A novel strategy for the recognition of anions in water using charge-neutral σ-hole halogen and chalcogen bonding acyclic hosts is demonstrated for the first time. Exploiting the intrinsic ...hydrophobicity of halogen and chalcogen bond donor atoms integrated into a foldamer structural molecular framework containing hydrophilic functionalities, a series of water-soluble receptors was constructed for an anion recognition investigation. Isothermal titration calorimetry (ITC) binding studies with a range of anions revealed the receptors to display very strong and selective binding of large, weakly hydrated anions such as I– and ReO4 –. This is achieved through the formation of 2:1 host–guest stoichiometric complex assemblies, resulting in an encapsulated anion stabilized by cooperative, multidentate, convergent σ-hole donors, as shown by molecular dynamics simulations carried out in water. Importantly, the combination of multiple σ-hole–anion interactions and hydrophobic collapse results in I– affinities in water that exceed all known σ-hole receptors, including cationic systems (β2 up to 1.68 × 1011 M–2). Furthermore, the anion binding affinities and selectivity trends of the first example of an all-chalcogen bonding anion receptor in pure water are compared with halogen bonding and hydrogen bonding receptor analogues. These results further advance and establish halogen and chalcogen bond donor functions as new tools for overcoming the challenging goal of anion recognition in pure water.
Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations ...have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.
The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of hepatocellular carcinoma (HCC) was published in ...2018, and covered the diagnosis, management, treatment and follow-up of early, intermediate and advanced disease. At the ESMO Asia Meeting in November 2018 it was decided by both the ESMO and the Taiwan Oncology Society (TOS) to convene a special guidelines meeting immediately after the Taiwan Joint Cancer Conference (TJCC) in May 2019 in Taipei. The aim was to adapt the ESMO 2018 guidelines to take into account both the ethnic and the geographic differences in practice associated with the treatment of HCC in Asian patients. These guidelines represent the consensus opinions reached by experts in the treatment of patients with intermediate and advanced/relapsed HCC representing the oncology societies of Taiwan (TOS), China (CSCO), India (ISMPO) Japan (JSMO), Korea (KSMO), Malaysia (MOS) and Singapore (SSO). The voting was based on scientific evidence, and was independent of the current treatment practices, the drug availability and reimbursement situations in the individual participating Asian countries.
Background and Aims
Mutations in the disheveled, Egl‐10 and pleckstrin domain‐containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. ...However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
Materials and Methods
We studied a kindred of familial focal epilepsy with variable foci using whole‐exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
Results
We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the
DEPDC5 gene.
Discussion and Conclusions
Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.
There are considerable challenges in directly targeting the mutant p53 protein, given the large heterogeneity of p53 mutations in the clinic. An alternative approach is to exploit the altered fitness ...of cells imposed by loss-of-wild-type p53. Here we identify niclosamide through a HTS screen for compounds selectively killing p53-deficient cells. Niclosamide impairs the growth of p53-deficient cells and of p53 mutant patient-derived ovarian xenografts. Metabolome profiling reveals that niclosamide induces mitochondrial uncoupling, which renders mutant p53 cells susceptible to mitochondrial-dependent apoptosis through preferential accumulation of arachidonic acid (AA), and represents a first-in-class inhibitor of p53 mutant tumors. Wild-type p53 evades the cytotoxicity by promoting the transcriptional induction of two key lipid oxygenation genes, ALOX5 and ALOX12B, which catalyzes the dioxygenation and breakdown of AA. Therefore, we propose a new paradigm for targeting cancers defective in the p53 pathway, by exploiting their vulnerability to niclosamide-induced mitochondrial uncoupling.
The unprecedented application of a chiral halogen‐bonding 3rotaxane host system for the discrimination of stereo‐ and E/Z geometric isomers of a dicarboxylate anion guest is described. Synthesised by ...a chloride anion templation strategy, the 3rotaxane host recognises dicarboxylates through the formation of 1:1 stoichiometric sandwich complexes. This process was analysed by molecular dynamics simulations, which revealed the critical synergy of halogen and hydrogen bonding interactions in anion discrimination. In addition, the centrally located chiral (S)‐BINOL motif of the 3rotaxane axle component facilitates the complexed dicarboxylate species to be sensed via a fluorescence response.
