Miracle-dz/UniFAR-FTUs huggingface dataset:
Fusion Genes and RNAs in Cancer Development

Fusion RNAs are a hallmark of some cancers. They result either from chromosomal rearrangements or from splicing mechanisms that are non-chromosomal rearrangements. Chromosomal rearrangements that result in gene fusions are particularly prevalent in sarcomas and hematopoietic malignancies; they are also common in solid tumors. The splicing process can also give rise to more complex RNA patterns in cells. Gene fusions frequently affect tyrosine kinases, chromatin regulators, or transcription factors, and can cause constitutive activation, enhancement of downstream signaling, and tumor development, as major drivers of oncogenesis. In addition, some fusion RNAs have been shown to function as noncoding RNAs and to affect cancer progression. Fusion genes and RNAs will therefore become increasingly important as diagnostic and therapeutic targets for cancer development. Here, we discuss the function, biogenesis, detection, clinical relevance, and therapeutic implications of oncogenic fusion genes and RNAs in cancer development. Further understanding the molecular mechanisms that regulate how fusion RNAs form in cancers is critical to the development of therapeutic strategies against tumorigenesis.
Synthesis of Natural Fimbrolides

Starting from citraconic anhydride, a three-step approach to fimbrolide congener is reported by taking the advantage of a regioselective Grignard reaction with an anhydride, followed by a dehydrative cyclization and double bromination-dehydrobromination sequence. Starting from N-(4-tolyl)maleimide, an eight-step synthesis of two natural fimbrolides is reported with good yields via the synthesis of requisite butylmaleic anhydride, its regioselective Grignard coupling reaction, and a bromination-dehydrobromination pathway.
The Effects of Textural Properties and Surface Chemistry of Activated Carbon on Its Catalytic Performance in Methane Decomposition for Hydrogen Production

Abstract In this article, catalytic decomposition of methane for hydrogen production over several domestic commercial activated carbons was performed at a fixed bed reactor. The effects of the textural properties and surface chemistry of the activated carbon on its catalytic performance in methane decomposition were investigated; furthermore, the correlation between these properties and the catalytic performance is studied as well. The results show that the initial rate of methane decomposition has no correlation to the surface area of the activated carbon, which indicates that only a portion of the entire surface is active for methane decomposition. On the other hand, the correlation between the total amount of methane conversion during the process and the pore volume of the activated carbon is nearly linear, because the bigger pore volume can accommodate more carbon deposition from methane decomposition, while it has no relation to the micropore volume of the activated carbon. The oxygenated functional groups of the activated carbon mainly decompose to CO and CO2 during the temperature-programmed desorption process and the concentration of these groups has a certain relation to the initial rate of methane decomposition.
Targeting the N-terminal domain of the RNA-binding protein of the SARS-CoV-2 with high affinity natural compounds to abrogate the protein-RNA interaction: a molecular dynamics study

Abstract The emergence of COVID-19 took the world by shock in December 2019, starting from Wuhan, China and swiftly spreading across the globe. The number of COVID-19 cases continues to rise which is a global burden on the health care system worldwide. Efforts are continuing to come up with a solution either to develop a small molecular inhibitor or vaccine, but still no success. In the fight against SARS-CoV-2, targeting a different protein of the SARS-CoV-2 is the need of the hour to impede and relinquish the current pandemic. Therefore, in this study, computational modelling and simulation approaches are used to target the N-terminal domain of the phosphor-nucleoprotein (RNA binding protein), which is primarily responsible for binding and packing the viral genome to get ribonucleoprotein complex (RNP). Our multi-step drug screening approach shortlisted potential drugs. These top hits were confirmed by re-docking which revealed that the interacting molecules block the key residues i.e. Thr57, His59, Ser105, Arg107, and Arg177 and thus ultimately block the NTD from RNA recognition. Furthermore, the activity of the top four hits was also confirmed by using molecular dynamics simulation and free energy calculation. Our analysis suggests that these top hits possess strong inhibitory properties and should be tested experimentally. In conclusion, we hope these top hits would abrogate the binding of RNA and the NTD of the SARS-CoV-2, which might be helpful to combat COVID-19. Communicated by Ramaswamy H. Sarma
Influenza and Pneumococcal Vaccination in Non-Infected Cardiometabolic Patients from the Americas during the COVID-19 Pandemic. A Sub-Analysis of the CorCOVID-LATAM Study

