Miracle-dz/UniFAR-FTUs huggingface dataset:
Cancer epigenetics: promises and pitfalls for cancer therapy

Over the past few decades, epigenetic regulators have emerged as major players in cellular processes that drive cancer initiation and progression, and subsequently modulate the responsiveness of cancers to therapeutic agents. This Special Issue of The FEBS Journal, Cancer Epigenetics, features an exciting collection of review articles that focus on the functions of a broad spectrum of epigenetic modulators in cancer. The diverse topics explored herein range from the roles of transposable elements and chromatin architecture in cancer and the most recent research advances on cancer‐associated histone variants (oncohistones), to the effects of altered epigenetics on transcription and advanced cancer cell phenotypes. Moreover, the prospective key function of cancer metabolism in linking epigenetics and transcriptional regulation, and the potential of epigenetics for targeted cancer therapeutics is discussed. We hope that this collection of articles will give readers an enlightening overview of the most recent advances in the fast‐moving field of cancer epigenetics.
Quantitative contribution of the spacer length in the supercoiling-sensitivity of bacterial promoters

DNA supercoiling acts as a global transcriptional regulator in bacteria, but the promoter sequence or structural determinants controlling its effect remain unclear. It was previously proposed to modulate the torsional angle between the -10 and -35 hexamers, and thereby regulate the formation of the closed-complex depending on the length of the “spacer” between them. Here, we develop a ther-modynamic model of this notion based on DNA elasticity, providing quantitative and parameter-free predictions on the relative activation of promoters containing a short vs long spacer when the DNA supercoiling level is varied. The model is tested through an analysis of in vitro and in vivo expression assays of mutant promoters with variable spacer lengths, confirming its accuracy for spacers ranging from 15 to 19 nucleotides, except those of 16 nucleotides where other regulatory mechanisms likely overcome the effect of this specific step. An analysis at the whole-genome scale in E. coli then demonstrates a significant effect of the spacer length on the genomic expression after transient or inheritable superhelical variations, validating the model’s predictions. Altogether, this study shows that the torsional constraints associated to promoter binding by RNA Polymerase underpin a basal and global regulatory mechanism independent of specific transcription factors.
EDUCAÇÃO PARA A SUSTENTABILIDADE NO DESENVOLVIMENTO DE PROJE

This article aims to describe two practices adopted in the architecture design activities of a School of Architecture and Urbanism in Southern Brazil, in order to make a comparative analysis of different pedagogical processes, as re- gards the implementation of sustainability strategies in activities practice of ar- chitecture design. The research is exploratory and the method comprises: litera- ture review, survey data from participant observation and questionnaires, ac- cording to research methods in social sciences. The study was conducted in the period between 2011 and 2012, during the course of two pedagogical pro- posals, adopted by the institution subject matter. The results indicate that the main barriers to the acquisition of knowledge are related to the relationship be- tween theory and practice in the different disciplines of architecture design ac- tivities. Relating to the application of the contents, the biggest challenges are related to habits already established in the professional and technical expertise and leaning/familiarity individual in performing interdisciplinary work. As a con- tribution, this article aims to foment the discussion about the Brazilians chal- lenges, pertinent to the formation of human agents responsible for conducting the activities of architectural design to more sustainable practices.
Global Distribution and Diversity of Prevalent Sewage Water Plasmidomes

