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The increase in telecommuting during COVID-19 and advances in digital technology have necessitated the establishment of guidelines for maximizing productivity through indoor space design for telecommuters. Additionally, understanding the physiological response of individuals working in indoor spaces has attracted attention. This study applied mixed-reality environment to alter the design of the indoor space in real-time, while monitoring the task performance and representative psycho-physiological indicators (electroencephalogram and heart rate variability) of 30 individuals with telecommuting experience. To this end, four tasks, including spatial memory, attention, execution, and working memory, were conducted, and the psycho-physiological data from these tests were statistically analyzed. The results revealed that the design of the indoor space did not affect the spatial memory; however, the parasympathetic nerves were stimulated in visually non-preferred spaces, thus reducing mental stress and leading to high efficiency in short-term work. According to the Yerkes-Dodson law, the working memory of an individual is generally efficient and physically stable over time if they adjust to a preferred or decision-making space. Thus, the future design of telecommuting spaces must consider the type of work being done, and guidelines for spatial design should be developed by recognizing the psycho-physiological status of users, while increasing efficiency.

Candida auris , an emerging fungal pathogen characterized by its multidrug resistance and high mortality rates, poses a significant public health challenge. Despite its importance, the signaling pathways governing virulence and antifungal resistance in C. auris remain poorly understood. This study investigates the calcineurin pathway in C. auris , critical for virulence and antifungal resistance in other fungal pathogens. Calcineurin, a calcium/calmodulin-dependent protein phosphatase, comprises a catalytic subunit (Cna1) and a regulatory subunit (Cnb1) in C. auris . Our findings reveal that deletion of CNA1 or CNB1 disrupts extreme thermotolerance and cell membrane and wall integrity, leading to increased susceptibility to azoles and echinocandins. Moreover, we identified a downstream transcription factor, Crz1, which plays a central role in this pathway in other fungal species. Deletion of CRZ1 resulted in thermotolerance and membrane integrity defects comparable to those of cna1 Δ and cnb1 Δ mutants, along with increased azole susceptibility. Supporting it, fluconazole treatment induced Crz1 nuclear translocation in a Cna1-dependent manner. However, unlike cna1 Δ and cnb1 Δ mutants, the crz1 Δ mutant displayed increased resistance to echinocandins, suggesting the opposing roles for Crz1 in regulating cell wall integrity. Nevertheless, echinocandins also promoted Crz1 nuclear translocation via Cna1, underscoring the complex regulatory mechanisms at play. Cna1 was found to be required for virulence in both the Drosophila systemic infection model and the murine skin infection model. However, in a systemic murine infection model, both calcineurin and Crz1 appeared dispensable for C. auris virulence. Our findings highlight that the evolutionarily conserved calcineurin pathway employs distinct regulatory mechanisms to perform divergent roles in regulating extreme thermotolerance, cell wall and membrane integrity, antifungal drug resistance, and virulence in C. auris .

This paper attempts to elucidate how material values (MV) and voluntary simplicity lifestyle (VSL) are related to Japanese consumers’ attitudes and intentions toward commercial sharing during the COVID-19 pandemic. This paper provides the following findings by employing the two-step structural equation modeling (SEM) approach to analyze the data (n = 750) collected in Japan during the pandemic from people with no experience in commercial sharing. (1) MV has a positive effect on attitudes. (2) VSL is divided into “simplicity,” “long-term usage,” and “planned buying.” (3) Simplicity and planned buying are negatively related to MV, but long-term usage is not significantly related to MV. (4) Simplicity and long-term usage significantly affect attitudes, whereas planned buying does not. (5) Attitudes and subjective norms have positive effects on intentions. Consequently, two conflicting consumption orientations, MV and VSL, positively affect consumers’ responses toward commercial sharing in a pandemic context. The author suggests that although the negative impact of the COVID-19 pandemic exists now, the sharing economy can still contribute to enhancing sustainability and alleviating technological inequality by attracting people with different values and lifestyles.

The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Korea Otsuka Pharmaceutical.

This study proposed a plan for implementing a pleasant and healthy indoor landscape in subway station space. To this end, it established a 3D landscape model of the subway interior by reviewing previous studies on indoor landscape and the greenness index of indoor spaces. Moreover, it investigated and analyzed psychophysiological responses of users to environmental indoor landscape design in subway station space. Subway stations were classified as underground subway stations and ground subway stations according to the presence of natural light inflow. The greenness index of indoor spaces was also divided into four types of 0%, 10%, 15%, and 20%. Through this process, eight 3D landscape models of the subway interior were implemented. In addition, this study investigated psychophysiological responses of 60 male and female adults in their 20 s and 30 s using the models implemented. The investigation result was analyzed based on a frequency analysis, the χ2 test, T-test, one-way analysis of variance, and multidimensional scaling, which were performed in SPSS Statistics 25. The results of this study can be summarized as follows. First, physiological responses of research subjects were analyzed based on their prefrontal α wave asymmetric values. The analytic result showed that the environment where interior landscape was adopted produced more positive effects than the environment where interior landscape was not adopted. Second, psychological responses of research subjects were examined based on their greenness index preference, awareness of interior landscape area, attention restoration effect, and space images. The analytic result indicated that, among eight 3D landscape models of the subway interior, they preferred the model with the greenness index of 15% for underground subway stations. In addition, they preferred the model with the greenness index of 10% the most for ground subway stations.

