Search

Modeling the overpressure of organic shales caused by thermal maturation and its elastic responses is crucial for geophysical characterization of source rocks and unconventional shale reservoirs. Thermal maturation involves the generation of excess fluid contents (oil and gas) and can cause the overpressure if an organic shale preserves the produced fluids partly or wholly. The solid organic matter (e.g., kerogen or solid bitumen) with the potential of generating hydrocarbon presents two types of morphology in organic shales: scattered patches as pore-fillings and continuous network as load-bearings. According to the kerogen morphology, two bulk volume models are devised to simulate the elasticity of organic shales using respective rock-physics modeling schemes. The rock physics modeling combined with the density and compressibility of pore-fillings are demonstrated to effectively capture the excess pore pressure characteristics due to thermal maturation in organic shales. The basic principle of solving the overpressure is that the pore space volume equals the total volume of all components within the pores before and after the maturation. According to the modeling results, the elastic characteristics of overpressure due to thermal maturation reveal a decrease in velocity and a slight decrease in density. Besides, for an organic shale with a relatively rigid framework, it tends to yield higher overpressure than a shale with a relatively compliant framework. With proper calibration, the modeling strategy shows its potential in quantitatively interpreting the well-log data of organic shale formation within the thermal maturation window. [ABSTRACT FROM AUTHOR]

Transcoelomic spread of cancer cells across the peritoneal cavity occurs in most initially diagnosed ovarian cancer (OC) patients and accounts for most cancer-related death. However, how OC cells interact with peritoneal stromal cells to evade the immune surveillance remains largely unexplored. Here, through an in vivo genome-wide CRISPR/Cas9 screen, we identified IL20RA, which decreased dramatically in OC patients during peritoneal metastasis, as a key factor preventing the transcoelomic metastasis of OC. Reconstitution of IL20RA in highly metastatic OC cells greatly suppresses the transcoelomic metastasis. OC cells, when disseminate into the peritoneal cavity, greatly induce peritoneum mesothelial cells to express IL-20 and IL-24, which in turn activate the IL20RA downstream signaling in OC cells to produce mature IL-18, eventually resulting in the polarization of macrophages into the M1-like subtype to clear the cancer cells. Thus, we show an IL-20/IL20RA-mediated crosstalk between OC and mesothelial cells that supports a metastasis-repressing immune microenvironment. [ABSTRACT FROM AUTHOR]

Building Information Modelling (BIM) has been adopted as the main technology in the construction qiindustry in many developed countries due to its notable advantages. However, its applications in developing countries are limited. This paper aims to investigate factors which impact on BIM adoption in the construction industry. Twelve external variables were identified by an integrated TAM (Technology Acceptance Model) and TOE (Technology Organization Environment) framework and a systematic review of past studies. A survey was conducted in development, construction, design and consulting companies to investigate the impacts of these 12 external variables on BIM adoption. Using the interval Decision Making Trial and Evaluation Laboratory (DEMATEL) method, retrieved 120 completed questionnaires were analysed. The "Requirements from national policies" was found to be the most significant driving variable of BIM adoption by investigated companies. A further simulation analysis revealed that the "Intention to Use" BIM varied significantly with the change of "Requirements from national policies", "Standardization of BIM", and "Popularity of BIM in the industry". The results lead to the conclusion that government incentives play critical roles in BIM adoption in China. Policy makers could put more efforts into motivation strategies, standardization measures, and BIM culture cultivation to promote BIM applications in the construction industry. [ABSTRACT FROM AUTHOR]

Chemical study on the methanol extract of aerial parts of Hypericum petiolulatum led to the isolation of one new polycyclic polyprenylated acylphloroglucinol (PPAP), dihroxuralodin ( 1), and one new chromone ( 2), together with four known PPAPs ( 3-6) and nine xanthones ( 7-15). Their structures were established on the basis of spectroscopic data, including IR, MS, 1D, and 2D NMR. All the isolated PPAPs ( 1, 3-6) were evaluated for their cytotoxicity against human prostate cancer cell line PC-3 and human breast cancer cell line MCF-7. Compounds 2 and 7-15 were tested for their antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals. Compounds 1 and 3 exhibited moderate cytotoxicity against MCF-7 tumor cell line with IC values of 8.9 and 10.3 μM, respectively. Compounds 2 and 7-15 exhibited potent antioxidant activity with IC values ranging from 5.6 to 36.8 μM, when compared to the positive control, butylated hydroxytoluene (BHT, IC = 78.8 μM). [ABSTRACT FROM AUTHOR]

Research of detailed chemical constituents from the root bark of Morus alba resulted in the isolation of thirteen compounds, including a new triterpenoid (1), three lupane-type triterpenoids (2-4), two tirucallane-type triterpenoids (5 , 6), three ursane-type triterpenoids (7–9), one incompletely cyclized triterpene alcohol (10), and three steroids (11–13). In this study, compound 1 was identified as a new triterpenoid. Among these known compounds, compounds 10 and 12 were firstly obtained from the Moraceae family, compound 5 was mentioned from the Morus genus for the first time, and this was the first report of compounds 6 and 13 in Morus alba species. Furthermore, chemotaxonomic significance of these isolates was also discussed in this paper. • Ten triterpenoids and three steroids were isolated from the root bark of Morus alba. • A new triterpenoid 3 β - O -acetyl-20-oxo-29(20. → 19) abeolupane (1) was reported from this plant. • Compounds 1 , 5 , 6 , 10 , 12 and 13 can be considered a characteristic compounds of Morus alba. [ABSTRACT FROM AUTHOR]