Antimicrobial resistance is a global threat to human health, as it inhibits our ability to treat infectious diseases. This study utilizes sewage water plasmidomes to identify plasmid-derived features and highlights antimicrobial resistance genes, particularly macrolide resistance genes, as abundant in sewage water plasmidomes in Firmicutes and Acinetobacter hosts. ABSTRACT Sewage water from around the world contains an abundance of short plasmids, several of which harbor antimicrobial resistance genes (ARGs). The global dynamics of plasmid-derived antimicrobial resistance and functions are only starting to be unveiled. Here, we utilized a previously created data set of 159,332 assumed small plasmids from 24 different global sewage samples. The detailed phylogeny, as well as the interplay between their protein domains, ARGs, and predicted bacterial host genera, were investigated to understand sewage plasmidome dynamics globally. A total of 58,429 circular elements carried genes encoding plasmid-related features, and MASH distance analyses showed a high degree of diversity. A single (yet diverse) cluster of 520 predicted Acinetobacter plasmids was predominant among the European sewage water. Our results suggested a prevalence of plasmid-backbone gene combinations over others. This could be related to selected bacterial genera that act as bacterial hosts. These combinations also mirrored the geographical locations of the sewage samples. Our functional domain network analysis identified three groups of plasmids. However, these backbone domains were not exclusive to any given group, and Acinetobacter was the dominant host genus among the theta-replicating plasmids, which contained a reservoir of the macrolide resistance gene pair msr(E) and mph(E). Macrolide resistance genes were the most common in the sewage plasmidomes and were found in the largest number of unique plasmids. While msr(E) and mph(E) were limited to Acinetobacter, erm(B) was disseminated among a range of Firmicutes plasmids, including Staphylococcus and Streptococcus, highlighting a potential reservoir of antibiotic resistance for these pathogens from around the globe. IMPORTANCE Antimicrobial resistance is a global threat to human health, as it inhibits our ability to treat infectious diseases. This study utilizes sewage water plasmidomes to identify plasmid-derived features and highlights antimicrobial resistance genes, particularly macrolide resistance genes, as abundant in sewage water plasmidomes in Firmicutes and Acinetobacter hosts. The emergence of macrolide resistance in these bacteria suggests that macrolide selective pressure exists in sewage water and that the resident bacteria can readily acquire macrolide resistance via small plasmids.
Biogeographical history shapes evolution of reproduction in a global warming scenario

Adaptive evolution might be critical for animal populations to thrive on the fast-changing natural environments. Ectotherms are particularly vulnerable to global warming and, although their limited coping ability has been suggested, few real-time evolution experiments have directly accessed their evolutionary potential. Here, we report a long-term experimental evolution study addressing the evolution of thermal reaction norms, after ∼30 generations under different thermal environments. We analyzed the evolutionary dynamics of Drosophila subobscura populations as a function of the thermally variable environments in which they evolved and their distinct biogeographical background. Our results showed clear differences between the historically differentiated populations: while the northern D. subobscura populations showed a temporal increase in performance at higher temperatures, their southern counterparts presented the opposite pattern. This suggests that the northern populations might be better equipped to cope with the current rising temperatures. Remarkably, no effect of thermal selection was found. The lack of a clear long-term adaptive response at higher temperatures after evolution under a global warming scenario raises concerns about the evolutionary potential of ectotherms. Our results highlight the complex nature of thermal responses in face of environmental heterogeneity and emphasize the importance of considering intra-specific variation in thermal evolution studies.
TGF-β1 induced S100 family protein expression is associated with epithelial to mesenchymal transition states and poor survival in pancreatic cancer

Epithelial-mesenchymal transition (EMT) is a continuum that includes epithelial, partial EMT (P-EMT) and mesenchymal states, each of which are associated with cancer progression, invasive capabilities and ultimately metastasis. We have employed a lineage traced sporadic model of pancreatic cancer to generate a murine organoid biobank from primary and secondary tumors, including sublines that have undergone P-EMT and complete EMT (C-EMT). Using an unbiased proteomics approach, we found that the morphology of the organoids predicts the EMT state, with solid organoids associated with a P-EMT signature. We also observed that exogenous TGFβ1 induces a solid organoid morphology that is associated with changes in the S100 family, C-EMT and the formation of high-grade tumors. S100A4 may represent a useful biomarker to predict EMT state, disease progression and outcome for pancreatic cancer patients.
A loss-of-function cysteine mutant in fibulin-3 (EFEMP1) forms aberrant extracellular disulfide-linked homodimers and alters extracellular matrix composition

