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1.
Front Public Health ; 12: 1361374, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38979046

RESUMO

Introduction: Many people expressed concern over coronavirus vaccinations' reliability and side effects. This research aimed to assess university students' perceptions and experiences regarding the side effects of the COVID-19 vaccines in Bangladesh. Method: We conducted an online cross-sectional survey to collect responses from university students vaccinated with any vaccines administered in Bangladesh between November 2021 to April 2022. Bangladeshi university students over the age of 18 and having an internet connection was included in the study. A binary logistic regression analysis along with Pearson's Chi-square test were used to identify COVID-19 vaccine-related side effects predictors after receiving the first dose. Results: A total of 1,176 participants responded voluntarily to the online study, and most were vaccinated. More than half of the participants received the Sinopharm vaccine (56.5%), while others received Covishield (8.9%), Moderna (7.3%), and Pfizer (5.8%) vaccine. Around 32% of the participants reported side effects after receiving the first dose of the vaccine, including pain and edema (78.4%), body temperature (20.3%), and headache (14.5%), while a few experienced allergy, anxiety, and uneasy feelings. About 17% of the participants reported experiencing side effects after the second dose of the vaccine, including pain and edema (7.5%), body temperature (8.8%), and headache (7.3%). Most side effects were significantly associated with the Moderna vaccine (p < 0.001). Female students and those previously infected with COVID-19 were significantly associated with the side effects after taking the first dose of the vaccine. Conclusion: We found that side effects are mild and did not pose a significant challenge to Bangladesh's effort in managing and reducing the risk associated with the COVID-19 pandemic.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Estudantes , Humanos , Estudos Transversais , Masculino , Feminino , Estudantes/psicologia , Estudantes/estatística & dados numéricos , Vacinas contra COVID-19/efeitos adversos , Vacinas contra COVID-19/administração & dosagem , Universidades , Bangladesh , COVID-19/prevenção & controle , Adulto Jovem , Inquéritos e Questionários , Adulto , Adolescente , SARS-CoV-2 , Vacinação/estatística & dados numéricos , Vacinação/psicologia
2.
Nat Commun ; 15(1): 4653, 2024 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-38821942

RESUMO

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Heterogeneidade Genética , Neoplasias Pulmonares , Camundongos Endogâmicos NOD , Camundongos SCID , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Feminino , Sequenciamento do Exoma , Genômica/métodos , Masculino , Ensaios Antitumorais Modelo de Xenoenxerto , Xenoenxertos , Modelos Animais de Doenças , Idoso , Pessoa de Meia-Idade
3.
Nat Commun ; 15(1): 3292, 2024 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-38632274

RESUMO

Cancers of Unknown Primary (CUP) remains a diagnostic and therapeutic challenge due to biological heterogeneity and poor responses to standard chemotherapy. Predicting tissue-of-origin (TOO) molecularly could help refine this diagnosis, with tissue acquisition barriers mitigated via liquid biopsies. However, TOO liquid biopsies are unexplored in CUP cohorts. Here we describe CUPiD, a machine learning classifier for accurate TOO predictions across 29 tumour classes using circulating cell-free DNA (cfDNA) methylation patterns. We tested CUPiD on 143 cfDNA samples from patients with 13 cancer types alongside 27 non-cancer controls, with overall sensitivity of 84.6% and TOO accuracy of 96.8%. In an additional cohort of 41 patients with CUP CUPiD predictions were made in 32/41 (78.0%) cases, with 88.5% of the predictions clinically consistent with a subsequent or suspected primary tumour diagnosis, when available (23/26 patients). Combining CUPiD with cfDNA mutation data demonstrated potential diagnosis re-classification and/or treatment change in this hard-to-treat cancer group.


