Recent Progress in Research on Mitochondrion-Targeted Antifungal Drugs: a Review.

Fungal infections, which commonly occur in immunocompromised patients, can cause high morbidity and mortality. Antifungal agents act by disrupting the cell membrane, inhibiting nucleic acid synthesis and function, or inhibiting ß-1,3-glucan synthase. Because the incidences of life-threatening fungal infections and antifungal drug resistance are continuously increasing, there is an urgent need for the development of new antifungal agents with novel mechanisms of action. Recent studies have focused on mitochondrial components as potential therapeutic drug targets, owing to their important roles in fungal viability and pathogenesis. In this review, we discuss novel antifungal drugs targeting mitochondrial components and highlight the unique fungal proteins involved in the electron transport chain, which is useful for investigating selective antifungal targets. Finally, we comprehensively summarize the efficacy and safety of lead compounds in clinical and preclinical development. Although fungus-specific proteins in the mitochondrion are involved in various processes, the majority of the antifungal agents target dysfunction of mitochondria, including mitochondrial respiration disturbance, increased intracellular ATP, reactive oxygen species generation, and others. Moreover, only a few drugs are under clinical trials, necessitating further exploration of possible targets and development of effective antifungal agents. The unique chemical structures and targets of these compounds will provide valuable hints for further exploiting new antifungals.

Magnetic covalent-organic frameworks-based extraction followed by UHPLC-MS/MS for determination and pharmacokinetic study of trace angoroside C in rat plasma after oral administration of Xuanbo Shuangsheng Granule.

The composition of the traditional Chinese medicine compound preparation is complex, while the content of each active ingredient is extremely low, which brings difficulties to the plasma concentration detection. In this study, the magnetic covalent-organic frameworks were synthesized by a simple one-step Schiff base reaction and applied for the specific extraction of trace angoroside C in rat plasma prior to ultra-high-performance liquid chromatography-tandem mass spectrometry detection. The synthesized magnetic covalent-organic frameworks have high magnetic responsiveness (35.67 emu·g-1 ), large surface area (110.9 m2 ·g-1 ), and strong stability. The as-prepared material can quickly extract angoroside C from plasma with high extraction efficiency, be easily separated with a magnet afterward, and can be reused for at least five times. The established method was systematically validated showing good linearity (0.1-5 ng·ml-1 ), low limit of quantification (0.1 ng·ml-1 ), good accuracy (93.18-105.36%), and good precision (percentage relative standard deviation 3.60-10.90%). Finally, the method was used to the pharmacokinetic study of trace angoroside C in rats after oral administration of Xuanbo Shuangsheng Granule.

Design, Synthesis and Antifungal Evaluation of Novel Pyrylium Salt In Vitro and In Vivo.

Nowadays, discovering new skeleton antifungal drugs is the direct way to address clinical fungal infections. Pyrylium salt SM21 was screened from a library containing 50,240 small molecules. Several studies about the antifungal activity and mechanism of SM21 have been reported, but the structure-activity relationship of pyrylium salts was not clear. To explore the chemical space of antifungal pyrylium salt SM21, a series of pyrylium salt derivatives were designed and synthesized. Their antifungal activity and structure-activity relationships (SAR) were investigated. Compared with SM21, most of the synthesized compounds exhibited equivalent or improved antifungal activities against Candida albicans in vitro. The synthesized compounds, such as XY10, XY13, XY14, XY16 and XY17 exhibited comparable antifungal activities against C. albicans with MIC values ranging from 0.47 to 1.0 µM. Fortunately, a compound numbered XY12 showed stronger antifungal activities and lower cytotoxicity was obtained. The MIC of compound XY12 against C. albicans was 0.24 µM, and the cytotoxicity decreased 20-fold as compared to SM21. In addition, XY12 was effective against fluconazole-resistant C. albicans and other pathogenic Candida species. More importantly, XY12 could significantly increase the survival rate of mice with a systemic C. albicans infection, which suggested the good antifungal activities of XY12 in vitro and in vivo. Our results indicated that structural modification of pyrylium salts could lead to the discovery of new antifungal drugs.

Studies on Left-Behind Children in China: Reviewing Paradigm Shifts.

