Conquering Neutrophils.
Ontology highlight
ABSTRACT:
SUBMITTER: Dohrmann S
PROVIDER: S-EPMC4965185 | biostudies-literature | 2016 Jul
REPOSITORIES: biostudies-literature
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Project description:Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors. Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities. Yet, no matter how a cancer is addicted to a specific target - cancer's genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions. Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.
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Project description:Machine learning methods, including Random Forests (RF), are increasingly used for genetic data analysis. However, the standard RF algorithm does not correctly model the effects of X chromosome single nucleotide polymorphisms (SNPs), leading to biased estimates of variable importance. We propose extensions of RF to correctly model X SNPs, including a stratified approach and an approach based on the process of X chromosome inactivation. We applied the new and standard RF approaches to case-control alcohol dependence data from the Study of Addiction: Genes and Environment (SAGE), and compared the performance of the alternative approaches via a simulation study. Standard RF applied to a case-control study of alcohol dependence yielded inflated variable importance estimates for X SNPs, even when sex was included as a variable, but the results of the new RF methods were consistent with univariate regression-based approaches that correctly model X chromosome data. Simulations showed that the new RF methods eliminate the bias in standard RF variable importance for X SNPs when sex is associated with the trait, and are able to detect causal autosomal and X SNPs. Even in the absence of sex effects, the new extensions perform similarly to standard RF. Thus, we provide a powerful multimarker approach for genetic analysis that accommodates X chromosome data in an unbiased way. This method is implemented in the freely available R package "snpRF" (http://www.cran.r-project.org/web/packages/snpRF/).
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Project description:Invasive fungal infections (IFIs) pose a serious clinical problem, but the antifungal arsenal is limited and has many disadvantages, such as drug resistance and toxicity. Hence, there is an urgent need to develop antifungal compounds that target novel target proteins of pathogenic fungi for treating IFIs. This review provides a comprehensive summary of the biological functions of novel promising target proteins for treating IFIs in pathogenic fungi and their inhibitors. Inhibitors of inositol phosphoramide (IPC) synthases (such as Aureobasidin A, Khafrefungin, Galbonolide A, and Pleofungin A) have potent antifungal activities by inhibiting sphingolipid synthesis. Disrupting glycosylphosphatidylinositol (GPI) biosynthesis by Jawsamycin (an inhibitor of Spt14), M720 (an inhibitor of Mcd4), and APX001A (an inhibitor of Gwt1) is a promising strategy for treating IFIs. Turbinmicin is a natural-compound inhibitor of Sec14 and has extraordinary antifungal efficacy, broad-antifungal spectrum, low toxicity, and is a promising new compound for treating IFIs. CMLD013075 targets fungal heat shock protein 90 (Hsp90) and has remarkable antifungal efficacy. Olorofim, as an inhibitor of dihydrolactate dehydrogenase, is a breakthrough drug treatment for IFIs. These novel target proteins and their inhibitors may overcome the limitations of currently available antifungal drugs and improve patient outcomes in the treatment of IFIs.
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Project description:Gammaherpesviruses are an important class of oncogenic pathogens that are exquisitely evolved to their respective hosts. As such, the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) do not naturally infect nonhuman primates or rodents. There is a clear need to fully explore mechanisms of gammaherpesvirus pathogenesis, host control, and immune evasion in the host. A gammaherpesvirus pathogen isolated from murid rodents was first reported in 1980; 40 years later, murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68) infection of laboratory mice is a well-established pathogenesis system recognized for its utility in applying state-of-the-art approaches to investigate virus-host interactions ranging from the whole host to the individual cell. Here, we highlight recent advancements in our understanding of the processes by which MHV68 colonizes the host and drives disease. Lessons that inform KSHV and EBV pathogenesis and provide future avenues for novel interventions against infection and virus-associated cancers are emphasized.
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Project description:Increasing bacterial drug resistance to antibiotics has posed a major threat to contemporary public health, which resulted in a large number of people suffering from serious infections and ending up dying without any effective therapies every year. Here, a dynamic covalent polymeric antimicrobial, based on phenylboronic acid (PBA)-installed micellar nanocarriers incorporating clinical vancomycin and curcumin, is developed to overcome drug-resistant bacterial infections. The formation of this antimicrobial is facilitated by reversible dynamic covalent interactions between PBA moieties in polymeric micelles and diols in vancomycin, which impart favorable stability in blood circulation and excellent acid-responsiveness in the infection microenvironment. Moreover, the structurally similar aromatic vancomycin and curcumin molecules can afford π-π stacking interaction to realize simultaneous delivery and release of payloads. In comparison with monotherapy, this dynamic covalent polymeric antimicrobial demonstrated more significant eradication of drug-resistant bacteria in vitro and in vivo due to the synergism of the two drugs. Furthermore, the achieved combination therapy shows satisfied biocompatibility without unwanted toxicity. Considering various antibiotics contain diol and aromatic structures, this simple and robust strategy can become a universal platform to combat the ever-threatening drug-resistant infectious diseases.
