The thermal behaviour was checked by the means of the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). Scanning electron microscopy (SEM) was also used to confirm the hypothesis about the dispersion/aggregation of the POSS molecules into the polymer matrix. The parameters chosen to evaluate the thermal stability of the investigated compounds, namely temperature at 5% of mass loss (T5%) and solid residue at 700 °C, showed a significant increase in the stability of the polymers reinforced with the three-cages POSS, in comparison to both PS and single-cage POSS reinforced PSs, which therefore turn out to be promising molecular fillers for nanocomposite production.Novel polystyrene (PS)/polyhedral oligomeric silsequioxanes (POSSs) nanocomposites were designed and prepared by in situ polymerization, using, for the first time, three-cage POSS molecules. The synthesized compounds were first characterized by Fourier transform infrared spectroscopy (FTIR) and  Starting from cyclopentyl trisilanol, the same procedure was followed for obtaining cyclopentyl POSS chloride. The so obtained POSS chloride were used in the preparation of the corresponding POSS mono-ol. A suspension of isobutyl POSS chloride and a mixture 2:1 of THF/H2O was refluxed for two days and then rotoevapored. The obtained white solid was dried and crystallized from toluene/acetonitrile thus obtaining Isobutyl POSS mono-ol [(C4H9)7Si8O12]-OH. Starting from cyclopentyl POSS chloride the same procedure was followed for obtaining white crystals of Cyclopentyl POSS mono-ol [(c-C5H9)7Si8O12]-OH. Once synthesized isobutyl and cyclopentyl POSS mono-ol, they were, separately and under a nitrogen atmosphere, dissolved in dry THF and added, under stirring, with p-tolyl trichloro silane. The clear solution was cooled at 0–5 °C in an ice bath, added with Et3N, and stirred maintaining the temperature at 0–5 °C for 24 h. Et3NHCl was removed by filtration and the filtrate was evaporated to dryness obtaining a solid that was then crystallized from a THF/MeCN mixture. White crystals of 4-methyl phenyl (trioxyisobutyl POSS) silane and 4-methyl phenyl (trioxycyclopentyl POSS) silane were thus obtained. 1H MNR characterization of the obtained POSS molecules are reported in our previous study [Trisilanol isobutyl POSS was dissolved in dry THF at 0–5 °C and added with SiClus study .w/w) POSS/styrene mixture in toluene for obtaining the desired nanocomposites. Each POSS and styrene monomer were dissolved in toluene and AIBN radical initiator. The so mixed solution was frozen in a liquid nitrogen bath, degassed with a vacuum pump, and then thawed. After repeating this operation three times, the tube, sealed under vacuum, was heated at 70 °C for 24 h under stirring. At the obtained solution was added an excess of methanol thus leading to the precipitation of the nanocomposite, which was collected by filtration and dried under vacuum at 40 °C. The same polymerization procedure was used to prepare neat PS. The obtained yields were 77.4%, 78.3%, 76.6%, and 83.2%, respectively for sample 1, 2, 3, and 4.An in situ polymerization were carried out with a 5%  analysis were performed in a spectrometer by Perkin Elmer  to verify the presence of POSSs in the synthesized nanocomposites an to investigate the nature of the solid residue obtained by the TGA. Investigations wer performed at r.t. from 4000 to 650 cm1H NMR spectra were recorded on a Varian Unity Inova spectrometer . The solvent used for performing measurements was CDCl3 whilst tetramethylsilane (TMS) was used as internal standard. The 1H NMR data found for the various samples investigated allowed the calculation of the actual POSS percentage in the nanocomposites by taking into account the ratio in the 1H NMR spectra among the POSS aliphatic hydrogens and the aromatic hydrogens of PS for compounds 1–2 and among the POSS aromatic hydrogens and the PS ones for samples 3–4.Tg) of the prepared nanocomposites. The apparatus was calibrated in temperature and enthalpy using indium, tin and zinc standard