Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel phosphoglucomutase‐deficient mouse model reveals aberrant glycosylation and early embryonic lethality

Patients with phosphoglucomutase (PGM1) deficiency, a congenital disorder of glycosylation (CDG) suffer from multiple disease phenotypes. Midline cleft defects are present at birth. Overtime, additional clinical phenotypes, which include severe hypoglycemia, hepatopathy, growth retardation, hormonal deficiencies, hemostatic anomalies, frequently lethal, early‐onset of dilated cardiomyopathy and myopathy emerge, reflecting the central roles of the enzyme in (glycogen) metabolism and glycosylation. To delineate the pathophysiology of the tissue‐specific disease phenotypes, we constructed a constitutive Pgm2 (mouse ortholog of human PGM1)‐knockout (KO) mouse model using CRISPR‐Cas9 technology. After multiple crosses between heterozygous parents, we were unable to identify homozygous life births in 78 newborn pups (P = 1.59897E‐06), suggesting an embryonic lethality phenotype in the homozygotes. Ultrasound studies of the course of pregnancy confirmed Pgm2‐deficient pups succumb before E9.5. Oral galactose supplementation (9 mg/mL drinking water) did not rescue the lethality. Biochemical studies of tissues and skin fibroblasts harvested from heterozygous animals confirmed reduced Pgm2 enzyme activity and abundance, but no change in glycogen content. However, glycomics analyses in serum revealed an abnormal glycosylation pattern in the Pgm2+/− animals, similar to that seen in PGM1‐CDG.
Abnormal thalamocortical network dynamics in migraine

Objective To investigate the dynamic functional connectivity of thalamocortical networks in interictal migraine patients and whether clinical features are associated with abnormal connectivity. Methods We investigated dynamic functional network connectivity (dFNC) of the migraine brain in 89 interictal migraine patients and 70 healthy controls. We focused on the temporal properties of thalamocortical connectivity using sliding window cross-correlation, clustering state analysis, and graph-theory methods. Relationships between clinical symptoms and abnormal dFNC were evaluated using a multivariate linear regression model. Results Five dFNC brain states were identified to characterize and compare dynamic functional connectivity patterns. We demonstrated that migraineurs spent more time in a strongly interconnected between-network state, but they spent less time in a sparsely connected state. Interestingly, we found that abnormal posterior thalamus (pulvinar nucleus) dFNC with the visual cortex and the precuneus were significantly correlated with headache frequency of migraine. Further topologic measures revealed that migraineurs had significantly lower efficiency of information transfer in both global and local dFNC. Conclusion Our results demonstrated a transient pathologic state with atypical thalamocortical connectivity in migraineurs and extended current findings regarding abnormal thalamocortical networks and dysrhythmia in migraine.
Measurement of CSF α‐synuclein improves early differential diagnosis of mild cognitive impairment due to Alzheimer’s disease

Previous studies have indicated the potential of cerebrospinal fluid (CSF) α‐synuclein (α‐syn) to be an additional biomarker for improving differential diagnosis of Alzheimer’s disease (AD). We evaluated α‐syn diagnostic performance across a well‐characterized patient cohort with long‐term follow‐up. For this purpose, CSF α‐syn levels were determined in 25 subjects diagnosed with stable mild cognitive impairment (stable MCI; n = 25), 27 MCI cases due to AD (MCI‐AD; n = 32), 24 MCI cases due to Lewy body disease (MCI‐LBD; n = 24) and control subjects (Ctrl; n = 18). CSF α‐syn levels discriminate between the four groups. There were higher α‐syn levels in MCI‐AD patients and lower levels in MCI‐LBD patients. The combination of α‐syn and P‐tau resulted in a specificity of 99% and a sensitivity of 97% for MCI‐AD. MCI‐AD patients with early psychotic symptoms (n = 9) displayed a trend towards a decrease in P‐tau and α‐syn compared to the MCI‐AD patients without psychotic symptoms (n = 23). We conclude that adding CSF α‐syn to central core AD biomarkers improves an early differential diagnosis of MCI‐AD from other forms of MCI.
Community participation in health services development, implementation, and evaluation: A systematic review of empowerment, health, community, and process outcomes

