Miracle-dz/UniFAR-FTUs huggingface dataset:
Alpha-5 Integrin Mediates Simvastatin-Induced Osteogenesis of Bone Marrow Mesenchymal Stem Cells

Simvastatin (SVS) promotes the osteogenic differentiation of mesenchymal stem cells (MSCs) and has been studied for MSC-based bone regeneration. However, the mechanism underlying SVS-induced osteogenesis is not well understood. We hypothesize that α5 integrin mediates SVS-induced osteogenic differentiation. Bone marrow MSCs (BMSCs) derived from BALB/C mice, referred to as D1 cells, were used. Alizarin red S (calcium deposition) and alkaline phosphatase (ALP) staining were used to evaluate SVS-induced osteogenesis of D1 cells. The mRNA expression levels of α5 integrin and osteogenic marker genes (bone morphogenetic protein-2 (BMP-2), runt-related transcription factor 2 (Runx2), collagen type I, ALP and osteocalcin (OC)) were detected using quantitative real-time PCR. Surface-expressed α5 integrin was detected using flow cytometry analysis. Protein expression levels of α5 integrin and phosphorylated focal adhesion kinase (p-FAK), which is downstream of α5 integrin, were detected using Western blotting. siRNA was used to deplete the expression of α5 integrin in D1 cells. The results showed that SVS dose-dependently enhanced the gene expression levels of osteogenic marker genes as well as subsequent ALP activity and calcium deposition in D1 cells. Upregulated p-FAK was accompanied by an increased protein expression level of α5 integrin after SVS treatment. Surface-expressed α5 integrin was also upregulated after SVS treatment. Depletion of α5 integrin expression significantly suppressed SVS-induced osteogenic gene expression levels, ALP activity, and calcium deposition in D1 cells. These results identify a critical role of α5 integrin in SVS-induced osteogenic differentiation of BMSCs, which may suggest a therapeutic strategy to modulate α5 integrin/FAK signaling to promote MSC-based bone regeneration.
Seasonal malaria chemoprevention packaged with malnutrition prevention in northern Nigeria: A pragmatic trial (SMAMP study) with nested case-control

Integrating seasonal malaria chemoprevention (SMC), recommended by the WHO since 2012 to prevent malaria infection, with nutrition interventions may improve health outcomes and operational efficiencies. This study assessed the effects of co-packaging interventions on distribution coverage, nutrition, and clinical malaria outcomes in northern Nigeria. From August to November 2014, community volunteers delivered sulfadoxine-pyrimethamine and amodiaquine (SP-AQ) door-to-door each month to approximately 7,000 children aged 6–24 months in seven wards of Madobi, Kano State, Nigeria. In three of the wards children additionally received a lipid-based nutrient supplement (LNS–medium quantity), Plumpy Doz. Coverage, adherence, and anthropometric outcomes were assessed through baseline, midline, and endline household surveys. A facility-based case-control study was also conducted to estimate impact on clinical malaria outcomes. Coverage of SP-AQ was similar between arms at 89% (n = 2,409 child-months [88–90%]) in the SP-AQ only arm and 90% (n = 1,947 child-months [88–92%]) in the SP-AQ plus LNS arm (p = 0.52). Coverage of LNS was 83% (n = 2,409 child-months [81–84%]). Whilst there were marked changes in anthropometric status between baseline, midline and endline, these were largely accounted for by socioeconomic status and must be interpreted with care due to possible measurement issues, especially length-based indices. Overall nutritional status of our most robust measure, weight-for-age, does appear to have improved by endline, but was similar in the two study arms, suggesting no additional benefit of the LNS. While the odds of clinical malaria among those who received the intended intervention were lower in each study arm compared to children who did not receive interventions (SP-AQ only OR = 0.23 [0.09–0.6]; SP-AQ plus LNS OR = 0.22 [0.09–0.55]), LNS was not shown to have an additional impact. Coverage of SMC was high regardless of integrating LNS delivery into the SMC campaign. Supplementation with LNS did not appear to impact nutritional outcomes, but appeared to enhance the impact of SP-AQ on clinical odds of malaria. These results indicate that combining nutritional interventions with seasonal malaria chemoprevention in high-risk areas can be done successfully, warranting further exploration with other products or dosing. Trial Registration: ISRCTN 11413895
Triglyceride-to-High-Density Lipoprotein Cholesterol Ratio and Systemic Inflammation in Patients with Idiopathic Pulmonary Arterial Hypertension

