensor. In addition, the robot's position parameters are also measured by encoders. The control algorithm is implemented on the STM32F4 Discovery board. Verified test of the proposed control method is shown in the experiments and shown good performance of the system.

This paper presents an approach to assess and improve the cybersecurity infras- tructure of developing countries. We have highlighted and addressed the critical gaps through a hybrid approach encompassing SWOT analysis, benchmarking using Data Envelopment Analysis (DEA) and, Root Cause Analysis (RCA). This approach has provided a strong basis for evaluating cybersecurity performance by combining qualitative insights with quantitative metrics. As a case study, we have compared an underdeveloped country’s (Pakistan) cybersecurity pos- ture to five highly developed countries (Lithuania, Estonia, Singapore, Spain,and Norway). Our analysis has identified cybersecurity shortcomings and pro- vided actionable recommendations within a flexible framework, applicable for all developing countries to identify and address vulnerabilities, and align their cybersecurity infrastructure with international standards.

The increasing energy consumption and industrial activities that release carbon dioxide (CO2) emissions into the atmosphere have become one of the most serious environmental issues of today. This article discusses the current status in Azerbaijan regarding the development of effective approaches to reduce carbon emissions and ensure sustainable development, and it proposes relevant strategies for managing the carbon footprint. By exploring the interrelationship between the economy and the environment, it aims to contribute to the formation of more effective policies for managing CO2 emissions in Azerbaijan. According to the results of the econometric model established within the research for the period of 1990-2023, as the Azerbaijan economy grows, per capita CO2 emissions tend to increase, which can be linked to rising industrial activity, energy consumption, and other factors driving economic growth. The presence of a positive long-term relationship between population growth and per capita CO2 emissions can be attributed to higher overall energy consumption, increased demand for goods and services, and rising transportation needs. The strong correlation between economic growth and CO2 emissions suggests that it may be too early to assert the validity of the Kuznets curve for Azerbaijan economy as a developing country.

Fluctuations in kynurenic acid (KYNA) and brain-derived neurotrophic factor (BDNF) levels in the brain reflect its neurological status. The aim of the study was to investigate the effect of transiently elevated KYNA concentration in the cerebroventricular circulation on the expression of BDNF and its high-affinity tropomyosin-related kinase receptor B (TrkB) in specific structures of the sheep brain. Intracerebroventricularly cannulated anestrous sheep were subjected to a series of four 30-min infusions of KYNA: 4×5 μg/60 μL/30 min (KYNA20, n=6) and 4×25 μg/60 μL/30 min (KYNA100, n=6) or a control infusion (n=6), at 30-min intervals. Sections of the hippocampal CA3 field, amygdala (AMG), prefrontal cortex (PCx), and the hypothalamic medial-basal (MBH) and preoptic (POA) areas were dissected from the brain immediately after the experiment. The highest concentration of BDNF protein was found in the CA3 field (P&lt;0.01), which was 8-fold higher than in the AMG and 12-fold higher than that in the PCx (MBH and POA were not analyzed). The most pronounced BDNF mRNA expression was observed in the MBH followed by the PCx, POA, AMG and CA3, while the highest abundance of TrkB mRNA was recorded in the AMG followed by the MBH, PCx, CA3 and POA. KYNA increased (P&lt;0.05-P&lt;0.01) BDNF protein levels and the expression of its gene in the brain structures examined, with the effect varying by dose and brain region. KYNA, particularly at the KYNA100 dose, also increased (P&lt;0.01) TrkB gene expression, except for the AMG, where the lower KYNA20 dose was more effective (P&lt;0.01). These findings suggest a positive relationships between KYNA levels in the cerebroventricular circulation and BDNF-TrkB expression in specific brain regions in a sheep model. This indicates that a transient increase in CSF KYNA concentration can potentially restore BDNF production, whose deficiency underlies numerous neurological disorders.

Diospyros kaki, the most widely cultivated species of persimmon, has been long used in traditional medicine since its leaves extracts contain high amounts of flavonoids and terpenoids, endowed with potential antioxidant, anti-inflammatory, anticancer, antidiabetic and antimicrobial effects. Re-cently, many in vitro and in vivo studies have assessed different potential health benefits of per-simmon leaves; however, its anticancer activity towards colorectal cancer (CRC), the second deadliest cancer in Western countries, has not been investigated in depth. Since CRC current therapies are associated with serious side effects and show no efficacy towards patients carrying RAS/BRAF mutations, the search for new and more effective therapies has turned to plant extracts, which could help reduce conventional drugs dosages and toxicity. The effect of Diospyros kaki al-coholic extract has been investigated on E705 CRC cell line, representative of most CRC patients, and on SW480 cells, carrying a KRAS activating mutation. This extract is effective in reducing tumor cells viability, without affecting the healthy mucosa cell line CCD 841, and it triggers apoptosis in CRC cells, by disrupting mitochondrial functionality and increasing oxidative stress.

Pre-transport management activities can cause stress, injuries, and mortality in poultry. This study aimed to gather information about the current pre-transport practices (selection of unfit chickens, catching preparations, catching, and crating) for spent hens and broilers by questioning Flemish poultry farmers. The results showed that catching preparations such as an extra selection of chickens unfit for transport was performed by a minority of the poultry farmers, and that layer farmers were less in line with the EU-legislation for water and feed withdrawal than broiler farmers. All birds were caught inverted except for one broiler farmer who used mechanical catching (not yet common in Flanders). Additionally, mechanical catching may involve extra costs, increased biosecurity risks, and specific recommendations for the stable (height and width). The broiler farmers preferred mechanical catching for broiler catchers' well-being, while upright catching was considered better for animal welfare than catching more than three chickens by one/two legs, mechanically, or by wings. Awareness of the need to perform an extra selection by the poultry farmers before catching is required. Preparations like closing areas under the aviary system and removing litter (layers) can further streamline the process and reduce animal suffering.

This stability analysis method is simply represented and understood on a Bode plot of two impedances without complex equations. The external impedance of the charging system is properly quantified and designed based on the stability criteria by analyzing.

Arbutus unedo (strawberry tree) is a small Mediterranean tree capable of vigorous regrowth after disturbances like fire. Traditionally used for biomass fuel, its bark and branches hold potential for higher-value products through ecovalorisation into liquid mixtures that could replace petro-leum-based materials. This study aimed to explore the chemical composition of various compo-nents of Arbutus unedo and to produce a liquefied material from its internal (IB) and external bark (EB). Chemical compositions of internal and external bark were determined using TAPPI standards including ash, extractive content, lignin, and cellulose. Metal cations were analyzed by ICP. Liquefaction of bark was optimized in a PARR reactor, evaluating factors such as particle size, temperature, and time and the best polyols were monitored by FTIR-ATR. Polyurethane foams were made with internal and external bark liquefied materials by polymerization with isocyanate, a catalyst and water as blowing agent. Results showed that EB has a higher extractive and lignin content, while IB contains more cellu-lose. Liquefaction yields were higher for IB (74%) than EB (68%), with IB yielding polyols that produced stronger and more resilient foams. Mechanical properties of the foams were influenced by the NCO/OH ratio and catalyst levels. Overall, the internal bark demonstrated superior performance for foam production, highlighting its potential as an eco-friendly alternative to petroleum-derived materials.

