Miracle-dz/UniFAR-FTUs huggingface dataset:
Accuracy of presepsin in neonatal sepsis: systematic review and meta-analysis

ABSTRACT Introduction: Neonatal sepsis represents a major cause of morbidity and mortality in neonates. No diagnostic test has been demonstrated to be sufficiently accurate to confirm or exclude neonatal sepsis. This study aimed to evaluate the diagnostic accuracy of presepsin (P-SEP) for neonatal sepsis. Areas covered: A systematic review of literature was performed on Medline and EMBASE. A meta-analysis was performed to calculate pooled sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver operating characteristic of P-SEP for neonatal sepsis. Eight studies were included, involving 636 neonates. Pooled sensitivity and specificity were 0.90 and 0.90, respectively. The pooled DOR was 120.94, and the Area Under Curve (AUC) was 0.968, indicating a high level of diagnostic accuracy. Using cut-off values <600 ng/L, sensitivity reached 0.93, with a specificity of 0.81 and AUC 0.8195, while using a threshold >600 ng/L, sensitivity was 0.87 and specificity 0.97, with higher diagnostic accuracy (AUC 0.976). Significant heterogeneity was found between studies. Expert commentary: Diagnostic accuracy of P-SEP resulted high in detecting neonatal sepsis. Even though it cannot be recommended as a single diagnostic test, P-SEP could be a helpful and valuable biomarker in neonates with suspected sepsis.
Age‐related changes in the marmoset gut microbiome

The gut microbiome is known to play a significant role in human health but its role in aging remains unclear. The objective of this study was to compare the gut microbiome composition between young adult and geriatric non‐human primates (marmosets) as a model of human health and disease. Stool samples were collected from geriatric (8+ years) and young adult males (2–5 years). Stool 16S ribosomal RNA V4 sequences were amplified and sequenced on the Illumina MiSeq platform. Sequences were clustered into operational taxonomic units and classified via Mothur's Bayesian classifier referenced against the Greengenes database. A total of 10 young adult and 10 geriatric marmosets were included. Geriatric marmosets had a lower mean Shannon diversity compared with young marmosets (3.15 vs. 3.46; p = 0.0191). Geriatric marmosets had a significantly higher mean abundance of Proteobacteria (0.22 vs. 0.09; p = 0.0233) and lower abundance of Firmicutes (0.15 vs. 0.19; p = 0.0032) compared with young marmosets. Geriatric marmosets had a significantly higher abundance of Succinivibrionaceae (0.16 vs. 0.01; p = 0.0191) and lower abundance of Porphyromonadaceae (0.07 vs. 0.11; p = 0.0494). In summary, geriatric marmosets had significantly altered microbiome diversity and composition compared with young adult marmosets. Further studies are needed to test microbiome‐targeted therapies to improve healthspan and lifespan.
Death by HDAC Inhibition in Synovial Sarcoma Cells

Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting the causative SS18-SSX fusion oncoprotein are currently available. Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell-cycle arrest, neuronal differentiation, and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb group targets were reactivated, including tumor suppressor CDKN2A, and proapoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and proapoptotic factors BIK, BIM, and BMF were important to apoptosis induction following HDAC inhibition in synovial sarcoma. HDAC inhibitor pathway activation results in apoptosis and decreased tumor burden following a 7-day quisinostat treatment in the Ptenfl/fl;hSS2 mouse model of synovial sarcoma. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of clinical treatment. Mol Cancer Ther; 16(12); 2656–67. ©2017 AACR.
Age- and brain region-associated alterations of cerebral blood flow in early Alzheimer's disease assessed in AβPPSWE/PS1ΔE9 transgenic mice using arterial spin labeling