Assuntos
Ácidos Nucleicos Livres , Neoplasias Primárias Desconhecidas , Humanos , Ácidos Nucleicos Livres/genética , Neoplasias Primárias Desconhecidas/genética , Biomarcadores Tumorais/genética , Metilação de DNA , Biópsia Líquida
4.
Proc Natl Acad Sci U S A ; 120(47): e2307773120, 2023 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-37963246

RESUMO

The expansion and intensification of livestock production is predicted to promote the emergence of pathogens. As pathogens sometimes jump between species, this can affect the health of humans as well as livestock. Here, we investigate how livestock microbiota can act as a source of these emerging pathogens through analysis of Streptococcus suis, a ubiquitous component of the respiratory microbiota of pigs that is also a major cause of disease on pig farms and an important zoonotic pathogen. Combining molecular dating, phylogeography, and comparative genomic analyses of a large collection of isolates, we find that several pathogenic lineages of S. suis emerged in the 19th and 20th centuries, during an early period of growth in pig farming. These lineages have since spread between countries and continents, mirroring trade in live pigs. They are distinguished by the presence of three genomic islands with putative roles in metabolism and cell adhesion, and an ongoing reduction in genome size, which may reflect their recent shift to a more pathogenic ecology. Reconstructions of the evolutionary histories of these islands reveal constraints on pathogen emergence that could inform control strategies, with pathogenic lineages consistently emerging from one subpopulation of S. suis and acquiring genes through horizontal transfer from other pathogenic lineages. These results shed light on the capacity of the microbiota to rapidly evolve to exploit changes in their host population and suggest that the impact of changes in farming on the pathogenicity and zoonotic potential of S. suis is yet to be fully realized.


Assuntos
Infecções Estreptocócicas , Streptococcus suis , Doenças dos Suínos , Animais , Humanos , Suínos , Infecções Estreptocócicas/veterinária , Fazendas , Doenças dos Suínos/epidemiologia , Virulência/genética , Streptococcus suis/genética , Gado
5.
Heliyon ; 9(10): e20636, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37842564

RESUMO

Mycobacterium tuberculosis is one of the major invasive intracellular pathogens causing most deaths by a single infectious agent. The interaction between host immune cells and this pathogen is the focal point of the disease, Tuberculosis. Host immune cells not only mount the protective action against this pathogen but also serve as the primary niche for growth. Thus, recognition of this pathogen by host immune cells and following signaling cascades are key dictators of the disease state. Immune cells, mainly belonging to myeloid cell lineage, recognize a wide variety of Mycobacterium tuberculosis ligands ranging from carbohydrate and lipids to proteins to nucleic acids by different membrane-bound and soluble pattern recognition receptors. Simultaneous interaction between different host receptors and pathogen ligands leads to immune-inflammatory response as well as contributes to virulence. This review summarizes the contribution of pattern recognition receptors of host immune cells in recognizing Mycobacterium tuberculosis and subsequent initiation of signaling pathways to provide the molecular insight of the specific Mtb ligands interacting with specific PRR, key adaptor molecules of the downstream signaling pathways and the resultant effector functions which will aid in identifying novel drug targets, and developing novel drugs and adjuvants.

6.
Elife ; 122023 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-36892933

RESUMO

Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.


Lung squamous cell carcinoma is the second most common lung cancer. However, very little is known about how normal tissues in the lung develop in to these tumours. Like many cancers, this transformation comprises of an intermediate phase where healthy cells begin to form lesions that may (or may not) progress in to tumours. Understanding the biology of these lesions in lung squamous cell carcinoma may help clinicians detect them before they become cancerous. Knowing which genes are switched on and off during this intermediary phase can provide clues as to how these lesions form. There are already some publicly available transcriptional datasets showing the activity of tens of thousands of genes in pre-cancerous lesions extracted from patients with lung squamous cell carcinoma. But not every laboratory has the bioinformatic tools and skills required to interrogate these extensive databases. To address this, Roberts et al. built an open-source platform called XTABLE (short for Exploring Transcriptomes of Bronchial Lesions) which can analyse transcriptional datasets in multiple ways depending on the needs of the user. For instance, the tool can stratify the data into groups based on different parameters, such as the lesions potential to progress in to cancer, to see how the genes of the groups compare. It can also analyse the activity of individual genes and sets of genes involved in the same biological processes. Using XTABLE, Roberts et al. showed that a biological process linked to lung squamous cell carcinoma is also involved in the formation of pre-cancerous lesions. This suggests that molecules and genes associated with this process could potentially help scientists design prevention strategies. XTABLE will help researchers to better understand the biology of pre-cancerous lesions and how they develop in to tumours. Moreover, it will make it easier for scientists to validate their hypotheses using data collected from patients. The tool could also be useful for scientists interested in other types of lung cancers that share a similar biology.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Lesões Pré-Cancerosas , Humanos , Carcinoma Pulmonar de Células não Pequenas/genética , Neoplasias Pulmonares/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Regulação Neoplásica da Expressão Gênica , Pulmão/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Biomarcadores Tumorais/genética
7.
SN Soc Sci ; 3(2): 26, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36685659