Background: Accurate discovery of molecular biomarkers that are prognostic of a clinical outcome is an important yet challenging task, partly due to the combination of the typically weak genomic signal for a clinical outcome and the frequently strong noise due to microarray handling effects. Effective strategies to resolve this challenge are in dire need. Methods: We set out to assess the use of careful study design and data normalization for the discovery of prognostic molecular biomarkers. Taking progression free survival in advanced serous ovarian cancer as an example, we conducted empirical analysis on two sets of microRNA arrays for the same set of tumor samples: arrays in one set were collected using careful study design (that is, uniform handling and randomized array-to-sample assignment) and arrays in the other set were not. Results: We found that (1) handling effects can confound the clinical outcome under study as a result of chance even with randomization, (2) the level of confounding handling effects can be reduced by data normalization, and (3) good study design cannot be replaced by post-hoc normalization. In addition, we provided a practical approach to define positive and negative control markers for detecting handling effects and assessing the performance of a normalization method. Conclusions: Our work showcased the difficulty of finding prognostic biomarkers for a clinical outcome of weak genomic signals, illustrated the benefits of careful study design and data normalization, and provided a practical approach to identify handling effects and select a beneficial normalization method. Our work calls for careful study design and data analysis for the discovery of robust and translatable molecular biomarkers. [ABSTRACT FROM AUTHOR]

Background Finding genes that share similar expression patterns across samples is an important question that is frequently asked in high-throughput microarray studies. Traditional clustering algorithms such as K-means clustering and hierarchical clustering base gene clustering directly on the observed measurements and do not take into account of the specific experimental design under which the microarray data were collected. A new model-based clustering method, the clustering of regression models method, takes into account the specific design of the microarray study and bases the clustering on how genes are related to sample covariates. It can find useful gene clusters for studies from complicated study designs such as replicated time course studies. Findings In this paper, we applied the clustering of regression models method to data from a time course study of yeast on two genotypes, wild type and YOX1 mutant, each with two technical replicates, and compared the clustering results with K-means clustering. We identified gene clusters that have similar expression patterns in wild type yeast, two of which were missed by K-means clustering. We further identified gene clusters whose expression patterns were changed in YOX1 mutant yeast compared to wild type yeast. Conclusions The clustering of regression models method can be a valuable tool for identifying genes that are coordinately transcribed by a common mechanism. [ABSTRACT FROM AUTHOR]

The FilmArray respiratory virus panel detects 15 viral agents in respiratory specimens using polymerase chain reaction. We performed FilmArray respiratory viral testing in a core laboratory at a regional children's hospital that provides service 24 hours a day, 7 days a week. The average and median turnaround time were 1.6 and 1.4 hours, respectively, in contrast to 7 and 6.5 hours documented 1 year previously at an on-site reference laboratory using a direct fluorescence assay (DFA) that detected 8 viral agents. During the study period, rhinovirus was detected in 20% and coronavirus in 6% of samples using FilmArray; these viruses would not have been detected with DFA. We followed 97 patients with influenza A or influenza B who received care at the emergency department (ED). Overall, 79 patients (81%) were given oseltamivir in a timely manner defined as receiving the drug in the ED, a prescription in the ED, or a prescription within 3 hours of ED discharge. Our results demonstrate that molecular technology can be successfully deployed in a nonspecialty, high-volume, multidisciplinary core laboratory. [ABSTRACT FROM AUTHOR]

Background: Methods for array normalization, such as median and quantile normalization, were developed for mRNA expression arrays. These methods assume few or symmetric differential expression of genes on the array. However, these assumptions are not necessarily appropriate for microRNA expression arrays because they consist of only a few hundred genes and a reasonable fraction of them are anticipated to have disease relevance. Methods: We collected microRNA expression profiles for human tissue samples from a liposarcoma study using the Agilent microRNA arrays. For a subset of the samples, we also profiled their microRNA expression using deep sequencing. We empirically evaluated methods for normalization of microRNA arrays using deep sequencing data derived from the same tissue samples as the benchmark. Results: In this study, we demonstrated array effects in microRNA arrays using data from a liposarcoma study. We found moderately high correlation between Agilent data and sequence data on the same tumors, with the Pearson correlation coefficients ranging from 0.6 to 0.9. Array normalization resulted in some improvement in the accuracy of the differential expression analysis. However, even with normalization, there is still a significant number of false positive and false negative microRNAs, many of which are expressed at moderate to high levels. Conclusions: Our study demonstrated the need to develop more efficient normalization methods for microRNA arrays to further improve the detection of genes with disease relevance. Until better methods are developed, an existing normalization method such as quantile normalization should be applied when analyzing microRNA array data. [ABSTRACT FROM AUTHOR]

Two new diterpenoids, (3 β,13 S)-3- O-[6- O-acetyl- β--glucopyranosyl]-13- O- α--rhamnopyranosyllabda-8(17),14-diene () and (4 R,13 S)-18- O- β--glucopyranosyllabda-8(17),14-dien-13-ol () have been isolated from the 95% EtOH extract of the dry fronds of Diplopterygium rufopilosum. Their structures were characterized by spectroscopic methods, including 1D-NMR, 2D-NMR, and HR-ESI-MS. [ABSTRACT FROM AUTHOR]

Two new triterpenoids, ursa-12-sene-3β,11β-diol 3-O-palmitate (1) and ursa-12-sene-1β,3β,11α-triol 3-O-palmitate (2), were isolated from the 70% aqueous acetone extract of the aerial parts of Viburnum betulifolium, together with the artificial diene derivative of 2, ursa-12-dien-1β,3β-diol 3-O-palmitate (2a). Their structures were characterized by various spectroscopic methods, including 1D NMR, 2D NMR, and HR-ESI-MS. [ABSTRACT FROM AUTHOR]

Lycojapodine A, a novel C16N-type Lycopodiumalkaloid with an unprecedented 6/6/6/7 tetracyclic ring system, was isolated from the club moss Lycopodium japonicum. The structure and relative stereochemistry were elucidated on the basis of spectroscopic data and were further confirmed by X-ray analysis. A possible biosynthetic pathway for 1was proposed. Its inhibitory activity on acetylcholinestrease and anti-HIV-1 activity were also evaluated. [ABSTRACT FROM AUTHOR]

