Miracle-dz/UniFAR-FTUs huggingface dataset:
Two Unanticipated Pregnancies While on Cystic Fibrosis Gene-Specific Drug Therapy

Women with cystic fibrosis (CF) desire to become pregnant and accomplish the same life goals as women without CF. The underlying pathology of CF and medications used to treat this genetically transmitted disease can affect women’s reproductive potential. An interview with Ana (pseudonym), who became pregnant twice while taking the medication lumacaftor/ivacaftor (LUMA/IVA), was analyzed using thematic analysis. She described her experiences related to “Fertility and Pregnancy Surrounding LUMA/IVA,” the major theme that emerged from her narrative. While there are anecdotal reports of infants conceived by women on LUMA/IVA and other CF precision medications, pregnancy rates and outcomes are not systematically tracked. Education about risks and benefits of these medications should be provided as part of comprehensive clinical care.
Virgin Coconut Oil Supplementation Prevents Airway Hyperreactivity of Guinea Pigs with Chronic Allergic Lung Inflammation by Antioxidant Mechanism

Asthma is a chronic inflammatory disease of the airways characterized by immune cell infiltrates, bronchial hyperresponsiveness, and declining lung function. Thus, the possible effects of virgin coconut oil on a chronic allergic lung inflammation model were evaluated. Morphology of lung and airway tissue exhibited peribronchial inflammatory infiltrate, epithelial hyperplasia, and smooth muscle thickening in guinea pigs submitted to ovalbumin sensitization, which were prevented by virgin coconut oil supplementation. Additionally, in animals with lung inflammation, trachea contracted in response to ovalbumin administration, showed a greater contractile response to carbachol (CCh) and histamine, and these responses were prevented by the virgin coconut oil supplementation. Apocynin, a NADPH oxidase inhibitor, did not reduce the potency of CCh, whereas tempol, a superoxide dismutase mimetic, reduced potency only in nonsensitized animals. Catalase reduced the CCh potency in nonsensitized animals and animals sensitized and treated with coconut oil, indicating the participation of superoxide anion and hydrogen peroxide in the hypercontractility, which was prevented by virgin coconut oil. In the presence of L-NAME, a nitric oxide synthase (NOS) inhibitor, the CCh curve remained unchanged in nonsensitized animals but had increased efficacy and potency in sensitized animals, indicating an inhibition of endothelial NOS but ineffective in inhibiting inducible NOS. In animals sensitized and treated with coconut oil, the CCh curve was not altered, indicating a reduction in the release of NO by inducible NOS. These data were confirmed by peribronchiolar expression analysis of iNOS. The antioxidant capacity was reduced in the lungs of animals with chronic allergic lung inflammation, which was reversed by the coconut oil, and confirmed by analysis of peribronchiolar 8-iso-PGF2α content. Therefore, the virgin coconut oil supplementation reverses peribronchial inflammatory infiltrate, epithelial hyperplasia, smooth muscle thickening, and hypercontractility through oxidative stress and its interactions with the NO pathway.
3D Intelligent Scissors for Dental Mesh Segmentation

Teeth segmentation is a crucial technologic component of the digital dentistry system. The limitations of the live-wire segmentation include two aspects: (1) computing the wire as the segmentation boundary is time-consuming and (2) a great deal of interactions for dental mesh is inevitable. For overcoming these disadvantages, 3D intelligent scissors for dental mesh segmentation based on live-wire is presented. Two tensor-based anisotropic metrics for making wire lie at valleys and ridges are defined, and a timesaving anisotropic Dijkstra is adopted. Besides, to improve with the smoothness of the path tracking back by the traditional Dijkstra, a 3D midpoint smoothing algorithm is proposed. Experiments show that the method is effective for dental mesh segmentation and the proposed tool outperforms in time complexity and interactivity.
The Length and Distribution of Plasma Cell-Free DNA Fragments in Stroke Patients

