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A previously undescribed triterpenoid (fortunefuroic acid J, 1) was isolated from the endangered conifer Keteleeria hainanensis, along with 20 other known terpenoids. Compound 1 is characterized by an unusual 3,4-seco-9βH-lanost-3-oic acid motif, featuring a rare furoic acid moiety in its lateral chain. The structure elucidation of this compound was achieved through a combination of spectroscopic and computational methods. The C-15 epimers of 15-methoxypinusolidic acid (15R-8 and 15S-9) were successfully separated and identified for the first time. Compound 1 demonstrated dual inhibitory effects against ATP-citrate lyase (ACL, IC50: 0.92 μM) and acetyl-CoA carboxylase 1 (ACC1, IC50: 10.76 μM). Compounds 2 and 11 exclusively inhibited ACL, exhibiting IC50 values of 2.64 and 6.35 μM, respectively. Compound 1 is classified among the fortunefuroic acid-type compounds, previously isolated from K. fortunei, distinguished by the presence of a rare furoic acid moiety in their lateral chain. The chemotaxonomic significance of the 9βH-lanost-26-oic acids in Keteleeria was briefly discussed. These findings highlight the importance of conserving plant species diversity, thereby enhancing the exploration of structurally diverse compounds and potential avenues for developing new therapeutics targeting ACL/ACC1-associated diseases., (© 2024 Wiley‐VCH GmbH.)

Dengue fever, caused by the Dengue virus (DENV) and transmitted by Aedes aegypti mosquitoes, has become endemic in over 100 countries. Despite considerable research, there is a lack of specific drugs for clinical use against dengue. Hence, further exploration to identify anti-- dengue compounds is essential. In recent years, natural products have gained attention for their antiviral properties. Plant-based medicines are particularly appealing due to their safety and low toxicity. This review summarizes natural compounds with potential antiviral activity against DENV, highlighting their mechanisms of action. Various compounds, from traditional herbal remedies to novel plant isolates, show promise against dengue, targeting crucial viral proteins like the envelope protein, proteases, and RNA polymerase. Exploring natural sources of antiviral agents against dengue is crucial. These compounds offer hope for effective treatments and mitigating dengue's global impact., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The androgen receptor (AR) is the main driver in the development of castration-resistant prostate cancer, where the emergence of AR splice variants leads to treatment-resistant disease. Through detailed molecular studies of the marine alkaloid manzamine A (MA), we identified transcription factor E2F8 as a previously unknown regulator of AR transcription that prevents AR synthesis in prostate cancer cells. MA significantly inhibited the growth of various prostate cancer cell lines and was highly effective in inhibiting xenograft tumor growth in mice without any pathophysiological perturbations in major organs. MA suppressed the full-length AR (AR-FL), its spliced variant AR-V7, and the AR-regulated prostate-specific antigen (PSA; also known as KLK3) and human kallikrein 2 (hK2; also known as KLK2) genes. RNA sequencing (RNA-seq) analysis and protein modeling studies revealed E2F8 interactions with DNA as a potential novel target of MA, suppressing AR transcription and its synthesis. This novel mechanism of blocking AR biogenesis via E2F8 may provide an opportunity to control therapy-resistant prostate cancer over the currently used AR antagonists designed to target different parts of the AR gene., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A comprehensive phytochemical investigation of the flower buds and leaves/twigs of Heptacodium miconioides, a cultivated ornamental plant native to China and categorized as 'vulnerable', has led to the isolation of 45 structurally diverse compounds, which comprise 18 phenylpropanoids (1-4, 7-20), 11 pentacyclic triterpenoids (5, 6, 21-29), eight secoiridoid glycosides (30-37), three quinic acid derivatives (38-40), and a few miscellaneous components (41-45). Among them, (+)-α-intermedianol (1), (+)-holophyllol A (2), and (-)-pseudolarkaemin A (3) represent previously unreported enantiomeric lignans, while (+)-7'(R)-hydroxymatairesinol (4) is an undescribed naturally occurring lignan. Heptacoacids A (5) and B (6) are undescribed 24-nor-urs-28-oic acid derivatives. Their chemical structures were determined by 2D-NMR, supplemented by evidence from specific rotations and circular dichroism spectra. Given the uncertainty surrounding the systematic position of Heptacodium, integrative taxonomy (ITA), a method utilized to define contentious species, is applied. Chemotaxonomy, a vital aspect of ITA, becomes significant. By employing hierarchical clustering analysis (HCA) and syntenic pattern analysis methods, a taxonomic examination based on the major specialized natural products from the flower buds of H. miconioides and two other Caprifoliaceae plants (i.e., Lonicera japonica and Abelia × grandiflora) could offer enhanced understanding of the systematic placement of Heptacodium. Additionally, compounds 39 and 40 displayed remarkable inhibitory activities against ATP-citrate lyase (ACL), with IC 50 values of 0.11 and 1.10 μM, respectively. In summary, the discovery of medical properties and refining systematic classification can establish a sturdy groundwork for conservation efforts aimed at mitigating species diversity loss while addressing human diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sine oculis homeoprotein 1 (SIX1), a prominent representative of the homeodomain transcription factors within the SIX family, has attracted significant interest owing to its role in tumorigenesis, cancer progression, and prognostic assessments. Initially recognized for its pivotal role in embryonic development, SIX1 has emerged as a resurgent factor across a diverse set of mammalian cancers. Over the past two decades, numerous investigations have emphasized SIX1's dual significance as a developmental regulator and central player in oncogenic processes. A mounting body of evidence links SIX1 to the initiation of diverse cancers, encompassing enhanced cellular metabolism and advancement. This review provides an overview of the multifaceted roles of SIX1 in both normal development and oncogenic processes, emphasizing its importance as a possible therapeutic target and prognostic marker. Additionally, this review discusses the natural product agents that inhibit various pro-oncogenic mechanisms associated with SIX1., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Malaria remains a significant global health threat despite extensive efforts aimed at its eradication. Numerous challenges persist in eliminating the disease, chief among them being the parasite's ability to mutate, resulting in drug resistance. The discovery of antimalarial drugs has relied on both phenotypic and target-based approaches. While phenotypic screening has identified promising candidates, target-based methods offer a more precise approach by leveraging chemically validated targets and computational tools. Analysis of Plasmodium spp. protein structures reveal druggable targets, offering opportunities for in silico screening. Combining compounds from natural and synthetic sources in a target-based approach accelerates the discovery of new antimalarial agents. This review explores previous breakthroughs in antimalarial drug discovery from natural products and synthetic origins, emphasizing their specific target proteins within Plasmodium species., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Two new bis anthraquinones, glabraquinone A and B ( 1 - 2 ) were isolated from the root of Prismatomeris glabra (Korth.) Valeton. In addition to the new glabraquinones, six known anthraquinones, that is, 1-hydroxy-2-methoxy-6-methylanthraquinone ( 3 ), 1,2-dimethoxy-7-methylanthraquinone ( 4 ), lucidin ( 5 ), nordamnacanthal ( 6 ), damnacanthal ( 7 ) and 2-carboxaldehyde-3-hydroxyanthraquinone ( 8 )) and an aromatic compound, that is, catechol diethyl ether ( 9 ) were isolated and characterized in this study. Compounds 1 , 4 and 9 showed mild activity, reducing N2A cell viability to 77%, 82% and 77%, respectively, in anti-neuroblastoma assay.