Normalization is an important step in the analysis of microarray data of transcription profiles as systematic non-biological variations often arise from the multiple steps involved in any transcription profiling experiment. Existing methods for data normalization often assume that there are few or symmetric differential expression, but this assumption does not always hold. Alternatively, non-differentially expressed genes may be used for array normalization. However, it is unknown at the outset which genes are non-differentially expressed. In this paper we propose a hierarchical mixture model framework to simultaneously identify non-differentially expressed genes and normalize arrays using these genes. The Fisher's information matrix corresponding to array effects is derived, which provides useful intuition for guiding the choice of array normalization method. The operating characteristics of the proposed method are evaluated using simulated data. The simulations conducted under a wide range of parametric configurations suggest that the proposed method provides a useful alternative for array normalization. For example, the proposed method has better sensitivity than median normalization under modest prevalence of differentially expressed genes and when the magnitudes of over-expression and under-expression are not the same. Further, the proposed method has properties similar to median normalization when the prevalence of differentially expressed genes is very small. Empirical illustration of the proposed method is provided using a liposarcoma study from MSKCC to identify genes differentially expressed between normal fat tissue versus liposarcoma tissue samples. [ABSTRACT FROM AUTHOR]

Background: MicroRNAs are believed to play an important role in gene expression regulation. They have been shown to be involved in cell cycle regulation and cancer. MicroRNA expression profiling became available owing to recent technology advancement. In some studies, both microRNA expression and mRNA expression are measured, which allows an integrated analysis of microRNA and mRNA expression. Results: We demonstrated three aspects of an integrated analysis of microRNA and mRNA expression, through a case study of human cancer data. We showed that (1) microRNA expression efficiently sorts tumors from normal tissues regardless of tumor type, while gene expression does not; (2) many microRNAs are down-regulated in tumors and these microRNAs can be clustered in two ways: microRNAs similarly affected by cancer and microRNAs similarly interacting with genes; (3) taking let-7f as an example, targets genes can be identified and they can be clustered based on their relationship with let-7f expression. Discussion: Our findings in this paper were made using novel applications of existing statistical methods: hierarchical clustering was applied with a new distance measure--the co-clustering frequency--to identify sample clusters that are stable; microRNA-gene correlation profiles were subject to hierarchical clustering to identify microRNAs that similarly interact with genes and hence are likely functionally related; the clustering of regression models method was applied to identify microRNAs similarly related to cancer while adjusting for tissue type and genes similarly related to microRNA while adjusting for disease status. These analytic methods are applicable to interrogate multiple types of -omics data in general. [ABSTRACT FROM AUTHOR]

The article discusses the effectiveness of perioperative chemotherapy in patients undergoing pulmonary resection for metastatic soft-tissue sarcoma (STS) of the extremity based on a study in the U.S. The study indicated that perioperative chemotherapy was not associated with disease-specific, overall or pulmonary progression-free survival. It found that systemic chemotherapy has minimal impact on the outcome of patients undergoing pulmonary resection.

Identification of differentially expressed genes and clustering of genes are two important and complementary objectives addressed with gene expression data. For the differential expression question, many “per-gene” analytic methods have been proposed. These methods can generally be characterized as using a regression function to independently model the observations for each gene; various adjustments for multiplicity are then used to interpret the statistical significance of these per-gene regression models over the collection of genes analyzed. Motivated by this common structure of per-gene models, we proposed a new model-based clustering method—the clustering of regression models method, which groups genes that share a similar relationship to the covariate(s). This method provides a unified approach for a family of clustering procedures and can be applied for data collected with various experimental designs. In addition, when combined with per-gene methods for assessing differential expression that employ the same regression modeling structure, an integrated framework for the analysis of microarray data is obtained. The proposed methodology was applied to two microarray data sets, one from a breast cancer study and the other from a yeast cell cycle study. [ABSTRACT FROM AUTHOR]

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non--small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure--activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC50: 0.54 μM] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent-mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2. [ABSTRACT FROM AUTHOR]

Background. Exercise is a regular behavioral activity that not only helps to lose weight but also reduces the risk of cardiovascular and cerebrovascular diseases. Diabetes is a common disease that plagues human health. It is shown that regular exercise can improve the insulin sensitivity of diabetic patients and have an important function in adjuvant therapy. Methods. We downloaded the GSE101931 dataset from the Gene Expression Omnibus (GEO) database, 10 samples were obtained from the GSE101931 dataset, including 5 before exercise and 5 postexercise samples, and GEO2R was used to screen the differentially expressed genes (DEGs) exhibited by a heat map. Then, the enrichment analysis of DEGs in Gene Ontology (GO) function was analyzed by Metascape, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway of DEGs was also analyzed by gene set enrichment analysis (GSEA). Next, the protein-protein interaction (PPI) network maps were drawn, and the hub genes were identified through Metascape. Finally, the expressions of the hub genes in the dataset were analyzed. Results. Totally, 116 upregulated DEGs and 1017 downregulated DEGs were identified from these data. These DEGs were mainly enriched in the platelet-derived growth factor receptor signaling pathway and mRNA processing. Then, the GSEA analysis showed that 6 KEGG pathways were associated with postexercise prediabetic samples, namely, ABC transporters, focal adhesion, MAPK signaling pathway, prion diseases, melanogenesis, and gap junction. Afterward, three hub genes (HSPA8, STIP1, and HSPH1) were highly expressed after exercise through the box plot analysis. Conclusion. A myriad of research results confirms that there is a certain connection between exercise and diabetes, which provides a favorable basis for emerging exercise into the treatment of diabetic patients. [ABSTRACT FROM AUTHOR]

