Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 58
Filtrar
Mais filtros

Base de dados
Tipo de documento
Intervalo de ano de publicação
1.
Infect Immun ; 91(1): e0019922, 2023 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-36537791

RESUMO

MicroRNAs (miRNAs), a class of small noncoding RNAs, are critical to gene regulation in eukaryotes. They are involved in modulating a variety of physiological processes, including the host response to intracellular infections. Little is known about miRNA functions during infection by Coxiella burnetii, the causative agent of human Q fever. This bacterial pathogen establishes a large replicative vacuole within macrophages by manipulating host processes such as apoptosis and autophagy. We investigated miRNA expression in C. burnetii-infected macrophages and identified several miRNAs that were down- or upregulated during infection. We further explored the functions of miR-143-3p, an miRNA whose expression is downregulated in macrophages infected with C. burnetii, and show that increasing the abundance of this miRNA in human cells results in increased apoptosis and reduced autophagy-conditions that are unfavorable to C. burnetii intracellular growth. In sum, this study demonstrates that C. burnetii infection elicits a robust miRNA-based host response, and because miR-143-3p promotes apoptosis and inhibits autophagy, downregulation of miR-143-3p expression during C. burnetii infection likely benefits the pathogen.


Assuntos
Coxiella burnetii , MicroRNAs , Febre Q , Humanos , Coxiella burnetii/fisiologia , MicroRNAs/genética , MicroRNAs/metabolismo , Interações Hospedeiro-Patógeno/genética , Febre Q/genética , Febre Q/metabolismo , Macrófagos/microbiologia , Vacúolos/microbiologia
2.
Mol Biol Evol ; 39(2)2022 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-35084505

RESUMO

Small RNAs (sRNAs) are important gene regulators in bacteria, but it is unclear how new sRNAs originate and become part of regulatory networks that coordinate bacterial response to environmental stimuli. Using a covariance modeling-based approach, we analyzed the presence of hundreds of sRNAs in more than a thousand genomes across Enterobacterales, a bacterial order with a confluence of factors that allows robust genome-scale sRNA analyses: several well-studied organisms with fairly conserved genome structures, an established phylogeny, and substantial nucleotide diversity within a narrow evolutionary space. We discovered that a majority of sRNAs arose recently, and uncovered protein-coding genes as a potential source from which new sRNAs arise. A detailed investigation of the emergence of OxyS, a peroxide-responding sRNA, revealed that it evolved from a fragment of a peroxidase messenger RNA. Importantly, although it replaced the ancestral peroxidase, OxyS continues to be part of the ancestral peroxide-response regulon, indicating that an sRNA that arises from a protein-coding gene would inherently be part of the parental protein's regulatory network. This new insight provides a fresh framework for understanding sRNA origin and regulatory integration in bacteria.


Assuntos
Enterobacteriaceae/genética , Peroxidase , Pequeno RNA não Traduzido , Regulação Bacteriana da Expressão Gênica , Peroxidase/genética , Peróxidos , RNA Bacteriano/genética , RNA Mensageiro/genética , Pequeno RNA não Traduzido/genética
3.
Parasitology ; 150(10): 859-865, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37722758

RESUMO

Ticks transmit pathogens and harbour non-pathogenic, vertically transmitted intracellular bacteria termed endosymbionts. Almost all ticks studied to date contain 1 or more of Coxiella, Francisella, Rickettsia or Candidatus Midichloria mitochondrii endosymbionts, indicative of their importance to tick physiology. Genomic and experimental data suggest that endosymbionts promote tick development and reproductive success. Here, we review the limited information currently available on the potential roles endosymbionts play in enhancing tick metabolism and fitness. Future studies that expand on these findings are needed to better understand endosymbionts' contributions to tick biology. This knowledge could potentially be applied to design novel strategies that target endosymbiont function to control the spread of ticks and pathogens they vector.