Background: Influenza vaccination (IV) and Pneumococcus vaccination (PV) are recommended for patients with cardiometabolic diseases. This study aimed to evaluate the immunization rate of ambulatory cardiometabolic patients during the COVID-19 pandemic in the Americas. Methods: Electronic surveys were collected from 13 Spanish speaking countries between 15 June and 15 July 2020. Results: 4216 patients were analyzed. Mean age 60 (±15) years and 49% females. Global IV rate was 46.5% and PV 24.6%. Vaccinated patients were older (IV = 63 vs. 58 years; PV = 68 vs. 59, p < 0.01) but without gender difference. Vaccination rates were greater in higher-risk groups (65+, diabetics, heart failure), but not in coronary artery disease patients. In the Southern cone, the rate of IV and PV was approximately double that in the tropical regions of the Americas. In a multivariate model, geographic zone (IV = OR 2.02, PV = OR 2.42, p < 0.001), age (IV = OR 1.023, PV = OR 1.035, p < 0.001), and incomes (IV = OR 1.28, PV = OR 1.58, p < 0.001) were predictors for vaccination. Conclusions: During the COVID-19 pandemic, ambulatory patients with cardiometabolic diseases from the Americas with no evidence of COVID-19 infection had lower-than-expected rates of IV and PV. Geographic, social, and cultural differences were found, and they should be explored in depth.
Vibrational adiabaticity and infrared multiphoton dynamics

The classical dynamics of a vibrating, rotating diatomic molecule in a strong laser field resonant with the vibration is examined. Particular attention is given to vibrational adiabaticity and its breakdown near resonance. The strong nonadiabatic effects seen in an earlier quantum calculation are explained in terms of the structure of the classical phase space. A connection between the breakdown of the vibrational adiabatic approximation and the onset of extensive intramolecular dephasing is explored.
Deciphering the structural attributes of protein-heparan sulfate interactions using chemo-enzymatic approaches and NMR spectroscopy.

Heparan sulfates (HS) is a polysaccharide found at the cell surface, where it mediates interactions with hundreds of proteins and regulates major pathophysiological processes. HS is highly heterogeneous and structurally complex and examples that define their structure-activity relationships remain limited. Here, to characterize a protein-HS interface and define the corresponding saccharide binding domain, we present a chemoenzymatic approach that generate 13C labeled HS-based oligosaccharide structures. NMR spectroscopy that efficiently discriminates between important or redundant chemical groups in the oligosaccharides, is employed to characterize these molecules alone and in interaction with proteins. Using chemokines as model system, docking based on NMR data on both proteins and oligosaccharides enable the identification of the structural determinant involved in the complex. This study shows that both the position of the sulfo-groups along the chain and their mode of presentation, rather than their overall number, are key determinant and further points out the usefulness of these 13C labeled oligosaccharides in obtaining detailed structural information on HS-protein complexes.
Yeast translation elongation factor eEF3 promotes late stages of tRNA translocation

In addition to the conserved translation elongation factors eEF1A and eEF2, fungi require a third essential elongation factor, eEF3. While eEF3 has been implicated in tRNA binding and release at the ribosomal A and E sites, its exact mechanism of action is unclear. Here, we show that eEF3 acts at the mRNA–tRNA translocation step by promoting the dissociation of the tRNA from the E site, but independent of aminoacyl‐tRNA recruitment to the A site. Depletion of eEF3 in vivo leads to a general slowdown in translation elongation due to accumulation of ribosomes with an occupied A site. Cryo‐EM analysis of native eEF3‐ribosome complexes shows that eEF3 facilitates late steps of translocation by favoring non‐rotated ribosomal states, as well as by opening the L1 stalk to release the E‐site tRNA. Additionally, our analysis provides structural insights into novel translation elongation states, enabling presentation of a revised yeast translation elongation cycle.
TP53 Mutations as a Driver of Metastasis Signaling in Advanced Cancer Patients

