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•Wastewater is a key hotspot for horizontal transfer of antimicrobial resistance.•Leclercia adecarboxylatacarrying mcr-1was isolated from wastewater in Seoul.•The ST3-IncHI2 plasmid can serve as a vehicle for mcr-1dissemination in wastewater.

This paper elucidates and rationalizes the ethical governance system for healthcare AI research, as outlined in the ‘Research Ethics Guidelines for AI Researchers in Healthcare’ published by the South Korean government in August 2023. In developing the guidelines, a four-phase clinical trial process was expanded to six stages for healthcare AI research: preliminary ethics review (stage 1); creating datasets (stage 2); model development (stage 3); training, validation, and evaluation (stage 4); application (stage 5); and post-deployment monitoring (stage 6). Researchers identified similarities between clinical trials and healthcare AI research, particularly in research subjects, management and regulations, and application of research results. In the step-by-step articulation of ethical requirements, this similarity benefits from a reliable and flexible use of existing research ethics governance resources, research management, and regulatory functions. In contrast to clinical trials, this procedural approach to healthcare AI research governance effectively highlights the distinct characteristics of healthcare AI research in research and development process, evaluation of results, and modifiability of findings. The model exhibits limitations, primarily in its reliance on self-regulation and lack of clear delineation of responsibilities. While formulated through multidisciplinary deliberations, its application in the research field remains untested. To overcome the limitations, the researchers’ ongoing efforts for educating AI researchers and public and the revision of the guidelines are expected to contribute to establish an ethical research governance framework for healthcare AI research in the South Korean context in the future.

Background: Medical information (MI) departments across pharmaceutical companies respond to medical inquiries about a company’s products to healthcare providers, payors, patients, and caregivers. Responses provided are constructed to be relevant, accurate, scientifically balanced and delivered in a timely manner. Benchmarking surveys of MI groups have been conducted in the past to assess current trends and identify areas of optimization that ultimately benefit the customers. Methods: From December 2017 to February 2018, 27 U.S. pharmaceutical member companies of phactMI™, Pharma Collaboration for Transparent Medical Information, were provided a survey of 307 questions divided among nine topics to capture attributes of pharmaceutical industry medical information organizations, including inquiry management and content development. Results: At the time of the survey, a total of 27 phactMI member companies existed and completed the survey. Detailed results are provided on the inquiry response process, including contact center services, escalation processes, use of unique delivery channels, and reported key performance indicators. The evolving nature of content formats and features, including page length, custom responses, and enhancements are addressed. Finally, resourcing and structure of these two areas are also detailed from the 27 member companies. Conclusion: The findings from this comprehensive benchmarking survey provide insights into the current state of inquiry response processes and content management. There continue to be opportunities to demonstrate and increase the value of MI to ensure that companies are meeting the expectations of the ever-changing needs of our customers. phactMI and the member companies continue to seek innovative ways of providing medical information in their commitment to enhancing patient care.

This study determined the fertilizer potentials of the dehydrated food waste powder (DFWP) and spent coffee grounds (SCGs) through assessing their effects on yield, antioxidant activities, mineral and proximate compositions of leaf lettuce and Japanese hogfennel their efficiencies to inorganic fertilizers (N-P2O5-K2O, NPK). In this study, both organic amendments were applied at rates that supplied half, double and recommended nitrogen (N) requirements of the leaf lettuce (15 Mg N/ha) and Japanese hogfennel (10 Mg N/ha) established in Daejeon, South Korea. The recommended treatment of DFWP produced the highest lettuce and Japanese hogfennel yields, respectively. Halving the application rates of the organic amendments generally limited the yielding capacities while doubling them invoked negative yield responses in both crops. The highest antioxidant activities, mineral and proximate contents in both crops were obtained with the recommended dosage of amendments. The SCGs outperformed NPK in all the parameters of the Japanese hogfennel assessed in this study even though its impact on the leaf lettuce was adverse. Therefore, both DFWP and SCGs can effectively supply plant nutrients but their application rates should be regulated so as to avoid NaCl toxicity and elevated phytotoxicity in DFWP and SCGs, respectively.

ABSTRACTSocial epigenomics is an emerging field in which social scientist collaborate with computational biologists, especially epigeneticists, to address the underlying pathway for biological embedding of life experiences. This social epigenomics study included long-term childhood cancer survivors enrolled in the St. Jude Lifetime Cohort. DNA methylation (DNAm) data were generated using the Illumina EPIC BeadChip, and three social determinants of health (SDOH) factors were assessed: self-reported educational attainment, personal income, and an area deprivation index based on census track data. An epigenome-wide association study (EWAS) was performed to evaluate the relation between DNAm at each 5’-cytosine-phosphate-guanine-3’ (CpG) site and each SDOH factor based on multivariable linear regression models stratified by ancestry (European ancestry, n = 1,618; African ancestry, n = 258). EWAS among survivors of European ancestry identified 130 epigenome-wide significant SDOH–CpG associations (P< 9 × 10−8), 25 of which were validated in survivors of African ancestry (P< 0.05). Thirteen CpGs were associated with all three SDOH factors and resided at pleiotropic loci in cigarette smoking–related genes (e.g., CLDND1and CPOX). After accounting for smoking and body mass index, these associations remained significant with attenuated effect sizes. Seven of 13 CpGs were associated with gene expression level based on 57 subsamples with blood RNA sequencing data available. In conclusion, DNAm signatures, many resembling the effect of tobacco use, were associated with SDOH factors among survivors of childhood cancer, thereby suggesting that biologically distal SDOH factors influence health behaviours or related factors, the epigenome, and subsequently survivors’ health.

