Miracle-dz/UniFAR-FTUs huggingface dataset:
Supplementation of Maternal Diets with Docosahexaenoic Acid and Methylating Vitamins Impacts Growth and Development of Fetuses from Malnourished Gilts

Abstract Background Like many species, pregnant swine mobilize and repartition body nutrient stores during extreme malnutrition to support fetal development. Objective The objective of this study was to model chronic human maternal malnutrition and measure effects of methylating-vitamins (MVs, containing choline, folate, B-6, B-12, and riboflavin) and docosahexaenoic acid (DHA) supplementation on fetal growth and development. Methods Pregnant gilts (n = 24) were either fully nourished (2.0 kg/d) with a corn-plus-isolated-soy-protein basal diet (control) supplemented with MVs and DHA or nourishment was restricted throughout gestation. Basal diet fed to malnourished gilts was reduced progressively from 50% to 70% restriction (1.0 to 0.6 kg/d) and was supplemented following a 2 (±MVs) x 2 (±DHA) factorial design. Full-term c-sections were performed to assess impacts on low and normal birth weight (LBW/NBW) fetuses (n = 238). Results Body weight gain of malnourished gilts was 10% of full-fed control dams (P < 0.05), but offspring birth weight, length, girth, and percentage of LBW fetuses were not different between treatments. The number of pigs per litter was reduced by 30% in malnourished control dams. Fetal brain weights were reduced by 7% compared to positive controls (P < 0.05). Micronutrient supplementation to malnourished dams increased fetal brain weights back to full-fed control levels. Dams with DHA produced offspring with higher DHA concentrations in brain and liver (P < 0.05). Plasma choline concentration was 4-fold higher in fetuses from unsupplemented malnourished dams (P < 0.0001). Global DNA methylation status of fetuses from restricted dams was higher than in control fetuses, including brain, liver, heart, muscle, and placenta tissues (P < 0.05). Addition of DHA increased methylation in LBW fetal brains (P < 0.05). Conclusions Despite the mobilization of maternal stores, malnourished litters displayed reduced brain development that was fully mitigated by micronutrient supplementation. Severe maternal malnutrition increased global DNA methylation in several fetal tissues that was unaltered by choline and B-vitamin supplementation.
Sexual compatibility between two heterochronic morphs in the Alpine newt, Triturus alpestris


Paedomorphosis, in which individuals retain ancestral characteristics in the adult stage, is widespread in newts and salamanders and is suspected to play an important role in evolution. In some species, paedomorphosis is facultative with some individuals forgoing metamorphosis. Optimality models have been proposed to explain the maintenance of this polymorphism, but require the integration of reproductive patterns into the models. We investigated the frequencies of inbreeding and outbreeding in two syntopic heterochronic morphs of the Alpine newt. The two morphs are sexually compatible: encounters between and within morphs were equally successful in terms of spermatophore transfer. Behavioural observations were in agreement with the sexual compatibility observed. Nevertheless, paedomorphic males displayed to females less frequently than metamorphic males. The two morphs differ largely on the basis of sexual secondary characteristics, but the majority of these traits did not affect mating success. Because of the large flow of genes between the two heterochronic morphs and because of the absence of spatial and temporal isolation, these results do not support sympatric speciation models, but are in favour of the maintenance of polymorphism in natural populations.
New Frontiers in Parkinson's Disease: From Genetics to the Clinic

The greatest unmet therapeutic need in Parkinson's disease (PD) is a treatment that slows the relentless progression of the symptoms and the neurodegenerative process. This review highlights the utility of genetics to understand the pathogenic mechanisms and develop novel therapeutic approaches for PD. The focus is on strategies provided by genetic studies: notably via the reduction and clearance of α-synuclein, inhibition of LRRK2 kinase activity, and modulation of glucocerebrosidase-related substrates. In addition, the critical role of precompetitive public-private partnerships in supporting trial design optimization, overall drug development, and regulatory approvals is illustrated. With these great advances, the promise of developing transformative therapies that halt or slow disease progression is a tangible goal.
Hybrid Self-Attention Network for Machine Translation