Men or mice with homozygous serine/threonine kinase 33 (STK33) mutations are sterile owing to defective sperm morphology and motility. To chemically evaluate STK33 for male contraception with STK33-specific inhibitors, we screened our multibillion-compound collection of DNA-encoded chemical libraries, uncovered potent STK33-specific inhibitors, determined the STK33 kinase domain structure bound with a truncated hit CDD-2211, and generated an optimized hit CDD-2807 that demonstrates nanomolar cellular potency (half-maximal inhibitory concentration = 9.2 nanomolar) and favorable metabolic stability. In mice, CDD-2807 exhibited no toxicity, efficiently crossed the blood-testis barrier, did not accumulate in brain, and induced a reversible contraceptive effect that phenocopied genetic STK33 perturbations without altering testis size. Thus, STK33 is a chemically validated, nonhormonal contraceptive target, and CDD-2807 is an effective tool compound. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of the leaves of Coriaria nepalensis led to the isolation of fourteen compounds, including five sesquiterpenoids (1 – 5), two oleanane-type triterpenoids (6 , 7), one cycloartane triterpenoid (8), one phytosterol (9), one diterpenoid (10), two α-tocopheroids (11 , 12), and two vitamins (13 , 14). These structures were elucidated on the basis of 1D and 2D NMR spectra (COSY, HSQC, HMBC, and NOESY) and HRESIMS data. To the best of our knowledge, compounds 2 , 3 , 5 , 7 , 8 , 11 , 12 , and 14 are reported from the Coriariaceae family for the first time, and compound 4 was isolated only from the Coriariaceae family. Importantly, compound 1 was identified as a new sesquiterpenoid. Furthermore, chemotaxonomic significance of these isolates was also discussed. • Fourteen compounds, including a new sesquiterpenoid (1), were isolated from the leaves of Coriaria nepalensis. • These compounds include triterpenoids, diterpenoids, sesquiterpenoids, phytosterols, α-tocopheroids, and vitamins. • Compounds 2 , 3 , 5 , 7 , 8 , 11 , 12 , and 14 are reported from the Coriariaceae family for the first time. [ABSTRACT FROM AUTHOR]

A new diterpenoid, 19-O-β-D-glucopyranosyl-labda-8(17),14-dien-13-ol (1), and nine known triterpenes (2-10) were isolated from the aerial parts of Tripterygium hypoglaucum. All structures were elucidated by NMR spectroscopic methods. Moreover, the inhibition of superoxide anion generation and elastase release were also examined. [ABSTRACT FROM AUTHOR]

Six previously undescribed diterpenoids, named euphorantins S–T and euphorneroids A–D, including ingol and ent -atisane types, along with eleven known diterpenoids, were isolated from Euphorbia neriifolia . Their structures were elucidated on the basis of extensive NMR analysis and high resolution mass spectrometry. Euphorneroid D and ent -3-oxoatisan-16 α ,17-acetonide exhibited moderate anti-HIV-1 activities, with EC 50 values of 34 μ M (SI = 2.3) and 24 μ M (SI = 1.9), respectively. [ABSTRACT FROM AUTHOR]

The phytochemical investigation of the roots of the traditional Chinese medicinal plant Sophora flavescens led to the isolation of two novel prenylflavonoids with an unusual cyclohexyl substituent instead of the common aromatic ring B, named 4′,4′-dimethoxy-sophvein (17) and sophvein-4′-one (18), and 34 known compounds (1–16, 19–36). The structures of these chemical compounds were determined by spectroscopic techniques, including 1D-, 2D-NMR, and HRESIMS data. Furthermore, evaluations of nitric oxide (NO) production inhibitory activity against lipopolysaccharide (LPS)-treated RAW264.7 cells indicated that some compounds exhibited obvious inhibition effects, with IC50 ranged from 4.6 ± 1.1 to 14.4 ± 0.4 μM. Moreover, additional research demonstrated that some compounds inhibited the growth of HepG2 cells, with an IC50 ranging from 0.46 ± 0.1 to 48.6 ± 0.8 μM. These results suggest that flavonoid derivatives from the roots of S. flavescens can be used as a latent source of antiproliferative or anti-inflammatory agents. [ABSTRACT FROM AUTHOR]

Two new iridoid glycosides, named productasperulosidic acid butyl ester (1) and E-6-O-3-hydroxy-p-methoxycinnamoyl scandoside methyl ester (2), along with nine known ones (3–11), were isolated from Hedyotis diffusa Willd. The structures of them were elucidated by extensive 1D, 2D NMR and HR-ESI-MS spectral data. Compounds 1–11 showed no significant cytotoxic activity against HeLa cells. [ABSTRACT FROM AUTHOR]

Phytochemical investigation of the root of Sophora flavescens Ait. led to the isolation of previously uncharacterized pterocarpan derivative sophoracarpanol A (1), along with eight known compounds, including seven pterocarpans (1 – 7) and two 2-arylbenzofurans (8 and 9). Their chemical structures were established based on extensive spectroscopic analysis. Among them, compounds 3 – 5 are the characteristic class of secondary metabolites of S. flavescens. And this is the first report of the presence of compounds 2 , 6 , and 7 from the genus Sophora and compounds 8 and 9 were firstly isolated from S. flavescens. Furthermore, the chemotaxonomic significance of the isolates was discussed. • Seven pterocarpans and two 2-arylbenzofurans were isolated from the roots of S. flavescens. • Interestingly, this study resulted in the isolation of a new pterocarpan derivative sophoracarpanol A. • Chemotaxonomic significance of these compounds was discussed. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has killed more than 4 million humans globally, but there is no bona fide Food and Drug Administration-approved drug-like molecule to impede the COVID-19 pandemic. The sluggish pace of traditional therapeutic discovery is poorly suited to producing targeted treatments against rapidly evolving viruses. Here, we used an affinity-based screen of 4 billion DNA-encoded molecules en masse to identify a potent class of virus-specific inhibitors of the SARS-CoV-2 main protease (Mpro) without extensive and time-consuming medicinal chemistry. CDD-1714, the initial three-building-block screening hit (molecular weight [MW] = 542.5 g/mol), was a potent inhibitor (inhibition constant [Ki] = 20 nM). CDD-1713, a smaller two-building-block analog (MW = 353.3 g/mol) of CDD-1714, is a reversible covalent inhibitor of Mpro (Ki = 45 nM) that binds in the protease pocket, has specificity over human proteases, and shows in vitro efficacy in a SARS-CoV-2 infectivity model. Subsequently, key regions of CDD-1713 that were necessary for inhibitory activity were identified and a potent (Ki = 37 nM), smaller (MW = 323.4 g/mol), and metabolically more stable analog (CDD-1976) was generated. Thus, screening of DNA-encoded chemical libraries can accelerate the discovery of efficacious drug-like inhibitors of emerging viral disease targets. [ABSTRACT FROM AUTHOR]

