Gigantic Thermal Shielding in 2D Oxide Nanosheets.

Thermal shielding materials that can block near-infrared (NIR) light from the sunlight while maintaining visible transparency have become increasingly important from an energy-saving perspective. Here, we demonstrate a gigantic NIR shielding by an engineered plasmonic material based on a two-dimensional (2D) polytungstate (Cs4-xW11O35-d). Starting from a charge-neutral polytungstate (Cs4W11O35), we synthesize charge-imbalanced 2D nanosheets (Cs4-xW11O35-d) that undergo an unusual structural change with the semiconductor-to-metal transition in a reduced atmosphere. Layer-by-layer engineering of the 2D nanosheets enables a plasmon-induced enhancement of the NIR reflectance (>53%) with a high visible transparency (>71%), realizing high-performance thermal shielding. Our approach offers a solution for future thermal management technology.

A 73-Year-Old Man With Refractory Hemoptysis.

CASE PRESENTATION: A 73-year-old man with fever and fatigue presented to his doctor. He had a history of smoking (52 pack-years) and COPD on home oxygen therapy. The patient had no significant family medical history, illicit drug-use history, or recent alcohol use. Chest CT scan showed a slight infiltrative shadow of the left lower lobe on a background of emphysema. Broad-spectrum antibiotics were administered for community-acquired pneumonia without any clinical or radiologic improvement after 2 weeks of therapy. Additional tests showed rapid deterioration of renal function (creatinine level, which was 0.68 mg/dL 2 years earlier, had worsened to 2.08 mg/dL), BUN level of 49.8 mg/dL (reference range, 8- to 20 mg/dL), myeloperoxidase-anti-neutrophil cytoplasmic antibodies 484.0 units/mL (range, 0.0 to 3.4 units/mL), C-reactive protein level of 11.1 mg/dL (range, 0.0 to 0.14 mg/dL), hemoglobin level of 9.0 g/dL (range, 13.7 to 16.8 g/dL), and urinalysis protein 1+ and occult blood 3+. On physical examination, multiple lesions of purpura were observed on the body surface, and hemoptysis was present. No sputum, urine, or blood cultures were done. Based on the examination, the previous doctors suspected microscopic polyangiitis (MPA) rather than an atypical/resistant infectious disease. The patient was treated with high-dose methylprednisolone (500 mg for 2 days and 125 mg for 13 days), but hemoptysis reappeared, and the patient was subsequently transported to our hospital.

Discovery and Characterization of a Novel Allosteric Small-Molecule Inhibitor of NADP+-Dependent Malic Enzyme 1.

NADP+-dependent malic enzyme 1 (ME1) decarboxylates malate to form pyruvate and NADPH in the cytoplasm, where it mediates diverse biological functions related to the generation of lipids and other cellular building blocks. As such, ME1 has been implicated in the progression of cancers and has received attention as a promising drug target. Here we report the identification of a novel small-molecule inhibitor of ME1, designated AS1134900. AS1134900 is highly selective for ME1 compared with ME2 and uncompetitively inhibits ME1 activity in the presence of its substrates NADP+ and malate. In addition, X-ray crystal structure analysis of the enzyme-inhibitor complex revealed that AS1134900 binds outside the ME1 active site in a novel allosteric site. Structural comparison of the ME1 quaternary complex with AS1134900, NADPH, and Mn2+, alongside known crystal structures of malic enzymes, indicated the determined crystal ME1-inhibitor complex is in the open form conformation. These results provide insights and a starting point for further discovery of drugs that inhibit ME1 activity in cancer cells.

Protective effect of different doses of trimethoprim-sulfamethoxazole prophylaxis for early severe infections among patients with antineutrophil cytoplasmic autoantibody-associated vasculitis.

OBJECTIVES: To analyse the protective effect of different doses of trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis for early severe infections in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), considering time-varying changes. METHODS: In this retrospective observational study, we assessed the protective effect of TMP/SMX within the first 6 months of diagnosis among Japanese patients with AAV. We included 250 consecutive patients with AAV who were admitted to our hospital. The protective effect of TMP/SMX against early severe infections was verified using Cox regression analysis along with potential confounding factors. Cox regression with inverse probability treatment weights for early severe infections was also performed as a sensitivity analysis. RESULTS: Cox regression analysis showed that the reduced TMP/SMX exposure group had a significant protective effect against early severe infections (standard-dose group versus no TMP/SMX group: hazard ratio [HR] 0.393, 95% confidence interval [CI]: 0.139-1.11, p=0.077; reduced-dose group versus no TMP/SMX group: HR 0.418, 95%CI: 0.216-0.807, p=0.009), even when considering time-dependent changes. In the sensitivity analysis, the reduced-dose group still had a significantly lower risk of early severe infections than the no TMP/SMX group (HR = 0.393, 95%CI: 0.177-0.873, p=0.022). During follow-up, 18.0% of the patients discontinued TMP/SMX due to side effects. CONCLUSIONS: TMP/SMX is highly effective in preventing severe infections among patients with AAV despite the high incidence of side effects. Further studies are needed to determine the optimal dose of TMP/SMX for preventing severe infections, especially considering renal impairment.

