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1.
Cell ; 184(24): 5932-5949.e15, 2021 11 24.
Artigo em Inglês | MEDLINE | ID: mdl-34798069

RESUMO

Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.


Assuntos
Autopsia/métodos , COVID-19/mortalidade , COVID-19/virologia , Bulbo Olfatório/virologia , Mucosa Olfatória/virologia , Mucosa Respiratória/virologia , Idoso , Anosmia , COVID-19/fisiopatologia , Endoscopia/métodos , Feminino , Glucuronosiltransferase/biossíntese , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Transtornos do Olfato , Neurônios Receptores Olfatórios/metabolismo , Sistema Respiratório , SARS-CoV-2 , Olfato
2.
Nat Methods ; 21(2): 228-235, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38233503

RESUMO

Single-cell genetic heterogeneity is ubiquitous in microbial populations and an important aspect of microbial biology; however, we lack a broadly applicable and accessible method to study this heterogeneity in microbial populations. Here, we show a simple, robust and generalizable method for high-throughput single-cell sequencing of target genetic loci in diverse microbes using simple droplet microfluidics devices (droplet targeted amplicon sequencing; DoTA-seq). DoTA-seq serves as a platform to perform diverse assays for single-cell genetic analysis of microbial populations. Using DoTA-seq, we demonstrate the ability to simultaneously track the prevalence and taxonomic associations of >10 antibiotic-resistance genes and plasmids within human and mouse gut microbial communities. This workflow is a powerful and accessible platform for high-throughput single-cell sequencing of diverse microbial populations.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Análise de Célula Única , Animais , Humanos , Camundongos , Sequenciamento de Nucleotídeos em Larga Escala/métodos
3.
Proc Natl Acad Sci U S A ; 120(50): e2311564120, 2023 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-38048468

RESUMO

Soils are common sources of metal(loid) contaminant exposure globally. Lead (Pb) and arsenic (As) are of paramount concern due to detrimental neurological and carcinogenic health effects, respectively. Pb and/or As contaminated soils require remediation, typically leading to excavation, a costly and environmentally damaging practice of removing soil to a central location (e.g., hazardous landfill) that may not be a viable option in low-income countries. Chemical remediation techniques may allow for in situ conversion of soil contaminants to phases that are not easily mobilized upon ingestion; however, effective chemical remediation options are limited. Here, we have successfully tested a soil remediation technology using potted soils that relies on converting soil Pb and As into jarosite-group minerals, such as plumbojarosite (PLJ) and beudantite, possessing exceptionally low bioaccessibility [i.e., solubility at gastric pH conditions (pH 1.5 to 3)]. Across all experiments conducted, all new treatment methods successfully promoted PLJ and/or beudantite conversion, resulting in a proportional decrease in Pb and As bioaccessibility. Increasing temperature resulted in increased conversion to jarosite-group minerals, but addition of potassium (K) jarosite was most critical to Pb and As bioaccessibility decreases. Our methods of K-jarosite treatment yielded <10% Pb and As bioaccessibility compared to unamended soil values of approximately 70% and 60%, respectively. The proposed treatment is a rare dual remediation option that effectively treats soil Pb and As such that potential exposure is considerably reduced. Research presented here lays the foundation for ongoing field application.


Assuntos
Arsênio , Poluentes do Solo , Arsênio/análise , Potássio , Solo , Chumbo , Poluentes do Solo/análise , Minerais , Disponibilidade Biológica
4.
Syst Biol ; 2024 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-38963801

RESUMO

Phylogenetic trees establish a historical context for the study of organismal form and function. Most phylogenetic trees are estimated using a model of evolution. For molecular data, modeling evolution is often based on biochemical observations about changes between character states. For example, there are four nucleotides, and we can make assumptions about the probability of transitions between them. By contrast, for morphological characters, we may not know a priori how many characters states there are per character, as both extant sampling and the fossil record may be highly incomplete, which leads to an observer bias. For a given character, the state space may be larger than what has been observed in the sample of taxa collected by the researcher. In this case, how many evolutionary rates are needed to even describe transitions between morphological character states may not be clear, potentially leading to model misspecification. To explore the impact of this model misspecification, we simulated character data with varying numbers of character states per character. We then used the data to estimate phylogenetic trees using models of evolution with the correct number of character states and an incorrect number of character states. The results of this study indicate that this observer bias may lead to phylogenetic error, particularly in the branch lengths of trees. If the state space is wrongly assumed to be too large, then we underestimate the branch lengths, and the opposite occurs when the state space is wrongly assumed to be too small.

