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1.
N Engl J Med ; 390(5): 409-420, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38294973

RESUMO

BACKGROUND: Studies evaluating surgical-site infection have had conflicting results with respect to the use of alcohol solutions containing iodine povacrylex or chlorhexidine gluconate as skin antisepsis before surgery to repair a fractured limb (i.e., an extremity fracture). METHODS: In a cluster-randomized, crossover trial at 25 hospitals in the United States and Canada, we randomly assigned hospitals to use a solution of 0.7% iodine povacrylex in 74% isopropyl alcohol (iodine group) or 2% chlorhexidine gluconate in 70% isopropyl alcohol (chlorhexidine group) as preoperative antisepsis for surgical procedures to repair extremity fractures. Every 2 months, the hospitals alternated interventions. Separate populations of patients with either open or closed fractures were enrolled and included in the analysis. The primary outcome was surgical-site infection, which included superficial incisional infection within 30 days or deep incisional or organ-space infection within 90 days. The secondary outcome was unplanned reoperation for fracture-healing complications. RESULTS: A total of 6785 patients with a closed fracture and 1700 patients with an open fracture were included in the trial. In the closed-fracture population, surgical-site infection occurred in 77 patients (2.4%) in the iodine group and in 108 patients (3.3%) in the chlorhexidine group (odds ratio, 0.74; 95% confidence interval [CI], 0.55 to 1.00; P = 0.049). In the open-fracture population, surgical-site infection occurred in 54 patients (6.5%) in the iodine group and in 60 patients (7.3%) in the chlorhexidine group (odd ratio, 0.86; 95% CI, 0.58 to 1.27; P = 0.45). The frequencies of unplanned reoperation, 1-year outcomes, and serious adverse events were similar in the two groups. CONCLUSIONS: Among patients with closed extremity fractures, skin antisepsis with iodine povacrylex in alcohol resulted in fewer surgical-site infections than antisepsis with chlorhexidine gluconate in alcohol. In patients with open fractures, the results were similar in the two groups. (Funded by the Patient-Centered Outcomes Research Institute and the Canadian Institutes of Health Research; PREPARE ClinicalTrials.gov number, NCT03523962.).


Assuntos
Anti-Infecciosos Locais , Clorexidina , Fixação de Fratura , Fraturas Ósseas , Iodo , Infecção da Ferida Cirúrgica , Humanos , 2-Propanol/administração & dosagem , 2-Propanol/efeitos adversos , 2-Propanol/uso terapêutico , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/efeitos adversos , Anti-Infecciosos Locais/uso terapêutico , Antissepsia/métodos , Canadá , Clorexidina/administração & dosagem , Clorexidina/efeitos adversos , Clorexidina/uso terapêutico , Etanol , Extremidades/lesões , Extremidades/microbiologia , Extremidades/cirurgia , Iodo/administração & dosagem , Iodo/efeitos adversos , Iodo/uso terapêutico , Cuidados Pré-Operatórios/efeitos adversos , Cuidados Pré-Operatórios/métodos , Pele/microbiologia , Infecção da Ferida Cirúrgica/etiologia , Infecção da Ferida Cirúrgica/prevenção & controle , Fraturas Ósseas/cirurgia , Estudos Cross-Over , Estados Unidos
2.
Nat Methods ; 21(6): 1122-1130, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38831210

RESUMO

Long-standing questions about human brain evolution may only be resolved through comparisons with close living evolutionary relatives, such as chimpanzees. This applies in particular to structural white matter (WM) connectivity, which continuously expanded throughout evolution. However, due to legal restrictions on chimpanzee research, neuroscience research currently relies largely on data with limited detail or on comparisons with evolutionarily distant monkeys. Here, we present a detailed magnetic resonance imaging resource to study structural WM connectivity in the chimpanzee. This open-access resource contains (1) WM reconstructions of a postmortem chimpanzee brain, using the highest-quality diffusion magnetic resonance imaging data yet acquired from great apes; (2) an optimized and validated method for high-quality fiber orientation reconstructions; and (3) major fiber tract segmentations for cross-species morphological comparisons. This dataset enabled us to identify phylogenetically relevant details of the chimpanzee connectome, and we anticipate that it will substantially contribute to understanding human brain evolution.