The discrimination between dicarboxylate stereo‐ and geometric isomers by a chiral halogen‐bonding 3rotaxane can be monitored in terms of the fluorescence response. Computational modelling studies revealed the critical synergy between the axle of the rotaxane host and macrocycle components in achieving dicarboxylate guest selectivity.
Vaping products were initially designed to deliver nicotine as a tobacco cigarette substitute (eg, electronic cigarettes) but are now frequently used to deliver psychoactive substances, such as ...cannabis and its derivatives. Large, nationally representative surveys, such as Monitoring the Future, found that approximately 1 in 3 grade-12 students vaped cannabis in 2018 alone.
To summarize the findings of epidemiological studies that reported the global prevalence of cannabis vaping in adolescents by survey year and school grades.
PubMed, PsycINFO, Scopus, and Web of Science were searched systematically on August 19, 2020, for studies published globally between January 1, 2003, and August 19, 2020.
Publications that reported the prevalence of cannabis vaping in adolescents in the general population were included.
Study characteristics and prevalence estimates were extracted from each article. Random-effects meta-analysis based on the DerSimonian and Laird method and meta-regression were performed on lifetime, 12-month, and 30-day prevalence estimates. Meta-regression was also conducted using survey year and school grades as moderators.
Prevalence of cannabis vaping.
Seventeen studies met the eligibility criteria (n = 198 845 adolescents). Although no restrictions were imposed on study location, all 17 studies were from the US and Canada. Across all school grades, the pooled prevalence increased for lifetime use (6.1% in 2013-2016 to 13.6% in 2019-2020), use in the past 12 months (7.2% in 2017-2018 to 13.2% in 2019-2020), and use in the past 30 days (1.6% in 2013-2016 to 8.4% in 2019-2020). Heterogeneity across studies was large. The limited evidence from studies using similar survey and study designs suggested that adolescents' preference for cannabis products other than dried herbs, which usually contain higher Δ9-tetrahydrocannabinol levels, may have shifted over time.
The findings of this study suggest that the prevalence of cannabis vaping has increased among adolescents in the US and Canada and that more effective preventive and response measures are required.
PROSPERO Identifier: CRD42020219644.
Impact of Microplastics on the Ocular Surface Wu, Duoduo; Lim, Blanche X H; Seah, Ivan ...
International journal of molecular sciences,
02/2023, Volume:
24, Issue:
4
Journal Article
Peer reviewed
Open access
Plastics are synthetic materials made from organic polymers that are ubiquitous in daily living and are especially important in the healthcare setting. However, recent advances have revealed the ...pervasive nature of microplastics, which are formed by degradation of existing plastic products. Although the impact on human health has yet to be fully characterised, there is increasing evidence that microplastics can trigger inflammatory damage, microbial dysbiosis, and oxidative stress in humans. Although there are limited studies investigating their effect on the ocular surface, studies of microplastics on other organs provide some insights. The prevalence of plastic waste has also triggered public outcry, culminating in the development of legislation aimed at reducing microplastics in commercial products. We present a review outlining the possible sources of microplastics leading to ocular exposure, and analyse the possible mechanisms of ocular surface damage. Finally, we examine the utility and consequences of current legislation surrounding microplastic regulation.
The RENO experiment reports more precisely measured values of θ_{13} and |Δm_{ee}^{2}| using ∼2200 live days of data. The amplitude and frequency of reactor electron antineutrino (νover ¯_{e}) ...oscillation are measured by comparing the prompt signal spectra obtained from two identical near and far detectors. In the period between August 2011 and February 2018, the far (near) detector observed 103 212 (850 666) νover ¯_{e} candidate events with a background fraction of 4.8% (2.0%). A clear energy and baseline dependent disappearance of reactor νover ¯_{e} is observed in the deficit of the measured number of νover ¯_{e}. Based on the measured far-to-near ratio of prompt spectra, we obtain sin^{2}2θ_{13}=0.0896±0.0048(stat)±0.0047(syst) and |Δm_{ee}^{2}|=2.68±0.12(stat)±0.07(syst)×10^{-3} eV^{2}.
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