Miracle-dz/UniFAR-FTUs huggingface dataset:
Hydrogel-mediated sustained systemic delivery of mesenchymal stem cell-derived extracellular vesicles improves hepatic regeneration in chronic liver failure.

Extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have been widely reported as promising cell-free products which show therapeutics effects of the parental cells, but not their limitations. Due to the intrinsic liver tropism of MSC-EVs, they have been widely used as therapeutics or drug carriers for treatment of liver diseases. However, rapid clearance from the target site may attenuate the efficiency of systemically administered MSC-EVs. Herein, sustained release into peritoneum has been proposed as a new strategy to prolong the bioavailability of the MSC-EVs in the target liver. During intraperitoneal injection, clickable polyethylene glycol (PEG) macromeres were mixed with MSC-EVs to form EV-encapsulated PEG hydrogels via a fast, biocompatible click reaction. Upon biodegradation, the EV-laden hydrogels were swollen gradually to release EVs in a sustained manner over one month. In-vivo tracking of the labeled EVs revealed that the accumulation of EVs in the liver was extended by hydrogel-mediated delivery for one month. Four weeks after injection in rats' model of chronic liver fibrosis, the physical and histopathological investigations of the harvested liver showed superior anti-fibrosis, anti-apoptosis and regenerative effects of the EVs, when delivered by the sustained systemic release (Gel-EV) rather than the conventional bolus injection (Free-EV). Specifically, the Gel-EV system improved the anti-fibrosis, anti-inflammation, anti-apoptosis and regenerative effects of the EVs nearly to 40%, 50%, 40% and 50% compared to Free-EV, respectively, as was specified by quantification of fibrotic area, α-SMA density and caspase-3 density in the harvested tissues and ALT enzyme in serum. This study may potentiate the use of MSC-EVs as cell-free therapeutics for chronic liver failure. The sustained systemic delivery strategy may open a new paradigm to extend the effects of disease-targeting EVs over time.
Fluorescence Studies of Carcinogens in Skin I. Histological Localization of 20-Methylcholanthrene in Mouse Skin after a Single Application

In the integrative study of the production of cancer in the epidermis of mice by treatment with methylcholanthrene, it is essential to relate the methylcholanthrene to the developing lesions as accurately as possible. For this reason an effort is herein described to follow the course of this carcinogen through the different parts of the skin. The strong characteristic fluorescence of methylcholanthrene suggests that this problem can be approached with the technic of fluorescence microscopy. Recent investigations in this laboratory have shown that in Swiss strain mice a single cutaneous application of approximately 0.3 mgm. of 20-methylcholanthrene in benzene solution is sufficient to induce a pronounced hyperplasia of the epidermis that leads to the development of carcinomas in a considerable fraction of the treated animals (4, 5). Definite chemical changes are demonstrable in the skin within a few days following this treatment (2, 9). These findings require a revision of the commonly accepted idea that chemical carcinogenesis is due to the repeated and prolonged stimulation of epidermal cells by externally applied chemical carcinogens, and make the study of changes following a single application of a carcinogen of great interest. Using this method we have studied the absorption, distribution, and persistence of methylcholanthrene in the skin of mice following a single application of the carcinogen in benzene solution. So far as we are aware no previous work has been reported on the exact localization of carcinogens applied to the skin, though Beck and Peacock (1) and Hieger (8) report using ultraviolet light to determine by gross examination the persistence of fluorescence on the surface of mouse skin.
Antimicrobial Susceptibility and Molecular Characterization Using Whole-Genome Sequencing of Clostridioides difficile Collected in 82 Hospitals in Japan between 2014 and 2016