Background and Objective: Conflict may happen when more than one classifier is used to perform prediction or classification. The recognition model error leads to conflicting evidence. These conflicts can cause decision errors in a baby cry recognition and further decrease its recognition accuracy. Thus, the objective of this study is to propose a method that can effectively minimize the conflict among deep learning models and improve the accuracy of baby cry recognition., Methods: An improved Dempster-Shafer evidence theory (DST) based on Wasserstein distance and Deng entropy was proposed to reduce the conflicts among the results by combining the credibility degree between evidence and the uncertainty degree of evidence. To validate the effectiveness of the proposed method, examples were analyzed, and applied in a baby cry recognition. The Whale optimization algorithm-Variational mode decomposition (WOA-VMD) was used to optimally decompose the baby cry signals. The deep features of decomposed components were extracted using the VGG16 model. Long Short-Term Memory (LSTM) models were used to classify baby cry signals. An improved DST decision method was used to obtain the decision fusion., Results: The proposed fusion method achieves an accuracy of 90.15% in classifying three types of baby cry. Improvement between 2.90% and 4.98% was obtained over the existing DST fusion methods. Recognition accuracy was improved by between 5.79% and 11.53% when compared to the latest methods used in baby cry recognition., Conclusion: The proposed method optimally decomposes baby cry signal, effectively reduces the conflict among the results of deep learning models and improves the accuracy of baby cry recognition., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The urgent need for new classes of orally available, safe, and effective antivirals─covering a breadth of emerging viruses─is evidenced by the loss of life and economic challenges created by the HIV-1 and SARS-CoV-2 pandemics. As frontline interventions, small-molecule antivirals can be deployed prophylactically or postinfection to control the initial spread of outbreaks by reducing transmissibility and symptom severity. Natural products have an impressive track record of success as prototypic antivirals and continue to provide new drugs through synthesis, medicinal chemistry, and optimization decades after discovery. Here, we demonstrate an approach using computational analysis typically used for rational drug design to identify and develop natural product-inspired antivirals. This was done with the goal of identifying natural product prototypes to aid the effort of progressing toward safe, effective, and affordable broad-spectrum inhibitors of Betacoronavirus replication by targeting the highly conserved RNA 2'- O -methyltransferase (2'-O-MTase). Machaeriols RS-1 ( 7 ) and RS-2 ( 8 ) were identified using a previously outlined informatics approach to first screen for natural product prototypes, followed by in silico -guided synthesis. Both molecules are based on a rare natural product group. The machaeriols ( 3 - 6 ), isolated from the genus Machaerium , endemic to Amazonia, inhibited the SARS-CoV-2 2'-O-MTase more potently than the positive control, Sinefungin ( 2 ), and in silico modeling suggests distinct molecular interactions. This report highlights the potential of computationally driven screening to leverage natural product libraries and improve the efficiency of isolation or synthetic analog development.

Three undescribed (1-3) and nine known (4-12) platanosides were isolated and characterized from a bioactive extract of the May leaves of Platanus × acerifolia that initially showed inhibition against Staphylococcus aureus. Targeted compound mining was guided by an LC-MS/MS-based molecular ion networking (MoIN) strategy combined with conventional isolation procedures from a unique geographic location. The novel structures were mainly determined by 2D NMR and computational (NMR/ECD calculations) methods. Compound 1 is a rare acylated kaempferol rhamnoside possessing a truxinate unit. 6 (Z,E-platanoside) and 7 (E,E-platanoside) were confirmed to have remarkable inhibitory effects against both methicillin-resistant S. aureus (MIC: ≤ 16 μg/mL) and glycopeptide-resistant Enterococcus faecium (MIC: ≤ 1 μg/mL). These platanosides were subjected to docking analyses against FabI (enoyl-ACP reductase) and PBP1/2 (penicillin binding protein), both of which are pivotal enzymes governing bacterial growth but not found in the human host. The results showed that 6 and 7 displayed superior binding affinities towards FabI and PBP2. Moreover, surface plasmon resonance studies on the interaction of 1/7 and FabI revealed that 7 has a higher affinity (K D  = 1.72 μM), which further supports the above in vitro data and is thus expected to be a novel anti-antibacterial drug lead., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Xenorhabdus and Photorhabdus, bacterial symbionts of entomopathogenic nematodes Steinernema and Heterorhabditis , respectively, have several biological activities including insecticidal and antimicrobial activities. Thus, XnChi, XhChi, and PtChi, chitinases of X. nematophila , X. hominickii , and P. temperata isolated from Korean indigenous EPNs S. carpocapsae GJ1-2, S. monticolum GJ11-1, and H. megidis GJ1-2 were cloned and expressed in Escherichia coli BL21 to compare their biological activities. Chitinase proteins of these bacterial symbionts purified using the Ni-NTA system showed different chitobiosidase and endochitinase activities, but N-acetylglucosamidinase activities were not shown in the measuring of chitinolytic activity through N-acetyl-D-glucosarmine oligomers. In addition, the proteins showed different insecticidal and antifungal activities. XnChi showed the highest insecticidal activity against Galleria mellonella , followed by PtChi and XhChi. In antifungal activity, XhChi showed the highest half-maximal inhibitory concentration (IC 50 ) against Fusarium oxysporum with 0.031 mg/mL, followed by PtChi with 0.046 mg/mL, and XnChi with 0.072 mg/mL. XhChi also showed the highest IC 50 against F. graminearum with 0.040 mg/mL, but XnChi was more toxic than PtChi with 0.055 mg/mL and 0.133 mg/mL, respectively. This study provides an innovative approach to the biological control of insect pests and fungal diseases of plants with the biological activity of symbiotic bacterial chitinases of entomopathogenic nematodes.

Objectives: Clear outcome reporting in clinical trials facilitates accurate interpretation and application of findings and improves evidence-informed decision-making. Standardized core outcomes for reporting neonatal trials have been developed, but little is known about how primary outcomes are reported in neonatal trials. Our aim was to identify strengths and weaknesses of primary outcome reporting in recent neonatal trials., Methods: Neonatal trials including ≥100 participants/arm published between 2015 and 2020 with at least 1 primary outcome from a neonatal core outcome set were eligible. Raters recruited from Cochrane Neonatal were trained to evaluate the trials' primary outcome reporting completeness using relevant items from Consolidated Standards of Reporting Trials 2010 and Consolidated Standards of Reporting Trials-Outcomes 2022 pertaining to the reporting of the definition, selection, measurement, analysis, and interpretation of primary trial outcomes. All trial reports were assessed by 3 raters. Assessments and discrepancies between raters were analyzed., Results: Outcome-reporting evaluations were completed for 36 included neonatal trials by 39 raters. Levels of outcome reporting completeness were highly variable. All trials fully reported the primary outcome measurement domain, statistical methods used to compare treatment groups, and participant flow. Yet, only 28% of trials fully reported on minimal important difference, 24% on outcome data missingness, 66% on blinding of the outcome assessor, and 42% on handling of outcome multiplicity., Conclusions: Primary outcome reporting in neonatal trials often lacks key information needed for interpretability of results, knowledge synthesis, and evidence-informed decision-making in neonatology. Use of existing outcome-reporting guidelines by trialists, journals, and peer reviewers will enhance transparent reporting of neonatal trials., (Copyright © 2023 by the American Academy of Pediatrics.)

