Search

Next-generation sequencing (NGS) analysis of thyroid samples aids in risk stratification of cytologically indeterminate nodules and contributes to our understanding of molecular mechanisms in thyroid neoplasia. Several genes, including BRAF, RAS , and EIF1AX , are known to play a role in thyroid tumorigenesis. Here we report a case of papillary thyroid carcinoma (PTC) in which a single lesion harbored a novel YWHAG-BRAF fusion and EIF1AX mutation and displayed mixed morphological findings. The patient is a 74-year-old female with multiple incidentally discovered thyroid nodules, two of which were sampled by ultrasound-guided fine needle aspiration (FNA). Cytologic diagnosis for both nodules was suspicious for follicular neoplasm (Bethesda Category IV). NGS testing of one nodule detected a novel in-frame YWHAG-BRAF fusion and a concurrent EIF1AX A113 splice mutation. The subsequent surgical resection specimen showed that this nodule exhibited two distinct morphologic patterns, conventional (classical) type and follicular variant (FV) of PTC, which were sharply demarcated and were found to harbor unique genetic alterations. Of note, this is the first report of BRAF activation through novel rearrangement with a gene encoding a 14–3–3 protein as a pathogenic factor, which underlines its significance both as a prognostic measurement and as a therapeutic target. [ABSTRACT FROM AUTHOR]

The aim of this work is to investigate the assembly of foxtail millet prolamin (FP) with chitosan hydrochloride (CHC) and carboxymethyl-beta-cyclodextrin (CMCD) in acetic acid aqueous solutions. The proportion of acetic acid has a positive impact on the disintegration of FP. With the use of 91.0 % (v /v) acetic acid, FP forms smaller particles of approximately 45 nm (naked FP particles) and 220 nm (FP − CHC − CMCD hybrid particles). In the case of using 61.5 % (v /v) acetic acid, the microstructures of bare FP particles and 570 nm composite FP nanoparticles (NPs) are looser, about 485 nm. Acetic acid inhibits the noncovalent bonds, including the hydrophobic interactions, hydrogen bonding and electrostatic attractions between FP and polysaccharides. Therefore, 3.8 % (v /v) acetic acid can nucleate FP to form more compact FP hybrid particles for delivering curcumin (Cur) with higher encapsulation efficiency, storage stability and release performance, and improve the antibacterial and anticancer activity of Cur. [Display omitted] • Acetic acid had a positive effect on the disintegration and dissolution of FP. • Acetic acid had a negative effect on the binding strength between polysaccharides and FP. • Acetic acid affected the encapsulation process via promoting the unfolding of FP to interact with Cur. • Acetic acid was a better solvent for the fabrication of Cur − loaded FP − based nanoparticles. [ABSTRACT FROM AUTHOR]

The high hydrophobicity of prolamin results in the mucoadhesive properties, enabling it suitable for oral delivery. Prolamin could self-assemble into nanospheres for a variety of hydrophobic and hydrophilic bioactive substances after the quality of solvent used to dissolve prolamin is reduced. Significant and emerging nanotechnologies tremendously contribute the preparation of prolamin-based nanomaterials with various microstructures and different characteristics, presenting the structure-activity relationship. Considering the structure-activity relationship, this review focuses on solid, hollow, solid/hollow core-shell, solid/hollow co-assembled, and layer-by-layer co-assembled/coated prolamin-based nanostructures for the encapsulation of bioactive molecules. The fabricated nanoparticles with various microstructures frequently affect the performances of prolamin-based nanoparticle. Moreover, due to the different microstructures resulted from various fabrication processes, bioactive substances with varied polarities are often entrapped into the different nanoparticle regions via polarity mediation, thus subsequently exhibiting diverse advantages and disadvantages. This review examined the nanostructures of prolamin-based particles achieved by different preparation technologies. The effects of different treatments such as acid, alkali, and heating on changing the microstructure, improving the physicochemical stability, and enhancing the biological activity of encapsulated particles are discussed, with the purpose to inspire the development of novel prolamin-based nanoparticles for improving the particle performances. By encapsulating functional compounds into the prolamin-based nanoparticles, their solubility/dissolution, gastrointestinal stability, retention in gastrointestinal tract and permeability are obviously enhanced, thereby improving oral bioavailability. Finally, trends of fabricating prolamin nanoparticles with improved performances are detailed in aid of the preparation of novel nanostructures. [Display omitted] • The degree of disintegration of prolamin is crucial for producing bioactive-loaded NPs. • Various prolamin microstructures with different advantages are examined. • Microstructure affects the encapsulation process and distribution of bioactives in the prolamin NPs. • Prolamin particles with different structures in improving oral bioavailability were reviewed. • The production of novel particle structure with improved performance are prospected. [ABSTRACT FROM AUTHOR]