Assuntos
Francisella , Rickettsia , Carrapatos , Animais , Rickettsia/genética , Francisella/genética , Vetores Aracnídeos , Simbiose
4.
J Bacteriol ; 204(4): e0057721, 2022 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-35285723

RESUMO

Streptococcus mutans is a major pathobiont involved in the development of dental caries. Its ability to utilize numerous sugars and to effectively respond to environmental stress promotes S. mutans proliferation in oral biofilms. Because of their quick action and low energetic cost, noncoding small RNAs (sRNAs) represent an ideal mode of gene regulation in stress response networks, yet their roles in oral pathogens have remained largely unexplored. We identified 15 novel sRNAs in S. mutans and show that they respond to four stress-inducing conditions commonly encountered by the pathogen in human mouth: sugar-phosphate stress, hydrogen peroxide exposure, high temperature, and low pH. To better understand the role of sRNAs in S. mutans, we further explored the function of the novel sRNA SmsR4. Our data demonstrate that SmsR4 regulates the enzyme IIA (EIIA) component of the sorbitol phosphotransferase system, which transports and phosphorylates the sugar alcohol sorbitol. The fine-tuning of EIIA availability by SmsR4 likely promotes S. mutans growth while using sorbitol as the main carbon source. Our work lays a foundation for understanding the role of sRNAs in regulating gene expression in stress response networks in S. mutans and highlights the importance of the underexplored phenomenon of posttranscriptional gene regulation in oral bacteria. IMPORTANCE Small RNAs (sRNAs) are important gene regulators in bacteria, but the identities and functions of sRNAs in Streptococcus mutans, the principal bacterium involved in the formation of dental caries, are unknown. In this study, we identified 15 putative sRNAs in S. mutans and show that they respond to four common stress-inducing conditions present in human mouth: sugar-phosphate stress, hydrogen peroxide exposure, high temperature, and low pH. We further show that the novel sRNA SmsR4 likely modulates sorbitol transport into the cell by regulating SMU_313 mRNA, which encodes the EIIA subunit of the sorbitol phosphotransferase system. Gaining a better understanding of sRNA-based gene regulation may provide new opportunities to develop specific inhibitors of S. mutans growth, thereby improving oral health.


Assuntos
Cárie Dentária , Pequeno RNA não Traduzido , Regulação Bacteriana da Expressão Gênica , Humanos , Peróxido de Hidrogênio/farmacologia , Fosfatos/metabolismo , Fosfotransferases/genética , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismo , Sorbitol/metabolismo , Sorbitol/farmacologia , Streptococcus mutans/metabolismo , Açúcares/metabolismo
5.
Biochem Biophys Res Commun ; 586: 14-19, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34823217

RESUMO

Plakophilin3 (PKP3) loss leads to tumor progression and metastasis of colon cancer cells. The goal of this report was to determine if PKP3 loss led to increased disease progression in mice. We generated a colonocyte-specific knockout of PKP3 in APCmin mice, which led to increased adenoma formation, the formation of rectal prolapse, and a significant decrease in survival. The observed increase in rectal prolapse formation and decrease in survival correlated with an increase in the expression of Lipocalin2 (LCN2). Increased disease progression was observed even upon treatment with 5-fluorouracil (5FU). These results suggest that an increase in LCN2 expression might lead to therapy resistance and that LCN2 might serve as a potential therapeutic target in colorectal cancer.


Assuntos
Adenoma/genética , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Lipocalina-2/genética , Placofilinas/genética , Prolapso Retal/genética , Adenoma/tratamento farmacológico , Adenoma/mortalidade , Adenoma/patologia , Animais , Antimetabólitos Antineoplásicos/farmacologia , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Progressão da Doença , Feminino , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Queratina-8/genética , Queratina-8/metabolismo , Lipocalina-2/metabolismo , Masculino , Metaloproteinase 7 da Matriz/genética , Metaloproteinase 7 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placofilinas/deficiência , Prolapso Retal/tratamento farmacológico , Prolapso Retal/mortalidade , Prolapso Retal/patologia , Transdução de Sinais , Análise de Sobrevida
6.
Microbiology (Reading) ; 167(10)2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34698627