The encoder-decoder is the typical framework for Neural Machine Translation (NMT), and different structures have been developed for improving the translation performance. Transformer is one of the most promising structures, which can leverage the self-attention mechanism to capture the semantic dependency from global view. However, it cannot distinguish the relative position of different tokens very well, such as the tokens located at the left or right of the current token, and cannot focus on the local information around the current token either. To alleviate these problems, we propose a novel attention mechanism named Hybrid Self-Attention Network (HySAN) which accommodates some specific-designed masks for self-attention network to extract various semantic, such as the global/local information, the left/right part context. Finally, a squeeze gate is introduced to combine different kinds of SANs for fusion. Experimental results on three machine translation tasks show that our proposed framework outperforms the Transformer baseline significantly and achieves superior results over state-of-the-art NMT systems.
Salivary Oxidant/Antioxidant Status in Chronic Temporomandibular Disorders Is Dependent on Source and Intensity of Pain – A Pilot Study

Temporomandibular disorders (TMD) have been associated with altered salivary oxidative status, but the relation with pain source and pain severity isn’t clarified. With the aim to assess their interaction with TMD, we compared levels of selected salivary oxidative stress (OS) markers (glutathione peroxidase, superoxide dismutase, total antioxidant capacity (TAC), uric acid, 8-hydroxydeoxyguanosine, malondialdehyde) and salivary cortisol (SC) as a stress indicator, between 20 TMD patients and 15 healthy control subjects. In order to record differences relating to pain source and severity, patients were respectively classified according to specific diagnoses (myofascial pain or disc displacement (DD)), and pain intensity (high or low). TAC was significantly higher in TMD patients than in controls (morning p = 0.015; afternoon p = 0.005). Significant differences were also observed when TAC levels between high-intensity pain patients and controls were compared, as well as between DD patients and controls. In logistic regression analysis, higher levels of TAC were related to DD (morning OR: 1.66, 95%CI: 1.05–2.64, p = 0.029; afternoon OR: 2.10, 95%CI: 1.11–3.98, p = 0.021) and to high-intensity pain (morning OR: 1.81, 95%CI: 1.04–3.15, p = 0.037; afternoon OR: 1.79, 95%CI: 1.02–3.14, p = 0.043). We also found that morning SC was positively correlated with antioxidant parameters in TMD patients. Our data suggest compensatory mechanism as response to higher level of stress. This stress could be extrinsic and lead toward TMD, or intrinsic, emerging from established TMD, or could be both. The intensity and the source of pain should be considered important factors in future investigations evaluating salivary OS markers in TMD patients.
Human Bocavirus Infection of Permanent Cells Differentiated to Air-Liquid Interface Cultures Activates Transcription of Pathways Involved in Tumorigenesis

The parvoviral human bocavirus (HBoV) is a respiratory pathogen, able to persist in infected cells. The viral DNA has been identified in colorectal and lung tumors and thus it was postulated that the virus could be associated with tumorigenesis. This assumption was supported by the fact that in HBoV-infected patients and in an in vitro cell culture system, pro-cancerogenic and -fibrotic cytokines were expressed. In this work, it is shown by a whole transcriptome analysis that, also at the mRNA level, several pathways leading to neoplasia and tumorigenesis are significantly upregulated. In total, a set of 54 transcripts are specifically regulated by HBoV, of which the majority affects canonical pathways that may lead to tumor development if they become deregulated. Moreover, pathways leading to necrosis, apoptosis and cell death are downregulated, supporting the hypothesis that HBoV might contribute to the development of some kinds of cancer.
The Importance of Heterogeneity to the Epidemiology of Tuberculosis

