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The Greater Cape Floristic Region (GCFR) is renowned for its exceptional biodiversity, accommodating over 11 000 plant species, notable degree of endemism, and substantial diversification within limited plant lineages, a phenomenon ascribed to historical radiation events. While both abiotic and biotic factors contribute to this diversification, comprehensive genomic alterations, recognized as pivotal in the diversification of angiosperms, are perceived as uncommon. This investigation focuses on the genus Pteronia, a prominent representative of the Asteraceae family in the GCFR. Employing NGS-based HybSeq and RADSeq methodologies, flow cytometry, karyology, and ecological modeling, we scrutinize the intricacies of its polyploid evolution. Phylogenetic reconstructions using 951 low-copy nuclear genes confirm Pteronia as a well-supported, distinct clade within the tribe Astereae. The ingroup displays a structure indicative of rapid radiation likely antedating polyploid establishment, with the two main groups demarcated by their presence or absence in the fynbos biome. Genome size analysis encompasses 1293 individuals across 347 populations, elucidating significant variation ranging from 6.1 to 34.2 pg (2C-value). Pteronia demonstrates substantially large genome sizes within Astereae and phanerophytes. Polyploidy is identified in 31% of the studied species, with four discerned ploidy levels (2x, 4x, 6x, 8x). Cytotypes exhibit marked distinctions in environmental traits, influencing their distribution across biomes and augmenting their niche differentiation. These revelations challenge the presumed scarcity of polyploidy in the Cape flora, underscoring the imperative need for detailed population studies. The intricate evolutionary history of Pteronia, characterized by recent polyploidy and genome size variation, contributes substantially to the comprehension of diversification patterns within the GCFR biodiversity hotspot.
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BACKGROUND: Main-duct (MD-) and mixed-type (MT-) IPMNs harbor an increased risk of pancreatic cancer and warrant surgical resection. Preoperative endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) are important in the diagnosis of IPMNs. The aim of this study was to investigate whether endoscopic procedures manipulating the MD impact postoperative adverse events in patients with MD- and MT-IPMNs. METHODS: We performed a retrospective study of 369 patients who underwent resections for MD- or MT-IPMN at two tertiary centers (2000-2019). Multivariable logistic regression analyses were performed for postoperative adverse events to compare the risks between intervention (ERCP, EUS-FNA with branch duct (BD) aspirated, EUS-FNA with MD aspirated from the duct directly or cyst/mass arising from MD) versus no-intervention group. RESULTS: 33.1 % of patients had a preoperative ERCP and 69.4 % had EUS-FNA. Postoperative adverse events included: 30-day readmission (12.7 %), delayed gastric emptying (13.8 %), pancreatic fistula (10.3 %), abdominal abscess (5.7 %), cardiopulmonary adverse events (11.4 %), and mortality (1.4 %). The model was adjusted for potential confounders. There were no significant differences between the ERCP and no-ERCP groups for specific adverse events. Compared to no-EUS-FNA groups, groups of EUS-FNA with BD aspiration and EUS-FNA with MD aspiration from the main pancreatic duct directly or cyst/mass arising from MD did not show a significant increase in specific adverse events. CONCLUSIONS: Postoperative adverse events were not significantly increased among patients who had ERCP or EUS-FNA before surgical resection for MD- or MT-IPMNs. Endoscopic procedures directly sampling the MD can be safely pursued for diagnostic purposes in selected cases.