RESUMO

Bacterial small RNAs (sRNAs) are important regulators of gene expression; however, the impact of natural mutations on sRNA functions has not been studied extensively. Here we show that the sRNA MgrR contains a unique 53 bp insertion in Escherichia fergusonii, a close relative of Escherichia coli and Salmonella enterica. The insertion is a repetitive extragenic palindromic (REP) sequence that could block transcription, but full-length MgrR is produced in E. fergusonii, showing that the insertion has not affected sRNA production. Additionally, despite containing the large insertion, the sRNA appears to be functional because deletion of mgrR made E. fergusonii more susceptible to H2O2. The molecular details of MgrR's roles in H2O2defence are yet to be defined, but our results suggest that having an alternative function allowed the sRNA to be retained in E. fergusonii despite it sustaining a large, potentially disruptive mutation.


Assuntos
Escherichia/genética , RNA Bacteriano/genética , Pequeno RNA não Traduzido/genética , Enterobacteriaceae/classificação , Enterobacteriaceae/genética , Escherichia/classificação , Escherichia/metabolismo , Regulação Bacteriana da Expressão Gênica , Peróxido de Hidrogênio/metabolismo , Magnésio/metabolismo , Mutação , Filogenia , RNA Bacteriano/metabolismo , Pequeno RNA não Traduzido/metabolismo
7.
Biol Reprod ; 104(4): 924-934, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33459759

RESUMO

Abnormally increased angiotensin II activity related to maternal angiotensinogen (AGT) genetic variants, or aberrant receptor activation, is associated with small-for-gestational-age babies and abnormal uterine spiral artery remodeling in humans. Our group studies a murine AGT gene titration transgenic (TG; 3-copies of the AGT gene) model, which has a 20% increase in AGT expression mimicking a common human AGT genetic variant (A[-6]G) associated with intrauterine growth restriction (IUGR) and spiral artery pathology. We hypothesized that aberrant maternal AGT expression impacts pregnancy-induced uterine spiral artery angiogenesis in this mouse model leading to IUGR. We controlled for fetal sex and fetal genotype (e.g., only 2-copy wild-type [WT] progeny from WT and TG dams were included). Uteroplacental samples from WT and TG dams from early (days 6.5 and 8.5), mid (d12.5), and late (d16.5) gestation were studied to assess uterine natural killer (uNK) cell phenotypes, decidual metrial triangle angiogenic factors, placental growth and capillary density, placental transcriptomics, and placental nutrient transport. Spiral artery architecture was evaluated at day 16.5 by contrast-perfused three-dimensional microcomputed tomography (3D microCT). Our results suggest that uteroplacental angiogenesis is significantly reduced in TG dams at day 16.5. Males from TG dams are associated with significantly reduced uteroplacental angiogenesis from early to late gestation compared with their female littermates and WT controls. Angiogenesis was not different between fetal sexes from WT dams. We conclude that male fetal sex compounds the pathologic impact of maternal genotype in this mouse model of growth restriction.


Assuntos
Retardo do Crescimento Fetal/fisiopatologia , Feto/fisiologia , Neovascularização Patológica , Placenta/irrigação sanguínea , Animais , Modelos Animais de Doenças , Feminino , Desenvolvimento Fetal/fisiologia , Retardo do Crescimento Fetal/imunologia , Retardo do Crescimento Fetal/patologia , Células Matadoras Naturais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neovascularização Patológica/etiologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/fisiopatologia , Placenta/imunologia , Placenta/patologia , Placentação/fisiologia , Gravidez , Caracteres Sexuais , Diferenciação Sexual/fisiologia , Útero/irrigação sanguínea , Útero/imunologia , Útero/patologia
8.
PLoS Genet ; 14(10): e1007709, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30296267

