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BACKGROUND: Tendon transfers are often utilized to improve shoulder external rotation and abduction in children with brachial plexus birth injuries and are designed to improve glenohumeral (GH) joint motion. However, changes in scapulothoracic (ST) and glenohumeral (GH) joint function after tendon transfer are not well defined. The purpose of this study was to quantify changes in GH, ST, and humerothoracic (HT) joint function before and after tendon transfer, and we hypothesized that tendon transfers would reorient the arc of motion into more external rotation and abduction, but not increase GH motion. METHODS: Motion analysis was performed in 15 children (ages 3-16) before and after transfer of teres major and/or latissimus dorsi. Scapulothoracic, GH, and HT joint angles were measured in a neutral, resting position and each of the modified Mallet positions. Joint angular displacements from the neutral position and the total arc of internal-external rotation for each joint were also calculated. Relevant joint angles, joint angular displacements, and internal-external rotation arcs were compared using multivariate analyses of variance with repeated measures and univariate post-hoc analyses. RESULTS: Glenohumeral and HT external rotation were significantly increased in all positions postoperatively. The arc of GH internal-external rotation was unchanged, but oriented in more external rotation after surgery. Only 6 patients gained active external rotation. Glenohumeral and HT internal rotation were significantly decreased after surgery, but ST internal rotation was significantly increased. Two patients had loss of midline function. In the abduction position, GH elevation joint angles were unchanged, but ST and HT elevation increased. DISCUSSION: Only four patients gained active GH external rotation and maintained their internal rotation. Each of those patients underwent isolated tendon transfer without concomitant joint release. Seven patients maintained their preoperative internal rotation, which was attributed to increased ST internal rotation. The other half of patients lost internal rotation and gained external rotation through reorientation of the arc of rotation. Nine patients gained HT elevation, with three attributed to increased ST upward rotation, five attributed to a combination of increased ST upward rotation and increased GH elevation, and one attributed to increased GH abduction contracture. These findings challenge the dogma that teres major/latissimus dorsi tendon transfers augment GH motion and highlight the importance of ST function for outcome determination.
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Kelp species function as important foundation organisms in coastal marine ecosystems where they provide biogenic habitat and ameliorate environmental conditions, often facilitating the development of diverse understorey assemblages. The structure of kelp forests is influenced by a variety of environmental factors, changes in which can result in profound shifts in ecological structure and functioning. Intense storm-induced wave action in particular, can severely impact kelp forest ecosystems. Given that storms are anticipated to increase in frequency and intensity in response to anthropogenic climate change, it is critical to understand their potential impacts on kelp forest ecosystems. During the 2021/22 northeast Atlantic storm season, the United Kingdom (UK) was subject to several intense storms, of which the first and most severe was Storm Arwen. Due to the unusual northerly wind direction, the greatest impacts of Storm Arwen were felt along the northeast coast of the UK where wind gusts exceeded 90 km/h, and inshore significant wave heights of 7.2 m and wave periods of 9.3 s were recorded. Here, we investigated temporal and spatial variation in the structure of L. hyperborea forests and associated understorey assemblages along the northeast coast of the UK over the 2021/22 storm season. We found significant changes in the cover, density, length, biomass, and age structure of L. hyperborea populations and the composition of understorey assemblages following the storm season, particularly at our most north facing site. We suggest continuous monitoring of these systems to further our understanding of temporal variation and potential recovery trajectories, alongside enhanced management to promote resilience to future perturbations.
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Cambio Climático , Ecosistema , Laminaria , Estaciones del Año , Algas Marinas , Biodiversidad , Biomasa , Monitoreo del Ambiente , Laminaria/fisiología , Algas Marinas/fisiología , Reino UnidoRESUMEN
The axon initial segment (AIS) constitutes not only the site of action potential initiation, but also a hub for activity-dependent modulation of output generation. Recent studies shedding light on AIS function used predominantly post-hoc approaches since no robust murine in vivo live reporters exist. Here, we introduce a reporter line in which the AIS is intrinsically labeled by an ankyrin-G-GFP fusion protein activated by Cre recombinase, tagging the native Ank3 gene. Using confocal, superresolution, and two-photon microscopy as well as whole-cell patch-clamp recordings in vitro, ex vivo, and in vivo, we confirm that the subcellular scaffold of the AIS and electrophysiological parameters of labeled cells remain unchanged. We further uncover rapid AIS remodeling following increased network activity in this model system, as well as highly reproducible in vivo labeling of AIS over weeks. This novel reporter line allows longitudinal studies of AIS modulation and plasticity in vivo in real-time and thus provides a unique approach to study subcellular plasticity in a broad range of applications.
