Explore the vast range of titles available.

Human microbiome studies have shown diversity to exist among different ethnic populations. However, studies pertaining to the microbial composition of CRC among the Indian population have not been well explored. We aimed to decipher the microbial signature in tumor tissues from North Indian CRC patients. Next-generation sequencing of tumor and adjacent tissue-derived bacterial 16S rRNA V3-V4 hypervariable regions was performed to investigate the abundance of specific microbes. The expression profile analysis deciphered a decreased diversity among the tumor-associated microbial communities. At the phyla level, Proteobacteria was differentially expressed in CRC tissues than adjacent normal. Further, DeSeq2 normalization identified 4 out of 79 distinct species (p < 0.005) only in CRC, Bacteroides massiliensis, Alistipes onderdonkii, Bifidobacterium pseudocatenulatum, and Corynebacterium appendicis. Thus, the findings suggest that microbial signatures can be used as putative biomarkers in diagnosis, prognosis and treatment management of CRC.

  [...]in fungi, the phosphorelay typically comprises four phosphorylation events: (1) the HK is autophosphorylated on a histidine residue within its histidine kinase domain; (2) the phosphate is transferred intramolecularly to an aspartate (His->Asp) in the HK receiver domain; (3) a third, intermolecular phosphotransfer occurs to the histidine residue present in the HPt domain on the transferase (His->Asp->His); and (4) the phosphoryl group is relayed to an aspartate on the RR protein (His->Asp->His->Asp). [...]two-component-like phosphorelay systems are unusual in terms of mechanism: the amino acids that accept phosphoryl groups are either aspartate or histidine residues. In response to environmental stimuli the histidine kinase (HK) is autophosphorylated on a histidine residue.\\n A conceptually different type of in vivo screening approach applied in both bacteria and fungi uses a strain where the function of a particular pathway is compromised by mutation; as a result, the screen strain shows exacerbated sensitivity relative to the wild-type strain to compounds that specifically inhibit this pathway [25,26]. Because two-component system genes are not essential, in this instance, growth rate or viability may not be informative screening end points.

Cervical cancer is one of the most common cancers among women worldwide. Current standards of care for cervical cancer includes surgery, radiation and chemotherapy. Conventional chemotherapy fails to elicit therapeutic responses and causes severe systemic toxicity. Thus, developing a natural product based, safe treatment modality would be a highly viable option. Curcumin (CUR) is a well-known natural compound, which exhibits excellent anti-cancer potential by regulating many proliferative, oncogenic and chemo-resistance associated genes/proteins. However, due to rapid degradation and poor bioavailability, its translational and clinical use has been limited. To improve these clinically relevant parameters, we report a poly(lactic- co -glycolic acid) based curcumin nanoparticle formulation (Nano-CUR). This study demonstrates that in comparison to free CUR, Nano-CUR effectively inhibits cell growth, induces apoptosis and arrests the cell cycle in cervical cancer cell lines. Nano-CUR treatment modulated entities such as miRNAs, transcription factors and proteins associated with carcinogenesis. Moreover, Nano-CUR effectively reduced the tumor burden in a pre-clinical orthotopic mouse model of cervical cancer by decreasing oncogenic miRNA-21, suppressing nuclear β-catenin and abrogating expression of E6/E7 HPV oncoproteins including smoking compound benzo[a]pyrene (BaP) induced E6/E7 and IL-6 expression. These superior pre-clinical data suggest that Nano-CUR may be an effective therapeutic modality for cervical cancer.

Multidrug resistant Klebsiella pneumoniae have caused major therapeutic problems worldwide due to the emergence of the extended-spectrum β-lactamase producing strains. Although there are >10 major facilitator super family (MFS) efflux pumps annotated in the genome sequence of the K. pneumoniae bacillus, apparently less is known about their physiological relevance. Insertional inactivation of kpnGH resulting in increased susceptibility to antibiotics such as azithromycin, ceftazidime, ciprofloxacin, ertapenem, erythromycin, gentamicin, imipenem, ticarcillin, norfloxacin, polymyxin-B, piperacillin, spectinomycin, tobramycin and streptomycin, including dyes and detergents such as ethidium bromide, acriflavine, deoxycholate, sodium dodecyl sulphate, and disinfectants benzalkonium chloride, chlorhexidine and triclosan signifies the wide substrate specificity of the transporter in K. pneumoniae. Growth inactivation and direct fluorimetric efflux assays provide evidence that kpnGH mediates antimicrobial resistance by active extrusion in K. pneumoniae. The kpnGH isogenic mutant displayed decreased tolerance to cell envelope stressors emphasizing its added role in K. pneumoniae physiology. The MFS efflux pump KpnGH involves in crucial physiological functions besides being an intrinsic resistance determinant in K. pneumoniae.