An 87-year-old woman with a medical history of stroke, paroxysmal atrial fibrillation, type 2 diabetes mellitus, diastolic heart failure, and chronic bilateral lymphedema presents with 1 week of shortness of breath. The patient had a 20-pack-year smoking history and at baseline was able to ambulate freely without assistance. Her symptoms of dyspnea were mostly exertional and progressively worsening for 1 week before admission, despite compliance with her home furosemide. On admission, her temperature was 36.3 °C, BP was 101/59 mm Hg, heart rate was 82 beats/min, respirations were 18 breaths/min, and oxygen saturation was 91% on room air. On physical examination, the patient was tachypneic at rest, and auscultation of the lungs revealed minimal breath sounds on the left side. Admission laboratory test results were notable for leukocyte count of 11.67 × 109/L (82.2% neutrophils, 8.3% monocytes, 6.4% lymphocytes, and 2.1% eosinophils). Results of HIV screening tests were negative.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures. Our validation studies for a CRISPR screen of 400 epigenetic targets identified SMARCA4 as a unique factor for long-term (but not short-term) tumor cell survival in ARMS. A SMARCA4/SMARCA2 protein degrader (ACBI-1) demonstrated similar long-term tumor cell dependence in vitro and in vivo. These results credential SMARCA4 as a tumor cell dependency factor and a therapeutic target in ARMS.

Estrogen receptor alpha gene (ESR1) mutations occur frequently in ER-positive metastatic breast cancer, and confer clinical resistance to aromatase inhibitors. Expression of the ESR1Y537S mutation induced an epithelial–mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro. When small subpopulations of Y537S ESR1mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estradiol (E2) withdrawal. Y537S ESR1mutant primary tumors metastasized efficiently in the absence of E2; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a nine-gene expression signature, which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1mutant tumors.

Vibrio parahaemolyticusis a marine bacterium that causes foodborne diarrhea. Many seafood restaurants keep live fish and shellfish in fish tanks for use in raw seafood dishes; thus, the present study aimed to investigate the prevalence, antibiotic-resistance, and virulence characteristics exhibited by V. parahaemolyticusdetected in restaurant fish-tank water samples collected in Seoul, South Korea. Fish-tank water samples were collected from 69 restaurants in Seoul, and screened for the presence of V. parahaemolyticusvia both a commercial detection kit, and a real-time polymerase chain reaction (RT-PCR) to detect the toxRgene. Antibiotic susceptibility and virulence determinants of V. parahaemolyticusisolates were evaluated and identified using standard disk-diffusion and RT-PCR methods, respectively. Thirty-five (50.7%) of the 69 analyzed water samples were found to be contaminated with V. parahaemolyticus. Those isolates were most often resistant to ampicillin (51.4% of isolates), followed by amikacin and tetracycline (11.4%), and ceftazidime (8.6%). Thirty (85.7%) out of the 35 isolates carried all four cytotoxicity-inducing type III secretion system 1 (T3SS1) genes [specifically, 34 (97.1%), 33 (94.3%), 35 (100%), and 32 (91.4%) isolates carried genes encoding the VP1670, VP1686, VP1689, and VP1694 T3SS1 proteins, respectively]. The type VI secretion systems (T6SS1 and T6SS2) genes were also detected in 11 (31.4%) and 27 (77.1%) isolates, respectively. However, virulence determinants such as the hemolysin (tdhand trh), urease (ureC), T3SS2α, or T3SS2β genes that are known to be associated with enterotoxicity were not detected in all isolates. Although some known major virulence genes were not detected in the V. parahaemolyticusisolates, the results of this study indicate that restaurant fish tanks are a potential source of antibiotic-resistant V. parahaemolyticus. The presented data support the need for strict guidelines to regulate the maintenance of restaurant fish tanks to prevent antibiotic-resistant foodborne vibriosis.

Vertically-aligned TiO2nanotube (NT) arrays prepared by electrochemical anodization are considered promising alternatives to the conventional nanoparticle (NP)-based electrodes for photovoltaic devices. Recently, such NT arrays have been employed in dye-sensitized solar cells (DSSCs) by transferring them onto NP-based electrodes, to obtain multi-layered nanoelectrodes. Here, we comparatively evaluate the photovoltaic and photoelectrochemical properties of TiO2NP-only electrodes and multi-layered electrodes comprising NP and NT arrays at the same thickness of 15 μm. Although the multi-layered electrodes have a smaller surface area compared to the NP-only electrodes, they show much higher transmittance. In addition, impedance studies reveal that the multi-layered electrodes have lower charge recombination with the electrolyte as well as enhanced electrolyte diffusion when applied as a photoanode in DSSCs. As a result, the multi-layered electrodes exhibit a photovoltaic conversion efficiency (η = 5.37%) comparable to that of the NP-only electrodes (η = 5.80%), despite 36.6% lower dye loading.

