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Angiotensin II (AngII), a component of the Renin-Angiotensin-Aldosterone System (RAAS), has been implicated in the dysregulation of adipose tissue function. Inhibition of AngII has been shown to improve adipose tissue function in mice with metabolic syndrome. It is well established that the Heme Oxygenase-1 (HO-1), an antioxidant improves oxidative stress and phenotypic change in adipocytes. Molecular effects of high oxidative stress include suppression of Sirtuin-1 (SIRT1), which is amenable to redox manipulations. However, the underlying mechanisms by which the Renin-Angiotensin-Aldosterone System (RAAS) exerts its metabolic effects are not fully understood. In this study, we propose that AngII-induced oxidative stress may suppress adipocyte SIRT1 through down-regulation of HO-1. Consequently, this suppression of SIRT1 may result in the up-regulation of the Mineralocorticoid Receptor (MR). We further hypothesize that the induction of HO-1 would rescue SIRT1, thereby improving oxidative stress and adipocyte phenotype. To establish this hypothesis, we conducted experiments using mouse preadipocytes treated with AngII, in the presence or absence of Cobalt Protoporphyrin (CoPP), an inducer of HO-1, and Tin Mesoporphyrin (SnMP), an inhibitor of HO-1. Our data demonstrate that treatment of mouse preadipocytes with AngII leads to increased lipid accumulation, elevated levels of superoxide and inflammatory cytokines (Interleukin-6 and Tumor necrosis factor alpha), and reduced levels of adiponectin. However, these effects were attenuated by the induction of HO-1, and this attenuation was reversed by SnMP, indicating that the beneficial effects on adipocyte phenotype are modulated by HO-1. Furthermore, our findings reveal that AngII-treated preadipocytes exhibit upregulated MR levels and suppressed SIRT1 expression, which are rescued by HO-1 induction. Following treatment with CoPP and SIRT1 siRNA in mouse preadipocytes resulted in increased lipid accumulation and elevated levels of fatty acid synthase, indicating that the beneficial effects of HO-1 are modulated through SIRT1. Our study provides evidence that HO-1 restores cellular redox balance, rescues SIRT1, and attenuates the detrimental effects of AngII on adipocytes and systemic metabolic profile.

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BACKGROUND AND OBJECTIVES: Despite their temporal lobe pathology, a significant subgroup of patients with temporal lobe epilepsy (TLE) is able to maintain normative cognitive functioning. In this study, we identify patients with TLE with intact vs impaired neurocognitive profiles and interrogate for the presence of both normative and highly individual intrinsic connectivity networks (ICNs)-all toward understanding the transition from impaired to intact neurocognitive status. METHODS: This retrospective cross-sectional study included patients with TLE and matched healthy controls (HCs) from the Thomas Jefferson Comprehensive Epilepsy Center. Functional MRI data were decomposed using independent component analysis to obtain individualized ICNs. In this article, we calculated the degree of match between individualized ICNs and canonical ICNs (e.g., 17 resting-state networks by Yeo et al.) and divided each participant's ICNs into normative or non-normative status based on the degree of match. RESULTS: 100 patients with TLE (mean age 42.0 [SD: 13.7] years, 47 women) and 92 HCs were included in this study. We found that the individualized networks matched to the canonical networks less well in the cognitively impaired (n = 24) compared with the cognitively intact (n = 63) patients with TLE by 2-way mixed-measures analysis of variance (impaired vs intact mean difference [MD] -0.165 [-0.317, -0.013], p = 0.028). The cognitively impaired patients showed significant abnormalities in the profiles of both normative (impaired vs intact MD -0.537 [-0.998, -0.076], p = 0.017, intact vs HC MD -0.221 [-0.536, 0.924], p = 0.220, and impaired vs HC MD -0.759 [-1.200, -0.319], p < 0.001) and non-normative networks (impaired vs intact MD 0.484 [0.030, 0.937], p = 0.033, intact vs HC MD 0.369 [0.059, 0.678], p = 0.014, and impaired vs HC MD 0.853 [0.419, 1.286], p < 0.001) while the intact patients showed abnormalities only in non-normative networks. At the same time, we found that normative networks held a strong, positive association with the neuropsychological measures, with this association negative in non-normative networks. DISCUSSION: Our data demonstrated that significant cognitive deficits are associated with the status of both canonical and highly individual ICNs, making clear that the transition from intact to impaired cognitive status is not simply the result of disruption to normative brain networks.