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PURPOSE: Lack of shoulder external rotation is common in children with brachial plexus birth injuries. Development of glenohumeral (GH) dysplasia is associated with progressive loss of passive external rotation. Some authors recommend measuring external rotation with the arm adducted, whereas others recommend measurement with the arm in 90° of abduction. The purpose of this study was to compare active and passive external rotation and internal rotation measured in adduction versus abduction. METHODS: Fifteen children with brachial plexus birth injuries held their affected arms in maximal external and internal rotation with the arm adducted and the arm at approximately 90° of abduction. Active and passive rotations were measured with three-dimensional motion capture. Scapulothoracic (ST) internal/external rotation and GH internal/external rotation joint angles were calculated and compared using multivariable, one-way repeated measures analyses of variance. RESULTS: There were no significant differences for active or passive ST rotation in external rotation in adduction versus abduction. Glenohumeral external rotation was significantly increased with the arm in abduction compared with adduction both actively and passively. There were no differences in ST rotation in active versus passive conditions, but all GH rotations were significantly greater passively. CONCLUSIONS: Shoulder internal/external rotation in abduction and adduction is not interchangeable. Comprehensive assessment of shoulder external and internal rotation should include both adduction and abduction. CLINICAL RELEVANCE: For children with brachial plexus birth injuries, both active and passive GH external rotations were greater in abduction. Therefore, early GH joint dysplasia may be missed if GH external rotation is measured in abduction. Additionally, consistency in arm position is important for comparison over time. The entire ST rotation capacity was used to perform maximal internal and external rotation, but the entire passive GH range of motion was not actively used. This highlights an area for potential surgical intervention to improve motion.
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BACKGROUND: Brachial plexus birth injuries (BPBI) occur in up 0.4 to 4.6 per 1000 live births. Weakness about the shoulder and development of glenohumeral joint contractures are common sequalae of BPBI. Shoulder function in children with BPBI is frequently assessed using the modified Mallet classification to evaluate upper extremity motion deficits. The purpose of this study was to assess the accuracy of the abduction, external rotation, and hand-to-mouth Mallet classification scores in children with BPBI using motion capture. METHODS: A retrospective study of 107 children with BPBI who underwent motion capture assessment and Mallet scores on the same date were reviewed. Motion capture measurements were used to calculate humerothoracic elevation and external rotation joint angles in the abduction/hand-to-mouth and external rotation positions, respectively. The humerothoracic joint angles were converted to the corresponding Mallet scores. Discrepancies between the Mallet scores determined by clinicians and those determined by motion capture were assessed. RESULTS: For abduction, 24.3% of Mallet scores were misclassified during clinical examination. Of the misclassified scores, 22 were overestimated by 1 point and 4 were underestimated by 1 point compared with motion capture. For external rotation, 72.9% of Mallet scores were misclassified during clinical examination. Only 5 patients had an HT elevation that was less than 40 degrees, with 4 of them (80%) having a Mallet hand-to-mouth score of 4. There were no differences in proportion of patients with HT elevation less than 40 degrees who had a Mallet score of 4 or a Mallet score less than 4. CONCLUSIONS: There was better agreement in global abduction Mallet scores compared with external rotation and hand-to-mouth Mallet scores. This difference was likely due to the complex compensatory strategies that patients employ while performing external rotation and hand-to-mouth positions. The inaccuracy of the clinically determined Mallet scores is alarming given that they are frequently utilized to assist with surgical indications and are commonly used as outcome measures. LEVEL OF EVIDENCE: Level IV Case series.
