Hydrogen sulfide coordinates glucose metabolism switch through destabilizing tetrameric pyruvate kinase M2.

Most cancer cells reprogram their glucose metabolic pathway from oxidative phosphorylation to aerobic glycolysis for energy production. By reducing enzyme activity of pyruvate kinase M2 (PKM2), cancer cells attain a greater fraction of glycolytic metabolites for macromolecule synthesis needed for rapid proliferation. Here we demonstrate that hydrogen sulfide (H2S) destabilizes the PKM2 tetramer into monomer/dimer through sulfhydration at cysteines, notably at C326, leading to reduced PKM2 enzyme activity and increased PKM2-mediated transcriptional activation. Blocking PKM2 sulfhydration at C326 through amino acid mutation stabilizes the PKM2 tetramer and crystal structure further revealing the tetramer organization of PKM2-C326S. The PKM2-C326S mutant in cancer cells rewires glucose metabolism to mitochondrial respiration, significantly inhibiting tumor growth. In this work, we demonstrate that PKM2 sulfhydration by H2S inactivates PKM2 activity to promote tumorigenesis and inhibiting this process could be a potential therapeutic approach for targeting cancer metabolism.

Oxygen-Binding Sites of Enriched Gold Nanoclusters for Capturing Mitochondrial Reverse Electrons.

Reverse electron transfer (RET), an abnormal backward flow of electrons from complexes III/IV to II/I of mitochondria, causes the overproduction of a reduced-type CoQ to boost downstream production of mitochondrial superoxide anions that leads to ischemia-reperfusion injury (IRI) to organs. Herein, we studied low-coordinated gold nanoclusters (AuNCs) with abundant oxygen-binding sites to form an electron-demanding trapper that allowed rapid capture of electrons to compensate for the CoQ/CoQH2 imbalance during RET. The AuNCs were composed of only eight gold atoms that formed a Cs-symmetrical configuration with all gold atoms exposed on the edge site. The geometry and atomic configuration enhance oxygen intercalation to attain a d-band electron deficiency in frontier orbitals, forming an unusually high oxidation state for rapid mitochondrial reverse electron capture under a transient imbalance of CoQ/CoQH2 redox cycles. Using hepatic IRI cells/animals, we corroborated that the CoQ-like AuNCs prevent inflammation and liver damage from IRI via recovery of the mitochondrial function.

Discovery of Uncommon Tryptophan-Containing Diketopiperazines from Aspergillus homomorphus CBS 101889 Using an Aspergillus nidulans Heterologous Expression System.

Fungal secondary metabolite (SM) biosynthetic gene clusters (BGCs) containing dimethylallyltryptophan synthases (DMATSs) produce structurally diverse prenylated indole alkaloids with wide-ranging activities that have vast potential as human therapeutics. To discover new natural products produced by DMATSs, we mined the Department of Energy Joint Genome Institute's MycoCosm database for DMATS-containing BGCs. We found a DMATS BGC in Aspergillus homomorphus CBS 101889, which also contains a nonribosomal peptide synthetase (NRPS). This BGC appeared to have a previously unreported combination of genes, which suggested the cluster might make novel SMs. We refactored this BGC with highly inducible promoters into the model fungus Aspergillus nidulans. The expression of this refactored BGC in A. nidulans resulted in the production of eight tryptophan-containing diketopiperazines, six of which are new to science. We have named them homomorphins A-F (2, 4-8). Perhaps even more intriguingly, to our knowledge, this is the first discovery of C4-prenylated tryptophan-containing diketopiperazines and their derivatives. In addition, the NRPS from this BGC is the first described that has the ability to promiscuously combine tryptophan with either of two different amino acids, in this case, l-valine or l-allo-isoleucine.

Lanthanium nitride LaN9 featuring azide units: the first metal nine-nitride as a high-energy-density material.