Asunto(s)

Cognición , Epilepsia del Lóbulo Temporal , Imagen por Resonancia Magnética , Red Nerviosa , Humanos , Epilepsia del Lóbulo Temporal/fisiopatología , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/complicaciones , Epilepsia del Lóbulo Temporal/psicología , Femenino , Masculino , Adulto , Estudios Transversales , Persona de Mediana Edad , Estudios Retrospectivos , Cognición/fisiología , Red Nerviosa/diagnóstico por imagen , Red Nerviosa/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/etiología , Pruebas Neuropsicológicas

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Objective: To determine the efficacy and safety of rectal diclofenac for relieving postoperative pain following diagnostic hystero-laparoscopy and dye test (dHLD). Methods: A prospective, double-blind, placebo-controlled, randomized trial was conducted among women who underwent dHLD to evaluate fertility. The women received either rectal diclofenac with intramuscular pentazocine or intramuscular pentazocine with rectal placebo for postoperative analgesia. The median pain scores at different time points were assessed as the primary outcome measures using the Numerical Rating Scale for pain. The secondary outcome measures were analgesic consumption, time at which first analgesic was requested, satisfaction with pain relief and any adverse events. Results: In total, 108 participants were analysed (54 in each group, 1:1 ratio). The median score for postoperative pain was lower for the diclofenac group compared with the placebo group at 4 h (52.53 vs 56.47; p = 0.507), 6 h (50.48 vs 58.52; p = 0.174), 8 h (51.42 vs 57.65; p = 0.296), 10 h (51.35 vs 57.65; p = 0.285) and 12 h (52.45 vs 56.55; p = 0.485) post surgery, although the difference was not significant (p > 0.05). Seventeen participants required rescue analgesia with 30 mg of pentazocine: 11 at 4 h post surgery [5 (62.5 %) vs 6 (66.7 %)], three at 6 h post surgery [2 (25.0 %) vs 1 (11.1 %)], two at 8 h post surgery [1 (12.5 %) vs 1 (11.1 %)], and one at 12 h post surgery [0 vs 1 (11.1 %)] for the diclofenac and placebo groups respectively (p = 0.713). There were no significant differences in postoperative adverse effect profiles, overall patient satisfaction, and need for rescue analgesia between the two groups (p > 0.05). Conclusions: Postoperative use of rectal diclofenac and pentazocine is safe, but did not significantly improve pain scores, patient satisfaction and need for rescue analgesia following dHLD, compared with patients who received pentazocine and placebo. While a multi-modal approach to pain relief following dHLD does not appear to be significantly beneficial, a multi-centre study is needed to confirm or refute these findings.

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Visceral white adipose tissues (WAT) regulate systemic lipid metabolism and inflammation. Dysfunctional WAT drive chronic inflammation and facilitate atherosclerosis. Adipose tissue-associated macrophages (ATM) are the predominant immune cells in WAT, but their heterogeneity and phenotypes are poorly defined during atherogenesis. The scavenger receptor CD36 mediates ATM crosstalk with other adipose tissue cells, driving chronic inflammation. Here, we combined the single-cell RNA sequencing technique with cell metabolic and functional assays on major WAT ATM subpopulations using a diet-induced atherosclerosis mouse model (Apoe-null). We also examined the role of CD36 using Apoe/Cd36 double-null mice. Based on transcriptomics data and differential gene expression analysis, we identified a previously undefined group of ATM displaying low viability and high lipid metabolism and labeled them as "unhealthy macrophages". Their phenotypes suggest a subpopulation of ATM under lipid stress. We also identified lipid-associated macrophages (LAM), which were previously described in obesity. Interestingly, LAM increased 8.4-fold in Apoe/Cd36 double-null mice on an atherogenic diet, but not in Apoe-null mice. The increase in LAM was accompanied by more ATM lipid uptake, reduced adipocyte hypertrophy, and less inflammation. In conclusion, CD36 mediates a delicate balance between lipid metabolism and inflammation in visceral adipose tissues. Under atherogenic conditions, CD36 deficiency reduces inflammation and increases lipid metabolism in WAT by promoting LAM accumulation.