Introduction: Leptin and ghrelin are two hormones that play a role in weight homeostasis. Leptin, which is produced primarily by adipocytes and is dependent on body fat mass, suppresses appetite and increases energy expenditure. Conversely, ghrelin is the “hunger hormone”, it stimulates appetite and promotes fat storage. Bariatric surgery significantly alters the levels and activity of these hormones, contributing to weight loss and metabolic improvements. Clarifying the interplay between bariatric surgery, weight loss, physical exercise, leptin, and ghrelin is essential for developing comprehensive strategies for optimizing long-term outcomes for candidates for bariatric surgery, especially sarcopenic patients. Methods: This was a randomized controlled study with two groups (n=22). The patients in both groups have obesity and sarcopenia. A Roux-en-Ygastric bypass (RYGB) procedure was performed in all patients. The intervention group participated in a structured exercise program three times per week beginning one month after surgery and lasting 16 weeks. Patient assessment was performed before surgery (baseline) and after completion of the exercise program. The control group received the usual standard of care and was assessed similarly. Results: After surgery, weight, BMI and lean mass decreased significantly in both groups from baseline to the second assessment. Leptin was not significantly different from baseline to the second assessment in the physical exercise group but was significantly lower in the control group (p=0.05). Ghrelin increased over time in both groups, but the differences were not significant. When we associated leptin (the dependent variable) with weight (the independent variable), we found that lower weight was associated with lower leptin levels. A similar relationship was also observed between leptin and sarcopenia parameters (muscle strength and mass), as well as with bone health parameters (bone mineral density and t-score). Higher ghrelin levels were significantly associated with higher t-scores and z-score (p<0.05). Conclusion: Exercise has been shown to have a significant effect on leptin and ghrelin levels after bariatric surgery. By incorporating regular physical activity into their lifestyle, bariatric patients can optimize their weight loss outcomes and improve their overall health. After the physical exercise protocol, patients in the intervention group revealed more established leptin levels, which may indicate a protected pattern concerning decreased leptin levels. An unfavorable profile was evidenced, according to which greater weight loss, sarcopenia, and osteoporosis were associated with lower leptin levels.

Among the theoretical problems with the prevailing theory of cosmology, Lambda Cold Dark Matter (λCDM), the most serious appears to be the twofold problem with the cosmological constant lambda: Dark Energy and Hubble Tension. Despite a two-decade search for systematic errors in astrometry the problems have not been resolved. This paper posits a potential source of error that may have affected astrometry related to the current and past measurements of lambda.

Differential beamforming has attracted much research since it can utilize the array with small aperture size to form frequency-invariant beampatterns and achieve high directional gains. It has recently been applied to the linear loudspeaker array to produce a broadside frequency-invariant radiation pattern. However, designing steerable frequency-invariant beampatterns for the linear loudspeaker array has yet to be explored. This paper proposes a method to design the steerable differential beamformer with the linear loudspeaker array. We first determine the target differential beampatterns according to the desired direction, the main lobe width, and the beampattern order. Then, we transform the target beampattern into the modal domain for representation. The Jacobi-Anger expansion is subsequently used to design the beamformer so that the resulting beam pattern matches the target differential beam pattern. Furthermore, based on the criterion of minimizing the mean square error between the synthesized beam pattern and the ideal one, a multi-constraint optimization problem is formulated to calculate the optimal desired weighting vector. Simulations and experimental results show that the proposed method can achieve steerable frequency-invariant beamforming over 300 Hz – 4 kHz.

N-(diisopropylphosphanyl)benzamide, PhC(O)NHPiPr2, has been synthesized in good yield following two alternative procedures that employ benzamide as the starting material. The first one is a two-step preparation, in which N-(trimetilsilyl)benzamide is reacted with PiPr2Cl, to give the title compound in good yield, whereas the second one is a straightforward synthesis which converts benzamide into N-(diisopropylphosphanyl)benzamide by reaction with PiPr2Cl in the presence of N,N-dimethylpyridin-4-amine (DMAP) and triethylamine. NMR spectroscopy and X-ray diffraction analyses have been performed to characterize the new compound and elucidate its molecular structure in the solid state. N-(diisopropylphosphanyl)benzamide adds to the limited family of amido-substituted phosphines, RC(O)NHPR’2, which can be classified as bidentate hybrid P,O-ligands, both in their neutral and anionic forms, the latter achievable by deprotonation of the NH group.

Background: The study was conducted to investigate if the mRNA vaccine technology could be adapted for the ectothermic vertebrate Atlantic salmon (Salmo salar). The lipid nanoparticle (LNP) technology has been developed and optimized for mRNA vaccines in mammals, stabilizing mRNA and facilitating delivery into cells. However, its utility at the temperature and specific biological environment in ectotherms remains unclear. In addition, it is unknown if modified mRNA containing non-canonical nucleotides can correctly translate in salmonid cells. Methods: We used an mRNA transcript coding for enhanced green fluorescence protein, flanked by the untranslated regions of the hemagglutinin-esterase gene of infectious salmon anemia virus, and a 120-base-long poly(A) tail. The mRNA was generated by in vitro transcription where uridine residues were replaced with N1-methyl-pseudouridines, and then encapsulated in LNPs. Results: When transfected into the salmonid cell line CHH-1, the mRNA-LNP construct induced expression of EGFP. Furthermore, when mRNA-LNPs were injected intramuscularly into salmon, in vivo protein expression was demonstrated by immunohistochemistry. EGFP was observed in cells infiltrating the space between the muscle cells in a focal inflammatory response. Conclusion: The results indicate that the N1-methyl-pseudouridine modified mRNA encapsulated in LNPs can be used to express antigens of interest in salmonid fish.

