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HIV-1 relies on host RNA polymeraseII (Pol II) to transcribe its genome and uses multiple transcription start sites (TSS), including three consecutive guanosines located near the U3-R junction, to generate transcripts containing three, two, and one guanosine at the 5' end, referred to as 3G, 2G, and 1G RNA, respectively. The 1G RNA is preferentially selected for packaging, indicating that these 99.9% identical RNAs exhibit functional differences and highlighting the importance of TSS selection. Here, we demonstrate that TSS selection is regulated by sequences between the CATA/TATA box and the beginning of R. Furthermore, we have generated two HIV-1 mutants with distinct 2-nucleotide modifications that predominantly express 3G RNA or 1G RNA. Both mutants can generate infectious viruses and undergo multiple rounds of replication in T cells. However, both mutants exhibit replication defects compared to the wild-type virus. The 3G-RNA-expressing mutant displays an RNA genome-packaging defect and delayed replication kinetics, whereas the 1G-RNA-expressing mutant exhibits reduced Gag expression and a replication fitness defect. Additionally, reversion of the latter mutant is frequently observed, consistent with sequence correction by plus-strand DNA transfer during reverse transcription. These findings demonstrate that HIV-1 maximizes its replication fitness by usurping the TSS heterogeneity of host RNA Pol II to generate unspliced RNAs with different specialized roles in viral replication. The three consecutive guanosines at the junction of U3 and R may also maintain HIV-1 genome integrity during reverse transcription. These studies reveal the intricate regulation of HIV-1 RNA and complex replication strategy.
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VIH-1 , ARN Polimerasa II , ARN Polimerasa II/genética , ARN Polimerasa II/metabolismo , VIH-1/fisiología , Sitio de Iniciación de la Transcripción , ARN Viral/genética , ARN Viral/metabolismo , Replicación Viral/genéticaRESUMEN
Ionizing radiation such as X-rays and γ-rays has been extensively studied and used in various fields such as medical imaging, radiographic nondestructive testing, nuclear defense, homeland security, and scientific research. Therefore, the detection of such high-energy radiation with high-sensitivity and low-cost-based materials and devices is highly important and desirable. Halide perovskites have emerged as promising candidates for radiation detection due to the large light absorption coefficient, large resistivity, low leakage current, high mobility, and simplicity in synthesis and processing as compared with commercial silicon (Si) and amorphous selenium (a-Se). In this review, we provide an extensive overview of current progress in terms of materials development and corresponding device architectures for radiation detection. We discuss the properties of a plethora of reported compounds involving organic-inorganic hybrid, all-inorganic, all-organic perovskite and antiperovskite structures, as well as the continuous breakthroughs in device architectures, performance, and environmental stability. We focus on the critical advancements of the field in the past few years and we provide valuable insight for the development of next-generation materials and devices for radiation detection and imaging applications.
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BACKGROUND: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates. METHODS: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches. RESULTS: CDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo. CONCLUSION: Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
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Chalcogel represents a unique class of meso- to macroporous nanomaterials that offer applications in energy and environmental pursuits. Here, the synthesis of an ion-exchangeable amorphous chalcogel using a nominal composition of K2CoMo2S10 (KCMS) at room temperature is reported. Synchrotron X-ray pair distribution function (PDF), X-ray absorption near-edge structure (XANES), and extended X-ray absorption fine structure (EXAFS) reveal a plausible local structure of KCMS gel consisting of Mo5+ 2 and Mo4+ 3 clusters in the vicinity of di/polysulfides which are covalently linked by Co2+ ions. The ionically bound K+ ions remain in the percolating pores of the Co-Mo-S covalent network. XANES of Co K-edge shows multiple electronic transitions, including quadrupole (1sâ3d), shakedown (1sâ4p + MLCT), and dipole allowed 1sâ4p transitions. Remarkably, despite a lack of regular channels as in some crystalline solids, the amorphous KCMS gel shows ion-exchange properties with UO2 2+ ions. Additionally, it also presents surface sorption via [SââââUO2 2+] covalent interactions. Overall, this study underscores the synthesis of quaternary chalcogels incorporating alkali metals and their potential to advance separation science for cations and oxo-cationic species by integrating a synergy of surface sorption and ion-exchange.
