Project description:Enteric viral and bacterial infections continue to be a leading cause of mortality and morbidity in young children in low-income and middle-income countries, the elderly, and immunocompromised individuals. Vaccines are considered an effective and practical preventive approach against the predominantly fecal-to-oral transmitted gastroenteritis particularly in the resource-limited countries or regions where implementation of sanitation systems and supply of safe drinking water are not quickly achievable. While vaccines are available for a few enteric pathogens including rotavirus and cholera, there are no vaccines licensed for many other enteric viral and bacterial pathogens. Challenges in enteric vaccine development include immunological heterogeneity among pathogen strains or isolates, a lack of animal challenge models to evaluate vaccine candidacy, undefined host immune correlates to protection, and a low protective efficacy among young children in endemic regions. In this article, we briefly updated the progress and challenges in vaccines and vaccine development for the leading enteric viral and bacterial pathogens including rotavirus, human calicivirus, Shigella, enterotoxigenic Escherichia coli (ETEC), cholera, nontyphoidal Salmonella, and Campylobacter, and introduced a novel epitope- and structure-based vaccinology platform known as MEFA (multiepitope fusion antigen) and the application of MEFA for developing broadly protective multivalent vaccines against heterogenous pathogens.
Project description:INTRODUCTION:Pulmonary lymphangioleiomyomatosis (LAM) is a rare progressive lung disease affecting almost exclusively women. Neoplastic growth of atypical smooth muscle-like cells in the lung induces destruction of lung parenchyma leading to the formation of lung cysts, rupture of which results in spontaneous pneumothorax. LAM occurs sporadically or in association with inherited hamartoma syndrome tuberous sclerosis complex (TSC). Progression of LAM often results in loss of pulmonary function and death. Increasing understanding of neoplastic LAM cell growth is driving the development of therapeutic approaches targeting the disease progression. AREAS COVERED:This review provides background to understand the rationale for current treatments used in patients with LAM, to critically appraise the evidence for these treatments, and to discuss future treatment approaches. The literature review includes publications from PubMed and clinicaltrials.gov/. EXPERT OPINION:Targeting mTOR activation with rapamycin analogs sirolimus and everolimus are awaiting approval by the FDA for treatment of LAM. A number of other treatment options have been investigated and are currently tested in clinical trials to target LAM cell survival and metastasis. Key remaining and poorly understood areas for development and validation of therapeutic targeting in LAM are destruction of lungs, pathological lymphangiogenesis, and hormonal regulation. Future will reveal whether they could be targeted therapeutically.
Project description:Recent breakthroughs in next-generation sequencing technologies have led to the discovery of several classes of non-coding RNAs (ncRNAs). It is now apparent that RNA molecules are not only just carriers of genetic information but also key players in many cellular processes. While there has been a rapid increase in the number of ncRNA sequences deposited in various databases over the past decade, the biological functions of these ncRNAs are largely not well understood. Similar to proteins, RNA molecules carry out a function by forming specific three-dimensional structures. Understanding the function of a particular RNA therefore requires a detailed knowledge of its structure. However, determining experimental structures of RNA is extremely challenging. In fact, RNA-only structures represent just 1% of the total structures deposited in the PDB. Thus, computational methods that predict three-dimensional RNA structures are in high demand. Computational models can provide valuable insights into structure-function relationships in ncRNAs and can aid in the development of functional hypotheses and experimental designs. In recent years, a set of diverse RNA structure prediction tools have become available, which differ in computational time, input data and accuracy. This review discusses the recent progress and challenges in RNA structure prediction methods.
Project description:HIV-1 causes AIDS, a syndrome that affects millions of people globally. Existing HAART is efficient in slowing down disease progression but cannot eradicate the virus. Furthermore the severity of the side effects and the emergence of drug-resistant mutants call for better therapy. Gene therapy serves as an attractive alternative as it reconstitutes the immune system with HIV-resistant cells and could thereby provide a potential cure. The feasibility of this approach was first demonstrated with the 'Berlin patient', who was functionally cured from HIV/AIDS with undetectable HIV-1 viral load after transplantation of bone marrow harboring a naturally occurring CCR5 mutation that blocks viral entry. Here, we give an overview of the current status of HIV gene therapy and remaining challenges and obstacles.
Project description:Purpose of reviewSchizophrenia is a heterogeneous psychiatric disorder with a different, but not necessarily milder clinical presentation in women as compared to men. These sex differences have largely been attributed to the protective role of estrogens. This article reviews the current state of estrogen research in schizophrenia.Recent findingsEstrogens regulate important pathophysiological pathways in schizophrenia, including dopamine activity, mitochondrial function, and the stress system. Estrogen deficiency is common in both sexes and is associated with increases in psychotic symptoms. Hyperprolactinemia causes secondary estrogen deficiency and can be a reaction to stress, or secondary to prolactin-raising antipsychotics. Therefore, prolactin-sparing antipsychotics should be preferred especially in premenopausal women, who are more prone to hyperprolactinemia. Premenopausal women furthermore require lower doses of antipsychotics than men, since estrogens raise the availability and efficacy of antipsychotics.SummaryThe past years have established the importance of estrogens in the pathophysiology of schizophrenia and have shown its relevance to clinical practice through its influence on antipsychotic drug efficacy. Future research should focus on the neurobiological and clinical effect of contraceptives in premenopausal women with schizophrenia. Furthermore, the potential of estrogen-like augmentation with raloxifene and phytoestrogens in schizophrenia should be established in the coming years.
