Miracle-dz/UniFAR-FTUs huggingface dataset:
Psychosocial Factors Affecting the Association between a Healthy Lifestyle Behavior Intervention and Depressive Symptoms in Low-Income Overweight or Obese Mothers with Young Children: A Mediational Analysis

Background: Depressive symptoms are particularly prevalent among low-income overweight or obese mothers with young children, indicating the importance of understanding and addressing this serious health condition. Although lifestyle behavior interventions are promising for alleviating depressive symptoms in low-income overweight or obese mothers with young children, mechanisms underlying the association between these interventions and depressive symptoms in this priority population remain unknown. Objective: A secondary analysis of data from a randomized controlled trial that tested a 16-week community-based lifestyle behavior intervention for low-income overweight or obese mothers with young children was conducted to examine whether autonomous motivation, coping self-efficacy, and emotional coping mediated the association between the intervention and depressive symptoms. Methods: The analysis included 338 participants who completed data collection at baseline and immediately after the intervention. Participants responded to validated surveys measuring autonomous motivation, coping self-efficacy, emotional coping, and depressive symptoms. To test mediation effects, composite indicator structural equation modeling was performed adjusting for baseline measures. The proportion of maximum possible (POMP) scores in the outcome variable per unit change in the predictor variables was used to calculate effect size. Results: The intervention alleviated depressive symptoms (B = −2.42, p = 0.015, POMP = −4.31%), and coping self-efficacy negatively and fully mediated the association between the intervention and depressive symptoms (B = −1.42, p = 0.002, POMP = −2.53%). Autonomous motivation and emotional coping were not significant mediators. Conclusions: Interventions aimed to alleviate depressive symptoms in low-income overweight or obese mothers with young children should include strategies to improve coping self-efficacy. However, continued research is needed to identify other mechanisms that may be contributing to the effect of lifestyle behavior interventions on depressive symptoms in this at-risk group. This information can then be used to simplify and strengthen the interventions and potentially lead to effective dissemination and implementation.
Examining the reliability and validity of two versions of the Effort-Expenditure for Rewards Task (EEfRT)

The Effort-Expenditure for Rewards Task (EEfRT) has gained validity evidence from several studies. However, various modifications have been applied to the original version, which have never been compared systematically. In Study 1, we tested 120 healthy participants to directly compare two versions of the EEfRT. In Study 2, we tested a larger sample of 394 healthy participants to further examine the original EEfRT. We replicated the split-half reliability of both task versions. However, self-reported personality traits (e.g., trait BAS) correlated with only some task performance parameters in Study 1, which did not replicate for the original EEfRT in Study 2. Our results indicate complex and sometimes inconsistent relations between different personality traits, task properties, and reward attributes.
The Community as the Unit of Healing: Conceptualizing Social Determinants of Health and Well-Being for Older American Indian Adults

Abstract Background and Objectives Multiple racial and social inequities shape health and access to health care for American Indian Elders, who have a lower life expectancy than all other aging populations in the United States. This qualitative study examines how upstream social determinants of health influence Elders’ ability to access and use health care. Research Design and Methods Between June 2016 and March 2017, we conducted individual, semistructured interviews with 96 American Indian Elders, aged 55 and older, and 47 professionals involved in planning or delivering care to Elders in 2 states in the U.S. Southwest. Transcripts were analyzed iteratively using grounded theory approaches, including open and focused coding. A group of American Indian Elders and allies called the Seasons of Care Community Action Board guided interpretation and prioritization of findings. Results Participants described multiple barriers that hindered Elders’ ability to access health care services and providers, which were largely tied to funding shortages and bureaucratic complexities associated with health care and insurance systems. Where available, community resources bridged service gaps and helped Elders navigate systems. Discussion and Implications Longstanding structural inequities for American Indians manifest in barriers to health equity, many of which are situated at the community level. These are compounded by additional disparities affecting older adults, rural residents, and marginalized citizens in general. Findings underscore the importance of health and policy initiatives for American Indian Elders that emphasize the community as the focus of intervention.
Obesity and Cerebral Blood Flow in the Reward Circuitry of Youth With Bipolar Disorder