Background and Objectives: There is variability in the selection and reporting of outcomes in neonatal trials with key information frequently omitted. This can impact applicability of trial findings to clinicians, families, and caregivers, and impair evidence synthesis. The Neonatal Core Outcomes Set describes outcomes agreed as clinically important that should be assessed in all neonatal trials, and Consolidated Standards of Reporting Trials (CONSORT)-Outcomes 2022 is a new, harmonized, evidence-based reporting guideline for trial outcomes. We reviewed published trials using CONSORT-Outcomes 2022 guidance to identify exemplars of neonatal core outcome reporting to strengthen description of outcomes in future trial publications., Methods: Neonatal trials including >100 participants per arm published between 2015 to 2020 with a primary outcome included in the Neonatal Core Outcome Set were identified. Primary outcome reporting was reviewed using CONSORT 2010 and CONSORT-Outcomes 2022 guidelines by assessors recruited from Cochrane Neonatal. Examples of clear and complete outcome reporting were identified with verbatim text extracted from trial reports., Results: Thirty-six trials were reviewed by 39 assessors. Examples of good reporting for CONSORT 2010 and CONSORT-Outcomes 2022 criteria were identified and subdivided into 3 outcome categories: "survival," "short-term neonatal complications," and "long-term developmental outcomes" depending on the core outcomes to which they relate. These examples are presented to strengthen future research reporting., Conclusions: We have identified examples of good trial outcome reporting. These illustrate how important neonatal outcomes should be reported to meet the CONSORT 2010 and CONSORT-Outcomes 2022 guidelines. Emulating these examples will improve the transmission of information relating to outcomes and reduce associated research waste., (Copyright © 2023 by the American Academy of Pediatrics.)

Triple-negative breast cancer (TNBC) is insensitive to target therapy for non-TNBC and needs novel drug discovery. Extracts of the traditional herb Boesenbergia plant in Southern Asia exhibit anticancer effects and contain novel bioactive compounds but merely show cytotoxicity. We recently isolated a new compound from B. stenophylla , stenophyllol B (StenB), but the impact and mechanism of its proliferation-modulating function on TNBC cells remain uninvestigated. This study aimed to assess the antiproliferative responses of StenB in TNBC cells and examine the drug safety in normal cells. StenB effectively suppressed the proliferation of TNBC cells rather than normal cells in terms of an ATP assay. This preferential antiproliferative function was alleviated by pretreating inhibitors for oxidative stress ( N -acetylcysteine (NAC)) and apoptosis (Z-VAD-FMK). Accordingly, the oxidative-stress-related mechanisms were further assessed. StenB caused subG1 and G2/M accumulation but reduced the G1 phase in TNBC cells, while normal cells remained unchanged between the control and StenB treatments. The apoptosis behavior of TNBC cells was suppressed by StenB, whereas that of normal cells was not suppressed according to an annexin V assay. StenB-modulated apoptosis signaling, such as for caspases 3, 8, and 9, was more significantly activated in TNBC than in normal cells. StenB also caused oxidative stress in TNBC cells but not in normal cells according to a flow cytometry assay monitoring reactive oxygen species, mitochondrial superoxide, and their membrane potential. StenB induced greater DNA damage responses (γH2AX and 8-hydroxy-2-deoxyguanosine) in TNBC than in normal cells. All these StenB responses were alleviated by NAC pretreatment. Collectively, StenB modulated oxidative stress responses, leading to the antiproliferation of TNBC cells with little cytotoxicity in normal cells.

The urgent need for SARS-CoV-2 controls has led to a reassessment of approaches to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. There are yet no clinically approved broad-spectrum antivirals available for beta-coronaviruses. Discovery pipelines for pan-virus medications against a broad range of betacoronaviruses are therefore a priority. A variety of marine natural product (MNP) small molecules have shown inhibitory activity against viral species. Access to large data caches of small molecule structural information is vital to finding new pharmaceuticals. Increasingly, molecular docking simulations are being used to narrow the space of possibilities and generate drug leads. Combining in-silico methods, augmented by metaheuristic optimization and machine learning (ML) allows the generation of hits from within a virtual MNP library to narrow screens for novel targets against coronaviruses. In this review article, we explore current insights and techniques that can be leveraged to generate broad-spectrum antivirals against betacoronaviruses using in-silico optimization and ML. ML approaches are capable of simultaneously evaluating different features for predicting inhibitory activity. Many also provide a semi-quantitative measure of feature relevance and can guide in selecting a subset of features relevant for inhibition of SARS-CoV-2., Competing Interests: BJW, MH and GH report grants from the National Institutes of Health during the conduct of the study. G.H acknowledges support from National Institute of Health (NIH) U54MD010706, U01DA045300 and QUB start-up funds. G.H. is a founder of Altomics Datamation Ltd. and a member of its scientific advisory board. The authors report no other conflicts of interest in this work., (© 2023 Boswell et al.)

The diuretic effect of the combined furosemide and aminophylline/theophylline among pediatric patients remains unclear. The primary aim of this systematic review was to examine the clinical diuretic effects (urine output and fluid balance) of co-administration of furosemide and aminophylline/theophylline as compared to furosemide alone in pediatric population. Ovid MEDLINE, CENTRAL, and EMBASE were searched from its inception until March 2022 for observational studies and randomized controlled trials (RCTs) comparing the administration of furosemide versus furosemide and aminophylline/theophylline in pediatric population. Case reports, case series, commentaries, letters to editors, systematic reviews, and meta-analyses were excluded. Five articles with a total sample population of 187 patients were included in this systematic review. As compared to the furosemide alone, our pooled data demonstrated that co-administration of furosemide and aminophylline/theophylline was associated with higher urine output (mean difference: 2.91 [90% CI 1.54 to 4.27], p < 0.0001, I 2  = 90%) and a more negative fluid balance (mean difference - 28.27 [95% CI: - 46.21 to - 10.33], p = 0.002, I 2  = 56%) than those who received furosemide alone., Conclusion: This is the first paper summarizing the evidence of combined use of furosemide with aminophylline/theophylline in pediatric population. Our systematic review demonstrated that the co-administration of furosemide and aminophylline/theophylline could potentially yield better diuretic effects of urine output and negative fluid balance than furosemide alone in pediatric patients with fluid overload. Given the substantial degree of heterogeneity and low level of evidence, future adequately powered trials are warranted to provide evidence regarding the combined use of aminophylline/theophylline and furosemide as diuretic in the pediatric population., What Is Known: • Fluid overload is associated with poor prognosis for children in the intensive care unit. • The ineffective result of furosemide alone, even at high dose, as diuretic agent for children with diuretic resistant fluid overload in the intensive care unit., What Is New: • This is the first systematic review that compares furosemide alone and co-administration of furosemide and aminophylline/theophylline. • This paper showed potential benefit of co-administration of furosemide and aminophylline/theophylline promoting urine output and negative fluid balance compared to furosemide alone., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Manzamine-A is a marine-derived alkaloid which has anti-viral and anti-proliferative properties and is currently being investigated for its efficacy in the treatment of certain viruses (malaria, herpes, HIV-1) and cancers (breast, cervical, colorectal). Manzamine-A has been found to exert effects via modulation of SIX1 gene expression, a gene critical to craniofacial development via the WNT, NOTCH, and PI3K/AKT pathways. To date little work has focused on Manzamine-A and how its use may affect bone. We hypothesize that Manzamine-A, through SIX1, alters bone cell activity. Here, we assessed the effects of Manzamine-A on cells that are responsible for the generation of bone, pre-osteoblasts and osteoblasts. PCR, qrtPCR, MTS cell viability, Caspase 3/7, and functional assays were used to test the effects of Manzamine-A on these cells. Our data suggests Six1 is highly expressed in osteoblasts and their progenitors. Further, osteoblast progenitors and osteoblasts exhibit great sensitivity to Manzamine-A treatment exhibited by a significant decrease in cell viability, increase in cellular apoptosis, and decrease in alkaline phosphatase activity. In silico binding experiment showed that manzamine A potential as an inhibitor of cell proliferation and survival proteins, i.e., Iκb, JAK2, AKT, PKC, FAK, and Bcl-2. Overall, our data suggests Manzamine-A may have great effects on bone health overall and may disrupt skeletal development, homeostasis, and repair.