5.
Nature ; 572(7768): 224-229, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391558

RESUMO

Living systems are capable of locomotion, reconfiguration and replication. To perform these tasks, cells spatiotemporally coordinate the interactions of force-generating, 'active' molecules that create and manipulate non-equilibrium structures and force fields of up to millimetre length scales1-3. Experimental active-matter systems of biological or synthetic molecules are capable of spontaneously organizing into structures4,5 and generating global flows6-9. However, these experimental systems lack the spatiotemporal control found in cells, limiting their utility for studying non-equilibrium phenomena and bioinspired engineering. Here we uncover non-equilibrium phenomena and principles of boundary-mediated control by optically modulating structures and fluid flow in an engineered system of active biomolecules. Our system consists of purified microtubules and light-activatable motor proteins that crosslink and organize the microtubules into distinct structures upon illumination. We develop basic operations-defined as sets of light patterns-to create, move and merge the microtubule structures. By combining these operations, we create microtubule networks that span several hundred micrometres in length and contract at speeds up to an order of magnitude higher than the speed of an individual motor protein. We manipulate these contractile networks to generate and sculpt persistent fluid flows. The principles of boundary-mediated control that we uncover may be used to study emergent cellular structures and forces and to develop programmable active-matter devices.


Assuntos
Bioengenharia/métodos , Cinesinas/metabolismo , Cinesinas/efeitos da radiação , Luz , Microtúbulos/química , Microtúbulos/efeitos da radiação , Cinesinas/química , Microtúbulos/metabolismo
6.
Dev Biol ; 498: 35-48, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36933633

RESUMO

Fibroblasts play an important role in maintaining tissue integrity by secreting components of the extracellular matrix and initiating response to injury. Although the function of fibroblasts has been extensively studied in adults, the embryonic origin and diversification of different fibroblast subtypes during development remain largely unexplored. Using zebrafish as a model, we show that the sclerotome, a sub-compartment of the somite, is the embryonic source of multiple fibroblast subtypes including tenocytes (tendon fibroblasts), blood vessel associated fibroblasts, fin mesenchymal cells, and interstitial fibroblasts. High-resolution imaging shows that different fibroblast subtypes occupy unique anatomical locations with distinct morphologies. Long-term Cre-mediated lineage tracing reveals that the sclerotome also contributes to cells closely associated with the axial skeleton. Ablation of sclerotome progenitors results in extensive skeletal defects. Using photoconversion-based cell lineage analysis, we find that sclerotome progenitors at different dorsal-ventral and anterior-posterior positions display distinct differentiation potentials. Single-cell clonal analysis combined with in vivo imaging suggests that the sclerotome mostly contains unipotent and bipotent progenitors prior to cell migration, and the fate of their daughter cells is biased by their migration paths and relative positions. Together, our work demonstrates that the sclerotome is the embryonic source of trunk fibroblasts as well as the axial skeleton, and local signals likely contribute to the diversification of distinct fibroblast subtypes.


Assuntos
Somitos , Peixe-Zebra , Animais , Diferenciação Celular , Linhagem da Célula , Fibroblastos
7.
J Intern Med ; 295(3): 346-356, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38011942