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Polar offshore environments are considered the last pristine soundscapes, but accelerating climate change and increasing human activity threaten their integrity. In order to assess the acoustic state of polar oceans, there is the need to investigate their soundscape characteristics more holistically. We apply a set of 14 ecoacoustic metrics (EAMs) to identify which metrics are best suited to reflect the characteristics of disturbed and naturally intact polar offshore soundscapes. We used two soundscape datasets: (i) the Arctic eastern Fram Strait (FS), which is already impacted by anthropogenic noise, and (ii) the quasi-pristine Antarctic Weddell Sea (WS). Our results show that EAMs when applied in concert can be used to quantitatively assess soundscape variability, enabling the appraisal of marine soundscapes over broad spatiotemporal scales. The tested set of EAMs was able to show that the eastern FS, which is virtually free from sea ice, lacks seasonal soundscape dynamics and exhibits low acoustic complexity owing to year-round wind-mediated sounds and anthropogenic noise. By contrast, the WS exhibits pronounced seasonal soundscape dynamics with greater soundscape heterogeneity driven in large part by the vocal activity of marine mammal communities, whose composition in turn varies with the prevailing seasonal sea ice conditions.

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Neuropsychiatric symptoms (including anxiety, depression, apathy, impulse-compulsive behaviors and hallucinations) are among the most common non-motor features of Parkinson's disease. Whether these symptoms should be considered as a direct consequence of the pathophysiologic mechanisms of Parkinson's disease is controversial. Morphometric similarity network analysis and epicenter mapping approach were performed on T1-weighted images of 505 patients with Parkinson's disease and 167 age- and sex-matched healthy participants from Parkinson's Progression Markers Initiative database to reveal the commonalities and specificities of distinct neuropsychiatric symptoms. Abnormal cortical co-alteration pattern in patients with neuropsychiatric symptoms was in somatomotor, vision and frontoparietal regions, with epicenters in somatomotor regions. Apathy, impulse-compulsive behaviors and hallucinations shares structural abnormalities in somatomotor and vision regions, with epicenters in somatomotor regions. In contrast, the cortical abnormalities and epicenters of anxiety and depression were prominent in the default mode network regions. By embedding each symptom within their co-alteration space, we observed a cluster composed of apathy, impulse-compulsive behaviors and hallucinations, while anxiety and depression remained separate. Our findings indicate different structural mechanisms underlie the occurrence and progression of different neuropsychiatric symptoms. Based upon these results, we propose that apathy, impulse-compulsive behaviors and hallucinations are directly related to damage of motor circuit, while anxiety and depression may be the combination effects of primary pathophysiology of Parkinson's disease and psychosocial causes.

Asunto(s)

Ansiedad , Apatía , Corteza Cerebral , Alucinaciones , Imagen por Resonancia Magnética , Enfermedad de Parkinson , Humanos , Enfermedad de Parkinson/diagnóstico por imagen , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/psicología , Enfermedad de Parkinson/patología , Masculino , Femenino , Anciano , Persona de Mediana Edad , Alucinaciones/fisiopatología , Alucinaciones/etiología , Alucinaciones/diagnóstico por imagen , Alucinaciones/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/fisiopatología , Apatía/fisiología , Ansiedad/fisiopatología , Ansiedad/diagnóstico por imagen , Depresión/diagnóstico por imagen , Depresión/fisiopatología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/fisiopatología , Trastornos Disruptivos, del Control de Impulso y de la Conducta/diagnóstico por imagen