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Cistos , Neoplasias Císticas, Mucinosas e Serosas , Neoplasias Pancreáticas , Humanos , Estudos Retrospectivos , Neoplasias Pancreáticas/cirurgia , Neoplasias Pancreáticas/diagnóstico , Colangiopancreatografia Retrógrada Endoscópica , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/efeitos adversos , Endossonografia/métodosRESUMO
BACKGROUND: VWF (von Willebrand factor) is an endothelial-specific procoagulant protein with a major role in thrombosis. Aging is associated with increased circulating levels of VWF, which presents a risk factor for thrombus formation. METHODS: Circulating plasma, cellular protein, and mRNA levels of VWF were determined and compared in young and aged mice. Major organs were subjected to immunofluorescence analyses to determine the vascular pattern of VWF expression and the presence of platelet aggregates. An in vitro model of aging, using extended culture time of endothelial cells, was used to explore the mechanism of age-associated increased VWF levels. RESULTS: Increased circulating plasma levels of VWF with elevated levels of larger multimers, indicative of VWF functional activity, were observed in aged mice. VWF mRNA and cellular protein levels were significantly increased in the brains, lungs, and livers but not in the kidneys and hearts of aged mice. Higher proportion of small vessels in brains, lungs, and livers of aged mice exhibited VWF expression compared with young, and this was concomitant with increased platelet aggregate formation. Prolonged culture of endothelial cells resulted in increased cell senescence that correlated with increased VWF expression; VWF expression was specifically detected in senescent cultured endothelial cells and abolished in response to p53 knockdown. A significantly higher proportion of VWF expressing endothelial cells in vivo exhibited senescence markers SA-ß-Gal (senescence-associated ß-galactosidase) and p53 in aged mouse brains compared with that of the young. CONCLUSIONS: Aging elicits a heterogenic response in endothelial cells with regard to VWF expression, leading to organ-specific increase in VWF levels and alterations in vascular tree pattern of expression. This is concomitant with increased platelet aggregate formation. The age-associated increase in VWF expression may be modulated through the process of cell senescence, and p53 transcription factor contributes to its regulation.
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Trombose , Doenças de von Willebrand , Camundongos , Animais , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo , Células Endoteliais/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Trombose/genética , Trombose/metabolismo , Envelhecimento/genética , RNA Mensageiro/metabolismoRESUMO
BACKGROUND AND AIMS: The Greater Cape Floristic Region is one of the world's biodiversity hotspots and is considered poor in polyploids. To test this assumption, ploidy variation was investigated in a widespread Cape shrub Dicerothamnus rhinocerotis (renosterbos, Asteraceae). The aim is to elucidate the cytotype distribution and population composition across the species range, and to assess differences in morphology, environmental niches, and genetics. METHODS: Ploidy level and genome size were determined via flow cytometry, cytotype assignment was confirmed by chromosome counting. RADseq analyses were used to infer genetic relationships. Cytotype climatic and environmental niches were compared using a range of environmental layers and a soil model, while morphological differences were examined using multivariate methods. KEY RESULTS: The survey of 171 populations and 2370 individuals showed that the species comprises diploid and tetraploid cytotypes, no intermediates and only 16.8 % of mixed populations. Mean 2C-values are 1.80-2.06 pg for diploids and 3.48-3.80 pg for tetraploids, with very similar monoploid genome sizes. Intra-cytotype variation showed a significant positive correlation with altitude and longitude in both cytotypes and with latitude in diploids. Although niches of both cytotypes are highly equivalent and similar, their optima and breadth are shifted due to differences mainly in isothermality and available water capacity. Morphometric analyses showed significant differences in the leaves and corolla traits, in the number of florets per capitulum, and cypsela dimensions between the two cytotypes. Genetic analyses revealed four groups, three of them including both cytotypes. CONCLUSIONS: Dicerothamnus rhinocerotis includes two distinct cytotypes that are genetically similar. While tetraploids arise several times independently within different genetic groups, morphological and ecological differences are evident between cytotypes. Our results open up new avenues for questions regarding the importance of ploidy in the megadiverse Cape flora, and exemplify the need for population-based studies focused on ploidy variation.