Background Community participation is widely believed to be beneficial to the development, implementation and evaluation of health services. However, many challenges to successful and sustainable community involvement remain. Importantly, there is little evidence on the effect of community participation in terms of outcomes at both the community and individual level. Our systematic review seeks to examine the evidence on outcomes of community participation in high and upper-middle income countries. Methods and findings This review was developed according to PRISMA guidelines. Eligible studies included those that involved the community, service users, consumers, households, patients, public and their representatives in the development, implementation, and evaluation of health services, policy or interventions. We searched the following databases from January 2000 to September 2016: Medline, Embase, Global Health, Scopus, and LILACs. We independently screened articles for inclusion, conducted data extraction, and assessed studies for risk of bias. No language restrictions were made. 27,232 records were identified, with 23,468 after removal of duplicates. Following titles and abstracts screening, 49 met the inclusion criteria for this review. A narrative synthesis of the findings was conducted. Outcomes were categorised as process outcomes, community outcomes, health outcomes, empowerment and stakeholder perspectives. Our review reports a breadth of evidence that community involvement has a positive impact on health, particularly when substantiated by strong organisational and community processes. This is in line with the notion that participatory approaches and positive outcomes including community empowerment and health improvements do not occur in a linear progression, but instead consists of complex processes influenced by an array of social and cultural factors. Conclusion This review adds to the evidence base supporting the effectiveness of community participation in yielding positive outcomes at the organizational, community and individual level. Trial registration Prospero record number: CRD42016048244.
Adaptive pull-based policies for wide area data delivery

Wide area data delivery requires timely propagation of up-to-date information to thousands of clients over a wide area network. Applications include web caching, RSS source monitoring, and email access via a mobile network. Data sources vary widely in their update patterns and may experience different update rates at different times or unexpected changes to update patterns. Traditional data delivery solutions are either push-based, which requires servers to push updates to clients, or pull-based, which require clients to check for updates at servers. While push-based solutions ensure timely data delivery, they are not always feasible to implement and may not scale to a large number of clients. In this article, we present adaptive pull-based policies that explicitly aim to reduce the overhead of contacting remote servers, compared to existing pull-based policies, while meeting freshness requirements. We model updates to data sources using update histories, and present two novel history-based policies to estimate when updates occur; they are based on individual history and aggregate history. These policies are presented within an architectural framework that supports their deployment either client-side or server-side. We further develop two adaptive policies to handle objects that initially may have insufficient history or objects that experience changes in update patterns. Extensive experimental evaluation using three data traces from diverse applications shows that history-based policies can reduce contact between clients and servers by up to 60% compared to existing pull-based policies while providing a comparable level of data freshness. Our experiments further demonstrate that our adaptive policies can select the best policy to match the behavior of an object and perform better than any individual policy, thus they dominate standalone policies.
Peripheral GABA receptors regulate colonic afferent excitability and visceral nociception

While the presence of GABA receptors on primary afferents has been well described, most functional analyses have focused on the regulation of transmitter release from central terminals and/or signalling in the sensory neuron cell body. Evidence that GABA receptors are transported to peripheral terminals and that there are several sources of GABA in the colon raise the possibility that GABA signalling in the periphery may influence colonic afferent excitability. GABAA and GABAB are present and functional in the colon, where exogenous agonists decrease the excitability of colonic afferents and suppress visceral nociception. Endogenous GABA release within the colon is sufficient to establish the resting excitability of colonic afferents as well as the behavioural response to noxious stimulation of the colon, primarily via GABAA receptors. Peripheral GABA receptors may serve as a viable target for the treatment of visceral pain.
Local and regional scale habitat heterogeneity contribute to genetic adaptation in a commercially important marine mollusc (Haliotis rubra) from southeastern Australia

