Miracle-dz/UniFAR-FTUs huggingface dataset:
FMR1 and AKT/mTOR Signaling in Human Granulosa Cells: Functional Interaction and Impact on Ovarian Response

We aimed to determine whether a functional link with impact on female ovarian reserve exists between FMR1 expression and expression ratios of AKT/mTOR signaling genes in human granulosa cells in vivo, as suggested from prior in vitro data. Three hundred and nine women, who were classified as normal (NOR; n = 225) and poor (POR; n = 84) responders based on their ovarian reserve, were recruited during stimulation for assisted reproductive techniques. Expressions of FMR1 and of key genes of the AKT/mTOR and AKT/FOXO1/3 signaling pathways were comparatively analyzed in their granulosa cells. FMR1 expression in granulosa cells of NOR and POR correlated significantly with AKT1, TSC2, mTOR, and S6K expression. No correlation was found between FMR1 and FOXO1 in all, and FOXO3 expression in POR, patients. AKT1 expression was significantly higher and FOXO1 expression lower in POR samples, whereas AKT1 expression was lower and FOXO1 expression was higher in NOR samples. In human native granulosa cells, FMR1 expression significantly correlated with the expression of key genes of the AKT/mTOR signaling pathway, but not with the FOXO1/3 signaling pathway. Our data point to a functional link between FMR1 expression and expression of the AKT/mTOR signaling pathway genes controlling human follicular maturation.
In Vitro and In Vivo Effects of Nobiletin on DRG Neurite Elongation and Axon Growth after Sciatic Nerve Injury

Sciatic nerve injury (SNI) leads to sensory and motor dysfunctions. Nobiletin is a major component of polymethoxylated flavonoid extracted from citrus fruits. The role of nobiletin on sciatic nerve regeneration is still unclear. Thus, the purpose of this study was to investigate whether nobiletin increases DRG neurite elongation and regeneration-related protein expression after SNI. Cytotoxicity of nobiletin was measured in a concentration–dependent manner using the MTT assay. For an in vitro primary cell culture, the sciatic nerve on the middle thigh was crushed by holding twice with forceps. Dorsal root ganglion (DRG) and Schwann cells were cultured 3 days after SNI and harvested 36 h later and 3 days later, respectively. In order to evaluate specific regeneration-related markers and axon growth in the injured sciatic nerve, we applied immunofluorescence staining and Western blot techniques. Nobiletin increased cell viability in human neuroblastoma cells and inhibited cytotoxicity induced by exposure to H2O2. Mean neurite length of DRG neurons was significantly increased in the nobiletin group at a dose of 50 and 100 μM compared to those at other concentrations. GAP-43, a specific marker for axonal regeneration, was enhanced in injury preconditioned Schwann cells with nobiletin treatment and nobiletin significantly upregulated it in injured sciatic nerve at only 3 days post crush (dpc). In addition, nobiletin dramatically facilitated axonal regrowth via activation of the BDNF-ERK1/2 and AKT pathways. These results should provide evidence to distinguish more accurately the biochemical mechanisms regarding nobiletin-activated sciatic nerve regeneration.
Rare sugars: metabolic impacts and mechanisms of action: a scoping review

Abstract Food manufacturers are under increasing pressure to limit the amount of free sugars in their products. Many have reformulated products to replace sucrose, glucose and fructose with alternative sweeteners, but some of these have been associated with additional health concerns. Rare sugars are ‘monosaccharides and their derivatives that hardly exist in nature’, and there is increasing evidence that they could have health benefits. This review aimed to scope the existing literature in order to identify the most commonly researched rare sugars, to ascertain their proposed health benefits, mechanisms of action and potential uses and to highlight knowledge gaps. A process of iterative database searching identified fifty-five relevant articles. The reported effects of rare sugars were noted, along with details of the research methodologies conducted. Our results indicated that the most common rare sugars investigated are d-psicose and d-tagatose, with the potential health benefits divided into three topics: glycaemic control, body composition and CVD. All the rare sugars investigated have the potential to suppress postprandial elevation of blood glucose and improve glycaemic control in both human and animal models. Some animal studies have suggested that certain rare sugars may also improve lipid profiles, alter the gut microbiome and reduce pro-inflammatory cytokine expression. The present review demonstrates that rare sugars could play a role in reducing the development of obesity, type 2 diabetes and/or CVD. However, understanding of the mechanisms by which rare sugars may exert their effects is limited, and their effectiveness when used in reformulated products is unknown.
Postoperative Drip-Infusion of Remifentanil Reduces Postoperative Pain—A Retrospective Observative Study

