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Specific microbial signals induce the differentiation of a distinct pool of RORγ+ regulatory T (Treg) cells crucial for intestinal homeostasis. We discovered highly analogous populations of microbiota-dependent Treg cells that promoted tissue regeneration at extra-gut sites, notably acutely injured skeletal muscle and fatty liver. Inflammatory meditators elicited by tissue damage combined with MHC-class-II-dependent T cell activation to drive the accumulation of gut-derived RORγ+ Treg cells in injured muscle, wherein they regulated the dynamics and tenor of early inflammation and helped balance the proliferation vs. differentiation of local stem cells. Reining in IL-17A-producing T cells was a major mechanism underlying the rheostatic functions of RORγ+ Treg cells in compromised tissues. Our findings highlight the importance of gut-trained Treg cell emissaries in controlling the response to sterile injury of non-mucosal tissues.
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Microbioma Gastrointestinal , Microbiota , Animales , Ratones , Linfocitos T Reguladores , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Ratones Endogámicos C57BLRESUMEN
A mesh of cytoskeletal fibers, consisting of microtubules, intermediate filaments, and fibrous actin, prevents the Brownian diffusion of particles with a diameter larger than 0.10 µm, such as vesicular stomatitis virus ribonucleoprotein (RNP) particles, in mammalian cells. Nevertheless, RNP particles do move in random directions but at a lower rate than Brownian diffusion, which is thermally driven. This nonthermal biological transport process is called "active diffusion" because it is driven by ATP. The ATP powers motor proteins such as myosin II. The motor proteins bend and cross-link actin fibers, causing the mesh to jiggle. Until recently, little was known about how RNP particles get through the mesh. It has been customary to analyze the tracks of particles like RNPs by computing the slope of the ensemble-averaged mean-squared displacement of the particles as a signature of mechanism. Although widely used, this approach "loses information" about the timing of the switches between physical mechanisms. It has been recently shown that machine learning composed of variational Bayesian analysis, Gaussian mixture models, and hidden Markov models can use "all the information" in a single track to reveal that that the positions of RNP particles are spatially clustered. Machine learning assigns a number, called a state, to each cluster. RNP particles remain in one state for 0.2-1.0 s before switching (hopping) to a different state. This earlier work is here extended to analyze the movements of a particle within a state and to determine particle directionality within and between states.
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HAND2 is a basic helix-loop-helix transcription factor with diverse functions during development. To facilitate the investigation of genetic and functional diversity among Hand2-expressing cells in the mouse, we have generated Hand2Dre, a knock-in allele expressing Dre recombinase. To avoid disrupting Hand2 function, the Dre cDNA is inserted at the 3' end of the Hand2 coding sequence following a viral 2A peptide. Hand2Dre homozygotes can therefore be used in complex crosses to increase the proportion of useful genotypes among offspring. Dre expression in mid-gestation Hand2Dre embryos is indistinguishable from wild-type Hand2 expression, and HandDre efficiently recombines rox target sites in vivo. In combination with existing Cre and Flp mouse lines, Hand2Dre will therefore extend the ability to perform genetic intersectional labeling, fate mapping, and functional manipulation of subpopulations of cells characterized by developmental expression of Hand2.