materials. About 6 × 10−3 g of the prepared compound was placed in punched aluminium crucibles, and subject to a heating rate of 10 °C∙min−1 from room temperature up to 150 °C in static air atmosphere.A calorimeter Shimadzu DSC-60  was used to evaluate the glass transition temperature  and static air atmosphere. TG data were plotted as percentage of undegraded sample, (1-D)% against temperature, where D = (Wo − W)/Wo, and Wo and W were the masses at the starting point and during scanning.The thermal properties of PS and corresponding POSSs reinforced nanocomposites were evaluated by thermogravimetric analysis in a Mettler Instrument . Preliminarily to the measurements the equipment was calibrated following the procedure suggested by the company and used by us in the past , which iThe nanocomposites morphology was studied by SEM . All of the samples were gold-sputtered up to a thickness of 20 nm by means of an Emitech K-550 sputter coater . In order to perform the analysis, an accelerating voltage of 15,000 KV was used. All the samples were treated overnight in an oven at 120 °C to remove any traces of toluene. Scans were carried out at different magnifications ranging from 500× to 25,000×.1H NMR investigations showed the successful outcome of the synthesis both from a qualitative view point (presence of the different POSS molecules in the polymer) and from a quantitative one (POSSs content in the polystyrene), thus validating a well-established preparation methodology. Calorimetric investigations showed no significant changes in glass transition temperature, thus demonstrating no changes in the degree of crosslinking and chain mobility. In the comparison with the classic, and widely used single-cage POSS these novel three-cage POSS molecules showed an increase in the matrix reinforcement ability with a prevalence, in agreement with the literature and with our previous results on different POSSs, of the replaced cyclopentyl substituted compared to the isobutyl ones. Furthermore, we recorded a considerable increase of T5% values in comparison to PS nanocomposite reinforced with montmorillonite organically modified [To the best of our knowledge, for the first time three-cages POSS molecules, previously synthesized by us in our laboratory, were used to prepare Polystyrene nanocomposites by in situ polymerization. FT-IR and modified . TGA ana


Family caregiving is associated with social isolation, but the role of geographic distance between caregiver and receiver in caregiving experience is unclear with mixed research findings. This study examined the relationship between geographic distance and caregiver social isolation (CSI), and explored the interaction between geographic distance and caregiving intensity in association with CSI. Based on the Ecological Model of Caregiver Isolation, hierarchical linear regression and ANCOVA analyses were applied to conduct data analysis with the 2012 Canadian General Social Survey . Caregivers living a short distance from receivers reported the lowest CSI than coresident, moderate and long distance caregivers. Being involved in higher intensity caregiving as the primary caregiver, undertaking more caregiving tasks, and providing care more frequently resulted in higher CSI scores. Additionally, long and moderate distance caregivers reported greater CSI than coresident and short distance caregivers only when providing higher intensity caregiving. Geographic distance is a salient contextual factor affecting CSI, and longer distance creates environmental barriers for caregiving provision. Employing a granulated measure of geographic distance positioned within an ecological framework facilitates an understanding of the nuanced association between geographic proximity and CSI. Furthermore, the identified interactive effects between geographic distance and caregiving intensity on CSI further reveal the complexity of caregiving experience. The findings are relevant for programs supporting caregivers in different contexts, especially physical distance.


