Miracle-dz/UniFAR-FTUs huggingface dataset:
Intracellular ATP Signaling Contributes to FAM3A-Induced PDX1 Upregulation in Pancreatic Beta Cells

FAM3A is a recently identified mitochondrial protein that stimulates pancreatic-duodenal homeobox 1 (PDX1) and insulin expressions by promoting ATP release in islet β cells. In this study, the role of intracellular ATP in FAM3A-induced PDX1 expression in pancreatic β cells was further examined. Acute FAM3A inhibition using siRNA transfection in mouse pancreatic islets significantly reduced PDX1 expression, impaired insulin secretion, and caused glucose intolerance in normal mice. In vitro , FAM3A overexpression elevated both intracellular and extracellular ATP contents and promoted PDX1 expression and insulin secretion. FAM3A-induced increase in cellular calcium (Ca 2+ ) levels, PDX1 expression, and insulin secretion, while these were significantly repressed by inhibitors of P2 receptors or the L-type Ca 2+ channels. FAM3A-induced PDX1 expression was abolished by a calmodulin inhibitor. Likewise, FAM3A-induced β-cell proliferation was also inhibited by a P2 receptor inhibitor and an L-type Ca 2+ channels inhibitor. Both intracellular and extracellular ATP contributed to FAM3A-induced PDX1 expression, insulin secretion, and proliferation of pancreatic β cells.
Disease activity prediction and prognosis of anti-GBM nephritis based on T lymphocyte subset ratios

Introduction Cell-mediated autoimmunity, especially the autoreactivity of T cells, is known to underlie the initiation of anti-glomerular basement membrane disease. However, the T lymphocyte subsets that determine the disease activity, renal fibrosis, and prognosis of anti-GBM disease have not been clearly elucidated. Methods The T lymphocyte subsets (CD4+ and CD8+) were examined on peripheral blood and renal biopsy tissues from 65 patients with biopsy proven anti-GBM disease. Patients were divided into the high ratio group and low ratio group according to the cutoff values in the receiver operating characteristic curve analysis. The correlations of T lymphocyte subsets with clinical, pathological data, and renal outcome were analyzed. Results By the end of follow-up, 45 patients (69.2%) developed end-stage renal disease (ESRD). In peripheral blood, the CD4+/CD8+ ratio showed a predictive ability with a sensitivity and specificity of 91.3% and 52.9%, respectively, which gave rise to a cutoff value of 0.89. There was a significant difference in the activity index between these two groups (3.91 ± 1.38 vs. 2.89 ± 1.13, p = 0.007). In the renal tissues, the CD4+/CD8+ ratio had the optimal cutoff point of 0.82 with a sensitivity of 57.8% and specificity of 85%. The renal activity index was higher for the renal tissues with high CD4+/CD8+ ratios than that of tissues with low CD4+/CD8+ ratios (4.32 ± 1.55 vs. 3.37 ± 1.41, p = 0.016). Peripheral blood CD4+/CD8+ ratios of ≥0.89 or renal tissue CD4+/CD8+ ratios of < 0.82 positively correlated with poor renal prognosis in patients with anti-GBM nephritis. Conclusions The CD4+/CD8+ ratio was associated with renal activity index both in peripheral blood and renal tissue and predicts the renal prognosis of patients with anti-GBM nephritis.
The Impact of Training on Human–Autonomy Team Communications and Trust Calibration

Objective This work examines two human–autonomy team (HAT) training approaches that target communication and trust calibration to improve team effectiveness under degraded conditions. Background Human–autonomy teaming presents challenges to teamwork, some of which may be addressed through training. Factors vital to HAT performance include communication and calibrated trust. Method Thirty teams of three, including one confederate acting as an autonomous agent, received either entrainment-based coordination training, trust calibration training, or control training before executing a series of missions operating a simulated remotely piloted aircraft. Automation and autonomy failures simulating degraded conditions were injected during missions, and measures of team communication, trust, and task efficiency were collected. Results Teams receiving coordination training had higher communication anticipation ratios, took photos of targets faster, and overcame more autonomy failures. Although autonomy failures were introduced in all conditions, teams receiving the calibration training reported that their overall trust in the agent was more robust over time. However, they did not perform better than the control condition. Conclusions Training based on entrainment of communications, wherein introduction of timely information exchange through one team member has lasting effects throughout the team, was positively associated with improvements in HAT communications and performance under degraded conditions. Training that emphasized the shortcomings of the autonomous agent appeared to calibrate expectations and maintain trust. Applications Team training that includes an autonomous agent that models effective information exchange may positively impact team communication and coordination. Training that emphasizes the limitations of an autonomous agent may help calibrate trust.
MYC Hyperactivates Wnt Signaling in APC/CTNNB1-Mutated Colorectal Cancer Cells through miR-92a–Dependent Repression of DKK3