RESUMO

BACKGROUND: Choline acetyltransferase (ChAT) is required for the biosynthesis of acetylcholine, the molecular mediator that inhibits cytokine production in the cholinergic anti-inflammatory pathway of the vagus nerve inflammatory reflex. Abundant work has established the biology of cytoplasmic ChAT in neurons, but much less is known about the potential presence and function of ChAT in the extracellular milieu. OBJECTIVES: We evaluated the hypothesis that extracellular ChAT activity responds to inflammation and serves to inhibit cytokine release and attenuate inflammation. METHODS: After developing novel methods for quantification of ChAT activity in plasma, we determined whether ChAT activity changes in response to inflammatory challenges. RESULTS: Active ChAT circulates within the plasma compartment of mice and responds to immunological perturbations. Following the administration of bacterial endotoxin, plasma ChAT activity increases for 12-48 h, a time period that coincides with declining tumor necrosis factor (TNF) levels. Further, a direct activation of the cholinergic anti-inflammatory pathway by vagus nerve stimulation significantly increases plasma ChAT activity, whereas the administration of bioactive recombinant ChAT (r-ChAT) inhibits endotoxin-stimulated TNF production and anti-ChAT antibodies exacerbate endotoxin-induced TNF levels, results of which suggest that ChAT activity regulates endogenous TNF production. Administration of r-ChAT significantly attenuates pro-inflammatory cytokine production and disease activity in the dextran sodium sulfate preclinical model of inflammatory bowel disease. Finally, plasma ChAT levels are also elevated in humans with sepsis, with the highest levels observed in a patient who succumbed to infection. CONCLUSION: As a group, these results support further investigation of ChAT as a counter-regulator of inflammation and potential therapeutic agent.


Assuntos
Acetilcolina , Colina O-Acetiltransferase , Humanos , Colina O-Acetiltransferase/metabolismo , Inflamação , Fator de Necrose Tumoral alfa/metabolismo , Citocinas , Endotoxinas
8.
J Virol ; 97(11): e0109423, 2023 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-37874153

RESUMO

IMPORTANCE: Despite the advent of highly active anti-retroviral therapy, people are still dying from HIV-related causes, many of whom are children, and a protective vaccine or cure is needed to end the HIV pandemic. Understanding the nature and activation states of immune cell subsets during infection will provide insights into the immunologic milieu associated with viremia suppression that can be harnessed via therapeutic strategies to achieve a functional cure, but these are understudied in pediatric subjects. We evaluated humoral and adaptive host immunity associated with suppression of viremia in rhesus macaques infected soon after birth with a pathogenic SHIV. The results from our study provide insights into the immune cell subsets and functions associated with viremia control in young macaques that may translate to pediatric subjects for the design of future anti-viral strategies in HIV-1-infected infants and children and contribute to an understudied area of HIV-1 pathogenesis in pediatric subjects.


Assuntos
Animais Recém-Nascidos , Modelos Animais de Doenças , Infecções por HIV , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios , Viremia , Animais , Criança , Humanos , Animais Recém-Nascidos/imunologia , Infecções por HIV/imunologia , Infecções por HIV/virologia , Macaca mulatta/imunologia , Macaca mulatta/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/imunologia , Vírus da Imunodeficiência Símia/fisiologia , Viremia/imunologia , Viremia/virologia , HIV/imunologia , HIV/fisiologia
9.
Soft Matter ; 20(5): 971-977, 2024 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-38190228

RESUMO

In vitro studies of actin filament networks crosslinked with dynamic actin binding proteins provide critical insights into cytoskeletal mechanics as well as inspiration for new adaptive materials design. However, discontinuous variance in the physiochemical properties of actin binding proteins impedes holistic relationships between crosslinker molecular parameters, network structure, and mechanics. Bio-synthetic constructs composed of synthetic polymer backbones and actin binding motifs would enable crosslinkers with engineered physiochemical properties to directly target the desired structure-property relationships. As a proof of concept, bio-synthetic crosslinkers composed of highly flexible polyethylene glycol (PEG) polymers functionalized with the actin binding peptide LifeAct, are explored as actin crosslinkers. Using bulk rheology and fluorescence microscopy, these constructs are shown to modulate actin filament network structure and mechanics in a contour length dependent manner, while maintaining the stress-stiffening behavior inherent to actin filament networks. These results encourage the design of more diverse and complex peptide-polymer crosslinkers to interrogate and control semi-flexible polymer networks.