[...]there is increasing and compelling evidence that modulating the amplitude and magnitude of the host inflammatory immune response can be beneficial for the outcome of invasive fungal diseases [60-62]. [...]chromatin-mediated adaptive changes during fungal pathogen host interplay opens new windows of opportunities and may hold great promises for future antifungal drug discovery. [...]the expansion of genome-scale genetic technologies, especially CRISPR/Cas9 approaches [63], makes it feasible to use dual-systems biology approaches to decipher the dynamic underlying host-pathogen relations [64] but also to better understand molecular mechanisms of KDAC/KAT functions under host immune surveillance.

Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections. Candida auris is an emerging multidrug-resistant human fungal pathogen refractory to treatment by several classes of antifungal drugs. Unlike other Candida species, C. auris can adhere to human skin for prolonged periods of time, allowing for efficient skin-to-skin transmission in the hospital environments. However, molecular mechanisms underlying pronounced multidrug resistance and adhesion traits are poorly understood. Two-component signal transduction and mitogen-activated protein (MAP) kinase signaling are important regulators of adherence, antifungal drug resistance, and virulence. Here, we report that genetic removal of SSK1 encoding a response regulator and the mitogen-associated protein kinase HOG1 restores the susceptibility to both amphotericin B (AMB) and caspofungin (CAS) in C. auris clinical strains. The loss of SSK1 and HOG1 alters membrane lipid permeability, cell wall mannan content, and hyperresistance to cell wall-perturbing agents. Interestingly, our data reveal variable functions of SSK1 and HOG1 in different C. auris clinical isolates, suggesting a pronounced genetic plasticity affecting cell wall function, stress adaptation, and multidrug resistance. Taken together, our data suggest that targeting two-component signal transduction systems could be suitable for restoring C. auris susceptibility to antifungal drugs. IMPORTANCE Candida auris is an emerging multidrug-resistant (MDR) fungal pathogen that presents a serious global threat to human health. The Centers for Disease Control and Prevention (CDC) have classified C. auris as an urgent threat to public health for the next decade due to its major clinical and economic impact and the lack of effective antifungal drugs and because of future projections concerning new C. auris infections. Importantly, the Global Antimicrobial Resistance Surveillance System (GLASS) has highlighted the need for more robust and efficacious global surveillance schemes enabling the identification and monitoring of antifungal resistance in Candida infections. Despite the clinical relevance of C. auris infections, our overall understanding of its pathophysiology and virulence, its response to human immune surveillance, and the molecular basis of multiple antifungal resistance remains in its infancy. Here, we show a marked phenotypic plasticity of C. auris clinical isolates. Further, we demonstrate critical roles of stress response mechanisms in regulating multidrug resistance and show that cell wall architecture and composition are key elements that determine antifungal drug susceptibilities. Our data promise new therapeutic options to treat drug-refractory C. auris infections.

microRNAs (miRNAs) are a class of small non-coding RNAs that regulate the expression of their target mRNAs post transcriptionally. miRNAs are known to regulate not just a gene but the whole gene network (signaling pathways). Accumulating evidence(s) suggests that miRNAs can work either as oncogenes or tumor suppressors, but some miRNAs have a dual nature since they can act as both. miRNA 205 (miR-205) is one such highly conserved miRNA that can act as both, oncomiRNA and tumor suppressor. However, most reports confirm its emerging role as a tumor suppressor in many cancers. This review focuses on the downregulated expression of miR-205 and discusses its dysregulation in breast, prostate, skin, liver, gliomas, pancreatic, colorectal and renal cancers. This review also confers its role in tumor initiation, progression, cell proliferation, epithelial to mesenchymal transition, and tumor metastasis. Restoration of miR-205 makes cells more sensitive to drug treatments and mitigates drug resistance. Additionally, the importance of miR-205 in chemosensitization and its utilization as potential biomedicine and nanotherapy is described. Together, this review research article sheds a light on its application as a diagnostic and therapeutic marker, and as a biomedicine in cancer.