A number of studies have shown that plasma cell-free DNA is closely related to the risk of stroke, but the fragmentation status of plasma cell-free DNA and its clinical application value in ischemic stroke are still unclear. In this study, 48 patients with new ischemic stroke and 20 healthy subjects were enrolled. The second-generation high-throughput sequencing technique was used to study the plasma cell-free fragment length and regional distribution of the subjects. As noted in our results, the ratio of plasma cell-free DNA fragments in the disease group was significantly greater than that of the healthy group in the 300–400 bp range; conversely for fragments at the 75–250 bp range, the ratio of plasma cell-free DNA fragments in the patient group was apparently lower than that of the healthy group. In-depth analysis of the proportion of fragments distributed on each component of the genome was carried out. Our results recorded that the plasma cell-free DNA fragments in the disease group were inclined to the EXON, CpG islands, and ALU regions in contrast to that of the healthy group. In particular, fragments within the 300–400 bp range of the disease group were enrichment in the regions of EXON, INTRON, INTERGENIC, LINE, Fragile, ALU, and CpG islands. In summary, our findings suggested that the intracellular DNA degradation profiles could be applied to distinguish the stroke group and the healthy group, which provided a theoretical basis for the clinical diagnosis and prognosis of stroke by profiling the characteristic of plasma cell-free DNA fragments.
The Urinary Exosomal miRNA Expression Profile is Predictive of Clinical Response in Lupus Nephritis

Data on exosomal-derived urinary miRNAs have identified several miRNAs associated with disease activity and fibrosis formation, but studies on prognosis are lacking. We conducted a qPCR array screening on urinary exosomes from 14 patients with biopsy-proven proliferative lupus glomerulonephritis with a renal outcome of clinical response (n = 7) and non-response (n = 7) following therapy. Validation studies were performed by qRT-PCR in a new lupus nephritis (LN) cohort (responders = 22 and non-responders = 21). Responder patients expressed significantly increased levels of miR-31, miR-107, and miR-135b-5p in urine and renal tissue compared to non-responders. MiR-135b exhibited the best predictive value to discriminate responder patients (area under the curve = 0.783). In vitro studies showed exosome-derived miR-31, miR-107, and miR-135b-5p expression to be mainly produced by tubular renal cells stimulated with inflammatory cytokines (e.g IL1, TNFα, IFNα and IL6). Uptake of urinary exosomes from responders by mesangial cells was superior compared to that from non-responders (90% vs. 50%, p < 0.0001). HIF1A was identified as a potential common target, and low protein levels were found in non-responder renal biopsies. HIF1A inhibition reduced mesangial proliferation and IL-8, CCL2, CCL3, and CXCL1 mesangial cell production and IL-6/VCAM-1 in endothelial cells. Urinary exosomal miR-135b-5p, miR-107, and miR-31 are promising novel markers for clinical outcomes, regulating LN renal recovery by HIF1A inhibition.
TRPC1 Regulates the Activity of a Voltage-Dependent Nonselective Cation Current in Hippocampal CA1 Neurons

The cation channel subunit TRPC1 is strongly expressed in central neurons including neurons in the CA1 region of the hippocampus where it forms complexes with TRPC4 and TRPC5. To investigate the functional role of TRPC1 in these neurons and in channel function, we compared current responses to group I metabotropic glutamate receptor (mGluR I) activation and looked for major differences in dendritic morphology in neurons from TRPC1+/+ and TRPC1−/− mice. mGluR I stimulation resulted in the activation of a voltage-dependent nonselective cation current in both genotypes. Deletion of TRPC1 resulted in a modification of the shape of the current-voltage relationship, leading to an inward current increase. In current clamp recordings, the percentage of neurons that responded to depolarization in the presence of an mGluR I agonist with a plateau potential was increased in TRPC1−/− mice. There was also a small increase in the minor population of CA1 neurons that have more than one apical dendrite in TRPC1−/− mice. We conclude that TRPC1 has an inhibitory effect on receptor-operated nonselective cation channels in hippocampal CA1 neurons probably as a result of heterotetramer formation with other TRPC isoforms, and that TRPC1 deletion has only minor effects on dendritic morphology.
Real-Time Mine Road Boundary Detection and Tracking for Autonomous Truck