Fibulin-3 (F3 or EFEMP1) is a disulfide-rich, secreted glycoprotein necessary for maintaining extracellular matrix (ECM) and connective tissue integrity. Two studies have identified distinct autosomal recessive F3 mutations in individuals with Marfan Syndrome-like phenotypes. Herein we characterized how one of these mutations, c.163T>C; p.Cys55Arg (C55R), disrupts F3 secretion, quaternary structure, and function by forming unique extracellular disulfide-linked homodimers. Dual cysteine mutants suggest that the C55R-induced disulfide species forms because of new availability of Cys70 on adjacent F3 monomers. Surprisingly, mutation of single cysteines located near C55 (i.e., C29, C42, C48, C61, C70, C159, and C171) also produced similar extracellular disulfide-linked dimers, suggesting that this is not a phenomenon isolated to the C55R mutant. To assess C55R functionality, F3 knockout (KO) retinal pigmented epithelial (RPE) were generated, followed by reintroduction of wild-type (WT) or C55R F3. F3 KO cells produced lower levels of the ECM remodeling enzyme, matrix metalloproteinase 2 and reduced formation of collagen VI ECM filaments, both of which were partially rescued by WT F3 overexpression. However, C55R F3 was unable to compensate for these same ECM-related defects. Our results highlight the unique behavior of particular cysteine mutations in F3 and uncover potential routes to restore C55R F3 loss-of-function.
NEDD8 activity is important for direct antigen MHC class I antigen presentation

Successful direct MHC class I antigen presentation is dependent on the protein degradation machinery of the cell to generate antigenic peptides which can be loaded onto MHC class I molecules for surveillance by CD8+ T cells of the immune system. Most often this process involves the ubiquitin-proteasome system, however other ubiquitin-like (UBL) proteins have also been implicated in protein degradation and direct antigen presentation. Here, we examine the role of neuronal precursor cell-expressed developmentally down-regulated protein 8 (NEDD8) in direct antigen presentation. NEDD8 is the UBL with highest similarity to ubiquitin and fusion of NEDD8 to the amino-terminus of a target protein can lead to the target proteins degradation. We find that appending NEDD8 to the N-terminus of the model antigen ovalbumin resulted in degradation by both the proteasome and autophagy protein degradation pathways, but only proteasomal degradation, involving the proteasomal subunit NEDD8 ultimate buster 1 (NUB1), resulted in peptide presentation. When directly compare to ubiquitin, NEDD8-fusion was less efficient at generating peptides. However, inactivation of the NEDD8-conugation machinery by treating cells with MLN4924, inhibited the presentation of peptides from Defective Ribosomal Products (DRiPs) derived from a model antigen. These results demonstrate that NEDD8 activity in the cell is important for direct antigen presentation, but not by directly targeting proteins for degradation.
Genetic Variants of MicroRNA and DROSHA Genes in Association With the Risk of Tuberculosis in the Amazon Population

Tuberculosis (TB) is a chronic infection caused by Mycobacterium tuberculosis (Mtb) with high incidence and mortality. Studies reported that host genetic variants might be associated with the risk of tuberculosis. The aim of this study was to perform an association study between 26 single nucleotide polymorphisms (SNPs) and tuberculosis and evaluate whether these SNPs may confer risk factors to tuberculosis in the Amazon population. There were 52 males and 126 females, with total of 178 healthy controls. Genotyping was performed using TaqMan Open Array Genotyping. Ancestry-informative markers were used to estimate the ancestral proportions of the individuals in the case and control groups. The results indicated that the SNPs rs10035440 (DROSHA), rs7372209 (miR26-a1), rs1834306 (miR100), rs4919510 (miR608), and rs10739971 (pri-let-7a-1) were significantly associated with high risk and rs3746444 (miR499) and rs6505162 (miR423), with low risk of developing tuberculosis in the Amazon population. Our study concluded that seven miRNA polymorphisms were associated with tuberculosis. Our study contributes to a better understanding of TB pathogenesis and may promote the development of new diagnostic tools against M. tuberculosis infection.
Metabolomic Insights Into Endophyte-Derived Bioactive Compounds