Characterising adaptive genetic divergence among conspecific populations is often achieved by studying genetic variation across defined environmental gradients. In marine systems this is challenging due to a paucity of information on habitat heterogeneity at local and regional scales and a dependency on sampling regimes that are typically limited to broad longitudinal and latitudinal environmental gradients. As a result, the spatial scales at which selection processes operate and the environmental factors that contribute to genetic adaptation in marine systems are likely to be unclear. In this study we explore patterns of adaptive genetic structuring in a commercially‐ harvested abalone species (Haliotis rubra) from southeastern Australia, using a panel of genome‐wide SNP markers (5,239 SNPs), and a sampling regime informed by marine LiDAR bathymetric imagery and 20‐year hindcasted oceanographic models. Despite a lack of overall genetic structure across the sampling distribution, significant genotype associations with heterogeneous habitat features were observed at local and regional spatial scales, including associations with wave energy, ocean current, sea surface temperature, and geology. These findings provide insights into the potential resilience of the species to changing marine climates and the role of migration and selection on recruitment processes, with implications for conservation and fisheries management. This study points to the spatial scales at which selection processes operate in marine systems and highlights the benefits of geospatially‐informed sampling regimes for overcoming limitations associated with marine population genomic research.
Interaction between the ADAMTS-12 metalloprotease and fibulin-2 induces tumor-suppressive effects in breast cancer cells

Balance between pro-tumor and anti-tumor effects may be affected by molecular interactions within tumor microenvironment. On this basis we searched for molecular partners of ADAMTS-12, a secreted metalloprotease that shows both oncogenic and tumor-suppressive effects. Using its spacer region as a bait in a yeast two-hybrid screen, we identified fibulin-2 as a potential ADAMTS-12-interacting protein. Fibulins are components of basement membranes and elastic matrix fibers in connective tissue. Besides this structural function, fibulins also play crucial roles in different biological events, including tumorigenesis. To examine the functional consequences of the ADAMTS-12/fibulin-2 interaction, we performed different in vitro assays using two breast cancer cell lines: the poorly invasive MCF-7 and the highly invasive MDA-MB-231. Overall our data indicate that this interaction promotes anti-tumor effects in breast cancer cells. To assess the in vivo relevance of this interaction, we induced tumors in nude mice using MCF-7 cells expressing both ADAMTS-12 and fibulin-2 that showed a remarkable growth deficiency. Additionally, we also found that ADAMTS-12 may elicit pro-tumor effects in the absence of fibulin-2. Immunohistochemical staining of breast cancer samples allowed the detection of both ADAMTS-12 and fibulin-2 in the connective tissue surrounding tumor area in less aggressive carcinomas. However, both proteins are hardly detected in more aggressive tumors. These data and survival analysis plots of breast cancer patients suggest that concomitant detection of ADAMTS-12 and fibulin-2 could be a good prognosis marker in breast cancer diagnosis.
CD276 and the gene signature composed of GATA3 and LGALS3 enable prognosis prediction of glioblastoma multiforme

Glioma is the most common type of primary brain tumor, accounting for 40% of malignant brain tumors. Although a single gene may not be a marker, an expression profiling and multivariate analyses for cancer immunotherapy must estimate survival of patients. In this study, we conducted expression profiling of immunotherapy-related genes, including those in Th1/2 helper T and regulatory T cells, and stimulatory and inhibitory checkpoint molecules associated with survival prediction in 571 patients with malignant and aggressive form of gliomas, glioblastoma multiforme (GBM). Expression profiling and Random forests analysis of 21 immunosuppressive genes and Kaplan-Meier analysis in 158 patients in the training data set suggested that CD276, also known as B7-H3, could be a single gene marker candidate. Furthermore, prognosis prediction formulas, composed of Th2 cell-related GATA transcription factor 3 (GATA3) and immunosuppressive galactose-specific lectin 3 (LGALS3), based on 67 immunotherapy-related genes showed poor survival with high scores in training data set, which was also validated in another 413 patients in the test data set. The CD276 expression helped distinguish survival curves in the test data set. In addition, inhibitory checkpoint genes, including T cell immunoreceptor with Ig and ITIM domains, V-set domain containing T cell activation inhibitor 1, T-cell immunoglobulin and mucin-domain containing 3, and tumor necrosis factor receptor superfamily 14, showed potential as secondary marker candidates. These results suggest that CD276 expression and the gene signature composed of GATA3 and LGALS3 are effective for prognosis in GBM and will help us understanding target pathways for immunotherapy in GBM.
Seifert-fibered surgeries which do not arise from primitive/Seifert-fibered constructions