High-pressure phase diagrams of the La-N binary system were systematically constructed using the CALYPSO method and first-principles calculations. In addition to the pressure-induced La-N compounds reported previously, we have uncovered a hitherto unknown LaN9 structure in Pm3̄ symmetry stabilized within a narrow pressure range of 20-24.5 GPa. Notably, LaN9 stands as the first thermodynamically stable metal nine-nitrogen compound, featuring centrosymmetric linear N3 anion units and an edge-sharing LaN12 icosahedron. Charge transfer between the La and N atoms plays a crucial role in facilitating structural stability. Furthermore, we identified a novel Cm phase for LaN8, which has a lower enthalpy compared to the previously reported phase. N atoms in Cm LaN8 are polymerized into infinite N∞ chains. Calculations demonstrate the potential recoverability of LaN9 and Cm LaN8 under atmospheric conditions while preserving their initial polynitrogen configuration. From the perspective of detonation pressure and detonation velocity, LaN9 and Cm LaN8 exhibit excellent explosive performance in comparison to TNT and HMX, with estimated energy densities of 0.9 and 1.54 kJ g-1, respectively, indicating their potential utility as high-energy-density materials.

A heterologous expression platform in Aspergillus nidulans for the elucidation of cryptic secondary metabolism biosynthetic gene clusters: discovery of the Aspergillus fumigatus sartorypyrone biosynthetic pathway.

Aspergillus fumigatus is a serious human pathogen causing life-threatening Aspergillosis in immunocompromised patients. Secondary metabolites (SMs) play an important role in pathogenesis, but the products of many SM biosynthetic gene clusters (BGCs) remain unknown. In this study, we have developed a heterologous expression platform in Aspergillus nidulans, using a newly created genetic dereplication strain, to express a previously unknown BGC from A. fumigatus and determine its products. The BGC produces sartorypyrones, and we have named it the spy BGC. Analysis of targeted gene deletions by HRESIMS, NMR, and microcrystal electron diffraction (MicroED) enabled us to identify 12 products from the spy BGC. Seven of the compounds have not been isolated previously. We also individually expressed the polyketide synthase (PKS) gene spyA and demonstrated that it produces the polyketide triacetic acid lactone (TAL), a potentially important biorenewable platform chemical. Our data have allowed us to propose a biosynthetic pathway for sartorypyrones and related natural products. This work highlights the potential of using the A. nidulans heterologous expression platform to uncover cryptic BGCs from A. fumigatus and other species, despite the complexity of their secondary metabolomes.

Real-Time Observation for Dynamic Oscillation during Self-Assembly and Clearance of Aß42.

The dynamic oscillation implicated in structural heterogeneity during the self-assembly of amyloid peptide 1-42 (Aß42) may play a crucial role in eliciting cellular responses. We developed a real-time monitoring platform to observe an oscillatory non-equilibrium interaction that dominated the Aß42 clearance by neuronal cells during interplay with an oscillator (lipopolysaccharide, LPS). Molecular dynamics studies indicated that the electrostatic and hydrophobic segments of LPS involved in the temporary heteromolecular association and slightly decelerated the intrinsic thermally-induced protein dynamics of Aß42. A bait-specific intervention strategy could temporarily slow down the self-propagation of Aß42 to extend the lifetime of autonomous oscillation and augment Aß42 clearance of neuronal cells. The lifetime increment of oscillation shows a bait concentration-dependent manner to reflect the non-equilibrium binding strength. This relationship may serve as a predictor for Alzheimer's disease drug discovery.

Polystyrene Upcycling into Fungal Natural Products and a Biocontrol Agent.

Polystyrene (PS) is one of the most used yet infrequently recycled plastics. Although manufactured on the scale of 300 million tons per year globally, current approaches toward PS degradation are energy- and carbon-inefficient, slow, and/or limited in the value that they reclaim. We recently reported a scalable process to degrade post-consumer polyethylene-containing waste streams into carboxylic diacids. Engineered fungal strains then upgrade these diacids biosynthetically to synthesize pharmacologically active secondary metabolites. Herein, we apply a similar reaction to rapidly convert PS to benzoic acid in high yield. Engineered strains of the filamentous fungus Aspergillus nidulans then biosynthetically upgrade PS-derived crude benzoic acid to the structurally diverse secondary metabolites ergothioneine, pleuromutilin, and mutilin. Further, we expand the catalog of plastic-derived products to include spores of the industrially relevant biocontrol agent Aspergillus flavus Af36 from crude PS-derived benzoic acid.