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Electroencephalogram (EEG) microstate analysis entails finding dynamics of quasi-stable and generally recurrent discrete states in multichannel EEG time series data and relating properties of the estimated state-transition dynamics to observables such as cognition and behavior. While microstate analysis has been widely employed to analyze EEG data, its use remains less prevalent in functional magnetic resonance imaging (fMRI) data, largely due to the slower timescale of such data. In the present study, we extend various data clustering methods used in EEG microstate analysis to resting-state fMRI data from healthy humans to extract their state-transition dynamics. We show that the quality of clustering is on par with that for various microstate analyses of EEG data. We then develop a method for examining test-retest reliability of the discrete-state transition dynamics between fMRI sessions and show that the within-participant test-retest reliability is higher than between-participant test-retest reliability for different indices of state-transition dynamics, different networks, and different data sets. This result suggests that state-transition dynamics analysis of fMRI data could discriminate between different individuals and is a promising tool for performing fingerprinting analysis of individuals.
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Cognición , Electroencefalografía , Humanos , Reproducibilidad de los Resultados , Factores de TiempoRESUMEN
Effective removal of chemically toxic selenium oxoanions at high-capacity and trace levels from contaminated water remains a challenge in current scientific pursuits. Here, we report the functionalization of the MgAl layered double hydroxide with molybdenum-oxysulfide (MoO2S2) anion, referred to as LDH-MoO2S2, and its potential to sequester SeVIO42- and SeIVO32- from aqueous solution. LDH-MoO2S2 nanosheets were synthesized by an ion exchange method in solution. Synchrotron X-ray pair distribution function (PDF) and extended X-ray absorption fine structure (EXAFS) revealed an unexpected transformation of the MoO2S22- to Mo2O2S62- like species during the intercalation process. LDH-MoO2S2 is remarkably efficient in removing SeO42- and SeO32- ions from the ppm to trace level (≤10 ppb), with distribution constant (Kd) ranging from 104 to 105 mL/g. This material showed exceptionally high sorption capacities of 237 and 358 mg/g for SeO42- and SeO32-, respectively. Furthermore, LDH-MoO2S2 demonstrates substantial affinity and efficiency to remove SeO32-/SeO42- even in the presence of competitive ions from contaminated water. Hence, the removal of selenium (VI/IV) oxoanions collectively occurs through reductive precipitation and ion exchange mechanisms. This work provides significant insights into the chemical structure of the MoO2S2 anion into LDH and emphasizes its exceptional potential for high-capacity selenium removal and positioning it as a premier sorbent for selenium oxoanions.
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BACKGROUND: The surge in digital media consumption, coupled with the ensuing consequences of digital addiction, has witnessed a rapid increase, particularly after the initiation of the COVID-19 pandemic. Despite some studies exploring specific technological addictions, such as internet or social media addiction, in Bangladesh, there is a noticeable gap in research focusing on digital addiction in a broader context. Thus, this study aims to investigate digital addiction among students taking the university entrance test, examining its prevalence, contributing factors, and geographical distribution using GIS techniques. METHODS: Data from a cross-sectional survey were collected from a total of 2,157 students who were taking the university entrance test at Jahangirnagar University, Bangladesh. A convenience sampling method was applied for data collection using a structured questionnaire. Statistical analyses were performed with SPSS 25 Version and AMOS 23 Version, whereas ArcGIS 10.8 Version was used for the geographical distribution of digital addiction. RESULTS: The prevalence of digital addiction was 33.1% (mean score: 16.05 ± 5.58). Those students who are attempting the test for a second time were more likely to be addicted (42.7% vs. 39.1%), but the difference was not statistically significant. Besides, the potential factors predicted for digital addiction were student status, satisfaction with previous mock tests, average monthly expenditure during the admission test preparation, and depression. No significant difference was found between digital addiction and districts. However, digital addiction was higher in the districts of Manikganj, Rajbari, Shariatpur, and Chittagong Hill Tract areas, including Rangamati, and Bandarban. CONCLUSIONS: The study emphasizes the pressing need for collaborative efforts involving educational policymakers, institutions, and parents to address the growing digital addiction among university-bound students. The recommendations focus on promoting alternative activities, enhancing digital literacy, and imposing restrictions on digital device use, which are crucial steps toward fostering a healthier digital environment and balanced relationship with technology for students.