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Religious fundamentalism, characterized by rigid adherence to a set of beliefs putatively revealing inerrant truths, is ubiquitous across cultures and has a global impact on society. Understanding the psychological and neurobiological processes producing religious fundamentalism may inform a variety of scientific, sociological, and cultural questions. Research indicates that brain damage can alter religious fundamentalism. However, the precise brain regions involved with these changes remain unknown. Here, we analyzed brain lesions associated with varying levels of religious fundamentalism in two large datasets from independent laboratories. Lesions associated with greater fundamentalism were connected to a specific brain network with nodes in the right orbitofrontal, dorsolateral prefrontal, and inferior parietal lobe. This fundamentalism network was strongly right hemisphere lateralized and highly reproducible across the independent datasets (r = 0.82) with cross-validations between datasets. To explore the relationship of this network to lesions previously studied by our group, we tested for similarities to twenty-one lesion-associated conditions. Lesions associated with confabulation and criminal behavior showed a similar connectivity pattern as lesions associated with greater fundamentalism. Moreover, lesions associated with poststroke pain showed a similar connectivity pattern as lesions associated with lower fundamentalism. These findings are consistent with the current understanding of hemispheric specializations for reasoning and lend insight into previously observed epidemiological associations with fundamentalism, such as cognitive rigidity and outgroup hostility.

Asunto(s)

Red Nerviosa , Humanos , Masculino , Femenino , Red Nerviosa/fisiopatología , Red Nerviosa/patología , Persona de Mediana Edad , Encéfalo/fisiopatología , Encéfalo/patología , Adulto , Religión , Imagen por Resonancia Magnética , Lesiones Encefálicas/patología , Lesiones Encefálicas/fisiopatología , Anciano

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Immune defenses are crucial for survival but costly to develop and maintain. Increased immune investment is therefore hypothesized to trade-off with other life-history traits. Here, we examined innate and adaptive immune responses to environmental heterogeneity in wild Antarctic fur seals. In a fully crossed, repeated measures design, we sampled 100 pups and their mothers from colonies of contrasting density during seasons of contrasting food availability. Biometric and cortisol data as well as blood for the analysis of 13 immune and oxidative status markers were collected at two key life-history stages. We show that immune responses of pups are more responsive than adults to variation in food availability, but not population density, and are modulated by cortisol and condition. Immune investment is associated with different oxidative status markers in pups and mothers. Our results suggest that early life stages show greater sensitivity to extrinsic and intrinsic effectors, and that immunity may be a strong target for natural selection even in low-pathogen environments such as Antarctica.

Asunto(s)

Lobos Marinos , Estrés Oxidativo , Animales , Lobos Marinos/inmunología , Lobos Marinos/fisiología , Lobos Marinos/metabolismo , Regiones Antárticas , Femenino , Masculino , Inmunidad Innata , Hidrocortisona/sangre , Inmunidad Adaptativa

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Inbreeding, the mating of individuals that are related through common ancestry, is of central importance in evolutionary and conservation biology due to its impacts on individual fitness and population dynamics. However, while advanced genomic approaches have revolutionised the study of inbreeding in animals, genomic studies of inbreeding are rare in plants and lacking in fungi. We investigated global patterns of inbreeding in the prized edible porcini mushroom Boletus edulis using 225 whole genomes from seven lineages distributed across the northern hemisphere. Genomic inbreeding was quantified using runs of homozygosity (ROHs). We found appreciable variation both among and within lineages, with some individuals having over 20% of their genomes in ROHs. Much of this variation could be explained by a combination of elevation and latitude, and to a lesser extent by predicted habitat suitability during the last glacial maximum. In line with this, the majority of ROHs were short, reflecting ancient common ancestry dating back approximately 200-1700 generations ago, while longer ROHs indicative of recent common ancestry (less than approximately 50 generations ago) were infrequent. Our study reveals the inbreeding legacy of major climatic events in a widely distributed forest mutualist, aligning with prevailing theories and empirical studies of the impacts of historical glaciation events on the dominant forest tree species of the northern hemisphere.