Among the various plant-associated microbiota, endophytes (the microbial communities inhabiting plant endosphere without causing disease symptoms) exhibit the most intimate and specific association with host plants. Endophytic microbes influence various aspects of plant responses (such as increasing availability of nutrients, tolerance against biotic and abiotic stresses, etc.) by modulating the primary and secondary metabolism of the host. Besides, endophytic microbes produce a diverse array of bioactive compounds, which have potential applications in the pharmaceutical, food, and cosmetic industries. Further, there is sufficient evidence for endophyte-derived plant metabolites, which could be pursued as alternative sources of commercially important plant metabolites. The field of bioprospecting, the discovery of novel chemistries, and endophyte-mediated production of plant metabolites have witnessed a boom with the advent of omics technologies (especially metabolomics) in endophyte research. The high throughput study of small metabolites at a particular timepoint or tissue forms the core of metabolomics. Being downstream to transcriptome and proteome, the metabolome provides the most direct reflection of the phenotype of an organism. The contribution of plant and microbial metabolomics for answering fundamental questions of plant-endophyte interaction, such as the effect of endophyte inoculation on plant metabolome, composition of metabolites on the impact of environmental stressors (biotic and abiotic), etc., have also been discussed.
A Classifier for Improving Early Lung Cancer Diagnosis Incorporating Artificial Intelligence and Liquid Biopsy

Lung cancer is the leading cause of cancer-related deaths worldwide and in China. Screening for lung cancer by low dose computed tomography (LDCT) can reduce mortality but has resulted in a dramatic rise in the incidence of indeterminate pulmonary nodules, which presents a major diagnostic challenge for clinicians regarding their underlying pathology and can lead to overdiagnosis. To address the significant gap in evaluating pulmonary nodules, we conducted a prospective study to develop a prediction model for individuals at intermediate to high risk of developing lung cancer. Univariate and multivariate logistic analyses were applied to the training cohort (n = 560) to develop an early lung cancer prediction model. The results indicated that a model integrating clinical characteristics (age and smoking history), radiological characteristics of pulmonary nodules (nodule diameter, nodule count, upper lobe location, malignant sign at the nodule edge, subsolid status), artificial intelligence analysis of LDCT data, and liquid biopsy achieved the best diagnostic performance in the training cohort (sensitivity 89.53%, specificity 81.31%, area under the curve [AUC] = 0.880). In the independent validation cohort (n = 168), this model had an AUC of 0.895, which was greater than that of the Mayo Clinic Model (AUC = 0.772) and Veterans’ Affairs Model (AUC = 0.740). These results were significantly better for predicting the presence of cancer than radiological features and artificial intelligence risk scores alone. Applying this classifier prospectively may lead to improved early lung cancer diagnosis and early treatment for patients with malignant nodules while sparing patients with benign entities from unnecessary and potentially harmful surgery. Clinical Trial Registration Number ChiCTR1900026233, URL: http://www.chictr. org.cn/showproj.aspx? proj=43370.
Time series analysis of China's primary energy production based on ARIMA model

The ARIMA model is one of the most popular models for time series forecasting analysis.This paper analyzes the datas of China’s primary energy output from 1950 to 2008 with ARIMA model,establishes the corresponding model with Eviews package software,using this model to predict the recent and future several years primary energy production.According to the result of prediction,the model predict well and can be used to predict future value for short-term.
Modeling Human Primary Microcephaly With hiPSC-Derived Brain Organoids Carrying CPAP-E1235V Disease-Associated Mutant Protein