Project description:Vaccines have had a profound impact on the management and prevention of infectious disease. In addition, the development of vaccines against chronic diseases has attracted considerable interest as an approach to prevent, rather than treat, conditions such as cancer, Alzheimer's disease, and others. Subunit vaccines consist of nongenetic components of the infectious agent or disease-related epitope. In this Review, we discuss peptide-based vaccines and their potential in three therapeutic areas: infectious disease, Alzheimer's disease, and cancer. We discuss factors that contribute to vaccine efficacy and how these parameters may potentially be modulated by design. We examine both clinically tested vaccines as well as nascent approaches and explore current challenges and potential remedies. While peptide vaccines hold substantial promise in the prevention of human disease, many obstacles remain that have hampered their clinical use; thus, continued research efforts to address these challenges are warranted.
Project description:Bacterial infections remain a formidable threat to human health, a situation exacerbated by the escalating problem of antibiotic resistance. While alternative antibacterial strategies such as oxidants, heat treatments, and metal nanoparticles (NPs) have shown potential, they come with significant drawbacks, ranging from non-specificity to potential environmental concerns. In the face of these challenges, the rapid evolution of micro/nanomotors (MNMs) stands out as a revolutionary development in the antimicrobial arena. MNMs harness various forms of energy and convert it into a substantial driving force, offering bright prospects for combating microbial threats. MNMs' mobility allows for swift and targeted interaction with bacteria, which not only improves the carrying potential of therapeutic agents but also narrows the required activation range for non-drug antimicrobial interventions like photothermal and photodynamic therapies, substantially improving their bacterial clearance rates. In this review, we summarized the diverse propulsion mechanisms of MNMs employed in antimicrobial applications and articulated their multiple functions, which include direct bactericidal action, capture and removal of microorganisms, detoxification processes, and the innovative detection of bacteria and associated toxins. Despite MNMs' potential to revolutionize antibacterial research, the translation from laboratory to clinical use remains challenging. Based on the current research status, we summarized the potential challenges and possible solutions and also prospected several key directions for future studies of MNMs for antimicrobial purposes. Collectively, by highlighting the important knowns and unknowns of antimicrobial MNMs, our present review would help to light the way forward for the field of antimicrobial MNMs and prevent unnecessary blindness and detours.
Project description:Personalized medicine has been identified as a powerful tool for addressing the myriad of health issues facing different health systems globally. Although recent studies have expanded our understanding of how different factors such as genetics and the environment play significant roles in affecting the health of individuals, there are still several other issues affecting their translation into personalizing health interventions globally. Since African populations have demonstrated huge genetic diversity, there is a significant need to apply the concepts of personalized medicine to overcome various African-specific health challenges. Thus, we review the current state, progress, and challenges facing the adoption of personalized medicine in Africa with a view to providing insights to critical stakeholders on the right approach to deploy.
Project description:Two-pore channels (TPCs) are cation-permeable channels located on endolysosomal membranes and important mediators of intracellular Ca2+ signalling. TPCs are involved in various pathophysiological processes, including cell growth and development, metabolism, and cancer progression. Most studies of TPCs have used TPC-/- cell or whole-animal models, or Ned-19, an indirect inhibitor. The TPC activation mechanism remains controversial, which has made it difficult to develop selective modulators. Recent studies of TPC structure and their interactomes are aiding the development of direct pharmacological modulators. This process is still in its infancy, but will facilitate future research and TPC targeting for therapeutical purposes. Here, we review the progress of current research into TPCs, including recent insights into their structures, functional roles, mechanisms of activation, and pharmacological modulators.
Project description:Multiple vaccines have recently been developed, and almost all the countries are presently vaccinating their population to tackle the COVID-19 pandemic. Most of the COVID-19 vaccines in use are administered via intramuscular (IM) injection, eliciting protective humor and cellular immunity. COVID-19 intranasal (IN) vaccines are also being developed that have shown promising ability to induce a significant amount of antibody-mediated immune response and a robust cell-mediated immunity as well as hold the added ability to stimulate protective mucosal immunity along with the additional advantage of the ease of administration as compared to IM injected vaccines. By inducing secretory IgA antibody responses specifically in the nasal compartment, the intranasal SARS-CoV-2 vaccine can prevent virus infection, replication, shedding, and disease development, as well as possibly limits virus transmission. This article highlights the current progress, advantages, prospects, and challenges in developing intranasal COVID-19 vaccines for countering the ongoing pandemic.