Vegetable oils having unsaturated fatty acids in the sn-2 position of triglyceride (TG) backbone might not raise serum cholesterol levels. We investigated the chronic effects of diets enriched with palm olein (IV64) (PO), cocoa butter (CB), or extra virgin olive oil (EVOO) with oleic acid primarily at the sn-2 position (66%, 75%, 87% sn-2 oleic acid, respectively) of the TG molecule in 40 healthy volunteers participated in this randomized, controlled, single-blinded, crossover trial. Following a 2-week run-in period, the subjects were given standardization meals (breakfast, lunch, and dinner) cooked with palm olein (IV72). Subjects were randomized to 1 of the 3 intervention groups; receiving baked products (brownies for breakfast and cookies for teatime) prepared with respective test fats accompanied with standardized low-fat meals for breakfast, lunch, and dinner prepared with palm olein (IV72) for all groups for 4 weeks in a crossover manner with 2-week washout period (given standardization meals). Anthropometric measurements, blood samples, and dietary intakes were measured before run-in and pre- and post-intervention. No significant difference was observed on the primary outcome of the study total: high-density lipoprotein cholesterol. All 3 test fats were found to exhibit similar lipid responses (total cholesterol, TG, lipoprotein (a), apolipoprotein-A1, apolipoprotein-B/A-1). Statistical difference was found on low-density lipoprotein cholesterol (CB>EVOO by 0.3 mmol/L, P = .003), high-density lipoprotein cholesterol (PO>CB by 0.04 mmol/L, P = .02) and apolipoprotein-B (EVOO

Oxidative stress plays an important role in acetaminophen (APAP)-induced hepatotoxicity. Platanosides (PTSs) isolated from the American sycamore tree ( Platanus occidentalis ) represent a potential new four-molecule botanical drug class of antibiotics active against drug-resistant infectious disease. Preliminary studies have suggested that PTSs are safe and well tolerated and have antioxidant properties. The potential utility of PTSs in decreasing APAP hepatotoxicity in mice in addition to an assessment of their potential with APAP for the control of infectious diseases along with pain and pyrexia associated with a bacterial infection was investigated. On PTS treatment in mice, serum alanine aminotransferase (ALT) release, hepatic centrilobular necrosis, and 4-hydroxynonenal (4-HNE) were markedly decreased. In addition, inducible nitric oxide synthase (iNOS) expression and c-Jun- N -terminal kinase (JNK) activation decreased when mice overdosed with APAP were treated with PTSs. Computational studies suggested that PTSs may act as JNK-1/2 and Keap1-Nrf2 inhibitors and that the isomeric mixture could provide greater efficacy than the individual molecules. Overall, PTSs represent promising botanical drugs for hepatoprotection and drug-resistant bacterial infections and are effective in protecting against APAP-related hepatotoxicity, which decreases liver necrosis and inflammation, iNOS expression, and oxidative and nitrative stresses, possibly by preventing persistent JNK activation.

The insect repellent methyl salicylate elicits excitatory responses upon interaction with CquiOR32, an odorant receptor (OR) from the southern house mosquito, Culex quinquefasciatus. By contrast, eucalyptol binds to CquiOR32 to generate electrophysiological and behavioral inhibitory responses. In an attempt to identify CquiOR32 variants displaying more robust inhibitory responses for more accurate current-voltage analysis, we sequenced 31 CquiOR32 clones. In the Xenopus oocyte recording system, CquiOR32V2/CquiOrco-expressing oocytes yielded eucalyptol-elicited outward (inhibitory) currents relatively larger than methyl salicylate-generated inward (excitatory) currents. Rescuing experiments showed that two of the amino acid substitutions in CquiOR32V2 located in a predicted transmembrane helix of the receptor are determinants of the outward/inward ratios. These findings, along with co-stimulus assays, suggest that odorant and inhibitor may bind to the same binding pocket. Current-voltage relationships obtained with standard perfusion buffer and those devoid of Na + or Cl - indicated that both excitatory and inhibitory currents are mediated, at least in part, by cation. We then concluded that eucalyptol is an inverse agonist, which shifts the open ⇔ closed equilibrium of the receptor toward the closed conformation, thus reducing the spontaneous activity. By contrast, the binding of methyl salicylate shifts the equilibrium towards the open conformation and, consequently, leads to an increase in cation influx., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

An efficient solid-phase method has been reported to prepare well-defined lysine defect dendrimers. Using orthogonally protected lysine residues, pure G2 to G4 lysine defect dendrimers were prepared with 48-95% yields within 13 h. Remarkably, high-purity products were collected via precipitation without further purification steps. This method was applied to prepare a pair of 4-carboxyphenylboronic acid-decorated defect dendrimers ( 16 and 17 ), which possessed the same number of boronic acids. The binding affinity of 16 , in which the ε-amines of G1 lysine are fractured, for glucose and sorbitol was 4 times that of 17 . This investigation indicated the role of allocation and distribution of peripheries for the dendrimer's properties and activity., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

Two new lactone lipids, scoriosin ( 1 ) and its methyl ester ( 2 ), with a rare furylidene ring joined to a tetrahydrofurandione ring, were isolated from Scorias spongiosa , commonly referred to as sooty mold. The planar structure of these compounds was assigned by 1D and 2D NMR. The conformational analysis of these molecules was undertaken to evaluate the relative and absolute configuration through GIAO NMR chemical shift analysis and ECD calculation. In addition to the potent antimicrobial activities, compound 2 strongly potentiated the activity of amphotericin B against Cryptococcus neoformans , suggesting the potential utility of this compound in combination therapies for treating cryptococcal infections.