Multifocal non–small cell lung cancer has historically been separated into synchronous primary lung cancers or intrapulmonary metastases with the use of histopathology. We hypothesize that using targeted next-generation sequencing of key driver mutations in multifocal non–small cell lung cancer will improve our ability to differentiate intrapulmonary metastases from synchronous primary lung cancers. We identified patients who underwent surgery for non–small cell lung cancer between 2013 and 2018 with multifocal tumors. Archived specimens were reviewed with a 4-gene next-generation sequencing panel identifying mutations of EGFR, KRAS, BRAF, and NRAS. Synchronous primary lung cancers were classified as lesions with different histopathologic subtypes or driver mutations. Tests of hypotheses were performed with the Fisher exact test. Calculations were performed in Stata (v13.0; StataCorp LLC, College Station, Tex). A total of 18 patients had non–small cell lung cancer tumor specimens (n = 41) available from 2 or more sites. The pathologic diagnosis was predominantly adenocarcinoma (39/41 specimens). We detected a driver mutation in 68.3% (28/41) of all tumors. The most common mutations observed were in KRAS (n = 17/41) and EGFR (n = 7/41). Eleven patients had synchronous primary lung cancers, and 4 patients had intrapulmonary metastases based on combined histopathologic and molecular profiling results. Three lacked driver mutations in either lesion. Eight synchronous primary lung cancers (8/18, 44%) were downstaged when compared with their original diagnosis (P =.08). Of these, 4 patients received adjuvant chemotherapy unnecessarily in hindsight. Molecular non–small cell lung cancer profiling using a 4-gene next-generation sequencing panel allows for better distinction between synchronous primary lung cancers and intrapulmonary metastases than histopathology alone. Routine use of next-generation sequencing for multifocal lesions prevents unnecessary adjuvant treatment for patients with histologically similar synchronous primary lung cancers. [ABSTRACT FROM AUTHOR]

Bioethanol is a renewable biofuel that has a strong inhibitory effect on cells in bioethanol fermentation by yeast. In this study, carbon nanotube (CNT)-mixed polydimethylsiloxane (PDMS) membranes were used for ethanol recovery from model solutions as well as for fermentation by self-flocculating yeast. Imbedding CNTs into the PDMS membrane led to enhanced ethanol recovery, with a maximum total flux of 128.7 g/m 2 h and an ethanol titer of 615.1 g/L in permeate. The CNTs can provide a flexible route for ethanol transport through the inner tubes or along the smooth surface. In fed-batch fermentation incorporating pervaporation, 112.3 g/L of ethanol was produced with an overall ethanol productivity and yield of 2.23 g/L h and 0.45 g/g, respectively. The membrane produced a highly concentrated condensate containing 400.3–487.5 g/L of ethanol. Furthermore, as yeast flocs can be throttled down in the bioreactor, self-flocculating yeast can be used to prevent membrane fouling induced by cell adsorption on the membrane. Therefore, the CNT-mixed membrane coupled with ethanol fermentation by self-flocculating yeast not only reduces ethanol-mediated inhibition of cells but also saves the production cost because of the reduced fouling risk. Thus, this combination approach has potential in industrial bioethanol production for long-time operation. [ABSTRACT FROM AUTHOR]