Abstract Although less well-recognized than for other infectious diseases, heterogeneity is a defining feature of tuberculosis (TB) epidemiology. To advance toward TB elimination, this heterogeneity must be better understood and addressed. Drivers of heterogeneity in TB epidemiology act at the level of the infectious host, organism, susceptible host, environment, and distal determinants. These effects may be amplified by social mixing patterns, while the variable latent period between infection and disease may mask heterogeneity in transmission. Reliance on notified cases may lead to misidentification of the most affected groups, as case detection is often poorest where prevalence is highest. Assuming that average rates apply across diverse groups and ignoring the effects of cohort selection may result in misunderstanding of the epidemic and the anticipated effects of control measures. Given this substantial heterogeneity, interventions targeting high-risk groups based on location, social determinants, or comorbidities could improve efficiency, but raise ethical and equity considerations.
Helicobacter pylori promotes invasion and metastasis of gastric cancer by enhancing heparanase expression

AIM To detect the mechanisms of Helicobacter pylori (H. pylori) infection in the invasion and metastasis of gastric cancer (GC). METHODS Specimens from 99 patients with GC were collected. The correlation among H. pylori infection, heparanase (HPA) and mitogen-activated protein kinase (MAPK) expression, which was determined by immunohistochemistry, and the clinical features of GC was analysed using SPSS 22.0. Overall survival (OS) and relapse-free survival (RFS) of GC patients were estimated by the Kaplan-Meier method. Independent and multiple factors of HPA and MAPK with prognosis were determined with COX proportional hazards models. HPA and MAPK expression in MKN-45 cells infected with H. pylori was analysed using Western blot. RESULTS H. pylori infection was observed in 70 of 99 patients with GC (70.7%), which was significantly higher than that in healthy controls. H. pylori infection was related to lymph metastasis and expression of HPA and MAPK (P < 0.05); HPA expression was relevant to MAPK expression (P = 0.024). HPA and MAPK expression in MKN-45 cells was significantly upregulated following H. pylori infection and peaked at 24 h and 60 min, before decreasing (P < 0.05). SB203580, an inhibitor of MAPK, significantly decreased HPA expression. HPA was related to lymph metastasis and invasive depth. HPA positive GC cases and H. pylori positive GC cases showed poorer prognosis than HPA negative cases (P < 0.05). COX models showed that the prognosis of GC was connected with HPA expression, lymph metastasis, tissue differentiation, and invasive depth. CONCLUSION H. pylori may promote the invasion and metastasis of GC by increasing HPA expression that may associate with MAPK activation, thus causing a poorer prognosis of GC.
Shoal choice in zebrafish, Danio rerio: the influence of shoal size and activity

Shoaling fish are expected, in many cases, to gain fitness benefits from being in a larger shoal and previous experiments have shown that fish are indeed capable of choosing between shoals of different sizes. We investigated the influence of shoal activity on shoal size preference in the zebrafish. We gave test fish the choice between shoals of one to four stimulus fish, presented at two different water temperatures, and so differing in their activity levels. Where all stimulus fish were in water of the same temperature, test fish generally preferred the larger shoal. However, this preference could be reduced by presenting the larger shoal in colder water and so reducing its activity. We discuss these findings with reference to the factors that may influence shoal activity, the effect of temperature on shoaling behaviour and the mechanisms that may be used by fish to discriminate shoal size.
Landscape of gene transposition–duplication within the Brassicaceae family

Gene duplication, deletion, and transposition erode co-linearity between genomes over time, providing a substantial source of genomic structural variations. We developed CLfinder-OrthNet pipeline to systematically trace gene duplication and transposition events by building networks based on co-linearity among orthologs (OrthNets) from multiple closely related genomes. Using this pipeline, we explored evolutionary events that result in erosion of co-linearity among six genomes in Brassicaceae, including the model plant Arabidopsis thaliana and two extremophyte wild-relatives of Brassica crops adapted to highly saline habitats. Out of 17,432 OrthNets derived from the six Brassicaceae genomes, 7,034 consisted of six co-linear orthologs, one from each genome, while the remaining included various degrees and combinations of gene duplication, deletion, and transposition. We focused on transposition-duplication (tr-d) events that lead to variations in both gene copy number and co-linearity. OrthNets identified a landscape of tr-d events including those with signatures of selective retention and putative sub-functionalization in all six genomes. These included lineage-specific tr-d of genes that may be critical for the local adaptation of extremophytes, such as orthologs of SALT TOLERANCE 32 and ZINC TRANSPORTER 3. Among tr-d events uniquely shared by the two extremophytes, those resulted in duplication of putatively functional full-length ORFs were mostly derived from their common ancestor rather than from parallel independent events. Our approach enabled systematic detection and representation of a complex mosaic of evolutionary events among multiple genomes, as well as identification of candidate genes that may have played roles in the adaptation uniquely found in specific lineages.
Modulation of NKG2D, NKp46, and Ly49C/I facilitates natural killer cell-mediated control of lung cancer