Candida auris is a World Health Organization fungal priority pathogen and an urgent public health threat recognized by the Centers for Disease Control and Prevention. C. auris has a unique ability to colonize human skin. It also persists on abiotic surfaces in healthcare environments for an extended period of time. These attributes facilitate the inter- and intrahospital clonal transmission of C. auris . Therefore, understanding C. auris skin colonization mechanisms is critical for infection control, especially in hospitals and nursing homes. However, despite its profound clinical relevance, the molecular and genetic basis of C. auris skin colonization mechanisms are poorly understood. Herein, we present data on the identification of the Hog1 MAP kinase as a key regulator of C. auris skin colonization. These findings lay the foundation for further characterization of unique mechanisms that promote fungal persistence on human skin.

Invasive fungal diseases affect approximately 6.5 million people every year, of which about 2.5 million people die worldwide. This number is expected to rise due to increasing numbers of immunosuppressed people, including the elderly, premature infants, organ transplant recipients, cancer, and HIV/AIDS patients. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) have both recently emphasized a critical need for the development of new antifungal therapeutics to address expanding drug resistance among human fungal pathogens. The necessity of new antifungal drugs is also underscored by the fact that mortality due to invasive candidiasis has remained unchanged for several decades. However, the discovery of new drugs acting on antifungal drug targets is complicated because fungi are eukaryotes. This greatly limits the number of feasible fungal-specific drug targets. One class of molecules that fulfills the criterion of fungal specificity is chromatin modification enzymes such as lysine acetyltransferase (KATs). The fungal KATs are structurally less well conserved, and some modifications are only found in fungi, minimizing the risk of toxicity, thus making KATs new promising tools for antifungal therapy. We report here that Gcn5 lysine acetyltransferase mediates antifungal drug resistance and virulence of C. auris and represents an important target for antifungal drug discovery.

The surge in antimicrobial drug resistance in some bacterial and fungal pathogens constitutes a significant challenge to health care facilities. The emerging human fungal pathogen Candida auris has been particularly concerning, as isolates can display pan-antifungal resistance traits against all drugs, including echinocandins. Candida auris emerged as a human fungal pathogen only during the past decade. Remarkably, C. auris displays high degrees of genomic diversity and phenotypic plasticity, with four major clades causing hospital outbreaks with high mortality and morbidity rates. C. auris can show clinical resistance to all classes of antifungal drugs, including echinocandins that are usually recommended as first-line therapies for invasive candidiasis. Here, we exploit transcriptomics coupled with phenotypic profiling to characterize a set of clinical C. auris isolates displaying pronounced echinocandin resistance (ECN-R). A hot spot mutation in the echinocandin FKS1 target gene is present in all resistant isolates. Moreover, ECN-R strains share a core signature set of 362 genes differentially expressed in ECN-R isolates. Among others, mitochondrial gene expression and genes affecting cell wall function appear to be the most prominent, with the latter correlating well with enhanced adhesive traits, increased cell wall mannan content, and altered sensitivity to cell wall stress of ECN-R isolates. Moreover, ECN-R phenotypic signatures were also linked to pathogen recognition and interaction with immune cells. Hence, transcriptomics paired with phenotyping is a suitable tool to predict resistance and fitness traits as well as treatment outcomes in pathogen populations with complex phenotypic diversity. IMPORTANCE The surge in antimicrobial drug resistance in some bacterial and fungal pathogens constitutes a significant challenge to health care facilities. The emerging human fungal pathogen Candida auris has been particularly concerning, as isolates can display pan-antifungal resistance traits against all drugs, including echinocandins. However, the mechanisms underlying this phenotypic diversity remain poorly understood. We identify transcriptomic signatures in C. auris isolates resistant to otherwise fungicidal echinocandins. We identify a set of differentially expressed genes shared by resistant strains compared to unrelated susceptible isolates. Moreover, phenotyping demonstrates that resistant strains show distinct behaviors, with implications for host-pathogen interactions. Hence, this work provides a solid basis to identify the mechanistic links between antifungal multidrug resistance and fitness costs that affect the interaction of C. auris with host immune defenses.