RESUMO

The most commonly studied prokaryotic sensory signal transduction systems include the one-component systems, phosphosignaling systems, extracytoplasmic function (ECF) sigma factor systems, and the various types of second messenger systems. Recently, we described the regulatory role of two separate sensory systems in Streptococcus mutans that jointly control bacteriocin gene expression, natural competence development, as well as a cell death pathway, yet they do not function via any of the currently recognized signal transduction paradigms. These systems, which we refer to as LytTR Regulatory Systems (LRS), minimally consist of two proteins, a transcription regulator from the LytTR Family and a transmembrane protein inhibitor of this transcription regulator. Here, we provide evidence suggesting that LRS are a unique uncharacterized class of prokaryotic sensory system. LRS exist in a basal inactive state. However, when LRS membrane inhibitor proteins are inactivated, an autoregulatory positive feedback loop is triggered due to LRS regulator protein interactions with direct repeat sequences located just upstream of the -35 sequences of LRS operon promoters. Uncharacterized LRS operons are widely encoded by a vast array of Gram positive and Gram negative bacteria as well as some archaea. These operons also contain unique direct repeat sequences immediately upstream of their operon promoters indicating that positive feedback autoregulation is a globally conserved feature of LRS. Despite the surprisingly widespread occurrence of LRS operons, the only characterized examples are those of S. mutans. Therefore, the current study provides a useful roadmap to investigate LRS function in the numerous other LRS-encoding organisms.


Assuntos
Streptococcus mutans/genética , Streptococcus mutans/metabolismo , Proteínas de Bactérias/genética , Bacteriocinas/biossíntese , Retroalimentação Sensorial , Óperon , Células Procarióticas/metabolismo , Regiões Promotoras Genéticas , Transdução de Sinais , Fatores de Transcrição/genética
9.
J Bacteriol ; 201(22)2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31451541

RESUMO

Coxiella burnetii is an obligate intracellular gammaproteobacterium and zoonotic agent of Q fever. We previously identified 15 small noncoding RNAs (sRNAs) of C. burnetii One of them, CbsR12 (Coxiella burnetiismall RNA 12), is highly transcribed during axenic growth and becomes more prominent during infection of cultured mammalian cells. Secondary structure predictions of CbsR12 revealed four putative CsrA-binding sites in stem loops with consensus AGGA/ANGGA motifs. We subsequently determined that CbsR12 binds to recombinant C. burnetii CsrA-2, but not CsrA-1, proteins in vitro Moreover, through a combination of in vitro and cell culture assays, we identified several in trans mRNA targets of CbsR12. Of these, we determined that CbsR12 binds and upregulates translation of carA transcripts coding for carbamoyl phosphate synthetase A, an enzyme that catalyzes the first step of pyrimidine biosynthesis. In addition, CbsR12 binds and downregulates translation of metK transcripts coding for S-adenosylmethionine synthetase, a component of the methionine cycle. Furthermore, we found that CbsR12 binds to and downregulates the quantity of cvpD transcripts, coding for a type IVB effector protein, in mammalian cell culture. Finally, we found that CbsR12 is necessary for expansion of Coxiella-containing vacuoles and affects growth rates in a dose-dependent manner in the early phase of infecting THP-1 cells. This is the first characterization of a trans-acting sRNA of C. burnetii and the first example of a bacterial sRNA that regulates both CarA and MetK synthesis. CbsR12 is one of only a few identified trans-acting sRNAs that interacts with CsrA.IMPORTANCE Regulation of metabolism and virulence in C. burnetii is not well understood. Here, we show that C. burnetii small RNA 12 (CbsR12) is highly transcribed in the metabolically active large-cell variant compared to the nonreplicative small-cell variant. We show that CbsR12 directly regulates several genes involved in metabolism, along with a type IV effector gene, in trans In addition, we demonstrate that CbsR12 binds to CsrA-2 in vitro and induces autoaggregation and biofilm formation when transcribed ectopically in Escherichia coli, consistent with other CsrA-sequestering sRNAs. These results implicate CbsR12 in the indirect regulation of a number of genes via CsrA-mediated regulatory activities. The results also support CbsR12 as a crucial regulatory component early on in a mammalian cell infection.