Assuntos
Encéfalo , Conectoma , Pan troglodytes , Substância Branca , Pan troglodytes/anatomia & histologia , Animais , Substância Branca/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/anatomia & histologia , Conectoma/métodos , Masculino , Vias Neurais/anatomia & histologia , Processamento de Imagem Assistida por Computador/métodos , Feminino , Mapeamento Encefálico/métodos
3.
PLoS Biol ; 22(5): e3002609, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38713644

RESUMO

Tool use is considered a driving force behind the evolution of brain expansion and prolonged juvenile dependency in the hominin lineage. However, it remains rare across animals, possibly due to inherent constraints related to manual dexterity and cognitive abilities. In our study, we investigated the ontogeny of tool use in chimpanzees (Pan troglodytes), a species known for its extensive and flexible tool use behavior. We observed 70 wild chimpanzees across all ages and analyzed 1,460 stick use events filmed in the Taï National Park, Côte d'Ivoire during the chimpanzee attempts to retrieve high-nutrient, but difficult-to-access, foods. We found that chimpanzees increasingly utilized hand grips employing more than 1 independent digit as they matured. Such hand grips emerged at the age of 2, became predominant and fully functional at the age of 6, and ubiquitous at the age of 15, enhancing task accuracy. Adults adjusted their hand grip based on the specific task at hand, favoring power grips for pounding actions and intermediate grips that combine power and precision, for others. Highly protracted development of suitable actions to acquire hidden (i.e., larvae) compared to non-hidden (i.e., nut kernel) food was evident, with adult skill levels achieved only after 15 years, suggesting a pronounced cognitive learning component to task success. The prolonged time required for cognitive assimilation compared to neuromotor control points to selection pressure favoring the retention of learning capacities into adulthood.


Assuntos
Força da Mão , Pan troglodytes , Comportamento de Utilização de Ferramentas , Animais , Pan troglodytes/fisiologia , Comportamento de Utilização de Ferramentas/fisiologia , Feminino , Masculino , Força da Mão/fisiologia , Côte d'Ivoire , Cognição/fisiologia , Comportamento Alimentar/fisiologia
4.
Nature ; 598(7882): 652-656, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34646009

RESUMO

Humans are considered as the main host for Mycobacterium leprae1, the aetiological agent of leprosy, but spillover has occurred to other mammals that are now maintenance hosts, such as nine-banded armadillos and red squirrels2,3. Although naturally acquired leprosy has also been described in captive nonhuman primates4-7, the exact origins of infection remain unclear. Here we describe leprosy-like lesions in two wild populations of western chimpanzees (Pan troglodytes verus) in Cantanhez National Park, Guinea-Bissau and Taï National Park, Côte d'Ivoire, West Africa. Longitudinal monitoring of both populations revealed the progression of disease symptoms compatible with advanced leprosy. Screening of faecal and necropsy samples confirmed the presence of M. leprae as the causative agent at each site and phylogenomic comparisons with other strains from humans and other animals show that the chimpanzee strains belong to different and rare genotypes (4N/O and 2F). These findings suggest that M. leprae may be circulating in more wild animals than suspected, either as a result of exposure to humans or other unknown environmental sources.