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Gamisoyosan (GSS) is an herbal formula which has been used to treat women’s diseases for several hundred years in Korea. GSS is one of the three most common prescriptions among women and is used to treat menopausal symptoms. Fatty liver disease is also common in postmenopausal women and can precede more severe diseases, such as steatohepatitis. The present study compared the effects of GSS on fatty liver using three different formulae, Dongui-Bogam (KIOM A), Korean Pharmacopeia (KIOM B) and Korean National Health Insurance (KIOM C).

To identify baseline factors associated with 1-year outcomes when treating neovascular age-related macular degeneration (nAMD) with ranibizumab biosimilar SB11 or reference ranibizumab (rRBZ), and to compare efficacy of the two products within subgroups judged to be clinically relevant.

The purpose of this study was to establish normative data for holistic health parameters in the general Korean population and to investigate the factor associated with ideal life expectancy (ILE) among these holistic health parameters and sociodemographic variables.

Background: Orthotopic liver transplantation is the only option for patients with end-stage liver disease and hepatocellular carcinoma. Post-transplant immunosuppressive therapy is important to prevent graft failure. We investigated the effectiveness of tacrolimus (FK506) and their mechanisms for liver transplant immune tolerance in an outbred rat LT model. Results: To investigate the therapeutic effect of the FK506 on outbred rat LT model, FK506 and postoperative therapy were administered subcutaneously once or twice daily to transplanted rats. Histopathological and immunohistochemical analyses were conducted for all groups. The regulation of inflammatory cytokine signaling in the spleen was analyzed by flow cytometry. FK506 attenuated allograft rejection and increased survival in rat orthotopic liver transplantation models. The FK506-treated group had reduced serum levels of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase. Furthermore, FK506 decreased the expression of inflammatory cytokines and the activation of pathogenic Th1 and Th17 cells in the liver. Conclusions: Taken together, we revealed that FK506 ameliorated strong allograft rejection in outbred liver transplantation model by anti-inflammatory effect and inhibitory peroperty of pathogenic T cells.

The megalin/cubilin complex is responsible for the majority of serum protein reclamation in the proximal tubules. The current study examined if decreases in their renal expression, along with the albumin recycling protein neonatal Fc receptor (FcRn) could account for proteinuria/albuminuria in the Zucker diabetic fatty rat model of type 2 diabetes. Immunoblots of renal cortex samples obtained at worsening disease stages demonstrated no loss in megalin, cubilin, or FcRn, even when proteinuria was measured. Additionally, early diabetic rats exhibited significantly increased renal megalin expression when compared with controls (adjusted P< 0.01). Based on these results, the ability of insulin to increase megalin was examined in a clonal subpopulation of the opossum kidney proximal tubule cell line. Insulin treatments (24 h, 100 nM) under high glucose conditions significantly increased megalin protein (P< 0.0001), mRNA (P< 0.0001), and albumin endocytosis. The effect on megalin expression was prevented with inhibitors against key effectors of insulin intracellular signaling, phosphatidylinositide 3-kinase and Akt. Studies using rapamycin to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) resulted in a loss of insulin-induced megalin expression. However, subsequent evaluation demonstrated these effects were independent of initial mTORC1 suppression. The presented results provide insight into the expression of megalin, cubilin, and FcRn in type 2 diabetes, which may be impacted by elevated insulin and glucose. Furthermore, proximal tubule endocytic activity in early diabetics may be enhanced, a process that could have a significant role in proteinuria-induced renal damage.

The formation and spectroscopic properties of quercetin (QCT)–divalent metal complexes were studied using Cu2+, Ni2+, Co2+, Mn2+, Zn2+, Mg2+, and Ca2+in a hydro‐organic mixed solvent. The change of UV/visible absorption spectra of QCT due to addition of a metal showed the complex formation. The intensity of fluorescence spectra increased gradually with titration of the metal. The experimental data and theoretical calculation suggest that Cu2+, Ni2+, Co2+, and Mn2+coordinate the site between C(3)OH and C(4)O but Zn2+prefers to bind to the site between C(5)OH and C(4)O. QCT–Cu2+, QCT–Ni2+, QCT–Co2+, and QCT–Mn2+complexes exhibit S2→ S0fluorescence only as S1→ S0emission is absent due to the excited‐state intramolecular proton transfer (ESIPT) at the S1state. As this ESIPT cannot occur at the QCT–Zn2+due to the chelation of Zn2+at a different site, QCT–Zn2+can produce characteristic S2→ S0and S1→ S0dual fluorescence.