Abstract Background Bipolar disorder (BD) is associated with elevated body mass index (BMI) and increased rates of obesity. Obesity among individuals with BD is associated with more severe course of illness. Motivated by previous research on BD and BMI in youth as well as brain findings in the reward circuit, the current study investigates differences in cerebral blood flow (CBF) in youth BD with and without comorbid overweight/obesity (OW/OB). Methods Participants consisted of youth, ages 13–20 years, including BD with OW/OB (BDOW/OB; n = 25), BD with normal weight (BDNW; n = 55), and normal-weight healthy controls (HC; n = 61). High-resolution T1-weighted and pseudo-continuous arterial spin labeling images were acquired using 3 Tesla magnetic resonance imaging. CBF differences were assessed using both region of interest and whole-brain voxel-wise approaches. Results Voxel-wise analysis revealed significantly higher CBF in reward-associated regions in the BDNW group relative to the HC and BDOW/OB groups. CBF did not differ between the HC and BDOW/OB groups. There were no significant region of interest findings. Conclusions The current study identified distinct CBF levels relating to BMI in BD in the reward circuit, which may relate to underlying differences in cerebral metabolism, compensatory effects, and/or BD severity. Future neuroimaging studies are warranted to examine for changes in the CBF-OW/OB link over time and in relation to treatment.
Genome‐wide sequence data show no evidence of hybridization and introgression among pollinator wasps associated with a community of Panamanian strangler figs

The specificity of pollinator host choice influences opportunities for reproductive isolation in their host plants. Similarly, host plants can influence opportunities for reproductive isolation in their pollinators. For example, in the fig and fig wasp mutualism, offspring of fig pollinator wasps mate inside the inflorescence that the mothers pollinate. Although often host specific, multiple fig pollinator species are sometimes associated with the same fig species, potentially enabling hybridization between wasp species. Here, we study the 19 pollinator species (Pegoscapus spp.) associated with an entire community of 16 Panamanian strangler fig species (Ficus subgenus Urostigma, section Americanae) to determine whether the previously documented history of pollinator host switching and current host sharing predicts genetic admixture among the pollinator species, as has been observed in their host figs. Specifically, we use genome‐wide ultraconserved element (UCE) loci to estimate phylogenetic relationships and test for hybridization and introgression among the pollinator species. In all cases, we recover well‐delimited pollinator species that contain high interspecific divergence. Even among pairs of pollinator species that currently reproduce within syconia of shared host fig species, we found no evidence of hybridization or introgression. This is in contrast to their host figs, where hybridization and introgression have been detected within this community, and more generally, within figs worldwide. Consistent with general patterns recovered among other obligate pollination mutualisms (e.g. yucca moths and yuccas), our results suggest that while hybridization and introgression are processes operating within the host plants, these processes are relatively unimportant within their associated insect pollinators.
Phase I clinical trial of DNA methyltransferase inhibitor decitabine and PARP inhibitor talazoparib combination therapy in relapsed/refractory acute myeloid leukemia.

PURPOSE Acute myeloid leukemia (AML) patients unfit for, or resistant to, intensive chemotherapy are often treated with DNA methyltransferase inhibitors (DNMTis). Novel combinations may increase efficacy. In addition to demethylating CpG island gene promoter regions, DNMTis enhance poly (ADP-ribose) polymerase (PARP1) recruitment and tight binding to chromatin, preventing PARP-mediated DNA repair, downregulating homologous recombination (HR) DNA repair and sensitizing cells to PARP inhibitor (PARPi). We previously demonstrated DNMTi and PARPi combination efficacy in AML in vitro and in vivo Here we report a phase I clinical trial combining the DNMTi decitabine and the PARPi talazoparib in refractory/relapsed AML. EXPERIMENTAL DESIGN Decitabine and talazoparib doses were escalated using a 3 + 3 design. Pharmacodynamic studies were performed on Cycle 1 Days 1 (pre-treatment), 5 and 8 blood blasts. RESULTS Doses were escalated in seven cohorts [25 patients, including 22 previously treated with DNMTi(s)] to a recommended phase II dose combination of decitabine 20 mg/m2 intravenously daily for 5 or 10 days and talazoparib 1 mg orally daily for 28 days, in 28-day cycles. Grade 3-5 events included fever in 19 and lung infections in 15, attributed to AML. Responses included complete remission with incomplete count recovery in two patients (8%) hematologic improvement in three. Pharmacodynamic studies showed the expected DNA demethylation, increased PARP trapping in chromatin, increased gH2AX foci and decreased HR activity in responders. gH2AX foci increased significantly with increasing talazoparib doses combined with 20 mg/m2 decitabine. CONCLUSIONS Decitabine/talazoparib combination was well tolerated. Expected pharmacodynamic effects occurred, especially in responders.
With Fearful Eyes: Exploring Relatives' Experiences With Out-of-Hospital Cardiac Arrest