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Alelos , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico , Técnicas de Sustitución del Gen , Animales , Femenino , Ratones , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Técnicas de Sustitución del Gen/métodos , Integrasas/genética , Integrasas/metabolismo , MasculinoRESUMEN
BACKGROUND: Hidradenitis suppurativa (HS) is associated with increased cardiovascular disease (CVD) risk. Systemic immune inflammation index (SII), neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR) and monocyte/lymphocyte ratios (MLR) are biomarkers of systemic inflammation and CVD. One small study identified a lower NLR and PLR in patients treated with adalimumab. OBJECTIVES: Our aim was to assess changes in SII, NLR, PLR and MLR in a larger cohort, and to evaluate their association with disease severity and treatment response. METHODS: This was a post-hoc analysis of PIONEER I and PIONEER II, two phase 3 randomised placebo-controlled clinical trials of adalimumab for HS. SII, NLR, PLR and MLR were log10-transformed and linear mixed model was used to estimate treatment effect. RESULTS: SII, NLR, PLR and MLR reduced from baseline levels with adalimumab treatment by week 12, when the primary response endpoint was assessed. Significant changes first appeared at week 4 and were maintained to week 36. In contrast, no significant changes were observed in placebo-treated patients. In patients re-randomised at week 12 from placebo to adalimumab, SII, NLR, PLR and MLR also reduced within 4 weeks. In patients re-randomised from adalimumab to placebo, these biomarkers returned to baseline by week 36. In addition, SII, NLR and PLR correlated with draining fistula count (r=0.26-0.43, p<0.001). Adalimumab non-responders in PIONEER I had a higher SII, NLR and PLR at baseline and week 12, but this was not significant when adjusted for draining fistulae. CONCLUSIONS: Treatment of HS patients with adalimumab results in rapid sustained reduction in systemic inflammation measured by SII, NLR, PLR and MLR which correlate with CVD risk. SII, NLR and PLR may predict adalimumab response, although dependent on their interaction with the number of draining fistulae.
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BACKGROUND: Systemic oral phosphodiesterase type 4 (PDE-4) inhibitors have been effective in the treatment of psoriasis. Roflumilast cream contains a PDE-4 inhibitor that is being investigated for the topical treatment of psoriasis. METHODS: In this phase 2b, double-blind trial, we randomly assigned adults with plaque psoriasis in a 1:1:1 ratio to use roflumilast 0.3% cream, roflumilast 0.15% cream, or vehicle (placebo) cream once daily for 12 weeks. The primary efficacy outcome was the investigator's global assessment (IGA) of a status of clear or almost clear at week 6 (assessed on a 5-point scale of plaque thickening, scaling, and erythema; a score of 0 indicates clear, 1 almost clear, and 4 severe). Secondary outcomes included an IGA score indicating clear or almost clear plus a 2-grade improvement in the IGA score for the intertriginous area and the change in the Psoriasis Area and Severity Index (PASI) score (range, 0 to 72, with higher scores indicating worse disease). Safety was also assessed. RESULTS: Among 331 patients who underwent randomization, 109 were assigned to roflumilast 0.3% cream, 113 to roflumilast 0.15% cream, and 109 to vehicle cream. An IGA score indicating clear or almost clear at week 6 was observed in 28% of the patients in the roflumilast 0.3% group, in 23% in the roflumilast 0.15% group, and in 8% in the vehicle group (P<0.001 and P = 0.004 vs. vehicle for roflumilast 0.3% and 0.15%, respectively). Among the approximately 15% of patients overall who had baseline intertriginous psoriasis of at least mild severity, an IGA score at week 6 indicating clear or almost clear plus a 2-grade improvement in the intertriginous-area IGA score occurred in 73% of the patients in the roflumilast 0.3% group, 44% of those in the roflumilast 0.15% group, and 29% of those in the vehicle group. The mean baseline PASI scores were 7.7 in the roflumilast 0.3% group, 8.0 in the roflumilast 0.15% group, and 7.6 in the vehicle group; the mean change from baseline at week 6 was -50.0%, -49.0%, and -17.8%, respectively. Application-site reactions occurred with similar frequency in the roflumilast groups and the vehicle group. CONCLUSIONS: Roflumilast cream administered once daily to affected areas of psoriasis was superior to vehicle cream in leading to a state of clear or almost clear at 6 weeks. Longer and larger trials are needed to determine the durability and safety of roflumilast in psoriasis. (Funded by Arcutis Biotherapeutics; ARQ-151 201 ClinicalTrials.gov number, NCT03638258.).