IgG4-related disease is a new disease entity, but little attention was drawn to urinary system involvement besides nephritis or nephropathy. Here, we described clinical, radiological, and pathological manifestations of IgG4-related urinary disease (IgG4-RUD) and assess its treatment responses.  We conducted a retrospective study enrolling 65 IgG4-RUD patients from an IgG4-related disease (IgG4-RD) cohort of the Peking Union Medical College Hospital. Clinical, laboratory, radiological, pathological data were collected, and treatment response to immunosuppressants were analysed.  IgG4-related interstitial nephritis , glomerular nephritis , renal pelvis and ureter involvement (21.5%), abnormal radiology with quiescent clinical presentation (13.8%), and renal parenchymal lesion plus retroperitoneal fibrosis  were major lesion types of IgG4-RUD. All patients had elevated serum IgG4, 76.9% had hyperglobulinemia, and 92.3% had elevated serum IgE at diagnosis. IgG4-TIN patients presented with renal dysfunction, and 94.3% had low serum complement C3 and IgG4-GN presented with nephrotic syndrome, while renal pelvis and ureter involvement had normal renal function and urinalysis. IgG4-RPF with renal parenchymal involvement presented with acute renal dysfunction and required emergency medical intervention. Renal cortex low-density areas, parenchyma or pelvis nodular mass, bilateral enlargement of the kidney, and renal pelvis and ureter mass/wall thickening were specific image patterns of IgG4-RUD. Infiltration of plasma lymphocytes and storiform fibrosis were histopathological features of IgG4-RUD. Patients showed satisfactory responses to immunosuppressive treatment, but complete recovery of renal function was difficult to achieve in IgG4-TIN. Four patients (6.2%) experienced clinical relapses during the maintenance period.  IgG4-RUD had diverse lesion types and distinctive manifestations. Radiological examinations were helpful for diagnosis and treatment evaluation. Patients showed good initial response to immunosuppressive treatment but relapses could occur at the maintenance period. IgG4-related disease (IgG4-RD) is an increasingly known systemic clinicopathological entity that is characterized by elevated serum IgG4 levels, tumescent enlargement of multiple organs, diffuse infiltration of plasma lymphocytes, and storiform fibrosis in lesioned organs. IgG4-RD was first proposed by Kamisawa et al. in 2003  and was The first case of IgG4-related kidney disease was tubulointerstitial nephritis (TIN), reported as an accompanying condition with autoimmune pancreatitis (AIP) in 2004 . Since tHere, we present the clinical, radiological, and pathogenic features and treatment response of 65 Chinese IgG4-RUD patients from a single centre to give a brief description of the clinical spectrum of IgG4-RUD. We excluded patients with only retroperitoneal fibrosis in this study.All patient data were collected from an IgG4-RD prospective cohort study of the Peking Union Medical College Hospital in China, which was conducted from January 2011 to October 2019. All participants fulfilled both the 2019 American College of Rheumatology/European League Against Rheumatism classification criteria for IgG4-RD  and the For urinary system involvement of IgG4-RD, patients needed to fulfil at least one of the following criteria: (1) histopathology: plasma-cell-rich tubulointerstitial nephritis, with >10 IgG4-positive plasma cells/HPF, and tubular basement membrane immune complex deposits; (2) imaging: small peripheral low-attenuation cortical round or wedge-shaped lesions, parenchymal masses or nodules, diffuse patchy involvement or bilateral diffuse enlargement of the kidneys, and a renal pelvis mass or a thickening of the ureteral wall or the soft tissue around the ureter; and (3) urinalysis: for IgG4-RPF patients, we enrolled only those with confirmed comorbid urine tubular lesions with urine tubular injury markers and urine protein quantification > 0.5 g per 24 hours.We excluded patients with incomplete clinical data and the suspicion of other autoimmune disorders , suspicion of malignancy , and infection. In addition, ureteral obstructive lesions caused only by RPF were excluded. Finally, 65 IgG4-RUD patients were enrolled.Demographic data, disease duration, and accompanying involved organs were collected. Routine blood examination; urinalysis and