The coronavirus disease (COVID-19) is a respiratory tract infection caused by the new virus SARS-CoV-2. In March 2020, the World Health Organization (WHO) declared a worldwide COVID-19 pandemic. Since then, there has been a rush to find preventative or curative treatment. This arrived with the appearance of the COVID-19 vaccine, months after the declaration of the pandemic. In the setting of global COVID-19 immunization, there have been reports of rare skin immune-mediated diseases (IMD) after COVID-19 vaccination, particularly systemic sclerosis. Systemic sclerosis (SSc) is the most reported new onset IMD following messenger RNA (mRNA) COVID-19 vaccination. The pathogenesis of SSc is not fully understood, and the diagnosis is based on clinical symptoms. We report a 54-year-old male, with no prior history of autoimmune disorder, with rapid and progressive skin thickening (Modified Rodnan skin score 30/51), weeks after his mRNA COVID-19 vaccination. Antinuclear antibodies (ANA) showed a strongly positive nuclear fine-speckled pattern, but no SSc autoantibodies were found. The patient was diagnosed with SSc based on the persistence of autoantibodies and the clinical criteria according to the 2013 American College of Rheumatology/European League Against Rheumatism classification. Due to the proximity of the two events, we hypothesized a cross-reaction between COVID-19 vaccination and, in genetically predisposed patients, an emergence of systemic sclerosis. Our case suggests a potential relationship between the mRNA COVID-19 vaccine and new-onset autoimmune diseases. Physicians should be aware of this possible association.

Introduction: Real-world safety studies can provide important evidence on the thromboembolic risk associated with COVID-19 vaccines, considering that millions of people have been already vaccinated against COVID-19. In this study, we aimed to estimate the incidence of thromboembolic events after COVID-19 vaccination and to compare the Oxford–AstraZeneca vaccine with other COVID-19 vaccines. Methods: We conducted a retrospective real-world safety study using data from two different data sources: the Italian Pharmacovigilance database (Rete Nazionale di Farmacovigilanza, RNF) and the Campania Region Health system (Sistema INFOrmativo saNità CampanIA, SINFONIA). From the start date of the COVID-19 vaccination campaign (December 27th, 2021) to September 27th, 2022, information on COVID-19 vaccinations and thromboembolic evets were extracted from the two databases. The reporting rate (RR) and its 95% confidence interval (95%CI) of thromboembolic events for 10,000 doses was calculated for each COVID-19 vaccine. Moreover, the odds of being vaccinated with the Oxford–AstraZeneca vaccine vs. the other COVID-19 vaccines in cases with thromboembolic events vs. controls without thromboembolic events were computed. Results: A total of 12,692,852 vaccine doses were administered in Campania Region, of which 6,509,475 (51.28%) were in female and mostly related to the Pfizer-BioNtech vaccine (65.05%), followed by Moderna (24.31%), Oxford–AstraZeneca (9.71%), Janssen (0.91%), and Novavax (0.02%) vaccines. A total of 641 ICSRs with a COVID-19 vaccines and a vascular events were retrieved from the RNF for the Campania Region, of which 453 (70.67%) were in female. Most ICSRs reported the Pfizer-BioNtech vaccine (65.05%), followed by Oxford–AstraZeneca (9.71%), Moderna (24.31%), and Janssen (0.91%). A total of 2,451 events were reported in the ICSRs (3.8 events for ICSRs) of which 292 were thromboembolic events. The highe RRs of thromboembolic events were found with the Oxford–AstraZeneca vaccine (RR: 4.62, 95%CI: 3.50-5.99) and Janssen vaccine (RR: 3.45, 95%CI: 0.94-8.82). Thromboembolic events were associated with a higher likelihood of exposure to the Oxford–AstraZeneca vaccine compared to Pfizer-BioNtech (OR: 6.06; 95%CI: 4.22-8.68) and Moderna vaccines (OR: 6.46; 95%CI: 4.00-10.80). Conclusion: We observed a higher reporting of thromboembolic events with viral-vector based vaccines (Oxford–AstraZeneca and Janssen) and an increased likelihood of being exposed to the Oxford–AstraZeneca vaccine compared to the mRNA vaccines (Pfizer-BioNtech and Moderna) among thromboembolic cases.

At 2.3 megabases in length, the dystrophin gene is enormous: transcription of a single mRNA requires approximately 16 hours. Principally expressed in skeletal muscle, the dystrophin protein product protects the muscle sarcolemma against contraction-induced injury, and dystrophin deficiency results in the fatal muscle-wasting disease, Duchenne muscular dystrophy. This gene is thus of key clinical interest, and therapeutic strategies aimed at eliciting dystrophin restoration require quantitative analysis of its expression. Approaches for quantifying dystrophin at the protein level are well established, however study at the mRNA level warrants closer scrutiny: measured expression values differ in a sequence-dependent fashion, with significant consequences for data interpretation. In this manuscript we discuss these nuances of expression and present evidence to support a transcriptional model whereby the long transcription time is coupled to a short mature mRNA half-life, with dystrophin transcripts being predominantly nascent as consequence. We explore the effects of such a model on cellular transcriptional dynamics, and then discuss key implications for the study of dystrophin gene expression, focussing both on conventional (qPCR) and next-gen (RNAseq) approaches.

Chemotherapy-related deaths, the result of treatment with faulty medications, account for nearly 10% of all breast cancer deaths (Rashbass, 2016). Patient-specific, personalized medicine is evidently required to administer optimized therapeutics and prevent treatment-related mortality. In order to develop a predictive model for breast cancer therapy, the following study analyzed the mRNA data of 4,704 genes derived from 20 breast cancer patients before and after doxorubicin treatment for 16 weeks (O’brien et al., 2006; Perou et al., 2000). The genomic data of each patient was first stratified into 9 groups (corresponding to the 9 Mechanisms defined in Figure 4) based on mRNA expression in response to the tumor and to the doxorubicin treatment. The study then employed the Planckian Distribution Equation (PDE) discovered at Rutgers University to model the stratified samples by transforming each mechanism into a single long-tailed histogram fitted by the PDE. Our PDE model is based on 3 parameters - A, B, and C - of which 2 were extracted from each model to generate the plots seen in figures 5e and 5f. The drug-induced slopes of the A vs C plots were then determined for all 9 mechanisms of each patient. The study observed an increase in post-treatment mRNA levels for longer surviving patients in 6 mechanisms. Further analysis displayed how the drug treatment uniquely altered each of the mechanisms based on the length of patient survival. These results indicate that the PDE-based procedures described herein may provide a novel tool for discovering potential anti-breast cancer pharmaceuticals.

Vaccines based on mRNA-containing lipid nanoparticles (LNPs) pioneered by Katalin Karikó and Drew Weissman at the University of Pennsylvania are a promising new vaccine platform used by two of the leading vaccine candidates against coronavirus disease in 2019 (COVID-19). However, there are many questions regarding their mechanism of action in humans that remain unanswered. Here we consider the immunological features of LNP components and off-target effects of the mRNA, both of which could increase the risk of side effects. We suggest ways to mitigate these potential risks by harnessing dendritic cell (DC) biology.