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Aminopiridinas/administración & dosificación , Benzamidas/administración & dosificación , Inhibidores de Fosfodiesterasa 4/administración & dosificación , Psoriasis/tratamiento farmacológico , Crema para la Piel/administración & dosificación , Administración Tópica , Adulto , Aminopiridinas/efectos adversos , Benzamidas/efectos adversos , Ciclopropanos/administración & dosificación , Ciclopropanos/efectos adversos , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Masculino , Persona de Mediana Edad , Inhibidores de Fosfodiesterasa 4/efectos adversos , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Treatment for the debilitating disease hidradenitis suppurativa (HS) is inadequate in many patients. Despite an incidence of approximately 1%, HS is often under-recognized and underdiagnosed, and is associated with a high morbidity and poor quality of life. OBJECTIVES: To gain a better understanding of the pathogenesis of HS, in order to design new therapeutic strategies. METHODS: We employed single-cell RNA sequencing to analyse gene expression in immune cells isolated from involved HS skin vs. healthy skin. Flow cytometry was used to quantify the absolute numbers of the main immune populations. The secretion of inflammatory mediators from skin explant cultures was measured using multiplex and enzyme-linked immunosorbent assays. RESULTS: Single-cell RNA sequencing analysis identified a significant enrichment in the frequency of plasma cells, T helper (Th) 17 cells and dendritic cell subsets in HS skin, and the immune transcriptome was distinct and more heterogeneous than healthy skin. Flow cytometry revealed significantly increased numbers of T cells, B cells, neutrophils, dermal macrophages and dendritic cells in HS skin. Genes and pathways associated with Th17 cells, interleukin (IL)-17, IL-1ß and the NLRP3 inflammasome were enhanced in HS skin, particularly in samples with a high inflammatory load. Inflammasome constituent genes principally mapped to Langerhans cells and a subpopulation of dendritic cells. The secretome of HS skin explants contained significantly increased concentrations of inflammatory mediators, including IL-1ß and IL-17A, and culture with an NLRP3 inflammasome inhibitor significantly reduced the secretion of these, as well as other, key mediators of inflammation. CONCLUSIONS: These data provide a rationale for targeting the NLRP3 inflammasome in HS using small-molecule inhibitors that are currently being tested for other indications.
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Hidradenitis Supurativa , Humanos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Calidad de Vida , Piel/patología , Inflamación , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/uso terapéuticoRESUMEN
Since first recognized in 1839, the pathogenesis of acne inversa (AI) has undergone repeated revisions. Although there is agreement that AI involves occlusion of hair follicles with subsequent inflammation and the formation of tracts, the histologic progression of this disease still requires refinement. The objective of this study was to examine the histologic progression of AI based on the examination of a large cohort of punch biopsies and excisional samples that were examined first by hematoxylin and eosin staining. The most informative of these samples were step-sectioned and stained by immunohistochemistry for epithelial and inflammatory markers. Based on this examination, the following observations were made: 1) AI arises from the epithelium of the infundibulum of terminal and vellus hairs; 2) These form cysts and epithelial tendrils that extend into soft tissue; 3) Immunohistochemical staining demonstrates the epithelium of AI is disordered with infundibular and isthmic differentiation and de novo expression of stem cell markers; 4) The inflammatory response in AI is heterogeneous and largely due to cyst rupture. The conclusions of this investigation were that AI is an epithelial-driven disease caused by infiltrative, cyst forming tendrils and most of the inflammation is due to cyst rupture and release of cornified debris and bacteria. Cyst rupture often occurs below the depths of punch biopsy samples indicating their use for analysis may give an incomplete picture of the disease. Finally, our data suggest that unless therapies inhibit tendril development, it is unlikely they will cause prolonged treatment-induced remission in AI.