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Sistemas de Información Geográfica , Trastorno de Adicción a Internet , Estudiantes , Humanos , Femenino , Masculino , Estudiantes/psicología , Estudiantes/estadística & datos numéricos , Universidades , Estudios Transversales , Prevalencia , Adulto Joven , Trastorno de Adicción a Internet/epidemiología , Trastorno de Adicción a Internet/psicología , Bangladesh/epidemiología , COVID-19/epidemiología , COVID-19/psicología , Conducta Adictiva/epidemiología , Conducta Adictiva/psicología , Adulto , Adolescente , Encuestas y CuestionariosRESUMEN
The Global Navigation Satellite System (GNSS) software-defined receivers offer greater flexibility, cost-effectiveness, customization, and integration capabilities compared to traditional hardware-based receivers, making them essential for a wide range of applications. The continuous evolution of GNSS research and the availability of new features require these software-defined receivers to upgrade continuously to facilitate the latest requirements. The Finnish Geospatial Research Institute (FGI) has been supporting the GNSS research community with its open-source implementations, such as a MATLAB-based GNSS software-defined receiver `FGI-GSRx' and a Python-based implementation `FGI-OSNMA' for utilizing Galileo's Open Service Navigation Message Authentication (OSNMA). In this context, longer datasets are crucial for GNSS software-defined receivers to support adaptation, optimization, and facilitate testing to investigate and develop future-proof receiver capabilities. In this paper, we present an updated version of FGI-GSRx, namely, FGI-GSRx-v2.0.0, which is also available as an open-source resource for the research community. FGI-GSRx-v2.0.0 offers improved performance as compared to its previous version, especially for the execution of long datasets. This is carried out by optimizing the receiver's functionality and offering a newly added parallel processing feature to ensure faster capabilities to process the raw GNSS data. This paper also presents an analysis of some key design aspects of previous and current versions of FGI-GSRx for a better insight into the receiver's functionalities. The results show that FGI-GSRx-v2.0.0 offers about a 40% run time execution improvement over FGI-GSRx-v1.0.0 in the case of the sequential processing mode and about a 59% improvement in the case of the parallel processing mode, with 17 GNSS satellites from GPS and Galileo. In addition, an attempt is made to execute v2.0.0 with MATLAB's own parallel computing toolbox. A detailed performance comparison reveals an improvement of about 43% in execution time over the v2.0.0 parallel processing mode for the same GNSS scenario.
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Ribosomally synthesized post-translationally modified peptides (RiPPs) are a novel category of bioactive natural products (NPs). Streptomyces bacteria are a potential source of many bioactive NPs. Limited opportunities are available to characterize all the bioactive NP gene clusters. In this study, 410 sequences of Streptomyces were analyzed for RiPPs through genome mining using the National Center for Biotechnology Information (NCBI), by combining BAGEL and anti-SMASH. A total of 4098 RiPPs were found; including both classified (lanthipeptide, RiPP-like, bacteriocin, LAPs, lassopeptide, thiopeptides) and nonclassified RiPPs. Soil was identified as a rich habitat for RiPPs. These data may offer alternative future remedies for various health issues.
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The new coronavirus (SARS-CoV-2) halts the world economy and caused unbearable medical emergency due to high transmission rate and also no effective vaccine and drugs has been developed which brought the world pandemic situations. The main protease (Mpro) of SARS-CoV-2 may act as an effective target for drug development due to the conservation level. Herein, we have employed a rigorous literature review pipeline to enlist 3063 compounds from more than 200 plants from the Asian region. Therefore, the virtual screening procedure helps us to shortlist the total compounds into 19 based on their better binding energy. Moreover, the Prime MM-GBSA procedure screened the compound dataset further where curcumin, gartanin and robinetin had a score of (-59.439, -52.421 and - 47.544) kcal/mol, respectively. The top three ligands based on binding energy and MM-GBSA scores have most of the binding in the catalytic groove Cys145, His41, Met165, required for the target protein inhibition. The molecular dynamics simulation study confirms the docked complex rigidity and stability by exploring root mean square deviations, root mean square fluctuations, solvent accessible surface area, radius of gyration and hydrogen bond analysis from simulation trajectories. The post-molecular dynamics analysis also confirms the interactions of the curcumin, gartanin and robinetin in the similar binding pockets. Our computational drug designing approach may contribute to the development of drugs against SARS-CoV-2.