Development of remifentanil-induced hyperalgesia (RIH) postoperatively is an unpleasant experience that requires further treatment. This study assessed the effects of gradual withdrawal combined with drip infusion of remifentanil on postoperative pain and the requirement for rescue analgesics. A total of 559 patients receiving total intravenous anesthesia with propofol and remifentanil were enrolled. All patients either underwent gradual withdrawal of remifentanil (GWR) or gradual withdrawal combined with drip infusion (GWDR) with a dose of 1 mcg·kg−1 for 30 min after extubation. The numeric rating scale (NRS) and the requirement of rescue analgesics were assessed. The requirement for rescue analgesics was significantly lower in the GWDR group than in the GWR group (13.2% vs. 35.7%; p < 0.001). At the post-anesthetic care unit (PACU), patients in the GWDR group had a lower NRS pain score (p < 0.001). In addition, in the postoperative 2nd hour, patients in the GWDR group had a significantly lower NRS than the GWR group (beta, −0.31; p = 0.003). No remifentanil-related adverse effects were observed. We found that gradual withdrawal combined with drip infusion of remifentanil required less rescue analgesics and reduced pain scores. The new way of remifentanil administration may be effective to prevent RIH.
Unconditioned and learned morphine tolerance influence hippocampal-dependent short-term memory and the subjacent expression of GABA-A receptor alpha subunits

Background ɣ-aminobutyric acid (GABA) facilitator valproic acid may be able to curb memory disruption induced by morphine exposure. Objective The effects of the GABA facilitator valproic acid on the behavioral tolerance induced by morphine were investigated. Then hippocampal-dependent tasks named spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Finally, the changes in the expression of hippocampal GABA-A receptors underlying morphine tolerance were also examined. Methods Rats were treated with daily morphine injections, with or without distinct contextual pairing. To examine the effect of valproic acid on morphine tolerance expression, valproic acid was pretreated an hour before morphine. Spatial-working and short-term memory procedures using the Y-maze apparatus were examined in morphine tolerant rats. Afterwards the changes in the expression of hippocampal GABAα receptors using the quantitative real-time PCR and western blot techniques to detect GABArα subunits mRNAs and protein level were studied. Results Our results showed that both learned and non-associative morphine tolerance influence short-term memory and the subjacent expression of GABArα mRNAs and protein level. Despite its attenuating effects on the development and expression of both learned and non-associative morphine tolerance, only associative morphine tolerance-induced memory dysfunction was ameliorated by valproic acid pretreatment. We also found that the expression of GABArα1, α2, α5 subunits mRNAs and GABAα protein level were affected heavier in associative morphine tolerant rats. Conclusion Our data supports the hypothesis that unconditioned and learned morphine tolerance influences short-term memory and the expression of GABArα 1, α2, α5 mRNAs and GABArα protein level differently, and adds to our understanding of the behavioral and molecular aspects of the learned tolerance to morphine effects.
Mental Health Outcomes in Barcelona: The Interplay between Gentrification and Greenspace