Activation of Wnt signaling is among the earliest events in colon cancer development. It is achieved either via activating mutations in the CTNNB1 gene encoding β-catenin, the key transcription factor in the Wnt pathway, or most commonly by inactivating mutations affecting APC, a major β-catenin binding partner and negative regulator. However, our analysis of recent Pan Cancer Atlas data revealed that CTNNB1 mutations significantly co-occur with those affecting Wnt receptor complex components (e.g., Frizzled and LRP6), underscoring the importance of additional regulatory events even in the presence of common APC/CTNNB1 mutations. In our effort to identify non-mutational hyperactivating events, we determined that KRAS-transformed murine colonocytes overexpressing direct β-catenin target MYC show significant upregulation of the Wnt signaling pathway and reduced expression of Dickkopf 3 (DKK3), a reported ligand for Wnt co-receptors. We demonstrate that MYC suppresses DKK3 transcription through one of miR-17-92 cluster miRNAs, miR-92a. We further examined the role of DKK3 by overexpression and knockdown and discovered that DKK3 suppresses Wnt signaling in Apc-null murine colonic organoids and human colon cancer cells despite the presence of downstream activating mutations in the Wnt pathway. Conversely, MYC overexpression in the same cell lines resulted in hyperactive Wnt signaling, acquisition of epithelial-to-mesenchymal transition markers, and enhanced migration/invasion in vitro and metastasis in a syngeneic orthotopic mouse colon cancer model. Implications: Our results suggest that the MYC→miR-92a-|DKK3 axis hyperactivates Wnt signaling, forming a feed-forward oncogenic loop. Graphical Abstract
Scheuermann Kyphosis Patients Have a Similar Revision and Infection Rate to Adolescent Idiopathic Scoliosis Patients

Postoperative complication rates (infection and revision) are similar between adolescent idiopathic scoliosis and Scheuermann kyphosis patients in a population matched by age, sex, and levels fused, contrary to previously published research. Study Design. Multicenter retrospective review. Objective. This study aims to address major postoperative complications associated with Scheuermann kyphosis (SK) when compared with adolescent idiopathic scoliosis (AIS) in a large population matched by demographic characteristics, levels fused and operative technique. Summary of Background Data. Prior studies have found that SK patients are 3.86 times more likely to experience major postoperative complications than in AIS. Historically, however, these studies have often had populations that were significantly different between the two groups in terms of disease severity, demographics, and small sample sizes. Methods. AIS patients were compared to SK patients between 2006 and 2018 contemporaneously. All surgeries were conducted by six surgeons among two institutions. Complications and revisions were calculated. A sub-analysis comparing SK and AIS patients by age, sex, and levels-fused in one-to-one matched pairs was performed as well as a sub-analysis matched by levels fused only in one-to-one matched pairs. Results. One thousand three hundred twenty two patients were reviewed (1222 AIS; 100 SK). There were 52 (4.3%) complications in the AIS group compared with 20 (20%) complications in the SK group (P < 0.001), with infections and revisions consisting of the majority of complication rates in both cohorts. When matched by age, sex, and levels fused, there were eight complications in the AIS group and 11 in the SK group (P = 0.63), with infection and revision rates being similar, (P = 0.29) and (P = 0.26) respectively. When matched by levels fused only, EBL, operative time and complication rates remained similar (P > 0.05). Conclusion. Contrary to previously published literature, our analyses indicate that in a matched population, postoperative complication rates (i.e., infection and revision rates) are not significantly different between SK and AIS patients. Level of Evidence: 4
The anger-depression mechanism in dynamic therapy: Experiencing previously avoided anger positively predicts reduction in depression via working alliance and insight.