After nearly 20 years of research, it is now established that mutations within the estrogen receptor (ER) gene, ESR1, frequently occur in metastatic breast cancer and influence response to hormone therapy. Though early studies presented differing results, sensitive sequencing techniques now show that ESR1mutations occur at a frequency between 20 and 40% depending on the assay method. Recent studies have focused on several “hot spot mutations,” a cluster of mutations found in the hormone-binding domain of the ESR1gene. Throughout the course of treatment, tumor evolution can occur, and ESR1mutations emerge and become enriched in the metastatic setting. Sensitive techniques to continually monitor mutant burden in vivo are needed to effectively treat patients with mutant ESR1. The full impact of these mutations on tumor response to different therapies remains to be determined. However, recent studies indicate that mutant-bearing tumors may be less responsive to specific hormonal therapies, and suggest that aromatase inhibitor (AI) therapy may select for the emergence of ESR1mutations. Additionally, different mutations may respond discretely to targeted therapies. The need for more preclinical mechanistic studies on ESR1mutations and the development of better agents to target these mutations are urgently needed. In the future, sequential monitoring of ESR1mutational status will likely direct personalized therapeutic regimens appropriate to each tumor’s unique mutational landscape.

Understanding the degradation mechanism of Lithium-ion batteries (LIBs) is critical in developing high-performance LIBs, and the investigation of their electrical conductivity evolution during cycling can lead to a better understanding of the degradation mechanism of the cathode materials for Li-ion batteries (LIBs). Here, we studied the evolution of the electrical conductivity of LiNi0.8Co0.15Al0.05O2(NCA) particles for LIB cathodes using scanning spreading resistance microscopy (SSRM). After 300 charge/discharge cycles, stepwise-increasing resistance distributions toward the centers of the secondary particles are observed. These distributions correspond to the degenerated granular structures of the secondary particles caused by the formation of microcracks. In addition, the correlation between the electrical conductivity and microstructure of the NCA cathode is established to explain the observed decay of the NCA discharge capacity. Our findings can provide an insight into the debatable degradation mechanism of LIB cathode materials such as NCA and NMC (LiNixMnyCozO2, x + y + z = 1).

As an injury heals, an embryo develops or a carcinoma spreads, epithelial cells systematically change their shape. In each of these processes cell shape is studied extensively whereas variability of shape from cell to cell is regarded most often as biological noise. But where do cell shape and its variability come from? Here we report that cell shape and shape variability are mutually constrained through a relationship that is purely geometrical. That relationship is shown to govern processes as diverse as maturation of the pseudostratified bronchial epithelial layer cultured from non-asthmatic or asthmatic donors, and formation of the ventral furrow in the Drosophilaembryo. Across these and other epithelial systems, shape variability collapses to a family of distributions that is common to all. That distribution, in turn, is accounted for by a mechanistic theory of cell–cell interaction, showing that cell shape becomes progressively less elongated and less variable as the layer becomes progressively more jammed. These findings suggest a connection between jamming and geometry that spans living organisms and inert jammed systems, and thus transcends system details. Although molecular events are needed for any complete theory of cell shape and cell packing, observations point to the hypothesis that jamming behaviour at larger scales of organization sets overriding geometric constraints.

The design of highly durable, electroactive, and cost-effective catalysts to replace the currently prevalent Pt-based ones has long been a major milestone for expanding the market penetration of fuel cell electric vehicles (FCEVs). Over the past decades, catalyst degradation in automotive fuel cells under transient conditions (e.g., startup/shutdown and cell reversal) has attracted much attention due to its irreversible consequences for the membrane electrode assembly (MEA). Herein, we evaluate IrRun/C as alternative catalysts to increase MEA anode durability under cell reversal conditions and investigate their suitability for use in FCEVs. Among the various Ir:Ru ratios, the best hydrogen oxidation activity was observed for Ir:Ru = 1:4 (mol/mol), as confirmed by rotating disk electrode measurements. The performances of IrRu4/C and Pt/C as anode catalysts were compared side by side, with the corresponding I-V and anode polarization tests carried out under various operating conditions (cell temperature, relative humidity, and backpressure). Importantly, IrRu4/C showed Pt-comparable ([?]100%) MEA performance and hydrogen oxidation activity, additionally exhibiting a [?]120 times better durability under cell reversal conditions.

Although apigenin possesses diverse pharmacological activities, its utilization as a bioactive substance is limited by poor oral bioavailability. The aim of this study was to improve the bioavailability of apigenin by co-administration of friedelin.

Autism spectrum disorder (ASD) is a heterogeneous disease, but genetically defined models can provide an entry point to studying the molecular underpinnings of this disorder. We generated germline mutant mice with loss-of-function mutations in Chd8, a de novo mutation strongly associated with ASD, and demonstrate that these mice display hallmark ASD behaviors, macrocephaly, and craniofacial abnormalities similar to patient phenotypes. Chd8+/–mice display a broad, brain-region-specific dysregulation of major regulatory and cellular processes, most notably histone and chromatin modification, mRNA and protein processing, Wnt signaling, and cell-cycle regulation. We also find altered synaptic physiology in medium spiny neurons of the nucleus accumbens. Perturbation of Chd8in adult mice recapitulates improved acquired motor learning behavior found in Chd8+/–animals, suggesting a role for CHD8 in adult striatal circuits. These results support a mechanism linking chromatin modification to striatal dysfunction and the molecular pathology of ASD.