Melanins are dark green, brown, or black pigments that serve as antioxidant, reactive oxygen species (ROS) scavengers that protect fungal pathogens from radiation and host immune responses. Cryptococcus neoformans , the major etiological agent of fungal meningoencephalitis, also utilizes melanin as a key virulence factor. In this basidiomycete pathogen, melanin production is regulated by the cAMP and high-osmolarity glycerol response (HOG) pathways, and yet its complex signaling networks remain poorly described. In this study, we uncovered novel melanin synthesis regulatory networks consisting of core transcription factors (TFs), including Bzp4, Usv101, Hob1, and Mbs1, and core kinases Gsk3 and Kic1. These networks were identified through coupling systematic analyses of the expression and epistatic relationships of TF and kinase mutant libraries in the presence of diverse melanin substrates with transcriptome profiling of the core TF mutants. Thus, this report provides comprehensive insight into the melanin-regulating pathways in C. neoformans and other fungal pathogens. Melanin is an antioxidant polyphenol pigment required for the pathogenicity of many fungal pathogens, but comprehensive regulatory mechanisms remain unidentified. In this study, we systematically analyzed melanin-regulating signaling pathways in Cryptococcus neoformans and identified four melanin-regulating core transcription factors (TFs), Bzp4, Usv101, Mbs1, and Hob1, required for induction of the laccase gene ( LAC1 ). Bzp4, Usv101, and Mbs1 independently regulate LAC1 induction, whereas Hob1 controls Bzp4 and Usv101 expression. Both Bzp4 and Usv101 are localized in the cytoplasm under nutrient-rich conditions (i.e., in the presence of yeast extract-peptone-dextrose [YPD] medium) but translocate into the nucleus upon nutrient starvation (i.e., in the presence of yeast nitrogen base [YNB] medium without glucose), and Mbs1 is constitutively localized in the nucleus. Notably, the cAMP pathway is not involved in regulation of the four TFs, but the high-osmolarity glycerol response (HOG) pathway negatively regulates induction of BZP4 and LAC1 . Next, we searched for potential kinases upstream of the core TFs and identified nine core kinases; their deletion led to defective melanin production and LAC1 induction. Deletion of GSK3 or KIC1 abolished induction of LAC1 and BZP4 and perturbed nuclear translocation of Bzp4. Notably, Gsk3 also regulated expression of HOB1 , USV101 , and MBS1 , indicating that it is a critical melanin-regulating kinase. Finally, an RNA sequencing-based transcriptome analysis of the wild-type strain and of bzp4 Δ, usv101 Δ, hob1 Δ, and mbs1 Δ strains under nutrient-rich and nutrient-starved conditions revealed that the melanin-regulating core TFs govern redundant and distinct classes of genes involved in a variety of biological processes. IMPORTANCE Melanins are dark green, brown, or black pigments that serve as antioxidant, reactive oxygen species (ROS) scavengers that protect fungal pathogens from radiation and host immune responses. Cryptococcus neoformans , the major etiological agent of fungal meningoencephalitis, also utilizes melanin as a key virulence factor. In this basidiomycete pathogen, melanin production is regulated by the cAMP and high-osmolarity glycerol response (HOG) pathways, and yet its complex signaling networks remain poorly described. In this study, we uncovered novel melanin synthesis regulatory networks consisting of core transcription factors (TFs), including Bzp4, Usv101, Hob1, and Mbs1, and core kinases Gsk3 and Kic1. These networks were identified through coupling systematic analyses of the expression and epistatic relationships of TF and kinase mutant libraries in the presence of diverse melanin substrates with transcriptome profiling of the core TF mutants. Thus, this report provides comprehensive insight into the melanin-regulating pathways in C. neoformans and other fungal pathogens.

