Miracle-dz/UniFAR-FTUs huggingface dataset:
Mannosylated Polyrotaxanes for Increasing Cellular Uptake Efficiency in Macrophages through Receptor-Mediated Endocytosis

Macrophages play an important role in the regulation of inflammation and immune response as well as the pathogenesis of chronic inflammatory diseases and cancer. Therefore, targeted delivery of therapeutic reagents to macrophages is an effective method for treatment and diagnosis. We previously examined the therapeutic applications of polyrotaxanes (PRXs) comprised of multiple cyclodextrins (CDs) threaded on a polymer chain and capped with bulky stopper molecules. In the present study, we designed an α-d-mannose-modified α-CD/poly(ethylene glycol)-based PRX (Man-PRX). The intracellular uptake of Man-PRX through the interaction with macrophage mannose receptor (MMR) in macrophage-like RAW264.7 cells was examined. Intracellular Man-PRX uptake was observed in MMR-positive RAW264.7 cells but was negligible in MMR-negative NIH/3T3 cells. In addition, the intracellular Man-PRX uptake in RAW264.7 cells was significantly inhibited in the presence of free α-d-mannose and an anti-MMR antibody, which suggests that MMR is involved in the intracellular uptake of Man-PRX. Moreover, the polarization of RAW264.7 cells affected the Man-PRX internalization efficiency. These results indicate that Man-PRX is an effective candidate for selective targeting of macrophages through a specific interaction with the MMR.
How the Skin Thickness and Thermal Contact Resistance Influence Thermal Tactile Perception

A few experimental studies on thermal tactile perception have shown the influence of the thermal contact resistance which relates to contact surface roughness and pressure. In this paper, the theoretical influence of the skin thickness and the thermal contact resistance is studied on the thermal model describing the temperature evolution in skin and materials when they come in contact. The thermal theoretical profile for reproducing a thermal cue for given contact thermal resistance is also presented. Compared to existing models of thermal simulation, the method proposed here has the advantage that the parameters of skin structure and thermal contact resistance in target temperature profiles can be adjusted in thermal perception simulation according to different skin features or surface roughness if necessary. The experimental results of surface roughness recognition were also presented.
Anti-inflammatory flurbiprofen nasal powders for nose-to-brain delivery in Alzheimer’s disease

Abstract Neuroinflammation occurs in the early stages of Alzheimer's disease (AD). Thus, anti-inflammatory drugs in this asymptomatic initial phase could slow down AD progression, provided they enter the brain. Direct nose-to-brain drug transport occurs along olfactory or trigeminal nerves, bypassing the blood-brain barrier. Nasal administration may enable the drug to access the brain. Here, flurbiprofen powders for nose-to-brain drug transport in early AD-related neuroinflammation were studied. Their target product profile contemplates drug powder deposition in the nasal cavity, prompt dissolution in the mucosal fluid and attainment of saturation concentration to maximise diffusion in the tissue. Aiming to increase drug disposition into brain, poorly soluble flurbiprofen requires the construction of nasal powder microparticles actively deposited in nose for prompt drug release. Two groups of powders were formulated, composed of flurbiprofen acid or flurbiprofen sodium salt. Two spray dryer apparatuses, differing for spray and drying mechanisms, and particle collection, were applied to impact on the characteristics of the microparticulate powders. Flurbiprofen sodium nasal powders disclosed prompt dissolution and fast ex vivo transport across rabbit nasal mucosa, superior to the acid form, in particular when the powder was prepared using the Nano B-90 spray dryer at the lowest drying air temperature.
Polygenic hazard score, amyloid deposition and Alzheimer’s neurodegeneration

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-β protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.
Evaluation of multiple-flows exhaled nitric oxide in idiopathic and non-idiopathic interstitial lung disease