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Acné Vulgar/patología , Progresión de la Enfermedad , Hidradenitis Supurativa/patología , Folículo Piloso/patología , Humanos , Inflamación/patologíaRESUMEN
Mammalian neonates are born at a wide range of maturity levels. Altricial newborns are born with limited sensory agency and require extensive parental care. In contrast, precocial neonates are relatively mature physically and often capable of independent function shortly after birth. In extant mammals, placental newborns vary from altricial to precocial, while marsupials and monotremes are all extremely altricial at birth. Bears (family Ursidae) have one of the lowest neonatal-maternal mass ratios in placental mammals, and are thought to also have the most altricial placental newborns. In particular, giant pandas (Ailuropoda melanoleuca) are thought to be exceptionally altricial at birth, and possibly marsupial-like. Here we used micro-computer (micro-computed) tomography scanning to visualize the skeletal anatomy of ursid neonates and compare their skeletal maturity with the neonates of other caniform outgroups. Specifically, we asked whether ursid neonates have exceptionally altricial skeletons at birth compared with other caniform neonates. We found that most bear neonates are similar to outgroup neonates in levels of skeletal ossification, with little variation in degree of ossification between ursine bears neonates (i.e. bears of the subfamily Ursinae). Perinatal giant pandas, however, have skeletal maturity levels most similar to a 42-45-day-old beagle fetus (~70% of total beagle gestation period). No bear exhibits the skeletal heterochronies seen in marsupial development. With regards to skeletal development, ursine bears are not exceptionally altricial relative to other caniform outgroups, but characterized largely by the drastic difference between newborn and adult body sizes. A review on the existing hypotheses for ursids' unique reproductive strategy suggests that the extremely small neonatal-maternal mass ratio of ursids may be related to the recent evolution of large adult body size, while life history characteristics retained an ancestral condition. A relatively short post-implantation gestation time may be the proximal mechanism behind the giant panda neonates' small size relative to maternal size and altricial skeletal development at birth.
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Huesos/anatomía & histología , Ursidae/anatomía & histología , Anatomía Comparada , Animales , Huesos/diagnóstico por imagen , Microtomografía por Rayos XRESUMEN
The fine interplay between the simultaneous stretching and confinement of amyloid fibrils is probed by combining a microcapillary setup with atomic force microscopy. Single-molecule statistics reveal how the stretching of fibrils changed from force to confinement dominated at different length scales. System order, however, is solely ruled by confinement. Coarse-grained simulations support the results and display the potential to tailor system properties by tuning the two effects. These findings may further help shed light on in vivo amyloid fibril growth and transport in highly confined environments such as blood vessels.
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Amiloide/química , Modelos Químicos , Amiloide/metabolismo , Simulación por Computador , Microscopía de Fuerza Atómica/métodosRESUMEN
Noradrenergic signaling plays a well-established role in promoting the stress response. Here we identify a subpopulation of noradrenergic neurons, defined by developmental expression of Hoxb1, that has a unique role in modulating stress-related behavior. Using an intersectional chemogenetic strategy, in combination with behavioral and physiological analyses, we show that activation of Hoxb1-noradrenergic (Hoxb1-NE) neurons decreases anxiety-like behavior and promotes an active coping strategy in response to acute stressors. In addition, we use cerebral blood volume-weighted functional magnetic resonance imaging to show that chemoactivation of Hoxb1-NE neurons results in reduced activity in stress-related brain regions, including the bed nucleus of the stria terminalis, amygdala, and locus coeruleus. Thus, the actions of Hoxb1-NE neurons are distinct from the well-documented functions of the locus coeruleus in promoting the stress response, demonstrating that the noradrenergic system contains multiple functionally distinct subpopulations.