A central tenet of psychodynamic theory of depression is the role of avoided anger. However empirical research has not yet addressed the question of for which patients and via what pathways experiencing anger in sessions can help. The therapeutic alliance and acquisition of patient insight are important change processes in dynamic therapy and may mediate the anger-depression association. This study was embedded into a randomized trial testing the efficacy of Intensive Short-Term Dynamic Psychotherapy (ISTDP) for treatment resistant depression. In-session patient affect experiencing (AE) was coded for every available session (475/481) by blinded observers in 27 patients randomized to ISTDP. Dynamic Structural Equation Modeling was used to examine within-person associations between variation in depression scores session-by-session and both patient ratings (alliance) and observer ratings (AE and insight) of the treatment process. Alliance and insight were independent mediators of the effect of anger on next-session depression. However, the relative importance of these two indirect effects of anger on depression was conditional on pretreatment patient personality pathology (PP). In patients with higher PP, in-session anger was negatively related to depressive symptoms next session, with this effect operating through higher alliance. In patients with low PP, in-session anger was negatively related to depressive symptoms next session, with this effect operating through enhanced patient insight. These findings highlight an anger-depression mechanism of change in dynamic therapy. Depending upon patient personality, either an "insight pathway" or a "relational pathway" may promote the effectiveness of facilitating arousal and expression of patients' in-session feelings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Relevance of organ(s)-on-a-chip systems to the investigation of food-gut microbiota-host interactions

Abstract The ever greater understanding of the composition and function of the gut microbiome has provided new opportunities with respect to understanding and treating human disease. However, the models employed for in vitro and in vivo animal studies do not always provide the required insights. As a result, one such alternative in vitro cell culture based system, organ-on-a-chip technology, has recently attracted attention as a means of obtaining data that is representative of responses in humans. Organ-on-a-chip systems are designed to mimic the interactions of different tissue elements that were missing from traditional two-dimensional tissue culture. While they do not traditionally include a microbiota component, organ-on-a-chip systems provide a potentially valuable means of characterising the interactions between the microbiome and human tissues with a view to providing even greater accuracy. From a dietary perspective, these microbiota-organ-on-a-chip combinations can help researchers to predict how the consumption of specific foods and ingredients can impact on human health and disease. We provide an overview of the relevance and interactions of the gut microbiota and the diet in human health, we summarise the components involved in the organ-on-a-chip systems, how these systems have been employed for microbiota based studies and their potential relevance to study the interplay between food-gut microbiota-host interactions.
Woman With Ptosis.

An 87-year-old woman, with a medical history of type 2 diabetes mellitus, hypertension, and dementia, reported right ptosis and ophthalmoplegia for 6 days. On arrival at the emergency department (ED), the patient was alert and oriented without acute distress. Her body temperature was 35.7°C, her heart rate was 82 beats/min, her respiratory rate was 16 breaths/min, and her blood pressure was 147/66 mm Hg. Tracing back her history, the patient had chronic nasal congestion for 1 year. There was no fever and no headache. Neurological examination showed paralysis of the right oculomotor nerve, presenting with right eye ptosis, mydriasis, and outer-down position. The blood laboratory results were unremarkable. Cranial computed tomography (CT) revealed a heterogeneous mass with calcifi cations in the right maxillary and left sphenoid sinuses with bony erosion (Fig. 1). Subsequently, contrast-enhanced magnetic resonance imaging (MRI) was performed, which showed a hypointense lesion with peripheral enhancement over the left sphenoid, right maxillary, right ethmoid sinuses, and compression of the right inferior rectus muscle (Fig. 2). After surgical debridement was performed, the pathology report of the specimen revealed aspergillosis. Antibiotics were discontinued and anti-fungal agents were started. Afrer 1 month after the initial treatment passed, she was able to the right eye halfway.
Bdellovibrio and like organisms: current understanding and knowledge gaps of the smallest cellular hunters of the microbial world