Asunto(s)

Genética de Población , Homocigoto , Endogamia , Agaricales/genética

RESUMEN

The Antarctic fur seal (Arctocephalus gazella) is an important top predator and indicator of the health of the Southern Ocean ecosystem. Although abundant, this species narrowly escaped extinction due to historical sealing and is currently declining as a consequence of climate change. Genomic tools are essential for understanding these anthropogenic impacts and for predicting long-term viability. However, the current reference genome ("arcGaz3") shows considerable room for improvement in terms of both completeness and contiguity. We therefore combined PacBio sequencing, haplotype-aware HiRise assembly and scaffolding based on Hi-C information to generate a refined assembly of the Antarctic fur seal reference genome ("arcGaz4_h1"). The new assembly is 2.53Gb long, has a scaffold N50 of 55.6Mb and includes 18 chromosome-sized scaffolds, which correspond to the 18 chromosomes expected in otariids. Genome completeness is greatly improved, with 23,408 annotated genes and a Benchmarking Universal Single-Copy Orthologs (BUSCO) score raised from 84.7% to 95.2%. We furthermore included the new genome in a reference-free alignment of the genomes of eleven pinniped species to characterize evolutionary conservation across the Pinnipedia using genome-wide Genomic Evolutionary Rate Profiling (GERP). We then implemented Gene Ontology (GO) enrichment analyses to identify biological processes associated with those genes showing the highest levels of either conservation or differentiation between the two major pinniped families, the Otariidae and Phocidae. We show that processes linked to neuronal development, the circulatory system and osmoregulation are overrepresented both in conserved as well as in differentiated regions of the genome.

RESUMEN

PURPOSE: The purpose of this study was to examine the effects of resistance training (RT) in physical education lessons on athletic motor skill competencies in secondary school children. METHOD: Seventy-eight males were randomized into experimental year groups or a control group. Experimental groups participated in RT during physical education lessons for a 6-week half-term. The control group continued with their games-based curriculum. Countermovement jump (CMJ) height, seated medicine ball throw (SMBT) distance, and RT skills battery scores were measured preintervention and postintervention. RESULTS: All experimental groups significantly improved SMBT distance and RT skills quotient (P < .05). All intervention year groups also significantly improved CMJ height (P < .05), except for year 9. Although the control group did not show improvements in CMJ height and RT skills quotient, there was a significant improvement in SMBT distance (P < .05). The year 7 and 8 males exhibited greater improvements in CMJ height and SMBT distance (d = 0.21-0.79) than in year 9 (d = 0.00-0.40). CONCLUSION: Results of the study indicated that a 6-week half-term RT intervention in physical education lessons can improve athletic motor skill competencies (P < .05, d = 0.21-2.51) in male youths.

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Parenteral nutrition (PN) is a complex preparation that contains multiple component products with the associated risk for incompatibilities and diminished stabilities when combined together as an admixture. Significant patient harm can result from prescribing, preparing, and administering PN without confirming compatibility and stability. Incompatibility or instability is rarely obvious to the unaided eye, so safe PN admixture relies on incorporating physicochemical properties of the included components into compatibility and stability decisions. Practices include applying active ingredient concentration limits to reduce risk for incompatibilities and instabilities. The purpose of the current article is to distill the wide-ranging information on PN compatibility and stability into a feasible blueprint that individual healthcare organizations can then use to design and implement practical initiatives. Compatibility and stability considerations can be incorporated into the routine tasks of PN prescribing, order reviewing, preparing, and administering. The focus of this review is on identifying potential physicochemical interactions that can be addressed at each step in the PN use process. Organizations should incorporate compatibility and stability considerations into the routine procedures and practices of all clinicians involved with PN therapy. Those clinicians in healthcare organizations and caregivers in the home should then be in a position to safely provide the appropriate PN admixtures in terms of compatibility and stability.