Chinese Herbal Fumigation Steam Therapy and Acupuncture in the Treatment of Knee Osteoarthritis: A Three-armed, Randomized, Controlled Trial.

Context: Knee osteoarthritis is a common form of joint disease found in humans and one of the leading causes of disability globally. Knee osteoarthritis (KOA) is responsible for a higher number of disabilities than any other medical condition affecting activities of daily living (ADL). To date no definitive, conventional medical protocol is available to deal with KOA. Objectives: The study intended to clinically investigate whether the benefits of acupuncture in the treatment of KOA) could be augmented by the addition of Chinese herbal fumigation steam therapy (CHFST) to the treatment protocol and to what degree it had benefits. Design: The research team designed a three-armed, randomized, controlled trial. The sample size was determined by analysis of power; for a sample size of 42, the power was 83.5%; the effect size was 0.5; and the α was 0.05. Setting: The setting was the traumatology department in the Chinese Medicine Branch of Taipei City Joint Hospital in Kun Ming, Taiwan. Participants: Participants were 45 males and females between the ages of 35 and 75, who were patients in the traumatology department and who were suffering from bilateral knee osteoarthritis. Three participants were lost to follow-up. Interventions: Participants were randomly assigned to one of three groups, each with 15 participants; (1) the control group, who received acupuncture only; (2) the normal CHFST group, an intervention group who received acupuncture plus a normal dose of CHFST; and (3) the one-sixteenth CHFST group, an intervention group who received acupuncture plus one-sixteenth of a normal dose of CHFST. Participants underwent biweekly treatments for four consecutive weeks. Outcomes Measures: The primary outcome measures included a visual analog scale (VAS) to assess variations in pain intensity and a goniometer measure for range of motion (ROM). Results: The addition of CHFST to acupuncture in the treatment of KOA significantly reduced pain (P = .0017) for the normal CHFST group compared to the control group and the one-sixteenth CHFST group. Chinese medical interventions overall for all groups showed a decrease in pain and increases in ROM, and health related quality of life (HrQoL). Conclusions: CHFST, in conjunction with acupuncture, showed promise in the treatment of KOA in reducing pain, increasing ROM, and improving quality of life (QoL).

Transdermal Delivery of Succinate Accelerates Energy Dissipation of Brown Adipocytes to Reduce Remote Fat Accumulation.

Weight loss by increasing energy consumption of thermogenic adipocytes to overcome obesity remains a challenge. Herein, we established a transdermal device that was based on the local and temporarily controlled delivery of succinate (SC), a tricarboxylic acid cycle metabolic intermediate to stimulate the thermogenesis pathway of uncoupling protein 1 (UCP1) and accelerate energy dissipation of brown adipose tissue (BAT) under the dorsal interscapular skin, further initiating the consumption of fatty acids by systemic metabolism. SC microneedle patches significantly suppressed weight gain and fat accumulation of remote organs, including liver and peripheral white adipose tissue (WAT) in high-fat diet-induced obese mice. mRNA expression levels of Ucp1 in BAT and other browning markers in WAT were significantly elevated in the mice that were treated with SC microneedle. Thus, the energy dissipation of BAT using UCP1-mediated thermogenesis accelerated by the transdermal delivery of SC may become a potential and effective strategy for preventing obesity.

Ambient-Pressure Recoverable Polynitrogen Solids Assembled by Pentazolate Rings with High Energy Density.

Crystal structure predictions and first-principles calculations were used to predict three polynitrogen solids (aP8-N, aP12-N, and oP24-N) that possess competitive enthalpies as compared to the synthesized open-chain N8 phase at pressures in the range of 0-60 GPa. aP8-N, aP12-N, and oP24-N contain edge-shared, N2-linked, and N-bridged pentazolate rings and form molecular N8, molecular N12, and quasi-one-dimensional N∞ ribbons, respectively. The calculations of formation enthalpies show that the three polynitrogen solids can be synthesized by compressing cyclo-N5 salts in hydrogen-saturated environments. Molecular simulations suggest that the three polynitrogen solids have the ability of quench recoverability under ambient conditions once being synthesized at high pressure. With estimated energy densities in the range of 5.6-6.5 kJ/g, these three polynitrogen phases show notable promise for applications as high-energy-density materials.