Road boundary detection is an important part of the perception of the autonomous driving. It is difficult to detect road boundaries of unstructured roads because there are no curbs. There are no clear boundaries on mine roads to distinguish areas within the road boundary line and areas outside the road boundary line. This paper proposes a real-time road boundary detection and tracking method by a 3D-LIDAR sensor. The road boundary points are extracted from the detected elevated point clouds above the ground point cloud according to the spatial distance characteristics and the angular features. Road tracking is to predict and update the boundary point information in real-time, in order to prevent false and missed detection. The experimental verification of mine road data shows the accuracy and robustness of the proposed algorithm.
AMP-Activated Protein Kinase Restricts Zika Virus Replication in Endothelial Cells by Potentiating Innate Antiviral Responses and Inhibiting Glycolysis

Key Points ZIKV inhibits AMPK signaling and increases glycolysis to promote viral replication. AMPK potentiates antiviral immune response and inhibits ZIKV-induced glycolysis. AMPK ablation increases ZIKV replication and reduces innate antiviral responses. Visual Abstract Viruses are known to perturb host cellular metabolism to enable their replication and spread. However, little is known about the interactions between Zika virus (ZIKV) infection and host metabolism. Using primary human retinal vascular endothelial cells and an established human endothelial cell line, we investigated the role of AMP-activated protein kinase (AMPK), a master regulator of energy metabolism, in response to ZIKV challenge. ZIKV infection caused a time-dependent reduction in the active phosphorylated state of AMPK and of its downstream target acetyl-CoA carboxylase. Pharmacological activation of AMPK using 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), metformin, and a specific AMPKα activator (GSK621) attenuated ZIKV replication. This activity was reversed by an AMPK inhibitor (compound C). Lentivirus-mediated knockdown of AMPK and the use of AMPKα−/− mouse embryonic fibroblasts provided further evidence that AMPK has an antiviral effect on ZIKV replication. Consistent with its antiviral effect, AMPK activation potentiated the expression of genes with antiviral properties (e.g., IFNs, OAS2, ISG15, and MX1) and inhibited inflammatory mediators (e.g., TNF-α and CCL5). Bioenergetic analysis showed that ZIKV infection evokes a glycolytic response, as evidenced by elevated extracellular acidification rate and increased expression of key glycolytic genes (GLUT1, HK2, TPI, and MCT4); activation of AMPK by AICAR treatment reduced this response. Consistent with this, 2-deoxyglucose, an inhibitor of glycolysis, augmented AMPK activity and attenuated ZIKV replication. Thus, our study demonstrates that the anti-ZIKV effect of AMPK signaling in endothelial cells is mediated by reduction of viral-induced glycolysis and enhanced innate antiviral responses.
Cellular and Molecular Mechanisms of Kidney Injury in 2,8-Dihydroxyadenine Nephropathy.

BACKGROUND Hereditary deficiency of adenine phosphoribosyltransferase causes 2,8-dihydroxyadenine (2,8-DHA) nephropathy, a rare condition characterized by formation of 2,8-DHA crystals within renal tubules. Clinical relevance of rodent models of 2,8-DHA crystal nephropathy induced by excessive adenine intake is unknown. METHODS Using animal models and patient kidney biopsies, we assessed the pathogenic sequelae of 2,8-DHA crystal-induced kidney damage. We also used knockout mice to investigate the role of TNF receptors 1 and 2 (TNFR1 and TNFR2), CD44, or alpha2-HS glycoprotein (AHSG), all of which are involved in the pathogenesis of other types of crystal-induced nephropathies. RESULTS Adenine-enriched diet in mice induced 2,8-DHA nephropathy, leading to progressive kidney disease, characterized by crystal deposits, tubular injury, inflammation, and fibrosis. Kidney injury depended on crystal size. The smallest crystals were endocytosed by tubular epithelial cells. Crystals of variable size were excreted in urine. Large crystals obstructed whole tubules. Medium-sized crystals induced a particular reparative process that we term extratubulation. In this process, tubular cells, in coordination with macrophages, overgrew and translocated crystals into the interstitium, restoring the tubular luminal patency; this was followed by degradation of interstitial crystals by granulomatous inflammation. Patients with adenine phosphoribosyltransferase deficiency showed similar histopathological findings regarding crystal morphology, crystal clearance, and renal injury. In mice, deletion of Tnfr1 significantly reduced tubular CD44 and annexin two expression, as well as inflammation, thereby ameliorating the disease course. In contrast, genetic deletion of Tnfr2, Cd44, or Ahsg had no effect on the manifestations of 2,8-DHA nephropathy. CONCLUSIONS Rodent models of the cellular and molecular mechanisms of 2,8-DHA nephropathy and crystal clearance have clinical relevance and offer insight into potential future targets for therapeutic interventions.
Association of TGF-β1 Polymorphisms with Breast Cancer Risk: A Meta-Analysis of Case–Control Studies †