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ABSTRACT: Houlton, LJ, Moody, JA, Bampouras, TM, and Esformes, JI. Acute effects of intracomplex rest after back squats on vertical jump performance during complex training. J Strength Cond Res XX(X): 000-000, 2024-Postactivation performance enhancement and complex-contrast sets are prevalent in sports science research. Typical complex-contrast sets consist of heavy back squats, an intracontrast rest period (ICRP) and vertical jumps (countermovement jumps [CMJs], or squat jumps [SJs]). Propulsive impulse (Jprop) is considered the leading indicator of jump performance. However, studies evaluating jump performance during complex-contrast sets use jump height as the primary performance measure, limiting insight into ICRP's effect on jump performance. We assessed the effect of a 3 repetition maximum (3RM) back squat and 6 ICRPs on vertical jump Jprop and associated force-time components. Fourteen subjects completed 12 experimental conditions, assigned equally to 4 testing sessions. Independent variables, in a 6 × 2 randomized, counterbalanced design, were ICRP (0, 60, 120, 180, 240, 300 seconds; ICRP0, ICRP60, ICRP120, ICRP180, ICRP240, ICRP300, respectively) and vertical jump (CMJ and SJ). Conditions consisted of baseline vertical jumps, followed by 3 back squat repetitions at 100% 3RM, an ICRP and experimental jumps. Symmetrized percentage changes between experimental and baseline jumps were assessed using repeated measures analysis of variance (ANOVA) and pairwise effect sizes. Results showed significant effects (p ≤ 0.05) on CMJ average rate of force development (RFD) between ICRP0 and ICRP120 and ICRP0 and ICRP300. Pairwise comparisons showed medium and large effect sizes for and increases in CMJ RFD (g = 0.83-2.69) whereas SJ RFD decreased (g = 0.81-2.57). Small effect sizes were found for Jprop, peak force, and mean force. Results suggest limited change in Jprop (g = 0.01-0.58), but back squats may potentiate RFD via the stretch-shortening cycle.

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BACKGROUND:  Clustering of cardiovascular disease (CVD) risk factors have been observed in children and adolescents, but its association with visceral adiposity index (VAI) and cardiorespiratory fitness (CRF) in adolescents has rarely been studied. AIM:  This study determines the independent associations of VAI and CRF with the clustering of cardiovascular disease risk (CVDr) among Nigerian adolescents. SETTING:  Adolescents from specific secondary schools in Kogi East, North Central Nigeria participated in the study. METHODS:  A cross-sectional sample of 403 adolescents (202 boys and 201 girls) aged 11 years - 19 years were evaluated for VAI, CRF and CVDr. Using identified risk factors, a clustered CVDr score was generated. The association between VAI, CRF and clustered CVDr was evaluated using regression models that controlled for age, gender and maturity status. RESULTS:  Fitness was negatively associated with CVDr (ß = -0.268, p  0.001), while VAI was positively correlated with CVDr (ß = 0.379, p  0.001). After CRF or VAI adjustment, the independent association with the dependent variable remained significant. The odds of an adolescent with elevated VAI being at risk of CVD was 4.7 times higher than his peers. Unfit adolescents were 2.1 times more likely to develop CVDr. CONCLUSION:  Both VAI and CRF were independently associated with the clustering of CVDr in Nigerian adolescents. The findings suggest that health promotion efforts focusing on healthy diet and aerobic-type physical activity programmes should be encouraged among the youth to reduce the risk of CVD.Contribution: This study shows that improving visceral adipose tissue and fitness may lower CVD risk factors in adolescents, which is significant for public health.

Asunto(s)

Capacidad Cardiovascular , Enfermedades Cardiovasculares , Obesidad Abdominal , Humanos , Masculino , Adolescente , Femenino , Nigeria/epidemiología , Estudios Transversales , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Capacidad Cardiovascular/fisiología , Niño , Obesidad Abdominal/epidemiología , Factores de Riesgo de Enfermedad Cardiaca , Grasa Intraabdominal , Factores de Riesgo , Adulto Joven

RESUMEN

For individuals to survive and function in society, it is essential that they recognize, interact with, and learn from other conspecifics. Observational fear (OF) is the well-conserved empathic ability of individuals to understand the other's aversive situation. While it is widely known that factors such as prior similar aversive experience and social familiarity with the demonstrator facilitate OF, the neural circuit mechanisms that explicitly regulate experience-dependent OF (Exp OF) were unclear. In this review, we examine the neural circuit mechanisms that regulate OF, with an emphasis on rodent models, and then discuss emerging evidence for the role of fear memory engram cells in the regulation of Exp OF. First, we examine the neural circuit mechanisms that underlie Naive OF, which is when an observer lacks prior experiences relevant to OF. In particular, the anterior cingulate cortex to basolateral amygdala (BLA) neural circuit is essential for Naive OF. Next, we discuss a recent study that developed a behavioral paradigm in mice to examine the neural circuit mechanisms that underlie Exp OF. This study found that fear memory engram cells in the BLA of observers, which form during a prior similar aversive experience with shock, are reactivated by ventral hippocampal neurons in response to shock delivery to the familiar demonstrator to elicit Exp OF. Finally, we discuss the implications of fear memory engram cells in Exp OF and directions of future research that are of both translational and basic interest.