Assuntos
Hanseníase/veterinária , Pan troglodytes/microbiologia , Animais , Autopsia/veterinária , Côte d'Ivoire , Fezes/microbiologia , Genótipo , Guiné-Bissau , Humanos , Hanseníase/microbiologia , Mycobacterium leprae/genética , Mycobacterium leprae/isolamento & purificação , Filogenia
5.
PLoS Biol ; 21(11): e3002350, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37917608

RESUMO

Tactical warfare is considered a driver of the evolution of human cognition. One such tactic, considered unique to humans, is collective use of high elevation in territorial conflicts. This enables early detection of rivals and low-risk maneuvers, based on information gathered. Whether other animals use such tactics is unknown. With a unique dataset of 3 years of simultaneous behavioral and ranging data on 2 neighboring groups of western chimpanzees, from the Taï National Park, Côte d'Ivoire, we tested whether chimpanzees make decisions consistent with tactical use of topography to gain an advantage over rivals. We show that chimpanzees are more likely to use high hills when traveling to, rather than away from, the border where conflict typically takes place. Once on border hills, chimpanzees favor activities that facilitate information gathering about rivals. Upon leaving hills, movement decisions conformed with lowest risk engagement, indicating that higher elevation facilitates the detection of rivals presence or absence. Our results support the idea that elevation use facilitated rival information gathering and appropriate tactical maneuvers. Landscape use during territorial maneuvers in natural contexts suggests chimpanzees seek otherwise inaccessible information to adjust their behavior and points to the use of sophisticated cognitive abilities, commensurate with selection for cognition in species where individuals gain benefits from coordinated territorial defense. We advocate territorial contexts as a key paradigm for unpicking complex animal cognition.


Assuntos
Pan troglodytes , Animais , Humanos , Côte d'Ivoire
6.
Mol Cell Proteomics ; 23(3): 100733, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38342410

RESUMO

Nitrotyrosine, or 3-nitrotyrosine, is an oxidative post-translational modification induced by reactive nitrogen species. Although nitrotyrosine is considered a marker of oxidative stress and has been associated with inflammation, neurodegeneration, cardiovascular disease, and cancer, identification of nitrotyrosine-modified proteins remains challenging owing to its low stoichiometric levels in biological samples. To facilitate a comprehensive analysis of proteins and peptides containing nitrotyrosine, we optimized an immunoprecipitation-based enrichment workflow using a cell line model. The identification of proteins and peptides containing nitrotyrosine residues was carried out after peroxynitrite treatment of cell lysates, which generated modified nitrotyrosine residues on susceptible sites on proteins. We evaluated the efficacy of enriching nitrotyrosine-modified proteins and peptides by employing four different commercially available monoclonal antibodies directed against nitrotyrosine. LC-MS/MS analysis resulted in the identification of 1377 and 1624 nitrotyrosine-containing peptides from protein- and peptide-based enrichment experiments, respectively. Although the yield of nitrotyrosine-containing peptides was higher in experiments where peptides rather than proteins were enriched, we found a substantial proportion (37-65%) of identified nitrotyrosine-containing peptides contained nitrotyrosine at the N-terminus. However, in protein-based immunoprecipitation <9% of nitrotyrosine-containing peptides had nitrotyrosine modification at the N-terminus of the peptide. Overall, our study resulted in the identification of 2603 nitrotyrosine-containing peptides of which >2000 have not previously been reported. We synthesized 101 novel nitrotyrosine-containing peptides identified in our analysis and analyzed them by LC-MS/MS to validate our findings. We have confirmed the validity of 70% of these peptides, as they demonstrated a similarity score exceeding 0.7 when compared to peptides identified through experimental methods. Finally, we also validated the presence of nitrotyrosine modification on PKM and EF2 proteins in peroxynitrite-treated samples by immunoblot analysis. The large catalog presented in this study along with the workflow should facilitate the investigation of nitrotyrosine as an oxidative modification in a variety of settings in greater detail.


Assuntos
Ácido Peroxinitroso , Espectrometria de Massas em Tandem , Tirosina/análogos & derivados , Cromatografia Líquida/métodos , Proteínas/química , Peptídeos/química , Tirosina/metabolismo , Anticorpos
7.
Proc Natl Acad Sci U S A ; 120(4): e2212338120, 2023 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-36649421

