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TWIK-related acid-sensitive potassium channel 1 (TASK-1) is expressed ubiquitously across various tissues and plays a significant role in neural activity and anesthetic modulation, making it a crucial target for pharmaceutical research. The high conservation of binding site residues within the TASK family, particularly between TASK-1 and TASK-3, necessitates the development of selective inhibitors for TASK-1. In this study, we utilized a combination of structure-based drug design (SBDD) and ligand-based drug design (LBDD) approaches. Initially, several bisamide-centered molecules were designed using the program MolAICal, which is recognized for its ability to generate selective inhibitors containing bisamide segments, and conducted preliminary screening via molecular docking. Subsequently, 3D-QSAR models were developed for 56 bisamide derivatives targeting TASK-1 and TASK-3, with the models exhibiting robust predictive capabilities (TASK-1: Q2 = 0.61, R2pred = 0.84; TASK-3: Q2 = 0.60, R2pred = 0.71). Using these models, the candidate molecules were subjected to activity prediction and subsequent filtering. Ultimately, molecular dynamics simulations, coupled with free energy calculations, pinpointed two bisamide-core molecules with favorable ADMET properties as potential selective inhibitors for TASK-1. Furthermore, molecular dynamics simulations revealed the critical role of the key residue Leu122 in conferring selectivity to bisamide compounds for TASK-1 channel proteins. [ABSTRACT FROM AUTHOR]

Candida albicans, an opportunistic fungal pathogen, is able to switch between two distinct cell types: white and opaque. While white‐to‐opaque switching is typically repressed by the a1/α2 heterodimer in MTLa/α cells, it was recently reported that switching can also occur in some natural MTLa/α strains under certain environmental conditions. However, the regulatory program governing white‐opaque switching in MTLa/α cells is not fully understood. Here, we collected 90 clinical isolates of C. albicans, 16 of which possess the ability to form opaque colonies. Among the known regulators implicated in white‐opaque switching, only OFI1 exhibited significantly higher expression in these 16 strains compared to the reference strain SC5314. Importantly, ectopic expression of OFI1 in both clinical isolates and laboratory strains promoted switching frequency even in the absence of N‐acetylglucosamine and high CO2, the optimal condition for white‐to‐opaque switching in MTLa/α strains. Deleting OFI1 resulted in a reduction in opaque‐formation frequency and the stability of the opaque cell in MTLa/α cells. Ofi1 binds to the promoters of WOR1 and WOR3 to induce their expression, which facilitates white‐to‐opaque switching. Ofi1 is conserved across the CTG species. Altogether, our study reported the identification of a transcription factor Ofi1 as the critical regulator that promotes white‐to‐opaque switching in natural MTLa/α isolates of C. albicans. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) loading ketoconazole (KCZ) have shown better efficacy on rats with tinea pedis than the marketed Daktarin® but clinical studies are still lacking. In this study, we described the clinical translation of ILs containing KCZ (KCZ‐ILs) from the lab into the clinic and evaluated the efficacy and safety of KCZ‐ILs in patients with tinea pedis. Thirty‐six enrolled participants were randomized to receive either KCZ‐ILs (KCZ, 4.72 mg/g) or Daktarin® (control group; KCZ, 20 mg/g) topically twice daily, making the lesion be covered with a thin layer of medication. The randomized controlled trial lasted for 8 weeks including 4 weeks of intervention and 4 weeks of follow‐up. Primary efficacy outcome was the proportion of treatment success responders, defined as patients achieving negative mycological result and ≥60% relative reduction in total clinical symptom score (TSS) from baseline at week 4. Secondary outcomes mainly for evaluating the relapse of disease included the proportion of treatment success individuals at week 8 and fungal recurrence rate at weeks 2, 3, 4, and 8. After 4 weeks of medication, 47.06% of the KCZ‐ILs subjects were treatment successes compared with only 25.00% of those using Daktarin®. Throughout the trial period, KCZ‐ILs induced a significantly lower recurrence rate (52.94%) than that of control patients (68.75%). Furthermore, KCZ‐ILs were found to be safe and well‐tolerated. In conclusion, ILs loading only 1/4 KCZ dose of Daktarin® showed a better efficacy and safety profile in the management of tinea pedis, creating a new opportunity for the treatment of skin diseases caused by fungal infection and is worthy of clinical application. [ABSTRACT FROM AUTHOR]