Asunto(s)

Miedo , Memoria , Miedo/fisiología , Animales , Humanos , Memoria/fisiología , Neuronas/metabolismo , Ratones , Amígdala del Cerebelo , Hipocampo , Empatía/fisiología , Giro del Cíngulo , Complejo Nuclear Basolateral

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Recent epidemiological studies propose an association between parkinsonism and seizures, but the direction of this association is unclear. Focal brain lesions causing new-onset parkinsonism versus seizures may provide a unique perspective on the causal relationship between the two symptoms and involved brain networks. We studied lesions causing parkinsonism versus lesions causing seizures and used the human connectome to identify their connected brain networks. Brain networks for parkinsonism and seizures were compared using spatial correlations on a group and individual lesion level. Lesions not associated with either symptom were used as controls. Lesion locations from 29 patients with parkinsonism were connected to a brain network with the opposite spatial topography (spatial r = -0.85) compared to 347 patients with lesions causing seizures. A similar inverse relationship was found when comparing the connections that were most specific on a group level (spatial r = -0.51) and on an individual lesion level (average spatial r = -0.042; P < 0.001). The substantia nigra was found to be most positively correlated to the parkinsonism network but most negatively correlated to the seizure network (spatial r > 0.8). Brain lesions causing parkinsonism versus seizures map to opposite brain networks, providing neuroanatomical insight into conflicting epidemiological evidence.

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Studying protein dynamics and conformational heterogeneity is crucial for understanding biomolecular systems and treating disease. Despite the deposition of over 215 000 macromolecular structures in the Protein Data Bank and the advent of AI-based structure prediction tools such as AlphaFold2, RoseTTAFold, and ESMFold, static representations are typically produced, which fail to fully capture macromolecular motion. Here, we discuss the importance of integrating experimental structures with computational clustering to explore the conformational landscapes that manifest protein function. We describe the method developed by the Protein Data Bank in Europe - Knowledge Base to identify distinct conformational states, demonstrate the resource's primary use cases, through examples, and discuss the need for further efforts to annotate protein conformations with functional information. Such initiatives will be crucial in unlocking the potential of protein dynamics data, expediting drug discovery research, and deepening our understanding of macromolecular mechanisms.

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BACKGROUND: Speculum lubrication may help to reduce the pain experienced during Pap-smear collection and hence increase uptake of cervical cancer screening and repeat testing, but there are fears of its interference with cytological results. AIM: To determine and compare the adequacy of cervical cytology smears and the mean pain scores of women undergoing cervical cancer screening with or without speculum lubrication. METHODS: This was a randomised controlled study of 132 women having cervical cancer screening at a tertiary hospital in Nigeria. Sixty-six participants were randomly assigned to the 'Gel' and 'No Gel' groups, respectively. Pap smears were collected from each participant with a lubricated speculum ('Gel group') or a non-lubricated speculum ('No Gel group'). The primary outcome measures were the proportion of women with unsatisfactory cervical cytology smears and the mean numeric rating scale pain scores, while the secondary outcome measures were the proportion of women who were willing to come for repeat testing and the cytological diagnosis of Pap-smear results. RESULTS: The baseline socio-demographic variables were similar in both groups. There was no significant difference in the proportion of unsatisfactory cervical smear results between the two groups (13.6% vs. 21.2%, p = 0.359). However, the mean pain scores were significantly lower in the gel group than in the no gel group (45.04 vs. 87.96; p<0.001). An equal proportion of the participants in each group (90.9% vs. 90.9%; p > 0.999) were willing to come for repeat cervical smears in the future. CONCLUSION: Speculum lubrication did not affect the adequacy of cervical smears but significantly reduced the pain experienced during pap smear collection. Also, it did not significantly affect the willingness to come for repeat cervical smears in the future. TRIAL REGISTRATION: The trial was registered with the Pan-African Clinical Trial Registry with a unique identification and registration number: PACTR2020077533364675.