RESUMO

To fertilize an oocyte, the membrane potential of both mouse and human sperm must hyperpolarize (become more negative inside). Determining the molecular mechanisms underlying this hyperpolarization is vital for developing new contraceptive methods and detecting causes of idiopathic male infertility. In mouse sperm, hyperpolarization is caused by activation of the sperm-specific potassium (K+) channel SLO3 [C. M. Santi et al., FEBS Lett. 584, 1041-1046 (2010)]. In human sperm, it has long been unclear whether hyperpolarization depends on SLO3 or the ubiquitous K+ channel SLO1 [N. Mannowetz, N. M. Naidoo, S. A. S. Choo, J. F. Smith, P. V. Lishko, Elife 2, e01009 (2013), C. Brenker et al., Elife 3, e01438 (2014), and S. A. Mansell, S. J. Publicover, C. L. R. Barratt, S. M. Wilson, Mol. Hum. Reprod. 20, 392-408 (2014)]. In this work, we identified the first selective inhibitor for human SLO3-VU0546110-and showed that it completely blocked heterologous SLO3 currents and endogenous K+ currents in human sperm. This compound also prevented sperm from hyperpolarizing and undergoing hyperactivated motility and induced acrosome reaction, which are necessary to fertilize an egg. We conclude that SLO3 is the sole K+ channel responsible for hyperpolarization and significantly contributes to the fertilizing ability of human sperm. Moreover, SLO3 is a good candidate for contraceptive development, and mutation of this gene is a possible cause of idiopathic male infertility.


Assuntos
Infertilidade Masculina , Canais de Potássio Ativados por Cálcio de Condutância Alta , Humanos , Masculino , Canais de Potássio Ativados por Cálcio de Condutância Alta/antagonistas & inibidores , Potenciais da Membrana/fisiologia , Sêmen , Espermatozoides/fisiologia
8.
Biotechnol Bioeng ; 121(2): 593-604, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37986639

RESUMO

The selective introduction of amine groups within deconstruction products of lignin could provide an avenue for valorizing waste biomass while achieving a green synthesis of industrially relevant building blocks from sustainable sources. Here, we built and characterized enzyme cascades that create aldehydes and subsequently primary amines from diverse lignin-derived carboxylic acids using a carboxylic acid reductase (CAR) and an ω-transaminase (TA). Unlike previous studies that have paired CAR and TA enzymes, here we examine multiple homologs of each of these enzymes and a broader set of candidate substrates. In addition, we compare the performance of these systems in cell-free and resting whole-cell biocatalysis formats using the conversion of vanillate to vanillyl amine as model chemistry. We also demonstrate that resting whole cells can be recycled for multiple batch reactions. We used the knowledge gained from this study to produce several amines from carboxylic acid precursors using one-pot biocatalytic reactions, several of which we report for the first time. These results expand our knowledge of these industrially relevant enzyme families to new substrates and contexts for environmentally friendly and potentially low-cost synthesis of diverse aryl aldehydes and amines.


Assuntos
Aminas , Lignina , Aminação , Aminas/química , Ácidos Carboxílicos , Aldeídos , Biocatálise
9.
Anesth Analg ; 138(4): 878-892, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-37788388

RESUMO

The Society of Cardiovascular Anesthesiologists (SCA) is committed to improving the quality, safety, and value that cardiothoracic anesthesiologists bring to patient care. To fulfill this mission, the SCA supports the creation of peer-reviewed manuscripts that establish standards, produce guidelines, critically analyze the literature, interpret preexisting guidelines, and allow experts to engage in consensus opinion. The aim of this report, commissioned by the SCA President, is to summarize the distinctions among these publications and describe a novel SCA-supported framework that provides guidance to SCA members for the creation of these publications. The ultimate goal is that through a standardized and transparent process, the SCA will facilitate up-to-date education and implementation of best practices by cardiovascular and thoracic anesthesiologists to improve patient safety, quality of care, and outcomes.


