Miracle-dz/UniFAR-FTUs huggingface dataset:
Alteration in the expression of the renin-angiotensin system in the myocardium of mice conceived by in vitro fertilization†

Abstract Epidemiological studies have revealed that offspring conceived by in vitro fertilization (IVF) have an elevated risk of cardiovascular malformations at birth, and are more predisposed to cardiovascular diseases. The renin-angiotensin system (RAS) plays an essential role in both the pathogenesis of congenital heart disease in fetuses and cardiovascular dysfunction in adults. This study aimed to assess the relative expression levels of genes in the RAS pathway in mice conceived using IVF, compared to natural mating with superovulation. Results demonstrated that expression of the angiotensin II receptor type 1 (AGTR1), connective tissue growth factor (CTGF), and collagen 3 (COL3), in the myocardial tissue of IVF-conceived mice, was elevated at 3 weeks, 10 weeks, and 1.5 years of age, when compared to their non-IVF counterparts. These data were supported by microRNA microarray analysis of the myocardial tissue of aged IVF-conceived mice, where miR-100, miR-297, and miR-758, which interact with COL3, AGTR1, and COL1 respectively, were upregulated when compared to naturally mated mice of the same age. Interestingly, bisulfite sequencing data indicated that IVF-conceived mice exhibited decreased methylation of CpG sites in Col1. In support of our in vivo investigations, miR-297 overexpression was shown to upregulate AGTR1 and CTGF and increased cell proliferation in cultured H9c2 cardiomyocytes. These findings indicate that the altered expression of RAS in myocardial tissue might contribute to cardiovascular malformation and/or dysfunction in IVF-conceived offspring. Furthermore, these cardiovascular abnormalities might be the result of altered DNA methylation and abnormal regulation of microRNAs. Summary Sentence Altered expression of the renin-angiotensin system in myocardial tissue might contribute to an increased risk of cardiovascular malformations and dysfunction in IVF offspring, and is involved in abnormal regulations of DNA methylation and microRNAs.
Cortisol and behavioral reaction of low and high sensation seekers differ in responding to a sport-specific stressor

ABSTRACT Background/objectives: Sensation seeking is closely related to practicing high-risk sports. This domain offers individuals an opportunity to achieve an increased level of arousal. Moreover, stress reactivity implies interindividual differences in the capacity to respond to a stressor. The purpose of this study was to examine whether high sensation seekers (HSS) compared to low sensation seekers (LSS) experience lower levels of stress on a physiological and psychological basis. Stress was induced in a sport-specific experimental paradigm with a climbing task through a jump into the rope. Methods: Two extreme groups (n = 28 male athletes) were examined in a mixed-factorial design (between: HSS vs. LSS; within: repeated measurements of several variables related to stress reactivity - cortisol, heart rate, anxiety). Results: In response to the stressor HSS compared to LSS released a significantly lower amount of cortisol and needed less time for the climbing task. Heart rate and anxiety were not significant. Conclusions: Individuals seem to react physiologically differently to a sport-specific stressor, depending on their level of sensation seeking. HSS seem to be less strained, and seem to perform better. These findings might be relevant not only for the evaluation of (sport-) psychological interventions but also for other contexts (e.g., special forces).
Loss of Sarm1 does not suppress motor neuron degeneration in the SOD1G93A mouse model of amyotrophic lateral sclerosis

Abstract: Axon degeneration occurs in all neurodegenerative diseases, but the molecular pathways regulating axon destruction during neurodegeneration are poorly understood. Sterile Alpha and TIR Motif Containing 1 (Sarm1) is an essential component of the prodegenerative pathway driving axon degeneration after axotomy and represents an appealing target for therapeutic intervention in neurological conditions involving axon loss. Amyotrophic lateral sclerosis (ALS) is characterized by rapid, progressive motor neuron degeneration and muscle atrophy, causing paralysis and death. Patient tissue and animal models of ALS show destruction of upper and lower motor neuron cell bodies and loss of their associated axons. Here, we investigate whether loss of Sarm1 can mitigate motor neuron degeneration in the SOD1G93A mouse model of ALS. We found no change in survival, behavioral, electrophysiogical or histopathological outcomes in SOD1G93A mice null for Sarm1. Blocking Sarm1‐mediated axon destruction alone is therefore not sufficient to suppress SOD1G93A‐induced neurodegeneration. Our data suggest the molecular pathways driving axon loss in ALS may be Sarm1‐independent or involve genetic pathways that act in a redundant fashion with Sarm1.
Changes in secondary metabolites, organic acids and soluble sugars during the development of plum fruit cv. 'Furongli' (Prunus salicina Lindl).

