N-terminal phosphorylation regulates the activity of Glycogen Synthase Kinase 3 from Plasmodium falciparum

As the decline of malaria cases stalled over the last five years, novel targets in Plasmodium falciparum are necessary for the development of new drugs. Glycogen Synthase Kinase (PfGSK3) has been identified as a potential target, since its selective inhibitors were shown to disrupt the parasite's life cycle. In the uncanonical N‑terminal region of the parasite enzyme, we identified several autophosphorylation sites and probed their role in activity regulation of PfGSK3. By combining molecular modeling with experimental small-angle X-ray scattering data, we show that increased PfGSK3 activity is promoted by conformational changes in the PfGSK3 N‑terminus, triggered by N‑terminal phosphorylation. Our work provides novel insights into the structure and regulation of the malarial PfGSK3.

Integrated Multi-Omics for Novel Aging Biomarkers and Antiaging Targets

Aging is closely related to the occurrence of human diseases; however, its exact biological mechanism is unclear. Advancements in high-throughput technology provide new opportunities for omics research to understand the pathological process of various complex human diseases. However, single-omics technologies only provide limited insights into the biological mechanisms of diseases. DNA, RNA, protein, metabolites, and microorganisms usually play complementary roles and perform certain biological functions together. In this review, we summarize multi-omics methods based on the most relevant biomarkers in single-omics to better understand molecular functions and disease causes. The integration of multi-omics technologies can systematically reveal the interactions among aging molecules from a multidimensional perspective. Our review provides new insights regarding the discovery of aging biomarkers, mechanism of aging, and identification of novel antiaging targets. Overall, data from genomics, transcriptomics, proteomics, metabolomics, integromics, microbiomics, and systems biology contribute to the identification of new candidate biomarkers for aging and novel targets for antiaging interventions.

Extracellular Vesicles and Ovarian Cancer

Extracellular vesicles (EVs) are a varied group of cell-derived, microscopic, fluid-filled pouches released from cells into neighboring microenvironments that are quickly gaining recognition as a potentially powerful tool against epithelial ovarian cancer (EOC). Recent studies show that not only do EVs play an integral part in the development of cancer through intercellular communication, cell survival, and immune modulation but also may assist with early diagnosis and improved treatments. EOC currently has few effective screening options for early detection of this disease; and, therefore, it is detected at an advanced stage where it is more likely to recur, develop chemoresistance, and ultimately become fatal. Newer research has evaluated EVs as biomarkers for early screening and diagnosis and as novel targets for treatment of EOC. Moreover, EVs are possible targets for novel immunomodulatory therapies to directly target cancer cells or make cancer cells more susceptible to other treatment modalities. Therefore, EVs present an exciting, promising approach which may improve clinical outcome for EOC patients.

Advances in Antifungal Drug Development: An Up-To-Date Mini Review

The utility of clinically available antifungals is limited by their narrow spectrum of activity, high toxicity, and emerging resistance. Antifungal drug discovery has always been a challenging area, since fungi and their human host are eukaryotes, making it difficult to identify unique targets for antifungals. Novel antifungals in clinical development include first-in-class agents, new structures for an established target, and formulation modifications to marketed antifungals, in addition to repurposed agents. Membrane interacting peptides and aromatherapy are gaining increased attention in the field. Immunotherapy is another promising treatment option, with antifungal antibodies advancing into clinical trials. Novel targets for antifungal therapy are also being discovered, allowing the design of new promising agents that may overcome the resistance issue. In this mini review, we will summarize the current status of antifungal drug pipelines in clinical stages, and the most recent advancements in preclinical antifungal drug development, with special focus on their chemistry.

Therapeutic Targets in Diffuse Midline Gliomas—An Emerging Landscape

Diffuse midline gliomas (DMGs) are invariably fatal pediatric brain tumours that are inherently resistant to conventional therapy. In recent years our understanding of the underlying molecular mechanisms of DMG tumorigenicity has resulted in the identification of novel targets and the development of a range of potential therapies, with multiple agents now being progressed to clinical translation to test their therapeutic efficacy. Here, we provide an overview of the current therapies aimed at epigenetic and mutational drivers, cellular pathway aberrations and tumor microenvironment mechanisms in DMGs in order to aid therapy development and facilitate a holistic approach to patient treatment.