The centrosome is composed of a pair of centrioles and serves as the major microtubule-organizing center (MTOC) in cells. Centrosome dysfunction has been linked to autosomal recessive primary microcephaly (MCPH), which is a rare human neurodevelopmental disorder characterized by small brain size with intellectual disability. Recently, several mouse models carrying mutated genes encoding centrosomal proteins have been generated to address the genotype–phenotype relationships in MCPH. However, several human-specific features were not observed in the mouse models during brain development. Herein, we generated isogenic hiPSCs carrying the gene encoding centrosomal CPAP-E1235V mutant protein using the CRISPR-Cas9 genome editing system, and examined the phenotypic features of wild-type and mutant hiPSCs and their derived brain organoids. Our results showed that the CPAP-E1235V mutant perturbed the recruitment of several centriolar proteins involved in centriole elongation, including CEP120, CEP295, CENTROBIN, POC5, and POC1B, onto nascent centrioles, resulting in the production of short centrioles but long cilia. Importantly, our wild-type hiPSC-derived brain organoid recapitulated many cellular events seen in the developing human brain, including neuronal differentiation and cortical spatial lamination. Interestingly, hiPSC-CPAP-E1235V-derived brain organoids induced p53-dependent neuronal cell death, resulting in the production of smaller brain organoids that mimic the microcephaly phenotype. Furthermore, we observed that the CPAP-E1235V mutation altered the spindle orientation of neuronal progenitor cells and induced premature neuronal differentiation. In summary, we have shown that the hiPSC-derived brain organoid coupled with CRISPR/Cas9 gene editing technology can recapitulate the centrosome/centriole-associated MCPH pathological features. Possible mechanisms for MCPH with centriole/centrosome dysfunction are discussed.
Humid Air Turbine Cycles With Water Recovery: How to Dispose Heat in an Efficient Way

Since the humid air turbine (HAT) cycle was first presented by Rao and Joiner (1990), several modifications were proposed to the original configuration to further improve its efficiency. In the last years, the attention was focused in the water recovery from flue gas and in determining the most suitable systems to separate water from gas and solving the problem of low temperature at the stack.In all the above studies it was shown that condensing water from flue gas requires a significant flow rate of a cooling medium (generally water) which is needed to remove condensation heat which must then be disposed in the environment. This worsens power plant performance because large cooling towers are needed. On the other hand, the reduced cost of water treatment may compensate the additional costs of the condensation equipment.In this paper, the introduction of an Organic Rankine Cycle (ORC), which transforms in mechanical power a fraction of the heat recovered from the HAT cycle, both in the water recovery system and in other heat exchangers, is presented. Results were obtained by using three different fluids and maximizing the ORC input exergy. The substances which were used are the conventional R502 refrigerant fluid, ammonia and the new HF134a, which is replacing phased-out CFCs in refrigeration systems. © 1998 ASME
Molecular and Clinical Repercussions of GABA Transporter 1 Variants Gone Amiss: Links to Epilepsy and Developmental Spectrum Disorders

The human γ-aminobutyric acid (GABA) transporter 1 (hGAT-1) is the first member of the solute carrier 6 (SLC6) protein superfamily. GAT-1 (SLC6A1) is one of the main GABA transporters in the central nervous system. Its principal physiological role is retrieving GABA from the synapse into neurons and astrocytes, thus swiftly terminating neurotransmission. GABA is a key inhibitory neurotransmitter and shifts in GABAergic signaling can lead to pathological conditions, from anxiety and epileptic seizures to schizophrenia. Point mutations in the SLC6A1 gene frequently give rise to epilepsy, intellectual disability or autism spectrum disorders in the afflicted individuals. The mechanistic routes underlying these are still fairly unclear. Some loss-of-function variants impair the folding and intracellular trafficking of the protein (thus retaining the transporter in the endoplasmic reticulum compartment), whereas others, despite managing to reach their bona fide site of action at the cell surface, nonetheless abolish GABA transport activity (plausibly owing to structural/conformational defects). Whatever the molecular culprit(s), the physiological aftermath transpires into the absence of functional transporters, which in turn perturbs GABAergic actions. Dozens of mutations in the kin SLC6 family members are known to exhort protein misfolding. Such events typically elicit severe ailments in people, e.g., infantile parkinsonism-dystonia or X-linked intellectual disability, in the case of dopamine and creatine transporters, respectively. Flaws in protein folding can be rectified by small molecules known as pharmacological and/or chemical chaperones. The search for such apt remedies calls for a systematic investigation and categorization of the numerous disease-linked variants, by biochemical and pharmacological means in vitro (in cell lines and primary neuronal cultures) and in vivo (in animal models). We here give special emphasis to the utilization of the fruit fly Drosophila melanogaster as a versatile model in GAT-1-related studies. Jointly, these approaches can portray indispensable insights into the molecular factors underlying epilepsy, and ultimately pave the way for contriving efficacious therapeutic options for patients harboring pathogenic mutations in hGAT-1.