In traditional Chinese medicine, a long term of improper diet causes the Dampness and disturbs Zang-Fu's functions including Kidney deficiency. Atractylodes lancea (Atr) and Magnolia officinalis (Mag) as a famous herb pair are commonly used to transform Dampness, with kidney protection. To explore how Atr and Mag protected against insulin signaling impairment in glomerular podocytes induced by high dietary fructose feeding, a major contributor for insulin resistance in glomerular podocyte dysfunction. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyze constituents of Atr and Mag. Rat model was induced by 10% fructose drinking water in vivo , and heat-sensitive human podocyte cells (HPCs) were exposed to 5 mM fructose in vitro. Animal or cultured podocyte models were treated with different doses of Atr, Mag or Atr and Mag combination. Western blot, qRT-PCR and immunofluorescence assays as well as other experiments were performed to detect adiponectin receptor protein 1 (AdipoR1), protein kinase B (AKT), Sirt1, p53 and miR-221 levels in rat glomeruli or HPCs, respectively. Fifty-five components were identified in Atr and Mag combination. Network pharmacology analysis indicated that Atr and Mag combination might affect insulin signaling pathway. This combination significantly improved systemic insulin resistance and prevented glomerulus morphological damage in high fructose-fed rats. Of note, high fructose decreased IRS1, AKT and AdipoR1 in rat glomeruli and cultured podocytes. Further data from cultured podocytes with Sirt1 inhibitor/agonist, p53 agonist/inhibitor, or miR-221 mimic/inhibitor showed that high fructose downregulated Sirt1 to stimulate p53-driven miR-221, resulting in insulin signaling impairment. Atr and Mag combination effectively increased Sirt1, and decreased p53 and miR-221 in in vivo and in vitro models. Atr and Mag combination improved insulin signaling in high fructose-stimulated glomerular podocytes possibly through upregulating Sirt1 to inhibit p53-driven miR-221. Thus, the regulation of Sirt1/p53/miR-221 by this combination may be a potential therapeutic approach in podocyte insulin signaling impairment. [Display omitted] • High fructose increased miR-221, causing impairment of podocyte insulin signaling. • Atr and Mag improved insulin signaling by inhibiting Sirt1/p53-driven miR-221. • Atr and Mag combination restored podocyte injury more significantly than alone. [ABSTRACT FROM AUTHOR]

There was an increase in the Clostridium difficile infection (CDI) rate in our bone marrow transplantation unit. To evaluate the role of unit-based transmission, C. difficile screening was performed on adult patients admitted for hematopoietic stem cell transplantation (HSCT) over a 2-year period, and C. difficile isolates were typed. C. difficile testing was performed using a 2-step C. difficile glutamate dehydrogenase antigen plus toxin A/B enzyme immunoassay (EIA) and cytotoxin assay (or molecular toxin assay). Multilocus sequence typing (MLST) was performed on toxin-positive whole stool samples. A retrospective chart review was performed on all patients with a positive toxin assay. Sixteen of 150 patients (10.7%) had toxigenic C. difficile colonization (CDC) on admission. The overall incidence of CDI within 100 days after HSCT was 24.7% (37 of 150). The median time to diagnosis of CDI was 3.5 days after HSCT. In an adjusted logistic regression model, CDC on admission was a significant risk factor for CDI (odds ratio, 68.5; 95% confidence interval, 11.4 to 416.2). MLST on 22 unit patient toxin-positive stool specimens revealed 15 distinct strain types. Further analysis identified at least 1 potential cross-transmission event; some events may have been missed because of incomplete typing from other specimens. Despite aggressive infection control interventions, there was no decline in the number of CDI cases during the study period. These data suggest that prior CDC plays a major role in CDI rates in this high-risk patient population. It remains unclear if CDI was cross-transmitted in the unit. [ABSTRACT FROM AUTHOR]