Assuntos
Coxiella burnetii/genética , Febre Q/microbiologia , RNA Bacteriano/fisiologia , Pequeno RNA não Traduzido/fisiologia , Proteínas de Ligação a RNA/metabolismo , Vacúolos/metabolismo , Animais , Cultura Axênica , Proteínas de Bactérias/metabolismo , Chlorocebus aethiops , Coxiella burnetii/crescimento & desenvolvimento , Coxiella burnetii/metabolismo , Humanos , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , Pequeno RNA não Traduzido/genética , Pequeno RNA não Traduzido/metabolismo , Células THP-1 , Células Vero
11.
BMC Genomics ; 19(1): 247, 2018 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-29642859

RESUMO

BACKGROUND: Coxiella burnetii is a Gram-negative gammaproteobacterium and zoonotic agent of Q fever. C. burnetii's genome contains an abundance of pseudogenes and numerous selfish genetic elements. MITEs (miniature inverted-repeat transposable elements) are non-autonomous transposons that occur in all domains of life and are thought to be insertion sequences (ISs) that have lost their transposase function. Like most transposable elements (TEs), MITEs are thought to play an active role in evolution by altering gene function and expression through insertion and deletion activities. However, information regarding bacterial MITEs is limited. RESULTS: We describe two MITE families discovered during research on small non-coding RNAs (sRNAs) of C. burnetii. Two sRNAs, Cbsr3 and Cbsr13, were found to originate from a novel MITE family, termed QMITE1. Another sRNA, CbsR16, was found to originate from a separate and novel MITE family, termed QMITE2. Members of each family occur ~ 50 times within the strains evaluated. QMITE1 is a typical MITE of 300-400 bp with short (2-3 nt) direct repeats (DRs) of variable sequence and is often found overlapping annotated open reading frames (ORFs). Additionally, QMITE1 elements possess sigma-70 promoters and are transcriptionally active at several loci, potentially influencing expression of nearby genes. QMITE2 is smaller (150-190 bps), but has longer (7-11 nt) DRs of variable sequences and is mainly found in the 3' untranslated region of annotated ORFs and intergenic regions. QMITE2 contains a GTAG repetitive extragenic palindrome (REP) that serves as a target for IS1111 TE insertion. Both QMITE1 and QMITE2 display inter-strain linkage and sequence conservation, suggesting that they are adaptive and existed before divergence of C. burnetii strains. CONCLUSIONS: We have discovered two novel MITE families of C. burnetii. Our finding that MITEs serve as a source for sRNAs is novel. QMITE2 has a unique structure and occurs in large or small versions with unique DRs that display linkage and sequence conservation between strains, allowing for tracking of genomic rearrangements. QMITE1 and QMITE2 copies are hypothesized to influence expression of neighboring genes involved in DNA repair and virulence through transcriptional interference and ribonuclease processing.


Assuntos
Coxiella burnetii/genética , Elementos de DNA Transponíveis , Sequências Repetidas Invertidas , Pequeno RNA não Traduzido/genética , Proteínas de Bactérias/genética , Sequência de Bases , Sequência Conservada , Evolução Molecular , Ligação Genética , Loci Gênicos , Genoma Bacteriano , Conformação de Ácido Nucleico , Peptídeos/genética , Pequeno RNA não Traduzido/química , Alinhamento de Sequência
12.
J Mol Evol ; 84(4): 204-213, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28405712

RESUMO

Non-coding small RNAs (sRNAs) are critical to post-transcriptional gene regulation in bacteria. However, unlike for protein-coding genes, the evolutionary forces that shape sRNAs are not understood. We investigated sRNAs in enteric bacteria and discovered that recently emerged sRNAs evolve at significantly faster rates than older sRNAs. Concomitantly, younger sRNAs are expressed at significantly lower levels than older sRNAs. This process could potentially facilitate the integration of newly emerged sRNAs into bacterial regulatory networks. Furthermore, it has previously been difficult to trace the evolutionary histories of sRNAs because rapid evolution obscures their original sources. We overcame this challenge by identifying a recently evolved sRNA in Escherichia coli, which allowed us to determine that novel sRNAs could emerge from vestigial bacteriophage genes, the first known source for sRNA origination.