Dunaimycin C3, a new GRP78 downregulator from Streptomyces sp. RAN389.

A new member of the dunaimycin family, dunaimycin C3 (2), was isolated from a fermented broth of Streptomyces sp. RAN389. The molecular formula of 2 was established as C42H70O10 by high-resolution FAB-MS, and the structure was elucidated by NMR spectroscopic analyses. Dunaimycin C3 inhibited the expression of the molecular chaperone GRP78 in HT1080 G-L cells in the presence of 10 mM of 2-deoxyglucose with an IC50 of 8.4 nM.

Therapeutic plasma exchange for clinically amyopathic dermatomyositis (CADM) associated with rapidly progressive interstitial pneumonia.

BACKGROUND: Patients with clinically amyopathic dermatomyositis (CADM) with anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) frequently develop rapidly progressive interstitial pneumonia (RPIP), often with fatal outcomes. Therapeutic plasma exchange (TPE) has been reported as effective against CADM-RPIP refractory to conventional immunosuppressive therapy. However, the detailed mechanisms by which TPE improves disease activity of CADM-RPIP remain unclear. AIM: To elucidate the clinical and demographic characteristics of patients with anti-MDA5 Ab-positive CADM-RPIP treated with TPE and to analyze changes in laboratory findings before, during, and after TPE. MATERIALS & METHODS: Patients hospitalized for CADM-RPIP and treated with TPE in 2017 and 2018 were analyzed retrospectively. RESULTS: Three patients were successfully treated with TPE, with good tolerance. Anti-MDA5 Ab titers decreased significantly over the course of TPE. CONCLUSION: We emphasize that TPE could represent an effective treatment option for CADM-RPIP refractory to traditional therapy. Removal of anti-MDA5 Ab and other pathogenic factors may facilitate favorable outcomes.

Synergy of Binary Substitutions for Improving the Cycle Performance in LiNiO2 Revealed by Ab Initio Materials Informatics.

We explore LiNiO2-based cathode materials with two-element substitutions by an ab initio simulation-based materials informatics (AIMI) approach. According to our previous study, a higher cycle performance strongly correlates with less structural change during the charge-discharge cycles; the latter can be used for evaluating the former. However, if we target the full substitution space, full simulations are infeasible even for all binary combinations. To circumvent such an exhaustive search, we rely on Bayesian optimization. Actually, by searching only 4% of all of the combinations, our AIMI approach discovered two promising combinations, Cr-Mg and Cr-Re, whereas each atom itself never improved the performance. We conclude that the synergy never emerges from a common strategy restricted to combinations of "good" elements that individually improve the performance. In addition, we propose a guideline for the binary substitutions by elucidating the mechanism of the crystal structure change.

A covalent small molecule inhibitor of glutamate-oxaloacetate transaminase 1 impairs pancreatic cancer growth.

Metabolic programs are rewired in cancer cells to support survival and tumor growth. Among these, recent studies have demonstrated that glutamate-oxaloacetate transaminase 1 (GOT1) plays key roles in maintaining redox homeostasis and proliferation of pancreatic ductal adenocarcinomas (PDA). This suggests that small molecule inhibitors of GOT1 could have utility for the treatment of PDA. However, the development of GOT1 inhibitors has been challenging, and no compound has yet demonstrated selectivity for GOT1-dependent cell metabolism or selective growth inhibition of PDA cell lines. In contrast, potent inhibitors that covalently bind to the transaminase cofactor pyridoxal-5'-phosphate (PLP), within the active site of the enzyme, have been reported for kynurenine aminotransferase (KAT) and gamma-aminobutyric acid aminotransferase (GABA-AT). Given the drug discovery successes with these transaminases, we aimed to identify PLP-dependent suicide substrate-type GOT1 inhibitors. Here, we demonstrate that PF-04859989, a known KAT2 inhibitor, has PLP-dependent inhibitory activity against GOT1 and shows selective growth inhibition of PDA cell lines.