Background Out-of-hospital cardiac arrest (OHCA) imposes significant consequences for a family, but little is known about relatives' experiences. Objective Our aim was to explore relatives' experiences with the OHCA and the following months after. Method A qualitative approach using phenomenological-hermeneutic methodology was applied. Data consisted of semistructured interviews with 12 relatives of OHCA survivors. We analyzed data based on Paul Ricoeur's theory of interpretation. Results Relatives experienced OHCA as an abrupt and stressful event filled with imposing concerns for the cardiac arrest survivor. Relatives were fellow sufferers confronted with the possibility of bereavement, watching from the sideline with fearful eyes. After the OHCA, relatives experienced a troubled time with anxiety and edginess, monitoring the survivor for signs of a new cardiac arrest and trying to adapt to a new normality. Relatives' previous identities and positions within their families were disrupted. Conclusion Relatives were challenged with the OHCA and the trajectory after it, experiencing a high level of distress and anxiety. Relatives took on an immense responsibility, always watching the survivor for potential symptoms of a new cardiac arrest. The cardiac arrest and the survivor's possible cognitive impairments gave rise to assuming a new authority as a relative. We advocate for a new family approach to relatives, acknowledging relatives' stress and central role in supporting cardiac arrest survivors.
Reanalysis of a novel variant in the IGF1R gene in a family with variable prenatal and postnatal growth retardation and dysmorphic features: benefits and feasibility of IUSM–URDC (Undiagnosed Rare Disease Clinic) program

IGF1R-related disorders are associated with intrauterine growth restriction (IUGR), postnatal growth failure, short stature, microcephaly, developmental delay, and dysmorphic facial features. We report a patient who presented to medical genetics at 7 mo of age with a history of IUGR, poor feeding, mild developmental delays, microcephaly, and dysmorphic facial features. Whole-exome sequencing revealed a novel c.1464T > G p.(Cys488Trp) variant in the IGF1R gene, initially classified as a variation of uncertain significance (VUS). We enrolled the patient in the URDC (Undiagnosed Rare Disease Clinic) and performed additional studies including deep phenotyping and familial segregation analysis, which demonstrated that the patient's IGF1R VUS was present in phenotypically similar family members. Furthermore, biochemical testing revealed an elevated serum IGF-1 level consistent with abnormal IGF-1 receptor function. Workup resulted in the patient's variant being upgraded from a VUS to likely pathogenic. Our report expands the variant and phenotypic spectrum of IGF1R-related disorders and illustrates benefits and feasibility of reassessing a VUS beyond the initial molecular diagnosis by deep phenotyping, 3D modeling, additional biochemical testing, and familial segregation studies through the URDC, a multidisciplinary clinical program whose major goal is to end the diagnostic odyssey in patients with rare diseases.
Enhanced autophagy alleviated corneal allograft rejection via inhibiting NLRP3 inflammasome activity