Assuntos
Escherichia coli/genética , RNA Bacteriano/genética , RNA não Traduzido/genética , Bactérias/genética , Sequência de Bases , Evolução Biológica , Sequência Conservada , Enterobacteriaceae/genética , Proteínas de Escherichia coli/genética , Evolução Molecular , Regulação Bacteriana da Expressão Gênica/genética , Genoma Bacteriano/genética , Filogenia , RNA não Traduzido/metabolismo
13.
J Clin Monit Comput ; 31(4): 845-850, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27270785

RESUMO

Use of an anesthesia information management system (AIMS) has been reported to improve accuracy of recorded information. We tested the hypothesis that analyzing the distribution of times charted on paper and computerized records could reveal possible rounding errors, and that this effect could be modulated by differences in the user interface for documenting certain event times with an AIMS. We compared the frequency distribution of start and end times for anesthesia cases completed with paper records and an AIMS. Paper anesthesia records had significantly more times ending with "0" and "5" compared to those from the AIMS (p < 0.001). For case start times, AIMS still exhibited end-digit preference, with times whose last digits had significantly higher frequencies of "0" and "5" than other integers. This effect, however, was attenuated compared to that for paper anesthesia records. For case end times, the distribution of minutes recorded with AIMS was almost evenly distributed, unlike those from paper records that still showed significant end-digit preference. The accuracy of anesthesia case start times and case end times, as inferred by statistical analysis of the distribution of the times, is enhanced with the use of an AIMS. Furthermore, the differences in AIMS user interface for documenting case start and case end times likely affects the degree of end-digit preference, and likely accuracy, of those times.


Assuntos
Anestesia , Monitorização Intraoperatória/instrumentação , Sistemas de Informação em Salas Cirúrgicas , Anestesiologia , Coleta de Dados , Registros Eletrônicos de Saúde , Humanos , Monitorização Intraoperatória/métodos , Salas Cirúrgicas , Reprodutibilidade dos Testes , Projetos de Pesquisa , Estudos Retrospectivos , Software , Fatores de Tempo , Interface Usuário-Computador
14.
Proc Natl Acad Sci U S A ; 109(36): 14504-7, 2012 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-22908296

RESUMO

Bacteria display considerable variation in their overall base compositions, which range from 13% to over 75% G+C. This variation in genomic base compositions has long been considered to be a strictly neutral character, due solely to differences in the mutational process; however, recent sequence comparisons indicate that mutational input alone cannot produce the observed base compositions, implying a role for natural selection. Because bacterial genomes have high gene content, forces that operate on the base composition of individual genes could help shape the overall genomic base composition. To explore this possibility, we tested whether genes that encode the same protein but vary only in their base compositions at synonymous sites have effects on bacterial fitness. Escherichia coli strains harboring G+C-rich versions of genes display higher growth rates, indicating that despite a pervasive mutational bias toward A+T, a selective force, independent of adaptive codon use, is driving genes toward higher G+C contents.


Assuntos
Composição de Bases/genética , Escherichia coli/genética , Evolução Molecular , Variação Genética , Seleção Genética , Adaptação Biológica/genética , Mutação/genética , Análise de Regressão
15.
Curr Opin Anaesthesiol ; 28(4): 379-97, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26087270

RESUMO

PURPOSE OF REVIEW: To provide an overview on drug targets and emerging pharmacological treatment options for chronic pain. RECENT FINDINGS: Chronic pain poses an enormous socioeconomic burden for the more than 30% of people who suffer from it, costing over $600 billion per year in the USA. In recent years, there has been a surge in preclinical and clinical research endeavors to try to stem this epidemic. Preclinical studies have identified a wide array of potential targets, with some of the most promising translational research being performed on novel opioid receptors, cannabinoid receptors, selective ion channel blockers, cytokine inhibitors, nerve growth factor inhibitors, N-methyl-D-aspartate receptor antagonists, glial cell inhibitors, and bisphosphonates. SUMMARY: There are many obstacles for the development of effective medications to treat chronic pain, including the inherent challenges in identifying pathophysiological mechanisms, the overlap and multiplicity of pain pathways, and off-target adverse effects stemming from the ubiquity of drug target receptor sites and the lack of highly selective receptor ligands. Despite these barriers, the number and diversity of potential therapies have continued to grow, to include disease-modifying and individualized drug treatments.