Background: fractional exhaled nitric oxide (FeNO) is a non-invasive and reproducible marker of nitrosative stress and lung inflammation. More recently, FeNO has been proposed as a marker of severity of idiopathic pulmonary fibrosis (IPF) and systemic sclerosis associated ILD. AIM and objectives: to evaluate the role of FeNO in the diagnostic pathway of ILDs. Methods: according to ERS guidelines for exhaled biomarkers in lung diseases, FeNO at multiple flow-rates (50-100-150 and 350 ml s−1) and alveolar concentration of NO (CaNO) were collected in 60 healthy controls and 134 patients affected by ILD: 50 with IPF, 19 with fibrotic non-specific interstitial pneumonia, 19 with chronic hypersensitivitis pneumonia (cHP) and 46 with connective tissue disease related ILD (CTD–ILD). ROC curves were performed to investigate the potential role of eNO parameters in discriminating between idiopathic and non-idiopathic ILDs. Results: all ILD groups reported higher levels of FeNO 150–350 ml s−1 and CaNO than controls. Among ILDs, CTD–ILD showed more elevated FeNO 350 ml s−1 and CaNO levels than other ILD. In particular, CaNO reported the best diagnostic accuracy to discriminate CTD–ILD from idiopathic ILDs. Conclusions: patients affected by ILD reported increased FeNO 150–350 ml s−1 and CaNO in respect with healthy controls, indicating a potential role of nitrosative stress in lung fibrosis. The significant difference of CaNO levels between idiopathic ILDs and CTD–ILD is interesting and may suggest that NO is also implicated in lung inflammation associated with rheumatological disease. Further evidence is necessary to establish if CaNO is worthy of attention in the differential diagnosis of ILDs.
CHARMM-GUI Glycan Modeler for modeling and simulation of carbohydrates and glycoconjugates

Characterizing glycans and glycoconjugates in the context of three-dimensional structures is important in understanding their biological roles and developing efficient therapeutic agents. Computational modeling and molecular simulation have become an essential tool complementary to experimental methods. Here, we present a computational tool, Glycan Modeler for in silico N-/O-glycosylation of the target protein and generation of carbohydrate-only systems. In our previous study, we developed Glycan Reader, a web-based tool for detecting carbohydrate molecules from a PDB structure and generation of simulation system and input files. As integrated into Glycan Reader in CHARMM-GUI, Glycan Modeler (Glycan Reader & Modeler) enables to generate the structures of glycans and glycoconjugates for given glycan sequences and glycosylation sites using PDB glycan template structures from Glycan Fragment Database (http://glycanstructure.org/fragment-db). Our benchmark tests demonstrate the universal applicability of Glycan Reader & Modeler to various glycan sequences and target proteins. We also investigated the structural properties of modeled glycan structures by running 2-μs molecular dynamics simulations of HIV envelope protein. The simulations show that the modeled glycan structures built by Glycan Reader & Modeler have the similar structural features compared to the ones solved by X-ray crystallography. We also describe the representative examples of glycoconjugate modeling with video demos to illustrate the practical applications of Glycan Reader & Modeler. Glycan Reader & Modeler is freely available at http://charmm-gui.org/input/glycan.
Alteration of the tumor suppressor SARDH in sporadic colorectal cancer: A functional and transcriptome profiling‐based study

Sporadic colorectal cancer (sCRC) is one of the leading causes of cancer death worldwide. As a highly heterogeneous complex disease, the currently reported classical genetic markers for sCRC, including APC, KRAS, BRAF, and TP53 gene mutations and epigenetic alterations, can explain only some sCRC patients. Here, we first reported a deleterious c.551C>T mutation in SARDH in sCRC. SARDH was identified as a novel tumor suppressor gene and was abnormally decreased in sCRC at both the transcriptional and the translational level. SARDH mRNA levels were also down‐regulated in oesophageal cancer, lung cancer, liver cancer, and pancreatic cancer in the TCGA database. SARDH overexpression inhibited the proliferation, migration, and invasion of CRC cell lines, whereas its depletion improved these processes. SARDH overexpression was down‐regulated in multiple pathways, especially in the chemokine pathway. The SARDH transcript level was positively correlated with the methylation states of CXCL1 and CCL20. Therefore, we concluded that SARDH depletion is involved in the development of sCRC.
Lynch‐like syndrome is as frequent as Lynch syndrome in early‐onset nonfamilial nonpolyposis colorectal cancer

Early‐onset (<50 years‐old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed “Lynch‐like syndrome” (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003–2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.
Changes in the Prevalence of Polypharmacy in People with and without Dementia from 2000 to 2014: A Nationwide Study.

BACKGROUND Polypharmacy, the use of multiple medications, has become increasingly widespread. Information on time trends in polypharmacy in people with dementia is limited, although they may be more susceptible to risks associated with polypharmacy. OBJECTIVE To examine changes in the prevalence of polypharmacy and excessive polypharmacy in people with dementia compared to changes in people without dementia. METHODS Repeated cross-sectional study of the entire Danish population aged≥65 from 2000 (n = 790,717) to 2014 (n = 1,028,377) using linked register data on diagnoses, filled prescriptions, and demographic data. Multivariate analyses were performed to explore changes in the prevalence of polypharmacy and excessive polypharmacy (≥5 and≥10 different prescription drugs). This was done before and after 2011 to examine whether increasing awareness of potential problems associated with polypharmacy has altered the trend. Estimates for people with and without dementia were compared. RESULTS In people with dementia, the prevalence of polypharmacy increased from 47.3% to 69.4% from 2000 to 2011 and excessive polypharmacy from 7.4% to 20.9%. In people without dementia, polypharmacy increased from 22.7% to 36.1% and excessive polypharmacy from 3.5% to 7.7%. The increase was significantly more marked in people with dementia across all age groups. From 2011 to 2014, the prevalence of polypharmacy and excessive polypharmacy remained relatively stable: Polypharmacy decreased negligibly from 69.4% to 68.1% in people with dementia and from 36.1% to 35.2% in people without dementia. CONCLUSION Although the increasing trend has halted, polypharmacy remains widespread in people with dementia. Further research is needed to explore possible implications.
Association of Vegetarian Diet with Chronic Kidney Disease