Two-dimensional Si2S with a negative Poisson's ratio and promising optoelectronic properties.

Two-dimensional materials with a negative Poisson's ratio, known as auxetic materials, are of great interest owing to their improved mechanical properties, which enable plenty of advanced nanomechanical devices. Here, by first-principles swarm-intelligence structural search methods, we predict a thermodynamically stable Si2S monolayer, which has a puckered 2D lattice in which the S atoms are adsorbed on the top of a distorted tetragonal silicene layer. The puckered 2D lattice makes the Si2S monolayer exhibit in-plane negative Poisson's ratios of -0.05 and -0.069 along the x and y directions, respectively. Moreover, electronic structure calculations reveal that the Si2S monolayer is a semiconductor with a quasi-direct band gap of 1.81 eV, which can be converted into a direct gap semiconductor of 1.43 eV by applying a low tensile strain (∼2%). The Si2S monolayer has a large visible light absorption coefficient of 105 cm-1. The hole (electron) mobility is 200 (81) cm2 V-1 s-1 along the y direction, 3.4 (1.5) times that along the x direction, comparable to MoS2. Moreover, the Si2S monolayer has the good ability of oxidation resistance. We provide a possible route to experimentally grow a Si2S monolayer on a suitable substrate such as the Cu(100) surface. The versatile properties render the Si2S monolayer potential for advanced application in nanodevices.

Factors associated with having home care physicians as an integrated source of medications for chronic conditions among homebound patients.

BACKGROUND: Inappropriate management of medications is a major threat to homebound patients with chronic conditions. Despite many efforts in improving medication reconciliation in ambulatory and inpatient settings, little research has focused on home care settings. In 2016, Taiwan initiated the Integrated Home Health Care programme, which was intended to reduce potentially inappropriate medication management and risks of uncontrolled polypharmacy through the integration of different medication sources for chronic conditions among homebound patients. This study investigated factors associated with having home care physicians as an integrated source of medications for chronic conditions among homebound patients. METHOD: This retrospective cohort study enrolled 3142 community-dwelling homebound patients from Taipei City Hospital. Homebound patients' adherence to using home care physicians as an integrated source of chronic condition medications was defined as having all prescriptions for their chronic conditions prescribed by a single home care physician for at least 6 months. Both patient and home care physician characteristics were analysed. Multivariable logistic regression was applied. RESULTS: Of the 3142 patients with chronic conditions, 1002 (31.9%) had consistently obtained all medications for their chronic illnesses from their home care physicians for 6 months and 2140 (68.1%) had not. The most common chronic diseases among homebound patients were hypertension, diabetes mellitus, dementia, cerebrovascular disease and constipation. Oldest-old patients with poor functional status, fewer daily medications, no co-payment exemption and no recent inpatient experience were more likely to adhere to this medication integration system. In addition, patients whose outpatient physicians were also their home care physicians were more likely to adhere to the system. CONCLUSIONS: The finding suggests that building trust and enhancing communication among homebound patients, caregivers and home care physicians are critical. Patient and provider variations highlight the need for further improvement and policy modification for medication reconciliation and management in home care settings. The improvement in medication management and care integration in home care settings may reduce misuse and polypharmacy and improve homebound patients' safety.

A B2N monolayer: a direct band gap semiconductor with high and highly anisotropic carrier mobility.

