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Abstract Background Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our envelopment. Methods Microarray assays with ontology and pathway analyses were performed with the lungs of mice. A comparison was made of the expression patterns of biological pathways between our model and those published for IPAH. Results Some pathways in our model showed the same expression patterns in IPAH, which included bone morphogenetic protein (BMP) signaling with down-regulation of BMP receptor type 2, activin-like kinase type 1, and endoglin. On the other hand, both Wnt/planar cell polarity (PCP) signaling and its downstream Rho/ROCK signaling were found alone to be activated in IPAH and not in our model. Conclusions Activation of Wnt/PCP signaling, in upstream positions of the pathway, found alone in lungs from end stage IPAH may play essential roles in the pathogenesis of the disease.

Abstract Introduction Scedosporium apiospermum is increasingly recognized as a cause of localized and disseminated mycotic infections in near-drowning victims. Case presentation We report the case of a 59-year-old Japanese woman who was a survivor of a tsunami in northeastern Japan and who had lung and brain abscesses caused by S. apiospermum. Initially, an aspergillus infection was suspected, so she was treated with micafungin. However, computed tomography scans of her chest revealed lung abscesses, and magnetic resonance images demonstrated multiple abscesses in her brain. S. apiospermum was cultured from her bronchoalveolar lavage fluid, and antimycotic therapy with voriconazole was initiated. Since she developed an increase in the frequency of premature ventricular contractions, an adverse drug reaction to the voriconazole was suspected. She was started on a treatment of a combination of low-dose voriconazole and liposomal amphotericin B. After combination therapy, further computed tomography scans of the chest and magnetic resonance images of her brain showed a demarcation of abscesses. Conclusions Voriconazole appeared to have a successful record in treating scedosporiosis after a near drowning but, owing to several adverse effects, may possibly not be recommended. Thus, a combination treatment of low-dose voriconazole and liposomal amphotericin B may be a safe and effective treatment for an S. apiospermum infection. Even though a diagnosis of scedosporiosis may be difficult, a fast and correct etiological diagnosis could improve the patient's chance of recovery in any case.

Abstract Background Group 1 introns (ribozymes) are among the most ancient and have the broadest phylogenetic distribution among the known self-splicing ribozymes. Fungi are known to be rich in rDNA group 1 introns. In the present study, five sequences of the 28S ribosomal RNA gene (rDNA) regions of pathogenic dematiaceous Phialophora verrucosa were analyzed using PCR by site-specific primers and were found to have three insertions, termed intron-F, G and H, at three positions of the gene. We investigated the distribution of group 1 introns in this fungus by surveying 34 strains of P. verrucosa and seven strains of Phialophora americana as the allied species. Results Intron-F's (inserted at L798 position) were found in 88% of P. verrucosa strains, while intron-G's (inserted at L1921) at 12% and intron-H's (inserted at L2563) at 18%. There was some correlation between intron distribution and geographic location. In addition, we confirmed that the three kinds of introns are group 1 introns from results of BLAST search, alignment analysis and Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Prediction of secondary structures and phylogenetic analysis of intron sequences identified introns-F and G as belonging to subgroup IC1. In addition, intron-H was identified as IE. Conclusion The three intron insertions and their insertion position in the 28S rDNA allowed the characterization of the clinical and environmental isolates of P. verrucosa and P. americana into five genotypes. All subgroups of introns-F and G and intron-H were characterized and observed for the first time in both species.

Maintenance of bone homeostasis and the balance between bone resorption and formation are crucial for maintaining skeletal integrity. This study sought to investigate the role of salt-inducible kinase 3 (SIK3), a key regulator in cellular energy metabolism, during the differentiation of osteoclasts. Despite osteoclasts being high energy-consuming cells essential for breaking down mineralized bone tissue, the specific function of SIK3 in this process remains unclear. To address this issue, we generated osteoclast-specific SIK3 conditional knockout mice and assessed the impact of SIK3 deletion on bone homeostasis. Our findings revealed that SIK3 conditional knockout mice exhibited increased bone mass and an osteopetrosis phenotype, suggesting a pivotal role for SIK3 in bone resorption. Moreover, we assessed the impact of pterosin B, a SIK3 inhibitor, on osteoclast differentiation. The treatment with pterosin B inhibited osteoclast differentiation, reduced the numbers of multinucleated osteoclasts, and suppressed resorption activity in vitro. Gene expression analysis demonstrated that SIK3 deletion and pterosin B treatment influence a common set of genes involved in osteoclast differentiation and bone resorption. Furthermore, pterosin B treatment altered intracellular metabolism, particularly affecting key metabolic pathways, such as the tricarboxylic acid cycle and oxidative phosphorylation. These results provide valuable insights into the involvement of SIK3 in osteoclast differentiation and the molecular mechanisms underlying osteoclast function and bone diseases. Lay Summary: Osteoporosis is a disease that causes bones to become weak and fragile, increasing the risk of fractures especially in elderly. It is caused by an imbalance between the formation of new bone and the destruction of old bone. Cells called osteoclasts are responsible for breaking down old bone. Excessive osteoclast activity results in bone loss and osteoporosis. Our research has identified a LKB1-SIK3 pathway, which acts as an energy sensor in osteoclasts. We found that this pathway is activated when osteoclast activity is increased, and we were able to reduce osteoclast activity by genetically removing or inhibiting SIK3. These findings suggest that targeting the LKB1-SIK3 pathway may be a promising new approach for the treatment of osteoporosis. Developing drugs that inhibit SIK3 may slow bone loss and reduce the risk of fractures in osteoporotic patients. Graphical Abstract [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between the severity and morphology of heterotopic ossification in the spinal ligaments including sacroiliac (SI) joints, and serum interleukin-17 (IL-17) levels in patients with ossification of the posterior longitudinal ligament (OPLL) with or without diffuse idiopathic skeletal hyperostosis (DISH), as well as a non-OPLL group. Methods A total of 103 patients with OPLL [DISH (−), n  =   50; DISH (+), n  =   53] and 53 age- and gender-matched controls were included. The serum levels of IL-17 were analysed, and the severity of ectopic ossification and the morphology of ectopic bone formation were evaluated. The SI joint morphological variations were categorized into four types. Results No significant differences were found in serum IL-17 levels between the OPLL and control groups. However, the DISH (+) group showed higher IL-17 levels than the DISH (−) group, especially in female patients (P   =  0.003). Additionally, IL-17 levels were positively correlated with the number of flat vertebral units, this being one of the characteristic DISH ossification types (R 2 = 0.199, P   =  0.012). IL-17 levels in the type showing bridging osteophyte and bone fusion were significantly higher in the DISH (+) group than in the DISH (−) group. Conclusion The morphological characteristics of paravertebral bone formation in the entire spine, including the SI joint, are likely associated with serum IL-17 levels in OPLL. These findings provide pathological and serological evidence of local inflammation contributing to paravertebral ossification of OPLL patients. [ABSTRACT FROM AUTHOR]