Simple Summary The DNA sequencing of cancer provides information about specific genetic changes that could help with treatment decisions. Tumors from different tissues change over time and acquire new genetic changes particularly with treatment. Our study analyzed the gene changes of 171 advanced cancer patients. We predicted that tumors gain new mutations but that TP53 mutations (guardian of the human genome) are conserved as the tumor progresses from primary to metastatic sites and across tissue types. We analyzed the primary and metastatic site gene changes in 25 tissue types and conducted in-depth analysis of colon and lung cancer sites for substantial changes. TP53 site specific mutations were different across tissue types and suggest different molecular changes. Other genetic changes that occur together with TP53 as drivers collectively alter how cells respond to signals which are important to tumor treatments. Abstract Molecular profiling with next generation sequencing (NGS) delivers key information on mutant gene sequences, copy number alterations, gene-fusions, and with immunohistochemistry (IHC), is a valuable tool in clinical decision making for patients entering investigational agent trials. Our objective was to elucidate mutational profiles from primary versus metastatic sites from advanced cancer patients to guide rational therapy. All phase I patients (n = 203) with advanced cancer were profiled by commercially available NGS platforms. The samples were annotated by histology, primary and metastatic site, biopsy site, gene mutations, mutation count/gene, and mutant TP53. A molecular profile of each patient was categorized into common and unique mutations, signaling pathways for each profile and TP53 mutations mapped to 3D-structure of p53 bound to DNA and pre/post therapy molecular response. Of the 171 patients analyzed, 145 had genetic alterations from primary and metastatic sites. The predominant histology was adenocarcinoma followed by squamous cell carcinoma, carcinoma of unknown primary site (CUPS), and melanoma. Of 790 unique mutations, TP53 is the most common followed by APC, KRAS, PIK3CA, ATM, PTEN, NOTCH1, BRCA2, BRAF, KMT2D, LRP1B, and CDKN2A. TP53 was found in most metastatic sites and appears to be a key driver of acquired drug resistance. We highlight examples of acquired mutational profiles pre-/post- targeted therapy in multiple tumor types with a menu of potential targeted agents. Conclusion: The mutational profiling of primary and metastatic lesions in cancer patients provides an opportunity to identify TP53 driver ‘pathways’ that may predict for drug sensitivity/resistance and guide rational drug combinations in clinical trials.
Validation and Practical Applications of Performance in a 6-Min Rowing Test in the Danish Armed Forces

Personnel of the Danish Armed Forces must complete a yearly basic physical fitness test consisting of a Cooper’s 12-min run test (CRT) and four strength-related bodyweight exercises. However, there is no validated alternative to the CRT allowing injured or sailing personnel to conduct the yearly basic physical fitness test. Therefore, the aim of this study was to validate performance in a 6-min rowing ergometer test (6MRT) against CRT performance. Thirty-one individuals (M/F: 20/11, age: 34 ± 12 years) employed at the Danish Armed Forces completed testing on two independent days; (I) the CRT on an outdoor track and (II) a 6MRT with pulmonary measurements of breath-by-breath oxygen uptake. In addition, 5 participants (M/F: 4/1, age: 40 ± 10 years) completed re-testing of the 6MRT. No difference was observed between VO2max estimated from the CRT and measured during the 6MRT. Absolute VO2max correlated strongly (r = 0.95; p < 0.001) to performance in the 6MRT, and moderately (r = 0.80; p < 0.001) to performance in the CRT. Bodyweight (BW) and fat free mass (FFM) correlated stronger to performance in the 6MRT compared to the CRT. 6MRT re-testing yielded similar performance results. The 6MRT is a valid and reliable alternative to the CRT, allowing injured or sailing personnel of the Danish Armed Forces to complete the basic physical fitness test as required, albeit 6MRT performance demands must be made relative to bodyweight.
Application of the isotope pairing technique in sediments where anammox and denitrification coexist