• Two generations of garnet under eclogite and granulite facies conditions were identified. • Zircon cores and rims grew under eclogite and granulite facies conditions, respectively. • Garnet and zircon have different behaviors under eclogite and granulite facies conditions. • The metabasites experienced a clockwise P-T-t evolution with an increase of metamorphic thermal gradients. • HREE zircon/garnet partitioning for a direct link between metamorphic zircon and garnet was evaluated. A combined study of garnet and zircon from the same growth stages can provide effective constraints on the pressure–temperature-time path of metamorphic processes. This is illustrated by distinguishing different episodes of garnet and zircon in metabasites from North Qaidam. Two different garnet domains grown under eclogite- and granulite-facies conditions were recognized to have different trace elements and inclusions. The variable trace elements are ascribed to the coexisting MREE-rich minerals and whole-rock compositions under eclogite-facies conditions, and to variable growth of feldspar and consumption of precursor garnet at the continuous granulite facies metamorphism. The majority of zircon cores with ages of 430–441 Ma and zircon rims with ages of 419–424 Ma record metamorphism at eclogite-facies and granulite-facies, respectively. They exhibit different trace elements and Hf-O isotopes, indicating zircon growth via different mechanisms with differential involvement of precursor zircon and other minerals as well as anatectic melts under eclogite- and granulite-facies conditions. The metabasites experienced an increase of metamorphic thermal gradients with time and thus the tectonic transition from deeply continental subduction for Alpine-type HP to UHP eclogite-facies metamorphism at 2.6–3.1 GPa and 827–864 °C through decompressional exhumation to the lower crust for Barrovian-type HP granulite-facies overprinting at 1.05–1.70 GPa and 725–872 °C, eventually to extensional exhumation to the mid-crustal level for Buchan-type low-pressure amphibolite-facies overprinting at 0.34–0.56 GPa and 528–667 °C in the collisional orogen. While HREE disequilibrium between the two minerals is common, the equilibrium HREE partitioning may be achieved between zircon and garnet rims during crustal anatexis at the late HP granulite-facies metamorphism. [ABSTRACT FROM AUTHOR]

The occurrence of microplastics was investigated in water, sediment and fish from the Fengshan River system. All collected samples contained microplastics with 334–1058 items/m3 in the water samples, 508-3987 items/kg dry weight in the sediment samples and 14–94 items/fish in the fish samples. The spatial distribution of microplastics in water and sediments was attributed to anthropogenic discharges, flow dynamics, tidal exchanges and microplastic density. This was evidenced by significant correlations of microplastics with the river pollution index (RPI), chemical oxygen demand (COD), suspended solid (SS), flow velocity and the presence of different polymer types of microplastics in water and sediment. Microplastic abundance in fish was correlated to SS, pH and conductivity, indicating that these water quality variables might affect bioavailability of microplastics to fish. Concentrations of microplastics/cm length of demersal fish at a higher trophic level (Leiognathus equulus and Pomadasys argenteus) were higher than those of a benthopelagic fish (Oreochromis niloticus niloticus). The significant relationships observed suggest that collected fish might prefer to ingest long fibrous microplastics from sediments and large fragmented microplastics from water. The high levels of 3- and 4-ring polycyclic aromatic hydrocarbons (PAHs), particularly fluoranthene and pyrene, in fish muscle revealed that the collected fish species might have a high ability to accumulate these PAHs from food and the environment. Significant relationships between some PAHs in fish and microplastic abundances in water/sediments/fish suggested that these PAHs might be accumulated by fish from contaminated microplastics. This study provides unique information on the factors influencing the spatial distribution of microplastics and the role of microplastics on the accumulation of PAHs by fish. Image 1 • Factors affecting microplastics distribution in an urban river were determined. • Microplastic abundance was correlated to some water quality variables. • Demersal fish contained higher levels of microplastic than benthopelagic fish. • Accumulation of some PAHs by fish might be from contaminated microplastics. Distribution and the role of microplastics in an urban river. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM), a cancer of plasma cells, is the second most common hematological malignancy which is characterized by aberrant plasma cells infiltration in the bone marrow and complex heterogeneous cytogenetic abnormalities. Over the past two decades, novel treatment strategies such as proteasome inhibitors, immunomodulators, and monoclonal antibodies have significantly improved the relative survival rate of MM patients. However, the development of drug resistance results in the majority of MM patients suffering from relapse, limited treatment options and uncontrolled disease progression after relapse. There are urgent needs to develop and explore novel MM treatment strategies to overcome drug resistance and improve efficacy. Here, we review the recent small molecule therapeutic strategies for MM, and introduce potential new targets and corresponding modulators in detail. In addition, this paper also summarizes the progress of multi-target inhibitor therapy and protein degradation technology in the treatment of MM. [Display omitted] • The current challenges and urgency of drug resistance in multiple myeloma (MM). • Emerging potential targets and innovative therapeutic strategies to overcome drug resistance in MM. • Mechanisms of action, structure-activity relationships, binding-modes to targets and efficacy of novel anti-MM drugs. [ABSTRACT FROM AUTHOR]

Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influence gene expression patterns and affect the function and development of the nervous system. The present promoter-based methylation microarray profiling study explored the extent to which developmental Pb exposure may modify the methylome of a brain region, hippocampus, known to be sensitive to the effects of Pb exposure. Male and female Long Evans rats were exposed to 0 ppm, 150 ppm, 375 ppm, or 750 ppm Pb through perinatal exposures (gestation through lactation), early postnatal exposures (birth through weaning), or long-term postnatal exposures (birth through postnatal day 55). Results showed a significant contribution of sex to the hippocampal methylome and effects of Pb exposure level, with non-linear dose response effects on methylation. Surprisingly, the developmental period of exposure contributed only a small amount of variance to the overall data and gene ontology (GO) analysis revealed the largest number of overrepresented GO terms in the groups with the lowest level of exposure. The highest number of significant differentially methylated regions was found in females exposed to Pb at the lowest exposure level. Our data reinforce the significant effect that low level Pb exposure may have on gene-specific DNA methylation patterns in brain and that this occurs in a sex-dependent manner. [ABSTRACT FROM AUTHOR]

Grinding forces are a key parameter in the grinding process, most previous studies on grinding forces, however, (i) were regardless of grain-workpiece micro interaction statuses and (ii) could only predict average/maximal grinding forces based on average/maximal cutting depths or chip thicknesses. In this study, a novel detailed modeling methodology of grinding forces has been analytically established, experimentally validated and utilised to study a specific issue that previous methods can not address. Based on the proposed method, grinding forces with detailed information (e.g. three components including rubbing, plowing and cutting forces) could be accurately predicted. Except for grinding forces, the proposed methodology also enable the availability of other grinding process details at the grain scale (e.g. the ratios of grains that are experiencing rubbing, plowing and cutting stages to the total engaging grain number). Validation experiment results have proved that, the proposed method could, to a large extent, describe the realistic grinding forces. Based on the proposed method, the effects of grinding conditions (including depths of cut, wheel speeds, workpiece feed speeds and grinding wheel abrasive sizes) on each component of grinding forces (rubbing, plowing, and cutting forces) have been analyzed. Some new findings, which could enhance the existing understandings of grinding forces and guide industrial manufacture, have been gained. The proposed method therefore is anticipated to be not only meaningful to provide a new way to model grinding forces in detail, but also promising to study other grinding issues (e.g. grinding heat, machined surface topography, grinding chatter), especially under the trend of miniaturization and microfabrication where grinding details at the grain scale are highly needed to optimise the micro grinding tool efficiency and micro-grinding accuracy. [ABSTRACT FROM AUTHOR]