More than 60 million children have been left behind in rural China by parents going to work in cities. Given the effects of child-parent separation (CPS) on development, this phenomenon has drawn considerable governmental and academic attention in recent years. Outlining developments with reference to relevant studies, this review characterizes the perspectives used to explore and understand this phenomenon in terms of three major paradigms: (1) the diagnostic approach, which takes for granted the assumption that CPS would be the only cause of negative effects observed among left-behind children (LBC), and has focused primarily on measuring psychological and behavioral disorders among these "problematic kids"; (2) the advanced diagnostic approach, which refines the previous approach by incorporating theories and techniques developed outside of China, elaborating on the early approach by bringing into consideration more factors and exploring the interactions between CPS and these factors, particularly social ones; (3) the sociologically oriented approach, which provides the research with a much broader framework in terms of how to orient the phenomenon of LBC, especially the transformation of China's social and economic systems during the last 30 years of urbanization, where the reproduction of labor has been based on a "splitting family structure," such that problems associated with the phenomenon of LBC cannot be solved without systematic social and economic changes. Based on these analyses, future directions for research on LBC in China are also discussed.

Treatment-naïve Gaucher disease patients achieve therapeutic goals and normalization with velaglucerase alfa by 4years in phase 3 trials.

Gaucher disease is an inherited metabolic disease characterized by ß-glucocerebrosidase deficiency and commonly treated with enzyme replacement therapy (ERT). The efficacy of ERT with velaglucerase alfa was assessed based on the achievement of published therapeutic goals and the normalization of disease parameters in 39 treatment-naïve patients with type 1 Gaucher disease, 6 to 62years of age, enrolled in phase 3 clinical trials. After 4years of ERT, therapeutic goals for thrombocytopenia and splenomegaly had been achieved in 100% of patients; goals for anemia and hepatomegaly had been achieved in 95% and 94% of patients, respectively. Consistent with the goal for bone mineral density, lumbar spine bone density improved in 87% of patients ≥18years of age. At year 4, compared with clinical ranges for healthy individuals, 86% of patients with a low baseline hemoglobin concentration had normalized, 60% with a low baseline platelet count had normalized, 67% with baseline splenomegaly had normalized, 58% with hepatomegaly had normalized, and lumbar spine bone density had normalized in 53% of adults. The decade-old therapeutic goals do not reflect the potential for normalization of clinical parameters in ERT-treated patients. Goals consistent with normalization or near-normalization should be considered. ClinicalTrials.gov identifiers: NCT00430625, NCT00553631, NCT00635427.

Development of anti-velaglucerase alfa antibodies in clinical trial-treated patients with Gaucher disease.

Anti-drug antibodies may develop with biological therapies, possibly leading to a reduction of treatment efficacy and to allergic and other adverse reactions. Patients with Gaucher disease were tested for anti-drug antibodies every 6 or 12weeks in clinical studies of velaglucerase alfa enzyme replacement therapy, as part of a range of safety endpoints. In 10 studies between April 2004 and March 2015, 289 patients aged 2-84years (median 43years) were assessed for the development of anti-velaglucerase alfa antibodies. Sixty-four patients were treatment-naïve at baseline and 225 patients were switched to velaglucerase alfa from imiglucerase treatment. They received velaglucerase alfa treatment for a median of 36.4weeks (interquartile range 26.4-155.4weeks). Four patients (1.4%) became positive for anti-velaglucerase alfa IgG antibodies, two of whom had antibodies that were neutralizing in vitro, but there were no apparent changes in patients' platelet counts, hemoglobin levels or levels of CCL18 and chitotriosidase, suggestive of clinical deterioration after anti-velaglucerase alfa antibodies were detected, and no infusion-related adverse events were reported. Less than 2% of patients exposed to velaglucerase alfa tested positive for antibodies and there was no apparent correlation between anti-velaglucerase alfa antibodies and adverse events or pharmacodynamic or clinical responses.

Molecule engineering strategy of toll-like receptor 7/8 agonists designed for potentiating immune stimuli activation.