Web-building spider Nephila clavata (Nephilidae: Arachnida) can represent 137Cs contamination of arthropod communities and bioavailable 137Cs in forest soils at Fukushima, Japan.

Large areas of Fukushima's forests were contaminated with radiocesium (137Cs) after the Fukushima Dai-ichi Nuclear Power Plant accident. Most of the contaminated forests have not been decontaminated, and bioavailable 137Cs is likely to circulate within the forest environment's food web. Nephila clavata (Nephilidae: Arachnida) is a top predator in the forest arthropod community, and this web-building spider potentially consumes many arthropod species presented in the grazing and detrital food chains. We tested whether 137Cs in the spider could serve as a proxy for 137Cs contamination of these arthropod communities. We also examined whether N. clavata could serve as a proxy for soil bioavailable 137Cs. Nephila clavata was similarly or more contaminated with 137Cs compared with lower-trophic-level arthropods such as herbivores and other predators at the same trophic level. Thus, the 137Cs activity of N. clavata could represent the extent to which the arthropod community was contaminated with 137Cs. Data from nine 137Cs-contaminated sites in Fukushima showed a significant positive correlation between soil bioavailable 137Cs and N. clavata's 137Cs activity05 but the coefficient of determination was only moderate (R2 = 0.43), suggesting that N. clavata is only a weak proxy of soil bioavailable 137Cs. Our results also showed that the bioavailable fraction of 137Cs in Fukushima was strongly correlated with the total inventory and that the K and Na contents of the soil determined the soil-to-spider transfer factor for 137Cs and the 137Cs activity in N. clavata, respectively. These results improve our understanding of 137Cs transfer from the soil to arthropod species.

Influenza A with hemorrhagic shock and encephalopathy syndrome in an adult: A case report.

INTRODUCTION: Hemorrhagic shock and encephalopathy syndrome (HSES) is a type of acute encephalopathy mainly seen in infants. It is a syndrome encompassing an onset of high fever, disturbance of consciousness, convulsion, and shock that rapidly progresses to watery diarrhea and liver and renal dysfunctions. It is extremely rare in adults, and the number of reports is limited worldwide. We report the case of an adult patient with HSES, which occurred after influenza A infection. PATIENT CONCERNS: A 52-year-old man visited his family doctor 2 days after he noticed fever and was diagnosed with influenza A using an influenza rapid diagnosis kit; he underwent treatment on an outpatient basis. He was immediately hospitalized after developing fever, abdominal pain, malaise, and shock 16 hours after the commencement of the treatment. Abrupt acute brain swelling was noted 24 hours after hospitalization. DIAGNOSES: The antibody titer to influenza A (H3N2) was 1:40. Computed tomography obtained 24 hours after treatment initiation confirmed acute cerebral edema and cerebral herniation. Electroencephalogram at that time showed a flat line. INTERVENTIONS: For the treatment of influenza A, laninamivir 150 mg was started immediately after the diagnosis by the family doctor, and 600 mg dose was given daily after hospitalization (or since 24 hours after the treatment initiation). For the management of shock, dobutamine 3 µg/kg/min and noradrenaline up to 0.2 µg/kg/min were used together with bolus infusion. OUTCOMES: The patient was declared brain dead on his 6th hospital day and he died on his 27th hospital day. CONCLUSION: Drastic courses such as that in our case with HSES can follow influenza infections even in adults.

Therapy with propylthiouracil for T3-predominant neonatal Graves' disease: a case report.

This case report describes a male neonate with Graves' disease. The mother's pregnancy was complicated by poorly controlled Graves' disease. The neonate was diagnosed with thyroxine (T3)-predominant Graves' disease with low free triiodothyronine (T4) and high free T3 during antithyroid drug therapy. The patient also presented with persistent pulmonary hypertension of the newborn due to hyperthyroidism and airway stenosis caused by goiter. It was difficult to control thyroid function and maintain free T4 levels with inorganic iodine, thiamazole, and levothyroxine sodium hydrate. We successfully controlled thyroid function using the previous treatments in combination with propylthiouracil. Propylthiouracil suppresses type 1 iodothyronine deiodinase, and its pharmacological action suppresses the conversion of T4 to T3. Therefore, we used propylthiouracil at an earlier stage of intervention in this case. We ceased administration of antithyroid drugs on day 85 of life. Subsequently, as the TRH loading test revealed central hypothyroidism, oral administration of levothyroxine sodium hydrate was continued. Its administration was discontinued at the age of 1 yr. Thyroid-stimulating hormone recovered to normal values, and his development had progressed without complications by the age of 2 yr.