Thanks to the superior machined surface integrity, high machining feasibility, and limited tool wear, the Abrasive Air Jet Polishing (AAJP) has been considered as a widely used finishing process, especially for high-valued small and complex optics products. Therefore, many experimental, theoretical and processing technology studies have focused on this topic. However, experimental studies cannot provide an in-depth understanding of the process principle while most of the theoretical models/methods have been established based on many unrealistic assumptions. To fill this gap, this paper suggests an analytical model of the polished surface topography (or footprint) considering (i) the horizontally asymmetric cross-section profiles of a single-abrasive impact footprint, (ii) the abrasive-workpiece elastic deformation and further springback when the abrasive bounces back, and (iii) the overlapping footprints generated by multiple abrasives having a normal-distributed size. The systematic validation trials proved the model accuracy and feasibility. Based on the validated model, the effects of the polishing parameters including the jet pressure, jet angle, and abrasive size on both machined surface roughness and removed material volume are studied. The proposed model is anticipated for not only exploring and laying the theoretical foundation of the AAJP process in more depth, but also to provide guidance for industrial manufacturing in terms of polishing parameter optimization and polished surface prediction. • This paper proposes the analytical model of footprints in abrasive air jet polishing of optical glass. • Experimental Validation is also performed, proving the model feasibility and accuracy. • The springback of the elastic deformation on the workpiece surface can be large and therefore should not be ignored. • There are three possibilities for the overlapping between successive impacting abrasives. [ABSTRACT FROM AUTHOR]

The therapeutic benefits of available FLT3 inhibitors for AML are limited by drug resistance, which is related to mutations, as well toxicity caused by off-target effects. In this study, we introduce a new small molecule FLT3 inhibitor called danatinib, which was designed to overcome the limitations of currently approved agents. Danatinib demonstrated greater potency and selectivity, resulting in cytotoxic activity specific to FLT3-ITD and/or FLT3-TKD mutated models. It also showed a superior kinome inhibition profile compared to several currently approved FLT3 inhibitors. In diverse FLT3-TKD models, danatinib exhibited substantially improved activity at clinically relevant doses, outperforming approved FLT3 inhibitors. In vivo safety evaluations performed on the granulopoiesis of transgenic myeloperoxidase (MPO) zebrafish and mice models proved danatinib to have an acceptable safety profile. Danatinib holds promise as a new and improved FLT3 inhibitor for the treatment of AML, offering long-lasting remissions and improved overall survival rates. [Display omitted] • Danatinib displayed increased potency and selectivity. • Danatinib showed a superior kinome inhibition profile. • Danatinib significantly enhanced activity at clinically relevant doses. • Danatinib had an acceptable safety profile. [ABSTRACT FROM AUTHOR]

[Display omitted] • This is the first study to estimate the impacts of wildfires on snow melt in the San Joaquin watershed. • Spatiotemporal visual variations in SWE were mapped in the San Joaquin watershed. • Random forest and deep analytics were performed to examine the SWE in the San Joaquin watershed. • Wildfires have increased the speed of snowmelt and shortened the timing of water availability. • The correlation between fire severity and SWE values was determined to be strongly positive. Farmers and ranchers living in snow mountainous regions heavily rely on melting snow for agricultural irrigation. However, major natural disturbances, such as wildfires, have markedly reduced melt durations, disrupting the local hydrological cycle. In this study, we estimate the impacts of wildfires on snow accumulation and retention in the San Joaquin watershed of Sierra Nevada around California during the 2000 to 2016 water year through spatiotemporal visual variations in the snow water equivalent (SWE). To better explore the relationship between SWE and wildfire, machine learning methods, including regression analysis and deep analytics, were performed to examine the original remote sensing dataset of SWE in the San Joaquin watershed. The results suggested that wildfires have greatly increased the speed of snowmelt and shortened the timing of water availability, which may result in water resource shortages. We also comparatively analyzed the peak SWE values in each year, in which two water year groups (group (1): 2000–2003, group (2): 2013–2016) were selected and compared based on the frequency of major wildfires. Interestingly, higher fluctuations in SWE curves were observed from 2010 to 2016 than from 2000 to 2003, which suggested that the frequency of wildfires was much higher in recent years than in the past twenty years. Ultimately, the correlation between fire severity and SWE values was determined to be strongly positive (p < 0.05). Overall, our study provides visual-mathematical perspectives for local ecology management authorities to understand the most related factors behind the shortened melt duration. [ABSTRACT FROM AUTHOR]