Non-coding small molecule RNAs are associated with a variety of diseases, including infectious diseases. However, small RNA-related studies in onychomycosis have not been reported. The aim of the present study was to conduct an initial investigation of small RNA in onychomycosis. The present study collected a total of 33 affected nail samples from patients with onychomycosis and 18 normal nail samples from healthy people. Through RNA sequencing, 37 differentially expressed microRNAs (miRNAs or miRs), including 15 upregulated and 22 downregulated miRNAs, were identified in 3 patients with onychomycosis compared with 3 healthy controls. Moreover, three differentially expressed miRNAs were analyzed for further verification by RT-qPCR in other 30 affected nail and 15 healthy nail samples. Among the three verified miRNAs, a significant difference between the downregulated hsa-miR-1-3p and hsa-miR-361-3p was observed (P<0.05). A total of 14,511 target genes of 37 differentially expressed miRNAs were predicted by the miRanda and RNAhybrid databases, while the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis showed that these target genes were enriched in multiple signaling pathways. The present study indicated that hsa-miR-1-3p and hsa-miR-361-3p may be potential biomarkers for onychomycosis. Furthermore, the findings of the present study can be used in future research on RNA in onychomycosis. [ABSTRACT FROM AUTHOR]

Candida albicans is a normal resident of humans and also a prevalent fungal pathogen. Lactate, a nonfermentative carbon source available in numerous anatomical niches, can be used by C. albicans as a carbon source. However, the key regulator(s) involved in this process remain unknown. Here, through a genetic screen, we report the identification of a transcription factor Zcf24 that is specifically required for lactate utilization in C. albicans. Zcf24 is responsible for the induction of CYB2, a gene encoding lactate dehydrogenase that is essential for lactate catabolism, in response to lactate. Chromatin immunoprecipitation showed a significantly higher signal of Zcf24 on the CYB2 promoter in lactate‐grown cells than that in glucose‐grown cells. Genome‐wide transcription profiling indicates that, in addition to CYB2, Zcf24 regulates genes involved in the β‐oxidation of fatty acids, iron transport, and drug transport. Surprisingly, deleting ZCF24 confers enhanced commensal fitness. This could be attributed to Crz1‐activated β‐glucan masking in the zcf24 mutant. The orthologs of Zcf24 are distributed in species most closely to C. albicans and some filamentous fungal species. Altogether, Zcf24 is the first transcription factor identified to date that regulates lactate catabolism in C. albicans and it is also involved in the regulation of commensalism. [ABSTRACT FROM AUTHOR]

This article discusses a case of palisaded neutrophilic granulomatous dermatitis (PNGD) associated with Sjögren's syndrome (SS). The patient, a 66-year-old woman, presented with recurrent edematous erythema on her trunk and limbs. Histopathological examination confirmed the diagnosis of PNGD. The patient also had a history of dry mouth and difficulty swallowing, and further testing revealed positive immune antibody indicators for SS. After treatment with medication, the patient's symptoms improved. The article highlights the rarity of PNGD in patients with SS and suggests a possible link between the two conditions. The study was conducted by a team of researchers and was supported by various funding sources. [Extracted from the article]

We present a case of subcutaneous granuloma caused by Kodamaea ohmeri and describe the histopathological characteristics and skin lesions caused by this pathogen. A 55‐year‐old woman, with a history of rheumatoid arthritis, presented with red, painless plaque on her forehead, persistent for 3 months; based on the histopathological and mycological findings and gene sequencing, the patient was diagnosed with subcutaneous granuloma caused by K. ohmeri. This report highlights that early identification and diagnosis and optimal regimens are vital in the management of this intractable infection. [ABSTRACT FROM AUTHOR]