Miracle-dz/UniFAR-FTUs huggingface dataset:
Calibration of an Electrical Analog Model of Liver Hemodynamics in Fontan Patients.

Fontan associated liver disease is a common complication in patients with Fontan circulation, who were born with a single functioning heart ventricle. The hepatic venous pressure gradient (HVPG) is used to assess liver health and is a surrogate measure of the pressure gradient across the entire liver (portal pressure gradient). However, it is thought to be inaccurate in Fontan patients. The main objectives of this study were (1) to apply an existing detailed lumped parameter model of the liver to Fontan patients using patient-specific clinical data and (2) to determine whether HVPG is a suitable measurement of portal pressure gradients in these patients. An existing lumped parameter model of the liver blood circulation was applied and tuned to simulate patient-specific liver hemodynamics. Geometries were collected from seven adult Fontan patients and used to evaluate model parameters. The model was solved and tuned using waveform measurements of flows, inlet and outlet pressures. The predicted ratio of portal to hepatic venous pressures is comparable to in vivo measurements. The results confirmed that HVPG is not suitable for Fontan patients, as it would underestimate the portal pressures gradient by a factor of 3 to 4. Our patient-specific liver model provides an estimate of the pressure drop across the liver, which differs from the clinically used metric HVPG. This work represents a first step towards models suitable to assess liver health in Fontan patients and improve its long-term management.
LINC00452 promotes ovarian carcinogenesis through increasing ROCK1 by sponging miR-501-3p and suppressing ubiquitin-mediated degradation

Ovarian cancer refers to all sorts of cancerous growth that starts from the ovary. Dysregulation of long non-coding RNAs (lncRNAs) is associated with ovarian cancer development and progression. Cellular expression and localization of LINC00452 in ovarian cancer cells were detected by qPCR and FISH. The roles of LINC00452 in ovarian carcinogenesis were characterized by MTT, transwell and colony-formation assays in vitro as well as xenograft mouse model. The underlying mechanism was explored by microarray, RIP, Co-IP and luciferase reporter assays. This study identified a novel lncRNA LINC00452 being elevated in both ovarian cancer cells and tumor tissues in patients. Such aberrant expression of LINC00452 was negatively correlated with relapse-free survival of ovarian cancer patients. Overexpression of LINC00452 potentiated CaOV3 cell viability, migration and invasion in vitro as well as xenograft tumor growth in vivo. Evidence from the current study suggests that the carcinogenicity of LINC00452 is partially due to competitive sponging of miR-501-3p followed with release of repression on the ROCK1, a key effector in Rho signaling pathway. Irrespective of its miRNA sponge function, LINC00452 is capable of preventing ROCK1 protein from ubiquitin/proteasome-mediated degradation via their mutual physical interaction. Our study makes LINC00452 a potential therapeutic target for ovarian cancer.
The p.Ser64Leu and p.Pro104Leu missense variants of PALB2 identified in familial pancreatic cancer patients compromise the DNA damage response

PALB2 has been identified as a breast and pancreatic cancer susceptibility gene. Utilizing a targeted sequencing approach, we discovered two novel germline missense PALB2 variants c.191C>T and c.311C>T, encoding p.Ser64Leu and p.Pro104Leu, respectively, in individuals in a pancreatic cancer registry. No missense PALB2 variants from familial pancreatic cancer patients, and few PALB2 variants overall, have been functionally characterized. Given the known role of PALB2, we tested the impact of p.Ser64Leu and p.Pro104Leu variants on DNA damage responses. Neither p.Ser64Leu nor p.Pro104Leu have clear effects on interactions with BRCA1 and KEAP1, which are mediated by adjacent motifs in PALB2. However, both variants are associated with defective recruitment of PALB2, and the RAD51 recombinase downstream, to DNA damage foci. Furthermore, p.Ser64Leu and p.Pro104Leu both largely compromise DNA double‐strand break‐initiated homologous recombination, and confer increased cellular sensitivity to ionizing radiation (IR) and the poly (ADP‐ribose) polymerase (PARP) inhibitor Olaparib. Taken together, our results represent the first demonstration of functionally deleterious PALB2 missense variants associated with familial pancreatic cancer and of deleterious variants in the N‐terminus outside of the coiled‐coil domain. Furthermore, our results suggest the possibility of personalized treatments, using IR or PARP inhibitor, of pancreatic and other cancers that carry a deleterious PALB2 variant.
Marine wild-capture fisheries after nuclear war