Previously, we have identified an odorant receptor (OR) from the southern house mosquito Culex quinquefasciatus, CquiOR32, which responded to both odorants (agonists) and inhibitory compounds (antagonists). CquiOR32/CquiOrco-expressing oocytes responded to methyl salicylate and other odorants with inward (regular) currents but gave currents in the reverse direction when challenged with eucalyptol and other inhibitors. To determine whether hitherto unknown ORs show this intrareceptor inhibition, we have now examined two other receptors in the same cluster, CquiOR27 and CquiOR28. We cloned and tested four variants of CquiOR28, but none of the 250 compounds in our panel of odorants, including an Orco ligand candidate (OLC12), elicited inward or upward deflections of the current traces. By contrast, CquiOR27/CquiOrco-expressing oocytes gave robust, dose-dependent inward currents when challenged with γ-octalactone and other odorants. On the other hand, octylamine and other phenolic compounds elicited dose-dependent currents in the reverse direction. When stimulatory and inhibitory compounds were presented in binary mixtures, γ-octalactone-elicited inward currents were attenuated in a dose-dependent manner according to the concentration of octylamine. As part of our chemical ecology approach, we tested the repellency activity of the most potent ligands in the surface landing and feeding assay and a newly reported hand-in cage assay. Protection elicited by γ-octalactone did not differ significantly from that of DEET at the same dose. In the hand-in cage assay, a cream formulation of γ-octalactone showed 97.0 ± 1.3% protection, with 47.6 ± 8.3% and 1.4 ± 0.7% landings per trial in the hands covered with a control and γ-octalactone cream, respectively (N = 8, p = 0.0078, Wilcoxon matched-pairs signed-rank test)., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Since the discovery of the kahalalide family of marine depsipeptides in 1993, considerable work has been done to develop these compounds as new and biologically distinct anti-cancer agents. Clinical trials and laboratory research have yielded a wealth of data that indicates tolerance of kahalalides in healthy cells and selective activity against diseased cells. Currently, two molecules have attracted the greates level of attention, kahalalide F (KF) and isokahalalide F (isoKF, Irvalec, PM 02734, elisidepsin). Both compounds were originally isolated from the sarcoglossan mollusk Elysia rufescens but due to distinct structural characteristics it has been hypothesized and recently shown that the ultimate origin of the molecules is microbial. The search for their true source has been a subject of considerable research in the anticipation of finding new analogs and a culturable expression system that can produce sufficient material through fermentation to be industrially relevant., (Copyright © 2022. Published by Elsevier Masson SAS.)

Background: This study explored the user experiences of paediatric postgraduate trainees in Malaysia and Thailand in using a 2 h and 15 min online module for breastfeeding developed for Southeast Asia, which was adapted from existing European online modules for European and German Continuing Medical Education (CME) credits., Methods: A qualitative study using focus group discussions (FGDs) was conducted with paediatric postgraduate trainees who used an online English-language breastfeeding module in two Thai universities (May 2020, done online) and two Malaysian universities (Sept- Nov 2019, in-person). FGDs explored module usability and utility. Sessions were transcribed verbatim and analysed thematically. The process of coding was done collaboratively by Thai and Malaysian researchers., Results: Twenty Six resident trainees participated (Thai, n = 13; Malaysian, n = 13). Ages ranged from 29-34 years old, with 21 females. Nineteen participants had never used online learning modules prior to this. Participants took between 1 to 5 sessions to complete the breastfeeding module. Four themes emerged from their experience. 1) The online learning module was more engaging and detailed than previous lectures, courses and/or books, but lacked hands-on training. 2) Using an online platform facilitated learning as eased navigation and resource searching, however, problems were encountered navigating the module on some devices. 3) Learners preferred less words and more graphics, as this helped them capture key messages. 4) Regionally tailored content elicited a mixed reaction from participants., Conclusions: Users found that the adapted module compared favourably with previous learning experiences. However, online learning modules lack hands-on training, and implementation should ideally incorporate a mix of both. Consideration of device diversity and preferences for how content was adapted for local settings are needed for tailoring., (© 2022. The Author(s).)

Three new compounds, i.e. stenophyllols A-C ( 1 - 3 ), were isolated from the rhizome of Boesenbergia stenophylla . The structures were determined by spectroscopic analysis (UV, IR, NMR and HRESIMS). In-vitro neuroblastoma cell viability assay showed stenophyllol A ( 1 ) was able to reduce the N2A cell viability to 20% within 24 h.

Skeletal muscle is a heterogeneous tissue composed of a variety of functionally different fiber types. Slow-twitch type I muscle fibers are rich with mitochondria, and mitochondrial biogenesis promotes a shift towards more slow fibers. Leucine, a branched-chain amino acid (BCAA), regulates slow-twitch muscle fiber expression and mitochondrial function. The BCAA content is increased in porcine whole-blood protein hydrolysates (PWBPH) but the effect of PWBPH on muscle fiber type conversion is unknown. Supplementation with PWBPH (250 and 500 mg/kg for 5 weeks) increased time to exhaustion in the forced swimming test and the mass of the quadriceps femoris muscle but decreased the levels of blood markers of exercise-induced fatigue. PWBPH also promoted fast-twitch to slow-twitch muscle fiber conversion, elevated the levels of mitochondrial biogenesis markers (SIRT1, p-AMPK, PGC-1α, NRF1 and TFAM) and increased succinate dehydrogenase and malate dehydrogenase activities in ICR mice. Similarly, PWBPH induced markers of slow-twitch muscle fibers and mitochondrial biogenesis in C2C12 myotubes. Moreover, AMPK and SIRT1 inhibition blocked the PWBPH-induced muscle fiber type conversion in C2C12 myotubes. These results indicate that PWBPH enhances exercise performance by promoting slow-twitch muscle fiber expression and mitochondrial function via the AMPK/SIRT1 signaling pathway.

The pressing need for SARS-CoV-2 controls has led to a reassessment of strategies to identify and develop natural product inhibitors of zoonotic, highly virulent, and rapidly emerging viruses. This review article addresses how contemporary approaches involving computational chemistry, natural product (NP) and protein databases, and mass spectrometry (MS) derived target-ligand interaction analysis can be utilized to expedite the interrogation of NP structures while minimizing the time and expense of extraction, purification, and screening in BioSafety Laboratories (BSL)3 laboratories. The unparalleled structural diversity and complexity of NPs is an extraordinary resource for the discovery and development of broad-spectrum inhibitors of viral genera, including Betacoronavirus , which contains MERS, SARS, SARS-CoV-2, and the common cold. There are two key technological advances that have created unique opportunities for the identification of NP prototypes with greater efficiency: (1) the application of structural databases for NPs and target proteins and (2) the application of modern MS techniques to assess protein-ligand interactions directly from NP extracts. These approaches, developed over years, now allow for the identification and isolation of unique antiviral ligands without the immediate need for BSL3 facilities. Overall, the goal is to improve the success rate of NP-based screening by focusing resources on source materials with a higher likelihood of success, while simultaneously providing opportunities for the discovery of novel ligands to selectively target proteins involved in viral infection.