The isotope pairing technique (IPT) is a well‐established 15N method for estimation of denitrification. Presence of anammox, the anaerobic oxidation of NH4+ to N2 with NO2− results in violation of central assumptions on which the IPT is built. It is shown that anammox activity causes overestimation of the N2 production calculated by the IPT. However, experiments with different additions of 15NO3− will reveal the problems posed by anammox. Two alternative calculation procedures are presented, which enable a more accurate quantification of anammox and denitrification activity in sediments where the processes coexist. One procedure is based on measurements of 15N‐N2 production in 15NOx−‐amended intact sediment cores and data addressing the contribution of anammox to total N2 production estimated from slurry incubations. The other procedure is based on measurements of 15N2 production in at least two parallel series of sediment cores incubated with different 15NOx− additions. The calculation procedure presented is used on field data from four studies where the IPT was used and the potential anammox rate measured. The IPT overestimated total 14N‐N2 production rates by 0%, 2.5%, 31%, and 82% relative to the revised estimates from the 4 different sites, where anammox accounted for 0%, 6%, 18%, and 69.8%, respectively, of N2 production. The overestimation of true denitrification was, however, up to several hundred percent. Our analysis suggests however that the IPT does not seriously overestimate N2 production in estuarine sediments because anammox accounts for <6% of N2 production in such sediments, according to present knowledge.
Investigating differential miRNA expression profiling using serum and urine specimens for detecting potential biomarkers for early prostate cancer diagnosis

Background/aim MicroRNAs (miRNAs) are known up-to-date candidate biomarkers for several diseases. In addition, obtaining miRNA from different body fluids such as serum, plasma, saliva, and urine is relatively easy to handle. Herein we aimed to detect miRNAs as biomarkers for early stage prostate cancer (PC). For this purpose, we used urine and serum samples to detect any significant differences in miRNA profiles between patients and healthy controls. Materials and methods Total ribonucleic acid (RNA) in urine and serum samples were isolated from eight untreated PC patients, thirty healthy individuals were screened for miRNA profile, and candidate miRNAs were validated. Whole urinary and serum miRNA profile was analyzed using Affymetrix GeneChip miRNA 4.0 Arrays. Candidate miRNAs were investigated by stem-loop reverse transcription-polymerase chain reaction. Results When we analyzed the urinary samples of PC patients, 49 miRNAs were detected to be upregulated and 14 miRNAs were found to be downregulated when compared with healthy controls. According to the serum samples, 19 miRNAs were found to be upregulated, and 21 miRNAs were found to be downregulated when compared with healthy individuals as well. Interestingly, we detected only four overlapping miRNAs (MIR320A, MIR4535, MIR4706, MIR6750) that commonly increase or decrease in both serum and urine samples. Among them, MIR320A was found to be downregulated, and MIR4535, MIR4706, and MIR6750 were found to be upregulated for urine samples. However, only MIR6750 was upregulated and the other three miRNAs were downregulated for serum samples. Conclusion Notably, the expression profile of MIR320A was significantly altered in urine specimens of prostate cancer patients. We considered that MIR320A has been evaluated as a valuable biomarker that can be used in the early diagnosis of PC.
The quality of maternal nutrition and infant feeding counselling during antenatal care in South Asia

Abstract Antenatal care (ANC) provides a platform to counsel pregnant women on maternal nutrition and to prepare the mother to breastfeed. Recent reviews suggest that gaps in the coverage and quality of counselling during pregnancy may partly explain why services do not consistently translate to improved behavioural outcomes in South Asia. This scoping literature review collates evidence on the coverage and quality of counselling on maternal nutrition and infant feeding during ANC in five South Asian countries and the effectiveness of approaches to improve the quality of counselling. Coverage data were extracted from the most recent national surveys, and a scoping review of peer‐reviewed and grey literature (1990–2019) was conducted. Only Afghanistan and Pakistan have survey data on the coverage of counselling on both maternal nutrition and breastfeeding, nine studies described the quality of counselling and three studies assessed the effectiveness of interventions to improve the quality of services. This limited body of evidence suggests that inequalities in access to services, gaps in capacity building opportunities for frontline workers and the short duration and frequency of counselling contracts constrain quality, while the format, duration, frequency and content of health worker training, together with supportive supervision, are probable approaches to improve quality. Greater attention is needed to integrate indicators into monitoring and supervision mechanisms, periodic surveys and programme evaluations to assess the status of and track progress in improving quality and to build accountability for quality counselling, while research is needed to understand how best to assess and strengthen quality in specific settings.
Comparative Analysis of Hepatitis C Virus NS5A Dynamics and Localization in Assembly-Deficient Mutants