Calcium-dependent inactivation of high voltage-activated Ca2+channels plays a crucial role in limiting rises in intracellular calcium (Ca2+i). A key mediator of these effects is calmodulin, which has been found to bind the C-terminus of the pore-forming αsubunit. In contrast, little is known about how Ca2+ican regulate low voltage-activated T-type Ca2+channels. Using whole cell patch clamp, we examined the biophysical properties of Ca2+current through the three T-type Ca2+channel isoforms, Cav3.1, Cav3.2, or Cav3.3, comparing internal solutions containing 27 nM and l μM free Ca2+. Both activation and inactivation kinetics of Cav3.3 current in l μM Ca2+isolution were more rapid than those in 27 nM Ca2+isolution. In addition, both activation and steady-state inactivation curves of Cav3.3 were negatively shifted in the higher Ca2+isolution. In contrast, the biophysical properties of Cav3.1 and Cav3.2 isoforms were not significantly different between the two internal solutions. Overexpression of CaM1234(a calmodulin mutant that doesn’t bind Ca2+) occluded the effects of l μM Ca2+ion Cav3.3, implying that CaM is involved in the Ca2+iregulation effects on Cav3.3. Yeast two-hybrid screening and co-immunoprecipitation experiments revealed a direct interaction of CaM with the carboxyl terminus of Cav3.3. Taken together, our results suggest that Cav3.3 T-type channel is potently regulated by Ca2+ivia interaction of Ca2+/CaM with the carboxyl terminus of Cav3.3.

ABSTRACTTwenty-two currently marketed antituberculosis drugs were comprehensively evaluated for their inhibitory effect on organic anionic transporter (OAT)- and organic cation transporter (OCT)-mediated uptake using stably transfected HEK293 cells in vitro. We observed moderate to strong inhibitory effects on OAT1- and OAT3-mediated para-aminohippurate (PAH) uptake and OCT1- and OCT2-mediated N-methyl-4-phenylpylidinium acetate (MPP+) uptake. Ciprofloxacin, linezolid, para-aminosalicylic acid (PAS), and rifampin were observed to have strong inhibitory effects, with the concentrations for a 50% inhibitory effect (IC50s) being 35.1, 31.1, 37.6, and 48.1 μM, respectively, for OAT1 and >100, 21.9, 24.6, and 30.2 μM, respectively, for OAT3. Similarly, pyrazinamide, rifabutin, and levofloxacin were observed to have inhibitory effects, with IC50values being 36.5, 42.7, and 30.3 μM, respectively, for OCT1 and with the IC50value for PAS being 94.2 μM for OCT2. In addition, we used zidovudine and metformin as clinically prescribed substrates of OATs and OCTs, respectively, and zidovudine and metformin uptake was also strongly inhibited by the antituberculosis drugs. Among the tested drugs, the highest drug-drug interaction (DDI) indexes were found for PAS, which were 9.3 to 13.9 for OAT1 and 12.0 to 17.7 for OAT3, and linezolid, which were 1.18 to 2.15 for OAT1 and 1.7 to 3.01 for OAT3. Similarly, the DDI indexes of pyrazinamide and levofloxacin were 0.57 and 0.30, respectively, for OCT1, and the DDI index of PAS was 3.8 for OCT2, suggesting a stronger possibility (DDI index value cutoff, >0.1) of in vivoDDIs. This is the first comprehensive report of the inhibitory potential of anti-TB drugs on OAT- and OCT-mediated uptake of prototype and clinically prescribed substrate drugs in vitro, providing an ability to predict DDIs between anti-TB drugs and other coprescribed drugs in clinical studies in vivo.

Pancreatic cysts were found to be more prevalent in patients with autosomal dominant polycystic kidney disease (ADPKD) compared with matched control subjects without ADPKD in this cross-sectional study and were associated with the presence of a mutation in the PKD2gene.

Background Although the World Health Organization has declared the eradication of smallpox in 1980, the fear of its potential use in bioterrorism has become a reality. Since the effectiveness of current vaccines and antiviral drugs is limited, development of new therapeutic strategies is needed. In this study, we investigated small interfering RNA (siRNA) as a therapeutic approach for preventing and treating smallpox infection.Methods Eight siRNA sequences were designed and evaluated for antiviral activity against vaccinia virus (VACV) in vitroand in vivo.Results Of eight siRNAs, A5R1 siRNA targeted the A5R gene and reduced VACV replication in cell culture by up to 85% at 100 nM concentration without inducing cytotoxicity. A prolonged prophylactic as well as therapeutic effect of siRNA was observed. In addition, real-time PCR analysis showed that A5R1 siRNA can especially reduce the target mRNA. Finally, intraperitoneal delivery of A5R1 siRNA in Balb/c mice significantly protected these animals from lethal challenge with VACV.Conclusions This study suggests the potential of A5R1 siRNA as a therapeutic antiviral agent against smallpox.