Assuntos
Dor Crônica/tratamento farmacológico , Manejo da Dor/métodos , Citocinas/antagonistas & inibidores , Difosfonatos/uso terapêutico , Humanos , Canais Iônicos/antagonistas & inibidores , Fator de Crescimento Neural/antagonistas & inibidores , Neuroglia , Receptores de Canabinoides/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores Opioides/efeitos dos fármacos
16.
Genome Res ; 21(9): 1487-97, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21665928

RESUMO

The intergenic regions in bacterial genomes can contain regulatory leader sequences and small RNAs (sRNAs), which both serve to modulate gene expression. Computational analyses have predicted the presence of hundreds of these noncoding regulatory RNAs in Escherichia coli; however, only about 80 have been experimentally validated. By applying a deep-sequencing approach, we detected and quantified the vast majority of the previously validated regulatory elements and identified 10 new sRNAs and nine new regulatory leader sequences in the intergenic regions of E. coli. Half of the newly discovered sRNAs displayed enhanced stability in the presence of the RNA-binding protein Hfq, which is vital to the function of many of the known E. coli sRNAs. Whereas previous methods have often relied on phylogenetic conservation to identify regulatory leader sequences, only five of the newly discovered E. coli leader sequences were present in the genomes of other enteric species. For those newly identified regulatory elements having orthologs in Salmonella, evolutionary analyses showed that these regions encoded new noncoding elements rather than small, unannotated protein-coding transcripts. In addition to discovering new noncoding regulatory elements, we validated 53 sRNAs that were previously predicted but never detected and showed that the presence, within intergenic regions, of σ(70) promoters and sequences with compensatory mutations that maintain stable RNA secondary structures across related species is a good predictor of novel sRNAs.


Assuntos
Escherichia coli/genética , Genoma Bacteriano/genética , Genômica , RNA não Traduzido/genética , Escherichia coli/metabolismo , Proteínas de Escherichia coli/metabolismo , Perfilação da Expressão Gênica , Regulação Bacteriana da Expressão Gênica , Magnésio/metabolismo , Fases de Leitura Aberta/genética , Reprodutibilidade dos Testes , Riboswitch/genética , Transcrição Gênica , Transcriptoma
17.
BMC Ecol Evol ; 23(1): 63, 2023 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-37891482

RESUMO

The transition from notochord to vertebral column is a crucial milestone in chordate evolution and in prenatal development of all vertebrates. As ossification of the vertebral bodies proceeds, involutions of residual notochord cells into the intervertebral discs form the nuclei pulposi, shock-absorbing structures that confer flexibility to the spine. Numerous studies have outlined the developmental and evolutionary relationship between notochord and nuclei pulposi. However, the knowledge of the similarities and differences in the genetic repertoires of these two structures remains limited, also because comparative studies of notochord and nuclei pulposi across chordates are complicated by the gene/genome duplication events that led to extant vertebrates. Here we show the results of a pilot study aimed at bridging the information on these two structures. We have followed in different vertebrates the evolutionary trajectory of notochord genes identified in the invertebrate chordate Ciona, and we have evaluated the extent of conservation of their expression in notochord cells. Our results have uncovered evolutionarily conserved markers of both notochord development and aging/degeneration of the nuclei pulposi.


Assuntos
Cordados , Núcleo Pulposo , Animais , Notocorda/metabolismo , Projetos Piloto , Expressão Gênica
18.
Magn Reson Med ; 68(5): 1346-56, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22287206