Toll-like receptor 7/8 (TLR-7/8) agonists serve as a promising class of pattern recognition receptors that effectively evoke the innate immune response, making them promising immunomodulatory agents for tumor immunotherapy. However, the uncontrollable administration of TLR-7/8 agonists frequently leads to the occurrence of severe immune-related adverse events (irAEs). Thus, it is imperative to strategically design tumor-microenvironment-associated biomarkers or exogenous stimuli responsive TLR-7/8 agonists in order to accurately evaluate and activate innate immune responses. No comprehensive elucidation has been documented thus far regarding TLR-7/8 immune agonists that are specifically engineered to enhance immune activation. In this feature article, we provide an overview of the advancements in TLR-7/8 agonists, aiming to enhance the comprehension of their mechanisms and promote the clinical progression through nanomedicine strategies. The current challenges and future directions of cancer immunotherapy are also discussed, with the hope that this work will inspire researchers to explore innovative applications for triggering immune responses through TLR-7/8 agonists.

Oxygen-Independent Radiodynamic Therapy: Radiation-Boosted Chemodynamics for Reprogramming the Tumor Immune Environment and Enhancing Antitumor Immune Response.

Radiodynamic therapy (RDT) has emerged as a promising modality for cancer treatment, offering notable advantages such as deep tissue penetration and radiocatalytic generation of oxygen free radicals. However, the oxygen-dependent nature of RDT imposes limitations on its efficacy in hypoxic conditions, particularly in modulating and eliminating radioresistant immune suppression cells. A novel approach involving the creation of a "super" tetrahedron polyoxometalate (POM) cluster, Fe12-POM, has been developed for radiation boosted chemodynamic catalysis to enable oxygen-independent RDT in hypoxic conditions. This nanoscale cluster comprises four P2W15 units functioning as energy antennas, while the Fe3 core serves as an electron receptor and catalytic center. Under X-ray radiation, a metal-to-metal charge transfer phenomenon occurs between P2W15 and the Fe3 core, resulting in the valence transition of Fe3+ to Fe2+ and a remarkable 139-fold increase in hydroxyl radical generation compared to Fe12-POM alone. The rapid generation of hydroxyl radicals, in combination with PD-1 therapy, induces a reprogramming of the immune environment within tumors. This reprogramming is characterized by upregulation of CD80/86, downregulation of CD163 and FAP, as well as the release of interferon-γ and tumor necrosis factor-α. Consequently, the occurrence of abscopal effects is facilitated, leading to significant regression of both local and distant tumors in mice. The development of oxygen-independent RDT represents a promising approach to address cancer recurrence and improve treatment outcomes.

Combined Transcriptome and Metabolome Analysis Reveals That the Potent Antifungal Pyrylium Salt Inhibits Mitochondrial Complex I in Candida albicans.

Based on the structural modification of SM21, xy12, a new pyrylium salt derivative with enhanced antifungal activities, was synthesized. The MICs (MIC90) of xy12 against Candida albicans ranged from 0.125 to 0.25 µg/mL, about 2-fold lower than those of SM21. In addition, xy12 inhibited hypha and biofilm formation in C. albicans in a dose-dependent manner. A total of 3,454 differentially expressed genes and 260 differential metabolites were identified in the xy12-treated C. albicans by RNA-seq and non-targeted metabolomics. By integrating KEGG pathway enrichment analysis, we found that inhibition of oxidative phosphorylation was the important antifungal mechanism of action of xy12. Electron transport through mitochondrial respiratory complexes I to IV is the common process of oxidative phosphorylation. Compared with the sensitivity of the wild-type SC5314 to xy12, decreased sensitivities in mitochondrial complex I (CI)-deficient mutants and increased sensitivities in mitochondrial complex III- and IV-deficient mutants suggested that the antifungal effects of xy12 were dependent on CI. Consistently, xy12 exhibited antagonism with rotenone, an inhibitor of CI, and significantly inhibited the expression and activity of CI. Meanwhile, the phenotypes in the xy12-treated C. albicans were similar to those in the CI-deficient mutants, such as decreased ATP production, reduced mitochondrial membrane potential, loss of mitochondrial DNA, inability to utilize nonfermentative carbon sources, and decreased cell wall N-linked mannoproteins. Collectively, our results revealed that the pyrylium salt xy12 could constrain oxidative phosphorylation by inhibiting mitochondrial complex I in C. albicans, providing a novel lead compound for the development of mitochondria-targeted antifungal drugs. IMPORTANCE The development of new antifungal drugs is critical for solving the problem of antifungal resistance and expanding the limited variety of clinical antifungal drugs. Based on the modification of the pyrylium salt SM21, a new lead compound, xy12, was synthesized which was effective against Candida species both in vitro and in vivo. In this study, conjoined analysis of the transcriptome and metabolome elucidated the antifungal mechanism of action of xy12, which inhibited the activity of mitochondrial complex I in C. albicans. Targeting fungi-specific mitochondrial complex proteins has been reported as a promising antifungal strategy. Our study provided a new lead compound for targeting C. albicans mitochondrial complex I, which could be beneficial for discovering novel antifungal drugs.

