关键词： pol II transcription elongation   nascent RNA structureome   co-transcriptional splicing   RNA editing   alternative splicing   splice site structure  

摘要： Most RNA processing occurs co-transcriptionally. We interrogated nascent pol II transcripts by chemical and enzymatic probing and determined how the "nascent RNA structureome'' relates to splicing, A-I editing and transcription speed. RNA folding within introns and steep structural transitions at splice sites are associated with efficient co-transcriptional splicing. A slow pol II mutant elicits extensive remodeling into more folded conformations with increased A-I editing. Introns that become more structured at their 30 splice sites get co-transcriptionally excised more efficiently. Slow pol II altered folding of intronic Alu elements where cryptic splicing and intron retention are stimulated, an outcome mimicked by UV, which decelerates transcription. Slow transcription also remodeled RNA folding around alternative exons in distinct ways that predict whether skipping or inclusion is favored, even though it occurs post-transcriptionally. Hence, co-transcriptional RNA folding modulates post-transcriptional alternative splicing. In summary, the plasticity of nascent transcripts has widespread effects on RNA processing.

关键词： alternative lengthening of telomeres   ALT   recombination   Rad51   Rad59   yeast   ultra-long sequencing   break-induced replication  

摘要： Alternative lengthening of telomeres (ALT) is a recombination process that maintains telomeres in the absence of telomerase and helps cancer cells to survive. Yeast has been used as a robust model of ALT;however, the inability to determine the frequency and structure of ALT survivors hinders understanding of the ALT mechanism. Here, using population and molecular genetics approaches, we overcome these problems and demonstrate that contrary to the current view, both RAD51-dependent and RAD51-independent mechanisms are required for a unified ALT survivor pathway. This conclusion is based on the calculation of ALT frequencies, as well as on ultra-long sequencing of ALT products that revealed hybrid sequences containing features attributed to both recombination pathways. Sequencing of ALT intermediates demonstrates that recombination begins with Rad51-mediated strand invasion to form DNA substrates that are matured by a Rad51-independent ssDNA annealing pathway. A similar unified ALT pathway may operate in other organisms, including humans.

关键词： Ruthenium complexes   Antitumor   Naphthoquinones   Zebrafish model  

摘要： The number of cancer cases continues to increase worldwide, and unfortunately the main systemic treatments available have numerous of side effects. Ruthenium complexes have shown to be promising chemotherapeutic agents, since they present low toxicity and are more selective for tumor tissues. We report the synthesis, characterization and biological properties of two new ruthenium (II) complexes containing Lapachol and Lawsone as ligands: (1) [Ru(Law)(dppb)(phen)]PF6 and (2) [Ru(Lap)(dppb)(-phen)]PF6, where Law = Lawsone, Lap = Lapachol, dppb = 1,4-bis(diphenylphosphine)butane and phen = 1,10-phenanthroline. The ability of the complexes (1) and (2) to interact with CT-DNA (Calf Thymus) was investigated, and the results indicate that the complexes have shown a weak interaction with this macromolecule. Complexes (1) and (2) showed a moderate interaction with BSA, via a spontaneous process with the involvement of van derWaals and hydrogen bond interactions. Both complexes were tested against human lung cancer cell lines, chronic human myeloid leukemia, murine melanoma and human cervical and non-tumoral murine fibroblast adenocarcinoma, human lung fibroblasts and monkey kidney epithelia. The potential for cytotoxicity was tested out using the MTT assay and the neutral red test, to calculate inhibitory concentrations (IC50) and selectivity indices (IS). Both complexes showed a higher selectivity index of 1.17 and 10.91, respectively, for the HeLa tumor line. Studies of toxicological evaluation, using the micronucleus test and the comet assay against non-tumor cells, as well as an assessment of the potential for acute toxicity and neurotoxicity in zebrafish (Danio rerio). In the in vitro micronucleus test, complex (1) showed the least genotoxic potential, and in the in vitro comet assay both compounds had revealed a genotoxic potential at 0.5 and 1.0 mg L-1, with no difference between 24 h and 48 h exposure times. In the acute toxicity tests on zebrafish embryos, complex (

关键词： COVID-19   inflammation   endothelial injury   children   multisystem   MIS-C  