Cyclin dependent kinase 1 (CDK1) has been primarily identified as a key cell cycle regulator in both mitosis and meiosis. Recently, an extramitotic function of CDK1 emerged when evidence was found that CDK1 is involved in many cellular events that are essential for cell proliferation and survival. In this review we summarize the involvement of active CDK1 in the initiation and elongation steps of protein synthesis in eukaryotes. During its activation CDK1 influences the initiation of protein synthesis, promotes the activity of specific translational initiation factors and affects the functioning of a subset of elongation factors. Our review provides insights into gene expression regulation during the transcriptionally silent cell cycle/M-phase and describes quantitative and qualitative translational changes based on the extramitotic role of the cell cycle master regulator CDK1, to optimize temporal synthesis of proteins to sustain division-related processes: mitosis and cytokinesis.

Background/Objectives: The function of adipokines, which play an important role in the etiopathogenesis of critical illness, has not been fully elucidated. We aim to investigate the sequential changes in serum adipokines and their association with clinical outcomes and nutritional parameters in ICU patients with SARS-CoV-2. Methods: This observational study was conducted prospectively in a Medical ICU. Blood samples were collected on admission and on the 7th day for analysis of adiponectin, GLP-1, resistin, visfatin, acyl ghrelin (AG), IGF-1, and leptin levels using ELISA kits. Results: This study included 30 critically ill patients and 10 healthy controls. Baseline and day 7 serum adiponectin, GLP-1, resistin, visfatin, baseline AG and day 7 IGF-1 levels are significantly lower in critically ill patients compared to the control group (p<0.05). A negative correlation was observed between time to initiate nutrition and serum adipokine levels (p<0.05). Patients with high mNUTRIC scores had elevated serum adiponectin and IGF-1 levels on day 7 (p<0.05). Positive correlations were found between MV duration and day 7 AG levels (p<0.05). Conclusions: This pilot study provides insights into serum adipokine dynamics in critically ill COVID-19 patients. Lower adiponectin, GLP-1, resistin, visfatin, AG, and IGF-1 levels suggest dysregulation in these pathways.

The positive relationship between species richness and area is a fundamental principle in ecology. However, this pattern deviates on small islands, where species richness either changes independently of area or increases at a slower rate—a phenomenon known as the Small-Island Effect (SIE). While the SIE has been well-documented in natural ecosystem, its presence in highly fragmented and disturbed urban ecosystem remains unexplored, posing challenges for urban vegetation conservation. Urban remnant vegetation, isolated by surrounding infrastructures, preserves intact zonal vegetation characteristics, serves as a benchmark for restoring near-natural habitats and offers ideal conditions to test the existence of SIE in human-altered landscapes. In this study, we surveyed 17 remnant vegetation patches in Qingdao City, China. In total of 331 plants attributed to 255 genus in 81 families been recorded. Firstly, by using six species-area relationship regression models tested SIE for remnant vegetation with different life form (i.e. annual herb, perennial herb, shrub and tree), we found SIE detected in only woody plants, with area threshold ranging from 6.38 ha (tree) to 11.91 ha (shrub). According to stepwise and generalized linear regression mode analysis we found SIE detected in only woody plants, with area threshold 6.38 ha for tree and 11.91 ha for shrub. Further analysis revealed that the SIE in shrub was driven by landscape shape index, perimeter-area ratio, and the proportion of sealed surface within patch. For trees, the SIE was influenced by the distance to the source of species, GDP, night light intensity and perimeter-area ratio. This finding justifies that conservation in urban planning, construction and development should focus not only on protecting large areas, but also on maintaining and promoting diverse habitats within these areas. At the same time, reducing anthropogenic disturbance and enhancing the connectivity of green spaces are important for the persistence of metacommunities and can contribute to the local species pool, thus potentially improving the ecological resilience of urban environments.

Cybersecurity threats pose a significant challenge to the operational resilience and sustainability of Small and Medium Enterprises (SMEs) globally, with distinct implications for regional business ecosystems. This research presents an in-depth investigation into the impact of cybersecurity threats on SMEs within the unique context of Kajiado County, Kenya. Against the backdrop of an increasingly digitized business environment, this study aims to comprehensively assess the challenges SMEs face in mitigating cyber risks and their consequent impact on performance. The research employed a mixed methods approach, combining quantitative and qualitative analyses to elucidate the multifaceted nature of cybersecurity challenges encountered by SMEs in Kajiado County. Utilizing interviews, and document analysis, the study gathered empirical data to identify prevalent cybersecurity threats, their frequency, and the subsequent repercussions on SMEs' operational efficiency, financial stability, and overall performance metrics. Initial findings reveal a diverse spectrum of cybersecurity threats SMEs face in Kajiado County, ranging from phishing attacks and data breaches to ransomware incidents. These threats significantly impede business operations, resulting in financial losses, service delivery disruptions, and customer trust erosion. Moreover, the study examined the cybersecurity measures adopted by SMEs, highlighting the challenges in implementing effective preventive strategies within resource-constrained environments. Notably, the research addresses the identified gap by offering a nuanced understanding of the interplay between cybersecurity threats and SME performance in Kajiado County. The study intends to propose tailored and pragmatic recommendations to fortify SMEs' cybersecurity resilience by contextualizing global best practices within the regional business landscape. The anticipated outcomes of this research endeavor extend beyond academic discourse, aiming to provide actionable insights to SME stakeholders, policymakers, and industry practitioners. The findings aspire to empower SMEs in Kajiado County to enhance their cybersecurity posture, enabling them to navigate the evolving threat landscape more effectively and bolster their long-term sustainability within the digital economy.

Background/Objectives: Recent advancements in artificial intelligence (AI) have spurred interest in developing computer-assisted analysis for imaging examinations. However, the lack of high-quality datasets remains a significant bottleneck. Labeling instructions are critical to improving dataset quality but are often lacking. This study aimed to establish a liver MRI segmentation protocol and assess its impact on annotation quality and inter-reader agreement; Methods: This retrospective study included 20 patients with chronic liver disease. Manual liver segmentations were performed by a radiologist in training and a radiology technician on T2 weighted imaging (wi) and T1wi at the portal venous phase. Based on the inter-reader discrepancies identified after the first segmentation round, a segmentation protocol was established, guiding the second round of segmentation, resulting in a total of 160 segmentations. Dice Similarity Coefficient (DSC) assessed inter-reader agreement pre- and post-protocol with a Wilcoxon signed-rank test. Slice selection at extreme cranial or caudal liver positions was evaluated using the McNemar test; Results: The per-volume DSC significantly increased after protocol implementation for both T2wi (p<0.001) and T1wi (p=0.03). Per-slice DSC also improved significantly for both T2wi and T1wi (p<0.001). The protocol reduced the number of liver segmentations with a non-annotated slice on T1wi (p=0.04), but the change was not significant on T2wi (p=0.16); Conclusions: Establishing a liver MRI segmentation protocol improves annotation robustness and reproducibility, paving the way for advanced computer-assisted analysis. Moreover, segmentation protocols could be extended to other organs and lesions and incorporated into guidelines, thereby expanding the potential applications of AI in daily clinical practice.

