Miracle-dz/UniFAR-FTUs huggingface dataset:
Elevated levels of extracellular vesicles in progranulin‐deficient mice and FTD‐GRN Patients

The goal of this study was to investigate the effect of progranulin insufficiency on extracellular vesicles (EVs), a heterogeneous population of vesicles that may contribute to progression of neurodegenerative disease. Loss‐of‐function mutations in progranulin (GRN) are a major cause of frontotemporal dementia (FTD), and brains from GRN carriers with FTD (FTD‐GRN) exhibit signs of lysosomal dysfunction. Lysosomal dysfunction may induce compensatory increases in secretion of exosomes, EVs secreted from the endolysosomal system, so we hypothesized that progranulin insufficiency would increase EV levels in the brain.
Severe Salmonella spp. or Campylobacter spp. Infection and the Risk of Biliary Tract Cancer: A Population-Based Study

Simple Summary Although it is known that bacterial infection may increase risk of cancer, the relationship between certain infections and cancer remains ill-quantified. To identify potential risk factors, this study compared the incidence of biliary tract cancer (BTC) in patients with Salmonella spp. or Campylobacter spp. infection to the general population in a large Western cohort of 16,252 salmonellosis and 27,668 campylobacteriosis patients. Standardized relative incidence ratio for BTC was 1.53 (95% CI 0.70–2.91) in salmonellosis patients and 0.97 (95% CI 0.39–2.00) in campylobacteriosis patients. Patients with Salmonella spp. infection and BTC were significantly younger than BTC patients without Salmonella spp. infection. Potentially, the study was underpowered to detect differences in cancer incidence, or cancer etiology in Western patients differs from those in non-Western countries and instead of bacterial infection, other factors contribute to cancer risk. Better understanding of cancer etiology is needed to identify risk factors and facilitate screening and early detection of cancer patients. Abstract Salmonella spp. infection has shown to have oncogenic transformative effects and thereby increases the risk of certain cancers. For Campylobacter spp. , similar effects have been demonstrated. Risk factor identification may allow for timely diagnosis and preventive treatment. To substantiate the oncogenic potential of Salmonella and Campylobacter spp. , this study compared the incidence of extrahepatic biliary tract cancer (BTC) in patients with diagnosed Salmonella or Campylobacter spp. infection with BTC incidence in the Netherlands. National infectious diseases surveillance records of patients diagnosed with a laboratory-confirmed Salmonella or Campylobacter spp. infection during 1999–2016 were linked to the Netherlands Cancer Registry. Incidence of BTC in Salmonella and Campylobacter spp. patients was compared to the incidence of BTC in the general population using Standardized Incidence Ratios (SIRs). In total, 16,252 patients were diagnosed with Salmonella spp. and 27,668 with Campylobacter spp. infection. Nine patients developed BTC at a median of 46 months (13–67) after Salmonella spp. infection and seven at a median of 60 months (18–138) after Campylobacter spp. infection. SIR of BTC in salmonellosis patients was 1.53 (95% CI 0.70–2.91). In patients aged <60 years, the SIR was 1.74 (95% CI 0.36–5.04). For campylobacteriosis patients, the SIR was 0.97 (95% CI 0.39–2.00). Even though Salmonella or Campylobacter spp. infection was not significantly associated with increased BTC risk in this cohort, it remains extremely important to study potential risk factors for cancer to facilitate screening and ultimately improve prognosis of cancer patients.
Mutation bias within oncogene families is related to proliferation-specific codon usage