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COVID-19/virología , Plantas/química , Inhibidores de Proteasas/metabolismo , SARS-CoV-2/enzimología , Humanos , Simulación de Dinámica MolecularRESUMEN
The development of the nervous system involves a coordinated succession of events including the migration of GABAergic (γ-aminobutyric-acid-releasing) neurons from ventral to dorsal forebrain and their integration into cortical circuits. However, these interregional interactions have not yet been modelled with human cells. Here we generate three-dimensional spheroids from human pluripotent stem cells that resemble either the dorsal or ventral forebrain and contain cortical glutamatergic or GABAergic neurons. These subdomain-specific forebrain spheroids can be assembled in vitro to recapitulate the saltatory migration of interneurons observed in the fetal forebrain. Using this system, we find that in Timothy syndrome-a neurodevelopmental disorder that is caused by mutations in the CaV1.2 calcium channel-interneurons display abnormal migratory saltations. We also show that after migration, interneurons functionally integrate with glutamatergic neurons to form a microphysiological system. We anticipate that this approach will be useful for studying neural development and disease, and for deriving spheroids that resemble other brain regions to assemble circuits in vitro.
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Neuronas/citología , Prosencéfalo/citología , Prosencéfalo/crecimiento & desarrollo , Esferoides Celulares/citología , Trastorno Autístico/genética , Trastorno Autístico/patología , Línea Celular , Movimiento Celular , Células Cultivadas , Femenino , Neuronas GABAérgicas/citología , Ácido Glutámico/metabolismo , Humanos , Interneuronas/citología , Interneuronas/patología , Síndrome de QT Prolongado/genética , Síndrome de QT Prolongado/patología , Masculino , Modelos Biológicos , Neurogénesis , Neuronas/patología , Células Madre Pluripotentes/citología , Prosencéfalo/anatomía & histología , Sinapsis/fisiología , Sindactilia/genética , Sindactilia/patologíaRESUMEN
BACKGROUND AND OBJECTIVES: The prevalence of occupational injuries among blue-collar workers is higher in the stone-crushing industries due to high-risk and iterant nature of the work. These occupational injuries, in turn, caused workers' ill health, as well as death, which eventually diminish the gross domestic product. We aimed at assessing the attributes of occupational injuries and the risk associated with the hazards in the stone-crushing industry. METHODS: This study utilized a questionnaire base cross-sectional survey that was conducted from September 2019 to February 2020. Data were collected from 32 stone-crushing factories of Eastern Bangladesh and analyzed to show their relationship with different variables. The risk levels associated with the frequent hazardous events were measured using a Semi-Quantitative Risk Assessment Matrix. RESULTS: Most of the injuries were found to occur between 12:00 and 16:00 h. Nearly a fifth of the injuries were serious or critical in nature, caused the workers to be absent at least a week. Exposure to excessive dust, working without personal protective equipment (PPE), and improper lifting and handling techniques caused one-third of injuries. Wrist and hand/fingers, back and lower back, feet/toe, eye, knee, arm, neck and head, and ankle were found as most injured body parts. The primary cause of most injuries was the workers' failure to use PPE. All major hazardous events were found to possess a high-risk level. CONCLUSION: Our finding suggests that stone crushing is one of the most hazardous industries and the practitioners must consider the findings when implementing a risk avoidance policy.