We construct two infinite families of knots each of which admits a Seifert fibered surgery with none of these surgeries coming from Dean's primitive/Seifert-fibered construction. This disproves a conjecture that all Seifert-fibered surgeries arise from Dean's primitive/Seifert-fibered construction. The (-3, 3,5)-pretzel knot belongs to both of the infinite families.
Extrinsic Primary Afferent Neurons Link Visceral Pain to Colon Motility Through a Spinal Reflex in Mice.

BACKGROUND & AIMS Proper colon function requires signals from extrinsic primary afferent neurons (ExPANs) located in spinal ganglia. Most ExPANs express the vanilloid receptor TRPV1 and a dense plexus of TRPV1-positive fibers is found around myenteric neurons. Capsaicin, a TRPV1 agonist, can initiate activity in myenteric neurons and produce muscle contraction. ExPANs might therefore form motility-regulating synapses onto myenteric neurons. ExPANs mediate visceral pain and myenteric neurons mediate colon motility, so we investigated communication between ExPANs and myenteric neurons and the circuits by which ExPANs modulate colon function. METHODS In live mice and colon tissues that express a transgene encoding the calcium indicator GCaMP, we visualized levels of activity in myenteric neurons during smooth muscle contractions induced by application of capsaicin, direct colon stimulation, stimulation of ExPANs, or stimulation of preganglionic parasympathetic neuron (PPN) axons. To localize central targets of ExPANs, we optogenetically activated TRPV1-expressing ExPANs in live mice and then quantified Fos immunoreactivity to identify activated spinal neurons. RESULTS Focal electrical stimulation of mouse colon produced phased-locked calcium signals in myenteric neurons and produced colon contractions. Stimulation of the L6 ventral root, which contains PPN axons, also produced myenteric activation and contractions that were comparable to those of direct colon stimulation. Surprisingly, capsaicin application to the isolated L6 dorsal root ganglia, which produced robust calcium signals in neurons throughout the ganglion, did not activate myenteric neurons. Electrical activation of the ganglia, which activated even more neurons than capsaicin, did not produce myenteric activation or contractions unless the spinal cord was intact, indicating that a complete afferent to efferent (PPN) circuit was necessary for ExPANs to regulate myenteric neurons. In TRPV1-channel rhodopsin-2 mice, light activation of ExPANs induced a pain-like visceromotor response and expression of Fos in spinal PPN neurons. CONCLUSIONS In mice, ExPANs regulate myenteric neuron activity and smooth muscle contraction via a parasympathetic spinal circuit, linking sensation and pain to motility.
Growing up with your airway microbiota: a risky business

Childhood is a critical time for respiratory health, with environmental and infectious exposures being linked to future respiratory disease and susceptibility.1 2 Respiratory microbiome research has introduced a new context for these exposures due to the presence of a pre-existing microbial community in both the upper and lower respiratory tract in healthy children.3–5 Variation in community composition has been observed in chronic lung diseases,6 7 and particular micro-organisms or combinations of organisms in infants have been associated with future disease development. Thus deviation from a healthy microbiota in early life appears to play an important role in disease development, with changes evident by 1 week of age.8 The dynamics of the infant airway microbiota and its relationship to disease development has therefore been the focus of increasing attention. Acute respiratory infections (ARIs) are common in children under 5 years of age,9 and indications suggest that susceptibility might be, at least partly, determined by the microbiota.5 8 Toivonen and colleagues10 have conducted the largest study of the respiratory microbiome in infants to date, obtaining a nasal swab at 2 months of age from 839 infants and parent-recorded data on respiratory infections until 24 months of age to look at the incidence of ARI. The study was conducted, described and controlled, taking into account many of the methodological issues that can arise when using the 16S …
An active differential broad-band phase splitter for quadrature-modulator applications