Autophagy has been reported to be involved in many aspects of innate and adaptive immunity. Manipulating autophagy is recognized as a promising therapeutic approach for treating immunological diseases, including allograft rejection, and graft‐versus‐host disease. However, whether autophagy was closely associated with the pathogenesis of corneal allograft rejection remains largely unknown. Here, we showed that rapamycin (RAPA)‐induced autophagy alleviated corneal allograft rejection. By contrast, blocking autophagic activity using 3‐methyladeine (3‐MA) aggravated corneal transplantation rejection. Mechanistically, we revealed that the enhanced autophagic turnover by RAPA inhibited NLRP3 inflammasome activity through NLRP3 degradation. While blocking the fusion of autophagosomes with lysosomes by bafilomycin A1(BafA1), the reduced NLRP3 inflammasome activity induced by RAPA was significantly restored, with increased protein levels of NLRP3 and cleaved Casp‐1(p10), as well as IL‐1β secretion. Moreover, we further revealed that pharmacologically blocking NLRP3 inflammasome signaling prolonged the survival of corneal allografts. Taken together, these findings underscored the critical roles of enhanced autophagy in treating corneal allograft rejection, which provided an alternative intervention strategy to control corneal transplantation rejection.
TP53 and EGFR Mutational Status in Thymoma: A Genetic Sequencing Study

Background and objective: Thymoma is a rare malignant tumor that usually with an indolent presentation, which was falsely assumed to be benign previously. The tumor suppressor P53 (TP53) and EGFR gene mutate most frequently in human cancers. We tried to investigate the presence of TP53 and EGFR mutations among thymoma patients referred to an Indonesian referral respiratory hospital and to discuss its potential role in thymoma management and prognosis. Material and methods: Surgically resected tumor tissues were collected from thymoma patients and then underwent genomic analysis. PCR was performed on the extracted Paraffinized DNA to amplify exon 6 of TP53 and exons 18, 19, and 21 of EGFR. The evaluation of mutational status was done using direct sequencing and sequence analysis of purified PCR products. Results: Among 27 collected samples, TP53 exon 6 mutation, namely missense mutation and nonsense mutation, was observed in two samples (7.4%). EGFR exon 18 mutation, namely E709K and nonsense mutation, was found in 2 samples (7.4%). An intronic mutation in EGFR exon 19 (3.7%) and exon 21 (3.7%) was observed in one sample. Conclusion: TP53 and EGFR mutations were not most frequent, so it seems that these genes are not involved in the pathogenesis of thymoma in Indonesian patients. Nevertheless, we found two samples with a significant mutation in p53 and EGFR genes, suggesting further research on thymoma prognostification and targeted therapy.
Evaluation of the potential impact of pharmacist interventions : development and validation of the CLEO multidimensional tool

In times of limited resources allocation, it is necessary for pharmacists to justify the added value of their pharmacist interventions (PIs) made during medication review (MR). The purpose of this thesis work is to research on methodologies of evaluation of value of PIs as well as development and validation of a new tool for assessing potential impacts of PIs. The work consists of 3 major parties: (i) context in which MR locates, characteristics of practice of MR, and methodologies of evaluation of impacts of PIs, (ii) systematic review of tools for assessing the potential significance of PIs in literature , (iii) process of development and validation of the new multidimensional tool - named CLEO for assessing potential impacts of PIs. The whole results of this research are useful to evaluate and demonstrate the value of PIs in efforts to expand clinical pharmacy services.
Mu Opioid Receptors Acutely Regulate Adenosine Signaling in Striatal Glutamate Afferents

Endogenous adenosine plays a crucial role in maintaining energy homeostasis, and adenosine levels are tightly regulated across neural circuits. In the dorsal medial striatum (DMS), adenosine inhibits neurotransmitter release, but the source and mechanism underlying its accumulation are largely unknown. Opioids also inhibit neurotransmitter release in the DMS and influence adenosine accumulation after prolonged exposure. However, how these two neurotransmitter systems interact acutely is also largely unknown. This study demonstrates that activation of µ opioid receptors, but not δ opioid receptors or κ opioid receptors, inhibits tonic activation of adenosine A1Rs via a cAMP-dependent mechanism in both male and female mice. Further, selectively knocking out µ opioid receptors from thalamic presynaptic terminals and postsynaptic medium spiny neurons (MSNs) revealed that activation of µ opioid receptors on D1R-positive MSNs, but not D2R-positive MSNs, is necessary to inhibit tonic adenosine signaling on presynaptic terminals. Given the role of D1R-positive MSNs in movement and motivated behaviors, these findings reveal a novel mechanism by which these neurons regulate their own synaptic inputs. SIGNIFICANCE STATEMENT Understanding interactions between neuromodulatory systems within brain circuits is a fundamental question in neuroscience. The present work uncovers a novel role of opioids in acutely inhibiting adenosine accumulation and subsequent adenosine receptor signaling in the striatum by inhibiting the production of cAMP. Adenosine receptor signaling regulates striatal neurotransmitters, including glutamate, GABA, dopamine, and acetylcholine. Furthermore, interactions between adenosine2A receptors and numerous other GPCRs, including D2 dopamine and CB1 cannabinoid receptors, suggest that endogenous adenosine broadly modulates striatal GPCR signaling. Additionally, this work discovered that the source of resting endogenous extracellular adenosine is likely D1, but not D2 receptor-positive medium spiny neurons, suggesting that opioid signaling and manipulation of D1R-expressing medium spiny neuron cAMP activity can broadly affect striatal function and behavior.
Disrupting the adult-globin promoter alleviates promoter competition and reactivates foetal-globin gene expression.