Korean river design standards set general design standards for rivers and river-related projects in Korea, which systematize the technologies and methods involved in river-related projects. This includes measurement methods for parts necessary for river design, but does not include information on shear stress. Shear stress is one of the factors necessary for river design and operation. Shear stress is one of the most important hydraulic factors used in the fields of water, especially for artificial channel design. Shear stress is calculated from the frictional force caused by viscosity and fluctuating fluid velocity. Current methods are based on past calculations, but factors such as boundary shear stress or energy gradient are difficult to actually measure or estimate. The point velocity throughout the entire cross-section is needed to calculate the velocity gradient. In other words, the current Korean river design standards use tractive force and critical tractive force instead of shear stress because it is more difficult to calculate the shear stress in the current method. However, it is difficult to calculate the exact value due to the limitations of the formula to obtain the river factor called the tractive force. In addition, tractive force has limitations that use an empirically identified base value for use in practice. This paper focuses on the modeling of shear-stress distribution in open channel turbulent flow using entropy theory. In addition, this study suggests a shear stress distribution formula, which can easily be used in practice after calculating the river-specific factor T. The tractive force and critical tractive force in the Korean river design standards should be modified by the shear stress obtained by the proposed shear stress distribution method. The present study therefore focuses on the modeling of shear stress distribution in an open channel turbulent flow using entropy theory. The shear stress distribution model is tested using a wide range of forty-two experimental runs collected from the literature. Then, an error analysis is performed to further evaluate the accuracy of the proposed model. The results reveal a correlation coefficient of approximately 0.95-0.99, indicating that the proposed method can estimate shear-stress distribution accurately. Based on this, the results of the distribution of shear stress after calculating the river-specific factors show a correlation coefficient of about 0.86 to 0.98, which suggests that the equation can be applied in practice.

Pandan (Pandanus amaryllifolius) is commonly used as a food ingredient in Southeast Asia due to its delicious flavor, appetizing aroma and bright green colour. Pandan plant is uniquely found only in certain parts of the world. Despite its increasing popularity worldwide, its export market is limited by practical issues. One of the main problems for exporting Pandan to global market is its stability during transport. Due to the volatility of its active constituent, the functional properties of Pandan are lost during storage and shipment. In this study, we explored the ability of ultrasound processing technology to encapsulate the aromatic Pandan extract using lysozyme or chitosan as a shell material. 20 kHz ultrasonicator was used to encapsulate the pandan extract at 150 W of applied power. Two parameters, the ultrasonic probe tip and the core-to-shell ratio were varied to control the properties of the encapsulates. The diameters of the probe tip used were 0.3 and 1.0 cm. The core-to-shell volume ratios used were 1:160 and 1:40. The size distribution and the stability of the synthesized microspheres were characterized to understand and explore the possible parameters variation impact. Both size and size distribution of the microspheres were found to be influenced by the parameters varied to certain extent. The results showed that the mean size of the microspheres was generally smallest when using 1 cm probe tip with lower core-to-shell volume ratio but largest when using the 3 mm tip with higher core-to-shell volume ratio. This indicates that the sonication parameters could be fine-tuned to achieve the encapsulation of Pandan extract for storage and export. The pandan-encapsulated microspheres were also found to be stable during storage at least for one month., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Forrestiacids A (1) and B (2) are a novel class of [4+2] type pentaterpenoids derived from a rearranged lanostane moiety (dienophile) and an abietane unit (diene). These unprecedented molecules were isolated using guidance by molecular ion networking (MoIN) from Pseudotsuga forrestii, an endangered member of the Asian Douglas Fir Family. The intermolecular hetero-Diels-Alder adducts feature an unusual bicyclo[2.2.2]octene ring system. Their structures were elucidated by spectroscopic analysis, GIAO NMR calculations and DP4+ probability analyses, electronic circular dichroism calculations, and X-ray diffraction analysis. This unique addition to the pentaterpene family represents the largest and the most complex molecule successfully assigned using computational approaches to predict accurately chemical shift values. Compounds 1 and 2 exhibited potent inhibitory activities (IC 50 s <5 μM) of ATP-citrate lyase (ACL), a new drug target for the treatment of glycolipid metabolic disorders including hyperlipidemia. Validating this activity 1 effectively attenuated the de novo lipogenesis in HepG2 cells. These findings provide a new chemical class for developing potential therapeutic agents for ACL-related diseases with strong links to traditional medicines., (© 2021 Wiley-VCH GmbH.)

Manzamines are complex polycyclic marine-derived β-carboline alkaloids with reported anticancer, immunostimulatory, anti-inflammatory, antibacterial, antiviral, antimalarial, neuritogenic, hyperlipidemia, and atherosclerosis suppression bioactivities, putatively associated with inhibition of glycogen synthase kinase-3, cyclin-dependent kinase 5, SIX1, and vacuolar ATPases. We hypothesized that additional, yet undiscovered molecular targets might be associated with Manzamine A's (MZA) reported pharmacological properties. We report here, for the first time, that MZA selectively inhibited a 90 kDa ribosomal protein kinase S6 (RSK1) when screened against a panel of 30 protein kinases, while in vitro RSK kinase assays demonstrated a 10-fold selectivity in the potency of MZA against RSK1 versus RSK2. The effect of MZA on inhibiting cellular RSK1 and RSK2 protein expression was validated in SiHa and CaSki human cervical carcinoma cell lines. MZA's differential binding and selectivity toward the two isoforms was also supported by computational docking experiments. Specifically, the RSK1-MZA (N- and C-termini) complexes appear to have stronger interactions and preferable energetics contrary to the RSK2-MZA ones. In addition, our computational strategy suggests that MZA binds to the N-terminal kinase domain of RSK1 rather than the C-terminal domain. RSK is a vertebrate family of cytosolic serine-threonine kinases that act downstream of the ras-ERK1/2 (extracellular-signal-regulated kinase 1/2) pathway, which phosphorylates substrates shown to regulate several cellular processes, including growth, survival, and proliferation. Consequently, our findings have led us to hypothesize that MZA and the currently known manzamine-type alkaloids isolated from several sponge genera may have novel pharmacological properties with unique molecular targets, and MZA provides a new tool for chemical-biology studies involving RSK1.

Since the 1960s, many rivers have been destroyed as a consequence of the process of rapid urbanization. As accurate figures are important to repair rivers, there have been many research reports on methods to obtain the exact river slope and elevation. Until now, many research efforts have analyzed the river using measured river topographic factors, but when the flow velocity changes rapidly, such as during a flood, surveying is not easy; and due to cost, frequent measurements are difficult. Previous research has focused on the cross section of the river, so the information on the river longitudinal profile is insufficient. In this research, using informational entropy theory, equations are presented that can calculate the average river slope, river slope, and river longitudinal elevation for a river basin in real time. The applicability was analyzed through a comparison with the measured data of river characteristic factors obtained from the river plan. The parameters were calculated using informational entropy theory and nonlinear regression analysis using actual data, and then the longitudinal elevation entropy equation for each river and the average river slope were calculated. As a result of analyzing the applicability of the equations presented in this study by R 2 and Root Mean Square Error, all R 2 values were over 0.80, while RMSE values were analyzed to be between 0.54 and 2.79. Valid results can be obtained by calculating river characteristic factors.

Pericardial effusion (PCE) and cardiac tamponade (CT) are rare but life-threatening complications of percutaneouslyinserted central catheter (PICC) use in neonates. There is often a lack in index of suspicion in a neonate with sudden deterioration, resulting in high mortality. We describe a series of three cases of PICC-related PCE/CT in low birth weight infants whose timely diagnosis with echocardiography and pericardiocentesis led to successful resuscitation and survival. We suggest that echocardiographic skills to determine tip position and pericardiocentesis be taught in neonatal resuscitation programs to ensure good outcomes of this otherwise fatal complication.