Abstract Almost sixty years ago, Bdellovibrio and like organisms (BALOs) were discovered as the first obligate bacterial predators of other bacteria known to science. Since then, they were shown to be diverse and ubiquitous in the environment, and to bear astonishing ecological, physiological, and metabolic capabilities. The last decade has seen important strides made in understanding the mechanistic basis of their life cycle, the dynamics of their interactions with prey, along with significant developments towards their use in medicine, agriculture, and industry. This review details these achievements, identify current understanding and knowledge gaps to encourage and guide future BALO research.
Ganglioside GD2: a novel therapeutic target in triple‐negative breast cancer

Triple‐negative breast cancer (TNBC) is a heterogeneous disease characterized by lack of hormone receptor expression and is known for high rates of recurrence, distant metastases, and poor clinical outcomes. TNBC cells lack targetable receptors; hence, there is an urgent need for targetable markers for the disease. Breast cancer stem‐like cells (BCSCs) are a fraction of cells in primary tumors that are associated with tumorigenesis, metastasis, and resistance to chemotherapy. Targeting BCSCs is thus an effective strategy for preventing cancer metastatic spread and sensitizing tumors to chemotherapy. The CD44hiCD24lo phenotype is a well‐established phenotype for identification of BCSCs, but CD44 and CD24 are not targetable markers owing to their expression in normal tissues. The ganglioside GD2 has been shown to be upregulated in primary TNBC tumors compared with normal breast tissue and has been shown to identify BCSCs. In this review, we discuss GD2 as a BCSC‐ and tumor‐specific marker in TNBC; epithelial‐to‐mesenchymal transition and the signaling pathways that are upstream and downstream of GD2 and the role of these pathways in tumorigenesis and metastasis in TNBC; direct and indirect approaches for targeting GD2; and ongoing clinical trials and treatments directed against GD2 as well as future directions for these strategies.
Distribution of gold nanoparticles into the brain: a systematic review and meta-analysis

Abstract Despite the widespread use of gold nanoparticles (GNPs), there is no consensus on their distribution to different tissues and organs. The present systematic review and meta-analysis addresses the accumulation of GNPs in brain tissue. Extensive searches were conducted in electronic databases, Medline, Web of Science, EMBASE, and Scopus. Based on inclusion and exclusion criteria, primary and secondary screening was performed. The value of brain accumulation of gold nanoparticle (the percentage of the injection dose of GNPs/gram of brain tissue that applied as effect size (ES) in analysis) and the standard error of the mean were extracted from articles and analyzed by calculating the pooled ES and the pooled confidence interval (CI) using STATA software. p ≤ 0.05 was considered significant. Thirty-eight studies were included in the meta-analysis. The results showed that the amount of GNPs was 0.06% of the injection dose/gram of brain tissue (ES = 0.06, %95 CI: 0.06–0.06, p < 0.0001). Considering the time between injection and tissue harvest (follow-up time), after 1 h the GNPs in brain tissue was 0.288% of the injection dose/gram of tissue (ES = 0.29, 95% CI: 0.25–0.33, p < 0.0001), while after four weeks it was only 0.02% (ES = 0.02, 95% CI: 0.01–0.03, p < 0.0001) of the injection dose/gram of tissue. The amount of GNPs in brain tissue was higher for PEG-coated GNPs compared to uncoated GNPs, and it was 5.6 times higher for rod-shaped GNPs compared to spherical GNPs. The mean amount of GNPs in the brain tissues of animals bearing a tumor was 5.8 times higher than in normal animals.
Robotic-arm assisted THA can achieve precise cup positioning in developmental dysplasia of the hip

Aims This study aimed to evaluate the accuracy of implant placement with robotic-arm assisted total hip arthroplasty (THA) in patients with developmental dysplasia of the hip (DDH). Methods The study analyzed a consecutive series of 69 patients who underwent robotic-arm assisted THA between September 2018 and December 2019. Of these, 30 patients had DDH and were classified according to the Crowe type. Acetabular component alignment and 3D positions were measured using pre- and postoperative CT data. The absolute differences of cup alignment and 3D position were compared between DDH and non-DDH patients. Moreover, these differences were analyzed in relation to the severity of DDH. The discrepancy of leg length and combined offset compared with contralateral hip were measured. Results The mean values of absolute differences (postoperative CT-preoperative plan) were 1.7° (standard deviation (SD) 2.0) (inclination) and 2.5° (SD 2.1°) (anteversion) in DDH patients, and no significant differences were found between non-DDH and DDH patients. The mean absolute differences for 3D cup position were 1.1 mm (SD 1.0) (coronal plane) and 1.2 mm (SD 2.1) (axial plane) in DDH patients, and no significant differences were found between two groups. No significant difference was found either in cup alignment between postoperative CT and navigation record after cup screws or in the severity of DDH. Excellent restoration of leg length and combined offset were achieved in both groups. Conclusion We demonstrated that robotic-assisted THA may achieve precise cup positioning in DDH patients, and may be useful in those with severe DDH. Cite this article: Bone Joint Res 2021;10(10):629–638.
MTH1 Inhibitor TH1579 Induces Oxidative DNA Damage and Mitotic Arrest in Acute Myeloid Leukemia