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Neuronas Adrenérgicas/fisiología , Proteínas de Homeodominio/genética , Estrés Fisiológico/genética , Adaptación Psicológica/fisiología , Neuronas Adrenérgicas/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/genética , Ansiedad/metabolismo , Conducta Animal/fisiología , Encéfalo/metabolismo , Femenino , Proteínas de Homeodominio/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismoRESUMEN
BACKGROUND: It has been established that delayed umbilical cord clamping in preterm infants results in improvement in neonatal anemia, need for transfusion, incidence of necrotizing enterocolitis, and intraventricular hemorrhage by increasing neonatal circulating blood volume. However, the effects of umbilical cord milking as an alternative to delayed clamping in preterm infants are unclear. OBJECTIVE: The primary objective of this study was to compare the effect of delayed clamping vs milking of the umbilical cord on the initial hematocrit concentration in preterm births (23-34 weeks gestation). In addition, we sought to compare the effects of delayed clamping vs milking on the incidences of intraventricular hemorrhage, necrotizing enterocolitis, and need for transfusion (secondary objectives). STUDY DESIGN: The study was an unblinded randomized controlled trial of singleton preterm infants who were born 23 weeks 0 days to 34 weeks 6 days gestation and were assigned to 1 of 2 controlled study groups: delayed cord clamping for 60 seconds or milking of the cord towards the infant 4 times before clamping. Randomization occurred via block randomization with an allocation ratio of 1 to 1. The patients' third stage of delivery was standardized for route of delivery and randomization arm. All comparisons were preformed with an intent-to-treat analysis approach. The study was powered at 80% with a probability value of .05 for the primary outcome measure of a hematocrit difference of 3% between the 2 groups. RESULTS: Of the 204 randomized patients, 104 were assigned to the delayed subgroup, and 100 were assigned to the milking subgroup. There were no significant differences in baseline maternal characteristics noted between groups. Though there was not any statistically significant difference in neonatal outcomes between the cord clamping and milking groups, the occurrences of transfusion (15.5% vs 9.1%; P=.24), necrotizing enterocolitis (5.8% vs 3.0%; P=.49), and intraventricular hemorrhage (15.5% vs 10.1%; P=.35) were all lower in the milking group. The milking group had higher initial hematocrit concentration compared with the delayed clamping group, although this was not significant (51.8 [6.2%] vs 49.9 [7.7%]; P=.07]. Peak bilirubin levels and need for phototherapy were similar between groups. CONCLUSION: This study demonstrates that milking the umbilical cord may be an acceptable alternative to delayed cord clamping because there were similar effects on neonatal hematocrit concentrations and the need for neonatal transfusions and no increased risk for complications or neonatal morbidity. The present data support the concept that milking of the umbilical cord may offer an efficient and timely method of providing increased blood volume to the infant.
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Constricción , Enfermedades del Prematuro/prevención & control , Recien Nacido Prematuro , Cordón Umbilical , Adolescente , Adulto , Transfusión Sanguínea/estadística & datos numéricos , Hemorragia Cerebral Intraventricular/prevención & control , Enterocolitis Necrotizante/prevención & control , Femenino , Hematócrito , Humanos , Recién Nacido , Persona de Mediana Edad , Embarazo , Factores de Tiempo , Adulto JovenRESUMEN
Genetics is believed to play a key role in the development of Autism Spectrum Disorder (ASD) and a plethora of potential candidate genes have been identified by genetic characterization of patients, their family members and controls. To make sense of this information investigators have searched for common pathways and downstream properties of neural networks that are regulated by these genes. For instance, several candidate genes encode synaptic proteins, and one hypothesis that has emerged is that disruption of the synaptic excitation and inhibition (E/I) balance would destabilize neural processing and lead to ASD phenotypes. Some compelling evidence for this has come from the analyses of mouse and culture models with defects in synaptic structural proteins, which influence several aspects of synapse biology and is the subject of this review. Remaining challenges include identifying the specifics that distinguish ASD from other psychiatric diseases and designing more direct tests of the E/I balance hypothesis.
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Trastorno del Espectro Autista/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/fisiología , Proteínas de la Membrana/fisiología , Sinapsis/fisiología , Animales , HumanosRESUMEN
We report a method to deposit amyloid fibrils on a substrate creating gradients in orientation and coverage on demand. For this purpose, we adapt a colloidal self-assembly method at liquid-liquid interfaces to deposit amyloid fibrils on a substrate from the water-hexane interface, while simultaneously compressing it. The amyloid fibril layers orient perpendicularly to the compression, ranging from isotropic to nematic distributions. We furthermore observe reproducible transitions from a monolayer to a bilayer and from a bilayer to multilayers with increasing surface pressures. The creation of each new layer is accompanied by a systematic drop in the structural order of the system, which is however regained upon further compression. This method shows great potential for overcoming the thin-film engineering challenges associated with the manipulation of sticky amyloid fibrils, and allows their ex situ visualisation under compression at the fluid-fluid interface, a situation relevant to understand the propagation of amyloid-related diseases, their functional role in biological systems, and their potential for technological applications.