At the time of accession, Ukraine will be covered by the full CAP instrumentarium, the system of direct payments included. Due to the size of the country, including agricultural land, the total amount of payments to Ukraine may reach the amount of EUR 96.5 billion (over 7 years) according to some estimates. The purpose of the article is to try to verify this amount. This will be done by reviewing the latest analyses, made in EU countries, on the estimates of future direct payments in Ukraine. At the same time, author’s own account of the amount of payments to agricultural producers in this country shall be presented. Unlike other studies, the calculation takes into account two elements that significantly reduce the amount of subsidies. Firstly, after accession, Ukrainian farmers will probably receive only part of the payments, which will be gradually increased (phasing-in mechanism), as was the case with Poland and other countries joining the European Union in 2004. Secondly, the calculation attempts to count the effects of the so-called capping, i.e. a ceiling for the amount of direct payments, which will probably also be applied. The result shows a smaller amount of future payments than the other studies.

Chikungunya is mosquito born disease that is spread across continents. This research provides valuable insights into the potential functional significance of the hydrophobic tail and cysteine-rich regions in E2 proteins. These findings lay the groundwork for future investigations into the specific roles of the C-terminal domain and post-translational modifications, which could ultimately lead to a better understanding of viral mechanisms and potential therapeutic targets.

Fanconi syndrome is a disorder of renal proximal tubule transport characterized by metabolic acidosis, amino aciduria, glucosuria, and phosphaturia. There are acquired and hereditary forms of this disorder. Fanconi syndrome in Basenjis was first described in 1976 and is now recognized as an inherited disease in these dogs. Linkage analysis within a large family of Basenjis that included both affected and unaffected individuals was performed to localize the causative variant within the genome. Significant linkage was identified between chromosome 3 (CFA3) makers and the disease phenotype. Fine mapping restricted the region to a 2.7 Mb section of CFA3. A whole genome sequence of a Basenji affected with Fanconi syndrome was generated, and the sequence data were examined for the presence of potentially deleterious homozygous variants within the mapped region. A homozygous 317 bp deletion was identified in the last exon of FAN1 of the proband. 78 Basenjis of known disease status were genotyped for the deletion variant. Among these dogs, there was almost complete concordance between genotype and phenotype. The only exception was one dog that was homozygous for the deletion variant but did not exhibit signs of Fanconi syndrome. These data indicate that the disorder is very likely the result of FAN1 deficiency. The mechanism by which this deficiency causes the disease signs remains to be elucidated. FAN1 has endonuclease and exonuclease activity that catalyzes incisions in regions of double-stranded DNA containing interstrand crosslinks. FAN1 inactivation may cause Fanconi syndrome in Basenjis by sensitization of kidney proximal tubule cells to toxin-mediated DNA crosslinking resulting in accumulation of genomic and mitochondrial DNA damage in the kidney. Differential exposure to environmental toxins that promote DNA crosslink formation may explain the wide age-at-onset variability for the disorder in Basenjis.

Background: Patients undergoing brain tumor resection experience neurological and cognitive (i.e., neurocognitive) changes reflected in altered performance on neuropsychological tests. These changes can be difficult to explain or predict. Brain connectivity, measured with neuroimaging, offers one potential model for examining these changes. In this study, we evaluated whether longitudinal changes in brain connectivity correlated with changes in neurocognitive abilities in patients before and after brain tumor resection. Methods: Patients underwent functional and diffusion MR scanning and neuropsychological evaluation before tumor resection followed by repeat scanning and evaluation two weeks post-resection. Using this functional and diffusion imaging data, we measured changes in the topology of the functional and structural networks. From the neuropsychological testing scores, we derived a composite score that described a patient’s overall level of neurocognitive functioning. We then used a multiple linear regression model to test whether structural and functional connectivity measures were correlated with changes in composite scores. Results: Multiple linear regression on 21 subjects showed that connectivity changes were highly correlated with changes in neuropsychological evaluation scores (R² adjusted = 0.79, p<0.001). Changes in functional local efficiency (p<0.001) and global efficiency (p<0.05) were inversely correlated with changes in composite score, while changes in modularity (p<0.01) as well as the patient’s age (p<0.05) were directly correlated with changes in composite score. Conclusion: Short interval changes in brain connectivity markers were strongly correlated with changes in the composite neuropsychological test scores in brain tumor resection patients. Our findings support the need for further exploration of brain connectivity as a biomarker relevant to brain tumor patients.

The gut, often referred to as the "second brain," has significant contributions in the maintaining of the good bacteria contribute enormous role such as digestion, produce essential vitamins, support the immune system, and protect against harmful bacteria. The beneficial flora including Akkermansia muciniphila, Adlercreutzia equolifasciens, Barnesiella, Christensenella minuta, and Oxalobacter formigenes, along with their derived bioactive metabolites emerged as a key player in maintaining host metabolic and immune health. Dietary choices such as blending of prebiotic, fermented, symbiotic, anti-inflammatory foods, and secondary metabolites from a wide variety of plants and fruits promotes the diversity, composition, and stability of beneficial intestinal microbes. The colourful plant foods rich in phytochemicals bioactive compounds such as carotenoids, flavonoids, polyphenols, alkaloids, anthocyanins, and capsaicin offer a wide array of unique properties such as analgesics, antioxidants, anti-inflammatory, antimicrobials effect and promoting the abundance of beneficial gut bacteria and their bioactive metabolites confer numerous health-promoting effects. Here, we present knowledge about most beneficial gut bacteria and their derived metabolites in terms of their sources and health benefits. Finally, we discuss best foods that skew towards promoting healthy intestinal microbes.

This article presents a method for detecting P, QRS, T, and U waves in electrocardiogram (ECG) signals through advanced signal processing techniques, including a Butterworth bandpass filter and peak finding algo- rithms. The results are evaluated against the voltage ranges recommended in the literature, underscoring the importance of accurate wave detection for the diagnosis of various cardiac conditions.

Additive Manufacturing (AM) methods are increasingly beign abopted in the industry as an alternative for mass production. In particular, Fused Deposition Modeling (FDM) technology is leading the way in this field. However, the adhesion of layers in products produced using FDM technology is an important issue. These products are particularly vulnerable to forces acting parallel to the layers and specially to impact strength. This study aims to optimize the impact strength against loads acting parallel to the layers (ZX orientation) of PA6, one of the most widely used materials in the industry. This orientation is critical in term of mechanical properties, and the mechanical characteristics are significantly lower compared to other orientation. In this study, filaments containing pure PA6 with 15% short carbon fiber and 30% glass fiber were utilized. Additionally, printing temperature, layer thickness and heat treatment duration were used as independent variables. An L9 orthogonal array was employed in this study, and each experiment was repeated three times to conduct impact strength tests. Characterization, Taguchi optimization, a factor analyses were performed, followed by fracture surface characterization by SEM. As a result, the highest impact strength was achieved with pure PA6 at 8.9 kJ/m2, followed by PA6 GF30 at 8.1 kJ/m2 and the lowest impact strength was obtained with PA6 CF15 at 6.258 kJ/m2. When compared to the literature and manufacturer datasheets, it was concluded that the impact strength values have significantly increased, and the chosen experimental factors and their levels, particularly nozzle temperature, were effective.