We studied the antimicrobial susceptibility and molecular characteristics, using draft whole-genome sequencing, of Clostridioides (Clostridium) difficile strains before and after treatment in adults with C. difficile infection (CDI) enrolled in a phase III, randomized, nationwide study of fidaxomicin versus vancomycin in Japan (ClinicalTrials.gov identifier NCT02179658). C. difficile strains were cultured from stool samples collected before and after standard treatment with either fidaxomicin or vancomycin. ABSTRACT We studied the antimicrobial susceptibility and molecular characteristics, using draft whole-genome sequencing, of Clostridioides (Clostridium) difficile strains before and after treatment in adults with C. difficile infection (CDI) enrolled in a phase III, randomized, nationwide study of fidaxomicin versus vancomycin in Japan (ClinicalTrials.gov identifier NCT02179658). C. difficile strains were cultured from stool samples collected before and after standard treatment with either fidaxomicin or vancomycin. Overall, 285 C. difficile strains were recovered, with 188 derived from CDI cases at baseline (87 patients received fidaxomicin, and 101 received vancomycin). No strains isolated from episodes of CDI at baseline were shown to have reduced susceptibilities to fidaxomicin (MIC, ≥1 mg/liter) or resistance to vancomycin and metronidazole. Thirty-three sequence types (STs) were identified, the most common being ST17 (n = 61 [32.4%]), ST8 (n = 26 [13.8%]), and ST2 (n = 21 [11.2%]). Core-genome single-nucleotide polymorphism analysis showed that outbreaks of C. difficile were unlikely to have occurred at each hospital. The predominant toxin gene profile was tcdA+ tcdB+ cdtA-cdtB− (n = 149 [79.3%]). Six of 87 patients who received fidaxomicin harbored C. difficile isolates with reduced fidaxomicin susceptibilities conferred by previously described mutations, Val1143Leu/Gly/Asp in RpoB or Arg89Gly in RpoC or putative mutations, Gln1149Pro in RpoB, or Arg326Cys in RpoC. Allelic exchange studies of these putative mutations were not performed. Prior to fidaxomicin use, we found no C. difficile strains with reduced fidaxomicin susceptibility causing CDI in Japan; however, mutant strains with reduced fidaxomicin susceptibility were detected after fidaxomicin treatment.
Distinct Transcriptional Programming Drive Response to MAPK Inhibition in BRAFV600-Mutant Melanoma Patient-Derived Xenografts

Inhibitors targeting BRAF and its downstream kinase MEK produce robust response in patients with advanced BRAFV600-mutant melanoma. However, the duration and depth of response vary significantly between patients; therefore, predicting response a priori remains a significant challenge. Here, we utilized the Novartis collection of patient-derived xenografts to characterize transcriptional alterations elicited by BRAF and MEK inhibitors in vivo, in an effort to identify mechanisms governing differential response to MAPK inhibition. We show that the expression of an MITF-high, “epithelial-like” transcriptional program is associated with reduced sensitivity and adaptive response to BRAF and MEK inhibitor treatment. On the other hand, xenograft models that express an MAPK-driven “mesenchymal-like” transcriptional program are preferentially sensitive to MAPK inhibition. These gene-expression programs are somewhat similar to the MITF-high and -low phenotypes described in cancer cell lines, but demonstrate an inverse relationship with drug response. This suggests a discrepancy between in vitro and in vivo experimental systems that warrants future investigations. Finally, BRAFV600-mutant melanoma relies on either MAPK or alternative pathways for survival under BRAF and MEK inhibition in vivo, which in turn predicts their response to further pathway suppression using a combination of BRAF, MEK, and ERK inhibitors. Our findings highlight the intertumor heterogeneity in BRAFV600-mutant melanoma, and the need for precision medicine strategies to target this aggressive cancer.
Predicting Design-Induced Error on the Flight Deck

Objective To explore the types of errors that commercial pilots may make when trying to resolve a suspected engine oil leak using the interfaces currently available. Background The decisions that pilots make often have to be made quickly and under time pressure, with the emphasis on avoiding critical situations from arising. To make the correct decisions, it is vital that pilots have accurate and up-to-date information available. However, interaction with flight deck interfaces may lead to error if they are not effectively designed. Method A hierarchical task analysis was conducted using evidence from pilot interview data to understand the pilots’ typical response to a suspected engine oil leak scenario. This was used as the primary input into the Systematic Human Error Reduction and Prediction Approach (SHERPA). Results A total of 108 possible errors were identified. The most common error type was a retrieval error, in which flight crews may retrieve the wrong information about the engine. A number of remedial measures are proposed to try and overcome such issues. Conclusion This analysis provides an initial starting point for identifying potential future design ideas that can assist the pilots in dealing with oil leaks. Application This work has identified the value of applying human error identification methodologies to the assessment of current flight deck processes surrounding engine oil leaks. The method presented permits the operational analysis of possible errors on the flight deck and facilitates the proposition of remedial measures to implement technological innovations that can mitigate error.
Smoking and the risk for bipolar disorder: evidence from a bidirectional Mendelian randomisation study