Asunto(s)

Detección Precoz del Cáncer , Lubrificación , Prueba de Papanicolaou , Neoplasias del Cuello Uterino , Frotis Vaginal , Humanos , Femenino , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal/métodos , Adulto , Detección Precoz del Cáncer/métodos , Persona de Mediana Edad , Método Doble Ciego , Instrumentos Quirúrgicos

RESUMEN

BACKGROUND AND OBJECTIVE: EVEREST is a phase 3 trial in patients with renal cell cancer (RCC) at intermediate-high or very high risk of recurrence after nephrectomy who were randomized to receive adjuvant everolimus or placebo. Longer recurrence-free survival (RFS) was observed with everolimus (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.72-1.00; p = 0.051), but the nominal significance level (p = 0.044) was not reached. To contextualize these results with positive phase 3 trials of adjuvant sunitinib and pembrolizumab, we conducted a secondary analysis in a similar population of EVEREST patients with very high-risk disease and clear cell histology. METHODS: Postnephrectomy patients with any clear cell component and very high-risk disease, defined as pT3a (grade 3-4), pT3b-c (any grade), T4 (any grade), or node-positive status (N+), were identified. A Cox regression model stratified by performance status was used to compare RFS and overall survival (OS) between the treatment arms. KEY FINDINGS AND LIMITATIONS: Of 1499 patients, 717 had clear cell histology and very high-risk disease; 699 met the eligibility criteria, of whom 348 were randomized to everolimus arm, and 351 to the placebo arm. Patient characteristics were similar between the arms. Only 163/348 (47%) patients in the everolimus arm completed all treatment as planned, versus 225/351 (64%) in the placebo arm. Adjuvant everolimus resulted in a statistically significant improvement in RFS (HR 0.80; 95%CI 0.65-0.99, p = 0.041). Evidence of a survival benefit was not seen (HR 0.85; 95%CI 0.64-1.14, p = 0.3) CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with clear cell RCC at very high-risk for recurrence, adjuvant everolimus resulted in significantly improved RFS compared to placebo but resulted in a high discontinuation rate due to adverse events. Although the treatment HR for OS was consistent with RFS findings, it did not reach statistical significance. With a focus on risk stratification tools and/or biomarkers to minimize toxicity risk in those not likely to benefit, this information can help inform the design of future adjuvant trials in high-risk RCC.

Asunto(s)

Carcinoma de Células Renales , Everolimus , Neoplasias Renales , Nefrectomía , Humanos , Everolimus/uso terapéutico , Everolimus/efectos adversos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Neoplasias Renales/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/cirugía , Neoplasias Renales/mortalidad , Masculino , Femenino , Quimioterapia Adyuvante , Persona de Mediana Edad , Anciano , Antineoplásicos/uso terapéutico , Medición de Riesgo , Estadificación de Neoplasias

RESUMEN

BACKGROUND: Exploring the dynamics of gut microbiome colonisation during early-life stages is important for understanding the potential impact of microbes on host development and fitness. Evidence from model organisms suggests a crucial early-life phase when shifts in gut microbiota can lead to immune dysregulation and reduced host condition. However, our understanding of gut microbiota colonisation in long-lived vertebrates, especially during early development, remains limited. We therefore used a wild population of common buzzard nestlings (Buteo buteo) to investigate connections between the early-life gut microbiota colonisation, environmental and host factors. RESULTS: We targeted both bacterial and eukaryotic microbiota using the 16S and 28S rRNA genes. We sampled the individuals during early developmental stages in a longitudinal design. Our data revealed that age significantly affected microbial diversity and composition. Nest environment was a notable predictor of microbiota composition, with particularly eukaryotic communities differing between habitats occupied by the hosts. Nestling condition and infection with the blood parasite Leucocytozoon predicted microbial community composition. CONCLUSION: Our findings emphasise the importance of studying microbiome dynamics to capture changes occurring during ontogeny. They highlight the role of microbial communities in reflecting host health and the importance of the nest environment for the developing nestling microbiome. Overall, this study contributes to understanding the complex interplay between microbial communities, host factors, and environmental variables, and sheds light on the ecological processes governing gut microbial colonisation during early-life stages.