It has been suggested that cerebral blood flow (CBF) alterations may be involved in the pathogenesis of Alzheimer's disease (AD). However, how CBF changes with age has not been detailed in AD, particularly in its early stages. The objective of the present study was to evaluate CBF in four brain regions (the hippocampus, entorhinal cortex, frontoparietal cortex and thalamus) of mice in four age groups, to mimic the respective stages of AD in humans [2 months (pre-clinical), 3.5 months (sub-clinical), 5 months (early-clinical) and 8 months (mid-clinical)], to understand the age-associated changes in selected brain regions and to elucidate the underlying vascular mechanisms. CBF was measured using magnetic resonance imaging-arterial spin labelling (ASL) under identical conditions across the age groups of AβPPSWE/PS1ΔE9 (APP/PS1) transgenic mice with AD. The results indicated age- and brain region-associated changes in CBF were associated with early AD. More precisely, an age-dependent increase in CBF (in the pre- and sub-clinical AD groups) was observed in the frontoparietal cortex and thalamus. Conversely, increased CBF demonstrated an age-dependent decline (in the early- and mid-clinical AD groups) in all examined brain regions. Among the regions, the thalamus had the greatest increase in CBF in the 2 and 3.5 months age groups, which was substantially different compared with the age-matched controls. An extension of vessel area was also noted to be age- and brain region-dependent. In particular, correlation analysis revealed significant associations of CBF with vessel area in the frontoparietal cortex and thalamus of APP/PS1 mice at ages 2 and 3.5 months, indicating that CBF increase may arise from vessel extension. The results of the present study suggested that ASL can detect age- and brain region-associated changes in CBF in mice with AD, and that ASL-measured CBF increase may be a potential diagnostic biomarker for early AD. The observation that CBF increase resulted from vessel extension may aid in the understanding of the vascular role in age-associated development of AD pathology, and provide preclinical evidence for AD patient management.
Tissue 2-Hydroxyglutarate as a Biomarker for Isocitrate Dehydrogenase Mutations in Gliomas

Purpose: Isocitrate dehydrogenase (IDH) mutations are common in low-grade gliomas and the IDH mutation status is now integrated into the WHO classification of gliomas. IDH mutations lead to preferential accumulation of the R- relative to the S-enantiomer of 2-hydroxyglutarate (2-HG). We investigated the utility of tissue total 2-HG, R-2-HG, and the R-2-HG/S-2-HG ratio (rRS) as diagnostic and prognostic biomarkers for IDH mutations in gliomas. Experimental Design: Glioma tissue and blood samples from 87 patients were analyzed with HPLC-MS/MS coupled with a CHIROBIOTIC column to quantify both enantiomers of 2-HG. ROC analysis was conducted to evaluate the sensitivity and specificity of 2-HG, R-2-HG, and rRS. The feasibility of real-time determination of IDH status was evaluated in 11 patients intraoperatively. The prognostic value of rRS was evaluated using the Kaplan–Meier method. Results: The rRS in glioma tissues clearly distinguished patients with IDH-mutant versus wild-type tumors (P < 0.001). Sensitivity and specificity using an rRS cut-off value of 32.26 were 97% and 100%, respectively. None of total 2-HG, R-2-HG, or rRS was elevated in serum samples. Among patients with IDH-mutant tumors, tissue rRS stratifies overall survival. The duration of tissue analysis is approximately 60 minutes. Conclusions: Our study demonstrates that rRS is a reliable biomarker of IDH mutation status. This technique can be used to determine IDH mutation status intraoperatively, and to guide treatment decisions based on IDH mutation status in real time. Finally, rRS values may provide additional prognostic information and further validation is required.
Sensory Neuropathy Affects Cardiac miRNA Expression Network Targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2 mRNAs