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Project description: Not available
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Project description:Septins are highly conserved filamentous proteins first characterized in budding yeast and subsequently identified in must eukaryotes. Septins can bind and hydrolyze GTP, which is intrinsically related to their formation of septin hexamers and functional protein interactions. The human septin family is composed of 14 loci, SEPT1-SEPT14, which encode dozens of different septin proteins. Their central GTPase and polybasic domain regions are highly conserved but they diverge in their N-terminus and/or C-terminus. The mechanism by which the different isoforms are generated is not yet well understood, but one can hypothesize that the use of different promoters and/or alternative splicing could give rise to these variants. Septins perform diverse cellular functions according to tissue expression and their interacting partners. Functions identified to date include cell division, chromosome segregation, protein scaffolding, cellular polarity, motility, membrane dynamics, vesicle trafficking, exocytosis, apoptosis, and DNA damage response. Their expression is tightly regulated to maintain proper filament assembly and normal cellular functions. Alterations of these proteins, by mutation or expression changes, have been associated with a variety of cancers and neurological diseases. The association of septins with cancer results from alterations of expression in solid tumors or translocations in leukemias [mixed lineage leukemia (MLL)]. Expression changes in septins have also been associated with neurological conditions such as Alzheimer's and Parkinson's disease, as well as retinopathies, hepatitis C, spermatogenesis and Listeria infection. Pathogenic mutations of SEPT9 were identified in the autosomal dominant neurological disorder hereditary neuralgic amyotrophy (HNA). Human septin research over the past decade has established their importance in cell biology and human disease. Further functional characterization of septins is crucial to our understanding of their possible diagnostic, prognostic, and therapeutic applications.
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Project description:The presence of highly modifiable chemical functional groups, abundance of functional groups, and their biological origin make proteins an important class of biomaterials from a fundamental science and applied engineering perspective. Hence, the utilization of proteins from the animal rendering industry (animal protein, AP) for high-value, nonfeed, and nonfertilizer applications is intensely pursued. Although this leads to the exploration of protein-derived plastics as a plausible alternative, the proposed methods are energy-intensive and not based on protein in its native form, which leads to high processing and production costs. Here, we propose, for the first time, novel pathways to develop engineered hybrid systems utilizing AP in its native form and epoxy resins with mechanical properties ranging from toughened thermosets to elastic epoxy-based systems. Furthermore, we demonstrate the capability to engineer the properties of epoxy-AP hybrids from high-strength hybrids to elastic films through controlling the interaction, hydrophilicity, as well as the extent of cross-linking and network density. Through the facile introduction of cochemicals, a sevenfold increase in the mechanical properties of the conventional epoxy-AP hybrid is achieved. Similarly, because of better compatibility afforded by the similar hydrophilicity, AP demonstrated higher cross-linking capability with a water-soluble epoxy (WEP) matrix, resulting in an elastic WEP-AP hybrid without any external aid.
| S-EPMC6644357 | biostudies-literature
Project description:Cataract is the leading cause of visual impairment, and posterior capsular opacification (PCO) is the most common long-term complication of modern cataract surgery, which can cause severe visual impairment after surgery. The proliferation, migration, and epithelial-mesenchymal transition (EMT) of residual lens epithelial cells (LECs) stimulated by growth factors and cytokines, are the key pathological mechanisms involved in the development of PCO. This study demonstrated that non-steroidal anti-inflammatory drug (NSAID), bromfenac, was capable of effectively inhibiting cell migration, overexpression of EMT markers, such as fibronectin (FN), matrix metalloproteinase 2 (MMP2), α-smooth muscle actin (α-SMA), and transcription factor Snail, and extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3β (GSK-3β) signaling induced by transforming growth factor-β2 (TGF-β2) in vitro. The inhibitory effect of bromfenac on TGF-β2-induced EMT was also verified on a primary lens epithelial cell model using human anterior capsules. Furthermore, based on ultrasonic spray technology, we developed a drug-eluting intraocular lens (IOL) using poly (lactic-co-glycolic acid) (PLGA) with sustained bromfenac release ability for the prevention of PCO development. In the rabbit models of cataract surgery, bromfenac-eluting IOL exhibited remarkable PCO prevention and inflammation suppression effects with excellent biocompatibility. In conclusion, bromfenac can inhibit TGF-β2-induced cell migration and the EMT of LECs via ERK/GSK-3β/Snail signaling. The present study offers a novel approach for preventing PCO through PLGA-based drug sustained-release IOLs.
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Project description:Lysine methylation is an abundant posttranslational modification, which has been most intensively studied in the context of histone proteins, where it represents an important epigenetic mark. Lysine methylation of histone proteins is primarily catalyzed by SET-domain methyltransferases (MTases). However, it has recently become evident that also another MTase family, the so-called seven-β-strand (7BS) MTases, often denoted METTLs (methyltransferase-like), contains several lysine (K)-specific MTases (KMTs). These enzymes catalyze the attachment of up to three methyl groups to lysine residues in specific substrate proteins, using S-adenosylmethionine (AdoMet) as methyl donor. About a decade ago, only a single human 7BS KMT was known, namely the histone-specific DOT1L, but 15 additional 7BS KMTs have now been discovered and characterized. These KMTs typically target a single nonhistone substrate that, in most cases, belongs to one of the following three protein groups: components of the cellular protein synthesis machinery, mitochondrial proteins, and molecular chaperones. This article provides an extensive overview and discussion of the human 7BS KMTs and their biochemical and biological roles.
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