Background There is increasing evidence that smoking is a risk factor for severe mental illness, including bipolar disorder. Conversely, patients with bipolar disorder might smoke more (often) as a result of the psychiatric disorder. Aims We conducted a bidirectional Mendelian randomisation (MR) study to investigate the direction and evidence for a causal nature of the relationship between smoking and bipolar disorder. Method We used publicly available summary statistics from genome-wide association studies on bipolar disorder, smoking initiation, smoking heaviness, smoking cessation and lifetime smoking (i.e. a compound measure of heaviness, duration and cessation). We applied analytical methods with different, orthogonal assumptions to triangulate results, including inverse-variance weighted (IVW), MR-Egger, MR-Egger SIMEX, weighted-median, weighted-mode and Steiger-filtered analyses. Results Across different methods of MR, consistent evidence was found for a positive effect of smoking on the odds of bipolar disorder (smoking initiation ORIVW = 1.46, 95% CI 1.28–1.66, P = 1.44 × 10−8, lifetime smoking ORIVW = 1.72, 95% CI 1.29–2.28, P = 1.8 × 10−4). The MR analyses of the effect of liability to bipolar disorder on smoking provided no clear evidence of a strong causal effect (smoking heaviness betaIVW = 0.028, 95% CI 0.003–0.053, P = 2.9 × 10−2). Conclusions These findings suggest that smoking initiation and lifetime smoking are likely to be a causal risk factor for developing bipolar disorder. We found some evidence that liability to bipolar disorder increased smoking heaviness. Given that smoking is a modifiable risk factor, these findings further support investment into smoking prevention and treatment in order to reduce mental health problems in future generations.
The relation between Malnutrition Universal Screening Tool (MUST), computed tomography-derived body composition, systemic inflammation, and clinical outcomes in patients undergoing surgery for colorectal cancer.

BACKGROUND Nutritional status is an important factor affecting a patient's clinical outcomes. Early identification of patients who are at risk of malnutrition is important to improve clinical outcomes and reduce health cost. The Malnutrition Universal Screening Tool (MUST) has been recommended as part of the routine nursing assessment for all patients at hospital admission. OBJECTIVE The aim of this study was to examine the association between nutritional status (MUST), systemic inflammatory response (SIR), body composition, and clinical outcomes in patients undergoing surgery for colorectal cancer. METHODS The malnutrition risk was examined using MUST in patients admitted for surgery for colorectal cancer between March 2013 and June 2016. Preoperative computed tomography scans were used to define the body composition. The presence of SIR was evidenced by the modified Glasgow prognostic score and the neutrophil to lymphocyte ratio. Postoperative complications, severity of complication, length of hospital stay, and mortality were considered as outcome measures. RESULTS The study included 363 patients (199 males, 164 females); 21% of the patients presented with a medium or high nutritional risk. There were significant associations between MUST and subcutaneous adiposity (P < 0.001), visceral obesity (P < 0.001), and low skeletal muscle index (P < 0.001). No statistically significant association was identified between MUST score and presence of any complication or severity of complication. On multivariate analysis, MUST remained independently associated with the length of hospital stay (OR: 2.17; 95% CI: 1.45, 3.26; P < 0.001). Kaplan-Meier survival curves showed an increased number of deaths for patients at medium or high risk of malnutrition (P < 0.001). This association was found to be independent of other confounding factors (HR: 1.45; 95% CI: 1.06, 1.99; P = 0.020). CONCLUSIONS MUST score is an independent marker of risk in those undergoing surgery for colorectal cancer and should remain a key part of preoperative assessment.
A Retrospective Comparative Analysis of Titanium Mesh and Custom Implants for Cranioplasty.

BACKGROUND Autologous bone removed during craniectomy is often the material of choice in cranioplasty procedures. However, when the patient's own bone is not appropriate (infection and resorption), an alloplastic graft must be utilized. Common options include titanium mesh and polyetheretherketone (PEEK)-based custom flaps. Often, neurosurgeons must decide whether to use a titanium or custom implant, with limited direction from the literature. OBJECTIVE To compare surgical outcomes of synthetic cranioplasties performed with titanium or vs custom implants. METHODS Ten-year retrospective comparison of patients undergoing synthetic cranioplasty with titanium or custom implants. RESULTS A total of 82 patients were identified for review, 61 (74.4%) receiving titanium cranioplasty and 21 (25.6%) receiving custom implants. Baseline demographics and comorbidities of the 2 groups did not differ significantly, although multiple surgical characteristics did (size of defect, indication for craniotomy) and were controlled for via a 2:1 mesh-to-custom propensity matching scheme in which 36 titanium cranioplasty patients were compared to 18 custom implant patients. The cranioplasty infection rate of the custom group (27.8%) was significantly greater (P = .005) than that of the titanium group (0.0%). None of the other differences in measured complications reached significance. Discomfort, a common cause of reoperation in the titanium group, did not result in reoperation in any of the patients receiving custom implants. CONCLUSION Infection rates are higher among patients receiving custom implants compared to those receiving titanium meshes. The latter should be informed of potential postsurgical discomfort, which can be managed nonsurgically and is not associated with return to the operating room.
Molecular links between Alzheimer's disease and Gastrointestinal microbiota with its-related metabolic syndrome: emphasis on Helicobacter pylori infection involvement.

Alzheimer's disease (AD) is a neurodegenerative disease and main form of dementia, charac-terized by progressive cognitive decline and detrimental consequences in both personal-family and global level. Within this narrative review, we provide recent molecular aspects of Tau, a microtubule AD-associated protein as well as amyloid beta, involved in AD pathophysi-ology. Moreover, we provide additional emerging data from basic research as well as clinical studies indicating an implicating role of gastrointestinal microbiota (GIM), including Helicobac-ter pylori infection (Hp-I), in AD pathophysiology. Likewise, we identify through a molecular prism the current evidence of AD pathogenesis as well as its linkage with GIM and emphasiz-ing the role of Hp-I. Furthermore, metabolic syndrome, the epidemic of mainly western socie-ties, is also related with alterations of GIM and Hp-I, which might in turn influence in a molecu-lar, immunological and endocrinological way the pathogenesis of AD. All in all, additional large-scale studies are required for the further clarification of AD pathophysiology and its connec-tion with GIM and and Hp-I, so as novel therapies on molecular basis become available.
Digital Libraries in Schools: The Best Practices of National Board Certified Library Media Specialists

Title of Document: DIGITAL LIBRARIES IN SCHOOLS: THE BEST PRACTICES OF NATIONAL BOARD CERTIFIED LIBRARY MEDIA SPECIALISTS Sheri Anita Massey Doctor of Philosophy, 2009 Co-Directed By: Dr. Allison Druin Associate Professor College of Information Studies Dr. Ann Carlson Weeks Professor of the Practice College of Information Studies This study investigated the digital library integration behaviors f school library media specialists (SLMSs) who have achieved certific ation from the National Board for Professional Teaching Standards (NBPTS). A qualitati ve interview study design was chosen to convert tacit knowledge related to digital libra ry use into explicit knowledge that can be shared with others. The goal of this research was to identify behaviors and techniques that exemplary SLMSs share whe n using digital libraries to support the curriculum in K-12 schools. The researcher interviewed and collected artifacts from 10 local National Board certified SLMSs and analyzed the resulting transcripts and mater ials using thematic analysis. A preliminary coding scheme was derived from the NBPTS Library Media technology innovation standard, which requires candidates to demonstrate expertise in providing technology access, teaching effecti ve technology use, engaging learners with technology, and using technology to enhance the curriculum. Themes related to these four areas emerged from the data, as di d subthemes in the form of barriers the SLMSs encountered and strategies they deve loped to meet the standard. The barriers are discussed using Ertmer’s (1999) fir stand second-order classifications. The strategies are the SLMSs’ best pra ctices. To provide digital library access the SLMSs made themselves and their assistants available to learners; demonstrated mental and resource flex ibility when they encountered obstacles; and, implemented creative funding strategies. T o t ach digital library use they used the research process to help students bridge knowle dge learned in various contexts; provided training; remained abreast of digital libr ary innovations; and, offered suggestions to product developers. To maintain engagement with digital libraries they used proven teaching techniques that build on strong instructional design principles. Finally, they relied on collaborative rela tionships when integrating digital libraries. They increased collaboration by buil ding trust among colleagues; extending their reach beyond the SLMC in person and virtually , diversifying their role within the school, and gathering curriculum information to incorporate information literacy skills into lessons. Key implications: encourage SLMS-teacher collaboration, build a knowledge management system that captures expertise and supports SLMS communication, reconsider blocking social networking tools in schools to bridge the disconnect between students’ home and school information-related behaviors. DIGITAL LIBRARIES IN SCHOOLS: THE BEST PRACTICES OF NATI ONAL BOARD CERTIFIED LIBRARY MEDIA SPECIALISTS
Structural and functional aspects of mannuronic acid–specific PL6 alginate lyase from the human gut microbe Bacteroides cellulosilyticus