Background: Here we examined myocardial microRNA (miRNA) expression profile in a sensory neuropathy model with cardiac diastolic dysfunction and aimed to identify key mRNA molecular targets of the differentially expressed miRNAs that may contribute to cardiac dysfunction. Methods: Male Wistar rats were treated with vehicle or capsaicin for 3 days to induce systemic sensory neuropathy. Seven days later, diastolic dysfunction was detected by echocardiography, and miRNAs were isolated from the whole ventricles. Results: Out of 711 known miRNAs measured by miRNA microarray, the expression of 257 miRNAs was detected in the heart. As compared to vehicle-treated hearts, miR-344b, miR-466b, miR-98, let-7a, miR-1, miR-206, and miR-34b were downregulated, while miR-181a was upregulated as validated also by quantitative real time polymerase chain reaction (qRT-PCR). By an in silico network analysis, we identified common mRNA targets (insulin-like growth factor 1 (IGF-1), solute carrier family 2 facilitated glucose transporter member 12 (SLC2a-12), eukaryotic translation initiation factor 4e (EIF-4e), and Unc-51 like autophagy activating kinase 2 (ULK-2)) targeted by at least three altered miRNAs. Predicted upregulation of these mRNA targets were validated by qRT-PCR. Conclusion: This is the first demonstration that sensory neuropathy affects cardiac miRNA expression network targeting IGF-1, SLC2a-12, EIF-4e, and ULK-2, which may contribute to cardiac diastolic dysfunction. These results further support the need for unbiased omics approach followed by in silico prediction and validation of molecular targets to reveal novel pathomechanisms.
Protocol for a randomised controlled trial to evaluate the effectiveness of the diabetes community exercise and education programme (DCEP) for long-term management of diabetes

Introduction Type 2 diabetes is common in Māori and Pacific peoples and in those living in areas of high socioeconomic deprivation in New Zealand (NZ). People with type 2 diabetes often have multimorbidity, which makes their diabetes management more complex. The Diabetes Community Exercise and Education Programme (DCEP) is an interprofessional, patient-centred, whānau (family)-supported package of care specifically developed to engage with Māori and Pacific people and those living in deprived areas. We have previously demonstrated the feasibility and acceptability of the DCEP. This study aims to determine the effectiveness and cost-effectiveness of the DCEP through a pragmatic randomised controlled trial (RCT). Methods and analysis 220 adults (age ≥35 years) with type 2 diabetes will be recruited from general practices in the lower South Island of NZ (Dunedin and Invercargill) to participate in an RCT. Participants will be randomised to intervention (DCEP) and control (usual care) groups. The DCEP participants will have their exercise goals agreed on with a physiotherapist and nurse and will attend two 90 min exercise and education sessions per week for 12 weeks. The primary outcome measure is blood glucose control (glycated haemoglobin). Secondary outcome measures include quality of life assessed using the Audit of Diabetes-Dependent Quality of Life questionnaire. Data will be collected at four time points: baseline, end of the 12-week intervention (3 months), 6 months postintervention (9 months) and 12 months after the intervention ends (15 months). We will also conduct a cost-effectiveness analysis and a qualitative process evaluation. Ethics and dissemination The study has been approved by the Health and Disability Ethics Committee, Ministry of Health (HDEC17/CEN/241/AM01). A key output will be the development of an evidence-based training package to facilitate implementation of the DCEP in other NZ regions. Trial registration number ACTRN 12617001624370 p; Pre-results.
Palmitate and Stearate are Increased in the Plasma in a 6-OHDA Model of Parkinson’s Disease