For Sir Ronald Fisher, it is important to consistently obtain significant p-values to support an experimental hypothesis. So, replicating experiments to obtain independent p-values is a legitimate and desirable research practice. Several simple statistics have been proposed to meta-analyze p-values, all assuming that they are genuine, i.e. observations from independent standard Uniform random variables. But, as publication bias favors the studies that report "significant" p-values, when a p&gt;0.05 is obtained for the outcome of an experiment, some researchers will "fall into temptation" and decide to replicate the experiment in the hope of getting a smaller second p-value, ideally a significant one. Consequently, if the smallest of two p-values is reported, this is a Beta(1,2) distributed "fake" p-value, not a uniformly distributed genuine p-value. This is an unacceptable scientific research practice, and moreover the detection of fake p-values is unpractical. Even when it is possible, the analytic results to accommodate their existence in combined tests are cumbersome. For an informed decision, inclusive when the presence of fake p-values in a sample of p-values to be meta-analyzed is probable, tables with simulated critical values for the usual combined testing are supplied. This will also allow comparisons to be made between several combined tests.

The global malaria community has picked up the theme of malaria elimination in greater than 90 % of the world’s population in the next decade. The recent reports of P. vivax in all sub-Saharan Africa, including Duffy negative individuals, threaten the efforts to achieve elimination. This is not only in view of strategies that are tailored only to P. falciparum elimination, but also due to currently revealed biological characteristics of P. vivax concerning the relapse patterns of hypnozoites and conservation of a large biomass at cryptic sites in the bone marrow and spleen. A typical scenario has been observed in Botswana from the period between 2008 to 2018, which palpably projects how P. vivax could endanger efforts at malaria elimination where the two parasites co-exist. The need for the global malaria community, NMPs, funding agencies and relevant stakeholders to engage in a forum to discuss and recommend clear pathways for sub-Saharan Africa regarding malaria elimination including P. vivax, is warranted.

Academic and corporate research has been focusing on analyzing stock performances, financial markets, and investment strategies for decades. According to Lynch and Rothchild (1989), certain investments can be described as plays. In this work, the authors use the term for investments in value stocks, spin-offs, and turnarounds to analyze the long-term stock performance and risk-adjusted excess returns of up to five years for those stocks. Additionally, stocks with a supe-rior return performance are identified within an investment play based on low P/E and P/B mul-tiples. The study finds that value stocks, spin-offs, and turnarounds outperform the S&P 500 on average on a one-, three- and five-year investment horizon. The analysis of the three investment plays confirms earlier studies that investment plays constitute a profitable investment opportunity. Moreover, the research exemplifies that private investors could achieve an excess return (alpha) through a passive buy-and-hold investment strategy. Overall, the analysis provides a deeper in-sight into the long-term performance of value stocks, spin-offs, and turnarounds.

Purpose: This study evaluates the impact of Medicaid expansion under the Affordable Care Act (ACA) on melanoma staging at diagnosis, treatment utilization, and 3-year mortality outcomes. The objective is to determine whether Medicaid expansion led to earlier melanoma diagnosis and improved survival rates among non-elderly adults (ages 40-64) by analyzing data from the National Cancer Database (NCDB). Methods: A total of 12,667 patients, aged 40-64, diagnosed with melanoma from 2010 to 2020 were identified using the NCDB. Difference-in-difference (DID) analysis was performed to analyze tumor staging at presentation between Medicaid expansion states and non-Medicaid expansion states both prior to the expansion and after the expansion. Results: Of the total patients 2,307 were from the pre-expansion time period residing in Medicaid Expansion states (MES) and 1,804 in non-Medicaid expansion states. In the post-expansion time period there were 5,571 residing in the MES and 2,985 in the non-MES. DID analysis revealed a decrease in stage IV melanoma at diagnosis (DID -0.222, p <0.001) between MES and non-MES before and after Medicaid expansion. After expansion, in stage IV, the occurrence of primary surgery was 0.42 in non-MES and 0.44 (difference 0.02), DID analysis was not statistically significant. The use of immunotherapy in MES was significantly higher than non-MES after expansion (p<0.001), although DID analysis did not reveal a statistically significant difference. DID analysis showed a statistically significant decrease in 3-year mortality (DID -0.05, p=0.001) between MES and non-MES before and after Medicaid expansion. Conclusions: This study revealed the positive impact of the ACA’s Medicaid expansion on melanoma stage at presentation showing improved access to healthcare services can facilitate the diagnosis of early-stage melanoma and decrease mortality rate.

Background: An accurate diagnosis of thyroid nodules is crucial for avoiding unnecessary surgical procedures and making timely treatment possible. The objective of the present study was to evaluate the diagnostic accuracy of FNAB (fine-needle aspiration biopsy) using histopathological findings as the reference standards. Patients with the diagnostic categories (DCs) III, IV, V were subjected to a special analysis. In addition, the authors assessed whether other factors, i.e. age, gender, BMI (body mass index), obesity and histopathologically confirmed lymphocytic thyroiditis had an impact on the occurrence of malignant tumors. Methods: A retrospective analysis was conducted on 535 patients who underwent thyroid surgery between October 2022 and September 2023. To assess the FNAB reliability, the result obtained using the Bethesda classification was compared with the histopathological result. Results: The ROM (risk of malignancy) values for DCs I-VI were 38.1%, 15.6%, 29.8%, 18.6%, 91.0%, 93.2%, respectively. DC V (OR 62.34, p< 0.0001) and age≤50 (OR=2.31, p<0.006) had a statistically significant effect on the risk of thyroid cancer. DCs III and IV were not statistically significantly associated with the risk of malignancy (OR=1.68,p=0.16; OR=1.51,p=0.3,respectively). There were no statistically significant differences in sex, BMI and obesity between the patients with benign and malignant lesions. Conclusion: DC V is associated with a high likelihood of malignancy, especially in patients under 50 years of age, and therefore surgery is indicated in this category of subjects. In the DCs III and IV categories, the risk of malignancy is lower and conservative management with active clinical and ultrasound surveillance can be considered. In patients < 50 years of age, with the Bethesda categories III and IV, surgical treatment should be considered.

Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic approach for a wide variety of diseases, offering the potential to modulate gene expression with a high degree of specificity. These small, synthetic nucleic acid-like molecules provide unique advantages over traditional pharmacological treatments, including the ability to target previously "undruggable" genes. Despite this promise, several biological barriers severely limit their clinical efficacy Upon administration, ASOs primarily enter cells through endocytosis, becoming trapped inside membrane-bound vesicles known as endosomes. Studies estimate that only 1-2% of ASOs successfully escape endosomal compartments to reach the cytosol, and ultimately the nucleus, where they bind target mRNA and exert their therapeutic effect. Endosomal entrapment and inefficient nuclear localization are therefore critical bottlenecks in the therapeutic application of ASOs. This review explores the current understanding of endosomal escape, and nuclear transport of ASOs. Furthermore, we examine strategies aimed at overcoming these challenges, including the use of endosomal escape agents, peptide-ASO conjugates, non-viral delivery vehicles, and nuclear localization signals. By improving both endosomal escape and nuclear localization, significant advances in ASO-based therapeutics can be realized, ultimately enhancing their potency and expanding their clinical utility

Rhynchocypris kumgangensis, endemic to Korea, is limited to the upper Hangang River and Gucheondongcheon Stream. As a key and climate-sensitive biological indicator species in Deogyusan National Park, it has a southern range limit in the Gucheondong Valley. Due to climate change, notable shifts in the activity, vertical distribution, and population of R. kumgangensis in the Gucheondongcheon Stream are expected. Owing to the rapidly changing climate, significant changes in the activity, vertical distribution, and population size of R. kumgangensis in the Gucheondongcheon Stream are anticipated, and continuous surveys of the distribution of R. kumgangensis in this river area have been conducted. This study assessed the habitat of R. kumgangensis at 13 sites, including five in the Gucheondongcheon Stream, from July to October 2020 and compared the results with historical data to evaluate the impacts of climate change. At the five Gucheondongcheon Stream sites, 102 individuals were recorded from April to October 2020, and 378 were recorded between June 2018 and July 2019. Additionally, the subdominant species shifted from R. kumgangensis (2014–2018) to Zacco koreanus (2020). In the two southernmost Gucheondongcheon Stream sites, only 18 R. kumgangensis were observed in 2020 compared to 82 in 2019, indicating a significant population decline.

This study presents the experimental and analytical evaluations on an innovative connection class under cyclic loading. The connection was an H- or I-shaped section as a short stub column (SSC) between the end-plate and the column. The stub section was bolted to the column flange on the one side and bolted to the beam along with the welded end-plate on the other side. Stiffeners were installed on the webs and flanges of the beam and stub to ensure the necessary stiffness of the connection. The variables included thickness of stub flange/web and height of stub web. The cyclic loading was applied on a sample of the proposed connection according to AISC ANSI/AISC 341-16 loading protocol. Experimental observations displayed that the proposed connection, one can either employ hot rolling sections or create the connection as a plate girder, in which case the flange thickness and stub web, as well as the distance between two flanges and their height, was obtained according to the demand and performance of the structure. The optimum cross-section of the stub was then obtained. Also, the analytical model was calibrated using the finite element method (FEM), and its performance was confirmed. The effective parameters of the proposed connection were determined by modeling in the FEM software, and the design method was presented.

Objective: In recent years, the field of Essential Thrombocythemia (ET) research has seen a significant accumulation of scientific findings, but comprehensive bibliometric analyses remain lacking. This study aims to fill that gap by performing a thorough bibliometric analysis of ET research, identifying key contributors and collaboration networks, and mapping the development trends to provide insights for future research directions. Methods: A bibliometric analysis of ET-related publications from 2001 to 2024 was conducted using CiteSpace, VOSviewer, and R packages. Data were retrieved from the Web of Science Core Collection, with a focus on publication volume, citation analysis, co-authorship networks, co-citation relationships, and citation bursts. Results: A total of 4,297 studies published in 778 journals were included in the analysis. ET research has seen rapid growth, with researcher clusters in the United States and Europe driving progress through extensive regional and international collaborations. Leading researchers, such as Ayalew Tefferi from the Mayo Clinic and Alessandro M. Vannucchi from the University of Florence, have made significant advances in ET classification, molecular mechanisms, targeted therapies, and disease management. The discovery of driver mutations, such as JAK2, has revolutionized the diagnostic and therapeutic approaches to ET. Research focus has shifted from clinical morphological diagnosis to molecular diagnostics, with the field now entering the era of targeted therapies. However, the inherent heterogeneity of ET continues to present challenges for the widespread implementation of personalized precision treatment. Conclusion: Bibliometric analysis demonstrates significant advances in ET research, particularly in molecular pathology and targeted therapies. However, the heterogeneity of ET remains a major obstacle to personalized treatment. Future research should focus on further elucidating the pathogenesis of ET and improving stratified management approaches to achieve individualized precision therapy.

Phosphorus (P) is an essential element in food production, but it is often largely unavailable for plants as it persists in soils in immobilized forms. Farmers have been using P fertilizers extensively to overcome this unavailability, leading to the exhaustion of non-renewable deposits of phosphorite, rising fertilizers prices and causing several environmental impacts such as eutrophication. Its large-scale utilization is also inefficient since most of the added P becomes quickly unavailable for the plants. Therefore, farming solutions that improve P uptake, P use efficiency of plants and P mobilization in soils are highly important. In this narrative review, we summarized and explored the link between the Silicon (Si) and P cycles in soils. Silicon is quasi-essential for plants, and it has been established that its presence in soil and uptake by plants has several benefits, especially in toxic and nutrient-deficient conditions. Here, we established that Si in soils can affect crop production in P-deficient conditions through: 1) the pH effect – Si improves organic matter decomposition and decreases Al3+ availability; the Si uptake effect – the deposited Si in the plant improves its photosynthetic performance, improves the root ability to uptake P, improves organic matter decomposition and increases P/Mn ration in plant, improving P use; and 3) the Si soil effect – Si stimulates phosphorite rocks weathering and competes with P for the binding places at the surface of Ak and Fe hydroxides, releasing P into soil solution. This positive effect of Si on P mobilization in soils and consequent use by crops should be further disseminated to farmers and other relevant stakeholders.