A phytochemical investigation on the aerial parts of Laggera pterodonta resulted in the isolation and identification of fourteen compounds, including six sesquiterpenoids (1 – 6), five flavonoids (7 – 11), one lignan (12), and two pyrrole alkaloids (13 , 14). Among them, compounds 1 – 3 , 7 – 9 , and 11 are the characteristic class of secondary metabolites of L. pterodonta. Compounds 4 and 5 were firstly isolated from L. pterodonta and this is the first report of the presence of compounds 6 , 10, and 12 from the genus Laggera. Pyrrole alkaloids 13 and 14 may serve as potential chemotaxonomic markers for L. pterodonta and could be used to distinguish among species of Compositae. • Fourteen compounds were isolated from the aerial parts of Laggera pterodonta. • The pyrrole alkaloids were isolated for the first time in the plants of Compositae. • Chemotaxonomic significance of these compounds was discussed. [ABSTRACT FROM AUTHOR]

Phytochemical investigation on the twigs and leaves of Lyonia ovalifolia led to the isolation of thirty-four compounds, including six grayanane diterpenoids ( 1–6 ), sixteen ursane triterpenoids and their glycosides ( 7–22 ), and twelve phenolic components ( 23–34 ). This study is the first report of compounds 1 , 4 , 5 and 7 – 34 in L. ovalifolia , while compounds 1 , 4 , 5 , 7 – 28 and 30 – 34 have not been recorded in the genus Lyonia previously. The structures of these compounds were elucidated using spectroscopic methods and by comparing their data to those reported in the literatures. The anti-HIV-1 and anti-influenza virus activities of compounds 1 – 7 , 10 – 14 , 16 , 18 – 22 , 24 , 25 , 30 – 34 were also evaluated. The chemotaxonomic significance of the isolates has been discussed. [ABSTRACT FROM AUTHOR]

Objective. In this report, we aim to describe the epidemiology of extended-spectrum cephalosporin-resistant (ESC-R) and carbapenem-resistant (CR) Enterobacteriaceae infections in children. Methods. ESC-R and CR Enterobacteriaceae isolates from normally sterile sites of patients aged <22 years from 4 freestanding pediatric medical centers were collected along with the associated clinical data. Results. The overall frequencies of ESC-R and CR isolates according to hospital over the 4-year study period ranged from 0.7% to 2.8%. Rates of ESC-R or CR Escherichia coli and Klebsiella pneumoniae varied according to hospital and ranged from 0.75 to 3.41 resistant isolates per 100 isolates (P < .001 for any differences). E coli accounted for 272 (77%) of the resistant isolates; however, a higher rate of resistance was observed in K pneumoniae isolates (1.78 vs 1.27 resistant isolates per 100 same-species isolates, respectively; P = .005). One-third of the infections caused by ESC-R or CR E coli were community-associated. In contrast, infections caused by ESC-R or CR K pneumoniae were more likely than those caused by resistant E coli to be healthcare- or hospital-associated and to occur in patients with an indwelling device (P ≤ .003 for any differences, multivariable logistic regression). Nonsusceptibility to 3 common non-β-lactam agents (ciprofloxacin, gentamicin, and trimethoprim-sulfamethoxazole) occurred in 23% of the ESC-R isolates. The sequence type 131-associated fumC/fimH-type 40-30 was the most prevalent sequence type among all resistant E coli isolates (30%), and the clonal group 258-associated allele tonB79 was the most prevalent allele among all resistant K pneumoniae isolates (10%). Conclusions. The epidemiology of ESC-R and CR Enterobacteriaceae varied according to hospital and species (E coli vs K pneumoniae). Both community and hospital settings should be considered in future research addressing pediatric ESC-R Enterobacteriaceae infection. [ABSTRACT FROM AUTHOR]

Direct inhibition of the protein--protein interaction of ERα and its endogenous coactivators with a cell permeable stabilized peptide may offer a novel, promising strategy for combating ERα positive breast cancers. Here, we report the co-crystal structure of a helical peptide stabilized by a N-terminal unnatural cross-linked aspartic acid (TD) in complex with the ERα ligand binding domain (LBD). We designed a series of peptides and peptide 6 that showed direct and high-affinity binding to ERα with selective antiproliferative activity in ERα positive breast cancer cells. The co-crystal structure of the TD-stabilized peptide 6 in complex with ERα LBD further demonstrates that it forms an α helical conformation and directly binds at the coactivator binding site of ERα. Further studies showed that peptide 6W could potently inhibit cellular ERα's transcriptional activity. This approach demonstrates the potential of TD stabilized peptides to modulate various intracellular protein--protein interactions involved in a range of disorders. [ABSTRACT FROM AUTHOR]