摘要： Introduction: COVID-19 is associated with a novel multi-system inflammatory syndrome that shares some characteristics with Kawasaki's Disease. The syndrome manifestation is delayed relative to COVID-19 onset, with a spectrum of clinical severity. Clinical signs may include persistent fever, gastrointestinal symptoms, cardiac inflammation and/or shock. Case Presentation: We measured 59 inflammatory and endothelial injury plasma analytes in an adolescent girl that presented with malaise, fever, cough, strawberry tongue and jaundice. Her COVID-19 status was positive with detection of 2 SARS-CoV-2 viral genes using polymerase chain reaction. She was treated with intravenous immunoglobulin prior to blood draw, but our plasma measurements suggested a unique analyte expression pattern associated with inflammation, endothelial injury and microvascular glycocalyx degradation. Conclusions: COVID-19 is associated with a multi-system inflammatory syndrome and a unique inflammatory and endothelial injury signature. Summary: Analyte markers of inflammation and endothelial cell injury might serve as putative biomarkers and/or be investigated further as potential therapeutic targets.

关键词： COVID-19   Vaccine attitudes   Non-pharmaceutical interventions   NPI   Conspiracy   Complementary and alternative medicine   CAM   Trust  

摘要： Background We investigated if people's response to the official recommendations during the COVID-19 pandemic is associated with conspiracy beliefs related to COVID-19, a distrust in the sources providing information on COVID-19, and an endorsement of complementary and alternative medicine (CAM). Methods The sample consisted of 1325 Finnish adults who filled out an online survey marketed on Facebook. Structural regression analysis was used to investigate whether: 1) conspiracy beliefs, a distrust in information sources, and endorsement of CAM predict people's response to the non-pharmaceutical interventions (NPIs) implemented by the government during the COVID-19 pandemic, and 2) conspiracy beliefs, a distrust in information sources, and endorsement of CAM are related to people's willingness to take a COVID-19 vaccine. Results Individuals with more conspiracy beliefs and a lower trust in information sources were less likely to have a positive response to the NPIs. Individuals with less trust in information sources and more endorsement of CAM were more unwilling to take a COVID-19 vaccine. Distrust in information sources was the strongest and most consistent predictor in all models. Our analyses also revealed that some of the people who respond negatively to the NPIs also have a lower likelihood to take the vaccine. This association was partly related to a lower trust in information sources. Conclusions Distrusting the establishment to provide accurate information, believing in conspiracy theories, and endorsing treatments and substances that are not part of conventional medicine, are all associated with a more negative response to the official guidelines during COVID-19. How people respond to the guidelines, however, is more strongly and consistently related to the degree of trust they feel in the information sources, than to their tendency to hold conspiracy beliefs or endorse CAM. These findings highlight the need for governments and health authorities to create co

关键词： flavor   astringency   proline-rich proteins   tannins   MUC1  

摘要： Flavor is one of the main drivers of food consumption and acceptability. It is associated with pleasure feels during eating. Flavor is a multimodal perception corresponding to the functional integration of information from the chemical senses: olfaction, gustation, and nasal and oral somatosensory inputs. As a result, astringency, as a sensation mediated by the trigeminal nerves, influences food flavor. Despite the importance of astringency in food consumer acceptance, the exact chemosensory mechanism of its detection and the nature of the receptors activated remain unknown. Herein, after reviewing the current hypotheses on the molecular origin of astringency, we proposed a ground-breaking hypothesis on the molecular mechanisms underpinning this sensation as a perspective for future research.

摘要： Vertebrate genomes contain major (>99.5%) and minor (<0.5%) introns that are spliced by the major and minor spliceosomes, respectively. Major intron splicing follows the exon-definition model, whereby major spliceosome components first assemble across exons. However, since most genes with minor introns predominately consist of major introns, formation of exon-definition complexes in these genes would require interaction between the major and minor spliceosomes. Here, we report that minor spliceosome protein U11-59K binds to the major spliceosome U2AF complex, thereby supporting a model in which the minor spliceosome interacts with the major spliceosome across an exon to regulate the splicing of minor introns. Inhibition of minor spliceosome snRNAs and U11-59K disrupted exon-bridging interactions, leading to exon skipping by the major spliceosome. The resulting aberrant isoforms contained a premature stop codon, yet were not subjected to nonsense-mediated decay, but rather bound to polysomes. Importantly, we detected elevated levels of these alternatively spliced transcripts in individuals with minor spliceosome-related diseases such as Roifman syndrome, Lowry-Wood syndrome and early-onset cerebellar ataxia. In all, we report that the minor spliceosome informs splicing by the major spliceosome through exon-definition interactions and show that minor spliceosome inhibition results in aberrant alternative splicing in disease.