Chronic kidney disease (CKD) and its complications are major global public health issues. Vegetarian diets are associated with a more favorable profile of metabolic risk factors and lower blood pressure, but the protective effect in CKD is still unknown. We aim to assess the association between vegetarian diets and CKD. A cross-sectional study was based on subjects who received physical checkups at the Taipei Tzu Chi Hospital from 5 September 2005, to 31 December 2016. All subjects completed a questionnaire to assess their demographics, medical history, diet pattern, and lifestyles. The diet patterns were categorized into vegan, ovo-lacto vegetarian, or omnivore. CKD was defined as an estimated GFR <60 mL/min/1.73 m2 or the presence of proteinuria. We evaluated the association between vegetarian diets and CKD prevalence by using multivariate analysis. Our study recruited 55,113 subjects. CKD was significantly less common in the vegan group compared with the omnivore group (vegan 14.8%, ovo-lacto vegetarians 20%, and omnivores 16.2%, P < 0.001). The multivariable logistic regression analysis revealed that vegetarian diets including vegan and ovo-lacto vegetarian diets were possible protective factors [odds ratios = 0.87 (0.77–0.99), P = 0.041; 0.84 (0.78–0.90), P < 0.001]. Our study showed a strong negative association between vegetarian diets and prevalence of CKD. If such associations are causal, vegetarian diets could be helpful in reducing the occurrence of CKD.
AGS Report on Engagement Related to the NIH Inclusion Across the Lifespan Policy

After passage of the 21st Century Cures Act, the National Institutes of Health held a workshop in 2017 to consider expanding its inclusion policy to encompass individuals of all ages. American Geriatrics Society (AGS) leaders and members participated in the workshop and formal feedback period. AGS advocacy clearly impacted the resulting workshop report and Inclusion Across the Lifespan policy that eliminates upper‐age limits for research participation unless risk justified and changes the language used to describe older adults and other vulnerable groups. AGS recommendations that were not specifically stated in the updated policy were to encourage active recruitment of older adults, add standard measures of function and/or frailty, and change review criteria to ensure the health status of a study population mirrors typical clinical populations. The updated inclusion policy ultimately offers academic geriatrics programs the opportunities to expand knowledge about health in aging and to continue to provide leadership for research and advocacy efforts on behalf of older adults. J Am Geriatr Soc 67:211–217, 2019.
Grammatical and Contextual Code Switching in the English Department Proposal Seminar

The fundamental characteristics of the lecturers and the students in the English Department should use English. Lack of English competence is widely considered to be the major cause of code switching. The aim of our work to broaden current knowledge of the phenomenon of grammatical and contextual code switching in the English Department proposal seminar at STKIP Budidaya Binjai. This study applied descriptive qualitative research with the data from the utterances of the lecturers and the students during the process of proposal seminar. The data were obtained from observation, interview, and field note. Grammatical code switching in the English Department proposal seminar were tag code switching consisted of 12 utterances, inter-sentential code switching consisted of 15 utterances, intra-sentential code switching consisted of 19 utterances, proper noun and noun phrase consisted of 7 utterances, negative words consisted of 4 utterances, languages similarity consisted of 11 utterances and discourse marker consisted of 16 utterances. Meanwhile, Contextual code switching in the English Department proposal seminar were situational code switching consisted of 84 utterances and metaphorical code switching consisted of 5 utterances. It can be concluded that contextual and grammatical code switching occurs in the English Department proposal seminar process. Keywords— Code Switching, Grammatical Code Switching, Contextual Code Switching
Validation of A Method to Compensate Multicenter Effects Affecting CT Radiomics.