RESUMO

Education is considered the most significant factor in producing human resource developments in terms of social, cultural, technological, economic, and overall national perspectives. Higher education is influenced by several factors that affect the quality of students' education and outcomes. Most students in Bangladesh study at private universities from various socioeconomic conditions. Some of the factors have restricted their ability to attain higher education and as a result, impacted their academic performance. The goal of this study was to explore those socioeconomic factors affecting the academic performance of private university students in Bangladesh. The primary dataset was collected through an online survey from three private universities in Bangladesh named Varendra University (VU), Daffodil International University (DIU), and City University (CU). The Chi-square tests indicate that the age, gender, studying on a subject of their own choice, getting the right direction to make studying comfortable, consulting with the teacher about learning, family status, etc. variables significantly impacted their cumulative grade point average (CGPA). Relationships with parents and the opportunity to share opinions with parents were also significantly associated with their results. According to the multinomial logistic regression model age, gender, employment status, choice of own study field, getting the right direction, previous academic result, consultation with teachers, father's annual income, family status, and relationship with parents are found to be statistically significant determinants of academic performance. Considering the reality and outcomes of this study, to improve academic performance, parental involvement needs to be increased, and they must provide financial and material support to their offspring for their academic success. Moreover, for achieving a satisfactory CGPA, the students need to build friendly relationships with their parents and have regular consultations with their teachers as well.

8.
Saudi Pharm J ; 30(9): 1360-1371, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36249945

RESUMO

This study intends to evaluate the development, importance, pre-clinical and clinical study evaluation of stem cell therapy for the treatment of cardiovascular disease. Cardiovascular disease is one of the main causes of fatality in the whole world. Though there are great progressions in the pharmacological and other interventional treatment options, heart diseases remain a common disorder that causes long-term warnings. Recent accession promotes the symptoms and slows down the adverse effects regarding cardiac remodelling. But they cannot locate the problems of immutable loss of cardiac tissues. In this case, stem cell treatment holds a promising challenge. Stem cells are the cells that are capable of differentiating into many cells according to their needs. So, it is assumed that these cells can distinguish into many cells and if these cells can be individualized into cardiac cells then they can be used to replace the damaged tissues of the heart. There is some abridgment in this therapy, none the less stem cell therapy remains a hopeful destination in the treatment of heart disease.

9.
Artigo em Inglês | MEDLINE | ID: mdl-35954512

RESUMO

BACKGROUND: Infection with COVID-19 and its control entailing steroids and immunomodulatory medications disrupted normal immune function. The ensuing immunological disorder led to the rise of another infection-Black Fungus (Mucormycosis). However, the spread of Black Fungus can be minimized through proper knowledge, informed attitude, and conscious preventive practice. This study aimed to assess students' knowledge, attitude, and practice (KAP) regarding Black Fungus amid the COVID-19 pandemic in Bangladesh. METHODS: This cross-sectional study was carried out among Bangladeshi students from June to July 2021. Using Google Forms, an e-questionnaire was developed for this web-based survey, and the participants were selected through a snowball sampling approach. RESULTS: Out of the 2009 participants, more than half were female (53.5%), and the majority were at an age between 18 and 25 years (31.5%) and had received higher secondary (HSC) schooling (77.8%), while around 61% resided in urban areas. Findings revealed that most of the students (63.8%) spent around 2 h on electronic and social media to become informed about COVID-19 and Black Fungus. Approximately 33% of the students showed low KAP scores (32.9%), whereas around 26% had high KAP scores. Our results show a significant association between KAP and sex, schooling, living status, residence, and media exposure. CONCLUSION: The knowledge of Black Fungus considerably varies among Bangladeshi students considering the place of residence, age, sex, living arrangement, and media exposure. Policymakers should emphasize awareness among people focusing on the results of this study to increase deterrent attitudes and protective practices to minimize the risks of being infected.