Assuntos
Actinas , Polietilenoglicóis , Actinas/metabolismo , Polietilenoglicóis/metabolismo , Biomimética , Citoesqueleto de Actina/metabolismo , Proteínas dos Microfilamentos/química , Polímeros/metabolismo , Peptídeos/metabolismo
10.
J Cardiovasc Pharmacol ; 83(6): 635-645, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38547515

RESUMO

ABSTRACT: Prepubertal obesity is growing at an alarming rate and is now considered a risk factor for renal injury. Recently, we reported that the early development of renal injury in obese Dahl salt-sensitive (SS) leptin receptor mutant (SS LepR mutant) rats was associated with increased T-cell infiltration and activation before puberty. Therefore, the current study investigated the effect of inhibiting T-cell activation with abatacept on the progression of renal injury in young obese SS LepR mutant rats before puberty. Four-week-old SS and SS LepR mutant rats were treated with IgG or abatacept (1 mg/kg; ip, every other day) for 4 weeks. Abatacept reduced the renal infiltration of T cells by almost 50% in SS LepR mutant rats. Treatment with abatacept decreased the renal expression of macrophage inflammatory protein-3 alpha while increasing IL-4 in SS LepR mutant rats without affecting SS rats. While not having an impact on blood glucose levels, abatacept reduced hyperinsulinemia and plasma triglycerides in SS LepR mutant rats without affecting SS rats. We did not observe any differences in the mean arterial pressure among the groups. Proteinuria was markedly higher in SS LepR mutant rats than in SS rats throughout the study, and treatment with abatacept decreased proteinuria by about 40% in SS LepR mutant rats without affecting SS rats. We observed significant increases in glomerular and tubular injury and renal fibrosis in SS LepR mutant rats versus SS rats, and chronic treatment with abatacept significantly reduced these renal abnormalities in SS LepR mutant rats. These data suggest that renal T-cell activation contributes to the early progression of renal injury associated with prepubertal obesity.


Assuntos
Abatacepte , Rim , Obesidade , Ratos Endogâmicos Dahl , Receptores para Leptina , Linfócitos T , Animais , Abatacepte/farmacologia , Obesidade/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Rim/patologia , Rim/efeitos dos fármacos , Rim/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Receptores para Leptina/deficiência , Masculino , Ratos , Progressão da Doença , Modelos Animais de Doenças , Proteinúria/tratamento farmacológico , Nefropatias/patologia , Nefropatias/tratamento farmacológico , Nefropatias/metabolismo , Maturidade Sexual/efeitos dos fármacos
11.
Environ Sci Technol ; 58(11): 5079-5092, 2024 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-38451152

RESUMO

Redox conditions in groundwater may markedly affect the fate and transport of nutrients, volatile organic compounds, and trace metals, with significant implications for human health. While many local assessments of redox conditions have been made, the spatial variability of redox reaction rates makes the determination of redox conditions at regional or national scales problematic. In this study, redox conditions in groundwater were predicted for the contiguous United States using random forest classification by relating measured water quality data from over 30,000 wells to natural and anthropogenic factors. The model correctly predicted the oxic/suboxic classification for 78 and 79% of the samples in the out-of-bag and hold-out data sets, respectively. Variables describing geology, hydrology, soil properties, and hydrologic position were among the most important factors affecting the likelihood of oxic conditions in groundwater. Important model variables tended to relate to aquifer recharge, groundwater travel time, or prevalence of electron donors, which are key drivers of redox conditions in groundwater. Partial dependence plots suggested that the likelihood of oxic conditions in groundwater decreased sharply as streams were approached and gradually as the depth below the water table increased. The probability of oxic groundwater increased as base flow index values increased, likely due to the prevalence of well-drained soils and geologic materials in high base flow index areas. The likelihood of oxic conditions increased as topographic wetness index (TWI) values decreased. High topographic wetness index values occur in areas with a propensity for standing water and overland flow, conditions that limit the delivery of dissolved oxygen to groundwater by recharge; higher TWI values also tend to occur in discharge areas, which may contain groundwater with long travel times. A second model was developed to predict the probability of elevated manganese (Mn) concentrations in groundwater (i.e., ≥50 µg/L). The Mn model relied on many of the same variables as the oxic/suboxic model and may be used to identify areas where Mn-reducing conditions occur and where there is an increased risk to domestic water supplies due to high Mn concentrations. Model predictions of redox conditions in groundwater produced in this study may help identify regions of the country with elevated groundwater vulnerability and stream vulnerability to groundwater-derived contaminants.