Assuntos
Anestesiologistas , Sociedades Médicas , Humanos , Consenso
10.
Curr Osteoporos Rep ; 22(1): 217-221, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38217755

RESUMO

PURPOSE OF REVIEW: Three review articles have been written that discuss the roles of the central and peripheral nervous systems in fracture healing. While content among the articles is overlapping, there is a key difference between them: the use of artificial intelligence (AI). In one paper, the first draft was written solely by humans. In the second paper, the first draft was written solely by AI using ChatGPT 4.0 (AI-only or AIO). In the third paper, the first draft was written using ChatGPT 4.0 but the literature references were supplied from the human-written paper (AI-assisted or AIA). This project was done to evaluate the capacity of AI to conduct scientific writing. Importantly, all manuscripts were fact checked and extensively edited by all co-authors rendering the final manuscript drafts significantly different from the first drafts. RECENT FINDINGS: Unsurprisingly, the use of AI decreased the time spent to write a review. The two AI-written reviews took less time to write than the human-written paper; however, the changes and editing required in all three manuscripts were extensive. The human-written paper was edited the most. On the other hand, the AI-only paper was the most inaccurate with inappropriate reference usage and the AI-assisted paper had the greatest incidence of plagiarism. These findings show that each style of writing presents its own unique set of challenges and advantages. While AI can theoretically write scientific reviews, from these findings, the extent of editing done subsequently, the inaccuracy of the claims it makes, and the plagiarism by AI are all factors to be considered and a primary reason why it may be several years into the future before AI can present itself as a viable alternative for traditional scientific writing.


Assuntos
Inteligência Artificial , Consolidação da Fratura , Humanos , Sistema Nervoso Periférico , Homeostase , Redação
11.
Curr Osteoporos Rep ; 22(1): 205-216, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38236509

RESUMO

PURPOSE OF REVIEW: Despite advances in orthopedics, there remains a need for therapeutics to hasten fracture healing. However, little focus is given to the role the nervous system plays in regulating fracture healing. This paucity of information has led to an incomplete understanding of fracture healing and has limited the development of fracture therapies that integrate the importance of the nervous system. This review seeks to illuminate the integral roles that the nervous system plays in fracture healing. RECENT FINDINGS: Preclinical studies explored several methodologies for ablating peripheral nerves to demonstrate ablation-induced deficits in fracture healing. Conversely, activation of peripheral nerves via the use of dorsal root ganglion electrical stimulation enhanced fracture healing via calcitonin gene related peptide (CGRP). Investigations into TLR-4, TrkB agonists, and nerve growth factor (NGF) expression provide valuable insights into molecular pathways influencing bone mesenchymal stem cells and fracture repair. Finally, there is continued research into the connections between pain and fracture healing with findings suggesting that anti-NGF may be able to block pain without affecting healing. This review underscores the critical roles of the central nervous system (CNS), peripheral nervous system (PNS), and autonomic nervous system (ANS) in fracture healing, emphasizing their influence on bone cells, neuropeptide release, and endochondral ossification. The use of TBI models contributes to understanding neural regulation, though the complex influence of TBI on fracture healing requires further exploration. The review concludes by addressing the neural connection to fracture pain. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.


Assuntos
Inteligência Artificial , Consolidação da Fratura , Humanos , Consolidação da Fratura/fisiologia , Peptídeo Relacionado com Gene de Calcitonina , Dor , Sistema Nervoso/metabolismo
12.
Curr Osteoporos Rep ; 22(1): 193-204, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38236511

RESUMO

PURPOSE OF REVIEW: The traditionally understated role of neural regulation in fracture healing is gaining prominence, as recent findings underscore the peripheral nervous system's critical contribution to bone repair. Indeed, it is becoming more evident that the nervous system modulates every stage of fracture healing, from the onset of inflammation to repair and eventual remodeling. RECENT FINDINGS: Essential to this process are neurotrophins and neuropeptides, such as substance P, calcitonin gene-related peptide, and neuropeptide Y. These molecules fulfill key roles in promoting osteogenesis, influencing inflammation, and mediating pain. The sympathetic nervous system also plays an important role in the healing process: while local sympathectomies may improve fracture healing, systemic sympathetic denervation impairs fracture healing. Furthermore, chronic activation of the sympathetic nervous system, often triggered by stress, is a potential impediment to effective fracture healing, marking an important area for further investigation. The potential to manipulate aspects of the nervous system offers promising therapeutic possibilities for improving outcomes in fracture healing. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.