Two-dimensional materials with a planar lattice, suitable direct band gap, and high and highly anisotropic carrier mobility are desirable for the development of advanced field-effect transistors. Here we predict three thermodynamically stable B-rich 2D B-N compounds with the stoichiometries of B2N, B3N, and B4N using a combination of crystal structure searches and first-principles calculations. Among them, B2N has an ultraflat surface and consists of eight-membered B6N2 and pentagonal B3N2 rings. The eight-membered B6N2 rings are linked to each other through both edge-sharing (in the y direction) and bridging B3N2 pentagons (in the x direction). B2N is a semiconductor with a direct band gap of 1.96 eV, and the nature of the direct band gap is well preserved in bilayer B2N. The hole mobility of B2N is as high as 0.6 × 103 cm2 V-1 s-1 along the y direction, 7.5 times that in the x direction. These combined novel properties render the B2N monolayer as a natural example in the field of two-dimensional functional materials with broad application potential for use in field-effect transistors.

Retrospective study of the differences in patient characteristics and revenue between male and female surgeons in Taiwan.

Surgery is traditionally a male-dominated field, and gender differences exist despite the growing numbers of female surgeons. A handful of studies have evaluated the condition in Asian societies. We aimed to examine the difference between female and male surgeons in urology, general surgery, and gynecology by analyzing a nationwide, population-based database. We identified surgeons with a clinical experience of six to thirteen years between 1995 to 2013 from the National Health Insurance Research Database. We collected patient numbers and revenue per month in outpatient and inpatient care, as well as monthly numbers of surgeries conducted by female and male surgeons in urology, general surgery, and gynecology, for analysis. Original student's t-test and wilcoxon rank sum test was used to compare the differences between female and male surgeons, and p values less than 0.05 were considered statistically significant. Female urologists and general surgeons had a significantly higher ratio of female patients in Taiwan. Female urologists had patient numbers, revenues, and numbers of surgeries comparable to male urologists. In contrast, female general surgeons had significantly less involvement in outpatient and inpatient care and had low monthly revenues. Female general surgeons contradictorily performed more oncological surgeries per month than males. However, the difference in numbers of oncological surgeries was not significant after excluding breast cancer surgeries. Female gynecologists had a similar amount of outpatients and outpatient revenue but significantly less inpatient care and numbers of surgeries per month. A gender-based gap exists among surgeons in Taiwan. The gap between females and males appeared narrower in urology than in general surgery and gynecology. Management of diseases related to female sex organs, including breast, were more common among female surgeons. Efforts should be made to decrease gender stereotypes, to ensure that patients receive the best care regardless of the sex of the surgeons.

Atrial Fibrillation Is Not Associated With Sudden Sensorineural Hearing Loss.

OBJECTIVES: The aim of this study is to assess the association between atrial fibrillation (AF) and sudden sensorineural hearing loss (SSNHL). METHODS: This study was conducted by searching the longitudinal health insurance database of the Taiwan National Health Insurance Program for relevant information from January 1, 2000, to December 31, 2011. Patients with AF were matched with non-AF controls with a 1:1 strategy according to propensity scores. Multiple logistic regression analyses were performed to determine the risk of SSNHL. RESULTS: In total, 14 698 patients with AF were matched with the same number of non-AF patients as controls. After propensity score matching, the use of antiplatelet or anticoagulation medications and the occurrence of SSNHL were found to have a significant difference between AF and non-AF patients. The occurrence of SSNHL was found to be higher in men, those of 45 to 74 years old, and patients with hypertension in both AF and non-AF groups. Multiple logistic regression analyses revealed that male gender, age between 45 and 74 years, hyperlipidemia, and hypertension are risk factors for SSNHL. The use of aspirin was found to reduce the rate of SSNHL (odds ratio [OR]: 0.67, 95% CI: 0.49-0.94, P = .019), but AF was not found to be a risk factor for SSNHL (OR: 0.89, 95% CI: 0.64-1.23, P = .467). CONCLUSION: The association between AF and SSNHL is not significant.

Pseudostellariawuyishanensis, a new species of Caryophyllaceae from Fujian, China.

Pseudostellariawuyishanensis, a new species from the Wuyishan National Park, Fujian, China, is described and illustrated. Morphologically, Pseudostellariawuyishanensis resembles P.heterantha. However, the new species can be distinguished by presence of stolons, 1 line of hairs on the stem, smaller leaf blades, shorter pedicels, and ovary with 2 styles.

Prevalence and Factors Associated with the Reuse of Mask during the COVID-19 Pandemic: A Nationwide Survey in Taiwan.