Introduction: Parkinson’s disease (PD) is the second most common neurodegenerative disorder, without any widely available curative therapy. Metabolomics is a powerful tool which can be used to identify unexpected pathway-related disease progression and pathophysiological mechanisms. In this study, metabolomics in brain, plasma and liver was investigated in an experimental PD model, to discover small molecules that are associated with dopaminergic cell loss. Methods: Sprague Dawley (SD) rats were injected unilaterally with 6-hydroxydopamine (6-OHDA) or saline for the vehicle control group into the medial forebrain bundle (MFB) to induce loss of dopaminergic neurons in the substantia nigra pars compacta. Plasma, midbrain and liver samples were collected for metabolic profiling. Multivariate and univariate analyses revealed metabolites that were altered in the PD group. Results: In plasma, palmitic acid (q = 3.72 × 10−2, FC = 1.81) and stearic acid (q = 3.84 × 10−2, FC = 2.15), were found to be increased in the PD group. Palmitic acid (q = 3.5 × 10−2) and stearic acid (q = 2.7 × 10−2) correlated with test scores indicative of motor dysfunction. Monopalmitin (q = 4.8 × 10−2, FC = −11.7), monostearin (q = 3.72 × 10−2, FC = −15.1) and myo-inositol (q = 3.81 × 10−2, FC = −3.32), were reduced in the midbrain. The liver did not have altered levels of these molecules. Conclusion: Our results show that saturated free fatty acids, their monoglycerides and myo-inositol metabolism in the midbrain and enteric circulation are associated with 6-OHDA-induced PD pathology.
Targeting mTOR in Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic disorder and constitutes approximately 25% of cancer diagnoses among children and teenagers. Pediatric patients have a favourable prognosis, with 5-years overall survival rates near 90%, while adult ALL still correlates with poorer survival. However, during the past few decades, the therapeutic outcome of adult ALL was significantly ameliorated, mainly due to intensive pediatric-based protocols of chemotherapy. Mammalian (or mechanistic) target of rapamycin (mTOR) is a conserved serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase family (PIKK) and resides in two distinct signalling complexes named mTORC1, involved in mRNA translation and protein synthesis and mTORC2 that controls cell survival and migration. Moreover, both complexes are remarkably involved in metabolism regulation. Growing evidence reports that mTOR dysregulation is related to metastatic potential, cell proliferation and angiogenesis and given that PI3K/Akt/mTOR network activation is often associated with poor prognosis and chemoresistance in ALL, there is a constant need to discover novel inhibitors for ALL treatment. Here, the current knowledge of mTOR signalling and the development of anti-mTOR compounds are documented, reporting the most relevant results from both preclinical and clinical studies in ALL that have contributed significantly into their efficacy or failure.
The MEK-ERK-MST1 Axis Potentiates the Activation of the Extrinsic Apoptotic Pathway during GDC-0941 Treatment in Jurkat T Cells

The discrete activation of individual caspases is essential during T-cell development, activation, and apoptosis. Humans carrying nonfunctional caspase-8 and caspase-8 conditional knockout mice exhibit several defects in the progression of naive CD4+ T cells to the effector stage. MST1, a key kinase of the Hippo signaling pathway, is often presented as a substrate of caspases, and its cleavage by caspases potentiates its activity. Several studies have focused on the involvement of MST1 in caspase activation and also reported several defects in the immune system function caused by MST1 deficiency. Here, we show the rapid activation of the MEK-ERK-MST1 axis together with the cleavage and activation of caspase-3, -6, -7, -8, and -9 after PI3K signaling blockade by the selective inhibitor GDC-0941 in Jurkat T cells. We determined the phosphorylation pattern of MST1 using a phosphoproteomic approach and identified two amino acid residues phosphorylated in an ERK-dependent manner after GDC-0941 treatment together with a novel phosphorylation site at S21 residue, which was extensively phosphorylated in an ERK-independent manner during PI3K signaling blockade. Using caspase inhibitors and the inhibition of MST1 expression using siRNA, we identified an exclusive role of the MEK-ERK-MST1 axis in the activation of initiator caspase-8, which in turn activates executive caspase-3/-7 that finally potentiate MST1 proteolytic cleavage. This mechanism forms a positive feed-back loop that amplifies the activation of MST1 together with apoptotic response in Jurkat T cells during PI3K inhibition. Altogether, we propose a novel MEK-ERK-MST1-CASP8-CASP3/7 apoptotic pathway in Jurkat T cells and believe that the regulation of this pathway can open novel possibilities in systemic and cancer therapies.
Optimization of Reconfigurable Satellite Constellations Using Simulated Annealing and Genetic Algorithm

Agile Earth observation can be achieved with responsiveness in satellite launches, sensor pointing, or orbit reconfiguration. This study presents a framework for designing reconfigurable satellite constellations capable of both regular Earth observation and disaster monitoring. These observation modes are termed global observation mode and regional observation mode, constituting a reconfigurable satellite constellation (ReCon). Systems engineering approaches are employed to formulate this multidisciplinary problem of co-optimizing satellite design and orbits. Two heuristic methods, simulated annealing (SA) and genetic algorithm (GA), are widely used for discrete combinatorial problems and therefore used in this study to benchmark against a gradient-based method. Point-based SA performed similar or slightly better than the gradient-based method, whereas population-based GA outperformed the other two. The resultant ReCon satellite design is physically feasible and offers performance-to-cost(mass) superior to static constellations. Ongoing research on observation scheduling and constellation management will extend the ReCon applications to radar imaging and radio occultation beyond visible wavelengths and nearby spectrums.
Stem cell-derived extracellular vesicles for myocardial infarction: a meta-analysis of controlled animal studies