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This review explores the concept of futility timeouts and the use of traumatic brain injury (TBI) as an independent predictor of the futility of resuscitation efforts in severely bleeding trauma patients. The national blood supply shortage has been exacerbated by the lingering influence of the COVID-19 pandemic on the number of blood donors available, as well as by the adoption of balanced hemostatic resuscitation protocols (such as the increasing use of 1:1:1 packed red blood cells, plasma, and platelets) with and without early whole blood resuscitation. This has underscored the urgent need for reliable predictors of futile resuscitation (FR). As a result, clinical, radiologic, and laboratory bedside markers have emerged which can accurately predict FR in patients with severe trauma-induced hemorrhage, such as the Suspension of Transfusion and Other Procedures (STOP) criteria. However, the STOP criteria do not include markers for TBI severity or transfusion cut points despite these patients requiring large quantities of blood components in the STOP criteria validation cohort. Yet, guidelines for neuroprognosticating patients with TBI can require up to 72 h, which makes them less useful in the minutes and hours following initial presentation. We examine the impact of TBI on bleeding trauma patients, with a focus on those with coagulopathies associated with TBI. This review categorizes TBI into isolated TBI (iTBI), hemorrhagic isolated TBI (hiTBI), and polytraumatic TBI (ptTBI). Through an analysis of bedside parameters (such as the proposed STOP criteria), coagulation assays, markers for TBI severity, and transfusion cut points as markers of futilty, we suggest amendments to current guidelines and the development of more precise algorithms that incorporate prognostic indicators of severe TBI as an independent parameter for the early prediction of FR so as to optimize blood product allocation.
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Colorectal cancer (CRC) is the third most prevalent cancer worldwide. Current studies have demonstrated that tumor-derived extracellular vesicles (EVs) from different cancer cell types modulate the fibroblast microenvironment to contribute to cancer development and progression. Here, we isolated and characterized circulating large EVs (LEVs), small EVs (SEVs) and non-EV entities released in the plasma from wild-type (WT) mice and the APCMin/+ CRC mice model. Our results showed that human colon fibroblasts exposed from APC-EVs, but not from WT-EVs, exhibited the phenotypes of cancer-associated fibroblasts (CAFs) through EV-mediated NF-κB pathway activation. Cytokine array analysis on secreted proteins revealed elevated levels of inflammatory cytokine implicated in cancer growth and metastasis. Finally, non-activated cells co-cultured with supernatant from fibroblasts treated with APC-EVs showed increased mRNA expressions of CAFs markers, the ECM, inflammatory cytokines, as well as the expression of genes controlled by NF-κB. Altogether, our work suggests that EVs and non-EV components from APCMin/+ mice are endowed with pro-tumorigenic activities and promoted inflammation and a CAF-like state by triggering NF-κB signaling in fibroblasts to support CRC growth and progression. These findings provide insight into the interaction between plasma-derived EVs and human cells and can be used to design new CRC diagnosis and prognosis tools.
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Vesículas Extracelulares , Fibroblastos , FN-kappa B , Transducción de Señal , Animales , Humanos , Ratones , Proteína de la Poliposis Adenomatosa del Colon/metabolismo , Proteína de la Poliposis Adenomatosa del Colon/genética , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Carcinogénesis/patología , Carcinogénesis/genética , Carcinogénesis/metabolismo , Colon/patología , Colon/metabolismo , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/genética , Citocinas/metabolismo , Vesículas Extracelulares/metabolismo , Fibroblastos/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Microambiente TumoralRESUMEN
Somatic mosaicism is a hallmark of malignancy that is also pervasively observed in human physiological aging, with clonal expansions of cells harboring mutations in recurrently mutated driver genes. Bulk sequencing of tissue microdissection captures mutation frequencies, but cannot distinguish which mutations co-occur in the same clones to reconstruct clonal architectures, nor phenotypically profile clonal populations to delineate how driver mutations impact cellular behavior. To address these challenges, we developed single-cell Genotype-to-Phenotype sequencing (scG2P) for high-throughput, highly-multiplexed, single-cell joint capture of recurrently mutated genomic regions and mRNA phenotypic markers in cells or nuclei isolated from solid tissues. We applied scG2P to aged esophagus samples from five individuals with high alcohol and tobacco exposure and observed a clonal landscape dominated by a large number of clones with a single driver event, but only rare clones with two driver mutations. NOTCH1 mutants dominate the clonal landscape and are linked to stunted epithelial differentiation, while TP53 mutants and double-driver mutants promote clonal expansion through both differentiation biases and increased cell cycling. Thus, joint single-cell highly multiplexed capture of somatic mutations and mRNA transcripts enables high resolution reconstruction of clonal architecture and associated phenotypes in solid tissue somatic mosaicism.