Background Radiomics extracts features from medical images more precisely and more accurately than visual assessment. However, radiomics features are affected by CT scanner parameters such as reconstruction kernel or section thickness, thus obscuring underlying biologically important texture features. Purpose To investigate whether a compensation method could correct for the variations of radiomic feature values caused by using different CT protocols. Materials and Methods Phantom data involving 10 texture patterns and 74 patients in cohorts 1 (19 men; 42 patients; mean age, 60.4 years; September-October 2013) and 2 (16 men; 32 patients; mean age, 62.1 years; January-September 2007) scanned by using different CT protocols were retrospectively included. For any radiomic feature, the compensation approach identified a protocol-specific transformation to express all data in a common space that were devoid of protocol effects. The differences in statistical distributions between protocols were assessed by using Friedman tests before and after compensation. Principal component analyses were performed on the phantom data to evaluate the ability to distinguish between texture patterns after compensation. Results In the phantom data, the statistical distributions of features were different between protocols for all radiomic features and texture patterns (P < .05). After compensation, the protocol effect was no longer detectable (P > .05). Principal component analysis demonstrated that each texture pattern was no longer displayed as different clusters corresponding to different imaging protocols, unlike what was observed before compensation. The correction for scanner effect was confirmed in patient data with 100% (10 of 10 features for cohort 1) and 98% (87 of 89 features for cohort 2) of P values less than . 05 before compensation, compared with 30% (three of 10) and 15% (13 of 89) after compensation. Conclusion Image compensation successfully realigned feature distributions computed from different CT imaging protocols and should facilitate multicenter radiomic studies. © RSNA, 2019 Online supplemental material is available for this article. See also the editorial by Steiger and Sood in this issue.
A Breakdown Enhanced AlGaN/GaN Schottky Barrier Diode with the T-Anode Position Deep into the Bottom Buffer Layer

In this paper, an AlGaN/GaN Schottky barrier diode (SBD) with the T-anode located deep into the bottom buffer layer in combination with field plates (TAI-BBF FPs SBD) is proposed. The electrical characteristics of the proposed structure and the conventional AlGaN/GaN SBD with gated edge termination (GET SBD) were simulated and compared using a Technology Computer Aided Design (TCAD) tool. The results proved that the breakdown voltage (VBK) in the proposed structure was tremendously improved when compared to the GET SBD. This enhancement is attributed to the suppression of the anode tunneling current by the T-anode and the redistribution of the electric field in the anode–cathode region induced by the field plates (FPs). Moreover, the T-anode had a negligible effect on the two-dimensional electron gas (2DEG) in the channel layer, so there is no deterioration in the forward characteristics. After being optimized, the proposed structure exhibited a low turn-on voltage (VT) of 0.53 V and a specific on-resistance (RON,sp) of 0.32 mΩ·cm2, which was similar to the GET SBD. Meanwhile, the TAI-BBF FP SBD with an anode-cathode spacing of 5 μm achieved a VBK of 1252 V, which was enhanced almost six times compared to the GET SBD with a VBK of 213 V.
Predictive value of the albumin-bilirubin grade on long-term outcomes of CT-guided percutaneous microwave ablation in intrahepatic cholangiocarcinoma

Abstract Purpose: To assess the efficacy of the albumin-bilirubin (ALBI) grade on assessing long-term outcomes of computed tomography (CT)-guided percutaneous microwave ablation (CT-PMWA) in the treatment of patients with intrahepatic cholangiocarcinoma (ICC). Methods: Between April 2011 and March 2018, 78 patients who underwent CT-PMWA were enrolled in this study. Overall survival (OS) and recurrence-free survival (RFS) were compared in the groups stratified by the ALBI grade and Child–Pugh score. Cox proportional hazard regression analyses were performed to determine independent predictors of OS and RFS. Results: After a median follow-up of 22.7 months (range 1–86.7 months), 67 patients had died. The cumulative 1-, 3-, and 5-year OS rates were 89.5%, 52.2%, and 35.0%, respectively. Stratified by the ALBI grade, the cumulative 1-, 3-, and 5-year OS rates were 100%, 69.2%, and 25.6% for patients with the grade 1, respectively. For patients with the ALBI grade 2, the cumulative 1-, 3-, and 5-year OS rates were 41.0%, 10.3%, and 10.3%, respectively. Patients with a hepatic function of the ALBI grade 1 had significantly higher OS rates than patients with the ALBI grade 2 (p < .001). The multivariate analysis showed tumor size (Hazard Ratio[HR] 95% Confidence Interval[CI]:9.03[1.01–80.52], p = .049) and the ALBI grade (HR[95%CI]:9.56[1.58–58.00], p = .014) were associated with OS, and tumor size (HR: 2.03[0.69–8.04], p = .049) was associated with RFS. Conclusions: The preliminary data of this study showed the ALBI grade was effective to predict long-term outcomes of CT-PMWA in ICCs. Further study is necessary to validate our results by a large, multi-center patient cohort.