Assuntos
Inteligência Artificial , Fraturas Ósseas , Humanos , Osteogênese , Consolidação da Fratura/fisiologia , Sistema Nervoso Periférico , Inflamação
13.
Curr Osteoporos Rep ; 22(1): 182-192, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38294715

RESUMO

PURPOSE OF REVIEW: Fractures are a prominent form of traumatic injury and shall continue to be for the foreseeable future. While the inflammatory response and the cells of the bone marrow microenvironment play significant roles in fracture healing, the nervous system is also an important player in regulating bone healing. RECENT FINDINGS: Considerable evidence demonstrates a role for nervous system regulation of fracture healing in a setting of traumatic injury to the brain. Although many of the impacts of the nervous system on fracture healing are positive, pain mediated by the nervous system can have detrimental effects on mobilization and quality of life. Understanding the role the nervous system plays in fracture healing is vital to understanding fracture healing as a whole and improving quality of life post-injury. This review article is part of a series of multiple manuscripts designed to determine the utility of using artificial intelligence for writing scientific reviews.


Assuntos
Consolidação da Fratura , Fraturas Ósseas , Humanos , Consolidação da Fratura/fisiologia , Inteligência Artificial , Qualidade de Vida , Calo Ósseo
14.
Am J Primatol ; : e23652, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38807168

RESUMO

Nematodes belonging to the genus Oesophagostomum frequently infect wild chimpanzees (Pan troglodytes) across widely separated field sites. Nodular lesions (granulomas) containing Oesophagostomum are commonly seen in the abdomen of infected chimpanzees post-mortem. At Taï National Park, Côte d'Ivoire, previous studies have identified larvae of a variety of Oesophagostomum spp. in wild chimpanzee stool, based on sequencing of larval DNA, and nodular lesions associated with Oesophagostomum, identified morphologically to the genus level but not sequenced. Here we present three recent cases of parasitic granulomas found post-mortem in chimpanzees at Taï. We complement descriptions of gross pathology, histopathology and parasitology with PCR and sequencing of DNA isolated from the parasitic nodules and from adult worms found inside the nodules. In all three cases, we identify Oesophagostomum stephanostomum as the causative agent. The sequences from this study were identical to the only other published sequences from nodules in nonhuman primates-those from the wild chimpanzees of Gombe, Tanzania.

15.
Proc Natl Acad Sci U S A ; 118(16)2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33846261

RESUMO

Understanding the vulnerability of trees to drought-induced mortality is key to predicting the fate of forests in a future climate with more frequent and intense droughts, although the underlying mechanisms are difficult to study in adult trees. Here, we explored the dynamic changes of water relations and limits of hydraulic function in dying adults of Norway spruce (Picea abies L.) during the progression of the record-breaking 2018 Central European drought. In trees on the trajectory to drought-induced mortality, we observed rapid, nonlinear declines of xylem pressure that commenced at the early onset of xylem cavitation and caused a complete loss of xylem hydraulic conductance within a very short time. We also observed severe depletions of nonstructural carbohydrates, though carbon starvation could be ruled out as the cause of the observed tree death, as both dying and surviving trees showed these metabolic limitations. Our observations provide striking field-based evidence for fast dehydration and hydraulic collapse as the cause of drought-induced mortality in adult Norway spruce. The nonlinear decline of tree water relations suggests that considering the temporal dynamics of dehydration is critical for predicting tree death. The collapse of the hydraulic system within a short time demonstrates that trees can rapidly be pushed out of the zone of hydraulic safety during the progression of a severe drought. In summary, our findings point toward a higher mortality risk for Norway spruce than previously assumed, which is in line with current reports of unprecedented levels of drought-induced mortality in this major European tree species.