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The literature on abusive supervision largely presumes that employees respond to abuse in a relatively straightforward way: When abuse is present, outcomes are unfavorable, and when abuse is absent, outcomes are favorable (or, at least less unfavorable). Yet despite the recognition that abusive supervision can vary over time, little consideration has been given to how past experiences of abuse may impact the ways employees react to it (or, its absence) in the present. This is a notable oversight, as it is widely acknowledged that past experiences create a context against which experiences in the present are compared. By applying a temporal lens to the experience of abusive supervision, we identify abusive supervision inconsistency as a phenomenon that may have different outcomes than would otherwise be predicted by the current consensus in this literature. We draw from theories on time and stress appraisal to develop a model that explains when, why, and for which employees, inconsistent abusive supervision may have negative outcomes (specifically, identifying anxiety as a proximal outcome of abusive supervision inconsistency that has downstream effects on turnover intentions). Moreover, the aforementioned theoretical perspectives dovetail in identifying employee workplace status as a moderator that may buffer employees from the stressful consequences of inconsistent abusive supervision. We test our model using two experience sampling studies with polynomial regression and response surface analyses. Our research makes important theoretical and practical contributions to the abusive supervision literature, as well as the literature on time. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
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Competition between languages affects the lives of people all over the globe, and a huge number of languages are at risk of extinction. In this work, statistical physics is applied to modelling the decline of one language in competition with another. A model from the literature is used and adapted to model the interactions among speakers in a population distribution over time, and is applied to historical data for Cornish and Welsh. Visual, geographical models show the simulated decline of the real languages studied, and a number of qualitative and quantitative features from the historical data are captured by the model. The applicability of the model to further real situations is discussed, as well as adaptations that would be needed to better take account of migration and population dynamics.
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INTRODUCTION: A recent meta-analysis [Lancet Oncol. 2010;11:908-909] has confirmed high sensitivity of indocyanine green (ICG) fluorescence mapping for sentinel node detection in early breast cancer. Concerns have previously been raised regarding the efficacy in patients with high body mass index (BMI). MATERIALS AND METHODS: All consecutive patients undergoing sentinel lymph node biopsies (SLNBs) for early breast cancer in NHS Tayside were included in a prospective audit of surgical and pathology findings. All patients included in the study received dual injection of patent blue dye and ICG. Approval was obtained from the local Caldicott guardian for collection and use of personal data. RESULTS: Of 239 cases, all were female patients of mean age 62 years (range 27-93). In 4.2% (10/239) of cases, neither blue dye nor ICG was present in the axilla. Of the remaining 229 SLNB cases in this series, surgeons documented retrieval of 451 nodes, with a mean surgical nodal count per case of 1.97 (range 1-5) and pathological nodal count of 2.15 (range 0-7). Eighty three cases were performed in patients with BMI 30-39.9 and 21 cases with BMI ≥40, with nodal detection rates of 96.4% (80/83) and 95.2% (20/21), respectively, in these groups of patients. Twenty percent (48/229) of cases had nodal metastases on histopathology. CONCLUSIONS: This is a large single-center study which demonstrates the safety and accuracy of the combined ICG and blue dye technique for SLNB in breast cancer. This is represented by nodal detection rates and node positivity rates which are comparable to previous multicenter studies of standard SLNB regardless of BMI.
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Neoplasias da Mama , Biópsia de Linfonodo Sentinela , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Biópsia de Linfonodo Sentinela/métodos , Verde de Indocianina , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Índice de Massa Corporal , Corantes , Metástase Linfática , Radioisótopos , Linfonodos/patologia , Linfonodos/cirurgiaRESUMO
An infant with nonsyndromic craniosynostosis is brought to clinic by his Jehovah's Witness parents to discuss treatment. Five potential courses of action are discussed in the context of biomedical ethics principles. The potential conflict between parents' autonomy to make decisions for their child and the surgeon's ethical duty of beneficence to the patient is explored.