BACKGROUND Organic acids, sugars and pigments are key components that determine the taste and flavor of plum fruit. However, metabolism of organic acid and sugar is not fully understood during the development of plum fruit cv. 'Furongli'. RESULTS Mature fruit of 'Furongli' has the highest content of anthocyanins and the lowest content of total phenol compounds and flavonoids. Malate is the predominant organic acid anion in 'Furongli' fruit, followed by citrate and isocitrate. Glucose was the predominant sugar form, followed by fructose and sucrose. Correlation analysis indicated that malate content increased with increasing phosphoenolpyruvate carboxylase (PEPC) activity and decreasing nicotinamide adenine dinucleotide-malate dehydrogenase (NAD-MDH) activity. Citrate and isocitrate content increased with increasing PEPC and aconitase (ACO) activities, respectively. Both acid invertase and neutral invertase had higher activities at the early stage than later stage of fruit development. Fructose content decreased with increasing phosphoglucoisomerase (PGI) activity, whereas glucose content increased with decreasing hexokinase (HK) activity. CONCLUSION Dynamics in organic acid anions were not solely controlled by a single enzyme but regulated by the integrated activity of enzymes such as nicotinamide adenine dinucleotide phosphate-malic enzyme (NADP-ME), NAD-ME, PEPC, ACO and NADP-isocitrate dehydrogenase. Sugar metabolism enzymes such as PGI, invertase and HK may play vital roles in the regulation of individual sugar metabolic processes. © 2018 Society of Chemical Industry.
Functional connectivity in category‐selective brain networks after encoding predicts subsequent memory

Activity in category selective regions of the temporal and parietal lobes during encoding has been associated with subsequent memory for face and scene stimuli. Reactivation theories of memory consolidation predict that after encoding connectivity between these category‐selective regions and the hippocampus should be modulated and predict recognition memory. However, support for this proposal has been limited in humans. Here, participants completed a resting‐state functional MRI (fMRI) scan, followed by face‐ and place‐encoding tasks, followed by another resting‐state fMRI scan during which they were asked to think about the stimuli they had previously encountered. Individual differences in face recognition memory were predicted by the degree to which connectivity between face‐responsive regions of the fusiform gyrus and perirhinal cortex increased following the face‐encoding task. In contrast, individual differences in scene recognition were predicted by connectivity between the hippocampus and a scene‐selective region of the retrosplenial cortex before and after the place‐encoding task. Our results provide novel evidence for category specificity in the neural mechanisms supporting memory consolidation.
Exome sequencing of 85 Williams–Beuren syndrome cases rules out coding variation as a major contributor to remaining variance in social behavior

Large, multigenic deletions at chromosome 7q11.23 result in a highly penetrant constellation of physical and behavioral symptoms known as Williams–Beuren syndrome (WS). Of particular interest is the unusual social‐cognitive profile evidenced by deficits in social cognition and communication reminiscent of autism spectrum disorders (ASD) that are juxtaposed with normal or even relatively enhanced social motivation. Interestingly, duplications in the same region also result in ASD‐like phenotypes as well as social phobias. Thus, the region clearly regulates human social motivation and behavior, yet the relevant gene(s) have not been definitively identified.
The BRG1/SOX9 axis is critical for acinar cell–derived pancreatic tumorigenesis