Significance In light of the genetic code, combinations of three nucleotides which are known as synonymous codons, can give rise to the same amino acid. Despite the homology at the protein level, these different codons are recognized distinctly by the translational machinery. The unequal use of synonymous codons influences protein expression. Surprisingly, we find that the coding sequences of KRAS and other frequently mutated cancer genes are adapted to be efficiently translated in proliferating cells in comparison to their family counterparts. Our work contributes to the unsolved question of why in tumors some members of cancer gene families show a higher mutation rate than their family counterparts. Thus, our results elucidate the relationship between tRNA expression, codon usage, and oncogenicity. It is well known that in cancer gene families some members are more frequently mutated in tumor samples than their family counterparts. A paradigmatic case of this phenomenon is KRAS from the RAS family. Different explanations have been proposed ranging from differential interaction with other proteins to preferential expression or localization. Interestingly, it has been described that despite the high amino acid identity between RAS family members, KRAS employs an intriguing differential codon usage. Here, we found that this phenomenon is not exclusive to the RAS family. Indeed, in the RAS family and other oncogene families with two or three members, the most prevalently mutated gene in tumor samples employs a differential codon usage that is characteristic of genes involved in proliferation. Prompted by these observations, we chose the RAS family to experimentally demonstrate that the translation efficiency of oncogenes that are preferentially mutated in tumor samples is increased in proliferative cells compared to quiescent cells. These results were further validated by assessing the translation efficiency of KRAS in cell lines that differ in their tRNA expression profile. These differences are related to the cell division rate of the studied cells and thus suggest an important role in context-specific oncogene expression regulation. Altogether, our study demonstrates that dynamic translation programs contribute to shaping the expression profiles of oncogenes. Therefore, we propose this codon bias as a regulatory layer to control cell context-specific expression and explain the differential prevalence of mutations in certain members of oncogene families.
Parental benefits and offspring costs reflect parent–offspring conflict over the age of fledging among songbirds

Significance Parent–offspring conflict has explained a variety of ecological phenomena across animal taxa, but its role in mediating when songbirds fledge remains controversial. Our analysis of nesting and postfledging survival rates within 18 songbird species found that offspring commonly leave safer nesting environments for riskier postfledging ones—known as postfledging bottlenecks. This timing of fledging incurs a cost for offspring survival, but benefits adults by increasing their likelihood of raising at least one offspring to independence. Parents therefore appear to manipulate offspring into fledging earlier than expected based on the offspring’s ensuing survival prospects. Our results suggest that parent–offspring conflict and associated variation in parental benefits explain variation in fledging age among songbird species and why postfledging bottlenecks occur. Parent–offspring conflict has explained a variety of ecological phenomena across animal taxa, but its role in mediating when songbirds fledge remains controversial. Specifically, ecologists have long debated the influence of songbird parents on the age of fledging: Do parents manipulate offspring into fledging to optimize their own fitness or do offspring choose when to leave? To provide greater insight into parent–offspring conflict over fledging age in songbirds, we compared nesting and postfledging survival rates across 18 species from eight studies in the continental United States. For 12 species (67%), we found that fledging transitions offspring from comparatively safe nesting environments to more dangerous postfledging ones, resulting in a postfledging bottleneck. This raises an important question: as past research shows that offspring would benefit—improve postfledging survival—by staying in the nest longer: Why then do they fledge so early? Our findings suggest that parents manipulate offspring into fledging early for their own benefit, but at the cost of survival for each individual offspring, reflecting parent–offspring conflict. Early fledging incurred, on average, a 13.6% postfledging survival cost for each individual offspring, but parents benefitted through a 14.0% increase in the likelihood of raising at least one offspring to independence. These parental benefits were uneven across species—driven by an interaction between nest mortality risk and brood size—and predicted the age of fledging among species. Collectively, our results suggest that parent–offspring conflict and associated parental benefits explain variation in fledging age among songbird species and why postfledging bottlenecks occur.
Aleutian mink disease: Spatio‐temporal variation of prevalence and influence on the feral American mink

Abstract Pathogens are one of the factors driving wildlife population dynamics. The spread of pathogens in wildlife is currently highly related to the transmission of pathogens from farmed animals, which has increased with the constant development of farming. Here, we analysed the spatio‐temporal variation in the prevalence of Aleutian mink disease virus (AMDV) antibodies in feral American mink (Neovison vison) populations in Poland (1,153 individuals from nine sites) in relation to mink farming intensity. AMDV was detected in feral mink at all study sites and the prevalence ranged from 0.461 in the northern region to 0.826 in the western region. Mink males and adults were infected more often than females and subadults; the infection was also more frequent during the mink breeding season than during non‐breeding. The prevalence of AMDV changed non‐linearly in consecutive years and the peak of prevalence was every 3–4 years. The predicted AMDV prevalence was low at sites where the number of farmed mink was also low and increased linearly with the increase in the number of mink kept on farms. The predicted AMDV prevalence at sites with low mink farming intensity strongly varied between years, whereas at sites with high mink farming intensity, the predicted prevalence did not change significantly. AMDV infection affected the mink's body condition and caused an increase in the size of the spleen, liver and kidneys. This study shows that Aleutian mink disease strongly affects feral mink but the spatio‐temporal variation of its prevalence is complex and partly related to the transmission of the virus from farmed mink to feral populations. The study highlights the complexity of AMDV circulation in feral mink populations and implicates a potential spillover of the virus to native species.
Colon cancer combined with obesity indicates improved survival- research on relevant mechanism