Assuntos
COVID-19 , Adolescente , Adulto , Bangladesh/epidemiologia , COVID-19/epidemiologia , Estudos Transversais , Feminino , Fungos , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pandemias/prevenção & controle , SARS-CoV-2 , Estudantes , Inquéritos e Questionários , Adulto Jovem
10.
Molecules ; 27(9)2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35566385

RESUMO

Cancer is a disorder that rigorously affects the human population worldwide. There is a steady demand for new remedies to both treat and prevent this life-threatening sickness due to toxicities, drug resistance and therapeutic failures in current conventional therapies. Researchers around the world are drawing their attention towards compounds of natural origin. For decades, human beings have been using the flora of the world as a source of cancer chemotherapeutic agents. Currently, clinically approved anticancer compounds are vincristine, vinblastine, taxanes, and podophyllotoxin, all of which come from natural sources. With the triumph of these compounds that have been developed into staple drug products for most cancer therapies, new technologies are now appearing to search for novel biomolecules with anticancer activities. Ellipticine, camptothecin, combretastatin, curcumin, homoharringtonine and others are plant derived bioactive phytocompounds with potential anticancer properties. Researchers have improved the field further through the use of advanced analytical chemistry and computational tools of analysis. The investigation of new strategies for administration such as nanotechnology may enable the development of the phytocompounds as drug products. These technologies have enhanced the anticancer potential of plant-derived drugs with the aim of site-directed drug delivery, enhanced bioavailability, and reduced toxicity. This review discusses mechanistic insights into anticancer compounds of natural origins and their structural activity relationships that make them targets for anticancer treatments.


Assuntos
Antineoplásicos , Neoplasias , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Plantas , Podofilotoxina/química , Relação Estrutura-Atividade
12.
PLoS Genet ; 17(11): e1009864, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34748531

RESUMO

Mutation rates vary both within and between bacterial species, and understanding what drives this variation is essential for understanding the evolutionary dynamics of bacterial populations. In this study, we investigate two factors that are predicted to influence the mutation rate: ecology and genome size. We conducted mutation accumulation experiments on eight strains of the emerging zoonotic pathogen Streptococcus suis. Natural variation within this species allows us to compare tonsil carriage and invasive disease isolates, from both more and less pathogenic populations, with a wide range of genome sizes. We find that invasive disease isolates have repeatedly evolved mutation rates that are higher than those of closely related carriage isolates, regardless of variation in genome size. Independent of this variation in overall rate, we also observe a stronger bias towards G/C to A/T mutations in isolates from more pathogenic populations, whose genomes tend to be smaller and more AT-rich. Our results suggest that ecology is a stronger correlate of mutation rate than genome size over these timescales, and that transitions to invasive disease are consistently accompanied by rapid increases in mutation rate. These results shed light on the impact that ecology can have on the adaptive potential of bacterial pathogens.


Assuntos
Adaptação Biológica/genética , Doenças Transmissíveis Emergentes/microbiologia , Taxa de Mutação , Infecções Estreptocócicas/microbiologia , Streptococcus suis/genética , Zoonoses/microbiologia , Animais , Ecologia , Streptococcus suis/isolamento & purificação , Streptococcus suis/patogenicidade , Virulência/genética
13.
Nat Commun ; 12(1): 6652, 2021 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789728

RESUMO

Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Etoposídeo/uso terapêutico , Neoplasias Pulmonares/metabolismo , Carcinoma de Pequenas Células do Pulmão/metabolismo , Guanilil Ciclase Solúvel/metabolismo , Animais , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores Enzimáticos/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Camundongos , Células Neoplásicas Circulantes/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Receptores Notch/metabolismo , Transdução de Sinais/genética , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/patologia , Guanilil Ciclase Solúvel/genética
14.
Clin Epidemiol Glob Health ; 12: 100836, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34693077