RESUMO

Although phosphorus-31 (³¹P) magnetic resonance spectroscopy holds potential as noninvasive tool to monitor treatment response of liver malignancies, the lack of appropriate coils has so far restricted its use to liver lesions close to the surface. A novel eight-channel phased-array dual-tuned ³¹P/¹H coil that can assess ³¹P metabolism in deeper liver tissue as well is presented in this article. Analysis of its performance demonstrates that this coil can provide good sensitivity across a width of 20 cm, thereby enabling magnetic resonance spectroscopic imaging (MRSI) scans that can fully cover axial views of the abdomen in lean subjects. In vivo results and reproducibility of ³¹P MRSI at 3 T of axial slices covering the full depth of the liver are shown in healthy volunteers. To minimize intrasubject and intersubject data variability, spectra are corrected for coil sensitivities. Methods to maximize the reproducibility of coil placement and spectroscopic planning are discussed. The phosphomonoesters/phosphodiesters ratio calculated in healthy volunteers has an average intrasubject variation of 23% averaged over voxels selected from the entire liver. Finally, the feasibility of using the coil in the clinic is shown by preliminary ³¹P liver MRSI data obtained from a patient with hepatocellular carcinoma.


Assuntos
Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/metabolismo , Fígado/metabolismo , Imageamento por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/instrumentação , Fósforo/análise , Transdutores , Adulto , Desenho de Equipamento , Análise de Falha de Equipamento , Estudos de Viabilidade , Feminino , Humanos , Imageamento por Ressonância Magnética/instrumentação , Magnetismo/instrumentação , Masculino , Imagem Molecular/métodos , Projetos Piloto , Prótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
19.
Adv Exp Med Biol ; 984: 231-48, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22711635

RESUMO

The biphasic developmental cycle of Coxiella burnetii is central to the pathogen's natural history and survival. A small, dormant cell morphotype (the small-cell variant or SCV) allows this obligate intracellular bacterium to persist for extended periods outside of host cells, resist environmental conditions that would be lethal to most prokaryotes, and is the major infectious stage encountered by eukaryotic hosts. In contrast, a large, metabolically-active morphotype (the large-cell variant or LCV) provides for replication of the agent within acidified parasitophorous vacuoles (PVs) of a host cell. The marked physiological changes, differential gene expression, and the regulatory and structural components involved in Coxiella's morphogenesis from LCV to SCV and back to the LCV are fascinating attributes of the pathogen and are reviewed in this chapter.


Assuntos
Proteínas de Bactérias/fisiologia , Coxiella burnetii/fisiologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Coxiella burnetii/genética , Coxiella burnetii/metabolismo , Biologia do Desenvolvimento/métodos , Regulação Bacteriana da Expressão Gênica , Transcrição Gênica
20.
Work ; 72(4): 1337-1348, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35723137

RESUMO

BACKGROUND: Plogging, an environment friendly trash workout is a combination of jogging with litter collection. People who are involved in the plogging carry a baggage for collecting the litter. Walking with a weight on one side causes the opposite side of the body to engage for stability and are also exposed to repetitive bending during the activity. OBJECTIVES: The purpose of this study is to evaluate the postural and physiological aspects of plogging activity. METHODS: Thirty six subjects performed the litter collection in stoop, semi-squat, full squat and lunge postures respectively. Postures were analyzed using Rapid Entire Body Assessment (REBA). Physiological aspects of plogging, as well as a comparison of physical activity assessment during jogging and plogging, were investigated using a Polar M430 optical heart rate monitor. Statistical analysis were performed using SPSS version 23. RESULTS: Mean±SD of full squat (5.13±0.59) and lunge (6.64±1.15) posture was found to have lesser risk score in comparison with the other two postures such as stoop (10.31±0.88) and semi-squat (8.11±1.40). Analysis from the Kruskal-Wallis and post hoc test showed that there is no significant interaction between the postures (p < 0.05). Paired Sample t-test showed that the energy expenditure for plogging and jogging are found to be similar (p > 0.05), but the fat percentages of calories burned is more in plogging (p < 0.05). Howerver plogging can be considered as a strenous activity as the % Cardiovascular strain of the activity had a mean value of (99.261%). CONCLUSIONS: Ergonomic interventions are needed to play a vital role in minimizing the musculoskeletal related injuries and the physical strain of the task.


Assuntos
Ergonomia , Doenças Musculoesqueléticas , Humanos , Doenças Musculoesqueléticas/etiologia , Postura , Medição de Risco , Fatores de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA