Miracle-dz/UniFAR-FTUs huggingface dataset:
Sea Buckthorn Oil as a Valuable Source of Bioaccessible Xanthophylls

Sea buckthorn oil, derived from the fruits of the shrub, also termed seaberry or sandthorn, is without doubt a strikingly rich source of carotenoids, in particular zeaxanthin and β-carotene. In the present study, sea buckthorn oil and an oil-in-water emulsion were subjected to a simulated gastro-intestinal in vitro digestion, with the main focus on xanthophyll bioaccessibility. Zeaxanthin mono- and di-esters were the predominant carotenoids in sea buckthorn oil, with zeaxanthin dipalmitate as the major compound (38.0%). A typical fatty acid profile was found, with palmitic (49.4%), palmitoleic (28.0%), and oleic (11.7%) acids as the dominant fatty acids. Taking into account the high amount of carotenoid esters present in sea buckthorn oil, the use of cholesterol esterase was included in the in vitro digestion protocol. Total carotenoid bioaccessibility was higher for the oil-in-water emulsion (22.5%) compared to sea buckthorn oil (18.0%) and even higher upon the addition of cholesterol esterase (28.0% and 21.2%, respectively). In the case of sea buckthorn oil, of all the free carotenoids, zeaxanthin had the highest bioaccessibility (61.5%), followed by lutein (48.9%), making sea buckthorn oil a potential attractive source of bioaccessible xanthophylls.
DPP4 deletion in adipose tissue improves hepatic insulin sensitivity in diet-induced obesity.

AIMS/HYPOTHESIS Besides a therapeutic target for type 2 diabetes, dipeptidyl peptidase 4 (DPP4) is an adipokine linked to human obesity. We aimed to explore role of adipocyte-derived DPP4 in diet-induced obesity and insulin resistance. METHODS Wild type (WT) and AT-specific KO mouse (AT-DPP4-KO) were fed for 24 weeks with a high fat diet (HFD) and characterized for body weight, glucose tolerance, insulin sensitivity by hyperinsulinemic-euglycemic clamp, and body composition and hepatic fat content. Image and molecular biology analysis of inflammation as well as adipocyte secretion was performed in AT by immunohistochemistry, Western blot, qRT- PCR and ELISA. Incretin levels were determined by multiplex. RESULTS Under high fat diet (HFD), AT-DPP4-KO displayed markedly reduced circulating DPP4 concentrations, proving AT as a relevant source of DPP4. Independently of glucose-stimulated incretin hormones, AT-DPP4-KO had improved glucose tolerance and hepatic insulin sensitivity. AT-DPP4-KO displayed smaller adipocytes and a shift in the inflammatory phenotype with more crown-like structures. IGF binding protein 3 (IGFBP3) levels were lower in AT and serum. CONCLUSIONS The absence of adipose DPP4 triggers beneficial AT remodeling with decreased production of IGFBP3 during HFD, likely contributing to the observed improved hepatic insulin sensitivity.
Ontogenic mRNA expression of RNA modification writers, erasers, and readers in mouse liver

RNA modifications are recently emerged epigenetic modifications. These diverse RNA modifications have been shown to regulate multiple biological processes, including development. RNA modifications are dynamically controlled by the “writers, erasers, and readers”, where RNA modifying proteins are able to add, remove, and recognize specific chemical modification groups on RNAs. However, little is known about the ontogenic expression of these RNA modifying proteins in various organs, such as liver. In the present study, the hepatic mRNA expression of selected RNA modifying proteins involve in m6A, m1A, m5C, hm5C, m7G, and Ψ modifications was analyzed using the RNA-seq technique. Liver samples were collected from male C57BL/6 mice at several ages from prenatal through neonatal, infant, child to young adult. Results showed that most of the RNA modifying proteins were highly expressed in prenatal mouse liver with a dramatic drop at birth. After birth, most of the RNA modifying proteins showed a downregulation trend during liver maturation. Moreover, the RNA modifying proteins that belong to the same enzyme family were expressed at different abundances at the same ages in mouse liver. In conclusion, this study unveils that the mRNA expression of RNA modifying proteins follows specific ontogenic expression patterns in mice liver during maturation. These data indicated that the changes in expression of RNA modifying proteins might have a potential role to regulate gene expression in liver through alteration of RNA modification status.
A multifunction lipid-based CRISPR-Cas13a genetic circuit delivery system for bladder cancer gene therapy.

The treatment of bladder cancer has recently shown minimal progress. Gene therapy mediated by CRISPR provides a new option for bladder cancer treatment. In this study, we developed a versatile liposome system to deliver the CRISPR-Cas13a gene circuits into bladder cancer cells. After in vitro studies and intravesical perfusion studies in mice, this system showed five advantages: 1) CRISPR-Cas13a, a transcriptional targeting and cleavage tool for gene expression editing, did not affect the stability of the cell genome; 2) the prepared liposome systems were targeted to hVEGFR2, which is always highly expressed in bladder cancer cells; 3) the CRISPR-Cas13a sequence was driven by an artificial tumor specific promoter to achieve further targeting; 4) a near-infrared photosensitizer released using near-infrared light was introduced to control the delivery system; and 5) the plasmids were constructed with three crRNA tandem sequences to achieve multiple targeting and wider therapeutic results. This tumor cell targeting lipid delivery system with near-infrared laser-controlled ability provided a versatile strategy for CRISPR-Cas13a based gene therapy of bladder cancer.
Autophagy-Like Cell Death Regulates Hydrogen Peroxide and Calcium Ion Distribution in Xa3/Xa26-Mediated Resistance to Xanthomonas oryzae pv. oryzae

The broad-spectrum and durable resistance gene Xa3/Xa26 against Xanthomonas oryzae pv. oryzae (Xoo) has been widely exploited in rice production in China. But the cytological features of the Xa3/Xa26-mediated resistance reaction have been rarely reported. This study reveals the cytological characteristics of the Xa3/Xa26-mediated resistance reaction against Xoo to uncover the functions of hypersensitive response programmed cell death (HR-PCD) in rice. Autophagy-like cell death, which was characterized by double-membrane bodies appearance in xylem parenchyma cell and mesophyll cell, was inhibited by autophagy inhibitor 3-methyladenin (3-MA). The autophagy-related genes were induced to reach a high level in resistance reaction. The hydrogen peroxide (H2O2) maintained a low concentration on the plasma membrane. The calcium ions localized on the apoplast were transferred into the vacuole. The autophagy inhibitor (3-MA) impaired Xa3/Xa26-mediated resistance by promoting the accumulation of H2O2, and inhibited the transfer of extracellular calcium ions into the vacuole in the xylem parenchyma cells and mesophyll cells. Therefore, the HR-PCD belongs to autophagy-like cell death in the Xa3/Xa26-mediated resistance reaction. These results suggest that the autophagy-like cell death participates in the Xa3/Xa26-mediated resistance by negatively regulating H2O2 accumulation, in order to abolish oxidative stress and possibly activate calcium ion signals in xylem parenchyma cells of the rice leaf.
Predictive sampling effort and species-area relationship models for estimating richness in fragmented landscapes

Loss of habitat, specifically deforestation, is a major driver of biodiversity loss. Species-area relationship (SAR) models traditionally have been used for estimating species richness, species loss as a function of habitat loss, and extrapolation of richness for given areas. Sampling-species relationships (SSRs) are interrelated yet separate drivers for species richness estimates. Traditionally, however, SAR and SSR models have been used independently and not incorporated into a single approach. We developed and compared predictive models that incorporate sampling effort species-area relationships (SESARS) along the entire Atlantic Forest of South America, and then applied the best-fit model to estimate richness in forest remnants of Interior Atlantic Forest of eastern Paraguay. This framework was applied to non-volant small mammal assemblages that reflect different tolerances to forest loss and fragmentation. In order to account for differences in functionality we estimated small mammal richness of 1) the entire non-volant small mammal assemblage, including introduced species; 2) the native species forest assemblage; and 3) the forest-specialist assemblage, with the latter two assemblages being subsets of the entire assemblage. Finally, we geospatially modeled species richness for each of the three assemblages throughout eastern Paraguay to identify remnants with high species richness. We found that multiple regression power-law interaction-term models that only included area and the interactions of area and sampling as predictors, worked best for predicting species richness for the entire assemblage and the native species forest assemblage, while several traditional SAR models (logistic, power, exponential, and ratio) best described forest-specialist richness. Species richness was significantly different between assemblages. We identified obvious remnants with high species richness in eastern Paraguay, and these remnants often were geographically isolated. We also found relatively high predicted species richness (in relation to the entire range of predicted richness values) in several geographically-isolated, medium-size forest remnants that likely have not been considered as possible priority areas for conservation. These findings highlight the importance of using an empirical dataset, created using sources representing diverse sampling efforts, to develop robust predictive models. This approach is particularly important in geographic locations where field sampling is limited yet the geographic area is experiencing rapid and dramatic land cover changes. When combined, area and sampling are powerful modeling predictors for questions of biogeography, ecology, and conservation, especially when addressing habitat loss and fragmentation.
Shannon entropy approach reveals relevant genes in Alzheimer’s disease

Alzheimer’s disease (AD) is the most common type of dementia and affects millions of people worldwide. Since complex diseases are often the result of combinations of gene interactions, microarray data and gene co-expression analysis can provide tools for addressing complexity. Our study aimed to find groups of interacting genes that are relevant in the development of AD. In this perspective, we implemented a method proposed in a previous work to detect gene communities linked to AD. Our strategy combined co-expression network analysis with the study of Shannon entropy of the betweenness. We analyzed the publicly available GSE1297 dataset, achieved from the GEO database in NCBI, containing hippocampal gene expression of 9 control and 22 AD human subjects. Co-expressed genes were clustered into different communities. Two communities of interest (composed by 72 and 39 genes) were found by calculating the correlation coefficient between communities and clinical features. The detected communities resulted stable, replicated on two independent datasets and mostly enriched in pathways closely associated with neuro-degenative diseases. A comparison between our findings and other module detection techniques showed that the detected communities were more related to AD phenotype. Lastly, the hub genes within the two communities of interest were identified by means of a centrality analysis and a bootstrap procedure. The communities of the hub genes presented even stronger correlation with clinical features. These findings and further explorations on the detected genes could shed light on the genetic aspects related with physiological aspects of Alzheimer’s disease.
Economic evaluations of screening strategies for the early detection of colorectal cancer in the average-risk population: A systematic literature review

Background Colorectal cancer (CRC) screening has proven effective in reducing CRC mortality. This study aimed to systematically review, and evaluate the reporting quality, of the economic evidence regarding CRC screening in average-risk individuals. Methods Databases searched included Medline, EMBASE, National Health Service Economic Evaluation, Database of Abstracts of Reviews of Effects, Cost-Effectiveness Analysis registry, EconLit, and Health Technology Assessment database. Eligible studies were cost-effectiveness and cost-utility analyses comparing CRC screening strategies in average-risk individuals, published in English or Spanish, between January 2012 and November 2018. Reporting quality was assessed using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. Results Of 1,993 publications initially retrieved, 477 were excluded by duplicate review, 1,449 by title/abstract review, and 34 by full-text review. Finally, 33 publications were included in the qualitative synthesis. Most studies were conducted in Europe (36,4%), followed by United States (24,2%) and Asia (24,2%). The main screening modalities considered were fecal immunochemical tests (70%), colonoscopy (67%), guaiac fecal occult blood test (42%) and flexible sigmoidoscopy (30%). In most studies, CRC screening was deemed cost-effective compared to no screening. Sensitivity analyses indicated that cost of CRC screening tests, adherence to screening, screening test sensitivity, and cost of CRC treatment had the greatest impact on cost-effectiveness results across studies. The majority of studies (73%) adequately reported at least 50% of the items included in the CHEERS checklist. Least well reported items included setting, study perspective, discount rate, model choice, and methods to identify effectiveness data or to estimate resource use and costs. Conclusions CRC screening is an efficient alternative to no screening. Nevertheless, it is not possible to conclude which strategy should be preferred for population-based screening programs. Although we observed an overall good adherence to CHEERS recommendations, there is still room for improvement in economic evaluations reporting in this field.
In vitro demonstration of intestinal absorption mechanisms of different sugars using 3D organotypic tissues in a fluidic device.