• Coqen zircon xenocrysts were originated from ancient recycled continental crustal. • Zircons record the temporal evolution of magmatism and crustal thickness in Coqen. • Lhasa terrane evolutionary process is restored by these zircon xenocrysts. The Cenozoic volcanic rocks of Coqen are located in the western central Lhasa subterrane, where knowledge of the regional lithospheric architecture and related magmatic processes is still lacking. To address this issue, we used in situ U–Pb dating, Lu–Hf isotopic and mineral inclusion analysis in zircon xenocrysts among trachyandesite. These zircons from volcanic samples yielded wide U–Pb ages from 18 Ma to 2424 Ma, showing three significant age peaks at ∼ 246 Ma, 193 Ma, and the most intense one at 128 Ma, which represent three major magmatic processes that developed in the area. The earliest zircon dates suggest the age of volcanic eruption in the Coqen area was not earlier than 18 Ma. Zircon xenocrysts trace elements data point to the continental crust origin of central Lhasa subterrane. We provide the evidence for evolutive magmatism of the Lhasa terrane by calculating ΔFMQ, and show that the oxygen fugacity goes from reduced to oxidized (Cambrian to Miocene). The very low ε Hf (t) indicate a long-term magmatic event sequence, with the Zenong Group having the most vigorous magmatic activity. The old U–Pb ages and T DM C confirmed that an ancient basement of the Precambrian exist in the middle Lhasa terrane. Our work also restores the tectonic and crustal thickness evolutionary process of Coqen area even entire Lhasa terrane. In the back of a series of thickening and thinning processes, the Tibetan crust drastically thickened at ∼ 54 Ma, and gradually created what is now believed to be the thickest crust in the world. [ABSTRACT FROM AUTHOR]

We have evaluated and validated the NXType™ workflow (One Lambda, Inc.) and the accompanying TypeStream™ software on the Ion Torrent Next Generation Sequencing (NGS) platform using a comprehensive testing panel. The panel consisted of 285 genomic DNA (gDNA) samples derived from four major ethnic populations and contained 59 PT samples and 226 clinical specimens. The total number of alleles from the six loci interrogated by NGS was 3420. This validation panel provided a wide range of HLA sequence variations including many rare alleles, new variants and homozygous alleles. The NXType™ system (reagents and software) was able to correctly genotype the vast majority of these specimens. The concordance rate between SBT-derived genotypes and those generated by TypeStream™ auto-analysis ranged from 99.5% to 99.8% for the HLA-A, B, C, DRB1 and DQB1 loci, and was 98.9% for HLA-DPB1. A strategy for data review was developed that would allow correction of most of the few remaining typing errors. The entire NGS workflow from gDNA amplification to genotype assignment could be completed within 3 working days. Through this validation study, the limitations and shortcomings of the platform, specific assay system, and software algorithm were also revealed for further evaluation and improvement. [ABSTRACT FROM AUTHOR]