Obesity contributes to the incidence of various tumors, including colon cancer. However, the impact of obesity on patients’ survival and related mechanisms remains unclear. Multi-omics data of 227 cases of colon cancer patients combined with clinical characteristics data were acquired from The Cancer Genome Atlas (TCGA) database. We confirmed obesity as an independent prognostic factor for improved overall survival of colon cancer patients. We demonstrated that hypoxia pathways were repressed in obese patients by regulating miR-210. Immune checkpoints PD-1 and LAG3 were also downregulated in obese patients, which indicated enhanced immune surveillance. The frequency of PIK3CA and KRAS mutations was decreased in obese patients. The sites and types of TP53 mutation were alternated in obesity patients. In conclusion, our research demonstrated the potential mechanisms of prolonged survival in colon cancer patients combined with obesity, which may provide potential value for improving the prognosis of colon cancer.
RGS12 Represses Oral Cancer via the Phosphorylation and SUMOylation of PTEN

Oral squamous cell carcinoma (OSCC) is the most common head and neck cancer characterized by aggressive local invasion and metastasis. The pathogenesis of OSCC is mainly due to the accumulation of genetic alterations in epithelial cells, but the underlying mechanism for its development remains unclear. Here, we found that the expression level of regulator of G protein signaling 12 (RGS12) was significantly reduced in human OSCC. To understand the role and mechanism of RGS12 in OSCC, we generated a novel RGS12 global knockout (CMVCre/+; RGS12fl/fl) mouse model by crossing RGS12fl/fl mice with CMV-Cre transgenic mice and then further induced the mice to develop OSCC by using 4-nitroquinoline 1-oxide (4NQO). Deletion of RGS12 exhibited aggressive OSCC in the tongue compared with the control RGS12fl/fl mice. Knockdown of RGS12 in OSCC cells significantly increased cell proliferation and migration. Mechanistically, we found that RGS12 associated with phosphatase and tension homolog (PTEN) via the PDZ domain to upregulate the phosphorylation and SUMOylation of PTEN and then correspondingly inactivated the AKT/mTOR signaling pathway. To test the potential therapeutic effect of RGS12 on OSCC, we overexpressed RGS12 in OSCC cells and found a significant inhibition of cancer cell proliferation and migration. Moreover, subcutaneous inoculation of RGS12-overexpressed OSCC cells in NOD scid mice showed a significant reduction in tumor formation. Our findings reveal that RGS12 is an essential tumor suppressor and highlights RGS12 as a potential therapeutic target and prognostic biomarker of OSCC.
Validation of the Hospital Asthma Severity Score (HASS) in children ages 2–18 years old

Abstract Introduction The Hospital Asthma Severity Score (HASS) was developed to communicate inpatient asthma severity between providers. The purpose of this prospective study was to validate the HASS against the Pediatric Respiratory Assessment Measure (PRAM) and spirometry for assessment of inpatient asthma exacerbation severity in patients 2–18 years old, at a single point-in-time. Methods This study was registered with clinicaltrials.gov (NCT02782065). Children admitted to a tertiary care, free-standing children’s hospital were assessed for asthma severity using the HASS, PRAM, and pulmonary function by spirometry. Inter-rater agreement of HASS and PRAM scores was assessed between two blinded clinician raters. Spirometry results were obtained by a certified pulmonary laboratory technician and correlated with HASS and PRAM scores. Results The sample included 58 subjects. Allowing for a one-point difference in continuous HASS and PRAM scores, inter-rater agreement was 79% for the HASS and 60% for the PRAM. When the scores were categorized as mild, moderate, and severe, inter-rater agreement was 62% for the HASS and 93% for the PRAM (p < .0001). Additionally, intra-rater agreement between HASS and PRAM severity categories was 71% for Rater 1 and 64% for Rater 2. A weak correlation was noted between both the HASS and FEV1 (r = –0.31; p = 0.11), and PRAM and FEV1 (r = –0.30; p = 0.11) for the 29 subjects with acceptable spirometry results. Conclusions The HASS and PRAM have acceptable inter-rater and intra-rater agreement. These results support validation of the HASS for managing hospitalized patients during asthma exacerbations.
Albumin-Mediated Uptake Improves Human Clearance Prediction for Hepatic Uptake Transporter Substrates Aiding a Mechanistic In Vitro-In Vivo Extrapolation (IVIVE) Strategy in Discovery Research