Because autism spectrum disorders are neurodevelopmental disorders and patients typically display symptoms before the age of three, one of the key questions in autism research is whether the pathology is reversible in adults. Here we investigate the developmental requirement of Shank3 in mice, a prominent monogenic autism gene that is estimated to contribute to approximately 1% of all autism spectrum disorder cases. SHANK3 is a postsynaptic scaffold protein that regulates synaptic development, function and plasticity by orchestrating the assembly of postsynaptic density macromolecular signalling complex. Disruptions of the Shank3 gene in mouse models have resulted in synaptic defects and autistic-like behaviours including anxiety, social interaction deficits, and repetitive behaviour. We generated a novel Shank3 conditional knock-in mouse model, and show that re-expression of the Shank3 gene in adult mice led to improvements in synaptic protein composition, spine density and neural function in the striatum. We also provide behavioural evidence that certain behavioural abnormalities including social interaction deficit and repetitive grooming behaviour could be rescued, while anxiety and motor coordination deficit could not be recovered in adulthood. Together, these results reveal the profound effect of post-developmental activation of Shank3 expression on neural function, and demonstrate a certain degree of continued plasticity in the adult diseased brain.

ABSTRACTWe investigated the inhibitory interaction potential of 22 currently marketed antituberculosis (TB) drugs on organic anion-transporting polypeptide 1B1 (OATP1B1)-, OATP2B1-, and OATP1B3-mediated uptake using in vitroXenopusoocytes and HEK cells. Rifabutin, ethambutol, amoxicillin, linezolid, p-amino salicylic acid, and rifapentine exhibited mild to moderate inhibitory effects on OATP-mediated uptake of estrone-3 sulfate, estradiol 17β-d-glucuronide, and rosuvastatin. The 50% inhibitory concentration (IC50) values of rifabutin, amoxicillin, ethambutol, p-amino salicylic acid, and linezolid were 35.4, 36.2, 57.6, 72.6, and 65.9 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B1 (OATP1B1) and 28.8, 28.9, 53.9, 31.5, and 61.0 μM, respectively, for uptake mediated by organic anionic transporter polypeptide 1B3 (OATP1B3). Streptomycin and linezolid showed greater inhibition of organic anionic transporter polypeptide 2B1 (OATP2B1)-mediated uptake, with IC50values of 33.2 and 35.6 μM, respectively, along with mild inhibition of other drugs. Furthermore, rifabutin, amoxicillin, and rifapentine significantly inhibited OATP1B1-mediated rosuvastatin uptake, with IC50values of 12.3, 13.0, and 11.0 μM, respectively, which showed a similar profile to estrone-3 sulfate uptake. The calculated Rvalues ([I]u inlet,max/Ki, where [I]u inlet,maxrepresents the maximum estimated inhibitor concentration inlet to the liver and Kiis the inhibition constant) as the drug-drug interaction (DDI) indexes of PAS, ethambutol, and amoxicillin were 26.1, 6.5, and 4.3 for OATP1B1 and 52.0, 8.0, and 4.6 for OATP1B3, and those for streptomycin, amikacin, and linezolid were 5.0, 4.2, and 4.4 for OATP2B1, respectively, suggesting a higher possibility of in vivoDDIs. This study is the first comprehensive report to show the novel inhibitory potential of 22 marketed anti-TB drugs on OATP-mediated uptake, providing evidence for future in vivoclinical DDI studies.

Objective:To compare the efficacy of mitiglinide and sitagliptin, alone or in combination, on postprandial excursion and glycemic variability assessed by continuous glucose monitoring (CGM) in a single-day treatment setting.Methods:This was a post hocanalysis of a randomized crossover study comparing the efficacy of sitagliptin, mitiglinide and the combination of these two drugs. Twenty-four hour CGM was performed before and after a single-day treatment with each drug alone or in combination.Results:Mean glucose levels were decreased in all groups. The average of three postprandial glucose excursions AUC (average of all three 4-h postprandial periods throughout the day) (AUCpp-average) decreased in the mitiglinide and combination treatment groups, but not in the sitagliptin group. The lowering effect on AUCpp-average was greater in patients given mitiglinide (–47 mg/dl, p < 0.001) or combination treatment (–66 mg/dl, p < 0.001) compared with sitagliptin alone (–18 mg/dl). The reduction in mean amplitude of glycemic excursion was greater with mitiglinide (–29.3 mg/dl, p < 0.001) and combination treatment (–28.3 mg/dl, p < 0.01) than with sitagliptin alone (–8.9 mg/dl).Conclusions:Mitiglinide or combination treatment resulted in lower glycemic variability and postprandial glucose excursion than sitagliptin alone; however, the results of this single-day pharmacodynamics study cannot be generalized to a clinical setting.

To achieve commercialization and widespread application of next-generation photovoltaics, it is important to develop flexible and cost-effective devices. Given this, the elimination of expensive transparent conducting oxides (TCO) and replacement of conventional glass substrates with flexible plastic substrates presents a viable strategy to realize extremely low-cost photovoltaics with a potentially wide applicability. To this end, we report a completely TCO-free and flexible dye-sensitized solar cell (DSSC) fabricated on a plastic substrate using a unique transfer method and back-contact architecture. By adopting unique transfer techniques, the working and counter electrodes were fabricated by transferring high-temperature-annealed TiO2and Pt/carbon films, respectively, onto flexible plastic substrates without any exfoliation. The fabricated working electrode with the conventional counter electrode exhibited a record efficiency for flexible DSSCs of 8.10%, despite its TCO-free structure. In addition, the completely TCO-free and flexible DSSC exhibited a remarkable efficiency of 7.27%. Furthermore, by using an organic hole-transporting material (spiro-MeOTAD) with the same transfer method, solid-state flexible TCO-free DSSCs were also successfully fabricated, yielding a promising efficiency of 3.36%.