Mask usage is an effective measure to prevent severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection; however, mask reuse is not recommended. Studies examining the factors associated with mask reuse during the coronavirus disease (COVID-19) pandemic are limited. This nationwide survey aimed to determine the prevalence and factors associated with mask reuse among Taiwanese citizens during the pandemic. From 18 May through 31 May 2020, a computer-assisted telephone interview system was used to randomly select Taiwanese citizens for interview regarding COVID-19-preventive behaviors and knowledge on mask usage. For a total of 1075 participants, the overall mean age was 57.4 years, and 82.2% of participants reported mask reuse during the COVID-19 pandemic. After controlling for other covariates, participants who had a greater knowledge of mask usage or had a high supply of masks were less likely to reuse masks during the pandemic. Moreover, generalized estimating equations (GEE) analysis showed that, compared with the participants' mask-wearing behaviors before the COVID-19 pandemic, they were more likely to reuse masks during the pandemic. Thus, it is imperative to educate people on the correct usage of masks. Furthermore, the government should provide sufficient masks to the general population to reduce mask reuse.

Type I Interferon Signaling Accelerates Liver Regeneration by Metabolic Modulation in Noninfectious Conditions.

Type I interferon (IFN-I) has a well-known function in controlling viral infections, but its contribution in hepatocyte proliferation and hepatocellular carcinoma (HCC) formation remains unclear. Mice deficient in IFN-α receptor expression in whole mice or only in hepatocytes (Ifnar-/- and IfnarΔliver) were used to investigate the role of IFN-I signaling in cell proliferation and cancer formation in the liver. Ifnar-/- mice were resistant to chemical-induced HCC formation in the absence of infection. The results show that low grade of IFN-I and interferon-stimulated gene were expressed substantially in naïve mouse liver. The low level of IFN-I activation is constantly present in mouse liver after weaning and negatively modulates forkhead box O hepatic expression. The IFN-I signaling can be partially blocked by the clearance of lipopolysaccharide. Mice lacking IFN-I signaling have lower basal proliferation activity and delayed liver regeneration processes after two-thirds partial hepatectomy. The activation of IFN-I signaling on hepatocyte controls glucose homeostasis and lipid metabolism to support proliferation potency and long-term tumorigenesis. Our results reveal a positive role of low-grade IFN-I singling to hepatocyte proliferation and HCC formation by modulating glucose homeostasis and lipid metabolism.

Ultra-Small Platinum Nanoparticle-Enabled Catalysis and Corrosion Susceptibility Reverse Tumor Hypoxia for Cancer Chemoimmunotherapy.

A major challenge in the use of chemotherapy and immunotherapy is hypoxia-induced progression of tumor cells. We aim to curb hypoxia using metal-based O2-producing nanomedicine. The key focus is therapeutic targeting of hypoxia-inducible factor 1α (HIF-1α), a major reactive oxygen species (ROS)-activated player that drives hypoxia-dependent tumor progression. Inhibition of tumor growth by blocking both HIF-1α and immune checkpoint molecules via ROS removal is a promising new strategy to avoid ROS-induced hypoxia signaling and boost antitumor immunity. Here, we investigated the synergistic effect of ultra-small platinum nanoparticles (Pt-nano) with dual functions of enzyme-mimicking catalysis and corrosion susceptibility to block hypoxia signaling of tumors. Ultra-small Pt-nano with highly corrosive susceptibility can efficiently catalyze ROS scavenging and promote oxygen accumulation for hypoxia reversal, leading to reduced HIF-1α expression. The unique corrosion susceptibility allows ultra-small Pt-nano to effectively exert platinum cytotoxicity, induce reversal of hypoxia-mediated immune suppression by promoting cytotoxic T-cell infiltration of tumors, and reduce the levels of tumoral immune checkpoint molecules and immunosuppressive cytokines. In combination with immune checkpoint blockade using monoclonal antibodies, nanoparticle-enabled enzyme-mimicking is a promising strategy for the enhancement of chemoimmunotherapeutic efficacy through the reversal of tumor hypoxia.