Chromatin remodeler Brahma related gene 1 (BRG1) is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDAs). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and that IPMN-derived PDA originated from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia–derived (PanIN-derived) PDA that originated from acinar cells remains elusive. Here, we found that exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1fl/fl mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independently of p53 mutation, while PDA formation was inhibited in the presence of p53 mutation. BRG1 bound to regions of the Sox9 promoter to regulate its expression and was critical for recruitment of upstream regulators, including PDX1, to the Sox9 promoter and enhancer in acinar cells. SOX9 expression was downregulated in BRG1-depleted ADMs/PanINs. Notably, Sox9 overexpression canceled this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1 deletion in established PanIN by using a dual recombinase system resulted in regression of the lesions in mice. Finally, BRG1 expression correlated with SOX9 expression in human PDAs. In summary, BRG1 is critical for PanIN initiation and progression through positive regulation of SOX9. Thus, the BRG1/SOX9 axis is a potential target for PanIN-derived PDA.
Iterative Surgical Resections of Diffuse Glioma With Awake Mapping: How to Deal With Cortical Plasticity and Connectomal Constraints?

BACKGROUND In diffuse glioma, a multistage approach with iterative tailored surgical resections can be considered. OBJECTIVE To compare results of iterative intrasurgical brain mappings to investigate the potential and limitation of neuroplasticity at the individual stage, and to highlight to what extent it can influence the therapeutic strategy. METHODS Glioma patients who underwent 2 consecutive awake surgeries with cortical and subcortical stimulation were classified into group 1 (n = 23) if cortical mappings exhibited high level of plasticity (displacement of ≥2 sites) or into group 2 (n = 19) with low level of plasticity. RESULTS Clinical characteristics did not differ significantly between both groups. The borders of the tumors were mostly sharp in group 1 (82.6%) and rather indistinct in group 2 (84.2%), (P = .00001). Tumor remnants were more often cortical (± subcortical) in group 1 (39.1%) and more often purely subcortical in group 2 (68.4%; P = .009). In group 1, the time needed to recover independence was significantly shorter at reoperation (37.6 h vs 78.3 h after the first surgery, P = .00003) while this difference was not significant in group 2. The iterative extents of resection (EOR) remain comparable in group 1 (94% vs 92%, P = .40) but were significantly smaller in group 2 at reoperation (94% vs 88%, P = .05). CONCLUSION More efficient plasticity mechanisms are facilitated by cortical tumors with sharp borders, are associated with an increase of EOR at reoperation and with earlier functional recovery. Tumoral invasion of the white matter tracts represents the main limitation of neuroplasticity: this connectomal constraint limits EOR during second surgery.
A similarity-based approach to leverage multi-cohort medical data on the diagnosis and prognosis of Alzheimer's disease

Abstract Motivation Heterogeneous diseases such as Alzheimer's disease (AD) manifest a variety of phenotypes among populations. Early diagnosis and effective treatment offer cost benefits. Many studies on biochemical and imaging markers have shown potential promise in improving diagnosis, yet establishing quantitative diagnostic criteria for ancillary tests remains challenging. Results We have developed a similarity-based approach that matches individuals to subjects with similar conditions. We modeled the disease with a Gaussian process, and tested the method in the Alzheimer's Disease Big Data DREAM Challenge. Ranked the highest among submitted methods, our diagnostic model predicted cognitive impairment scores in an independent dataset test with a correlation score of 0.573. It differentiated AD patients from control subjects with an area under the receiver operating curve of 0.920. Without knowing longitudinal information about subjects, the model predicted patients who are vulnerable to conversion from mild-cognitive impairment to AD through the similarity network. This diagnostic framework can be applied to other diseases with clinical heterogeneity, such as Parkinson's disease.
An update on expression and function of P-gp/ABCB1 and BCRP/ABCG2 in the placenta and fetus