The MTH1 inhibitor TH1579 is a potential novel AML treatment, targeting both blasts and the pivotal leukemic stem cells while sparing normal bone marrow cells. Acute myeloid leukemia (AML) is an aggressive hematologic malignancy, exhibiting high levels of reactive oxygen species (ROS). ROS levels have been suggested to drive leukemogenesis and is thus a potential novel target for treating AML. MTH1 prevents incorporation of oxidized nucleotides into the DNA to maintain genome integrity and is upregulated in many cancers. Here we demonstrate that hematologic cancers are highly sensitive to MTH1 inhibitor TH1579 (karonudib). A functional precision medicine ex vivo screen in primary AML bone marrow samples demonstrated a broad response profile of TH1579, independent of the genomic alteration of AML, resembling the response profile of the standard-of-care treatments cytarabine and doxorubicin. Furthermore, TH1579 killed primary human AML blast cells (CD45+) as well as chemotherapy resistance leukemic stem cells (CD45+Lin−CD34+CD38−), which are often responsible for AML progression. TH1579 killed AML cells by causing mitotic arrest, elevating intracellular ROS levels, and enhancing oxidative DNA damage. TH1579 showed a significant therapeutic window, was well tolerated in animals, and could be combined with standard-of-care treatments to further improve efficacy. TH1579 significantly improved survival in two different AML disease models in vivo. In conclusion, the preclinical data presented here support that TH1579 is a promising novel anticancer agent for AML, providing a rationale to investigate the clinical usefulness of TH1579 in AML in an ongoing clinical phase I trial. Significance: The MTH1 inhibitor TH1579 is a potential novel AML treatment, targeting both blasts and the pivotal leukemic stem cells while sparing normal bone marrow cells.
Functional Luminal Imaging Probe in the Management of Pediatric Esophageal Disorders

ABSTRACT Background: Functional luminal imaging probe (FLIP) measures pressure–geometry relationships of digestive luminal space. When used in esophageal disorders, it provides several luminal parameters that help better understand the pathophysiology. Data about the potential utility of FLIP in pediatrics are scarce and there is no standardized use in children. We aim to describe the use of FLIP in our center, its safety, feasibility, and clinical impact in esophageal disorders in children. Methods: Consecutive FLIP recordings performed at the Centre Hospitalier Universitaire-Sainte-Justine, Montréal, Canada between February 2018 and January 2021 were extracted. A chart review was conducted for demographics and medical history. Symptomatology after the procedure was evaluated with validated dysphagia scores. Key Results: Nineteen patients were included (11 girls, median age 16 years, range 3.2–19.6) with achalasia (n = 5), post-Heller's myotomy dysphagia (n = 3), esophagogastric junction outflow obstruction (n = 3), congenital esophageal stenosis (n = 2); post-esophageal atresia repair stricture (n = 3), and post-fundoplication dysphagia (n = 3). There was no significant correlation between integrated relaxation pressure measured with high resolution manometry and distensibility index (DI). The use of FLIP made it possible to differentiate between dysphagia related to an esophageal obstruction (DI < 2.8 mm2/mmHg) and dysphagia without major motility disorder (DI > 2.8 mm2/mmHg) that guided the indication for dilation. FLIP led to a change in management in 47% of the patients. Forty-seven percent of the patients were symptom free at the time of the evaluation. Conclusions & Inferences: FLIP provides key esophageal luminal values and therefore can play an important role in pediatric esophageal disorders management.