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With increasingly intense marine heatwaves affecting nearshore regions, foundation species are coming under increasing stress. To better understand their impacts, we examine responses of critical, habitat-forming foundation species (macroalgae, seagrass, corals) to marine heatwaves in 1322 shallow coastal areas located across 85 marine ecoregions. We find compelling evidence that intense, summer marine heatwaves play a significant role in the decline of foundation species globally. Critically, detrimental effects increase towards species warm-range edges and over time. We also identify several ecoregions where foundation species don't respond to marine heatwaves, suggestive of some resilience to warming events. Cumulative marine heatwave intensity, absolute temperature, and location within a species' range are key factors mediating impacts. Our results suggest many coastal ecosystems are losing foundation species, potentially impacting associated biodiversity, ecological function, and ecosystem services provision. Understanding relationships between marine heatwaves and foundation species offers the potential to predict impacts that are critical for developing management and adaptation approaches.
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Ecosistema , Animales , Biodiversidad , Antozoos/fisiología , Algas Marinas/fisiología , Organismos Acuáticos/fisiología , Calor , Calentamiento Global , Estaciones del Año , Cambio ClimáticoRESUMEN
BACKGROUND AND OBJECTIVE: Assessment of drug cardiotoxicity is critical in the development of new compounds and modeling of drug-binding dynamics to hERG can improve early cardiotoxicity assessment. We previously developed a methodology to generate Markovian models reproducing preferential state-dependent binding properties, trapping dynamics and the onset of IKr block using simple voltage clamp protocols. Here, we test this methodology with real IKr blockers and investigate the impact of drug dynamics on action potential prolongation. METHODS: Experiments were performed on HEK cells stably transfected with hERG and using the Nanion SyncroPatch 384i. Three protocols, P-80, P0 and P 40, were applied to obtain the experimental data from the drugs and the Markovian models were generated using our pipeline. The corresponding static models were also generated and a modified version of the O´Hara-Rudy action potential model was used to simulate the action potential duration. RESULTS: The experimental Hill plots and the onset of IKr block of ten compounds were obtained using our voltage clamp protocols and the models generated successfully mimicked these experimental data, unlike the CiPA dynamic models. Marked differences in APD prolongation were observed when drug effects were simulated using the dynamic models and the static models. CONCLUSIONS: These new dynamic models of ten well-known IKr blockers constitute a validation of our methodology to model dynamic drug-hERG channel interactions and highlight the importance of state-dependent binding, trapping dynamics and the time-course of IKr block to assess drug effects even at the steady-state.
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Potenciales de Acción , Humanos , Potenciales de Acción/efectos de los fármacos , Células HEK293 , Canal de Potasio ERG1/metabolismo , Canal de Potasio ERG1/antagonistas & inhibidores , Técnicas de Placa-Clamp , Unión Proteica , Bloqueadores de los Canales de Potasio/farmacologíaRESUMEN
Activation of PINK1 and Parkin in response to mitochondrial damage initiates a response that includes phosphorylation of RAB7A at Ser72. Rubicon is a RAB7A binding negative regulator of autophagy. The structure of the Rubicon:RAB7A complex suggests that phosphorylation of RAB7A at Ser72 would block Rubicon binding. Indeed, in vitro phosphorylation of RAB7A by TBK1 abrogates Rubicon:RAB7A binding. Pacer, a positive regulator of autophagy, has an RH domain with a basic triad predicted to bind an introduced phosphate. Consistent with this, Pacer-RH binds to phosho-RAB7A but not to unphosphorylated RAB7A. In cells, mitochondrial depolarization reduces Rubicon:RAB7A colocalization whilst recruiting Pacer to phospho-RAB7A-positive puncta. Pacer knockout reduces Parkin mitophagy with little effect on bulk autophagy or Parkin-independent mitophagy. Rescue of Parkin-dependent mitophagy requires the intact pRAB7A phosphate-binding basic triad of Pacer. Together these structural and functional data support a model in which the TBK1-dependent phosphorylation of RAB7A serves as a switch, promoting mitophagy by relieving Rubicon inhibition and favoring Pacer activation.