Changes in the brain intrinsic organization in both on-task state and post-task resting state.

The dynamic and robust characteristics of intrinsic functional connectivity of coherent spontaneous activity are critical for the brain functional stability and flexibility. Studies have demonstrated modulation of intrinsic connectivity within local spatial patterns during or after task performance, such as the default mode network (DMN) and task-specific networks. Moreover, recent studies have compared the global spatial pattern in different tasks or over time. However, it is still unclear how the large-scale intrinsic connectivity varies during and after a task. To better understand this issue, we conducted a functional MRI experiment over three sequential periods: an active semantic-matching task period and two rest periods, before and after the task respectively (namely, on-task state and pre-/post-task resting states), to detect task-driven effect on the dynamic large-scale intrinsic organization in both on-task state and post-task resting state. Three hierarchical levels were investigated, including (a) the whole brain small-world topology, (b) the whole pairwise functional connectivity patterns both within the DMN and between the DMN and other regions (i.e., the global/full DMN topography), and (c) the DMN nodal graph properties. The major findings are: (1) The large-scale small-world configuration of brain functional organization is robust, regardless of the behavioral state changing, while it varies adaptively with significantly higher local efficiency and lower global efficiency during the on-task state (P<0.05, Monte-Carlo corrected); (2) The DMN may be essentially engaged during both task and post-task processes with adaptively varied spatial patterns and nodal graph properties. The present study provides further insights into the robustness and plasticity of the brain intrinsic organization over states, which may be the basis of memory and learning in the brain.

Phase I Study of the Pharmacodynamics and Safety of Sodium Zirconium Cyclosilicate in Healthy Chinese Adults.

Sodium zirconium cyclosilicate (SZC) is an effective potassium binder for patients with hyperkalemia. This single-center, open-label, phase I study (NCT03283267) characterized the pharmacodynamics and safety of SZC in Chinese individuals. Twenty-two healthy Chinese adults (mean age, 33.5 years) randomized 1:1 received daily oral SZC 5 or 10 g for 4 days, following 4 days on a low-sodium, high-potassium diet (continued throughout the study). End points were mean change from baseline in 24-hour urinary potassium (primary) and sodium excretion, and serum potassium concentration. Urinary potassium excretion significantly decreased with SZC 5 g (mean change [mmol], -13.0; P < .001) and 10 g (-15.4; P < .001). Although urinary sodium excretion decreased significantly with SZC 5 g (-11.5; P = .030), there was no significant change with SZC 10 g (-5.1; P = .299). Serum potassium concentrations decreased significantly with SZC 5 g (-0.14; P = .031) and 10 g (-0.20; P = .002). All treatment-emergent adverse events were mild, and none were considered causally related to SZC. Over 4 days, the pharmacodynamics and safety of SZC were consistent in healthy Chinese adults with global studies and patients of Japanese ethnicity.

Development and validation of a sensitive LC-MS/MS method for determination of intracellular concentration of fluconazole in Candida albicans.