Hybridization of nitric oxide (NO) donors with known anti-cancer agents have been emerged as a strategy to achieve improved therapeutic effect and to overcome chemo-resistance in cancer therapy. In this study, furoxan moiety as an efficient NO donor was introduced to phenstatin, a microtubule-interfering agent (MIA), leading to the design and synthesis of a series of furoxan-based NO-releasing arylphenones derivatives. In biological evaluation, the synthesized compounds showed moderate to potent anti-tumor activities against several human cancer cell lines. Among them, compound 15h showed the most potent activities against both chemo-sensitive and resistant cancer cell lines with IC 50 values ranging from 0.008 to 0.021 μM. Further mechanistic studies revealed that 15h worked as a bifunctional agent exhibiting both tubulin polymerized inhibition and NO-releasing activities, resulting in potent anti-angiogenesis, colony formation inhibition, cell cycle arrest and apoptosis induction effects. In the nude mice xenograft model, 15h significantly inhibited the paclitaxel-resistant tumor growth with low toxicity, demonstrating the promising potential for further preclinical evaluation as a therapeutic agent, particularly for the treatment of chemo-resistant cancers. [Display omitted] • A series of furoxan-based NO-releasing arylphenones derivatives were synthesized and evaluated for anti-tumor activities. • Compound 15h showed enhanced anti-tumor activities on both chemo-sensitive and resistance cells in vitro and in vivo. • Compound 15h exhibited bifunctional effects on both tubulin polymerization and NO-releasing. [ABSTRACT FROM AUTHOR]

Abstract: The design and synthesis of novel non-peptide CXCR4 antagonists is described. The peptide backbone of highly potent cyclic peptide-based CXCR4 antagonists was entirely replaced by an indole framework, which was expected to reproduce the disposition of the key pharmacophores consistent with those of potential bioactive conformations of the original peptides. A structure–activity relationship study on a series of modified indoles identified novel small-molecule antagonists having three pharmacophore functional groups through the appropriate linkers. [Copyright &y& Elsevier]

Abstract: Metastin (kisspeptin-54) is an endogenous ligand that modulates gonadotropin-releasing hormone (GnRH) secretion through the interaction with a G protein-coupled receptor (GPCR), GPR54. The short-chain C-terminal decapeptide amide, metastin (45–54) (kisspeptin-10), exerts the identical bioactivities to metastin, such as metastasis suppression of cancer cells and inhibition of trophoblast migration and invasion. In order to understand the structural requirement for GPR54 agonistic activity, structure–activity relationship (SAR) study on pentapeptide-based C-terminal metastin analogues was carried out. As a result, H-Amb-Nal(2)-Gly-Leu-Arg-Trp-NH2 34 was identified as a novel GPR54 agonist that possessed the most potent GPR54 agonistic activity reported so far. [Copyright &y& Elsevier]

Since an outbreak of vaping-related deaths in the US has been reported as a public health crisis, the cardiovascular safety of nicotine nowadays receives increasing attention due to use of tobacco cigarette alternatives, such as electronic cigarettes. However, whether and how nicotine contributes to cardiac detrimental effects are in great controversy, especially less understood in young adult population. We report that chronic nicotine exposure, a major component of Electronic cigarettes, resulted in directly inhibited cardiomyocytes viability, increased cardiac fibrosis, and markedly suppressed cardiac function compared with sham. Gene array combined with bioinformatics analysis identified cardiac apoptosis and mitophagy were the key signals responsible for nicotine induced cardiac detrimental effect. Mechanistically, nicotine exposure markedly increased cleaved Caspase 3 and cleaved Caspase 9 indicating the involvement of intrinsic apoptotic pathway (mitochondrial cell death pathway). Meanwhile, nicotine-induced ROS outbreak promoted lysomal alkalization, furthermore blocked mitophagic degradation, thereby disrupted mitophagic flux promoted mitochondrial cell death cascade. Taken together, these findings indicate that nicotine confers cardiotoxicity via ROS-induced mitophagic flux blockage and provide the first demonstration of a causative link between nicotine and cardiac toxicity in young adult rat which may suggest nicotine induces cardiomyocytes impairment leading to cardiotoxicity in young adult population. [ABSTRACT FROM AUTHOR]