Aims Stem cell-derived extracellular vesicles (EVs) have emerged as a promising therapy for myocardial infarction, but its effects remain incompletely understood. We aim to systematically review the efficacy of EVs on myocardial infarction in both small and large animals. Methods On April 5, 2018, we searched the PubMed, Embase and Web of Science databases using variations of “myocardial infarction” and “extracellular vesicle”. Controlled studies about the treatment effects of stem cell-derived EVs in myocardial infarction animal model were included. Meta-regression analysis was used to reveal the factors affecting the EVs treatments. Results Of 1210 studies retrieved, 24 were eligible for meta-analysis. EVs injection was associated with the improvements of left ventricular ejection fraction (12.65%), fractional shortening (7.54%) and the reduction of infarct size/area at risk (-15.55%). Meta-regression analysis did not reveal the association between treatment efficacy and type of stem cell, ligation-to-injection interval, route of delivery, dosage of delivery or follow-up period (all P values > 0.05). The median quality score of eligible studies was only 1, indicating potential risks of bias. Conclusion Stem cell-derived EVs improve cardiac function and reduce infarct size in myocardial infarction animals, but current pool-up study reveals no associations between common factors and treatment effects.
Is it possible to overcome the 'long arm' of childhood socioeconomic disadvantage through upward socioeconomic mobility?

OBJECTIVES Socioeconomically disadvantaged children have worse adult health; we test if this 'long arm' of childhood disadvantage can be overcome through upward socioeconomic mobility in adulthood. METHODS Four SES trajectories (stable low, upwardly mobile, downwardly mobile and stable high) were created from median dichotomized childhood socioeconomic status (SES; childhood human and financial capital) and adult SES (wealth at age 67) from Health and Retirement Study respondents (N = 6669). Healthy ageing markers, in tertiles, were walking speed, peak expiratory flow (PEF), and grip strength measured in 2008 and 2010. Multinomial logistic regression models, weighted to be nationally representative, controlled for age, gender, race, birthplace, outcome year and childhood health and social capital. RESULTS Upwardly mobile individuals were as likely as the stable high SES group to be in the best health tertile for walking speed (OR = 0.81; 95% CI: 0.63, 1.05; P = 0.114), PEF (OR = 0.97; 95% CI: 0.78, 1.21; P = 0.810) and grip strength (OR = 0.97; 95%CI: 0.74, 1.27; P = 0.980). DISCUSSION Findings suggest the 'long arm' of childhood socioeconomic disadvantage can be overcome for these markers of healthy ageing through upward socioeconomic mobility.
A Review of Design and Fabrication of the Bionic Flapping Wing Micro Air Vehicles

Bionic flapping-wing micro air vehicles (FWMAVs) are promising for a variety of applications because of their flexibility and high mobility. This study reviews the state-of-the-art FWMAVs of various research institutes driven by electrical motor, mechanical transmission structure and “artificial muscle” material and then elaborates on the aerodynamic mechanism of micro-winged birds and insects. Owing to their low mass budget, FWMAVs require actuators with high power density from micrometer to centimeter scales. The selection and design of the mechanical transmission should be considered in parallel with the design of the power electronic interface required to drive it. Finally, power electronic topologies suitable for driving “artificial muscle” materials used in FWMAVs are stated.
The effect of the mTOR inhibitor rapamycin on glucoCEST signal in a preclinical model of glioblastoma

The mammalian target of rapamycin is an enzyme that regulates cell metabolism and proliferation. It is up‐regulated in aggressive tumors, such as glioblastoma, leading to increased glucose uptake and consumption. It has been suggested that glucose CEST signals reflect the delivery and tumor uptake of glucose. The inhibitor rapamycin (sirolimus) has been applied as a glucose deprivation treatment; thus, glucose CEST MRI could potentially be useful for monitoring the tumor responses to inhibitor treatment.