Non-albicans Candida infections have recently gained worldwide attention due to their intrinsic resistance to different antifungal agents and the limited therapeutic options for treating them. Although the Candida parapsilosis complex is reported to be the second or third most prevalent Candida spp., little information is available on the prevalence of antifungal resistance along with genotyping of the C. parapsilosis complex. In this study, we aimed to evaluate the prevalence of antifungal resistance, the genetic basis of such resistance, and the genotyping of C. parapsilosis complex isolates that were recovered from hospitalized patients in Japan from 2005 to 2019. Our results indicated that, with the exception of one single C. metapsilosis isolate that was dose-dependently susceptible to fluconazole, all other isolates were susceptible or showed wild phenotypes to all tested antifungals, including azoles, echinocandins, amphotericin B, and flucytosine. Molecular analyses for azole and echinocandin resistance via evaluating ERG11 mutation and FKS1 hotspot one (HS1) and hotspot two (HS2) mutations, respectively, confirmed the phenotypic results. Genotyping of our isolates confirmed that they belong to 53 different but closely related genotypes, with a similarity percentage of up to 90%. Our results are of significant concern, since understanding the genetic basis of echinocandin resistance in the C. parapsilosis complex as well their genotyping is essential for directing targeted therapy, identifying probable infection sources, and developing strategies for overcoming epidemic spread. [ABSTRACT FROM AUTHOR]

Background: Allergic bronchopulmonary mycosis (ABPM) is an allergic disease caused by type I and type III hypersensitivity to environmental fungi. Schizophyllum commune, a basidiomycete fungus, is one of the most common fungi that causes non‐Aspergillus ABPM. Objective: Herein, we attempted to clarify the clinical characteristics of ABPM caused by S. commune (ABPM‐Sc) compared with those of allergic bronchopulmonary aspergillosis (ABPA). Methods: Patients with ABPM‐Sc or ABPA were recruited from a nationwide survey in Japan, a multicenter cohort, and a fungal database at the Medical Mycology Research Center of Chiba University. The definition of culture‐positive ABPM‐Sc/ABPA is as follows: (1) fulfills five or more of the 10 diagnostic criteria for ABPM proposed by Asano et al., and (2) positive culture of S. commune/Aspergillus spp. in sputum, bronchial lavage fluid, or mucus plugs in the bronchi. Results: Thirty patients with ABPM‐Sc and 46 with ABPA were recruited. Patients with ABPM‐Sc exhibited less severe asthma and presented with better pulmonary function than those with ABPA (p = 0.008–0.03). Central bronchiectasis was more common in ABPM‐Sc than that in ABPA, whereas peripheral lung lesions, including infiltrates/ground‐glass opacities or fibrotic/cystic changes, were less frequent in ABPM‐Sc. Aspergillus fumigatus‐specific immunoglobulin (Ig)E was negative in 10 patients (34%) with ABPM‐Sc, who demonstrated a lower prevalence of asthma and levels of total serum IgE than those with ABPM‐Sc positive for A. fumigatus‐specific IgE or ABPA. Conclusions: Clinical characteristics of ABPM‐Sc, especially those negative for A. fumigatus‐specific IgE, differed from those of ABPA. [ABSTRACT FROM AUTHOR]

A spergillus fumigatus is known as an opportunistic pathogen of fungal infection and causes a high mortality rate among immunosuppressed patients (1,2). Azole drugs are considered the first-line therapy in [...]