The hepatitis C virus (HCV) life cycle is a tightly regulated process, during which structural and non-structural proteins cooperate. However, the interplay between HCV proteins during genomic RNA replication and progeny virion assembly is not completely understood. Here, we studied the dynamics and intracellular localization of non-structural 5A protein (NS5A), which is a protein involved both in genome replication and encapsidation. An NS5A-eGFP (enhanced green fluorescent protein) tagged version of the strain JFH-1-derived wild-type HCV was compared to the corresponding assembly-deficient viruses Δcore, NS5A basic cluster 352–533 mutant (BCM), and serine cluster 451 + 454 + 457 mutant (SC). These analyses highlighted an increase of NS5A motility when the viral protein core was lacking. Although to a lesser extent, NS5A motility was also increased in the BCM virus, which is characterized by a lack of interaction of NS5A with the viral RNA, impairing HCV genome encapsidation. This observation suggests that the more static NS5A population is mainly involved in viral assembly rather than in RNA replication. Finally, NS4B exhibited a reduced co-localization with NS5A and lipid droplets for both Δcore and SC mutants, which is characterized by the absence of interaction of NS5A with core. This observation strongly suggests that NS5A is involved in targeting NS4B to lipid droplets (LDs). In summary, this work contributes to a better understanding of the interplay between HCV proteins during the viral life cycle.
Endocrine Disruptors Acting on Estrogen and Androgen Pathways Cause Reproductive Disorders through Multiple Mechanisms: A Review

Increasing contamination of the environment by toxic compounds such as endocrine disrupting chemicals (EDCs) is one of the major causes of reproductive defects in both sexes. Estrogen/androgen pathways are of utmost importance in gonadal development, determination of secondary sex characteristics and gametogenesis. Most of the EDCs mediate their action through respective receptors and/or downstream signaling. The purpose of this review is to highlight the mechanism by which EDCs can trigger antagonistic or agonistic response, acting through estrogen/androgen receptors causing reproductive defects that lead to infertility. In vitro, in vivo and in silico studies focusing on the impact of EDCs on estrogen/androgen pathways and related proteins published in the last decade were considered for the review. PUBMED and PUBCHEM were used for literature search. EDCs can bind to estrogen receptors (ERα and ERβ) and androgen receptors or activate alternative receptors such as G protein-coupled receptors (GPCR), GPR30, estrogen-related receptor (ERRγ) to activate estrogen signaling via downstream kinases. Bisphenol A, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethylene, polychlorinated biphenyls and phthalates are major toxicants that interfere with the normal estrogen/androgen pathways leading to infertility in both sexes through many ways, including DNA damage in spermatozoids, altered methylation pattern, histone modifications and miRNA expression.
Prenatal Opioid Exposure and ADHD Childhood Symptoms: A Meta-Analysis

To systematically investigate the association between prenatal opioid exposure (POE) and attention-deficit hyperactivity disorder (ADHD) symptoms in children 2–18 years old, studies were searched using PubMed, CINAHL, PsycINFO, and Web of Science from January of 1950 to October of 2019. Inclusion criteria were observational studies reporting ADHD symptoms of children with POE compared with non-exposed children or normative data. The study protocol was registered with PROSPERO: CRD42018115967. Two independent reviewers extracted data on hyperactivity/impulsivity, inattention symptoms, ADHD combined subscale symptoms, and sample characteristics. Of 223 articles screened, seven met the inclusion criteria. Data represent 319 children with POE and 1308 non-exposed children from 4.3 to 11.2 mean years from five countries. POE was positively associated with childhood hyperactivity/impulsivity (d = 1.40; 95% CI, 0.49–2.31; p = 0.003), inattention (d = 1.35; 95% CI, 0.69–2.01; p < 0.0001), and combined ADHD symptoms scores (d = 1.27; 95% CI = 0.79–1.75; p < 0.0001). POE was positively associated with ADHD combined symptom scores at preschool (d = 0.83, 95% CI, 0.57, 1.09; p < 0.0001) and school age (d = 1.45, 95% CI, 0.85 to 2.04; p < 0.0001). Results suggest increased risk of ADHD symptoms during school age. Future research is needed to clarify the relationship between biological, social, and environmental risk and ADHD symptoms for children who experienced POE.