Intestinal permeability is crucial in regulating the bioavailability and consecutively the biological effects of drugs and compounds. However, systematic and quantitative studies of absorption of molecules are quite limited due to the lack of reliable experimental models able to mimic in vivo responses. In this work, we present a novel platform as in vitro fluidic model of healthy and pathological small intestinal barrier using 3D reconstructed intestinal epithelium integrated with a fluid-dynamic bioreactor resembling the physiological stimuli of the intestinal environment (MIVO®). The platform has been investigated, both in healthy and induced pathological conditions, by monitoring the absorption of two non-metabolized sugars, lactulose and mannitol, frequently used as indicators of intestinal barrier dysfunctions. The results showed that an in vivo-like plateau of the percentage of absorbed sugars was reached for lactulose and mannitol and that the mannitol absorbed was much greater than the lactulose, in line with clinical data, thus revealing the good reliability of the model. Moreover, a model of altered intestinal permeability has been generated by depleting extracellular Ca2+ using calcium specific chelator. Interestingly, after calcium depletion treatment, the pattern of sugar passage comparable with the healthy tissue was completely restored only in dynamic conditions within MIVO® chamber, due to the beneficial role of the dynamic fluid flow beneath the membrane. Therefore, the MIVO® combined with EpiIntestinalTM™ platform can represent a reliable in vitro model of healthy and pathological small intestinal barrier to study the passage of molecules, by discriminating the two main intestinal absorption mechanisms.
Microfluidic device for on-chip isolation and detection of circulating exosomes in blood of breast cancer patients.

Tumor-derived circulating exosomes have been recognized as a promising biomarker source for cancer diagnosis via a less invasive procedure. The integration of isolation and detection of exosomes in routine clinical settings is still challenging. In this study, we developed a new microfluidic device for immunomagnetic separation and detection of blood exosomes in situ. The microfluidic device may empower the integration of target exosome analysis via high surface to volume ratios of immunomagnetic beads and highly precise fluid control with the aid of microvalves. The obtained microfluidic device was capable of on-chip isolation and detection of circulating exosomes within 1.5 h. The captured exosomes could be directly visualized with an inverted fluorescence microscope in situ by tetramethylbenzidine-based colorimetric sensing. It was revealed that a statistically significant increase (p < 0.01) in EpCAM-positive exosomes was captured for cancer patients (n = 10) on the device when compared to healthy individuals (n = 10). The device also demonstrated high predicting accuracy for tumor exosomal markers with a sensitivity of 90% and a specificity of >95% using receiver operating characteristic curves. The microfluidic device might provide a new platform to assist cancer diagnosis and molecular classification in an automated and simple fashion.
Identification of avoidance genes through neural pathway-specific forward optogenetics

Understanding how the nervous system bridges sensation and behavior requires the elucidation of complex neural and molecular networks. Forward genetic approaches, such as screens conducted in C. elegans, have successfully identified genes required to process natural sensory stimuli. However, functional redundancy within the underlying neural circuits, which are often organized with multiple parallel neural pathways, limits our ability to identify ‘neural pathway-specific genes’, i.e. genes that are essential for the function of some, but not all of these redundant neural pathways. To overcome this limitation, we developed a ‘forward optogenetics’ screening strategy in which natural stimuli are initially replaced by the selective optogenetic activation of a specific neural pathway. We used this strategy to address the function of the polymodal FLP nociceptors mediating avoidance of noxious thermal and mechanical stimuli. According to our expectations, we identified both mutations in ‘general’ avoidance genes that broadly impact avoidance responses to a variety of natural noxious stimuli (unc-4, unc-83, and eat-4) and mutations that produce a narrower impact, more restricted to the FLP pathway (syd-2, unc-14 and unc-68). Through a detailed follow-up analysis, we further showed that the Ryanodine receptor UNC-68 acts cell-autonomously in FLP to adjust heat-evoked calcium signals and aversive behaviors. As a whole, our work (i) reveals the importance of properly regulated ER calcium release for FLP function, (ii) provides new entry points for new nociception research and (iii) demonstrates the utility of our forward optogenetic strategy, which can easily be transposed to analyze other neural pathways.
Detection and analysis of pulse waves during sleep via wrist-worn actigraphy