Greenspace is widely related to mental health benefits, but this relationship may vary by social group. Gentrification, as linked to processes of unequal urban development and conflict, potentially impacts health outcomes. This study explores the relationships between greenspace and mental health and between gentrification and mental health associations. It also further examines gentrification as an effect modifier in the greenspace–mental health association and SES as an effect modifier in the gentrification-mental health association. We used cross-sectional Barcelona (Spain) data from 2006, which included perceived mental health status and self-reported depression/anxiety from the Barcelona Health Survey. Greenspace exposure was measured as residential access to (1) all greenspace, (2) greenways and (3) parks in 2006. Census-tract level gentrification was measured using an index including changes in sociodemographic indicators between 1991 and 2006. Logistic regression models revealed that only greenways were associated with better mental health outcomes, with no significant relationship between mental health and parks or all greenspace. Living in gentrifying neighborhoods was protective for depression/anxiety compared to living in non-gentrifying neighborhoods. However, only residents of gentrifiable census tracts benefited from the exposure to greenways. SES was not found to be an effect modifier in the association between gentrification and mental health. Future research should tackle this study’s limitations by incorporating a direct measure of displacement in the gentrification status indicator, accounting for qualitative aspects of greenspace and user’s perceptions. Gentrification may undermine the health benefits provided by greenspace interventions.
Chondrocytes from Osteoarthritis Patients Adopt Distinct Phenotypes in Response to Central TH1/TH2/TH17 Cytokines

Chronic low-grade inflammation plays a central role in the pathogenesis of osteoarthritis (OA), and several pro- and anti-inflammatory cytokines have been implicated to mediate and regulate this process. Out of these cytokines, particularly IFNγ, IL-1β, IL-4 and IL-17 are associated with different phenotypes of T helper (TH) cells and macrophages, both examples of cells known for great phenotypic and functional heterogeneity. Chondrocytes also display various phenotypic changes during the course of arthritis. We set out to study the hypothesis of whether chondrocytes might adopt polarized phenotypes analogous to TH cells and macrophages. We studied the effects of IFNγ, IL-1β, IL-4 and IL-17 on gene expression in OA chondrocytes with RNA-Seq. Chondrocytes were harvested from the cartilage of OA patients undergoing knee replacement surgery and then cultured with or without the cytokines for 24 h. Total RNA was isolated and sequenced, and GO (Gene Ontology) functional analysis was performed. We also separately investigated genes linked to OA in recent genome wide expression analysis (GWEA) studies. The expression of more than 2800 genes was significantly altered in chondrocytes treated with IL-1β [in the C(IL-1β) phenotype] with a fold change (FC) > 2.5 in either direction. These included a large number of genes associated with inflammation, cartilage degradation and attenuation of metabolic signaling. The profile of genes differentially affected by IFNγ (the C(IFNγ) phenotype) was relatively distinct from that of the C(IL-1β) phenotype and included several genes associated with antigen processing and presentation. The IL-17-induced C(IL-17) phenotype was characterized by the induction of a more limited set of proinflammatory factors compared to C(IL-1β) cells. The C(IL-4) phenotype induced by IL-4 displayed a differential expression of a rather small set of genes compared with control, primarily those associated with TGFβ signaling and the regulation of inflammation. In conclusion, our results show that OA chondrocytes can adopt diverse phenotypes partly analogously to TH cells and macrophages. This phenotypic plasticity may play a role in the pathogenesis of arthritis and open new therapeutic avenues for the development of disease-modifying treatments for (osteo)arthritis.
Evaluation of Frailty Syndrome and Adherence to Recommendations in Elderly Patients with Hypertension

Frailty syndrome (FS) often coexists with many diseases of the elderly, including arterial hypertension, and may affect the disease course and adherence to therapeutic recommendations. This study aimed to evaluate the relationship between frailty and adherence to therapeutic recommendations in elderly hypertensive patients. The study included 259 patients hospitalized between January 2019 and November 2020 due to exacerbation of hypertension symptoms. Medical records were used to obtain basic sociodemographic and clinical data. The study was based on the Tilburg Frailty Indicator (TFI) and the Hill–Bone Scale (HBCS). The obtained data were analyzed within a cross-sectional design. The mean frailty score indicated by the TFI questionnaire was 7.09 ± 3.73. The most prominent FS component was associated with the physical domain (4.24 ± 2.54). The mean overall adherence measured with the HBCS was 20.51 ± 3.72. The linear regression model testing the Hill–Bone “reduced sodium intake” score against the TFI domains showed no relationships between the variables. Another regression model for the Hill–Bone “appointment-keeping” subscale indicated significant predictors for physical and social TFI domains (p = 0.002 and p < 0.0001, respectively). For the Hill–Bone “taking antihypertensive drugs” variable, the regression model found significant relationships with all TFI domains: physical (p < 0.0001), psychological (p = 0.003) and social (p < 0.0001). Our study suggests that frailty in patients with arterial hypertension can negatively impact their adherence to therapeutic recommendations.
Sensitivity analyses informed by tests for bias in observational studies