关键词： Cancer Immunotherapy   clinical trials   placebo double blind study   mega data   personalized medicine  

摘要： Background: This evaluation emphasizes the main points of the original article 'Position paper: new insights into the immunobiology and dynamics of tumor-host interactions require adaptations of clinical studies' by Sprenger et al. and provides further justification for the use of an alternative approach in the design of human clinical trials for new investigational drugs in the field of immuno-oncology. Objective: Standard trial design utilizing the double blind placebo trial approach, while effective for drugs that directly treat tumors, is too costly, slow, and not effective for drugs and protocols that depend on activation of the immune system for killing of tumors. Methods/results: This paper has proposed through the use of detailed diagnostic profiling, small groups of patients with similar tumor microenvironment characteristics be grouped to determine the clinical benefit of immunological combinations that enter clinical trials. In addition, mega data from larger trials in which patients are subcategorized as above can provide the necessary data as a substitute for current double blind placebo trials which do not take into account the immune status of the host and tumor. Conclusion: There needs to be evolution of the clinical trial landscape so that it matches the exponential growth of the field of immunotherapy.

摘要： Consumers' dietary patterns have a significant impact on planetary and personal health. To address health and environmental challenges one of the many possible solutions is to substitute meat consumption with alternative protein sources. This systematic review identifies 91 articles with a focus on the drivers of consumer acceptance of five alternative proteins: pulses, algae, insects, plant-based alternative proteins, and cultured meat. This review demonstrates that acceptance of the alternative proteins included here is relatively low (compared to that of meat);acceptance of insects is lowest, followed by acceptance of cultured meat. Pulses and plant-based alternative proteins have the highest acceptance level. In general, the following drivers of acceptance consistently show to be relevant for the acceptance of various alternative proteins: motives of taste and health, familiarity, attitudes, food neophobia, disgust, and social norms. However, there are also differences in relevance between individuals and between alternative proteins. For example, for insects and other novel alternative proteins the drivers of familiarity and affective processes of food neophobia and disgust seem more relevant. As part of gaining full insight in relevant drivers of acceptance, the review also shows an overview of the intervention studies that were included in the 91 articles of the review, providing implications on how consumer acceptance can be increased. The focal areas of the intervention studies included here do not fully correspond with the current knowledge of drivers. To date, intervention studies have mainly focussed on conscious deliberations, whereas familiarity and affective factors have also been shown to be key drivers. The comprehensive overview of the most relevant factors for consumer acceptance of various categories of alternative proteins thus shows large consistencies across bodies of research. Variations can be found in the nuances showing different prioritie

关键词： 医保药品目录   眼科用药   对比分析  

摘要： 目的通过比对分析中国(大陆及台湾地区)、澳大利亚、英国医保目录及世界卫生组织基本药物目录中眼科用药的收录情况,为动态调整我国医保目录提供参考。方法对比我国《国家基本医疗保险、工伤保险和生育保险药品目录》(以下简称国家医保目录)、我国台湾地区《全民健康保险用药品项表》(以下简称我国台湾地区健保目录)、澳大利亚发布的药物福利计划(PBS)、《英国国家处方集》(BNF)及《世界卫生组织基本药物标准清单》(EML)中眼科用药的收录情况,并对其进行比对分析。结果5个目录共收录了143种眼科用药,其中国家医保目录收录67种,占比46.85%,我国台湾地区健保目录收录86种,PBS、BNF及EML分别收录47种、101种和16种。5个目录同时收录眼科用药7种,占比4.90%。国家医保目录包含其他目录不包含眼科用药15种,占比10.49%。国家医保目录未收录其他国家及地区目录中的眼科用药84种,占比58.74%。结论国家医保目录中的眼科用药品种与其他目录有一定差别,但对眼科的每类疾病均有涉及,可以满足临床需求。靶向制剂是所有目录中收录最多的品种,眼用复方制剂的品种还需增加。