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Amiloide/metabolismo , Hexanos/química , Membranas Artificiales , Conformación Proteica , Agua/químicaRESUMEN
BACKGROUND: Despite the critical nature of the residency interview process, few metrics have been shown to adequately predict applicant success in matching to a given program. While evaluating and ranking potential candidates, bias can occur when applicants make commitment statements to a program. Survey data show that pressure to demonstrate commitment leads applicants to express commitment to multiple institutions including telling >1 program that they will rank them #1. The primary purpose of this cross-sectional observational study is to evaluate the frequency of commitment statements from applicants to 5 anesthesiology departments during a single interview season, report how often each statement is associated with a successful match, and identify how frequently candidates incorrectly represented commitments to rank a program #1. METHODS: During the 2014 interview season, 5 participating anesthesiology programs collected written and verbal communications from applicants. Three residency program directors independently reviewed the statements to classify them into 1 of 3 categories; guaranteed commitment, high rank commitment, or strong interest. Each institution provided a deidentified rank list with associated commitment statements, biographical data, whether candidates were ranked-to-match, and if they successfully matched. RESULTS: Program directors consistently differentiated among strong interest, high rank, and guaranteed commitment statements with κ coefficients of 0.9 (95% CI, 0.8-0.9) or greater between any pair of reviewers. Overall, 35.8% of applicants (226/632) provided a statement demonstrating at least strong interest and 5.4% (34/632) gave guaranteed commitment statements. Guaranteed commitment statements resulted in a 95.7% match rate to that program in comparison to statements of high rank (25.6%), strong interest (14.6%), and those who provided no statement (5.9%). For those providing guaranteed commitment statements, it can be assumed that the 1 candidate (4.3%) who did not match incorrectly represented himself. Variables such as couples match, "R" positions, and not being ranked-to-match on both advanced and categorical rank lists were eliminated because they can result in a nonmatch despite truthfully ranking a program #1. CONCLUSIONS: Each level of commitment statement resulted in a progressively increased frequency of a successful match to the recipient program. Only 5.4% of applicants committed to rank a program #1, but these statements were very reliable. These data can help program directors interpret commitment statements and assist accurate evaluation of the interest of candidates throughout the match process.
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Anestesiología/educación , Anestesiología/normas , Internado y Residencia/normas , Solicitud de Empleo , Adulto , Femenino , Humanos , Masculino , Estudios Prospectivos , Reproducibilidad de los ResultadosRESUMEN
In living cells, DNA is highly confined in space with the help of condensing agents, DNA binding proteins and high levels of supercoiling. Due to challenges associated with experimentally studying DNA under confinement, little is known about the impact of spatial confinement on the local structure of the DNA. Here, we have used well characterized slits of different sizes to collect high resolution atomic force microscopy images of confined circular DNA with the aim of assessing the impact of the spatial confinement on global and local conformational properties of DNA. Our findings, supported by numerical simulations, indicate that confinement imposes a large mechanical stress on the DNA as evidenced by a pronounced anisotropy and tangent-tangent correlation function with respect to non-constrained DNA. For the strongest confinement we observed nanometer sized hairpins and interwound structures associated with the nicked sites in the DNA sequence. Based on these findings, we propose that spatial DNA confinement in vivo can promote the formation of localized defects at mechanically weak sites that could be co-opted for biological regulatory functions.