RESUMO

INTRODUCTION: Due to the extended lockdown imposed for SARS-CoV-2 pandemic, many people have experienced problematic sleep patterns and associated health issues worldwide. This study was conducted to assess the sleep quality and psychological states of the Bangladeshi population during the COVID-19 pandemic, respondent's behavioral traits as well as psychological or sleep-related problems induced self-medication practice among the respondents, along with the probability of development of drug dependency. METHODS: The survey was conducted among 2941 respondents from 25th November 2020 to 4th December 2020 where the responses were analyzed by SPSS V22. RESULTS: 10-29.5% experienced a significant degree of sleep problems whereas some experienced severe anxiety and depression. The associations between the behavioral traits and parameters concerning sleep quality, anxiety and depression showed 5% level of significance in all cases. Self-medication practice of sleep aids during this pandemic was reported by 7.14% of the respondents, with a greater percentage belonging to the female or senior age group. Tendency to repeatedly self-medication was observed in 18.86% of this self-medicating populace, and a greater number of male (10.26%) respondents displayed such tendency as opposed to their female (8.6%) equivalents. However, 48.10% of the respondents reported perceptions of improved physical and/or psychological health following self-medication, and this trait was predominant in men (52.14%). CONCLUSION: Results showed a significant number of Bangladeshi populaces were suffering from psychological issues during this COVID-19 which also influenced a certain number of people towards self-medication practice where signs of drug dependency were observed in a significant number of respondents.

15.
Int J Pharm ; 579: 119137, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32057889

RESUMO

Niacinamide (NIA) has been widely used in cosmetic and personal care formulations for several skin conditions. Permeation of topical NIA has been confirmed in a number of studies under infinite dose conditions. However, there is limited information in the literature regarding permeation of NIA following application of topical formulations in amounts that reflect the real-life use of such products by consumers. The aim of the present work was therefore to investigate skin delivery of NIA from single solvent systems in porcine skin under finite dose conditions. A secondary aim was to probe the processes underlying the previously reported low recovery of NIA following in vitro permeation and mass balance studies. The solubility and stability of NIA in various single solvent systems was examined. The solvents investigated included Transcutol® P (TC), propylene glycol (PG), 1-2 hexanediol (HEX), 1-2 pentanediol (1-2P), 1-5 pentanediol (1-5P), 1-3 butanediol (1-3B), glycerol (GLY) and dimethyl isosorbide (DMI). Skin permeation and deposition of the molecule was investigated in full thickness porcine skin in vitro finite dose Franz-type diffusion experiments followed by mass balance studies. Stability of NIA for 72 h in the solvents was confirmed. The solubility of NIA in the solvents ranged from 82.9 ± 0.8 to 311.9 ± 4.5 mg/mL. TC delivered the highest percentage permeation of NIA at 24 h, 32.6 ± 12.1% of the applied dose. Low total recovery of NIA after mass balance studies was observed for some vehicles, with values ranging from 55.2 ± 12.8% to 106.3 ± 2.3%. This reflected the formation of a number of NIA degradation by-products in the receptor phase during the permeation studies. Identification of other vehicles for synergistic enhancement of NIA skin delivery will be the subject of future work.


Assuntos
Cosméticos/administração & dosagem , Composição de Medicamentos/métodos , Niacinamida/administração & dosagem , Solventes/química , Complexo Vitamínico B/administração & dosagem , Administração Cutânea , Animais , Cosméticos/química , Cosméticos/farmacocinética , Estabilidade de Medicamentos , Niacinamida/química , Niacinamida/farmacocinética , Permeabilidade , Pele/metabolismo , Solubilidade , Suínos , Complexo Vitamínico B/química , Complexo Vitamínico B/farmacocinética
16.
Pharmaceutics ; 11(10)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31652587