Background Idiopathic pulmonary arterial hypertension (IPAH) patients are characterized by elevated triglyceride (TG)-to-HDL cholesterol (HDL-C) ratio, which has been proposed to be an important prognostic factor in this population. The mechanism of this phenomenon remains unknown. We therefore investigated the potential determinants of increased TG/HDL-C ratio in IPAH patients. Material/Methods We prospectively recruited consecutive clinically stable IPAH patients between January 2016 and February 2017. Patients with diabetes or using statins were excluded. Anthropometric measurements included body mass index (BMI) and skinfold thickness; body fat mass was calculated using age and sex-specific equations. We assessed lipid profile, homeostatic model assessment of insulin resistance (HOMA-IR), serum adipokine levels (adiponectin, resistin, leptin, and visfatin), and circulating cytokines (IL-1β, IL-6, MCP-1, and TNF-α). Results We assessed 47 IPAH patients: 9 of them had been diagnosed with diabetes and 10 were treated with statins; therefore, were excluded them from further analysis. Age, sex distribution, and BMI were similar irrespectively of TG/HDL-C ratio. Patients with increased TG/HDL-C ratio (>3) as compared to patients with TG/HDL-C ≤3 were characterized by higher levels of IL-1β, MCP-1, and IL-6. TG level was correlated with IL-1β (R=0.76, p<0.001), IL-6 (R=0.52, p=0.005), TNF-α (R=0.62, p<0.001), and MCP-1 (R=0.63, p<0.001). IL-1β was also inversely correlated with HDL-C (R=−0.44, p=0.02). We found no differences in concentration of fasting glucose, insulin, HOMA-IR, body fat content, or adipokine levels between patients with higher and lower TG/HDL-C ratios. Conclusions In IPAH patients, elevated TG/HDL-C ratio is a marker of systemic inflammation.
Effect of Sec61 interaction with Mpd1 on endoplasmic reticulum-associated degradation

Proteins that misfold in the endoplasmic reticulum (ER) are transported back to the cytosol for ER-associated degradation (ERAD). The Sec61 channel is one of the candidates for the retrograde transport conduit. Channel opening from the ER lumen must be triggered by ERAD factors and substrates. Here we identified new lumenal interaction partners of Sec61 by chemical crosslinking and mass spectrometry. In addition to known Sec61 interactors we detected ERAD factors including Cue1, Ubc6, Ubc7, Asi3, and Mpd1. We show that the CPY* ERAD factor Mpd1 binds to the lumenal Sec61 hinge region. Deletion of the Mpd1 binding site reduced the interaction between both proteins and caused an ERAD defect specific for CPY* without affecting protein import into the ER or ERAD of other substrates. Our data suggest that Mpd1 binding to Sec61 is a prerequisite for CPY* ERAD and confirm a role of Sec61 in ERAD of misfolded secretory proteins.
Evidence that nonsignificant results are sometimes preferred: Reverse P-hacking or selective reporting?

There is increased concern about poor scientific practices arising from an excessive focus on P-values. Two particularly worrisome practices are selective reporting of significant results and ‘P-hacking’. The latter is the manipulation of data collection, usage, or analyses to obtain statistically significant outcomes. Here, we introduce the novel, to our knowledge, concepts of selective reporting of nonsignificant results and ‘reverse P-hacking’ whereby researchers ensure that tests produce a nonsignificant result. We test whether these practices occur in experiments in which researchers randomly assign subjects to treatment and control groups to minimise differences in confounding variables that might affect the focal outcome. By chance alone, 5% of tests for a group difference in confounding variables should yield a significant result (P < 0.05). If researchers less often report significant findings and/or reverse P-hack to avoid significant outcomes that undermine the ethos that experimental and control groups only differ with respect to actively manipulated variables, we expect significant results from tests for group differences to be under-represented in the literature. We surveyed the behavioural ecology literature and found significantly more nonsignificant P-values reported for tests of group differences in potentially confounding variables than the expected 95% (P = 0.005; N = 250 studies). This novel, to our knowledge, publication bias could result from selective reporting of nonsignificant results and/or from reverse P-hacking. We encourage others to test for a bias toward publishing nonsignificant results in the equivalent context in their own research discipline.
In Vitro–In Vivo Extrapolation of Key Transporter Activity at the Blood–Brain Barrier