urine protein quantitation; kidney function tests; erythrocyte sedimentation rate (ESR); and high-sensitivity C reactive protein (hsCRP), complement, serum immunoglobulin (Ig), serum immunoglobulin G (IgG) subclass, total IgE, and autoantibody  levels were tested.All patients underwent imaging examinations, such as ultrasound, CT scan, and magnetic resonance imaging (MRI). Some patients underwent positron emission tomography-computed tomography (PET-CT).All renal needle biopsy samples were embedded in paraffin and stained with hematoxylin and eosin, periodic acid-Schiff, periodic acid-methenamine silver, and Masson's trichrome. For other biopsy samples and surgical autopsy samples, hematoxylin and eosin staining was conducted. Biopsy samples were examined by light microscopy or fluorescence microscopy. Antibodies against CD3, CD20, CD38, CD138, IgG, and IgG4 were used for immunohistological staining.Clinical manifestations; laboratory tests such as urinalysis and 24-hour urine protein (24hUP) quantitation; liver and kidney function tests; ESR; and hsCRP, complement, serum Ig, serum IgG subclass, and total IgE levels were evaluated at months 1, 3, and 6 and every 6 to 12 months afterwards.t-test was used for the analysis of continuous, normally distributed data, while the Mann-Whitney U test was used for the analysis of continuous nonnormally distributed data. One-way ANOVAs were used to analyse categorical variables for normally distributed data, and the Kruskal-Wallis test was used to analyse nonnormally distributed data. A P value less than 0.5 was considered statistically significant.Statistical analysis was performed using SPSS version 21.0 . The Student Among the 65 enrolled IgG4-RUD patients, 21 were diagnosed with TIN (32.3%), 5 with IgG4-related glomerular nephritis , 3 with both TIN and glomerular nephritis , 14 with renal pelvis or ureter involvement (21.5%), and 1 with bladder involvement (1.5%). Nine patients presented abnormal renal radiological findings, such as renal parenchymal nodule lesions (13.8%). Twelve patients had renal parenchymal lesions accompanied by retroperitoneal fibrosis (18.5%).For the accompanying involved organs, the pancreas was the most commonly involved organ , followed by the submandibular gland and lacrimal gland .IgG4-RUD patients were predominantly male , with a mean diagnostic age of 59.0 (52.5-67.0) years, and had multiple organ involvement. The mean disease duration was 1.5 (0.4-10.0) years. A total of 52.3% of patients had an allergy history  The mean follow-up duration was 1.9 (0.9-3.1) years .All IgG4-RUD patients had elevated serum IgG4, 76.9% presented with hyperglobulinemia, and 92.3% had hyper-IgE.μmol/L, and the mean 24-hour urine protein was 0.68 (0.35-1.41) g/24 h. No anaemia, Fanconi syndrome, or renal tubular acidosis was observed. Hypocomplementemia was another important serological feature of TIN; 94.3% of IgG4-TIN patients had low levels of C3, and 61.3% had hypo-C4. The mean C3 concentration of IgG4-TIN patients was 0.482 (0.430-0.739) g/L, which was significantly lower than that of other patients (P < 0.05). The mean serum C4 concentration was 0.065 (0.028-0.145) g/L.Compared with other types, patients with IgG4-TIN presented with markedly elevated serum IgG1 [12400 (9020-15500) mg/L] and high serum IgG4 concentration [17500 (10536-30950) mg/L] and tended to have renal dysfunction with different degrees of proteinuria. The mean serum creatinine (SCr) was 151.5 (78.3-256.8) μmol/L]. Their serum IgG4 level was also markedly elevated to 10270 (8310-2950) mg/L. One patient showed low serum C3 and C4, while others had normal complement. Negative serum antiphospholipase 2 receptor (PLA2R) antibody was essential for the exclusion of primary membranous nephropathy.IgG4-related glomerular nephritis patients mainly had membranous nephropathy in our study. Patients presented with oedema and nephrotic syndrome. The mean 24-hour urine protein was 11.1 (6.3-16.7) g/24 h, and the mean serum albumin was 18 (14-25) g/L. However, most patients had normal SCr . The mean urine protein level was 0.99 (0.68-1.27) g/24 h. Hypocomplementemia was not a common feature in these patients  patients . Eight  bilateral renal cortical patchy, low-density lesions ; (2) isoApart from renal parenchymal lesions, IgG4-related renal pelvis, ureter, and bladder lesions also presented with a solid mass