Assuntos
Água Subterrânea , Poluentes Químicos da Água , Humanos , Algoritmo Florestas Aleatórias , Monitoramento Ambiental , Abastecimento de Água , Solo , Manganês , Oxirredução , Poluentes Químicos da Água/análise
12.
Environ Sci Technol ; 58(21): 9339-9349, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38748567

RESUMO

Residential lead (Pb) exposure is of critical concern to families globally as Pb promotes severe neurological effects in children, especially those less than 5 years old, and no blood lead level is deemed safe by the US Center for Disease Control. House dust and soils are commonly thought to be important sources of Pb exposure. Probing the relationship between house dust and soil Pb is critical to understanding residential exposure, as Pb bioavailability is highly influenced by Pb sources and/or species. We investigated paired house dust and soil collected from homes built before 1978 to determine Pb speciation, source, and bioaccessibility with the primary goal of assessing chemical factors driving Pb exposure in residential media. House dust was predominately found to contain (hydro)cerussite (i.e., Pb (hydroxy)carbonate) phases commonly used in Pb-based paint that, in-turn, promoted elevated bioaccessibility (>60%). Pb X-ray absorption spectroscopy, µ-XRF mapping, and Pb isotope ratio analysis for house dust and soils support house dust Pb as chemically unique compared to exterior soils, although paint Pb is expected to be a major source for both. Soil pedogenesis and increased protection from environmental conditions (e.g., weathering) in households is expected to greatly impact Pb phase differences between house dust and soils, subsequently dictating differences in Pb exposure.


Assuntos
Poeira , Chumbo , Poluentes do Solo , Solo , Poeira/análise , Chumbo/análise , Poluentes do Solo/análise , Estados Unidos , Solo/química , Habitação , Humanos , Monitoramento Ambiental
13.
Environ Sci Technol ; 58(9): 4155-4166, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38385246

RESUMO

Permafrost soils store ∼50% of terrestrial C, with Yedoma permafrost containing ∼25% of the total C. Permafrost is undergoing degradation due to thawing, with potentially hazardous effects on landscape stability and water resources. Complicating ongoing efforts to project the ultimate fate of deep permafrost C is the poorly constrained role of the redox environment, Fe-minerals, and its redox-active phases, which may modulate organic C-abundance, composition, and reactivity through complexation and catalytic processes. We characterized C fate, Fe fractions, and dissolved organic matter (DOM) isolates from permafrost-thaw under varying redox conditions. Under anoxic incubation conditions, 33% of the initial C was lost as gaseous species within 21 days, while under oxic conditions, 58% of C was lost. Under anoxic incubation, 42% of the total initial C was preserved in a dissolved fraction. Lignin-like compounds dominated permafrost-thaw, followed by lipid- and protein-like compounds. However, under anoxic incubation conditions, there was accumulation of lipid-like compounds and reduction in the nominal oxidation state of C over time, regardless of the compound classes. DOM dynamics may be affected by microbial activity and abiotic processes mediated by Fe-minerals related to selective DOM fractionation and/or its oxidation. Chemodiversity DOM signatures could serve as valuable proxies to track redox conditions with permafrost-thaw.


Assuntos
Pergelissolo , Ferro , Matéria Orgânica Dissolvida , Carbono , Minerais , Oxirredução , Lipídeos , Solo
14.
Environ Sci Technol ; 58(22): 9559-9569, 2024 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-38710655