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ADN Circular/química , Proteínas de Unión al ADN/química , ADN/química , Conformación de Ácido Nucleico , Secuencia de Bases/genética , ADN/ultraestructura , Roturas del ADN de Cadena Simple , ADN Circular/genética , ADN Circular/ultraestructura , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/ultraestructura , Microscopía de Fuerza Atómica , Modelos MolecularesRESUMEN
Recombinase responsive mouse lines expressing diphtheria toxin subunit A (DTA) are well established tools for targeted ablation of genetically defined cell populations. Here we describe a new knock-in allele at the Gt(Rosa)26Sor locus that retains the best features of previously described DTA alleles-including a CAG promoter, attenuated mutant DTA cDNA, and ubiquitous EGFP labeling-with the addition of a Cre-dependent FLEx switch for tight control of expression. The FLEx switch consists of two pairs of antiparallel lox sites requiring Cre-mediated recombination for inversion of the DTA to the proper orientation for transcription. We demonstrate its utility by Cre-dependent ablation of both a broad domain in the embryonic nervous system and a discrete population of cells in the fetal gonads. We conclude that this new DTA line is useful for targeted ablation of genetically-defined cell populations.
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Toxina Diftérica/genética , Técnicas de Sustitución del Gen/métodos , Animales , Toxina Diftérica/metabolismo , Gónadas/citología , Gónadas/embriología , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Integrasas/genética , Integrasas/metabolismo , Ratones , Sistema Nervioso/citología , Sistema Nervioso/embriología , Regiones Promotoras Genéticas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismoRESUMEN
Animals may improve camouflage by both dynamic colour change and local evolutionary adaptation of colour but we have little understanding of their relative importance in colour-changing species. We tested for differences in colour change in response to background colour and light intensity in two populations of central bearded dragon lizards (Pogona vitticeps) representing the extremes in body coloration and geographical range. We found that bearded dragons change colour in response to various backgrounds and that colour change is affected by illumination intensity. Within-individual colour change was similar in magnitude in the two populations but varied between backgrounds. However, at the endpoints of colour change, each population showed greater similarity to backgrounds that were representative of the local habitat compared with the other population, indicating local adaptation to visual backgrounds. Our results suggest that even in species that change colour, both phenotypic plasticity and geographic divergence of coloration may contribute to improved camouflage.
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Mimetismo Biológico , Lagartos/fisiología , Animales , Evolución Biológica , Color , Ecosistema , Luz , MasculinoRESUMEN
Binge drinking is associated with impaired cognitive functioning, but the relationship of cognitive impairments and white matter integrity is less known. We used diffusion tensor imaging (DTI) to investigate the relationships of binge drinking, whole brain white matter integrity and cognitive performance during young adulthood (18 to 25 years), a period of continued brain development in two sessions 1 year apart. Binge drinkers (n = 20) and non-binge drinkers (n = 20) underwent DTI and completed measures of spatial working memory and motor impulsivity. Fractional anisotropy (FA), a measure derived from DTI, was estimated from whole brain and from five segments of the corpus callosum (CC): prefrontal, premotor/supplementary motor, motor, (SMA) sensory and parietal/temporal/occipital (PTO). FA was lower for binge than for non-binge men but not women at Session 1 and 2 for all measurements except for FA in the motor segment, which was significantly increased from Session 1 to Session 2. Lower FA in the prefrontal and PTO CC segments was associated with higher binge score, whereas lower FA in all five segments was associated with greater drug use in men and worse spatial working memory both in men and women. These findings extend the literature by showing that in early adulthood, binge drinking and drug use are linked with degradations in neural white matter and that compromised white matter at this period of brain development is linked with impaired cognitive functioning.