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Craniossinostoses , Testemunhas de Jeová , Humanos , Criança , Lactente , Transfusão de Sangue , Craniossinostoses/cirurgia , PaisRESUMO
While chemotherapy is a key treatment strategy for many solid tumors, it is rarely curative, and most tumor cells eventually become resistant. Because of this, there is an unmet need to develop systemic treatments that capitalize on the unique mutational landscape of each patient's tumor. The most frequently mutated protein in cancer, p53, has a role in nearly all cancer subtypes and tumorigenesis stages and therefore is one of the most promising molecular targets for cancer treatment. Unfortunately, drugs targeting p53 have seen little clinical success despite promising preclinical data. Most of these drug compounds target specific aspects of p53 inactivation, such as through inhibiting negative regulation by the mouse double minute (MDM) family of proteins. These treatment strategies fail to address cancer cells' adaptation mechanisms and ignore the impact that p53 loss has on the entire p53 network. However, recent gene therapy successes show that targeting the p53 network and cellular dysfunction caused by p53 inactivation is now possible and may soon translate into successful clinical responses. In this review, we discuss p53 signaling complexities in cancer that have hindered the development and use of p53-targeted drugs. We also describe several current therapeutics reporting promising preclinical and clinical results.
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Non-coding repetitive DNA (repeatome) is an active part of the nuclear genome, involved in its structure, evolution and function. It is dominated by transposable elements (TEs) and satellite DNA and is prone to the most rapid changes over time. The TEs activity presumably causes the global genome reorganization and may play an adaptive or regulatory role in response to environmental challenges. This assumption is applied here for the first time to plants from the Cape Floristic hotspot to determine whether changes in repetitive DNA are related to responses to a harsh, but extremely species-rich environment. The genus Pteronia (Asteraceae) serves as a suitable model group because it shows considerable variation in genome size at the diploid level and has high and nearly equal levels of endemism in the two main Cape biomes, Fynbos and Succulent Karoo. First, we constructed a phylogeny based on multiple low-copy genes that served as a phylogenetic framework for detecting quantitative and qualitative changes in the repeatome. Second, we performed a comparative analysis of the environments of two groups of Pteronia differing in their TEs bursts. Our results suggest that the environmental transition from the Succulent Karoo to the Fynbos is accompanied by TEs burst, which is likely also driving phylogenetic divergence. We thus hypothesize that analysis of rapidly evolving repeatome could serve as an important proxy for determining the molecular basis of lineage divergence in rapidly radiating groups.
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Ehlers-Danlos syndrome (EDS) is a rare, genetically variable, heterogenous group of (currently recognized) thirteen connective tissue disorders characterized by skin hyperextensibility, tissue fragility, and generalized joint hypermobility. In addition to these commonly recognized phenotypes, recent studies have notably highlighted variable ophthalmic features in EDS. In this review, we comprehensively gather and discuss the ocular manifestations of EDS and its thirteen subtypes in the clinical setting.
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SUMMARY: Genetic medicine has emerged as an innovative class of therapeutics, allowing the development of new and powerful approaches to address a myriad of diseases that were previously untreatable. At the same time, our improved understanding of the mechanisms underlying aging has created novel opportunities to intervene therapeutically in the aging process itself through the targeting of key pathways driving this process. As individuals age, the onset of a multitude of age-related diseases can significantly impact lifespan. The ultimate goal of their treatment is the maximization of healthy, disease-free years, or healthspan. Here, we discuss a number of promising genetic medicine approaches to target both general and specific mechanisms of age-related disease, and their potential impact on healthspan extension. Essential to this topic is the challenge of nucleic acid delivery, and we discuss the technologies that have been developed to address this challenge in highly promising preclinical and clinical development efforts. In particular, we describe a next-generation delivery technology for healthspan applications called proteo-lipid vehicles.