Redescription of the Indo-West Pacific cardinalfishes (Perciformes: Apogonidae) Rhabdamia spilota Allen Kuiter 1994 and R. gracilis (Bleeker 1856).

Rhabdamia spilota Allen Kuiter 1994 (Apogonidae), a poorly known cardinalfish previously known only from the Philippines, Indonesia and the Red Sea, is redescribed on the basis of 70 specimens (20.9-61.2 mm standard length) (including types), from the Indo-West Pacific (Red Sea, Andaman Sea, Japan, South China Sea, the Philippines, Indonesia, New Caledonia, and Australia). Because most reports of the similar species R. gracilis (Bleeker 1856), following its original description, were based on misidentifications, R. gracilis is also redescribed (based on 98 Indo-West Pacific specimens from Seychelles, Maldives, Andaman Sea, Japan, Malaysia, Indonesia, New Caledonia, and Australia, 27.9-59.3 mm standard length); a lectotype is designated for it. Rhabdamia spilota differs from R. gracilis in having 27-33 (mode 30-31) developed gill rakers [vs. 22-27 (mode 24) in the latter], 27-33 (30) gill rakers including rudiments [vs. 23-27 (24-25)], a black stripe from the jaw tips to the anterior margin of the orbit (vs. black pigments only at snout and tip of lower jaw), 3-6 reddish brown to blackish blotches on the opercle and anterior of body (vs. blotches absent), and indistinct black pigment restricted to caudal fin outer margins (vs. pigment scattered over entire fin). Rhabdamia gracilis exhibits sexual dichromatism, female specimens larger than 41.3 mm SL having one or two black stripes on the lateral surface of the body; the stripes are absent in males and smaller females. No evidence of sexual dichromatism was found in R. spilota.

Difference in substrate specificity of carboxylesterase and arylacetamide deacetylase between dogs and humans.

Carboxylesterase (CES) and arylacetamide deacetylase (AADAC) are the major enzymes responsible for the hydrolysis of various clinical drugs. Our recent study demonstrated that the identity of the responsible hydrolase can be roughly surmised based on the chemical structures of compounds in humans. Dogs are used for preclinical studies in drug development, but the substrate specificities of dog CES and AADAC remain to be clarified. The purpose of this study is to characterize their substrate specificities. We prepared recombinant dog CES1, CES2, and AADAC. p-Nitrophenyl acetate, a general substrate for esterases, was hydrolyzed by dog CES1 and AADAC, while it was not hydrolyzed by CES2. CES2 protein was not substantially detected in the recombinant system or in the dog liver and intestinal microsomes by Western blot using anti-human CES2 antibodies. In silico analyses demonstrated slight differences in the three-dimensional structures of dog CES2 and human CES2, indicating that dog CES2 might be unstable or inactive. By evaluating the hydrolase activities of 22 compounds, which are known to be substrates of human CES and/or AADAC, we found that the activities of dog recombinant CES1 and AADAC as well as dog tissue preparations for nearly all compounds were lower than those of human enzymes. The dog enzymes that were responsible for the hydrolysis of most compounds corresponded to the human enzymes, but the following differences were observed: oseltamivir, irinotecan, and rifampicin were not hydrolyzed in the dog liver or by any of the recombinant esterases and procaine, a human CES2 substrate, was hydrolyzed by dog CES1. In conclusion, the present study could provide new finding to facilitate our understanding of species differences in drug hydrolysis, which can facilitate drug development and drug safety evaluation.

Streptococcal toxic shock syndrome caused by the dissemination of an invasive emm3/ST15 strain of Streptococcus pyogenes.

BACKGROUND: Streptococcus pyogenes (group A Streptococcus [GAS]) is a major human pathogen that causes a wide spectrum of clinical manifestations. Although invasive GAS (iGAS) infections are relatively uncommon, emm3/ST15 GAS is a highly virulent, invasive, and pathogenic strain. Global molecular epidemiology analysis has suggested that the frequency of emm3 GAS has been recently increasing. CASE PRESENTATION: A 14-year-old patient was diagnosed with streptococcal toxic shock syndrome and severe pneumonia, impaired renal function, and rhabdomyolysis. GAS was isolated from a culture of endotracheal aspirates and designated as KS030. Comparative genome analysis suggested that KS030 is classified as emm3 (emm-type) and ST15 (multilocus sequencing typing [MLST]), which is similar to iGAS isolates identified in the UK (2013) and Switzerland (2015). CONCLUSIONS: We conclude that the global dissemination of emm3/ST15 GAS strain has the potential to cause invasive disease.