Background. Metagenomic next-generation sequencing (mNGS) has been used to uncover unusual causes of infectious diseases but has not been used routinely for the investigation of putative nosocomial outbreaks. Here, we describe the use of mNGS during investigation of a cluster of human rhinovirus (HRV)-positive infections on a high-risk pulmonary ward. Methods. We performed mNGS on 6 midnasal turbinate swabs from 4 case-patients and 10 swabs from 9 control outpatients that tested positive for enterovirus/rhinovirus by the FilmArray system. Results. HRV reads were recovered in 15 (94%) of the 16 samples sequenced. Phylogenetic analysis of HRV whole genomes from the 4 case-patients and 5 outpatient controls along with partial genomes from additional outpatient controls revealed that isolates from the case-patients were not directly related and that the 2 closest case HRV genomes had an estimated time to most recent common ancestor of 172 years. Our turnaround time from receipt of the sample to phylogenetic analysis was 24 hours. Conclusions. We found the use of mNGS downstream of a rapid polymerase chain reaction respiratory panel during an investigation of 4 hospital-acquired rhinovirus infections to rapidly dispel concern of a single-source transmission event. [ABSTRACT FROM AUTHOR]

The article presents a study which examines the chemical composition of the medicinal plant Viburnum (V.) betulifolium. The study uses the spectroscopic analysis to determine the structure of the 230 species of V. betulifolium from Caojian Town in Yunnan Province in China. Results show that the chemical composition of the plant includes lupeol, oleanolic acid, maslinic acid, and kaempferol.

Ten new neo -clerodane derivatives ( 1 – 10 ) and 10 known diterpenoids were identified from the aerial parts of Salvia leucantha . The structures of 1 – 10 were established by 1D and 2D NMR spectroscopic data analysis. The absolute configurations of 1 , 3 , 6 , and 7 were determined by X-ray diffraction data. Compound 16 exhibited cytotoxicity against HCT116, BT474, and HepG2 cancer cell lines and was identified as a heat shock protein 90 inhibitor. Compounds 8 , 15 , and 16 exhibited moderate acetyl cholinesterase inhibitory activity. [ABSTRACT FROM AUTHOR]

Seven new vibsane-type diterpenes, vibsanols C–H ( 1 – 6 ) and vibsanin X ( 7 ), together with seven analogues, were isolated from the leaves and twigs of Viburnum odoratissimum . The structures of the new compounds were elucidated by extensive spectroscopic methods. All the new compounds were detected for their cytotoxicity. Compound 1 showed significant cytotoxicity against all the tested cell lines (HL-60, SMMC-7721, A-594, MCF-7, and SW-480), with IC 50 values of 3.35, 4.41, 5.18, 11.30, and 3.70 μM, respectively. Compounds 4 and 5 also displayed significant cytotoxicity against hepatocellular carcinoma SMMC-7721 cell line, with IC 50 values of 3.69 and 3.52 μM, respectively. [ABSTRACT FROM AUTHOR]

The article focuses on children suffering from rhinoviral infections in tertiary pediatric emergency care. It states lower respiratory tract infection predictors such as coinfections or viral loads are not well characterized in child outpatients. It reports on samples collected from child patients with a subset of sampled tested with real-time polymerase chain reaction for rhinovirus viral load. It comments rhinovirus was the most frequent respiratory virus found in young children.

The molecular etiology of uterine leiomyosarcoma (ULMS) is poorly understood, which accounts for the wide disparity in outcomes among women with this disease. We examined and compared the molecular profiles of ULMS and normal myometrium (NL) to identify clinically relevant molecular subtypes. Discovery cases included 29 NL and 23 ULMS specimens. RNA was hybridized to Affymetrix U133A 2.0 transcription microarrays. Differentially expressed genes and pathways were identified using standard methods. Fourteen NL and 44 ULMS independent archival samples were used for external validation. Molecular subgroups were correlated with clinical outcome. Pathway analyses of differentially expressed genes between ULMS and NL samples identified overrepresentation of cell cycle regulation, DNA repair, and genomic integrity. External validation confirmed differential expression in 31 genes (P b 4.4 x 10-4, Bonferroni corrected), with 84% of the overexpressed genes, including CDC7, CDC20, GTSE1, CCNA2, CCNB1, and CCNB2, participating in cell cycle regulation. Unsupervised clustering of ULMS identified two clades that were reproducibly associated with progression-free (median, 4.0 vs 26.0 months; P = .02; HR, 0.33) and overall (median, 18.2 vs 77.2 months; P = .04; HR, 0.33) survival. Cell cycle genes play a key role in ULMS sarcomagenesis, providing opportunities for therapeutic targeting. Reproducible molecular subtypes associated with clinical outcome may permit individualized adjuvant treatment after clinical trial validation. [ABSTRACT FROM AUTHOR]

A phytochemical investigation on the leaves of Elsholtzia rugulosa resulted in the isolation and identification of thirty compounds, including four flavonoids (1–4), two benzene derivatives, two lignans (7 and 8), three phenylpropanoids (9–11), three phenolic acid (12–14), five sesquiterpenes (15–19), five nor-sesquiterpenes (20–24), one diterpenoids (25), and four monoterpenoids (26–30). Among of them, compounds 2–8 and 10–30 were firstly reported in the genus Elsholtzia , all compounds were originally obtained from Elsholtzia rugulosa. Furthermore, the anti-H1N1 activities of these compounds were evaluated in vitro. The results showed compounds 1 , 9 , 14 and 29 possessed moderate anti-influenza activity, with the inhibition rates (%) to be 49.69, 59.1, 48.21 and 44.99 at 100 μ g/mL, respectively. The chemotaxonomic significance of these isolated compounds has been discussed. • Thirty compounds were isolated from the leaves of Elsholtzia regulosa Hemsl. • Phytochemicals of Elsholtzia regulosa Hemsl were studied for the first time. • Chemotaxonomic significance of these compounds was discussed. • In vitro anti-H1N1 activities of these compounds were evaluated. [ABSTRACT FROM AUTHOR]