Significance Nuclear conflict poses the chilling prospect of triggering abrupt global cooling, and consequently, severely reduced crop production. However, the impacts on marine fisheries are unknown. If agricultural yields fall on land, could we turn to the sea instead? Here, we show that agricultural losses could not be offset by the world’s fisheries, especially given widespread overfishing. Cold temperatures and reduced sunlight would decrease the growth of fish biomass, at worst as much as under unmitigated climate change. Although intensified postwar fishing could yield a small catch increase, dramatic declines would ensue due to overharvesting. However, effective prewar fisheries management would create a substantial buffer of fish in the ocean, greatly increasing the oceans’ potential contribution during a global food emergency. Nuclear war, beyond its devastating direct impacts, is expected to cause global climatic perturbations through injections of soot into the upper atmosphere. Reduced temperature and sunlight could drive unprecedented reductions in agricultural production, endangering global food security. However, the effects of nuclear war on marine wild-capture fisheries, which significantly contribute to the global animal protein and micronutrient supply, remain unexplored. We simulate the climatic effects of six war scenarios on fish biomass and catch globally, using a state-of-the-art Earth system model and global process-based fisheries model. We also simulate how either rapidly increased fish demand (driven by food shortages) or decreased ability to fish (due to infrastructure disruptions), would affect global catches, and test the benefits of strong prewar fisheries management. We find a decade-long negative climatic impact that intensifies with soot emissions, with global biomass and catch falling by up to 18 ± 3% and 29 ± 7% after a US–Russia war under business-as-usual fishing—similar in magnitude to the end-of-century declines under unmitigated global warming. When war occurs in an overfished state, increasing demand increases short-term (1 to 2 y) catch by at most ∼30% followed by precipitous declines of up to ∼70%, thus offsetting only a minor fraction of agricultural losses. However, effective prewar management that rebuilds fish biomass could ensure a short-term catch buffer large enough to replace ∼43 ± 35% of today’s global animal protein production. This buffering function in the event of a global food emergency adds to the many previously known economic and ecological benefits of effective and precautionary fisheries management.
Converging Evidence for Differential Specialization and Plasticity of Language Systems

Functional specialization and plasticity are fundamental organizing principles of the brain. Since the mid-1800s, certain cognitive functions have been known to be lateralized, but the provenance and flexibility of hemispheric specialization remain open questions. Language is a uniquely human phenomenon that requires a delicate balance between neural specialization and plasticity, and language learning offers the perfect window to study these principles in the human brain. In the current study, we conducted two separate functional MRI experiments with language learners (male and female), one cross-sectional and one longitudinal, involving distinct populations and languages, and examined hemispheric lateralization and learning-dependent plasticity of the following three language systems: reading, speech comprehension, and verbal production. A multipronged analytic approach revealed a highly consistent pattern of results across the two experiments, showing (1) that in both native and non-native languages, while language production was left lateralized, lateralization for language comprehension was highly variable across individuals; and (2) that with increasing non-native language proficiency, reading and speech comprehension displayed substantial changes in hemispheric dominance, with languages tending to lateralize to opposite hemispheres, while production showed negligible change and remained left lateralized. These convergent results shed light on the long-standing debate of neural organization of language by establishing robust principles of lateralization and plasticity of the main language systems. Findings further suggest involvement of the sensorimotor systems in language lateralization and its plasticity. SIGNIFICANCE STATEMENT The human brain exhibits a remarkable ability to support a vast variety of languages that may be acquired at different points in the life span. Language is a complex construct involving linguistic as well as visual, auditory, and motor processes. Using functional MRI, we examined hemispheric specialization and learning-dependent plasticity of three language systems—reading, speech comprehension, and verbal production—in cross-sectional and longitudinal experiments in language learners. A multipronged analytic approach revealed converging evidence for striking differences in hemispheric specialization and plasticity among the language systems. The results have major theoretical and practical implications for our understanding of fundamental principles of neural organization of language, language testing and recovery in patients, and language learning in healthy populations.
An Unbiased Approach to Mapping the Signaling Network of the Pseudorabies Virus US3 Protein

The US3 serine/threonine protein kinase is conserved among the alphaherpesvirus family and represents an important virulence factor. US3 plays a role in viral nuclear egress, induces dramatic alterations of the cytoskeleton, represses apoptosis, enhances gene expression and modulates the immune response. Although several substrates of US3 have been identified, an unbiased screen to identify US3 phosphorylation targets has not yet been described. Here, we perform a shotgun and phosphoproteomics analysis of cells expressing the US3 protein of pseudorabies virus (PRV) to identify US3 phosphorylation targets in an unbiased way. We identified several cellular proteins that are differentially phosphorylated upon US3 expression and validated the phosphorylation of lamin A/C at serine 404, both in US3-transfected and PRV-infected cells. These results provide new insights into the signaling network of the US3 protein kinase and may serve as a basis for future research into the role of the US3 protein in the viral replication cycle.
Diagnostic Accuracy of Electrical Impedance Spectroscopy in Non-melanoma Skin Cancer