Exposure to an Extremely-Low-Frequency Magnetic Field Stimulates Adrenal Steroidogenesis via Inhibition of Phosphodiesterase Activity in a Mouse Adrenal Cell Line.

Extremely low-frequency magnetic fields (ELF-MFs) are generated by power lines and household electrical devices. In the last several decades, some evidence has shown an association between ELF-MF exposure and depression and/or anxiety in epidemiological and animal studies. The mechanism underlying ELF-MF-induced depression is considered to involve adrenal steroidogenesis, which is triggered by ELF-MF exposure. However, how ELF-MFs stimulate adrenal steroidogenesis is controversial. In the current study, we investigated the effect of ELF-MF exposure on the mouse adrenal cortex-derived Y-1 cell line and the human adrenal cortex-derived H295R cell line to clarify whether the ELF-MF stimulates adrenal steroidogenesis directly. ELF-MF exposure was found to significantly stimulate adrenal steroidogenesis (p < 0.01-0.05) and the expression of adrenal steroid synthetic enzymes (p < 0.05) in Y-1 cells, but the effect was weak in H295R cells. Y-1 cells exposed to an ELF-MF showed significant decreases in phosphodiesterase activity (p < 0.05) and intracellular Ca2+ concentration (p < 0.01) and significant increases in intracellular cyclic adenosine monophosphate (cAMP) concentration (p < 0.001-0.05) and cAMP response element-binding protein phosphorylation (p < 0.05). The increase in cAMP was not inhibited by treatment with NF449, an inhibitor of the Gs alpha subunit of G protein. Our results suggest that ELF-MF exposure stimulates adrenal steroidogenesis via an increase in intracellular cAMP caused by the inhibition of phosphodiesterase activity in Y-1 cells. The same mechanism may trigger the increase in adrenal steroid secretion in mice observed in our previous study.

Arylacetamide Deacetylase is Responsible for Activation of Prasugrel in Human and Dog.

Prasugrel, a thienopyridine anti-platelet agent, is pharmacologically activated by hydrolysis and hydroxylation. It is efficiently hydrolyzed in the intestine after oral administration, and the enzyme responsible for the hydrolysis in humans was demonstrated to be carboxylesterase (CES)2. Prasugrel hydrolase activity is detected in dog intestines, where CES enzymes are absent; therefore, this prompted us to investigate the involvement of an enzyme(s) other than CES. Human arylacetamide deacetylase (AADAC) is highly expressed in the small intestine, catalyzing the hydrolysis of several clinical drugs containing small acyl moieties. In the present study, we investigated whether AADAC catalyzes prasugrel hydrolysis. Recombinant human AADAC was shown to catalyze prasugrel hydrolysis with a CLint value of 50.0 ± 1.2 ml/min/mg protein with a similar Km value to human intestinal and liver microsomes, whereas the CLint values of human CES1 and CES2 were 4.6 ± 0.1 and 6.6 ± 0.3 ml/min/mg protein, respectively. Inhibition studies using various chemical inhibitors and the relative activity factor approach suggested that the contribution of AADAC to prasugrel hydrolysis in human intestine is comparable to that of CES2. In dog intestine, the expression of AADAC, but not CES1 and CES2, was confirmed by measuring the marker hydrolase activities of each human esterase. The similar Km values and inhibition profiles between recombinant dog AADAC and small intestinal microsomes suggest that AADAC is a major enzyme responsible for prasugrel hydrolysis in dog intestine. Collectively, we found that AADAC largely contributes to prasugrel hydrolysis in both human and dog intestine.

Topological Crystalline Superconductivity in Locally Noncentrosymmetric Multilayer Superconductors.

Topological crystalline superconductivity in locally noncentrosymmetric multilayer superconductors (SCs) is proposed. We study the odd-parity pair-density wave (PDW) state induced by the spin-singlet pairing interaction through the spin-orbit coupling. It is shown that the PDW state is a topological crystalline SC protected by a mirror symmetry, although it is topologically trivial according to the classification based on the standard topological periodic table. The topological property of the mirror subsectors is intuitively explained by adiabatically changing the Bogoliubov-de Gennes Hamiltonian. A subsector of the bilayer PDW state reduces to the two-dimensional noncentrosymmetric SC, while a subsector of the trilayer PDW state is topologically equivalent to the spinless p-wave SC. Chiral Majorana edge modes in trilayers can be realized without Cooper pairs in the spin-triplet channel and chemical potential tuning.