A chemical study of the 80% aqueous acetone extract of aerial parts of Setaria viridis led to the isolation of three new naphthol rhamnosides, 8-O-α-L-rhamnosyl-β-sorigenin ( 1), 6-hydroxy-8-O-α-L-rhamnosyl-β-sorigenin ( 2), and 6-methoxy-8-O-α-L-rhamnosyl-β-sorigenin ( 3), together with nine ( 4-12) known compounds. Their structures were established on the basis of spectroscopic data, including IR, MS, 1D, and 2D NMR. All the 12 compounds were tested for their antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, as well as antimicrobial activity. Compounds 1-3 exhibited strong antioxidant activity with IC values of 10.5, 13.8, and 15.3 μM, respectively, and modest activity against Staphylococcus aureus (ATCC 29213). [ABSTRACT FROM AUTHOR]

Abstract: Our previous study showed that citrate excretion coupled with a concomitant release of protons was involved in aluminum (Al) resistance in the broad bean. Furthermore, genes encoding plasma membrane (PM) H+-ATPase (vha2) and the 14-3-3 protein (vf14-3-3b) were up-regulated by Al in Al-resistant (YD) broad bean roots. In this study, the roles of PM H+-ATPase (E.C. 3.6.3.6) and the 14-3-3 protein in the regulation of citrate secretion were further investigated in Al-resistant (YD) and Al-sensitive (AD) broad bean cultivars under Al stress. The results showed that greater citrate exudation was positively correlated with higher activities of PM H+-ATPase in roots of YD than AD. Real-time RT-PCR analysis revealed that vha2 was clearly up-regulated by Al in YD but not in AD roots, whereas the transcription levels of vf14-3-3b were elevated in a time-dependent manner in both YD and AD roots. Immunoprecipitation and Western analysis suggested that phosphorylation and interaction with the vf14-3-3b protein of the VHA2 were enhanced in YD roots but not in AD roots with increasing Al treatment time. Fusicoccin or adenosine 5′-monophosphate increased or decreased the interaction between the phosphorylated VHA2 and the vf14-3-3b protein, followed by an enhancement or reduction of the PM H+-ATPase activity and citrate exudation in both cultivars under Al stress conditions, respectively. Taken together, these results suggested that Al enhanced the expression and interaction of the PM H+-ATPase and the 14-3-3 protein, which thereby led to higher activity of the PM H+-ATPase and more citrate exudation from YD plants. [Copyright &y& Elsevier]

Abstract: Three new norditerpenoids, castanol A–C (1–3), along with eighteen known diterpenoids, were isolated from Salvia castanea Diels f. pubescens. Their structures were elucidated by extensive spectroscopic analysis. All compounds were evaluated for their cytotoxic activities against five human cancer cell lines. The known compounds neo-tanshinlactone (12) and methyltanshinoate (17) exhibited significant cytotoxic activities against some cells. [Copyright &y& Elsevier]

Background: One-fifth of patients with seemingly 'curable' pancreatic ductal adenocarcinoma (PDA) experience an early recurrence and death, receiving no definable benefit from a major operation. Some patients with advanced stage tumors are deemed 'unresectable' by conventional staging criteria (e.g. liver metastasis), yet progress slowly. Effective biomarkers that stratify PDA based on biologic behavior are needed. To help researchers sort through the maze of biomarker data, a compendium of ,2500 published candidate biomarkers in PDA was compiled (PLoS Med, 2009. 6(4) p. e1000046). Methods and Findings: Building on this compendium, we constructed a survival tissue microarray (termed s-TMA) comprised of short-term (cancer-specific death <12 months, n = 58) and long-term survivors (>30 months, n = 79) who underwent resection for PDA (total, n = 137). The s-TMA functions as a biological filter to identify bona fide prognostic markers associated with survival group extremes (at least 18 months separate survival groups). Based on a stringent selection process, 13 putative PDA biomarkers were identified from the public biomarker repository. Candidates were tested against the s-TMA by immunohistochemistry to identify the best markers of tumor biology. In a multivariate model, MUC1 (odds ratio, OR = 28.95, 3+ vs. negative expression, p = 0.004) and MSLN (OR = 12.47, 3+ vs. negative expression, p = 0.01) were highly predictive of early cancer-specific death. By comparison, pathologic factors (size, lymph node metastases, resection margin status, and grade) had ORs below three, and none reached statistical significance. ROC curves were used to compare the four pathologic prognostic features (ROC area = 0.70) to three univariate molecular predictors (MUC1, MSLN, MUC2) of survival group (ROC area = 0.80, p = 0.07). Conclusions: MUC1 and MSLN were superior to pathologic features and other putative biomarkers as predicting survival group. Molecular assays comparing cancers from short and long survivors are an effective strategy to screen biomarkers and prioritize candidate cancer genes for diagnostic and therapeutic studies. [ABSTRACT FROM AUTHOR]

Multilocus sequence typing (MLST) is usually based on the sequencing of 5 to 8 housekeeping loci in the bacterial chromosome and has provided detailed descriptions of the population structure of bacterial species important to human health. However, even strains with identical MLST profiles (known as sequence types or STs) may possess distinct genotypes, which enable different ecoor pathotypic lifestyles. Here we describe a two-locus, sequence-based typing scheme for Escherichia coil that utilizes a 489-n ucleotide (nt) internal fragment offimH (encoding the type 1 fimbrial adhesin) and the 469-nt internal fumC fragment used in standard MLST. Based on sequence typing of 191 model commensal and pathogenic isolates plus 853 freshly isolated clinical E. coii strains, this 2-locus approach-which we call CH (fumçlfimff) typing-consistently yielded more haplotypes than standard 7-locus MLST, splitting large STs into multiple clonal subgroups and often distinguishing different within-ST ecoand pathotypes. Furthermore, specific CH profiles corresponded to specific STs, or ST complexes, with 95% accuracy, allowing excellent prediction of MLST-based profiles. Thus, 2-locus CH typing provides a genotyping tool for molecular epidemiology analysis that is more economical thah standard 7-locus MLST but has superior clonal discrimination power and, at the same time, corresponds closely to MLST-based clonal groupings. [ABSTRACT FROM AUTHOR]

The article provides information on a retrospective study which determined statistically the likelihood of response to a given salvage therapy in different clinical subsets of pediatric patients with chemoresistant neuroblastoma (NB). A background on the clinical characteristics of patients treated with high-dose cyclophosphamide, topotecan, and vincristine (HD-CTV) is given. A discussion on the research findings is detailed.