Systemic candidiasis is the fourth leading cause of healthcare-associated infections worldwide. The combination therapy based on existing antifungal agents is well-established to overcome drug resistance and restore antifungal efficacy against drug-resistant strains. In this study, a simple and sensitive liquid chromatography with tandem mass spectrometry (LC-MS/MS) method was developed to quantify the intracellular fluconazole (FLC) content in the opportunistic human fungal pathogen Candida albicans. The cell lysates were prepared by lysing C. albicans cells with Precellys homogenizers and FLC was extracted with methylene chloride. The entire extraction approach was simple, precise and reliable. The extracts were separated on a Zorbax SB-C18 column using a mobile phase of acetonitrile (solvent A) and deionized water plus 0.1% formic acid. FLC and ketoconazole (KCZ, internal standard) were monitored in positive mode using electrospray ionization source. The multiple reaction monitoring transitions (precursor to product) were monitored for FLC m/z 307.1 → 238.2 and for the internal standard KCZ m/z 531.2 → 489.1. The linear for this method were in the range from 5.0 to 1000.0 ng/mL. The precision and accuracy of the samples were relative standard deviations (RSD) < 1.0% for intra-day and RSD < 0.51% for inter-day. The overall recovery of FLC from samples was higher than 77.61%. Furthermore, this method was successfully applied and validated in 36 clinical isolated strains. Taken together, we established a highly accurate, efficient, and reproducible method for quantifying the intracellular content of FLC in C. albicans.

Brain regions engaged by part- and whole-task performance in a video game: a model-based test of the decomposition hypothesis.

Part- and whole-task conditions were created by manipulating the presence of certain components of the Space Fortress video game. A cognitive model was created for two-part games that could be combined into a model that performed the whole game. The model generated predictions both for behavioral patterns and activation patterns in various brain regions. The activation predictions concerned both tonic activation that was constant in these regions during performance of the game and phasic activation that occurred when there was resource competition. The model's predictions were confirmed about how tonic and phasic activation in different regions would vary with condition. These results support the Decomposition Hypothesis that the execution of a complex task can be decomposed into a set of information-processing components and that these components combine unchanged in different task conditions. In addition, individual differences in learning gains were predicted by individual differences in phasic activation in those regions that displayed highest tonic activity. This individual difference pattern suggests that the rate of learning of a complex skill is determined by capacity limits.

Amnestic mild cognitive impairment: functional MR imaging study of response in posterior cingulate cortex and adjacent precuneus during problem-solving tasks.

PURPOSE: To compare the blood oxygen level-dependent (BOLD) response, measured with functional magnetic resonance (MR) imaging, in the posterior cingulate cortex (PCC) and adjacent precuneus regions between healthy control subjects and patients with amnestic mild cognitive impairment (MCI) during problem-solving tasks. MATERIALS AND METHODS: This study was approved by the institutional review board. Each subject provided written informed consent. Thirteen patients with amnestic MCI and 13 age- and sex-matched healthy control subjects participated in the study. The functional magnetic resonance (MR) imaging tasks were simplified 4 × 4-grid number placement puzzles that were divided into a simple task (using the row rule or the column rule to solve the puzzle) and a complex task (using both the row and column rules to solve the puzzle). Behavioral results and functional imaging results between the healthy control group and the amnestic MCI group were analyzed. RESULTS: The accuracy for the complex task in the healthy control group was significantly higher than that in the amnestic MCI group (P < .05). The healthy control group exhibited a deactivated BOLD signal intensity (SI) change in the bilateral PCC and adjacent precuneus regions during the complex task, whereas the amnestic MCI group showed activation. The positive linear correlations between the BOLD SI change in bilateral PCC and adjacent precuneus regions and in bilateral hippocampi in the amnestic MCI group were significant (P < .001), while in the healthy control group, they were not (P ≥ .23). CONCLUSION: These findings suggest that an altered BOLD response in amnestic MCI patients during complex tasks might be related to a decline in problem-solving ability and to memory impairment and, thus, may indicate a compensatory response to memory impairment.

The Impact of Social Media Use on Job Burnout: The Role of Social Comparison.

Through an online survey of a working population sample (N = 530), this study examines the role of social comparison between social media use and job burnout. The results show that: (1) there is a significant positive correlation between social media use and job burnout; (2) social comparison plays a moderating role in social media's impact on burnout. In high social comparative groups, the moderating role develops into an mediating role, which means that job burnout is only significant when social media addiction and the inclination of social comparison are simultaneously strong; (3) Social media users who often make downward comparison and get positive emotions from it are more prone to job burnout. This study reveals the possible negative effects of overuse of new media and enriches the understanding of how social media shapes individuals' psychology and behavior. Studies have also shown that regulating and controlling social comparisons and avoiding excessive use of social media may be effective in reducing job burnout.