This study focused on exploring various in vitro to in vivo extrapolation (IVIVE) approaches with the primary goal of improving human hepatic clearance (CL) prediction for OATP substrates. To that effect, the impact of albumin-mediated uptake in human hepatocytes was investigated. In vitro hepatic uptake assay using suspended human hepatocytes was performed with 16 selected OATP substrates to determine the uptake CL in the absence and presence of 4% BSA and unbound hepatocyte to media partition coefficient (Kpuu). Substantial enhancement of the unbound uptake CL (PSu,inf) was observed in the presence of 4% BSA, demonstrating “albumin-mediated” uptake. Prediction of human hepatic CL was performed using two non-traditional IVIVE approaches: initial uptake CL (PSu,inf) and intrinsic metabolic CL (CLint,met) corrected by Kpuu based on extended clearance concept. Compared to traditional IVIVE using CLint,met only, the two tested IVIVE approaches significantly improved the prediction of human hepatic CL. Particularly, direct extrapolation from PSu,inf (+BSA) showed the most robust correlation with in vivo human hepatic CL for all 16 compounds with bias of 1.9–2.0 for two lots of human hepatocytes, respectively. In addition, PSu,inf (+BSA) and Kpuu were also determined in suspended cynomolgus monkey hepatocytes. Prediction of monkey hepatic CL was improved by both approaches, although with more bias compared to human. These results suggested supplementing 4% BSA in human hepatocyte uptake assay provides a useful tool to characterize hepatic uptake CL for OATP substrates, enabling more accurate human CL prediction without any empirical scaling factor (ESF).
Brain Endothelial P-Glycoprotein Level Is Reduced in Parkinson’s Disease via a Vitamin D Receptor-Dependent Pathway

The progressive neurodegeneration in Parkinson’s disease (PD) is accompanied by neuroinflammation and endothelial vascular impairment. Although the vitamin D receptor (VDR) is expressed in both dopamine neurons and brain endothelial cells, its role in the regulation of endothelial biology has not been explored in the context of PD. In a 6-hydroxydopamine (6-OHDA)-induced PD mouse model, we observed reduced transcription of the VDR and its downstream target genes, CYP24 and MDR1a. The 6-OHDA-induced transcriptional repression of these genes were recovered after the VDR ligand—1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) treatment. Similarly, reduced vascular protein expression of P-glycoprotein (P-gp), encoded by MDR1a, after 6-OHDA administration was reversed by 1,25(OH)2D3. Moreover, marked reduction of endothelial P-gp expression with concomitant α-synuclein aggregation was found in a combinatorial AAV-αSyn/αSyn preformed fibril (PFF) injection mouse model and postmortem PD brains. Supporting the direct effect of α-synuclein aggregation on endothelial biology, PFF treatment of human umbilical vein endothelial cells (HUVECs) was sufficient to induce α-synuclein aggregation and repress transcription of the VDR. PFF-induced P-gp downregulation and impaired functional activity in HUVECs completely recovered after 1,25(OH)2D3 treatment. Taken together, our results suggest that a dysfunctional VDR-P-gp pathway could be a potential target for the maintenance of vascular homeostasis in PD pathological conditions.
Effect of Internal Microstructure Distribution on Quasi-Static Compression Behavior and Energy Absorption of Hollow Truss Structures