Significance Lung cancer is unique among solid tumors as robust natural killer (NK) cell function correlates with resistance to disease. Here we describe that NK cell education by major histocompatibility class I (MHCI) leads to the up-regulation of NKG2D- and NKp46-activating receptors that recognize lung cancer. We further demonstrate that upon activation NK cells down-regulate the expression of the Ly49C/I inhibitory receptor, thus eliminating target interference by MHCI. Our findings are significant based on the demonstration that NK cells that arise in an MHCI+/+ environment present a substantial barrier to the growth of lung cancer, and expression of both activating and inhibitory receptors is not fixed but varies based on environmental context. Natural killer (NK) cells play a critical role in controlling malignancies. Susceptibility or resistance to lung cancer, for example, specifically depends on NK cell function. Nevertheless, intrinsic factors that control NK cell-mediated clearance of lung cancer are unknown. Here we report that NK cells exposed to exogenous major histocompatibility class I (MHCI) provide a significant immunologic barrier to the growth and progression of malignancy. Clearance of lung cancer is facilitated by up-regulation of NKG2D, NKp46, and other activating receptors upon exposure to environmental MHCI. Surface expression of the inhibitory receptor Ly49C/I, on the other hand, is down-regulated upon exposure to tumor-bearing tissue. We thus demonstrate that NK cells exhibit dynamic plasticity in surface expression of both activating and inhibitory receptors based on the environmental context. Our data suggest that altering the activation state of NK cells may contribute to immunologic control of lung and possibly other cancers.
National incidence and survival of patients with non-invasive papillary urothelial carcinoma: a Danish population study

Abstract Objective: To estimate national relative survival of low and high grade non-invasive papillary urothelial carcinoma (Ta LG and Ta HG) and urothelial carcinoma in situ (CIS). Materials and methods: All Danish citizens (17,941 patients) with a primary urothelial bladder tumour diagnosis in the period 2000– 2010 were followed until 1 January 2016 and recorded in the Danish Bladder Cancer Cohort database. Survival was compared to the background population matched on age and gender and adjusted by civil status, income, education, and comorbidity. Results: Patients treated in daily practice with Ta LG have 46% (HR = 1.46 (1.42–1.51) p < 0.001) higher risk of death compared to a background population matched for age and gender. This risk of death ceases to 28% (HR = 1.28 (1.24–1.32) p < 0.001) after adjustment for civil status, income, education, and comorbidity. Relative survival of Ta LG patients is 0.94 (0.93–0.95). These estimates are constant throughout the observation period. Significantly higher mortality is found for patients with Ta HG and CIS, but, in contrast to Ta LG, the relative risk of death of Ta HG (HR = 1.79 (1.69–1.90) p < 0.001) and CIS (HR = 2.02 (1.79–2.26) p < 0.001) decreases considerably after 5 years survival (HR = 1.43 (1.30–1.57) p < 0.001 and HR = 1.64 (1.36–1.98) p < 0.001, respectively). Conclusion: Patients with Ta LG have a continuous lower survival and a 28% higher risk of death at any time compared to a matched background population when treated in daily practice.
Evolutionary conservation of Y Chromosome ampliconic gene families despite extensive structural variation