Reports on the association of TGF-β1 polymorphisms with breast cancer (BC) have been conflicting, inconsistent, inconclusive, and controversial. PubMed, EMBASE, and Google Scholar were used to identify studies on TGF-β1 polymorphisms and BC risk. Data were extracted independently, and of the initial 3043 studies, 39 case-control studies were eligible for inclusion in the meta-analysis. Information from these studies was extracted, and the overall associations of three TGF-β1 polymorphisms (TGF-β1 29>T/C, TGF-β1-509 C/T, and TGF-β1*6A) with BC risk were analyzed using overall allele, homozygous, heterozygous, recessive, and dominant models. None of the three TGF-β1 polymorphisms studied had a significant influence on the development of BC. However, stratified analysis revealed a positive correlation between the TGF-β1 29T>C polymorphism and BC risk according to a heterozygous model of the Asian population (odds ratio (OR) = 1.115, 95% confidence interval (CI) = 1.006–1.237, p = 0.039). Interestingly, this polymorphism was associated with lower odds of BC according to a heterozygous model of the Middle Eastern population (OR = 0.602, 95% CI = 0.375–0.966, p = 0.035). Thus, our analysis of large datasets indicates that the TGF-β1 29T>C polymorphism is significantly associated with BC risk in the Asian population. In contrast, the TGF-β1*6A and TGF-β1-509 C/T polymorphisms failed to show an association with BC.
Modelling the resilience of seagrass communities exposed to pulsed freshwater discharges: A seascape approach

Submerged aquatic vegetation (SAV) communities display complex patch dynamics at seascape scales that are presently poorly understood as most studies of disturbance on SAV habitats have focused on changes in biomass at small, quadrat-level scales. In this study, analyses of remote sensing imagery and population modelling were applied to understand SAV patch dynamics and forecast the fate of these important communities in Biscayne Bay, Miami, Florida, US. We evaluated how the proximity of freshwater canals influences seagrass-dominated SAV patch dynamics and, in turn, how patch-size structure influences the stability of seagrass seascapes under different salinity scenarios. Seagrass fragmentation rates were higher in sites adjacent to freshwater canals compared to sites distant from the influences of freshwater deliveries. Furthermore, we documented a clear trend in patch mortality rates with respect to patch size, with the smallest patches (50 m2) undergoing 57% annual mortality on average. The combination of higher fragmentation rates and the higher mortality of smaller seagrass patches in habitats exposed to pulses of low salinity raises concern for the long-term persistence of seagrass meadows in nearshore urban habitats of Biscayne Bay that are presently targets of Everglades restoration. Our model scenarios that simulated high fragmentation rates resulted in SAV population collapses, regardless of SAV recruitment rates. The combined remote sensing and population modelling approach used here provides evaluation and predictive tools that can be used by managers to track seagrass status and stress-response at seascape levels not available previously for the seagrasses of South Florida.
TiO2-Assisted Halide Ion Segregation in Mixed Halide Perovskite Films.