RESUMO

Harmful cyanobacterial blooms are frequent and intense worldwide, creating hazards for aquatic biodiversity. The potential estrogen-like effect of Microcystin-LR (MC-LR) is a growing concern. In this study, we assessed the estrogenic potency of MC-LR in black-spotted frogs through combined field and laboratory approaches. In 13 bloom areas of Zhejiang province, China, the MC-LR concentrations in water ranged from 0.87 to 8.77 µg/L and were correlated with sex hormone profiles in frogs, suggesting possible estrogenic activity of MC-LR. Tadpoles exposed to 1 µg/L, an environmentally relevant concentration, displayed a female-biased sex ratio relative to controls. Transcriptomic results revealed that MC-LR induces numerous and complex effects on gene expression across multiple endocrine axes. In addition, exposure of male adults significantly increased the estradiol (E2)/testosterone (T) ratio by 3.5-fold relative to controls. Downregulation of genes related to male reproductive endocrine function was also identified. We also showed how MC-LR enhances the expression of specific estrogen receptor (ER) proteins, which induce estrogenic effects by activating the ER pathway and hypothalamic-pituitary-gonadal (HPG) axis. In aggregate, our results reveal multiple lines of evidence demonstrating that, for amphibians, MC-LR is an estrogenic endocrine disruptor at environmentally relevant concentrations. The data presented here support the need for a shift in the MC-LR risk assessment. While hepatoxicity has historically been the focus of MC-LR risk assessments, our data clearly demonstrate that estrogenicity is a major mode of toxicity at environmental levels and that estrogenic effects should be considered for risk assessments on MC-LR going forward.


Assuntos
Estrogênios , Animais , Masculino , Feminino , Microcistinas/toxicidade , Ranidae/genética , Ranidae/metabolismo , Toxinas Marinhas , Poluentes Químicos da Água/toxicidade
15.
Cell ; 136(1): 17-9, 2009 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-19135882

RESUMO

By investigating host-pathogen interactions in zebrafish using intravital imaging, Davis and Ramakrishnan (2009) provide evidence that aggregates of immune cells known as granulomas, long thought to constrain mycobacterial infection, may instead facilitate its spread.


Assuntos
Granuloma/imunologia , Granuloma/microbiologia , Interações Hospedeiro-Patógeno , Infecções por Mycobacterium/imunologia , Infecções por Mycobacterium/microbiologia , Animais , Mycobacterium/imunologia , Peixe-Zebra
16.
Am J Dermatopathol ; 46(6): 337-345, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38133527

RESUMO

INTRODUCTION: Although many individual cases and small series of toxic erythema of chemotherapy (TEC) have been described, the full spectrum of findings is not well understood. OBJECTIVE: To provide a comprehensive review of the clinical and histopathologic features of TEC with an emphasis on novel histopathologic findings. METHODS: We searched our electronic medical record for "toxic erythema of chemotherapy" or "neutrophilic eccrine hidradenitis." Fifty-six cases meeting clinical and histopathologic criteria were identified. The electronic medical record and accompanying hematoxylin and eosin-stained slides were retrospectively reviewed. RESULTS: The clinical findings were heterogeneous but included classic presentations such as intertriginous eruptions (34%) and acral erythema (25%). The most common histopathologic features were apoptotic keratinocytes (95%), basal vacuolar change (91%), and epithelial dysmaturation (79%). Eccrine squamous syringometaplasia was seen in over half of the cases (33/56; 59%), whereas neutrophilic eccrine hidradenitis was uncommon (16%). Interestingly, many cases showed prominent interstitial histiocytes (55%). Other novel findings included irregular orthohyperkeratosis (23%), irregular epidermal hyperplasia (14%), and acantholysis (9%). LIMITATIONS: As a retrospective study, it is subject to information bias. CONCLUSION: This is the largest reported series of TEC. In addition to confirming previously reported features, we identify novel histopathologic findings to add to the spectrum of TEC.


Assuntos
Antineoplásicos , Toxidermias , Eritema , Humanos , Estudos Retrospectivos , Feminino , Pessoa de Meia-Idade , Masculino , Toxidermias/patologia , Toxidermias/etiologia , Idoso , Adulto , Antineoplásicos/efeitos adversos , Eritema/induzido quimicamente , Eritema/patologia , Adulto Jovem , Hidradenite/induzido quimicamente , Hidradenite/patologia , Idoso de 80 Anos ou mais
17.
Proc Natl Acad Sci U S A ; 118(39)2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34551980