Understanding the quantitative implications of P-glycoprotein and breast cancer resistance protein efflux is a key hurdle in the design of effective, centrally acting or centrally restricted therapeutics. Previously, a comprehensive physiologically based pharmacokinetic model was developed to describe the in vivo unbound brain-to-plasma concentration ratio as a function of efflux activity measured in vitro. In the present work, the predictive utility of this framework was examined through application to in vitro and in vivo data generated on 133 unique compounds across three preclinical species. Two approaches were examined for the scaling of efflux activity to in vivo, namely relative expression as determined by independent proteomics measurements and relative activity as determined via fitting the in vivo neuropharmacokinetic data. The results with both approaches indicate that in vitro efflux data can be used to accurately predict the degree of brain penetration across species within the context of the proposed physiologically based pharmacokinetic framework.
A large scale screening study with a SMR-based BCI: Categorization of BCI users and differences in their SMR activity

Brain-Computer Interfaces (BCIs) are inefficient for a non-negligible part of the population, estimated around 25%. To understand this phenomenon in Sensorimotor Rhythm (SMR) based BCIs, data from a large-scale screening study conducted on 80 novice participants with the Berlin BCI system and its standard machine-learning approach were investigated. Each participant performed one BCI session with resting state Encephalography, Motor Observation, Motor Execution and Motor Imagery recordings and 128 electrodes. A significant portion of the participants (40%) could not achieve BCI control (feedback performance > 70%). Based on the performance of the calibration and feedback runs, BCI users were stratified in three groups. Analyses directed to detect and elucidate the differences in the SMR activity of these groups were performed. Statistics on reactive frequencies, task prevalence and classification results are reported. Based on their SMR activity, also a systematic list of potential reasons leading to performance drops and thus hints for possible improvements of BCI experimental design are given. The categorization of BCI users has several advantages, allowing researchers 1) to select subjects for further analyses as well as for testing new BCI paradigms or algorithms, 2) to adopt a better subject-dependent training strategy and 3) easier comparisons between different studies.
Dairy Product Consumption and Metabolic Diseases in the Di@bet.es Study