Area-efficient single-ended-to-differential phase-splitter (balun) integration is difficult for frequencies below 6 GHz. Few broad-band solutions are available, and those given in the literature often introduce quite high amplitude and/or phase errors to differential signaling. In this paper, a cascade of differential pairs is shown always to outperform any single-stage solution, and the measurement data for a two-amplifier prototype are supplied to support the theory. The prototype circuit was realized on 0.8-mum SiGe as a 2.5-V RF integrated circuit measuring 1.2times1. 2 mm2 including pads. The measured gain error is better than -1 dB up to 4.6 GHz, while phase difference is between 179.7deg-180.9deg in 0.6-4.1 GHz. The application of the realized phase splitter in a broad-band quadrature modulator is discussed
Nano‐selenium attenuates nickel‐induced testosterone synthesis disturbance through inhibition of MAPK pathways in Sprague‐Dawley rats

The aim of this study was to investigate the protective effects of Nano‐Se against Ni‐induced testosterone synthesis disorder in rats and determine the underlying protective mechanism. Sprague‐Dawley rats were co‐treated with Ni (5.0 mg/kg, i.p.) and Nano‐Se (0.5, 1.0, and 2.0 mg/kg, oral gavage) for 14 days after which various endpoints were evaluated. The Ni‐induced abnormal pathological changes and elevated 8‐OHdG levels in the testes were attenuated by Nano‐Se administration. Importantly, decreased serum testosterone levels in the Ni‐treated rats were significantly restored by Nano‐Se treatment, particularly at 1.0 and 2.0 mg/kg. Furthermore, the mRNA and protein levels of testosterone synthetase were increased by Nano‐Se compared to the Ni group, whereas phosphorylated protein expression levels of mitogen‐activated protein kinase (MAPK) pathways were suppressed by Nano‐Se administration in the Ni‐treated rats. Overall, the results suggest that Nano‐Se may ameliorate the Ni‐induced testosterone synthesis disturbance via the inhibition of ERK1/2, p38, and JNK MAPK pathways.
Pro-Inflammatory Cytokine IL-1β Up-Regulates CXC Chemokine Receptor 4 via Notch and ERK Signaling Pathways in Tongue Squamous Cell Carcinoma

Chronic inflammation contributes to tumor development through the induction of oncogenic mutations, genomic instability, early tumor promotion, and enhanced angiogenesis. Here, we report that IL-1 receptor 1 (IL-1R1) was expressed in 40 of 41 human tongue squamous cell carcinomas (TSCC). IL-1β up-regulated the expression of CXCR4, a CXC chemokine receptor that mediates cancer growth and metastasis, at both mRNA and protein levels in Tca8113 TSCC cells. IL-1β treatment of Tca8113 cells promoted migration in response to CXCR4 ligand stromal-derived factor α (SDF-1α). The inhibition of IL-1R1 by its antagonist IL-1Ra or RNA interference significantly reversed the up-regulation of CXCR4 induced by IL-1β. IL-1R1 activation also up-regulated the expression of IL-1β itself, suggesting a positive feedback regulation of CXCR4 expression. Furthermore, IL-1β induced the activation of Notch, which was originally considered a stem cell regulator. Pharmacological inhibition of Notch signaling reversed the up-regulation of CXCR4 induced by IL-1β, suggesting that Notch signaling may be involved in the growth and metastasis of cancers via up-regulation of CXCR4. In addition, IL-1β induced the activation of extracellular signal regulated kinase (ERK) and ERK inhibition decreased the up-regulation of CXCR4 induced by IL-1β, suggesting the involvement of ERK signaling in cancer metastasis. Taken together these data suggest that IL-1β and IL-1R1 promote cancer growth and metastasis by up-regulating CXCR4 expression and that CXCR4 may be a link between inflammation and cancer.