RESUMO

Terbinafine (TBF) is commonly used in the management of fungal infections of the skin because of its broad spectrum of activity. Currently, formulations containing the free base and salt form are available. However, there is only limited information in the literature about the physicochemical properties of this drug and its uptake by the skin. In this work, we conducted a comprehensive characterisation of TBF, and we also examined its percutaneous absorption in vitro in porcine skin. TBF-free base was synthesised from the hydrochloride salt by a simple proton displacement reaction. Both the free base and salt form were further analysed using Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA). Delivery of TBF-free base in excised porcine skin was investigated from the following solvents: Isopropyl myristate (IPM), propylene glycol monolaurate (PGML), Transcutol® (TC), propylene glycol (PG), polyethylene glycol 200 (PEG 200), oleic acid (OL), ethanol (EtOH), and isopropyl alcohol (IPA). Permeation and mass balance studies confirmed that PG and TC were the most efficacious vehicles, delivering higher amounts of TBF-free base to the skin compared with a commercial gel (p < 0.05). These preliminary results are promising and will inform the development of more complex formulations in future work.

17.
Mol Biol Evol ; 34(1): 185-203, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28053012

RESUMO

Viral phylogenetic methods contribute to understanding how HIV spreads in populations, and thereby help guide the design of prevention interventions. So far, most analyses have been applied to well-sampled concentrated HIV-1 epidemics in wealthy countries. To direct the use of phylogenetic tools to where the impact of HIV-1 is greatest, the Phylogenetics And Networks for Generalized HIV Epidemics in Africa (PANGEA-HIV) consortium generates full-genome viral sequences from across sub-Saharan Africa. Analyzing these data presents new challenges, since epidemics are principally driven by heterosexual transmission and a smaller fraction of cases is sampled. Here, we show that viral phylogenetic tools can be adapted and used to estimate epidemiological quantities of central importance to HIV-1 prevention in sub-Saharan Africa. We used a community-wide methods comparison exercise on simulated data, where participants were blinded to the true dynamics they were inferring. Two distinct simulations captured generalized HIV-1 epidemics, before and after a large community-level intervention that reduced infection levels. Five research groups participated. Structured coalescent modeling approaches were most successful: phylogenetic estimates of HIV-1 incidence, incidence reductions, and the proportion of transmissions from individuals in their first 3 months of infection correlated with the true values (Pearson correlation > 90%), with small bias. However, on some simulations, true values were markedly outside reported confidence or credibility intervals. The blinded comparison revealed current limits and strengths in using HIV phylogenetics in challenging settings, provided benchmarks for future methods' development, and supports using the latest generation of phylogenetic tools to advance HIV surveillance and prevention.


Assuntos
Infecções por HIV/epidemiologia , Infecções por HIV/virologia , HIV-1/genética , África Subsaariana/epidemiologia , Simulação por Computador , Epidemias , Feminino , Infecções por HIV/prevenção & controle , Infecções por HIV/transmissão , Humanos , Incidência , Masculino , Filogenia
18.
Genome Biol Evol ; 7(8): 2102-16, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26139831

RESUMO

Evolutionary studies usually use a two-step process to investigate sequence data. Step one estimates a multiple sequence alignment (MSA) and step two applies phylogenetic methods to ask evolutionary questions of that MSA. Modern phylogenetic methods infer evolutionary parameters using maximum likelihood or Bayesian inference, mediated by a probabilistic substitution model that describes sequence change over a tree. The statistical properties of these methods mean that more data directly translates to an increased confidence in downstream results, providing the substitution model is adequate and the MSA is correct. Many studies have investigated the robustness of phylogenetic methods in the presence of substitution model misspecification, but few have examined the statistical properties of those methods when the MSA is unknown. This simulation study examines the statistical properties of the complete two-step process when inferring sequence divergence and the phylogenetic tree topology. Both nucleotide and amino acid analyses are negatively affected by the alignment step, both through inaccurate guide tree estimates and through overfitting to that guide tree. For many alignment tools these effects become more pronounced when additional sequences are added to the analysis. Nucleotide sequences are particularly susceptible, with MSA errors leading to statistical support for long-branch attraction artifacts, which are usually associated with gross substitution model misspecification. Amino acid MSAs are more robust, but do tend to arbitrarily resolve multifurcations in favor of the guide tree. No inference strategies produce consistently accurate estimates of divergence between sequences, although amino acid MSAs are again more accurate than their nucleotide counterparts. We conclude with some practical suggestions about how to limit the effect of MSA uncertainty on evolutionary inference.