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Proteínas Relacionadas con la Autofagia , Mitofagia , Proteínas Serina-Treonina Quinasas , Ubiquitina-Proteína Ligasas , Proteínas de Unión a GTP rab7 , Humanos , Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Relacionadas con la Autofagia/genética , Células HEK293 , Células HeLa , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genéticaRESUMEN
In somatic tissue differentiation, chromatin accessibility changes govern priming and precursor commitment towards cellular fates1-3. Therefore, somatic mutations are likely to alter chromatin accessibility patterns, as they disrupt differentiation topologies leading to abnormal clonal outgrowth. However, defining the impact of somatic mutations on the epigenome in human samples is challenging due to admixed mutated and wild-type cells. Here, to chart how somatic mutations disrupt epigenetic landscapes in human clonal outgrowths, we developed genotyping of targeted loci with single-cell chromatin accessibility (GoT-ChA). This high-throughput platform links genotypes to chromatin accessibility at single-cell resolution across thousands of cells within a single assay. We applied GoT-ChA to CD34+ cells from patients with myeloproliferative neoplasms with JAK2V617F-mutated haematopoiesis. Differential accessibility analysis between wild-type and JAK2V617F-mutant progenitors revealed both cell-intrinsic and cell-state-specific shifts within mutant haematopoietic precursors, including cell-intrinsic pro-inflammatory signatures in haematopoietic stem cells, and a distinct profibrotic inflammatory chromatin landscape in megakaryocytic progenitors. Integration of mitochondrial genome profiling and cell-surface protein expression measurement allowed expansion of genotyping onto DOGMA-seq through imputation, enabling single-cell capture of genotypes, chromatin accessibility, RNA expression and cell-surface protein expression. Collectively, we show that the JAK2V617F mutation leads to epigenetic rewiring in a cell-intrinsic and cell type-specific manner, influencing inflammation states and differentiation trajectories. We envision that GoT-ChA will empower broad future investigations of the critical link between somatic mutations and epigenetic alterations across clonal populations in malignant and non-malignant contexts.
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Cromatina , Epigénesis Genética , Genotipo , Mutación , Análisis de la Célula Individual , Animales , Femenino , Humanos , Masculino , Ratones , Antígenos CD34/metabolismo , Diferenciación Celular/genética , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Epigénesis Genética/genética , Epigenoma/genética , Genoma Mitocondrial/genética , Técnicas de Genotipaje , Hematopoyesis/genética , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Inflamación/genética , Inflamación/patología , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Megacariocitos/metabolismo , Megacariocitos/patología , Proteínas de la Membrana/genética , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/metabolismo , Trastornos Mieloproliferativos/patología , ARN/genética , Células Clonales/metabolismoRESUMEN
Interspecific interactions are fundamental drivers of animal space use. Yet while non-consumptive effects of predation risk on prey space use are well-known, the risk of aggressive interactions on space use of competitors is largely unknown. We apply the landscape of risk framework to competition-driven space use for the first time, with the hypothesis that less aggressive competitors may alter their behaviour to avoid areas of high competitor density. Specifically, we test how aggressive risk from territorial algal-farming damselfishes can shape the spatial distribution of herbivore fish competitors. We found that only the most aggressive damselfish had fewer competitors in their surrounding area, demonstrating that individual-level behavioural variation can shape spatial distributions. In contradiction to the landscape of risk framework, abundances of farming damselfish and other fishes were positively associated. Our results suggest that reef fishes do not simply avoid areas of high damselfish abundance, but that spatial variation in aggressive behaviour, rather than of individuals, created a competitive landscape of risk. We emphasize the importance of individual-level behaviour in identifying patterns of space use and propose expanding the landscape of risk framework to non-predatory interactions to explore cascading behavioural responses to aggressive risk.
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Arrecifes de Coral , Animales , Conducta Competitiva , Agresión , Perciformes/fisiología , Conducta Animal/fisiología , Peces/fisiologíaRESUMEN
Purpose: We examined the performance of artificial intelligence chatbots on the PREview Practice Exam, an online situational judgment test for professionalism and ethics. Methods: We used validated methodologies to calculate scores and descriptive statistics, χ2 tests, and Fisher's exact tests to compare scores by model and competency. Results: GPT-3.5 and GPT-4 scored 6/9 (76th percentile) and 7/9 (92nd percentile), respectively, higher than medical school applicant averages of 5/9 (56th percentile). Both models answered 95 + % of questions correctly. Conclusions: Chatbots outperformed the average applicant on PREview, suggesting their potential for healthcare training and decision-making and highlighting risks of online assessment delivery.