Pyroptosis: Mechanisms and Links with Fibrosis

Fibrosis is responsible for approximately 45% of deaths in the industrialized world and has been a major global healthcare burden. Excessive fibrosis is the primary cause of organ failure. However, there are currently no approved drugs available for the prevention or treatment of fibrosis-related diseases. It has become evident that fibrosis is characterized by inflammation. In a large number of studies of various organs in mice and humans, pyroptosis has been found to play a significant role in fibrosis. Pyroptosis is a form of programmed cell death mediated by the N-terminal fragment of cysteinyl aspartate-specific proteinase (caspase)-1-cleaved gasdermin D (GSDMD, producing GSDMD-N) that gives rise to inflammation via the release of some proinflammatory cytokines, including IL-1β, IL-18 and HMGB1. These cytokines can initiate the activation of fibroblasts. Inflammasomes, an important factor upstream of GSDMD, can activate caspase-1 to trigger the maturation of IL-1β and IL-18. Moreover, the inhibition of inflammasomes, proinflammatory cytokines and GSDMD can prevent the progression of fibrosis. This review summarizes the growing evidence indicating that pyroptosis triggers fibrosis, and highlights potential novel targets for antifibrotic therapies.

Identification and characterization of bisbenzimide compounds that inhibit human cytomegalovirus replication

The shortcomings of current anti-human cytomegalovirus (HCMV) drugs has stimulated a search for anti-HCMV compounds with novel targets. We screened collections of bioactive compounds and identified a range of compounds with the potential to inhibit HCMV replication. Of these compounds, we selected bisbenzimide compound RO-90-7501 for further study. We generated analogues of RO-90-7501 and found that one compound, MRT00210423, had increased anti-HCMV activity compared to RO-90-7501. Using a combination of compound analogues, microscopy and biochemical assays we found RO-90-7501 and MRT00210423 interacted with DNA. In single molecule microscopy experiments we found RO-90-7501, but not MRT00210423, was able to compact DNA, suggesting that compaction of DNA was non-obligatory for anti-HCMV effects. Using bioinformatics analysis, we found that there were many putative bisbenzimide binding sites in the HCMV DNA genome. However, using western blotting, quantitative PCR and electron microscopy, we found that at a concentration able to inhibit HCMV replication our compounds had little or no effect on production of certain HCMV proteins or DNA synthesis, but did have a notable inhibitory effect on HCMV capsid production. We reasoned that these effects may have involved binding of our compounds to the HCMV genome and/or host cell chromatin. Therefore, our data expand our understanding of compounds with anti-HCMV activity and suggest targeting of DNA with bisbenzimide compounds may be a useful anti-HCMV strategy.

Transference of Self Concept in First Impressions of Similar Others

<p>Forming rapid and reasonably accurate impressions of other people to determine the potential for threat is a crucial human skill that has evolved over millennia. That said, often these first impressions may be inaccurate as the processes underlying person perception are subject to bias. Transference is one such bias which occurs when an encountered novel individual, for whatever reason, is similar enough that he or she activates the mental representation of a ‘significant other’ which is then “transferred” to that novel individual. In particular, judgments of the new person are assimilated to both evaluations (positive or negative) as well as the specific trait content of the activated representation. The current research proposed that the self-concept as activated by self-similar stimuli can act in a similar fashion. Specifically, it was proposed that activation of the self-concept – through encountering an individual who is similar to the self – may trigger transference of self-concept-related feelings and emotions to a novel other. The current research tested this prediction in four experiments by comparing participant judgements of own self-concept with trait-related judgements about novel targets, half of which were modified to resemble the perceiver. It was expected that participants would rate participant-similar stimuli as more similar to themselves than non-similar stimuli. Overall, experimental results did not support this hypothesis in that participant judgements and evaluations of self-resembling faces did not differ significantly from judgements and evaluations of stranger-similar faces in any reliable pattern. The implications of these findings are discussed in relation to previous research on first impressions, transference, and self-concept.</p>

Transference of Self Concept in First Impressions of Similar Others

<p>Forming rapid and reasonably accurate impressions of other people to determine the potential for threat is a crucial human skill that has evolved over millennia. That said, often these first impressions may be inaccurate as the processes underlying person perception are subject to bias. Transference is one such bias which occurs when an encountered novel individual, for whatever reason, is similar enough that he or she activates the mental representation of a ‘significant other’ which is then “transferred” to that novel individual. In particular, judgments of the new person are assimilated to both evaluations (positive or negative) as well as the specific trait content of the activated representation. The current research proposed that the self-concept as activated by self-similar stimuli can act in a similar fashion. Specifically, it was proposed that activation of the self-concept – through encountering an individual who is similar to the self – may trigger transference of self-concept-related feelings and emotions to a novel other. The current research tested this prediction in four experiments by comparing participant judgements of own self-concept with trait-related judgements about novel targets, half of which were modified to resemble the perceiver. It was expected that participants would rate participant-similar stimuli as more similar to themselves than non-similar stimuli. Overall, experimental results did not support this hypothesis in that participant judgements and evaluations of self-resembling faces did not differ significantly from judgements and evaluations of stranger-similar faces in any reliable pattern. The implications of these findings are discussed in relation to previous research on first impressions, transference, and self-concept.</p>