Assuntos
Secas/mortalidade , Picea/metabolismo , Estresse Fisiológico/fisiologia , Carbono/metabolismo , Cycadopsida/metabolismo , Florestas , Folhas de Planta/metabolismo , Traqueófitas/metabolismo , Árvores/metabolismo , Água/metabolismo , Xilema/metabolismo
16.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33526653

RESUMO

Exacerbated immune responses and loss of self-tolerance lead to the development of autoimmunity and immunopathology. Novel therapies to target autoreactive T cells are still needed. Here, we report that Th2-polarized T cells lacking the transcription factor T-bet harbor strong immunomodulatory potential and suppress antigen-specific CD8+ T cells via IL-10. Tbx21-/- Th2 cells protected mice against virus-induced type 1 diabetes development and suppressed not only naive but also memory CD8+ T cell responses. IL-10-producing, but not IL-10-deficient Tbx21-/- Th2 cells down-regulated costimulatory molecules on dendritic cells and reduced their IL-12 production after lymphocytic choriomeningitis virus infection. Impaired dendritic cell activation hindered effector and cytotoxic CD8+ T cell development after infection. These findings indicate that Tbx21-/- Th2 cells strongly suppress proinflammatory responses of naive and memory T cells via IL-10. Thus, in vivo IL-10-secreting Th2 cells could harbor a therapeutic potential for the treatment of T cell-mediated inflammatory disorders.


Assuntos
Memória Imunológica , Interleucina-10/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/metabolismo , Células Th2/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/prevenção & controle , Regulação para Baixo , Epitopos/imunologia , Ativação Linfocitária/imunologia , Coriomeningite Linfocítica/imunologia , Coriomeningite Linfocítica/virologia , Vírus da Coriomeningite Linfocítica/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Proc Natl Acad Sci U S A ; 118(15)2021 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-33876746

RESUMO

Humans harbor diverse communities of microorganisms, the majority of which are bacteria in the gastrointestinal tract. These gut bacterial communities in turn host diverse bacteriophage (hereafter phage) communities that have a major impact on their structure, function, and, ultimately, human health. However, the evolutionary and ecological origins of these human-associated phage communities are poorly understood. To address this question, we examined fecal phageomes of 23 wild nonhuman primate taxa, including multiple representatives of all the major primate radiations. We find relatives of the majority of human-associated phages in wild primates. Primate taxa have distinct phageome compositions that exhibit a clear phylosymbiotic signal, and phage-superhost codivergence is often detected for individual phages. Within species, neighboring social groups harbor compositionally and evolutionarily distinct phageomes, which are structured by superhost social behavior. Captive nonhuman primate phageome composition is intermediate between that of their wild counterparts and humans. Phage phylogenies reveal replacement of wild great ape-associated phages with human-associated ones in captivity and, surprisingly, show no signal for the persistence of wild-associated phages in captivity. Together, our results suggest that potentially labile primate-phage associations have persisted across millions of years of evolution. Across primates, these phylosymbiotic and sometimes codiverging phage communities are shaped by transmission between groupmates through grooming and are dramatically modified when primates are moved into captivity.


Assuntos
Bacteriófagos/patogenicidade , Microbioma Gastrointestinal , Hominidae/virologia , Viroma , Animais , Bacteriófagos/genética , Meio Ambiente , Evolução Molecular , Hominidae/classificação , Hominidae/genética , Hominidae/microbiologia , Filogenia , Comportamento Social
18.
Wiad Lek ; 77(3): 591-596, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38691805

RESUMO

OBJECTIVE: Aim: To investigate and analyze legal conflicts in forensic dentistry of Ukraine. PATIENTS AND METHODS: Materials and Methods: A comparative research method for determining the common and distinctive features of the legal regulation of forensic dental expertise as a subcluster in the legislation of Ukraine. The descriptive (monographic) method reveals the problematic aspects of forensic dental examination through the lens of local normative and general normative connotations. The structural-functional research method made it possible to systematize the peculiarities of forensic medical and forensic dental expert activity. CONCLUSION: Conclusions: The analysis of legal conflicts made it possible to come to the following conclusions, that in Ukraine today there is no specific legal act that would regulate the aspects of performing dental activities. Forensic dental examination in Ukraine, in accordance with the legislation, is an examination of the actions and inactions of the dentist. The adoption of normative legal acts in the field of dental activity and forensic dental examination in Ukraine would make it possible to determine the specifics of establishing facts and circumstances that indicate a violation of the patient's rights.