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Exposición Profesional , Salud Laboral , Traumatismos Ocupacionales , Humanos , Traumatismos Ocupacionales/epidemiología , Estudios Transversales , Medición de Riesgo , Industrias , Exposición Profesional/efectos adversosRESUMEN
This investigation is centered on the effectiveness of methylene blue (MB), a cationic dye, adsorbed from an aqueous media by H3PO4 activated papaya skin/peels (PSPAC), with initial pH (2-10), contact time (30-180 min), MB dye concentration (varying from 10 to 50 mg/L), and MB dose (0.1-0.5 gm). The findings show that the best optimal conditions for MB dye removal occur at a 6 pH, 0.3 gm dose of PSPAC adsorbent for 10 mg/L MB dye concentration, with 90 min of contact time. To optimize and validate the extraction efficiency of MB dye, a response surface methodology (RSM) study was conducted using a central composite design (CCD) with a regression model showing R2 = 0.9940. FT-IR spectroscopy shows, CO, and O-H stretching functional groups while FE-SEM is assessed to supervise morphological features of the PSPAC adsorbent. The peak adsorption capacity with 46.95 mg/g for the Langmuir isotherm model conveniently satisfies the adsorption process with R2 = 0.9984 while with R2 = 0.999, a kinetic model, pseudo-second-order, confirms MB dye adsorption by PSPAC adsorbent. Moreover, thermodynamic parameters including ΔGáµ, ΔH°, and ΔS° were computed and found to be spontaneous and exothermic. Furthermore, regeneration studies employed with NaOH (0.1 M) and HCl (0.1 M) solution media show an acceptable MB removal efficiency consecutive up to three cycles. The study highlights that H3PO4 papaya skin/peel (PSPAC) is an effectual, sustainable, reasonably available biosorbent to remove industrial cationic dyes disposal.
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Carica , Contaminantes Químicos del Agua , Azul de Metileno/química , Colorantes/química , Cinética , Espectroscopía Infrarroja por Transformada de Fourier , Concentración de Iones de Hidrógeno , Termodinámica , Agua , AdsorciónRESUMEN
The present study captures the precipitation synthesis of zinc nanoparticles and modification with alumina and oleic acid. The crystalline size evaluated from the XRD profile of the zinc oxide nanoparticles was 18.05 nm but was reduced to 14.20 and 14.50 nm upon modification with oleic acid and alumina. The XRD spectra also showed evidence of the amorphous nature of zinc oxide nanoparticles and subsequent enhancement upon modification. A porous appearance was observed in the SEM instrumentation but seems to be enhanced by modification. The FTIR absorption spectra of the nanoparticles showed a peak associated with ZnO vibration around 449 cm, but the enhanced intensity was observed due to modification. The prepared ZnO-NPs and the modified samples were good materials for the adsorption removal of glyphosate from water, recording efficiencies above 94% at neutral pH and showing a possible incremental trend with an enhanced period of contact and adsorbent dosage. The adsorbents showed maximum capacity that ranged from 82.85 to 82. 97 mg/g. The adsorption models of Freundlich, Temkin, Dubinin-Radushkevich and BET showed excellent fitness. Results from computational results complemented experimental data and were used to identify the sites for adsorption and characteristics of molecular descriptors for the systems.
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Nanopartículas del Metal , Nanopartículas , Plaguicidas , Contaminantes Químicos del Agua , Óxido de Zinc , Óxido de Zinc/química , Nanopartículas del Metal/química , Ácido Oléico , Zinc , Monitoreo del Ambiente , Nanopartículas/química , Agua/química , Óxido de Aluminio , Adsorción , Contaminantes Químicos del Agua/análisis , Cinética , Concentración de Iones de Hidrógeno , GlifosatoRESUMEN
BACKGROUND: Coinfection with human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1) diminishes the value of the CD4+ T-cell count in diagnosing AIDS, and increases the rate of HTLV-1-associated myelopathy. It remains elusive how HIV-1/HTLV-1 coinfection is related to such characteristics. We investigated the mutual effect of HIV-1/HTLV-1 coinfection on their integration sites (ISs) and clonal expansion. METHODS: We extracted DNA from longitudinal peripheral blood samples from 7 HIV-1/HTLV-1 coinfected, and 12 HIV-1 and 13 HTLV-1 monoinfected individuals. Proviral loads (PVL) were quantified using real-time polymerase chain reaction (PCR). Viral ISs and clonality were quantified by ligation-mediated PCR followed by high-throughput sequencing. RESULTS: PVL of both HIV-1 and HTLV-1 in coinfected individuals was significantly higher than that of the respective virus in monoinfected individuals. The degree of oligoclonality of both HIV-1- and HTLV-1-infected cells in coinfected individuals was also greater than in monoinfected subjects. ISs of HIV-1 in cases of coinfection were more frequently located in intergenic regions and transcriptionally silent regions, compared with HIV-1 monoinfected individuals. CONCLUSIONS: HIV-1/HTLV-1 coinfection makes an impact on the distribution of viral ISs and clonality of virus-infected cells and thus may alter the risks of both HTLV-1- and HIV-1-associated disease.
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Coinfección , Infecciones por VIH/complicaciones , VIH-1 , Infecciones por HTLV-I/complicaciones , Virus Linfotrópico T Tipo 1 Humano , Paraparesia Espástica Tropical/epidemiología , Recuento de Linfocito CD4 , Infecciones por VIH/epidemiología , VIH-1/genética , VIH-1/aislamiento & purificación , Infecciones por HTLV-I/epidemiología , Secuenciación de Nucleótidos de Alto Rendimiento , Virus Linfotrópico T Tipo 1 Humano/genética , Virus Linfotrópico T Tipo 1 Humano/aislamiento & purificación , Humanos , Paraparesia Espástica Tropical/diagnóstico , Provirus/genética , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Hyperpolarized orthohydrogen (o-H2 ) is a frequent product of parahydrogen-based hyperpolarization approaches like signal amplification by reversible exchange (SABRE), where the hyperpolarized o-H2 signal is usually absorptive. We describe a novel manifestation of this effect wherein large antiphase o-H2 signals are observed, with 1 H enhancements up to ≈500-fold (effective polarization PH ≈1.6 %). This anomalous effect is attained only when using an intact heterogeneous catalyst constructed using a metal-organic framework (MOF) and is qualitatively independent of substrate nature. This seemingly paradoxical observation is analogous to the "partial negative line" (PNL) effect recently explained in the context of Parahydrogen Induced Polarization (PHIP) by Ivanov and co-workers. The two-spin order of the o-H2 resonance is manifested by a two-fold higher Rabi frequency, and the lifetime of the antiphase HP o-H2 resonance is extended by several-fold.
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Recent years, Burkholderia species have emerged as a new source of natural products (NPs) with increasing attractions. Genome mining suggests the Burkholderia genomes include many natural product biosynthetic gene clusters (BGCs) which are new targets for drug discovery. In order to collect more Burkholderia, here, a strain S-53 was isolated from the soil samples on a mountain area in Changde, P.R. China and verified by comparative genetic analysis to belong to Burkholderia. The complete genome of Burkholderia strain S-53 is 8.2 Mbps in size with an average G + C content of 66.35%. Its taxonomy was both characterized by 16S rRNA- and whole genome-based phylogenetic trees. Bioinformatic prediction in silico revealed it has a total of 15 NP BGCs, some of which may encode unknown products. It is expectable that availability of these BGCs will speed up the identification of new secondary metabolites from Burkholderia and help us understand how sophisticated BGC regulation works.
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Burkholderia , Burkholderia/genética , Genoma Bacteriano , Filogenia , ARN Ribosómico 16S/genética , Secuenciación Completa del Genoma , Familia de MultigenesRESUMEN
BACKGROUND: Common memory aids for people with dementia at home are recommended. However, rigorous evaluation is lacking, particularly what guidance or support is valued. OBJECTIVE: To investigate effects of memory aids and guidance by dementia support practitioners (DSPs) for people in early-stage dementia through a pragmatic, randomised controlled trial. METHODS: Of 469 people with mild-to-moderate dementia and their informal carers, 468 were randomised to a DSP with memory aids or to usual care plus existing dementia guide. Allocation was stratified by Trust/Health Board; time since first attendance at memory service; gender; age; and living with primary carer or not. Primary outcome was Bristol Activities of Daily Living Scale (BADLS) Score at 3 and 6 months (primary end-point). Secondary outcomes for people with dementia: quality of life (CASP-19; DEMQOL); cognition and functioning (Clinical Dementia Rating Scale; S-MMSE); capability (ICECAP-O); social networks (LSNS-R); and instrumental daily living activities (R-IDDD). Secondary outcomes for carers: psychological health (GHQ-12); sense of competence (SSCQ). RESULTS: DSPs were successfully trained, compliance was good and welcomed by participants. Mean 6 months BADLS Score increased to 14.6 (SD: 10.4) in intervention and 12.6 (SD: 8.1) in comparator, indicative of greater dependence in the activities of daily living. Adjusted between-group difference was 0.38 (95% CI: -0.89 to 1.65, p=0.56). Though this suggests greater dependency in the intervention group the difference was not significant. No differences were found in secondary outcomes. CONCLUSIONS: This intervention did not maintain independence in the activities of daily living with no improvement in other outcomes for people with dementia or carers. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN12591717.
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Demencia , Actividades Cotidianas/psicología , Cuidadores/psicología , Cognición , Demencia/psicología , Demencia/terapia , Humanos , Calidad de VidaRESUMEN
Repurposing the large arsenal of existing non-cancer drugs is an attractive proposition to expand the clinical pipelines for cancer therapeutics. The earlier successes in repurposing resulted primarily from serendipitous findings, but more recently, drug or target-centric systematic identification of repurposing opportunities continues to rise. Kinases are one of the most sought-after anti-cancer drug targets over the last three decades. There are many non-cancer approved drugs that can inhibit kinases as "off-targets" as well as many existing kinase inhibitors that can target new additional kinases in cancer. Identifying cancer-associated kinase inhibitors through mining commercial drug databases or new kinase targets for existing inhibitors through comprehensive kinome profiling can offer more effective trial-ready options to rapidly advance drugs for clinical validation. In this review, we argue that drug repurposing is an important approach in modern drug development for cancer therapeutics. We have summarized the advantages of repurposing, the rationale behind this approach together with key barriers and opportunities in cancer drug development. We have also included examples of non-cancer drugs that inhibit kinases or are associated with kinase signalling as a basis for their anti-cancer action.
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Antineoplásicos , Neoplasias , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bases de Datos Farmacéuticas , Reposicionamiento de Medicamentos/métodos , Humanos , Neoplasias/tratamiento farmacológicoRESUMEN
BACKGROUND: Migraine is one of the main causes of long-term morbidity, and it is one of the major contributors of all types of headaches in worldwide. Despite its disruptive effect, it is frequently underdiagnosed and undertreated in Bangladesh. The aim of the present study was to determine the prevalence of migraines and its impact on daily life of university students in Bangladesh. METHODS: This cross-sectional study was conducted among 2,352 students of Rajshahi University and Jahangirnagar University during March 2020 through a self-administered online survey. ID Migraine™ scale and HIT-6 scale were used to screen migraine and its impact respectively. Frequency distribution, Chi-square test and t-test along with multiple logistic regressions model were used to determine the prevalence and associated factors of migraine respectively. RESULTS: The overall prevalence of migraine among the participants was 21.4%. The prevalence was higher among females (29%) than males (12%). A multivariable logistic regression model provided the following eight risk factors of migraine: (i) gender (p < 0.01), (ii) family income (p < 0.01), (iii) marital status (p < 0.01), (iv) infrequent exercise (p < 0.01), (v) family history of headache (p < 0.01), (vi) high screen time (p < 0.05), (vii) depressive symptoms (p < 0.05) and (viii) anxiety disorder (p < 0.01). More than two-thirds of the people with migraines reported more than five attacks during the past month with moderate to severe intense headache. Stress was the most reported trigger of migraine among university students (71%) followed by irregular sleep (47%), academic pressure (33%), and external noise (28%). Almost 37% of the participants who had migraines reported that headache caused severe impact in their day to day life. CONCLUSIONS: The prevalence of migraine among university students of Bangladesh is alarmingly high. Frequent migraine attacks and severe intensity of headache cause a substantial level of impact among the sufferers. Cautious avoidance of the triggering factors through appropriate interventions and prophylactic medication can mitigate the negative impact of migraine as well as improve the quality of life.