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A subset of patients with IDH-mutant glioma respond to inhibitors of mutant IDH (IDHi), yet the molecular underpinnings of such responses are not understood. Here, we profiled by single-cell or single-nucleus RNA-sequencing three IDH-mutant oligodendrogliomas from patients who derived clinical benefit from IDHi. Importantly, the tissues were sampled on-drug, four weeks from treatment initiation. We further integrate our findings with analysis of single-cell and bulk transcriptomes from independent cohorts and experimental models. We find that IDHi treatment induces a robust differentiation toward the astrocytic lineage, accompanied by a depletion of stem-like cells and a reduction of cell proliferation. Furthermore, mutations in NOTCH1 are associated with decreased astrocytic differentiation and may limit the response to IDHi. Our study highlights the differentiating potential of IDHi on the cellular hierarchies that drive oligodendrogliomas and suggests a genetic modifier that may improve patient stratification.
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Neoplasias Encefálicas , Diferenciación Celular , Isocitrato Deshidrogenasa , Mutación , Oligodendroglioma , Oligodendroglioma/genética , Oligodendroglioma/patología , Oligodendroglioma/tratamiento farmacológico , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/antagonistas & inhibidores , Humanos , Diferenciación Celular/efectos de los fármacos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/tratamiento farmacológico , Linaje de la Célula/efectos de los fármacos , Receptor Notch1/genética , Receptor Notch1/metabolismo , Proliferación Celular/efectos de los fármacos , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Astrocitos/patología , Ratones , Análisis de la Célula Individual/métodosRESUMEN
Kelp forests occur on more than a quarter of the world's coastlines, serving as foundation species supporting high levels of biodiversity. They are also a major source of organic matter in coastal ecosystems, with the majority of primary production released and exported as detritus. Kelp detritus also provides food and shelter for macroinvertebrates, which comprise important components of inshore food-webs. Hitherto, research on kelp detritus-associated macroinvertebrate assemblages remains relatively limited. We quantified spatiotemporal variability in the structure of detritus-associated macroinvertebrate assemblages within Laminaria hyperborea forests and evaluated the influence of putative drivers of the observed variability in assemblages across eight study sites within four regions of the United Kingdom in May and September 2015. We documented 5167 individuals from 106 taxa with Malacostraca, Gastropoda, Isopoda and Bivalvia the most abundant groups sampled. Assemblage structure varied across months, sites, and regions, with highest richness in September compared to May. Many taxa were unique to individual regions, with few documented in all regions. Finally, key drivers of assemblage structure included detritus tissue nitrogen content, depth, sea surface temperature, light intensity, as well as L. hyperborea canopy density and canopy biomass. Despite their dynamic composition and transient existence, accumulations of L. hyperborea detritus represent valuable repositories of biodiversity and represent an additional kelp forest component which influences secondary productivity, and potentially kelp forest food-web dynamics.
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Biodiversidad , Invertebrados , Laminaria , Animales , Laminaria/fisiología , Invertebrados/fisiología , Ecosistema , Monitoreo del Ambiente , Cadena Alimentaria , Océano Atlántico , Reino Unido , Biomasa , Algas MarinasRESUMEN
We examined spatiotemporal variability in the structure of faunal assemblages associated with the warm-temperate pseudo-kelp Saccorhiza polyschides towards its range centre (Western English Channel, southwest UK), to better understand its role as a habitat-former in the northeast Atlantic. A total of 180 sporophytes and their associated fauna were sampled across three months, three sites, and two depths. Assemblage abundance and biomass varied markedly between three morpho-functional sporophyte components (i.e., holdfast, stipe, blade). We recorded rich and abundant macroinvertebrate assemblages, comprising nine phyla, 28 coarse taxonomic groups, and 57 species of molluscs, which consistently dominated assemblages. We observed pronounced seasonality in faunal assemblage structure, marked variability between sites and depths, and strong positive relationships between biogenic habitat availability and faunal abundance/biomass. S. polyschides sporophytes are short-lived and offer temporary, less-stable habitat compared with dominant perennial Laminaria species, so shifts in the relative abundances of habitat-formers will likely alter local biodiversity patterns.