Electrical impedance spectroscopy is a non-invasive technique that can help clinicians in diagnosing malignant skin tumours. Depending on the cellular irregularity of the lesion, electrical impedance spectroscopy can reveal changes in the structure and form of the cells, using a harmless electrical current applied to the skin. A score between 0 and 10 is generated by the electrical impedance spectrometer, where 0 is considered benign and 10 is malignant. This prospective study was conducted in 101 patients with a total of 200 skin lesions; 62 benign and 138 malignant. There was a significant difference between the electrical impedance of malignant and benign lesions (p < 0.001). The sensitivity, specificity, positive predictive value and negative predictive value of electrical impedance spectroscopy for non-melanoma skin cancer were 94.2%, 41.9%, 78.3% and 76.5%, respectively, when the cut-off for the electrical impedance spectroscopy score was set between 5 and 6. The area under the curve in receiver operating characteristics analyses was 0.758.
Cementitious Composites with High Compaction Potential: Modeling and Calibration

There is an increasing need for the development of novel technologies for tunnel construction in difficult geological conditions to protect segmental linings from unexpected large deformations. In the context of mechanized tunneling, one method to increase the damage tolerance of tunnel linings in such conditions is the integration of a compressible two-component grout for the annular gap between the segmental linings and the deformable ground. In this regard, expanded polystyrene (EPS) lightweight concrete/mortar has received increasing interest as a potential “candidate material” for the aforementioned application. In particular, the behavior of the EPS lightweight composites can be customized by modifying their pore structure to accommodate deformations due to specific geological conditions such as squeezing rocks. To this end, novel compressible cementitious EPS-based composite materials with high compaction potential have been developed. Specimens prepared from these composites have been subjected to compressive loads with and without lateral confinement. Based on these experimental data a computational model based on the Discrete Element Method (DEM) has been calibrated and validated. The proposed calibration procedure allows for modeling and prognosis of a wide variety of composite materials with a high compaction potential. The calibration procedure is characterized by the identification of physically quantifiable parameters and the use of phenomenological submodels. Model prognoses show excellent agreement with new experimental measurements that were not incorporated in the calibration procedure.
16p11.2 microdeletion imparts transcriptional alterations in human iPSC-derived models of early neural development

Microdeletions and microduplications of the 16p11.2 chromosomal locus are associated with syndromic neurodevelopmental disorders and reciprocal physiological conditions such as macro/microcephaly and high/low body mass index. To facilitate cellular and molecular investigations into these phenotypes, 65 clones of human induced pluripotent stem cells (hiPSCs) were generated from 13 individuals with 16p11.2 copy number variations (CNVs). To ensure these cell lines were suitable for downstream mechanistic investigations, a customizable bioinformatic strategy for the detection of random integration and expression of reprogramming vectors was developed and leveraged towards identifying a subset of ‘footprint’-free hiPSC clones. Transcriptomic profiling of cortical neural progenitor cells derived from these hiPSCs identified alterations in gene expression patterns which precede morphological abnormalities reported at later neurodevelopmental stages. Interpreting clinical information—available with the cell lines by request from the Simons Foundation Autism Research Initiative—with this transcriptional data revealed disruptions in gene programs related to both nervous system function and cellular metabolism. As demonstrated by these analyses, this publicly available resource has the potential to serve as a powerful medium for probing the etiology of developmental disorders associated with 16p11.2 CNVs.
Protein and mRNA Expression Levels of Interleukin-17A, -17F and -22 in Blood and Skin Samples of Patients with Mycosis Fungoides

This study investigated the expression of interleukin (IL)-17A, -17F and -22 in mycosis fungoides. Blood samples were collected from 50 patients with mycosis fungoides and 50 healthy controls. Skin samples were obtained from 26 patients with mycosis fungoides and 5 healthy controls. Protein levels of IL-17A, -17F and -22 were measured in serum by multiplex enzyme-linked immunosorbent assay, and mRNA expression levels were measured in blood and skin samples by real-time quantitative reverse transcription PCR. Both IL-17A and IL-17F mRNA expression levels were significantly lower in blood of patient swith mycosis fungoides in comparison with healthy controls. IL-22 serum levels and expression levels of IL-22 mRNA in skintissue,weresignificantlyincreasedinpatients with mycosis fungoides in comparison with healthy controls. These results suggest that low levels of IL-17A and IL-17F in mycosis fungoides may be connected to impaired immune surveillance contributing to tumourigenesis. Upregulation of IL-22 may play a role in the establishment of the tumour microenvironment in mycosis fungoides.
Effect of gut microbiome on minor complications after a colonoscopy