Cystic fibrosis (CF) diagnosis can be a challenge due to the large spectrum of pathogenic variants in the CFTR gene and the effects of complex alleles. Next-generation sequencing has improved our understanding of the contribution of these complex alleles to the wide spectrum of CF clinical symptoms and to the response to medications. Herein, we studied nine CF patients from six unrelated families carrying the complex allele p.[Ile148Thr;Ile1023_Val1024del] with a frequency of 0.18%. All the patients were from Central Mexico. This complex allele was found in trans with Class I and II pathogenic variants (PVs) such as [c.1521_1523del, p.(Phe508del), and c.3231_3232del, p.(Phe1078Profs*77)]. A targeted search of a dataset of 2,217 exomes from healthy individuals revealed that eight individuals (0.18%) carried the p.(Ile148Thr) variant, but only one (0.022%), who was also born in Central Mexico, was a carrier of the complex allele. These findings led us to hypothesize a founder effect for the p.[Ile148Thr;Ile1023_Val1024del] complex allele in Mexican patients with CF, probably through migration from the French-Canadian population in Mexico. Finally, protein modeling revealed that this complex allele disrupts the secondary structure of the CFTR protein and might alter the ion flow.

In this paper, various Ni-P composite coatings containing toner, MoS2, and nano-SiO2 particles were deposited on steel substrates by the electroless method. Then, the electrochemical properties of these coatings after a heat treatment process were compared. The microstructural evaluations were also done by using the optical and electron microscopy methods. Both Tafel polarization and electrochemical impedance spectroscopy techniques were utilized to survey the electrochemical behavior of such coatings. The surface morphology of all coatings contained cauliflower-like nodules. The X-ray diffraction patterns showed the crystalline phases of Ni and Ni3P for all coatings after the heat-treatment step. Obtained results showed that all composite coatings exhibited lower corrosion rates with respect to Ni-P coatings. Such a reduction was about 21.6-92.2%. This behavior was attributed to the presence of reinforcement as barriers for corrosive ion diffusion through the coating plus the changes in detected phases and thickness. Electrochemical impedance spectroscopy test results also demonstrated that the increase in the polarization resistance for composites coatings was about 18.4-85.3% after 1 h immersion in a 0.6M NaCl solution; however, when the immersion time increased to 24 h, such increased resistance changed to 18.1 to 73.1%. Totally, despite the lower deposition rate, the presence of MoS2 and nano-SiO2 particles were more effective than toner particles to raise the corrosion rate of the Ni-P coating.

In this paper, we investigate p-adic q-integral (q-Volkenborn integral) on Z_p of p-adic gamma function via their Mahler expansions. We also derived two q-Volkenborn integrals of p-adic gamma function in terms of q-Daehee polynomials and numbers and q-Daehee polynomials and numbers of the second kind. Moreover, we discover q-Volkenborn integral of the derivative of p-adic gamma function. We acquire the relationship between the p-adic gamma function and Stirling numbers of the first kind. We finally develop a novel and interesting representation for the p-adic Euler constant by means of the q-Daehee polynomials and numbers.

It is known that the class of p-normed spaces (0 < p ≤ 1) is an important generalization of usual normed spaces with rich topological and geometrical structure, but the most of tools and general principles in nature with nonlinearity have not been developed yet, thus the main goal of this paper is to develop tools for nonlinear analysis under the framework of p-vector spaces. In particular, we first develop the general fixed point theorems which provide solutions to answer Schauder conjecture since 1930’s in the affirmative for p-vector spaces when p = 1 (which is just general topological vector spaces); then the one best approximation result for upper semi-continuous mappings is given, which is used as a powerful tool to establish fixed points for non-self set-valued mappings with either inward or outward set conditions; and finally we establish comprehensive existence results of solutions for Birkhoff-Kellogg Problems, and the general principle of nonlinear alternative by including Leray-Schauder alternative and related results. The results given in this paper not only include the corresponding results in the existing literature as special cases, but also expected to be useful tools for the study of nonlinear problems arising from theory to practice.

المستخلص تصنيع لقاح مكون من الحمض النووي الريبوزي الرسول الخاص بالبروتينات المسئولة عن انتاج البروتينات نيورامنيديز والهيم اجليوتونين لفيروسي الانفلونزا الخنازير والطيورمحاط بجزيئات دهنية بحجم النانوميتر عدوى انفلونزا الخنازير وانفلونزا الطيور مشكلة خطيرة تؤرق العالم كله هذه الايام خصوصا انها مميتة لكثير من اطفال العالم . بعد فترة التعافي من الاصابة تتكون المناعة المكتسبة ضدها لمدة عام تقريبا. هذه الانفلونزا تسبب تسمم فيروسي في الدم بالاضافة للالتهاب الرئوي وهذامن بين اكبرالاسباب للوفاة بين الاطفال قبل سن عامين عالميا بشكل مباشر. الهدف من الدراسة هو انتاج لقاح الحمض النووي الريبوزي الرسول من نوع الام بالنانوتكنولوجي لبروتينات الهيم اجليوتونين والنيورامنيديز الموجودة على سطح هذه الفيروسات التي تساعدتها في الاتصاق بالعائل الذي ستتكاثر داخل خلاياه بالجهاز التنفسي. هذه الدراسة دراسة استكشافية ومن خلالها استطاعنا تصميم هذا اللقاح باستعمال نظام توصيل للقاح بالنانوتكنولوجي حجم جزيئاته 70نانوميمتر. اللقاح الجديد اظهر فاعلية بنسبة 60% واظهر فاعلية حيوية مقاربة واثار جانبية اقل بالمقارنة باللقاحات المتوفرة حاليا بالسوق الدوائي ضد هذا النوع من الفيروسات الوبائية. ABSTRACT Background: Worldwide, Swine and Avian influenza, or the H1N1 and H5N1 serotypes of the Influenza A virus, is a highly contagious illness. In recent years, the global incidence of mortality rate has surpassed 284,000 fatalities. Aim of the study: The production of mRNA vaccine lipid nanoparticles (LNP) to combat the deadly strains of Avian and Swine influenza (H1N1 and H5N1 of the influenza A serotype). Methodology: Polymerase chain reaction (PCR) was used to clone genes of interest encoding Haemagglutinin (HA) and Neuraminidase (NA) of Influenza A virus strains (H5N1 and H1N1) known as Avian flu and Swine flu, respectively. The genes were then inserted using the EcoR1, BAM Hind II restriction endonuclease type II, and Ligase enzyme into the pET-21(+) transcription vector plasmid. On the other hand, the hybrid transcription vectors were mixed with T7 RNA polymerase and ribonucleotides within a test tube after being linearized using EcoR II. Following their purification via reversed-phase high-performance liquid chromatography (RP-HPLC), the mRNAs of the HA and NA were encased in 70 nm LNPs and subjected to reverse-phase high-performance liquid chromatography (RP-HPLC). Lastly, immunogenicity studies were performed in stages 1/2 of randomized human and preclinical clinical trials. Results: The bivalent vaccination had around 63% efficacy in preclinical studies and approximately 60% efficacy in randomized human clinical trials. As shown by the ELISA test, strong neutralizing antibodies against HA were prevalent. Conclusion: The current study is a promising effort because of the development of the novel LNP-mRNA vaccine, which could lower the incidence of Avian and Swine flu infectious disorders.