Background. We evaluated the frequency of recovery of pathogens from children with diarrhea who presented to a pediatric emergency department and characterized the associated illnesses, to develop guidelines for performing a bacterial enteric culture. Methods. We conducted a prospective cohort study of all patients with diarrhea who presented to a large regional pediatric emergency department during the period from November 1998 through October 2001. A thorough microbiologic evaluation was performed on stool specimens, and the findings were correlated with case, physician, and laboratory data. Results. A total of 1626 stool specimens were studied to detect diarrheagenic bacteria and, if there was a sufficient amount of stool, Clostridium difficile toxin (688 specimens), parasites (656 specimens), and viruses (417 specimens). One hundred seventy-six (47%) of 372 specimens that underwent complete testing yielded a bacterial pathogen (Shiga toxin-producing Escherichia coli, 39 specimens [of which 28 were serotype O157:H7]; Salmonella species, 39; Campylobacter species, 25; Shigella species, 14; and Yersinia enterocolitica, 2), a viral pathogen (rotavirus, 85 specimens; astrovirus, 27; adenovirus, 18; or rotavirus and astrovirus, 8), a diarrheagenic parasite (5 specimens); or C. difficile toxin (46 specimens). Samples from 2 patients yielded both bacterial and viral pathogens. A model to identify predictors of bacterial infection found that international travel, fever, and the passing of 110 stools in the prior 24 h were associated with the presence of a bacterial pathogen. Physician judgment regarding the need to perform a stool culture was almost as accurate as the model in predicting bacterial pathogens. Conclusions. Nearly one-half of the patients who presented to the emergency department with diarrhea had a definite or plausible pathogen in their stool specimens. We were unable to develop a model that was substantially better than physician judgment in identifying patients for whom bacterial culture would yield positive results. The unexpectedly high rate of C. difficile toxin warrants further examination. [ABSTRACT FROM AUTHOR]

[Display omitted] • Four underscribed ent -kaurane and three undescribed abietane diterpenoids were isolated from T. wilfordii. • Compounds 1 and 2 were a pair of C-19 epimers of ent -kaurane diterpenoids. Compound 3 possessed a rare naturally occurring 1,3-dioxacyclohexane moiety. • Abietane diterpenoids 7 – 13 showed significant activity to inhibit NO production. • Compounds 7 and 8 significantly suppressed the protein expression of iNOS and COX-2. Four undescribed ent -kaurane diterpenoids, wilkaunoids A − D (1 – 4), and three undescribed abietane diterpenoids, wilabinoids A − C (13 – 15), along with thirteen known ones (5 – 12 and 16 – 20), were isolated from Tripterygium wilfordii. Their structures were elucidated by extensive spectroscopic methods, electronic circular dichroism calculation, and X-ray diffraction analysis. Compounds 1 and 2 were a pair of C-19 epimers of ent -kaurane diterpenoids, featuring a rare 19,20-epoxy-19,20-dimethoxy-kaurane fragment. Compound 3 possessed a rare naturally occurring 1,3-dioxacyclohexane moiety. Compounds 13 and 15 represented the first example of abietane diterpenoids with an isovalerate substitution from the genus of Tripterygium. The possible biosynthetic pathways of 1 – 3 were postulated. The effect of 1 – 20 on nitric oxide production was examined in lipopolysaccharide-stimulated RAW 264.7 cells. Abietane diterpenoid quinones 7 – 13 (IC 50 : 1.9–10.2 μM) exhibited the significant activity to inhibit nitric oxide production versus positive control (NG-monomethyl- l -arginine acetate salt, IC 50 = 24.9 μM). The structure activity relationship of 7 – 13 in inhibiting nitric oxide production was then discussed. The most potent 7 and 8 were found to significantly suppress the expression of cyclooxygenase-2 and inducible nitric oxide synthase proteins, showing a good anti-inflammatory potential. The findings provided some valuable insights for the discovery and structural modification of abietane diterpenoids towards anti-inflammatory lead compounds. [ABSTRACT FROM AUTHOR]

Twelve ent -isopimarane diterpenoids, including six undescribed ones, eupnerias J−O, were isolated from the stem barks of Euphorbia neriifolia L. Structurally, eupnerias J−M were the first examples of 18 (or 19)-norditerpenoid with ent -isopimarane skeleton from E. neriifolia. The absolute configuration of eupneria J was established based on the X-ray diffraction analysis and the experimental and calculated electronic circular dichroism (ECD), while the absolute configuration of eupnerias K–N were determined by the experimental and calculated ECD. In addition, the absolute configuration of the known compound, 3 β -hydroxysandaracopimaric acid, was determined by comparing its ECD spectrum with eupneria J, and renamed as eupneria P. Furthermore, eupneria J and eurifoloid H showed significant anti-HIV-1 activities with IC 50 values of 0.31 and 6.70 μ g/mL, respectively, and ent -isopimara-8(14),15-dien-3 β ,12 β -diol possessed obvious anti-influenza virus activity against A/Puerto Rico/8/1934, with an IC 50 at 3.86 μ g/mL. Image 1 • Six undescribed ent -isopimarane diterpenoids were isolated from E. neriifolia. • Eupnerias J-M possessed ent -18 (or 19)-nor-isopimarane diterpenoid skeleton. • Eupneria J and eurifoloid H showed significant anti-HIV-1 activity. • Ent -isopimara-8(14),15-dien-3 β ,12 β -diol had obvious anti-influenza virus activity. [ABSTRACT FROM AUTHOR]

Androforin A (I) and hyperandrone A (II) are isolated from the aerial parts together with a series of known constituents. [ABSTRACT FROM AUTHOR]