Rheumatoid meningitis is a rare complication of rheumatoid arthritis that requires a meningeal biopsy for diagnosis.

We report a new ternary Zn2SnO4(ZSO) electron-transporting electrode of a CH3NH3PbI3perovskite solar cell as an alternative to the conventional TiO2electrode. The ZSO-based perovskite solar cells have been prepared following a conventional procedure known as a sequential (or two-step) process with ZSO compact/mesoscopic layers instead of the conventional TiO2counterparts, and their solar cell properties have been investigated as a function of the thickness of either the ZSO compact layer or the ZSO mesoscopic layer. The presence of the ZSO compact layer has a negligible influence on the transmittance of the incident light regardless of its thickness, whereas the thickest compact layer blocks the back-electron transfer most efficiently. The open-circuit voltage and fill factor increase with the increasing thickness of the mesoscopic ZSO layer, whereas the short-circuit current density decreases with the increasing thickness except for the thinnest one (∼100 nm). As a result, the device with a 300 nm-thick mesoscopic ZSO layer shows the highest conversion efficiency of 7%. In addition, time-resolved and frequency-resolved measurements reveal that the ZSO-based perovskite solar cell exhibits faster electron transport (∼10 times) and superior charge-collection capability compared to the TiO2-based counterpart with similar thickness and conversion efficiency.

The simple irradiation of 355 nm nanosecond laser pulses to SiO2@Pt core–shell nanospheres at fluence of 2.7 mJ cm–2during the preparation process of hollow platinum nanospheres has been found to enhance the catalytic performances of platinum nanocatalysts on a large scale. Laser irradiation has transformed platinum nanoclusters topped on silica nanospheres into well-defined platinum nanoshells having uniform and smooth surfaces; the thickness of platinum nanoshells has been tuned easily by adjusting the irradiation time only. Laser irradiation increases the catalytic performances of hollow platinum nanospheres in the degradation of rhodamine B in the presence of KBH4by five times via lowering the energy barrier. The energetically more favorable formation of the activated complexes in the nanocavity surfaces is suggested to reduce the activation energy substantially. The restructuring of surface atoms induced by photothermal annealing during laser irradiation has rendered the metallic surfaces much easier to chemisorb reactants and to facilitate electron relays, enhancing the catalytic performances of platinum nanocatalysts extensively.

In this paper, we describe the influence of speaking rate on speech recognition. Speaking rate of input speech is controlled by applying a time-scale modification (TSM) algorithm and speaking rate normalisation is achieved by selecting a scale factor of TSM. The scale factor selection for training and testing of a speech recognition system is performed based on a maximum likelihood criterion during HMM decoding. From the experimental results, we showed that optimal selection of a TSM scale factor in speaking rate normalisation can reduce WER by 47.6% compared to the baseline.

A facile method for increasing the reaction rate of dye adsorption, which is the most time-consuming step in the production of dye-sensitized solar cells (DSSCs), was developed. Treatment of a TiO2photoanode with aqueous nitric acid solution (pH 1) remarkably reduced the reaction time required to anchor a carboxylate anion of the dye onto the TiO2nanoparticle surface. After optimization of the reaction conditions, the dye adsorption process became 18 times faster than that of the conventional adsorption method. We studied the influence of the nitric acid treatment on the properties of TiO2nanostructures, binding modes of the dye, and adsorption kinetics, and found that the reaction rate improved via the synergistic effects of the following: (1) electrostatic attraction between the positively charged TiO2surface and ruthenium anion increases the collision frequency between the adsorbent and the anchoring group of the dye; (2) the weak anchoring affinity of NO3–in nitric acid with metal oxides enables the rapid coordination of an anionic dye with the metal oxide; and (3) sufficient acidity of the nitric acid solution effectively increases the positive charge density on the TiO2surface without degrading or transforming the TiO2nanostructure. These results demonstrate the developed method is effective for reducing the overall fabrication time without sacrificing the performance and long-term stability of DSSCs.

The article discusses the relationship between globalization and music composition with special attention to an alleged dominance of European music and composers. Other topics mentioned in this article include the political and economic aspects of music, contemporary classical musicians including Steve Reich, Philip Glass, and Klaus Huber, as well as Asian music.

Recognizing the seriousness of global warming, various policies transforming an energy-consuming city into a low-carbon green city are being introduced. Among them, transit oriented urban development is a kind of policy realizing fundamental energy saving through reorganizing urban forms and spatial structures. Daegu City implemented a transit mall in its downtown area in order to transform the city from car-oriented to transit-oriented, and other cities are also planning to install transit malls. In this study, the policy process of Daegu Transit Mall Project (DTMP) was analyzed from the policy network perspective. In this analysis, the issues raised during the policy process were identified and the process of policy implementation through interactions among stakeholders and network structures were studied. A number of stakeholders were involved in the transit mall project. Interactions among policy actors occurred individually around Daegu City, the project leader and central operating body. In addition, the types of interactions are formed in conflict rather than cooperation. Network structure in policy phase I was horizontal, but developed a horizontal and vertical structure as the project was further planned and implemented. The following policy implications were derived through the analysis of DTMP: (1) a policy coordinating committee is required to coordinate the ongoing management and operation of the project; (2) in order to achieve the policy goal – cutting car use and increasing public transport use – public-transit promotion policy should be accompanied with the transit mall installation; (3) building a collaborative network among stakeholders and relevant departments is required to vitalize the market.

This study describes a method for discriminating Rangifer antlers from true Cervus antlers using agarose gel electrophoresis, capillary electrophoresis, quantitative real-time PCR, and allelic discrimination. Specific primers labeled with fluorescent tags were designed to amplify fragments from the mitochondrial D-loop genes for various Cervus subspecies and Rangifer tarandus differentially. A 466-bp fragment that was observed for both Cervus and Rangifer antlers served as a positive control, while a 270-bp fragment was specifically amplified only from Rangifer antlers. Allelic discrimination was used to differentiate between Cervus and Rangifer antlers, based on the amplification of specific alleles for both types of antlers. These PCR-based assays can be used for forensic and quantitative analyses of Cervus and Rangifer antlers in a single step, without having to obtain any sequence information. In addition, multiple PCR-based assays are more accurate and reproducible than a single assay for species-specific analysis and are especially useful in this study for the identification of original Cervus deer products from fraudulent Rangifer antlers.

ABSTRACTA coexpression strategy in Saccharomyces cerevisiaeusing episomal and integrative vectors for the Escherichia coliheat-labile enterotoxin B subunit (LTB) and a fusion protein of an ApxIIA toxin epitope produced by Actinobacillus pleuropneumoniaecoupled to LTB, respectively, was adapted for the hetero-oligomerization of LTB and the LTB fusion construct. Enzyme-linked immunosorbent assay (ELISA) with GM1 ganglioside indicated that the LTB fusion construct, along with LTB, was oligomerized to make the functional heteropentameric form, which can bind to receptors on the mucosal epithelium. The antigen-specific antibody titer of mice orally administered antigen was increased when using recombinant yeast coexpressing the pentameric form instead of recombinant yeast expressing either the LTB fusion form or antigen alone. Better protection against challenge infection with A. pleuropneumoniaewas also observed for coexpression in recombinant yeast compared with others. The present study clearly indicated that the coexpression strategy enabled the LTB fusion construct to participate in the pentameric formation, resulting in an improved induction of systemic and mucosal immune responses.

Abstract: Ethanol extract derived from Hericium erinaceum cultivated with Artemisia capillaries (HEAC) and its primary compound, scoparone, were utilized and incorporated in studying the protective effects on Carbon tetrachloride (CCl4)-induced hepatic damage in male Sprague-Dawley rats. Male Sprague-Dawley rats were randomly divided into control, CCl4, CCl4+ursodeoxycholic acid (UDCA), CCl4+silymarin, CCl4+scoparone, CCl4+HEAC, CCl4+80% ethanol extract of H. Erinaceum (HE), and CCl4+80% ethanol extract of Artemisia capillaries (AC). Each group contained eight rats supplemented with UDCA, silymarin, scoparone, HEAC, HE, and AC with continuous normal diet after CCl4 treatment. Physiological results shows control group gained weight 4.0 g day−1 and that of CCl4 group decreased 6.4 g day−1. Supplementation of UDCA, silymarin, scoparone, HEAC, HE, and AC decreased weight loss at 5.5, 4.1, 2.2, 5.5, and 4.2 g day−1, respectively. Supplementation of UDCA, silymarin, scoparone, HEAC, HE, and AC significantly decreased serum alanine aminotransferase and aspartate aminotransferase activity as well as hepatic cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglycerides. Hepatic highdensity lipoprotein (HDL)-cholesterol in CCl4 group was reduced after CCl4 treatment, and supplementation of UDCA, scoparone, HEAC, HE, and AC increased HDL-cholesterol level to that of control level. Atherogenic index and cardiac risks factor in CCl4 group increased after CCl4 treatment, and supplementation of tested compounds reduced both parameters. Taken together, HEAC and scoparone exerted protective effect against CCl4-induced liver injury by attenuating hepatic lipid depots and reducing oxidative stress.

In this paper we present a transparent and stretchable dielectric elastomer actuator(DEA). The device, called "active skin" is under development as a new means of human interfaces. The active skin consists of elastomeric films sandwiched between compliant patterned electrodes. Thus, depending on the properties of the elastomer or electrodes, it is possible to realize a wide variety of implementations as transducers. As a critical issue of the transparent active skin, transparency in the electrode including that of the substrate is challenging, which has not been solved yet. In this paper, a compliant, transparent and highly conductive electrode layer on the elastomeric film by using graphene is presented. The fabrication method of graphene electrodes dedicated to the elastomeric materials is addressed and its compatibility to the existing materials is discussed. Also, preliminary implementations on the embossed actuator are given to validate the proposed idea.