To date it is not clear what the role of dairy products is in metabolic diseases like diabetes, obesity, and hypertension. Therefore, the aim of this study is to test the association between dairy product consumption and those pathologies. A cross-sectional study was conducted with 5081 adults included in the di@bet.es study, from 100 health centers around Spain. Food frequency questionnaires were carried out concerning consumption habits, which included dairy product consumption. Logistic regression models were used for the association analyses between the variables controlling confounding variables. Women had a higher consumption of milk, cheese, or yogurt than men (p < 0.0001), but men consumed more sugar dairy products (p < 0.001). People who live in the North of Spain consume more dairy products than those who live in the East. Dairy product consumption was inversely associated with the presence of hypertension regardless of age, sex, geographical region, and body mass index (BMI) (Odds Ratio (OR) 0.743; p = 0.022). The presence of obesity was inversely associated with dairy consumption regardless of age, sex, and geographical region (OR 0.61; p < 0.001). Milk consumption was not associated with diabetes. Our results show that consuming dairy products is associated with a better metabolic profile in the Spanish population.
A Polymeric Nanogel-Based Treatment Regimen for Enhanced Efficacy and Sequential Administration of Synergistic Drug Combination in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers. A combination of cisplatin (CDDP) and gemcitabine (Gem) treatment has shown favorable clinical results for metastatic disease; both are limited by toxicities and nontargeted delivery. More than 80% of PDAC aberrantly expresses the sialyl Tn (STn) antigen due to the loss of function of the core 1β3-Gal-T–specific molecular chaperone, a specific chaperone for the activity of core 1 β3-galactosyltransferase or C1GalT. Here, we report the development of polymeric nanogels (NGs) loaded with CDDP and coated with an anti-STn antigen–specific antibody (TKH2 monoclonal antibody) for the targeted treatment of PDAC. TKH2-functionalized, CDDP-loaded NGs delivered a significantly higher amount of platinum into the cells and tumors expressing STn antigens. We also confirmed that a synergistic cytotoxic effect of sequential exposure of pancreatic cancer cells to Gem followed by CDDP can be mimicked by the codelivery of CDDP-loaded NGs (NG/CDDP) and free Gem. In a murine orthotopic model of PDAC, combined simultaneous treatment with Gem and targeted NG/CDDP significantly attenuated tumor growth with no detectable acute toxicity. Altogether, these results suggest that combination therapy consisting of Gem followed by TKH2-conjugated CDDP NGs induces highly synergistic therapeutic efficacy against pancreatic cancer. Our results offer the basis for development of combination drug regimens using targeted nanomedicines to increase treatment effectiveness and improve outcomes of PDAC therapy.
Constrained Unscented Particle Filter for SINS/GNSS/ADS Integrated Airship Navigation in the Presence of Wind Field Disturbance

Due to the disturbance of wind field, it is difficult to achieve precise airship positioning and navigation in the stratosphere. This paper presents a new constrained unscented particle filter (UPF) for SINS/GNSS/ADS (inertial navigation system/global navigation satellite system/atmosphere data system) integrated airship navigation. This approach constructs a wind speed model to describe the relationship between airship velocity and wind speed using the information output from ADS, and further establishes a mathematical model for SINS/GNSS/ADS integrated navigation. Based on these models, it also develops a constrained UPF to obtain system state estimation for SINS/GNSS/ADS integration. The proposed constrained UPF uses the wind speed model to constrain the UPF filtering process to effectively resist the influence of wind field on the navigation solution. Simulations and comparison analysis demonstrate that the proposed approach can achieve optimal state estimation for SINS/GNSS/ADS integrated airship navigation in the presence of wind field disturbance.
It takes a village: channeling fatty acid metabolism and triacylglycerol formation via protein interactomes

Diet, hormones, gene transcription, and posttranslational modifications control the hepatic metabolism of FAs; metabolic dysregulation causes chronic diseases, including cardiovascular disease, and warrants exploration into the mechanisms directing FA and triacylglycerol (TAG) synthesis and degradation. Long-chain FA metabolism begins by formation of an acyl-CoA by a member of the acyl-CoA synthetase (ACSL) family. Subsequently, TAG synthesis begins with acyl-CoA esterification to glycerol-3-phosphate by a member of the glycerol-3-phosphate acyltransferase (GPAT) family. Our studies of the isoforms ACSL1 and GPAT1 strongly suggest that these proteins are members of larger protein assemblies (interactomes). ACSL1 targeted to the ER interacts with peroxisomal, lipid droplet, and tethering proteins, uncovering a dynamic role for ACSL1 in organelle and lipid droplet interactions. On the outer mitochondrial membrane (OMM), PPARα upregulates ACSL1, which interacts with proteins believed to tether lipid droplets to the OMM. In contrast, GPAT1 is upregulated nutritionally by carbohydrate and insulin in a coordinated sequence of enzyme reactions, from saturated FA formation via de novo lipogenesis to FA esterification by GPAT1 and entry into the TAG biosynthesis pathway. We propose that involved enzymes form a dynamic protein interactome that facilitates esterification and that other lipid-metabolizing pathways will exist in similar physiologically regulated interactomes. Graphical Abstract
A double-hit pre-eclampsia model results in sex-specific growth restriction patterns