Despite claims that the mammalian Y Chromosome is on a path to extinction, comparative sequence analysis of primate Y Chromosomes has shown the decay of the ancestral single-copy genes has all but ceased in this eutherian lineage. The suite of single-copy Y-linked genes is highly conserved among the majority of eutherian Y Chromosomes due to strong purifying selection to retain dosage-sensitive genes. In contrast, the ampliconic regions of the Y Chromosome, which contain testis-specific genes that encode the majority of the transcripts on eutherian Y Chromosomes, are rapidly evolving and are thought to undergo species-specific turnover. However, ampliconic genes are known from only a handful of species, limiting insights into their long-term evolutionary dynamics. We used a clone-based sequencing approach employing both long- and short-read sequencing technologies to assemble ∼2.4 Mb of representative ampliconic sequence dispersed across the domestic cat Y Chromosome, and identified the major ampliconic gene families and repeat units. We analyzed fluorescence in situ hybridization, qPCR, and whole-genome sequence data from 20 cat species and revealed that ampliconic gene families are conserved across the cat family Felidae but show high transcript diversity, copy number variation, and structural rearrangement. Our analysis of ampliconic gene evolution unveils a complex pattern of long-term gene content stability despite extensive structural variation on a nonrecombining background.
Artificial colour mutation: do red-painted great tits experience increased or decreased predation?

A brightly coloured mutant may suffer increased predation (by being conspicuous) or may be favoured by reduced predation (if predators avoid novel or rare varieties). These alternatives were examined in a 2-year study of great tits,Parus majorby painting and ringing 1655 fledglings near 27 pairs of nesting sparrowhawks,Accipiter nisusA minority (<10%) of the great tits in each hawk territory were manipulated. On average, 40.7%of the fledglings in each brood were bright red, the others controls (yellow). Based on ring recoveries at hawk nests, the percentage of red tits taken was 5.5%, compared with 4.0% for controls, indicating an increase in predation rate by 38% for red birds. The results were similar in both years. However, using hawk pairs as sample units, predation risk was not significantly higher for red tits. Hawks that caught only one painted tit did not take red ones more often than expected, whereas those that caught two or more tits tended to take red ones more often. A predation cost for bright mutants may initially be low or absent, later increasing with the frequency of the mutant. In addition, tit parents fed red fledglings more often than controls, indicating a possible parental preference for red.
Cell engineering with microfluidic squeezing preserves functionality of primary immune cells in vivo

Significance Ex vivo manipulation of primary cells is critical to the success of this emerging generation of cell-based therapies, such as chimeric antigen receptor T cells for the treatment of cancer and CRISPR for the correction of developmental diseases. However, the limitations of existing delivery approaches may dramatically restrict the impact of genetic engineering to study and treat disease. In this paper, we compared electroporation to a microfluidic membrane deformation technique termed “squeezing” and found that squeezed cells had dramatically fewer side effects than electroporation and gene expression profiles similar to those of unmanipulated cells. The significant differences in outcomes from the two techniques underscores the importance of understanding the impact of intracellular delivery methods on cell function for research and clinical applications. The translational potential of cell-based therapies is often limited by complications related to effectively engineering and manufacturing functional cells. While the use of electroporation is widespread, the impact of electroporation on cell state and function has yet to be fully characterized. Here, we use a genome-wide approach to study optimized electroporation treatment and identify striking disruptions in the expression profiles of key functional transcripts of human T cells. These genetic disruptions result in concomitant perturbation of cytokine secretion including a 648-fold increase in IL-2 secretion (P < 0.01) and a 30-fold increase in IFN-γ secretion (P < 0.05). Ultimately, the effects at the transcript and protein level resulted in functional deficiencies in vivo, with electroporated T cells failing to demonstrate sustained antigen-specific effector responses when subjected to immunological challenge. In contrast, cells subjected to a mechanical membrane disruption-based delivery mechanism, cell squeezing, had minimal aberrant transcriptional responses [0% of filtered genes misregulated, false discovery rate (FDR) q < 0.1] relative to electroporation (17% of genes misregulated, FDR q < 0.1) and showed undiminished effector responses, homing capabilities, and therapeutic potential in vivo. In a direct comparison of functionality, T cells edited for PD-1 via electroporation failed to distinguish from untreated controls in a therapeutic tumor model, while T cells edited with similar efficiency via cell squeezing demonstrated the expected tumor-killing advantage. This work demonstrates that the delivery mechanism used to insert biomolecules affects functionality and warrants further study.