In metal halide perovskite solar cells, electron transport layers (ETLs) such as TiO2 dictate the overall photovoltaic per-formance. However, the same electron capture property of ETL indirectly impacts halide ion mobility as evident from the TiO2-assisted halide ion segregation in mixed halide perovskite (MHP) films under pulsed laser excitation (387 nm, 500 Hz). This segregation is only observed when deposited on an ETL such as TiO2, but not on insulating ZrO2 substrate. Injection of electrons from excited MHP into the ETL (ket = 1011 s-1) followed by scavenging of electrons by O2 causes hole accumulation in the MHP film. Localization of holes on the iodide-site in the MHP induces instability causing iodide from the lattice to move away towards grain boundaries. Suppression of segregation occurs when holes are extracted by a hole transport layer (spiro-OMeTAD) deposited on the MHP, thus avoiding hole build-up. These results provide further insight into the role of holes in the phase segregation of MHPs and hole mobility in perovskite solar cells.
Comparison of BCR-ABL1 quantification in peripheral blood and bone marrow using an International Scale-standardized assay for assessment of deep molecular response in chronic myeloid leukemia

Abstract Background Monitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens. Methods We examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS. Results A good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates. Conclusions In summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.
Potential Therapeutic Approaches Against Brain Diseases Associated with Cytomegalovirus Infections

Cytomegalovirus (CMV) is one of the major human health threats worldwide, especially for immunologically comprised patients. CMV may cause opportunistic infections, congenital infections, and brain diseases (e.g., mental retardation and glioblastoma). The etiology of brain diseases associated with human CMV (HCMV) infections is usually complex and it is particularly difficult to treat because HCMV has a life-long infection in its hosts, high mutation rate, and latent infections. Moreover, it is almost impossible to eradicate latent viruses in humans. Although there has been progress in drug discovery recently, current drugs used for treating active CMV infections are still limited in efficacy due to side effects, toxicity, and viral resistance. Fortunately, letermovir which targets the HCMV terminase complex rather than DNA polymerase with fewer adverse reactions has been approved to treat CMV infections in humans. The researchers are focusing on developing approaches against both productive and latent infections of CMV. The gene or RNA targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being investigated to remove acute and/or latent CMV infections. For the treatment of glioblastoma, vaccine therapy through targeting specific CMV antigens has improved patients’ survival outcomes significantly and immunotherapy has also emerged as an alternative modality. The advanced research for developing anti-CMV agents and approaches is promising to obtain significant outcomes and expecting to have a great impact on the therapy of brain diseases associated with CMV infections.
Predicting Acute Graft-Versus-Host Disease Using Machine Learning and Longitudinal Vital Sign Data From Electronic Health Records

PURPOSE Acute graft-versus-host disease (aGVHD) remains a significant complication of allogeneic hematopoietic cell transplantation (HCT) and limits its broader application. The ability to predict grade II to IV aGVHD could potentially mitigate morbidity and mortality. To date, researchers have focused on using snapshots of a patient (eg, biomarkers at a single time point) to predict aGVHD onset. We hypothesized that longitudinal data collected and stored in electronic health records (EHRs) could distinguish patients at high risk of developing aGVHD from those at low risk. PATIENTS AND METHODS The study included a cohort of 324 patients undergoing allogeneic HCT at the University of Michigan C.S. Mott Children’s Hospital during 2014 to 2017. Using EHR data, specifically vital sign measurements collected within the first 10 days of transplantation, we built a predictive model using penalized logistic regression for identifying patients at risk for grade II to IV aGVHD. We compared the proposed model with a baseline model trained only on patient and donor characteristics collected at the time of transplantation and performed an analysis of the importance of different input features. RESULTS The proposed model outperformed the baseline model, with an area under the receiver operating characteristic curve of 0.659 versus 0.512 (P = .019). The feature importance analysis showed that the learned model relied most on temperature and systolic blood pressure, and temporal trends (eg, increasing or decreasing) were more important than the average values. CONCLUSION Leveraging readily available clinical data from EHRs, we developed a machine-learning model for aGVHD prediction in patients undergoing HCT. Continuous monitoring of vital signs, such as temperature, could potentially help clinicians more accurately identify patients at high risk for aGVHD.