Assuntos
Odontologia Legal , Ucrânia , Humanos , Odontologia Legal/legislação & jurisprudência
19.
Proteomics ; 23(10): e2200507, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36752121

RESUMO

A quadrupole time-of-flight mass spectrometer coupled with a trapped ion mobility spectrometry (timsTOF) operated in parallel accumulation-serial fragmentation (PASEF) mode has recently emerged as a platform capable of providing four-dimensional (4D) features comprising of elution time, collision cross section (CCS), mass-to-charge ratio, and intensity of peptides. The PASEF mode provides ∼100% ion sampling efficiency both in data-dependent acquisition (DDA) and data-independent acquisition (DIA) modes without sacrificing sensitivity. In addition, targeted measurements using PASEF integrated parallel reaction monitoring (PRM) mode have also been described. However, only limited number of studies have used timsTOF for analysis of clinical samples. Although Orbitrap mass spectrometers have been used for biomarker discovery from cerebrospinal fluid (CSF) in a variety of neurological diseases, these Orbitrap-derived datasets cannot readily be applied for driving experiments on timsTOF mass spectrometers. We generated a catalog of peptides and proteins in human CSF in DDA mode on a timsTOF mass spectrometer and used these data to build a spectral library. This strategy allowed us to use elution times and ion mobility values from the spectral library to design PRM experiments for quantifying previously discovered biomarkers from CSF samples in Alzheimer's disease. When the same samples were analyzed using a DIA approach combined with a spectral library search, a higher number of proteins were identified than in a library-free approach. Overall, we have established a spectral library of CSF as a resource and demonstrated its utility for PRM and DIA studies, which should facilitate studies of neurological disorders.


Assuntos
Espectrometria de Mobilidade Iônica , Proteômica , Humanos , Proteômica/métodos , Peptídeos/análise , Espectrometria de Massas/métodos , Proteínas
20.
Metab Eng ; 77: 294-305, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-37100193

RESUMO

Aldehydes are attractive chemical targets both as end products in the flavors and fragrances industry and as synthetic intermediates due to their propensity for C-C bond formation. Here, we identify and address unexpected oxidation of a model collection of aromatic aldehydes, including many that originate from biomass degradation. When diverse aldehydes are supplemented to E. coli cells grown under aerobic conditions, as expected they are either reduced by the wild-type MG1655 strain or stabilized by a strain engineered for reduced aromatic aldehyde reduction (the E. coli RARE strain). Surprisingly, when these same aldehydes are supplemented to resting cell preparations of either E. coli strain, under many conditions we observe substantial oxidation. By performing combinatorial inactivation of six candidate aldehyde dehydrogenase genes in the E. coli genome using multiplexed automatable genome engineering (MAGE), we demonstrate that this oxidation can be substantially slowed, with greater than 50% retention of 6 out of 8 aldehydes when assayed 4 h after their addition. Given that our newly engineered strain exhibits reduced oxidation and reduction of aromatic aldehydes, we dubbed it the E. coli ROAR strain. We applied the new strain to resting cell biocatalysis for two kinds of reactions - the reduction of 2-furoic acid to furfural and the condensation of 3-hydroxybenzaldehyde and glycine to form a non-standard ß-hydroxy-α-amino acid. In each case, we observed substantial improvements in product titer 20 h after reaction initiation (9-fold and 10-fold, respectively). Moving forward, the use of this strain to generate resting cells should allow aldehyde product isolation, further enzymatic conversion, or chemical reactivity under cellular contexts that better accommodate aldehyde toxicity.


Assuntos
Aldeídos , Escherichia coli , Aldeídos/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Oxirredução , Aldeído Desidrogenase/genética , Biocatálise
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