In general, this new equation is significant for designing and operating a pipeline to predict flow discharge. In order to predict the flow discharge, accurate determination of the flow loss due to pipe friction is very important. However, existing pipe friction coefficient equations have difficulties in obtaining key variables or those only applicable to pipes with specific conditions. Thus, this study develops a new equation for predicting pipe friction coefficients using statistically based entropy concepts, which are currently being used in various fields. The parameters in the proposed equation can be easily obtained and are easy to estimate. Existing formulas for calculating pipe friction coefficient requires the friction head loss and Reynolds number. Unlike existing formulas, the proposed equation only requires pipe specifications, entropy value and average velocity. The developed equation can predict the friction coefficient by using the well-known entropy, the mean velocity and the pipe specifications. The comparison results with the Nikuradse's experimental data show that the R2 and RMSE values were 0.998 and 0.000366 in smooth pipe, and 0.979 to 0.994 or 0.000399 to 0.000436 in rough pipe, and the discrepancy ratio analysis results show that the accuracy of both results in smooth and rough pipes is very close to zero. The proposed equation will enable the easier estimation of flow rates.

Objective: An ongoing third epidemic of retinopathy of prematurity (ROP) is contributed largely by developing nations. We describe a cohort of infants in a single neonatal unit where two limits of oxygen saturation were administered, to show real-world outcomes from trend in neonatology for higher oxygen to improve survival., Methods and Analysis: This retrospective, comparative study of prospectively collected data in an ROP screening programme included infants indicated by gestational age ≤32 weeks, birth weight <1501 g, ventilation for 7 days or requiring oxygen >1 month, who underwent dilated fundoscopic examination from age 4 weeks, every 2 weeks until full retinal vascularisation. Infants with ROP were examined weekly and treated where indicated. Data were divided into two epochs. Epoch 1 oxygen saturation targets were [88-92%], epoch 2 targets [90-95% (99%)] with allowance of increase to 20% for several hours after procedures. Outcome measures included development of ROP, treatment, mortality, sepsis and intraventricular haemorrhage., Results: A total of 651 infants underwent examination between 2003 and 2016. The incidence of ROP in epoch 1 was 29.1% and epoch 2 was 29.3% (p=0.24). ROP progression doubled in epoch 2 (5 vs 11%, p=0.006), proportion of cases treated halved (14% vs 6%, p=0.0005), sepsis was halved (78.5% vs 41.2%, p<0.0001) and intraventricular haemorrhage doubled (20.2% vs 43.8%, p=0.0001) in epoch 2. Mortality was 4% and 0% in epochs 1 and 2, respectively., Conclusion: Incidence of ROP did not differ, although ROP cases that worsened doubled with higher oxygen targets. ROP cases requiring treatment decreased, as did sepsis and mortality. Intraventricular haemorrhage cases doubled., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Emerging evidence has shown a link between the perturbations and development of the gut microbiota in infants with their immediate and long-term health. To better understand the assembly of the gut microbiota in preterm infants, faecal samples were longitudinally collected from the preterm (n = 19) and term (n = 20) infants from birth until month 12. 16S rRNA gene sequencing (n = 141) and metabolomics profiling (n = 141) using nuclear magnetic resonance spectroscopy identified significant differences between groups in various time points. A panel of amino acid metabolites and central metabolism intermediates significantly correlated with the relative abundances of 8 species of bacteria were identified in the preterm group. In contrast, faecal metabolites of term infants had significantly higher levels of metabolites which are commonly found in milk such as fucose and β-hydroxybutyrate. We demonstrated that the early-life factors such as gestational age, birth weight and NICU exposures, exerted a sustained effect to the dynamics of gut microbial composition and metabolism of the neonates up to one year of age. Thus, our findings suggest that intervention at this early time could provide 'metabolic rescue' to preterm infants from aberrant initial gut microbial colonisation and succession.

Natural products remain an important source of drug leads covering unique chemical space and providing significant therapeutic value for the control of cancer and infectious diseases resistant to current drugs. Here, we determined the antiproliferative activity of a natural product manzamine A ( 1 ) from an Indo-Pacific sponge following various in vitro cellular assays targeting cervical cancer (C33A, HeLa, SiHa, and CaSki). Our data demonstrated the antiproliferative effects of 1 at relatively low and non-cytotoxic concentrations (up to 4 μM). Mechanistic investigations confirmed that 1 blocked cell cycle progression in SiHa and CaSki cells at G1/S phase and regulated cell cycle-related genes, including restoration of p21 and p53 expression. In apoptotic assays, HeLa cells showed the highest sensitivity to 1 as compared to other cell types (C33A, SiHa, and CaSki). Interestingly, 1 decreased the levels of the oncoprotein SIX1, which is associated with oncogenesis in cervical cancer. To further investigate the structure-activity relationship among manzamine A ( 1 ) class with potential antiproliferative activity, molecular networking facilitated the efficient identification, dereplication, and assignment of structures from the manzamine class and revealed the significant potential in the design of optimized molecules for the treatment of cervical cancer. These data suggest that this sponge-derived natural product class warrants further attention regarding the design and development of novel manzamine analogues, which may be efficacious for preventive and therapeutic treatment of cancer. Additionally, this study reveals the significance of protecting fragile marine ecosystems from climate change-induced loss of species diversity.

In this study, Auricularia auricula - judae (Bull.) extract (AAE) had potent antioxidant activity in vitro and promoted the biosynthesis of procollagen, a precursor of collagen in HaCaT cells. In addition, the expression of HAS - 3 (hyaluronic acid synthase), which is a moisturizing factor, was increased in HaCaT cells in response to AAE. Therefore, this work suggests that AAE has the potential to exhibit antioxidant activity and promote procollagen biosynthesis in HaCaT cells.

How chemical signals are integrated at the peripheral sensory system of insects is still an enigma. Here we show that when coexpressed with Orco in Xenopus oocytes, an odorant receptor from the southern house mosquito, CquiOR32, generated inward (regular) currents when challenged with cyclohexanone and methyl salicylate, whereas eucalyptol and fenchone elicited inhibitory (upward) currents. Responses of CquiOR32-CquiOrco-expressing oocytes to odorants were reduced in a dose-dependent fashion by coapplication of inhibitors. This intrareceptor inhibition was also manifested in vivo in fruit flies expressing the mosquito receptor CquiOR32, as well in neurons on the antennae of the southern house mosquito. Likewise, an orthologue from the yellow fever mosquito, AaegOR71, showed intrareceptor inhibition in the Xenopus oocyte recording system and corresponding inhibition in antennal neurons. Inhibition was also manifested in mosquito behavior. Blood-seeking females were repelled by methyl salicylate, but repellence was significantly reduced when methyl salicylate was coapplied with eucalyptol., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

A novel mass spectrometry detection technique based on a multi-period and multi- experiment (MRM-EPI-MRM3) with library matching in a single run for fast and rapid screening and identification of amphetamine type stimulants (ATS) related drugs in whole blood, urine and dried blood stain was developed and validated. The ATS-related drugs analyzed in this study include ephedrine, pseudoephedrine, amphetamine, methamphetamine, MDMA (3,4-Methylenedioxymethamphetamine), MDA (3,4-Methylenedioxyamphetamine), MDEA (3,4-Methylenedioxy-N-ethylamphetamine) and phentermine. The relative standard deviation for inter and intraday was less than 15% while recoveries ranged from 80% to 120% for all three matrices, i.e., whole blood, urine and dried blood stain. All compounds gave library matching percentage of more than 85% based on the purity. This method was proven to be simple and robust, and provide high confident results complemented with library matching confirmation., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Mycotoxins are common food contaminants which cause poisoning and severe health risks to humans and animals. The present study applied chemometric approach in liquid chromatography-tandem mass spectrometry (LC-MS/MS) optimization for simultaneous determination of mycotoxins, i.e., aflatoxins B1, B2, G1, and G2, and ochratoxin A. The validated quick, easy, cheap, effective, rugged, and safe (QuEChERS)-LC-MS/MS method was used to study the occurrence of mycotoxins in 120 food matrices. The recovery ranges from 81.94% to 101.67% with relative standard deviation (RSD) lesser than 11%. Through the developed method, aflatoxins were detected in raisin, pistachio, peanut, wheat flour, spice, and chili samples with concentration ranges from 0.45 to 16.93 µg/kg. Trace concentration of ochratoxin A was found in wheat flour and peanut samples which ranged from 1.2 to 3.53 µg/kg. Some of the tested food samples contained mycotoxins of above the European legal maximum limit.

Objective: To determine rates of death or neurodevelopmental impairment (NDI) at 2 years corrected age (primary outcome) in children <32 weeks' gestation randomized to initial resuscitation with a fraction of inspired oxygen (FiO 2 ) value of 0.21 or 1.0., Study Design: Blinded assessments were conducted at 2-3 years corrected age with the Bayley Scales of Infant and Toddler Development, Third Edition or the Ages and Stages Questionnaire by intention to treat., Results: Of the 290 children enrolled, 40 could not be contacted and 10 failed to attend appointments. Among the 240 children for whom outcomes at age 2 years were available, 1 child had a lethal congenital anomaly, 1 child had consent for follow-up withdrawn, and 23 children died. The primary outcome, which was available in 238 (82%) of those randomized, occurred in 47 of the 117 (40%) children assigned to initial FiO 2 0.21 and in 38 of the 121 (31%) assigned to initial FiO 2 1.0 (OR, 1.47; 95% CI, 0.86-2.5; P = .16). No difference in NDI was found in 215 survivors randomized to FiO 2 0.21 vs 1.0 (OR, 1.26; 95% CI, 0.70-2.28; P = .11). In post hoc exploratory analyses in the whole cohort, children with a 5-minute blood oxygen saturation (SpO 2 ) <80% were more likely to die or to have NDI (OR, 1.85; 95% CI, 1.07-3.2; P = .03)., Conclusions: Initial resuscitation of infants <32 weeks' gestation with initial FiO 2 0.21 had no significant effect on death or NDI compared with initial FiO 2 1.0. Further evaluation of optimum initial FiO 2 , including SpO 2 targeting, in a large randomized controlled trial is needed., Trial Registration: Australian and New Zealand Clinical Trials Network Registry ACTRN 12610001059055 and the National Malaysian Research Registry NMRR-07-685-957., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Serine proteases and serine protease homologs are involved in the prophenoloxidase (proPO)-activating system leading to melanization. The Bombyx mori serine protease homolog BmSPH-1 regulates nodule melanization. Here, we show the dual role of BmSPH-1 in the development and immunity of B. mori. BmSPH-1 was expressed in hemocytes after molting and during the larval-pupal transformation in normal development. In contrast, following infection, BmSPH-1 was expressed in hemocytes and cleaved in the hemolymph, which resulted in the induction of PO activity. Moreover, BmSPH-1 was cleaved in the cuticle during the larval-pupal transformation and early pupal stages. In BmSPH-1 RNAi-treated silkworms, the reduced BmSPH-1 mRNA levels during the spinning stage or the prepupal stage resulted in the arrest of pupation or pupal cuticular melanization, respectively. The binding assays revealed that BmSPH-1 interacts with B. mori immulectin, proPO, and proPO-activating enzyme. Our findings demonstrate that BmSPH-1 paticipates larval-pupal transformation, pupal cuticular melanization and innate immunity of silkworms, illustrating the dual role of BmSPH-1 in development and immunity., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

We have previously found that mycelia culture broth of eight kinds of traditional herbal extracts fermented with Phellinus linteus (previously named as 8-HsPLCB) not only inhibited melanin and tyrosinase activity, but also reduced the contents of melanogenesis-related proteins, including tyrosinase and microphthalmia-associated transcription factor, in 3-isobutyl-1-methylxanthine-stimulated B16F0 melanoma cells. For a further study, the effect of 8-HsPLCB against skin pigmentation in brown guinea pigs with ultraviolet B (UVB)-induced hyperpigmentation was investigated. 8-HsPLCB (3%) and arbutin (2%) as positive controls were applied topically twice daily for 4 weeks to the hyperpigmented areas. 8-HsPLCB showed skin-lightening effect as effective as arbutin, one of the most widely used in whitening cosmetics. Melanin index values as the degree of pigmentation showed a significant reduction week by week post 8-HsPLCB treatment and then substantially reduced by 4 weeks. The degree of depigmentation after 4 weeks of topical application with 8-HsPLCB was 32.2% as compared with before treatment (0 week). Moreover, using Fontana-Masson staining and hematoxylin-eosin staining, 8-HsPLCB reduced melanin pigmentation in the basal layer of the epidermis and epidermal thickness changes exposed to the UV-B irradiation as compared with non-treatment and vehicle treatment. The intensity of the skin-lightening effect of 8-HsPLCB was similar to arbutin. These results suggest that the skin-lightening effect of 8-HsPLCB might be resulted from inhibition of melanin synthesis by tyrosinase in melanocytes. To conclude, 8-HsPLCB treatment showed reduction of the melanin pigment and histological changes induced by UV irradiation in brown guinea pigs.

Objective: The chronic obstructive pulmonary disease (COPD) integrated care pathway (ICP) programme was designed and implemented to ensure that the care for patients with COPD is comprehensive and integrated across different care settings from primary care to acute hospital and home. We evaluated the effectiveness of the ICP programme for patients with COPD., Design, Setting and Participants: A retrospective propensity score matched cohort study was conducted comparing differences between programme enrolees and propensity-matched non-enrolees in a Regional Health System in Singapore. Data on patients diagnosed with COPD who enrolled in the programme (n=95) and patients who did not enrol (n=6330) were extracted from the COPD registry and hospital administrative databases. Enrolees and non-enrolees were propensity score matched., Outcome Measures: The risk of COPD hospitalisations and COPD hospital bed days savings were compared between the groups using a difference-in-difference strategy and generalised estimating equation approach. Adherence with recommended care elements for the COPD-ICP group was measured quarterly at baseline and during a 2-year follow-up period., Results: Compared with non-enrolees, COPD hospitalisation risk for ICP programme enrolees was significantly lower in year 2 (incidence rate ratio (IRR): 0.73; 95% CI 0.54 to 1.00). Similarly, COPD hospital bed days was significantly lower for enrolees in year 2 (IRR: 0.78; 95% CI 0.64 to 0.95). ICP programme patients had sustained improvements in compliance with all recommended care elements for patients with COPD. The overall all-or-none care bundle compliance rate had improved from 28% to 54%., Conclusion: The study concluded that the COPD-ICP programme was associated with reductions in COPD hospitalisation risk and COPD health utilisation in a 2-year follow-up period., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)