The high temporal and intensity resolution of modern accelerometers gives the opportunity of detecting even tiny body movements via motion-based sensors. In this paper, we demonstrate and evaluate an approach to identify pulse waves and heartbeats from acceleration data of the human wrist during sleep. Specifically, we have recorded simultaneously full-night polysomnography and 3d wrist actigraphy data of 363 subjects during one night in a clinical sleep laboratory. The acceleration data was segmented and cleaned, excluding body movements and separating episodes with different sleep positions. Then, we applied a bandpass filter and a Hilbert transform to uncover the pulse wave signal, which worked well for an average duration of 1.7 h per subject. We found that 81 percent of the detected pulse wave intervals could be correctly associated with the R peak intervals from independently recorded ECGs and obtained a median Pearson cross-correlation of 0.94. While the low-frequency components of both signals were practically identical, the high-frequency component of the pulse wave interval time series was increased, indicating a respiratory modulation of pulse transit times, probably as an additional contribution to respiratory sinus arrhythmia. Our approach could be used to obtain long-term nocturnal heartbeat interval time series and pulse wave signals from wrist-worn accelerometers without the need of recording ECG or photoplethysmography. This is particularly useful for an ambulatory monitoring of high-risk cardiac patients as well as for assessing cardiac dynamics in large cohort studies solely with accelerometer devices that are already used for activity tracking and sleep pattern analysis.
Identification of loci of functional relevance to Barrett’s esophagus and esophageal adenocarcinoma: Cross-referencing of expression quantitative trait loci data from disease-relevant tissues with genetic association data

Esophageal adenocarcinoma (EA) and its precancerous condition Barrett’s esophagus (BE) are multifactorial diseases with rising prevalence rates in Western populations. A recent meta-analysis of genome-wide association studies (GWAS) data identified 14 BE/EA risk loci located in non-coding genomic regions. Knowledge about the impact of non-coding variation on disease pathology is incomplete and needs further investigation. The aim of the present study was (i) to identify candidate genes of functional relevance to BE/EA at known risk loci and (ii) to find novel risk loci among the suggestively associated variants through the integration of expression quantitative trait loci (eQTL) and genetic association data. eQTL data from two BE/EA-relevant tissues (esophageal mucosa and gastroesophageal junction) generated within the context of the GTEx project were cross-referenced with the GWAS meta-analysis data. Variants representing an eQTL in at least one of the two tissues were categorized into genome-wide significant loci (P < 5×10−8) and novel candidate loci (5×10−8 ≤ P ≤ 5×10−5). To follow up these novel candidate loci, a genetic association study was performed in a replication cohort comprising 1,993 cases and 967 controls followed by a combined analysis with the GWAS meta-analysis data. The cross-referencing of eQTL and genetic data yielded 2,180 variants that represented 25 loci. Among the previously reported genome-wide significant loci, 22 eQTLs were identified in esophageal mucosa and/or gastroesophageal junction tissue. The regulated genes, most of which have not been linked to BE/EA etiology so far, included C2orf43/LDAH, ZFP57, and SLC9A3. Among the novel candidate loci, replication was achieved for two variants (rs7754014, Pcombined = 3.16×10−7 and rs1540, Pcombined = 4.16×10−6) which represent eQTLs for CFDP1 and SLC22A3, respectively. In summary, the present approach identified candidate genes whose expression was regulated by risk variants in disease-relevant tissues. These findings may facilitate the elucidation of BE/EA pathophysiology.