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Longevidade , Ácidos Nucleicos , Envelhecimento/genética , Nível de Saúde , Humanos , Lipídeos , Longevidade/genéticaRESUMO
Although a litany of theoretical accounts exists to explain why mistreated employees engage in counterproductive work behaviors (CWBs), little is known about whether these mechanisms are complementary or mutually exclusive, or the effect of context on their explanatory strength. To address these gaps, this meta-analytic investigation tests four theoretically-derived mechanisms simultaneously to explain the robust relationship between leader mistreatment and employee CWB: (1) a social exchange perspective, which argues that mistreated employees engage in negative reciprocal behaviors to counterbalance experienced mistreatment; (2) a justice perspective, whereby mistreated employees experience moral outrage and engage in retributive behaviors against the organization and its members; (3) a stressor-emotion perspective, which suggests that mistreated employees engage in CWBs to cope with their negative affect; and (4) a self-regulatory perspective, which proposes that mistreated employees are simply unable to inhibit undesirable behaviors. Moreover, we also examine whether the above model holds across cultures that vary on power distance. Our meta-analytic structural equation model demonstrated that all but the justice mechanism significantly mediated the relationship between leader mistreatment and employee CWBs, with negative affect emerging as the strongest explanatory mechanism in both high and low power distance cultures. Given these surprising results, as the stressor-emotion perspective is less frequently invoked in the literature, this paper highlights not only the importance of investigating multiple mechanisms together when examining the leader mistreatment-employee CWB relationship, but also the need to develop more nuanced theorizing about these mechanisms, particularly for negative affect.
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Limiting or withdrawing nonbeneficial medical care is considered ethically responsible throughout most of critical care and medical ethics literature. Practically, however, setting limits to treatment is often challenging. We review the literature to identify best practices for using the definition of futility as an anchoring concept to aid the ethical practice of ICU clinicians. DATA SOURCES: Source data were obtained from a PubMed literature review. STUDY SELECTION: English language articles were chosen based on relevance to medical futility ethics, end-of-life care in the ICU, or communication and conflict mitigation strategies. DATA EXTRACTION: Independent evaluation of selected articles for recurrent content themes as relevant to our clinical case were compared among authors and based on consensus, quantitative and qualitative data from these sources were referenced directly. DATA SYNTHESIS: When life-sustaining treatment is unlikely to achieve a meaningful benefit such as symptom improvement, continued care may be discordant with the patient's goals. Institutional and cultural norms, unconscious biases, and difficulty with navigating conflicts all influence how un(comfortable) clinicians feel in setting limits to futile care. Defining futility in light of the patient's goals and values, focusing on outcomes rather than interventions, and being proactive in communication with families are the staples of medically meaningful critical care. Palliative measures should be framed affirmatively, and clinicians should be transparent about the limits of medicine. CONCLUSIONS: Clinicians have an ethical obligation not to provide futile care. To practice accordingly, we must clearly understand the nature and forms of futility. Armed with this understanding, our discussions with family and surrogates in the ICU should fundamentally comprise 1) eliciting the patient's values and goals, 2) communicating which interventions serve those values and goals and which do not, and 3) offering only those interventions whose likely outcomes are in line with said values and goals.
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HER2-positive breast cancers, representing up to 20% of all breast cancers, are more aggressive and have poorer outcomes. Systemic therapy has been proven to prevent disease recurrence and improve survival. Existing literature provides only limited evidence to support this in smaller HER2-positive tumors. The study aimed to evaluate HER-2 positive breast cancer management and treatment of all T1N0 tumors in the North of Scotland, diagnosed 2012-2019. Clinical-pathological details, comorbidities, treatments and clinical events were retrieved from the Scottish North Cancer Alliance audit database and analyzed using univariate and multivariate analysis including cox-regression and log-rank testing (SPSSv23).Overall, 299 patients (41% screen detected/ 56.9% symptomatic /2.1% other), median age 63 years and median tumor size 13 mm, were included. Most cancers were grade 2/3 (43.1%/ 55.5%). Most patients (59.5%) received treatment with trastuzumab (tT); 40.8% concurrent with chemotherapy and endocrine therapy. 7.7% of patients received neo adjuvant chemotherapy. Median follow-up time was 2.6 years, with recurrence on average occurring 2.9 years after diagnosis. Patients receiving trastuzumab were younger, had a higher grade and larger size tumor. 78.5% of patients in the untreated group (non-tT) were ER positive compared to 65.2% in the treated group (tT). Trastuzumab significantly lowered breast cancer recurrence (Tt=3.4% versus non-Tt=8.3%, p = 0.022 HR= 0.096, 95% CI 0.025-0.361). In conclusion, receiving anti-HER2 treatment significantly improved clinical outcome in this T1N0 patient group. Consideration, at the very least informed discussions with patients, should be undertaken to treat these early stage HER2-positive breast cancers.