In this work, hollow truss structures with different internal microstructure distributions, i.e., basic hollow truss structure (specimen HT), hollow truss structure with internal microstructure at joints (specimen HTSJ), and hollow truss structure with internal microstructure on tube walls (specimen HTSW), were designed and manufactured using a selective laser melting technique. The effect of internal microstructure distribution on quasi-static compressive behavior and energy absorption was investigated by experimental tests and numerical simulations. The experimental results show that compressive strength and specific compressive strength of specimen HTSW increase by nearly 50% and 14% compared to specimen HT, and its energy absorption per volume and mass also increase by 52% and 15% at a strain of 0.5, respectively. However, the parameters of specimen HTSJ exhibit limited improvement or even a decrease in different degrees in comparison to specimen HT. The numerical simulation indicates that internal microstructures change the bearing capacity and structural weaknesses of the cells, resulting in the different mechanical properties and energy absorptions of the specimens. Based on the internal microstructure design in this study, adding microstructures into the internal weaknesses of the cells parallel to the loading direction is an effective way to improve the compressive properties, energy absorption and compressive stability of hollow truss structures.
Effects of Crystallite Sizes of Pt/HZSM-5 Zeolite Catalysts on the Hydrodeoxygenation of Guaiacol

Herein, Pt/HZSM-5 zeolite catalysts with different crystallite sizes ranging from nanosheet (~2 nm) to bulk crystals (~1.5 μm) have been prepared for the hydrodeoxygenation of guaiacol, and their effects on the reaction pathway and product selectivity were explored. HZSM-5 zeolites prepared by seeding (Pt/Z-40: ~40 nm) or templating (Pt/NS-2: ~2 nm) fabricated intra-crystalline mesopores and thus enhanced the reaction rate by promoting the diffusion of various molecules, especially the bulky ones such as guaiacol and 2-methoxycyclohexanol, leading to a higher cyclohexane selectivity of up to 80 wt % (both for Pt/Z-40 and Pt/NS-2) compared to 70 wt % for bulky HZSM-5 (Pt/CZ: ~1.5 μm) at 250 °C and 120 min. Furthermore, decreased crystallite sizes more effectively promoted the dispersion of Pt particles than bulky HZSM-5 (Pt/Z-400: ~400 nm and Pt/CZ). The relatively low distance between Pt and acidic sites on the Pt/Z-40 catalyst enhanced the metal/support interaction and induced the reaction between the guaiacol molecules adsorbed on the acidic sites and the metal-activated hydrogen species, which was found more favorable for deoxygenation than for hydrogenation of oxygen-containing molecules. In addition, Pt/NS-2 catalyst with a highly exposed surface facilitated more diverse reaction pathways such as alkyl transfer and isomerization.
1,25(OH)2 vitamin D3 stimulates active phosphate transport but not paracellular phosphate absorption in mouse intestine

Intestinal absorption of phosphate proceeds via an active/transcellular route mostly mediated by NaPi‐IIb/Slc34a2 and a poorly characterized passive/paracellular pathway. Intestinal phosphate absorption and expression of NaPi‐IIb are stimulated by 1,25(OH)2 vitamin D3 but whether NaPi‐IIb is the only target under hormonal control remains unknown. We report that administration of 1,25(OH)2 vitamin D3 to wild‐type mice resulted in the expected increase in active transport of phosphate in jejunum, without changing paracellular fluxes. Instead, the same treatment failed to alter phosphate transport in intestinal‐depleted Slc34a2‐deficient mice. In both genotypes, 1,25(OH)2 vitamin D3 induced similar hyperphosphaturic responses and changes in the plasma levels of FGF23 and PTH. While urinary phosphate loss induced by administration of 1,25(OH)2 vitamin D3 did not alter plasma phosphate, further studies should investigate whether chronic administration would lead to phosphate imbalance in mice with reduced active intestinal absorption.
Specific ion effects and the molecular structure of water, ions and amphiphiles on nanoscopic hydrophobic interfaces

Keywords: interfaces ; water ; amphiphiles ; specific ion effects ; hydrophobic effect ; charge asymmetry ; sum frequency scattering ; second harmonic scattering ; time-resolved sum frequency scattering These Ecole polytechnique federale de Lausanne EPFL, n° 6060 (2014)Programme doctoral PhotoniqueFaculte des sciences et techniques de l'ingenieurInstitut interfacultaire de Bioingenierie (STI)Chaire Julia Jacobi de photomedecine - Laboratoire de biophotonique fondamentaleJury: Prof. A. Radenovic (presidente); Prof. S. Roke (directrice); Dr M. A. Brown, Dr R. K. Campen, Prof. T. Rizzo (rapporteurs) Public defense: 2014-2-19 Reference doi:10.5075/epfl-thesis-6060Print copy in library catalog Record created on 2014-02-17, modified on 2017-05-10