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Consumo Excesivo de Bebidas Alcohólicas/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Cuerpo Calloso/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adolescente , Adulto , Disfunción Cognitiva/fisiopatología , Imagen de Difusión Tensora , Femenino , Humanos , Masculino , Memoria a Corto Plazo/fisiología , Corteza Motora/diagnóstico por imagen , Lóbulo Occipital/diagnóstico por imagen , Lóbulo Parietal/diagnóstico por imagen , Factores Sexuales , Corteza Somatosensorial/diagnóstico por imagen , Memoria Espacial/fisiología , Lóbulo Temporal/diagnóstico por imagen , Adulto JovenRESUMEN
The paracellular pathway through the tight junction provides an important route for transepithelial chloride reabsorption in the kidney, which regulates extracellular salt content and blood pressure. Defects in paracellular chloride reabsorption may in theory cause deregulation of blood pressure. However, there is no evidence to prove this theory or to demonstrate the in vivo role of the paracellular pathway in renal chloride handling. Here, using a tissue-specific KO approach, we have revealed a chloride transport pathway in the kidney that requires the tight junction molecule claudin-4. The collecting duct-specific claudin-4 KO animals developed hypotension, hypochloremia, and metabolic alkalosis due to profound renal wasting of chloride. The claudin-4-mediated chloride conductance can be regulated endogenously by a protease-channel-activating protease 1 (cap1). Mechanistically, cap1 regulates claudin-4 intercellular interaction and membrane stability. A putative cap1 cleavage site has been identified in the second extracellular loop of claudin-4, mutation of which abolished its regulation by cap1. The cap1 effects on paracellular chloride permeation can be extended to other proteases such as trypsin, suggesting a general mechanism may also exist for proteases to regulate the tight junction permeabilities. Together, we have discovered a theory that paracellular chloride permeability is physiologically regulated and essential to renal salt homeostasis and blood pressure control.
Asunto(s)
Presión Sanguínea , Cloruros/metabolismo , Claudina-4/metabolismo , Riñón/metabolismo , Reabsorción Renal , Serina Endopeptidasas/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular/efectos de los fármacos , Electrólitos/sangre , Electrólitos/orina , Células HEK293 , Humanos , Riñón/efectos de los fármacos , Túbulos Renales Colectores/efectos de los fármacos , Túbulos Renales Colectores/metabolismo , Ratones Noqueados , Especificidad de Órganos/efectos de los fármacos , Unión Proteica/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Interferencia de ARN/efectos de los fármacos , Proteínas Recombinantes/farmacología , Reabsorción Renal/efectos de los fármacos , Telemetría , Tripsina/metabolismoRESUMEN
PURPOSE: The purpose of this study was to identify pressure injury knowledge in critical care nurses related to prevention and staging following multimodal education initiatives. DESIGN: Postintervention descriptive study. SETTING AND SAMPLE: The sample comprised 32 RNs employed in medical intensive care/coronary intensive care or surgical intensive care units. The study setting was a 237-bed Veterans Affairs acute care hospital in the Midwestern United States. METHODS: Critical care RNs were asked to participate in this project over a 3-week period following a multimodal 2-year education initiative. Nurses completed the paper version of the 72-item Pieper-Zulkowski Pressure Ulcer Knowledge Test (PZ-PUKT) to determine pressure injury knowledge level. Calculated mean cumulative scores and subscores for items related to prevention and staging, respectively. Pearson correlations were used to examine associations between nursing staff characteristics and the PZ-PUKT prevention and staging scores. RESULTS: The cumulative score on the PZ-PUKT was 51.66 (72%); nurses with 5 to 10 years' experience had a higher mean score than nurses with experiences of 20 years or more (mean ± SD = 54.25 ± 4.37 vs 49.5 ± 7.12), but the difference was not statistically significant. Nurses scored higher on the staging system-related items as compared to the prevention-related items (81% vs 70%). Nurses achieved higher staging subscale scores if they were younger (r =-0.41, P < .05), had less experience (r =-0.43, P < .05), and if they worked in the medical intensive care unit (r = 0.37, P < .05). CONCLUSIONS: Study findings indicate gaps in knowledge related to pressure injury practice; participants had greater knowledge of staging rather than prevention. Cumulative and subscale findings can be used to direct educational efforts needed to improve and maintain an effective pressure injury prevention program.