ABSTRACT Introduction: P-glycoprotein (P-gp)/ABCB1 and breast cancer resistance protein (BCRP)/ABCG2 are highly expressed in the placenta and fetus throughout gestation and can modulate exposure and toxicity of drugs and xenobiotics to the vulnerable fetus during the sensitive times of growth and development. We aim to provide an update on current knowledge on placental and fetal expressions of the two transporters in different species, and to provide insight on interpreting transporter expression and fetal exposure relative to the concept of fraction of drug transported. Areas covered: Comprehensive literature review through PubMed (primarily from July 2010 to February 2018) on P-gp and BCRP expression and function in the placenta and fetus of primarily human, mouse, rat, and guinea pig. Expert opinion: While there are many commonalities in the expression and function of P-gp and BCRP in the placenta and fetal tissues across species, there are distinct differences in expression levels and temporal changes. Further studies are needed to quantify protein abundance of these transporters and functionally assess their activities at various gestational stages. Combining the knowledge of interspecies differences and the concept of fraction of drug transported, we may better predict the magnitude of impact these transporters have on fetal drug exposure.
Delayed Graft Function: The AKI of Kidney Transplantation

With the growing wait list of individuals waiting for kidney transplantation, there has been renewed interest in the quality and function of donor organs. In particular, concern about the development of delayed allograft function (DGF) after transplantation continues to lead to the avoidance of donor organs offered to a transplant center. DGF is associated with worse short-and long-term outcomes and associated with higher rejection rates. There are no FDA-approved therapies to mitigate the ischemic injury that occurs. Risk factors include both donor and recipient characteristics, although their prediction is not precise. With new understanding about mechanisms of injury and new focus on the function of the deceased donor, there is opportunity to identify not only novel therapies to improve allograft function but to identify potential biomarkers of DGF. DGF remains a significant factor in impacting kidney transplant outcome, and finding biomarkers will assist in the development and approval of novel agents to ameliorate early and later injury. This mini-review highlights our presentation at the 23rd International Conference on Advances in Critical Care Nephrology and UAB/UCSD O’Brien Center Acute Kidney Injury (AKI) Pre-Meeting.
Machine Learning of Toxicological Big Data Enables Read-Across Structure Activity Relationships (RASAR) Outperforming Animal Test Reproducibility

Abstract Earlier we created a chemical hazard database via natural language processing of dossiers submitted to the European Chemical Agency with approximately 10 000 chemicals. We identified repeat OECD guideline tests to establish reproducibility of acute oral and dermal toxicity, eye and skin irritation, mutagenicity and skin sensitization. Based on 350–700+ chemicals each, the probability that an OECD guideline animal test would output the same result in a repeat test was 78%–96% (sensitivity 50%–87%). An expanded database with more than 866 000 chemical properties/hazards was used as training data and to model health hazards and chemical properties. The constructed models automate and extend the read-across method of chemical classification. The novel models called RASARs (read-across structure activity relationship) use binary fingerprints and Jaccard distance to define chemical similarity. A large chemical similarity adjacency matrix is constructed from this similarity metric and is used to derive feature vectors for supervised learning. We show results on 9 health hazards from 2 kinds of RASARs—“Simple” and “Data Fusion”. The “Simple” RASAR seeks to duplicate the traditional read-across method, predicting hazard from chemical analogs with known hazard data. The “Data Fusion” RASAR extends this concept by creating large feature vectors from all available property data rather than only the modeled hazard. Simple RASAR models tested in cross-validation achieve 70%–80% balanced accuracies with constraints on tested compounds. Cross validation of data fusion RASARs show balanced accuracies in the 80%–95% range across 9 health hazards with no constraints on tested compounds.
Automated Layer Segmentation of Retinal Optical Coherence Tomography Images Using a Deep Feature Enhanced Structured Random Forests Classifier

Optical coherence tomography (OCT) is a high-resolution and noninvasive imaging modality that has become one of the most prevalent techniques for ophthalmic diagnosis. Retinal layer segmentation is very crucial for doctors to diagnose and study retinal diseases. However, manual segmentation is often a time-consuming and subjective process. In this work, we propose a new method for automatically segmenting retinal OCT images, which integrates deep features and hand-designed features to train a structured random forests classifier. The deep convolutional features are learned from deep residual network. With the trained classifier, we can get the contour probability graph of each layer; finally, the shortest path is employed to achieve the final layer segmentation. The experimental results show that our method achieves good results with the mean layer contour error of 1.215 pixels, whereas that of the state of the art was 1.464 pixels, and achieves an F1-score of 0.885, which is also better than 0.863 that is obtained by the state of the art method.
Polymorphisms of dopamine receptor genes DRD2 and DRD4 in African populations of Hadza and Datoga differing in the level of culturally permitted aggression