Alginate is a linear polysaccharide from brown algae consisting of 1,4-linked β-d-mannuronic acid (M) and α-l-guluronic acid (G) arranged in M, G, and mixed MG blocks. Alginate was assumed to be indigestible in humans, but bacteria isolated from fecal samples can utilize alginate. Moreover, genomes of some human gut microbiome–associated bacteria encode putative alginate-degrading enzymes. Here, we genome-mined a polysaccharide lyase family 6 alginate lyase from the gut bacterium Bacteroides cellulosilyticus (BcelPL6). The structure of recombinant BcelPL6 was solved by X-ray crystallography to 1.3 Å resolution, revealing a single-domain, monomeric parallel β-helix containing a 10-step asparagine ladder characteristic of alginate-converting parallel β-helix enzymes. Substitutions of the conserved catalytic site residues Lys-249, Arg-270, and His-271 resulted in activity loss. However, imidazole restored the activity of BcelPL6-H271N to 2.5% that of the native enzyme. Molecular docking oriented tetra-mannuronic acid for syn attack correlated with M specificity. Using biochemical analyses, we found that BcelPL6 initially releases unsaturated oligosaccharides of a degree of polymerization of 2–7 from alginate and polyM, which were further degraded to di- and trisaccharides. Unlike other PL6 members, BcelPL6 had low activity on polyMG and none on polyG. Surprisingly, polyG increased BcelPL6 activity on alginate 7-fold. LC–electrospray ionization–MS quantification of products and lack of activity on NaBH4-reduced octa-mannuronic acid indicated that BcelPL6 is an endolyase that further degrades the oligosaccharide products with an intact reducing end. We anticipate that our results advance predictions of the specificity and mode of action of PL6 enzymes.
Acetylation of Eugenol over 12-Molybdophosphoric Acid Anchored in Mesoporous Silicate Support Synthesized from Flint Kaolin

A new prepared catalyst, 12-molybdophosphoric acid (HPMo) anchored to the mesoporous aluminosilicate AlSiM, synthesized from Amazon kaolin, was characterized and used as a heterogeneous acid catalyst for the production of eugenyl acetate by acetylation of eugenol with acetic anhydride. The effect of various reaction parameters, such as catalyst concentration, eugenol/acetic anhydride molar ratio, temperature and reaction time, was studied to optimize the conditions of maximum conversion of eugenol. The kinetics studies showed that in eugenol acetylation, the substrate concentration follows a first order kinetics. The results of activation energy was 19.96 kJ mol−1 for HPMo anchored to AlSiM. The reuse of the catalyst was also studied and there was no loss of catalytic activity after four cycles of use (from 99.9% in the first cycle to 90% in the fifth cycle was confirmed), and an excellent stability of the material was observed. Based on catalytic and kinetic studies, HPMo anchored to AlSiM is considered an excellent catalyst.