RESUMO

As a common protein modification, asparagine-linked (N-linked) glycosylation has the capacity to greatly influence the biological and biophysical properties of proteins. However, the routine use of glycosylation as a strategy for engineering proteins with advantageous properties is limited by our inability to construct and screen large collections of glycoproteins for cataloguing the consequences of glycan installation. To address this challenge, we describe a combinatorial strategy termed shotgun scanning glycomutagenesis in which DNA libraries encoding all possible glycosylation site variants of a given protein are constructed and subsequently expressed in glycosylation-competent bacteria, thereby enabling rapid determination of glycosylatable sites in the protein. The resulting neoglycoproteins can be readily subjected to available high-throughput assays, making it possible to systematically investigate the structural and functional consequences of glycan conjugation along a protein backbone. The utility of this approach was demonstrated with three different acceptor proteins, namely bacterial immunity protein Im7, bovine pancreatic ribonuclease A, and human anti-HER2 single-chain Fv antibody, all of which were found to tolerate N-glycan attachment at a large number of positions and with relatively high efficiency. The stability and activity of many glycovariants was measurably altered by N-linked glycans in a manner that critically depended on the precise location of the modification. Structural models suggested that affinity was improved by creating novel interfacial contacts with a glycan at the periphery of a protein-protein interface. Importantly, we anticipate that our glycomutagenesis workflow should provide access to unexplored regions of glycoprotein structural space and to custom-made neoglycoproteins with desirable properties.


Assuntos
Asparagina/química , Proteínas de Transporte/metabolismo , Proteínas de Escherichia coli/metabolismo , Glicoproteínas/metabolismo , Polissacarídeos/metabolismo , Processamento de Proteína Pós-Traducional , Ribonuclease Pancreático/metabolismo , Anticorpos de Cadeia Única/metabolismo , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Proteínas de Transporte/genética , Bovinos , Proteínas de Escherichia coli/química , Proteínas de Escherichia coli/genética , Glicoproteínas/química , Glicoproteínas/genética , Glicosilação , Humanos , Polissacarídeos/química , Polissacarídeos/genética , Conformação Proteica , Engenharia de Proteínas , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/imunologia , Ribonuclease Pancreático/química , Ribonuclease Pancreático/genética , Anticorpos de Cadeia Única/química , Anticorpos de Cadeia Única/genética
18.
Acta Neurochir (Wien) ; 166(1): 302, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39037618

RESUMO

PURPOSE: Sinus thrombosis is a common post-operative finding after posterior fossa surgery performed in the vicinity of the dural venous sinuses. The SARS-CoV-2 virus has been shown to confer an increased risk of venous thromboembolic events owing to eliciting a hyper-inflammatory and pro-thrombotic state. In this study, we examine the incidence of post-operative venous sinus thrombosis in patients undergoing peri-sigmoid posterior fossa surgery in the pre- and post-COVID era and investigate whether COVID infection confers an increased risk of sinus thrombosis. METHODS: A retrospective review of a single institution case series of patients underwent peri-sigmoid surgery (retrosigmoid, translabyrinthine, or far lateral) approach. Relevant clinical variables were investigated that may confer an increased risk of sinus thrombosis. RESULTS: A total of 311 patients (178 in the pre-COVID era, and 133 operated on after the pandemic began in March 2020) are included in the study. The composite incidence of sinus thrombosis seen on post-operative imaging was 7.8%. The incidence of sinus thrombosis in the pre-COVID cohort was N = 12 patients (6.7%) versus N = 12 (9%) in the post-COVID cohort (p = 0.46). A history of COVID infection was not shown to confer an increased risk of post-operative sinus thrombosis (OR: 0.61; 95% CI: 0.08-4.79, p = 0.64). Only a small number of patients (N = 7, 2.3%) required either medical or surgical intervention for post-operative sinus thrombosis. CONCLUSION: The overall incidence of post-operative sinus thrombosis is similar in the pre- and post-COVID era. The findings of this study suggest that COVID infection is not associated with a higher risk of venous sinus thrombosis.