Assuntos
Filogenia , Alinhamento de Sequência/métodos , Artefatos , Modelos Estatísticos , Incerteza
19.
Philos Trans R Soc Lond B Biol Sci ; 370(1676)2015 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-26194754

RESUMO

Identifying the germline genes involved in immunoglobulin rearrangements is an essential first step in the analysis of antibody repertoires. Based on our prior work in analysing diverse recombinant viruses, we present IgSCUEAL (Immunoglobulin Subtype Classification Using Evolutionary ALgorithms), a phylogenetic approach to assign V and J regions of immunoglobulin sequences to their corresponding germline alleles, with D regions assigned using a simple pairwise alignment algorithm. We also develop an interactive web application for viewing the results, allowing the user to explore the frequency distribution of sequence assignments and CDR3 region length statistics, which is useful for summarizing repertoires, as well as a detailed viewer of rearrangements and region alignments for individual query sequences. We demonstrate the accuracy and utility of our method compared with sequence similarity-based approaches and other non-phylogenetic model-based approaches, using both simulated data and a set of evaluation datasets of human immunoglobulin heavy chain sequences. IgSCUEAL demonstrates the highest accuracy of V and J assignment amongst existing approaches, even when the reassorted sequence is highly mutated, and can successfully cluster sequences on the basis of shared V/J germline alleles.


Assuntos
Diversidade de Anticorpos/genética , Algoritmos , Simulação por Computador , Bases de Dados Genéticas , Rearranjo Gênico do Linfócito B , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Modelos Genéticos , Modelos Imunológicos , Filogenia , Alinhamento de Sequência/estatística & dados numéricos , Recombinação V(D)J
20.
J Integr Med ; 11(5): 343-51, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24063782

RESUMO

OBJECTIVE: To elucidate potential antioxidant, antidiarrheal, cytotoxic, and antibacterial activities of the ethanol extract of Alocasia indica Schott tuber in different experimental models established in vitro and in vivo. METHODS: In vitro antioxidant activity was evaluated by 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay. Phenolic content was estimated by using Folin-Ciocalteu's reagent while reducing ability was measured by ferric reducing power assay. In vivo antidiarrheal studies were carried out in mice, and the activity was evaluated in castor oil and magnesium sulfate-induced diarrhea. Disk diffusion assay was utilized to determine antibacterial activity against a number of pathogenic bacterial strains. Acute toxicity test was carried out to measure the safe doses for the extract. RESULTS: In DPPH radical-scavenging assay, the extract exhibited strong radical-scavenging activity with the 50% inhibitory concentration value of 42.66 µg/mL. Total phenolic content was found to be 542.26 mg gallic acid equivalent per 100 g of dried tuber extract, whereas flavonoid content was found to be 4.30 mg quercetin equivalent/g of dried tuber extract. In reducing power assay, the extract showed strong reducing power in a concentration-dependent manner. The extract significantly (P < 0.01) enhanced the latent period and decreased defecation in both castor oil- and magnesium sulfate-induced diarrhea. The extract also lessened gastrointestinal motility in mice. Potential antibacterial activity was exhibited by the extract against all the tested bacterial strains in disk diffusion assay. The 50% lethal concentration against brine shrimp nauplii was 81.09 µg/mL. CONCLUSION: The results demonstrated that the ethanol extract of A. indica has potential antioxidant, antidiarrheal, cytotoxic, and antibacterial activity.


Assuntos
Alocasia , Extratos Vegetais/farmacologia , Alocasia/química , Animais , Antibacterianos/farmacologia , Antidiarreicos/farmacologia , Antioxidantes/farmacologia , Artemia/efeitos dos fármacos , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Masculino , Camundongos , Extratos Vegetais/toxicidade
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