Measuring effects on intima-media thickness: an evaluation of rosuvastatin in Chinese subjects with subclinical atherosclerosis-design, rationale, and methodology of the METEOR-China study.

BACKGROUND: The beneficial effect of statins on atherosclerosis and cardiovascular outcomes has been well established. The Measuring Effects on intima media Thickness: an Evaluation Of Rosuvastatin (METEOR) global study demonstrated that a 2-year orally administered treatment with rosuvastatin 40 mg daily significantly slowed the progression of carotid intima-media thickness (CIMT) compared to placebo. The current METEOR-China study is designed to evaluate the effect of rosuvastatin 20 mg daily versus placebo on the progression of atherosclerosis measured by CIMT in asymptomatic Chinese subjects. METHODS: This is a phase 3, randomised, double-blind, placebo-controlled, multicentre parallel-group study. Asymptomatic Chinese subjects with a 10-year ischaemic cardiovascular disease (ICVD) risk < 10% will be recruited at 25 study sites. They will be treated with rosuvastatin 20 mg or placebo for 104 weeks. The primary endpoint is the annualised rate of change in CIMT measured by B-mode ultrasonography. Secondary endpoints include the annualised rate of change in CIMT at three different sections of the carotid artery and changes in the serum lipid profile. Safety parameters will also be assessed. CONCLUSION: The study will evaluate whether rosuvastatin 20 mg slows the progression of CIMT in asymptomatic Chinese subjects at low risk of ICVD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02546323 . Registered on September 10, 2015.

A central circuit of the mind.

The methodologies of cognitive architectures and functional magnetic resonance imaging can mutually inform each other. For example, four modules of the ACT-R (adaptive control of thought - rational) cognitive architecture have been associated with four brain regions that are active in complex tasks. Activity in a lateral inferior prefrontal region reflects retrieval of information in a declarative module; activity in a posterior parietal region reflects changes to problem representations in an imaginal module; activity in the anterior cingulate cortex reflects the updates of control information in a goal module; and activity in the caudate nucleus reflects execution of productions in a procedural module. Differential patterns of activation in such central regions can reveal the time course of different components of complex cognition.

Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung.

The lung is an organ for host defense to clear up pathogens through innate and adaptive immunity. This process involves up-regulation of proinflammatory cytokines and chemokines that lead to activation of the signal transducers and activators of the transcription 3 (Stat3) signaling pathway. Overexpression of Stat3C in alveolar type II epithelial cells of CCSP-rtTA/(tetO)(7)-Stat3C bitransgenic mice leads to severe pulmonary inflammation, including immune cell infiltration and up-regulation of proinflammatory cytokines and chemokines in the lung. As a consequence, spontaneous lung bronchoalveolar adenocarcinoma was observed in bitransgenic mice. Aberrantly expressed genes in the bitransgenic model were identified and served as biomarkers for human bronchoalveolar adenocarcinoma. During tumorigenesis, genes that are critical to epithelial cell proliferation in lung development were reactivated. Therefore, Stat3 is a potent proinflammatory molecule that directly causes spontaneous lung cancer in vivo.

Using FMRI to test models of complex cognition.

This article investigates the potential of fMRI to test assumptions about different components in models of complex cognitive tasks. If the components of a model can be associated with specific brain regions, one can make predictions for the temporal course of the BOLD response in these regions. An event-locked procedure is described for dealing with temporal variability and bringing model runs and individual data trials into alignment. Statistical methods for testing the model are described that deal with the scan-to-scan correlations in the errors of measurement of the BOLD signal. This approach is illustrated using a "sacrificial" ACT-R model that involves mapping 6 modules onto 6 brain regions in an experiment from Ravizza, Anderson, and Carter (in press) concerned with equation solving. The model's visual encoding predicted the BOLD response in the fusiform gyrus, its controlled retrieval predicted the BOLD response in the lateral inferior prefrontal cortex, and its subgoal setting predicted the BOLD response in the anterior cingulate cortex. On the other hand, its motor programming failed to predict anticipatory activation in the motor cortex, its representational changes failed to predicted the pattern of activity in the posterior parietal cortex, and its procedural component failed to predict an initial spike in caudate. The results illustrate the power of such data to direct the development of a theory of complex problem solving, both at the level of a specific task model as well as at the level of the cognitive architecture.