The key regulator in the control of aggressive behavior is dopamine receptors. Association of variants in these genes with aggression has been shown in modern populations. However, these studies have not been conducted in traditional cultures. The aim of our study was to investigate population features in distributions of allele and genotype frequencies of DRD2 rs1800497, DRD4 120 bp Ins, and DRD4 exon III polymorphisms and their associations with aggressive behavior in the traditional African populations of Hadza and Datoga, which display a contrast in their culturally permitted aggression. Overall, 820 healthy unrelated Hadza and Datoga individuals were studied. Self‐rated scores of aggression were collected using Buss and Perry's Aggression Questionnaire. Polymerase chain reaction‐Restriction fragment length polymorphism (PCR‐RFLP) was used to determine the genotype of each individual. We show that the Hadza and the Datoga differed significantly in allele and genotype frequencies of all studied loci. Our association analysis detected that only ethnicity and sex of individuals significantly influenced their aggression rank, but we failed to identify any associations of DRD2 rs1800497, DRD4 120 bp Ins, or DRD4 exon III polymorphisms with aggression. Thus, our data have no strong evidence to support the involvement of polymorphisms of DRD2 and DRD4 in controlling aggressive behavior.
Primary extra-nodal diffuse large B-cell lymphoma: A prognostic analysis of 141 patients

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma. Approximately 40% of DBLCL originates from extra-nodal sites, but the diversity of clinical presentations and the genetic and molecular alterations indicate that extra-nodal DLBCLs may be distinct disease entities. The aim of the present study was to highlight the various aspects of primary extra-nodal DLBCL (PE-DLBCL) based on a single center cohort. The data from 141 patients with PE-DLBCL treated at Peking Union Medical College Hospital were retrospectively evaluated. The primary extra-nodal sites involved were the gastrointestinal tract (n=42), central nervous system (CNS; n=38), breast (n=19), adrenal gland (n=15), female genital system (FGS; n=12), thyroid (n=8) and bone (n=7). The median overall survival rate was 28 months (range, 1–116). Multivariate analysis demonstrated that an International Prognostic Index (IPI) ≤2 (P=0.049), complete remission (CR) achieved following first-line therapy (P=0.001) and chemotherapy combined with rituximab (P<0.001) were positive prognostic factors. Patients with DLBCL with primary adrenal gland or female genital system (FGS) involvement exhibited a significantly higher risk of CNS recurrence (P<0.05). Rituximab treatment may have reduced the likelihood of CNS recurrence (P=0.005), whereas prophylaxis with intrathecal injection alone was not sufficient for prevention (P>0.05). In conclusion, IPI >2 and the lack of a CR following first-line therapy were independent prognostic risk factors for PE-DLBCL. Patients with primary adrenal gland or FGS involvement exhibited a higher risk of CNS relapse. Rituximab had a positive impact on the survival of patients with PE-DLBCL, also reducing the likelihood of CNS relapse.
Trop-2 plasticity is controlled by epithelial-to-mesenchymal transition

The cell surface glycoprotein Trop-2 is commonly overexpressed in carcinomas and represents an exceptional antigen for targeted therapy. Here, we provide evidence that surface Trop-2 expression is functionally connected with an epithelial phenotype in breast and prostate cell lines and in patient tumor samples. We further show that Trop-2 expression is suppressed epigenetically or through the action of epithelial-to-mesenchymal transition transcription factors and that deregulation of Trop-2 expression is linked with cancer progression and poor patient prognosis. Moreover, our data suggest that the cancer plasticity-driven intratumoral heterogeneity in Trop-2 expression may significantly contribute to response and resistance to therapies targeting Trop-2-expressing cells.