Background/Aims Minor complications that might occur after colonoscopy, including abdominal discomfort, bloating, diarrhea, and constipation, could a barrier for patients to undergo a screening colonoscopy. In this study, we aimed to identify the effect of gut microbial diversity and composition on minor complications after colonoscopy. Methods A total of 24 healthy subjects provided their stools before bowel preparation and on the 7th and 28th day after colonoscopy. On the 7th day after colonoscopy, the presence of minor complications was investigated using a questionnaire. We divided patients into 2 groups, the no complication group and complications group. The fecal microbial diversity, distribution, and composition were then compared between the groups. Results Five of the 24 subjects reported that they had undergone minor complications after colonoscopy. Most of the symptoms were mild and self-limited, but 1 patient needed medication. Interestingly, the Firmicutes/Bacteroidetes ratio of the initial stool samples before bowel preparation in the complication group was significantly higher than that in no complication group. After bowel preparation, the Firmicutes/Bacteroidetes ratio of the complication group decreased, but not in the no complication group. The microbial diversity of the no complication group decreased after bowel preparation, but not in the complication group. Conclusions The gut microbial composition and diversity before and after bowel preparation could be considered as one of the causes of minor complications after colonoscopy. Further studies are needed to delineate the role of gut microbiota in the occurrence of minor complications after colonoscopy.
Assessing the practice of data quality evaluation in a national clinical data research network through a systematic scoping review in the era of real-world data

Abstract Objective To synthesize data quality (DQ) dimensions and assessment methods of real-world data, especially electronic health records, through a systematic scoping review and to assess the practice of DQ assessment in the national Patient-centered Clinical Research Network (PCORnet). Materials and Methods We started with 3 widely cited DQ literature—2 reviews from Chan et al (2010) and Weiskopf et al (2013a) and 1 DQ framework from Kahn et al (2016)—and expanded our review systematically to cover relevant articles published up to February 2020. We extracted DQ dimensions and assessment methods from these studies, mapped their relationships, and organized a synthesized summarization of existing DQ dimensions and assessment methods. We reviewed the data checks employed by the PCORnet and mapped them to the synthesized DQ dimensions and methods. Results We analyzed a total of 3 reviews, 20 DQ frameworks, and 226 DQ studies and extracted 14 DQ dimensions and 10 assessment methods. We found that completeness, concordance, and correctness/accuracy were commonly assessed. Element presence, validity check, and conformance were commonly used DQ assessment methods and were the main focuses of the PCORnet data checks. Discussion Definitions of DQ dimensions and methods were not consistent in the literature, and the DQ assessment practice was not evenly distributed (eg, usability and ease-of-use were rarely discussed). Challenges in DQ assessments, given the complex and heterogeneous nature of real-world data, exist. Conclusion The practice of DQ assessment is still limited in scope. Future work is warranted to generate understandable, executable, and reusable DQ measures.
Structural distinctions between NAD+ riboswitch domains 1 and 2 determine differential folding and ligand binding

Abstract Riboswitches are important gene regulatory elements frequently encountered in bacterial mRNAs. The recently discovered nadA riboswitch contains two similar, tandemly arrayed aptamer domains, with the first domain possessing high affinity for nicotinamide adenine dinucleotide (NAD+). The second domain which comprises the ribosomal binding site in a putative regulatory helix, however, has withdrawn from detection of ligand-induced structural modulation thus far, and therefore, the identity of the cognate ligand and the regulation mechanism have remained unclear. Here, we report crystal structures of both riboswitch domains, each bound to NAD+. Furthermore, we demonstrate that ligand binding to domain 2 requires significantly higher concentrations of NAD+ (or ADP retaining analogs) compared to domain 1. Using a fluorescence spectroscopic approach, we further shed light on the structural features which are responsible for the different ligand affinities, and describe the Mg2+-dependent, distinct folding and pre-organization of their binding pockets. Finally, we speculate about possible scenarios for nadA RNA gene regulation as a putative two-concentration sensor module for a time-controlled signal that is primed and stalled by the gene regulation machinery at low ligand concentrations (domain 1), and finally triggers repression of translation as soon as high ligand concentrations are reached in the cell (domain 2).
Hemodynamic response varies across tactile stimuli with different temporal structures

Tactile stimuli can be distinguished based on their temporal features (e.g., duration, local frequency, and number of pulses), which are fundamental for vibrotactile frequency perception. Characterizing how the hemodynamic response changes in shape across experimental conditions is important for designing and interpreting fMRI studies on tactile information processing. In this study, we focused on periodic tactile stimuli with different temporal structures and explored the hemodynamic response function (HRF) induced by these stimuli. We found that HRFs were stimulus‐dependent in tactile‐related brain areas. Continuous stimuli induced a greater area of activation and a stronger and narrower hemodynamic response than intermittent stimuli with the same duration. The magnitude of the HRF increased with increasing stimulus duration. By normalizing the characteristics into topographic matrix, nonlinearity was obvious. These results suggested that stimulation patterns and duration within a cycle may be key characters for distinguishing different stimuli. We conclude that different temporal structures of tactile stimuli induced different HRFs, which are essential for vibrotactile perception and should be considered in fMRI experimental designs and analyses.