In an observational study, the treatment received and the outcome exhibited may be associated in the absence of an effect caused by the treatment, even after controlling for observed covariates. Two tactics are common: (i) a test for unmeasured bias may be obtained using a secondary outcome for which the effect is known and (ii) a sensitivity analysis may explore the magnitude of unmeasured bias that would need to be present to explain the observed association as something other than an effect caused by the treatment. Can such a test for unmeasured bias inform the sensitivity analysis? If the test for bias does not discover evidence of unmeasured bias, then ask: Are conclusions therefore insensitive to larger unmeasured biases? Conversely, if the test for bias does find evidence of bias, then ask: What does that imply about sensitivity to biases? This problem is formulated in a new way as a convex quadratically constrained quadratic program and solved on a large scale using interior point methods by a modern solver. That is, a convex quadratic function of N variables is minimized subject to constraints on linear and convex quadratic functions of these variables. The quadratic function that is minimized is a statistic for the primary outcome that is a function of the unknown treatment assignment probabilities. The quadratic function that constrains this minimization is a statistic for subsidiary outcome that is also a function of these same unknown treatment assignment probabilities. In effect, the first statistic is minimized over a confidence set for the unknown treatment assignment probabilities supplied by the unaffected outcome. This process avoids the mistake of interpreting the failure to reject a hypothesis as support for the truth of that hypothesis. The method is illustrated by a study of the effects of light daily alcohol consumption on high‐density lipoprotein (HDL) cholesterol levels. In this study, the method quickly optimizes a nonlinear function of N=800$N=800$ variables subject to linear and quadratic constraints. In the example, strong evidence of unmeasured bias is found using the subsidiary outcome, but, perhaps surprisingly, this finding makes the primary comparison insensitive to larger biases.
Validation of the Eating Disorder Examination Questionnaire in Danish Eating Disorder Patients and Athletes

The Eating Disorder Examination Questionnaire (EDE-Q) is a gold standard questionnaire to identify eating disorder symptoms but has not yet been validated in Danish. The scale consists of four theoretical constructs of disordered eating: Restraint eating, Eating concerns, Shape concerns and Weight concerns. However, the four-factor structure has been difficult to replicate across cultures. This study aimed to examine the factor structure and psychometric properties of the EDE-Q in Danish. The study consisted of four samples (aged 15–70): Patients with anorexia, bulimia and unspecified eating disorders (n = 101), patients with symptoms of binge-eating disorder (n = 300), recreational athletes (n = 404), and elite athletes (n = 526). Depending on the analysis performed, participants had to complete the EDE-Q, the SCOFF questionnaire for eating disorders or the Binge Eating Disorders Questionnaire. In accordance with international research, we found no evidence for a four-factor structure in the EDE-Q among patients or among athletes. But our results showed significant, positive associations between EDE-Q and SCOFF, BED-Q and MDI in all samples. We conclude that the internal structure of EDE-Q is low, while construct validity is high, making EDE-Q useful as an instrument to identify individuals with eating disorder symptoms, including recreational, and elite athletes.
Structural analysis of receptors and actin polarity in platelet protrusions