The benign condition Hereditary Persistence of Foetal Haemoglobin (HPFH) is known to ameliorate symptoms when co-inherited with b-haemoglobinopathies, such as sickle cell disease and b-thalassaemia. The condition is sometimes associated with point mutations in the foetal globin promoters that disrupt the binding of the repressors BCL11A or ZBTB7A/LRF, which have been extensively studied. HPFH is also associated with a range of deletions within the b-globin locus that all reside downstream of the foetal HBG2 gene. These deletional forms of HPFH are poorly understood and are the focus of this study. Numerous different mechanisms have been proposed to explain how downstream deletions can boost the expression of the foetal globin genes, including the deletion of silencer elements, of genes encoding non-coding RNA, and bringing downstream enhancer elements into proximity with the foetal globin gene promoters. Here we systematically analyse the deletions associated with both HPFH and a related condition known as db-thalassaemia and propose a unifying mechanism. In all cases where foetal globin is up-regulated, the proximal adult b-globin (HBB) promoter is deleted. We use CRISPR gene editing to delete or disrupt elements within the promoter and find that virtually all mutations that reduce HBB promoter activity, result in elevated foetal globin expression. These results fit with previous models where the foetal and adult globin genes compete for the distal Locus Control Region and suggest that targeting the HBB promoter might be explored to elevate foetal globin and reduce sickle globin expression as a treatment for b-haemoglobinopathies.
Metabolomic and Transcriptomic Signatures of Chemogenetic Heart Failure.

The failing heart is characterized by elevated levels of reactive oxygen species. We have developed an animal model of heart failure induced by chemogenetic production of oxidative stress in the heart using a recombinant adeno-associated virus (AAV9) expressing yeast D-amino acid oxidase (DAAO) targeted to cardiac myocytes. When DAAO-infected animals are fed the DAAO substrate D-alanine, the enzyme generates hydrogen peroxide (H2O2) in the cardiac myocytes, leading to dilated cardiomyopathy. However, the underyling mechanisms of oxidative stress induced heart failure remain incompletely understood. Therefore, we investigated the effects of chronic oxidative stress on the cardiac transcriptome and metabolome. Rats infected with recombinant cardiotropic AAV9 expressing DAAO or control AAV9 were treated for 7 weeks with D-alanine to stimulate chemogenetic H2O2 production by DAAO and generate dilated cardiomyopathy. After hemodynamic assessment, left and right ventricular tissues were processed for RNA sequencing and metabolomic profiling. DAAO induced dilated cardiomyopathy was characterized by marked changes in the cardiac transcriptome and metabolome both in the left and right ventricle. Downregulated transcripts related to energy metabolism and mitochondrial function, accompanied by striking alterations in metabolites involved in cardiac energetics redox homeostasis, and amino acid metabolism. Upregulated transcripts involved cytoskeletal organization and extracellular matrix. Finally, we noted increased metabolite levels of antioxidants glutathione and ascorbate. These findings provide evidence that chemogenetic generation of oxidative stress leads to a robust heart failure model with distinct transcriptomic and metabolomic signatures and set the basis for understanding the underlining pathophysiology of chronic oxidative stress in the heart.