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Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Receptor ErbB-2 , TrastuzumabRESUMO
Subordinates who are abused by a supervisor tend to experience violated perceptions of interpersonal justice and deteriorated well-being. One way in which they may seek to cope with these consequences is by engaging in retaliatory behaviors intended to "get back" at their supervisor and even the score. Based on research suggesting that acts of retaliation can restore perceptions of justice, we propose a model whereby retaliation alleviates the effect of abusive supervision on subordinate well-being by restoring subordinates' interpersonal justice perceptions. In two studies, using multiwave (Study 1) and time-lagged (Study 2) designs, we found general support for our predictions, even when controlling for the alternative mechanism of victim identity and subordinates' baseline well-being. These results suggest that retaliation reduces the harmful consequences of supervisory abuse on well-being not only in the short term but also in the long run. Theoretical and practical implications surrounding this increased understanding of the effectiveness of retaliation as a strategy for coping with the effects of abusive supervision over time are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Justiça Social , Percepção Social , Adaptação Psicológica , HumanosRESUMO
Drawing upon Stress-as-Offense-to-Self theory, we develop a moderated mediation model whereby subordinate poor performance and leader well-being is linked by abusive supervision and this mediated relationship is further moderated by leaders' motives for abuse. Specifically, we posit that higher performance promotion motives will attenuate, whereas higher injury motives will exacerbate the relationship between abusive supervision and leader emotional exhaustion, due to their differential implications for leaders' ability to see themselves in a positive light. In a pilot study, we first examined and found support for the theorized mediation chain in a multiwave field study of organizational leaders (N = 71). In Study 1, we conducted a multiwave and multisource field study of leader-follower dyads (N = 274), which supported our predictions that the indirect effect between subordinate poor performance and leader emotional exhaustion via abusive supervision was strengthened for leaders higher on injury motives. In Study 2, we undertook a 2-week daily diary study with leaders (N = 129) to hone in on the latter half of our model, focusing on within-person dynamics linking abusive supervision and leader well-being and the moderating role of leader motives for abuse. Although the within-person relationship between abusive supervision and emotional exhaustion was positive within a given day across leaders, the lagged within-person relationship between abusive supervision and emotional exhaustion unfolded differently for leaders higher versus lower on injury motives. Namely, abusive supervision had a lingering detrimental effect on leader emotional exhaustion among leaders higher on injury motives. (PsycInfo Database Record (c) 2022 APA, all rights reserved).
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Motivação , Local de Trabalho , Emoções , Humanos , Projetos PilotoRESUMO
Electric field mediated gene delivery methods have the ability to efficiently transfect cells in vivo with an excellent safety profile. The method has historically used a fixed number of electric pulses with identical characteristics in induce delivery. Electrical treatment does not typically compensate for subject-to-subject variation and other differences. This study was designed to investigate if delivery/expression could be increased using a novel electropulsation method that compensated for variation using real-time electrical impedance measurements. The method involved delivering plasmid DNA encoding luciferase to murine skin. Tissue impedance in a 1-3 KHz range was measured before electric pulses were applied. Impedance was also measured after each successive pulse. Pulsation was stopped when impedance values were reduced by either 80% or 95% relative to prepulse values. Standard/fixed pulsing parameters were also used for comparison. The results indicated that up to 15-fold increases in luciferase expression could be obtained when electrical treatment was ceased based upon impedance reductions. Furthermore, peak expression levels of all treatment groups pulsed using the novel pulsing method were statistically higher than those that employed standard pulsing. These results strongly suggest that applying pulses until a defined impedance-based endpoint results in higher expression.