ABSTRACT Pre-eclampsia is a multifactorial pregnancy-associated disorder characterized by angiogenic dysbalance and systemic inflammation; however, animal models that combine these two pathophysiological conditions are missing. Here, we introduce a novel double-hit pre-eclampsia mouse model that mimics the complex multifactorial conditions present during pre-eclampsia and allows for the investigation of early consequences for the fetus. Adenoviral overexpression of soluble fms-like tyrosine kinase (sFlt-1) and lipopolysaccharide (LPS) administration at mid-gestation in pregnant mice resulted in hypertension and albuminuria comparable to that of the manifestation in humans. A metabolomics analysis revealed that pre-eclamptic dams have increased plasma concentrations of phosphadytilcholines. The fetuses of both sexes were growth restricted; however, in males a brain-sparing effect was seen as compensation for this growth restriction. According to the plasma metabolomics, male fetuses showed changes in amino acid metabolism, while female fetuses showed pronounced alterations in lipid metabolism. Our results show that combined exposure to sFlt-1 and LPS mimics the clinical symptoms of pre-eclampsia and affects fetal growth in a sex-specific manner, with accompanying metabolome changes. Summary: Double-hit exposure to the anti-angiogenic factor soluble fms-like tyrosine kinase and the pro-inflammatory endotoxin lipopolysaccharide in mice provides a novel, comprehensive model of pre-eclampsia, which leads to sex-specific metabolomic differences in fetuses.
The Abbreviated Vigilance Task and Its Attentional Contributors

Objective: To measure contributing attentional processes, particularly that of executive attention, to two iterations of the abbreviated vigilance task. Background: Joel Warm was at the forefront of vigilance research for decades, and resource theory is currently the dominant explanation for the vigilance decrement. The underlying mechanisms contributing to both overall performance and the decrement are only partly understood. Method: Seventy-eight participants answered questionnaires about their attentional skills and stress state, performed the Attention Network Test and two blocks of the 12-min abbreviated vigilance task, with a brief break between the two vigils during which they viewed images intended to affect performance. Changes in oxygenated hemoglobin were measured with functional near-infrared imaging. Results: Expected patterns were observed for both iterations of the abbreviated vigilance task, with performance declining after the first 2 min. Manipulations intended to evaluate whether executive processes contributed to vigilance performance failed to observe an effect. Other factors, particularly orienting and alerting attentional networks, task engagement, and subclinical ADHD symptomology were associated with performance. Significant factors for the first and second vigilance blocks were different. Conclusion: We suggest that (a) cognitive control is not a predominant factor, at least for the abbreviated vigilance task, and (b) attentional mechanisms and stress states affecting performance on the abbreviated vigilance task change over time. Application: Potential applications of this research include the use of breaks for sustained attention tasks involving high sensory load, and implications for the use of the abbreviated vigilance task as a proxy for general vigilance processes.
LANA oligomeric architecture is essential for KSHV nuclear body formation and viral genome maintenance during latency

The molecular basis for the formation of functional, higher-ordered macro-molecular domains is not completely known. The Kaposi’s Sarcoma-Associated Herpesvirus (KSHV) genome forms a super-molecular domain structure during latent infection that is strictly dependent on the DNA binding of the viral nuclear antigen LANA to the viral terminal repeats (TR). LANA is known to form oligomeric structures that have been implicated in viral episome maintenance. In this study, we show that the LANA oligomerization interface is required for the formation of higher-order nuclear bodies that partially colocalize with DAXX, EZH2, H3K27me3, and ORC2 but not with PML. These nuclear bodies assemble at the periphery of condensed cellular chromosomes during mitotic cell division. We demonstrate that the LANA oligomerization interface contributes to the cooperative DNA binding at the viral TR and the recruitment of ORC to the viral episome. Oligomerization mutants failed to auto-regulate LANA/ORF73 transcription, and this correlated with the loss of a chromosome conformational DNA-loop between the TR and LANA promoter. Viral genomes with LANA oligomerization mutants were subject to genome rearrangements including the loss of subgenomic DNA. Our data suggests that LANA oligomerization drives stable binding to the TR and formation of an epigenetically stable chromatin architecture resulting in higher-order LANA nuclear bodies important for viral genome integrity and long-term episome persistence.