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Biodiversidad , Ecosistema , Invertebrados , Animales , Invertebrados/fisiología , Biomasa , Monitoreo del Ambiente , Reino Unido , Océano Atlántico , Organismos Acuáticos/fisiologíaRESUMEN
ABSTRACT: The overall prognosis of acute myeloid leukemia (AML) remains dismal, largely because of the inability of current therapies to kill leukemia stem cells (LSCs) with intrinsic resistance. Loss of the stress sensor growth arrest and DNA damage-inducible 45 alpha (GADD45A) is implicated in poor clinical outcomes, but its role in LSCs and AML pathogenesis is unknown. Here, we define GADD45A as a key downstream target of G protein-coupled receptor (LGR)4 pathway and discover a regulatory role for GADD45A loss in promoting leukemia-initiating activity and oxidative resistance in LGR4/HOXA9-dependent AML, a poor prognosis subset of leukemia. Knockout of GADD45A enhances AML progression in murine and patient-derived xenograft (PDX) mouse models. Deletion of GADD45A induces substantial mutations, increases LSC self-renewal and stemness in vivo, and reduces levels of reactive oxygen species (ROS), accompanied by a decreased response to ROS-associated genotoxic agents (eg, ferroptosis inducer RSL3) and acquisition of an increasingly aggressive phenotype on serial transplantation in mice. Our single-cell cellular indexing of transcriptomes and epitopes by sequencing analysis on patient-derived LSCs in PDX mice and subsequent functional studies in murine LSCs and primary AML patient cells show that loss of GADD45A is associated with resistance to ferroptosis (an iron-dependent oxidative cell death caused by ROS accumulation) through aberrant activation of antioxidant pathways related to iron and ROS detoxification, such as FTH1 and PRDX1, upregulation of which correlates with unfavorable outcomes in patients with AML. These results reveal a therapy resistance mechanism contributing to poor prognosis and support a role for GADD45A loss as a critical step for leukemia-initiating activity and as a target to overcome resistance in aggressive leukemia.
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Proteínas de Ciclo Celular , Ferroptosis , Leucemia Mieloide Aguda , Células Madre Neoplásicas , Animales , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/metabolismo , Ratones , Humanos , Ferroptosis/genética , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Ratones Noqueados , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Proteinas GADD45RESUMEN
Salmonella spp. is one of the most isolated microorganisms reported to be responsible for human foodborne diseases and death. Water constitutes a major reservoir where the Salmonella spp. can persist and go undetected when present in low numbers. In this study, we assessed the viability of 12 serotypes of Salmonella enterica subsp. enterica for 160 days in nuclease-free water at 4 and 25°C using flow cytometry and Tryptic Soy Agar (TSA) plate counts. The results show that all 12 serotypes remain viable after 160 days in distilled water using flow cytometry, whereas traditional plate counts failed to detect ten serotypes incubated at 25°C. Moreover, the findings demonstrate that 4°C constitutes a more favorable environment where Salmonella can remain viable for prolonged periods without nutrients. Under such conditions, however, Salmonella exhibits a higher susceptibility to all tested antibiotics and benzalkonium chloride (BZK). The pre-enrichment with Universal Pre-enrichment Broth (UP) and 1/10 × Tryptic Soy broth (1/10 × TSB) resuscitated all tested serotypes on TSA plates, nevertheless cell size decreased after 160 days. Furthermore, phenotype microarray (PM) analysis of S. Inverness and S. Enteritidis combined with principal component analysis (PCA) revealed an inter-individual variability in serotypes with their phenotype characteristics, and the impact of long-term storage at 4 and 25°C for 160 days in nuclease-free water. This study provides an insight to Salmonella spp. long-term survivability at different temperatures and highlights the need for powerful tools to detect this microorganism to reduce the risk of disease transmission of foodborne pathogens via nuclease-free water.
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This study provides new evidence on the influential role of external auditors in enhancing the informativeness of form 10-K annual reports to shareholders. Specifically, we find that the client's choice of a Big 4 auditor (PwC, EY, KPMG, and Deloitte) versus a non-Big 4 auditor contributes to cross-sectional variations in 10-K disclosure volume. We also document that the benefit of enhanced disclosures provided by Big 4 auditors is more pronounced for audit clients with poorer accrual quality and those with higher information asymmetry. Furthermore, we introduce the portion of 10-K length unexplained by operating complexity and observable client characteristics as a new proxy for audit firm effort. Specifically, we find that abnormally long disclosures are associated with higher audit fees and longer audit report lag, which implies that an incremental level of audit effort can be inferred from the discretionary component of 10-K disclosures. As audit effort is costly, a greater volume of 10-K disclosures can be expected to be associated with an improvement in the quality of financial reporting. Overall, our findings show that auditors play more than a simple attestation role in the financial reporting process, and that the quality of financial reporting in a company's 10-K annual report is a joint product of the effort and decisions of both a company's managers and its auditors.