Assuntos
COVID-19 , Complicações Pós-Operatórias , Trombose dos Seios Intracranianos , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Incidência , Estudos Retrospectivos , Trombose dos Seios Intracranianos/epidemiologia , Trombose dos Seios Intracranianos/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Idoso , Adulto , Base do Crânio/cirurgia , Procedimentos Neurocirúrgicos/efeitos adversos , Fatores de Risco
19.
J Strength Cond Res ; 38(6): e310-e319, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38781474

RESUMO

ABSTRACT: Morgan, RM, Wheeler, TD, Poolman, MA, Haugen, ENJ, LeMire, SD, and Fitzgerald, JS. Effects of photobiomodulation on pain and return to play of injured athletes: A systematic review and meta-analysis. J Strength Cond Res 38(6): e310-e319, 2024-The aims of this systematic review and meta-analysis were to evaluate the effect of photobiomodulation (PBM) on musculoskeletal pain in injured athletes and to determine if the effects of PBM allowed injured athletes to return to play faster. Electronic databases (MEDLINE Complete, CINAHL, and SPORTDiscus, PubMed, Web of Science, and Embase) were systematically searched (up to and including November 7, 2023) for peer-reviewed randomized controlled trials (RCTs) meeting criteria. Six RCTs, representing 205 competitive and recreational athletes with a mean age of 24 years, were included in the analysis. There were 6 intervention groups using standard physical therapy (n = 1), placebo PBM (n = 4), and aloe gel (n = 1) lasting between 10 minutes and 8 weeks in duration. The level of significance set for the study was p < 0.05. Overall, the use of PBM indicated a positive effect on pain reduction for PBM vs. control groups, standardized mean differences = 1.03, SE = 0.22, 95% confidence intervals = [0.43-1.63], p = 0.0089, but the 2 RCTs found evaluating the effect of PBM on time to return to play after injury in athletes do not support a benefit. Allied healthcare professionals may use PBM to reduce pain, thus allowing an athlete to return to their normal biomechanical movement faster; however, limited evidence suggests that PBM does not reduce time to return to play after an injury.


Assuntos
Traumatismos em Atletas , Terapia com Luz de Baixa Intensidade , Dor Musculoesquelética , Volta ao Esporte , Humanos , Traumatismos em Atletas/radioterapia , Traumatismos em Atletas/fisiopatologia , Traumatismos em Atletas/reabilitação , Terapia com Luz de Baixa Intensidade/métodos , Dor Musculoesquelética/radioterapia , Atletas , Ensaios Clínicos Controlados Aleatórios como Assunto
20.
J Perianesth Nurs ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-39001740

RESUMO

PURPOSE: Compare and evaluate the effectiveness of transversus abdominis plane (TAP) block versus intrathecal morphine (ITM) on elective postcesarean section pain, opioid consumption, and related side effects. DESIGN: Systematic review and meta-analysis. METHODS: A search for evidence was conducted in PubMed, Google Scholar, CINAHL, Cochrane Collaboration Database, UpToDate, Health Source, and gray literature. Only randomized controlled trials (RCTs) were included in the study. The methodological quality of evidence assessment was conducted using the Risk of Bias and Grades of Recommendation, Assessment, Development, and Evaluation system. The meta-analysis used Review Manager (RevMan 5.4, The Cochrane Collaboration). FINDINGS: A total of 11 RCTs involving 1,129 patients were analyzed. Compared to ITM, TAP has a similar effect on static (mean difference [MD]; 0.37; 95% confidence interval [CI], -0.04 to 0.79; P = .08) and dynamic pain scores (MD, 0.43; 95% CI, -0.06 to 0.92; P = .09) within the first 48 hours after surgery. Additionally, the TAP block had a lower incidence of postoperative nausea and vomiting (risk ratio, 0.45; 95% CI, 0.31 to 0.66; P < .0001) and increased opioid consumption (MD, 6.78; 95% CI, 3.79 to 9.77; P < .00001). Overall, TAP block and ITM did not differ in the time to first to rescue analgesia, incidence of sedation, and pruritus. CONCLUSIONS: Evidence suggests that TAP blocks are equivalent to ITM in pain scores and more effective at lowering the incidence of postoperative nausea and vomiting, yet ITM has been shown to be more effective in reducing postoperative opioid consumption.

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