Significance Platelet activation induces reorganization of the cell and the formation of cellular protrusions, pseudopodia. These processes are accompanied by remodeling of the actin cytoskeleton and the activation of platelet integrins, which mediate strong adhesion to the extracellular matrix. In this work, we analyzed the actin polarity and integrin architecture in pseudopodia. A nonuniform polarity of actin filaments in pseudopodia indicates that these protrusions may be involved in contractile acto-myosin forces. Heterogeneity in integrin conformation was found, while solely a bent integrin structure was resolved, ∼50 to 70 nm above the support. During activation the platelet cytoskeleton is reorganized, inducing adhesion to the extracellular matrix and cell spreading. These processes are critical for wound healing and clot formation. Initially, this task relies on the formation of strong cellular–extracellular matrix interactions, exposed in subendothelial lesions. Despite the medical relevance of these processes, there is a lack of high-resolution structural information on the platelet cytoskeleton controlling cell spreading and adhesion. Here, we present in situ structural analysis of membrane receptors and the underlying cytoskeleton in platelet protrusions by applying cryoelectron tomography to intact platelets. We utilized three-dimensional averaging procedures to study receptors at the plasma membrane. Analysis of substrate interaction-free receptors yielded one main structural class resolved to 26 Å, resembling the αIIbβ3 integrin folded conformation. Furthermore, structural analysis of the actin network in pseudopodia indicates a nonuniform polarity of filaments. This organization would allow generation of the contractile forces required for integrin-mediated cell adhesion.
Patient-Reported Outcome Measurements in Temporomandibular Disorders and Headaches: Summary of Measurement Properties and Applicability

Introduction: Several patient-reported outcome measurements (PROMs) are available in the literature to support the evaluation and diagnosis of temporomandibular disorders and headaches. However, clinicians and researchers usually complain that they had no education on PROMs and low overall knowledge about PROMs. Objective: This study aimed to summarize, describing the measurement properties and clinical applicability of the main condition-specific PROMs available in the literature to the assessment of patients with Temporomandibular Disorders and Headaches. Methods: The current manuscript reviewed 10 PROMs commonly used in the field. Four instruments about functioning and disability: 1. Mandibular Function Impairment Questionnaire (MFIQ), 2. Craniofacial Pain and Disability Inventory (CF-PDI), 3. 8-item and 20-item Jaw Functional Limitation Scale (JFLS), and 4. Manchester Orofacial Pain Disability Scale (MOPDS). Two instruments about headache-related disability: 5. Headache-Related Disability Index (HDI) and 6. Headache Impact Test-6 (HIT-6). Three instruments focused on TMD and headache screening: 7. 3Q/TMD, 8. Short-Form Anamnestic Fonseca Index (SFAI), 9. Headache Screening Questionnaire. In addition, one instrument about maladaptive beliefs regarding pain and injury: 10. Tampa Scale for Kinesiophobia for Temporomandibular Disorders (TSK-TMD). Conclusions: The knowledge about the limitations and applicability of the PROMs commonly used to assess TMDs and Headaches can help clinicians and researchers to obtain reliable and valid outcomes to support the decision-making process. The current review recognizes the importance of using patient-reported outcome measures in research and clinical practice. However, our findings call the attention that further studies on the measurement properties of such instruments are imperative.
Addressing Gaps for Health Systems Strengthening: A Public Perspective on Health Systems’ Response towards COVID-19

Strengthening the health systems through gaps identification is necessary to ensure sustainable improvements especially in facing a debilitating outbreak such as COVID-19. This study aims to explore public perspective on health systems’ response towards COVID-19, and to identify gaps for health systems strengthening by leveraging on WHO health systems’ building blocks. A qualitative study was conducted using open-ended questions survey among public followed by in-depth interviews with key informants. Opinions on Malaysia’s health systems response towards COVID-19 were gathered. Data were exported to NVIVO version 12 and analysed using content analysis approach. The study identified various issues on health systems’ response towards COVID-19, which were then mapped into health systems’ building blocks. The study showed the gaps were embedded among complex interactions between the health systems building blocks. The leadership and governance building block had cross-cutting effects, and all building blocks influenced service deliveries. Understanding the complexities in fostering whole-systems strengthening through a holistic measure in facing an outbreak was paramount. Applying systems thinking in addressing gaps could help addressing the complexity at a macro level, including consideration of how an action implicates other building blocks and approaching the governance effort in a more adaptive manner to develop resilient systems.