Chrysanthemum boreale is a plant widespread in East Asia, used in folk medicine to treat various disorders, such as pneumonia, colitis, stomatitis, and carbuncle. Whether the essential oil from C. boreale (ECB) and its active constituents have anti-proliferative activities in lung cancer is unknown. Therefore, we investigated the cytotoxic effects of ECB in A549 and NCI-H358 human lung cancer cells. Culture of A549 and NCI-H358 cells with ECB induced apoptotic cell death, as revealed by an increase in annexin V staining. ECB treatment reduced mitochondrial membrane potential (MMP), disrupted the balance between pro-apoptotic and anti-apoptotic Bcl-2 proteins, and activated caspase-8, -9, and -3, as assessed by western blot analysis. Interestingly, pretreatment with a broad-spectrum caspase inhibitor (z-VAD-fmk) significantly attenuated ECB-induced apoptosis. Furthermore, gas chromatography–mass spectrometry (GC/MS) analysis of ECB identified six compounds. Among them, β-caryophyllene exhibited a potent anti-proliferative effect, and thus was identified as the major active compound. β- Caryophyllene induced G1 cell cycle arrest by downregulating cyclin D1, cyclin E, cyclin-dependent protein kinase (CDK) -2, -4, and -6, and RB phosphorylation, and by upregulating p21CIP1/WAF1 and p27KIP1. These results indicate that β-caryophyllene exerts cytotoxic activity in lung cancer cells through induction of cell cycle arrest.

The current treatment options for inflammatory bowel disease (IBD) are unsatisfactory. Therefore, novel and safer therapies are needed. We previously reported that koreanaside A (KA) showed high radical scavenging activity and suppressed vascular cell adhesion molecule 1 (VCAM-1) expression in vascular smooth muscle cells. However, the molecular mechanisms involved in its anti-inflammatory effect have not been reported. KA inhibited pro-inflammatory mediators such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), nitric oxide (NO), and prostaglandin E2 (PGE2). KA inhibited the production and mRNA expression of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) induced by LPS. KA downregulated the myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expressions in the MyD88-overexpressed cells. KA suppressed the LPS-induced transcriptional and DNA-binding activities of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-κB). KA was found to inhibit the phosphorylation of Janus kinase 1/2 (JAK1/2) and signal transducers and activators of transcription 1/3 (STAT1/3). In DSS-induced colitis mice, KA relieved the symptoms of colitis by suppressing inflammatory cell infiltration, restoring tight junction (TJ)- and epithelial–mesenchymal transition (EMT)-related protein expression, and inactivating AP-1, NF-κB, and STAT1/3. Therefore, KA reduced inflammatory responses by downregulating AP-1, NF-κB, and JAK/STAT signaling in LPS-induced macrophages and DSS-induced colitis mice.

Cryptococcus neoformans causes fatal fungal meningoencephalitis. Here, we study the roles played by fungal kinases and transcription factors (TFs) in blood-brain barrier (BBB) crossing and brain infection in mice. We use a brain infectivity assay to screen signature-tagged mutagenesis (STM)-based libraries of mutants defective in kinases and TFs, generated in the C. neoformans H99 strain. We also monitor in vivo transcription profiles of kinases and TFs during host infection using NanoString technology. These analyses identify signalling components involved in BBB adhesion and crossing, or survival in the brain parenchyma. The TFs Pdr802, Hob1, and Sre1 are required for infection under all the conditions tested here. Hob1 controls the expression of several factors involved in brain infection, including inositol transporters, a metalloprotease, PDR802 , and SRE1 . However, Hob1 is dispensable for most cellular functions in Cryptococcus deuterogattii R265, a strain that does not target the brain during infection. Our results indicate that Hob1 is a master regulator of brain infectivity in C. neoformans . Cryptococcus neoformans causes fatal fungal meningoencephalitis. Here, the authors identify fungal kinases and transcription factors involved in blood-brain barrier crossing and brain infection in mice.

V-ATPase, which comprises 13–14 subunits, is essential for pH homeostasis in all eukaryotes, but its proper function requires a regulator to assemble its subunits. While RAVE ( r egulator of H + - A TPase of v acuolar and e ndosomal membranes) and Raboconnectin-3 complexes assemble V-ATPase subunits in Saccharomyces cerevisiae and humans, respectively, the function of the RAVE complex in fungal pathogens remains largely unknown. In this study, we identified two RAVE complex components, Rav1 and Wdr1, in the fungal meningitis pathogen Cryptococcus neoformans , and analyzed their roles. Rav1 and Wdr1 are orthologous to yeast RAVE and human Rabconnectin-3 counterparts, respectively, forming the hybrid RAVE (hRAVE) complex. Deletion of RAV1 caused severe defects in growth, cell cycle control, morphogenesis, sexual development, stress responses, and virulence factor production, while the deletion of WDR1 resulted in similar but modest changes, suggesting that Rav1 and Wdr1 play central and accessary roles, respectively. Proteomics analysis confirmed that Wdr1 was one of the Rav1-interacting proteins. Although the hRAVE complex generally has V-ATPase-dependent functions, it also has some V-ATPase-independent roles, suggesting a unique role beyond conventional intracellular pH regulation in C . neoformans . The hRAVE complex played a critical role in the pathogenicity of C . neoformans , and RAV1 deletion attenuated virulence and impaired blood-brain barrier crossing ability. This study provides comprehensive insights into the pathobiological roles of the fungal RAVE complex and suggests a novel therapeutic strategy for controlling cryptococcosis.