or wall thickening without enhancement Figures . For thoBiopsies were carried out in 36 (55.4%) IgG4-RUD patients before treatment, of whom 20 (55.6%) received renal needle biopsies, 3 (8.3%) underwent renal operation, and 1 (2.8%) patient had bladder wall biopsy. Others received biopsies at other involved organs, such as the submandibular glands, lymph nodes, and intestine. Diffuse plasma cell and lymphocyte infiltration and storiform fibrosis were typical pathological features found in renal biopsy samples from IgG4-TIN patients, together with an IgG4/IgG-positive plasma cell ratio > 40% and >10 IgG4-positive plasma cell high-power field Figures  . EosinoFor renal glomerular lesions, it is difficult to differentiate IgG4-MN from primary MN merely through the analysis of renal biopsy samples, in which all had IgG4 deposition in mesangial areas, unless glomerular lesions were accompanied by typical IgG4-TIN pathological lesions or were negative for anti-PLA2R antibody under immunohistochemical staining .For renal pelvis, ureter, or bladder involvement, plasma-lymphocyte-rich infiltration, storiform fibrosis, and obliterative phlebitis were easily observed. An IgG4/IgG-positive plasma cell ratio > 40% and >40 IgG4-positive plasma cells/HPF were sufficient for diagnosis Figures .IgG4-RUD patients showed good initial treatment response to glucocorticoids (GC). We started with 40~60 mg prednisone per day (0.6~0.8 mg/kg/d) for 1 month , which was then tapered to 5 mg every two weeks until 20 mg per day was reached. GC was gradually tapered 2.5~5 mg every 2 to 4 weeks until ≤10 mg/d was reached for long-term maintenance, except in one patient who was maintained at 12.5 mg/d and in one patient in whom prednisone was withdrawn 6 months after therapy . ImmunosSerum IgG4 showed satisfactory decline after initial treatment but was reelevated at 36 months in IgG4-MN and IgG4-related renal pelvis patients . For IgGSixteen patients (24.6%) had serum IgG4 reelevation during follow-up. Four cases (6.2%) of clinical relapse were observed in IgG4-RUD patients, and all presented with exacerbated renal impairment with serum creatinine reelevation. Two cases of clinical relapse occurred in IgG4-TIN patients: one had a relapse at 30 months after prednisone withdrawal, with baseline IgG4 concentrations of 3090 mg/dL; the other had an initial serum IgG4 concentration of 36400 mg/dL and relapsed at 18 months with prednisone at 12.5 mg per day, but immunosuppressant treatment was stopped due to skin infection. The other two patients, with TIN+GN, both relapsed at 15 months, one with prednisone at 10 mg per day and cyclosporine for maintenance and the other with prednisone at 10 mg per day and tripterygium glycosides.In our study, we analysed the clinical, laboratory, radiological, and histological data of 65 primary IgG4-RUD patients in our prospective IgG4-RD cohort, including renal parenchymal, renal pelvis, ureter, and bladder involvement.Patients were predominantly middle-aged and male with multiple organ involvement. The pancreas, lacrimal glands, and salivary glands were the most common accompanying involved organs.All IgG4-RUD patients had remarkably elevated serum IgG4, most of whom presented with hyperglobulinemia and elevated serum IgE. The clinical presentations of IgG4-RUD varied among different types. IgG4-TIN was the most common lesion type in IgG4-RUD. IgG4-TIN patients came to the clinic with renal dysfunction and a low level of urine protein. Hypocomplementemia, especially low serum C3, was a noteworthy feature in IgG4-TIN but not in other lesion types. IgG4-GN includes various pathological types, such as MN and mesangial proliferative nephritis . In our Imaging examinations were important for IgG4-RUD diagnosis. Bilateral renal enlargement, a nodule or wedge-shaped mass without enhancement, and wall thickening were characteristic radiological changes seen in IgG4-RUD patients, though they were sometimes difficult to differentiate from malignancies. High uptake of 18F-FDG in PET-CT also had diagnostic value for IgG4-RUD.The infiltration of IgG4-positive plasma cells and lymphocytes and storiform fibrosis were common histological characteristics of IgG4-RUD. Eosinophil infiltration could also be found in lesioned tissue. For IgG4-MN patients, the coexistence of interstitial inflammatory infiltration and negative anti-PLA2R staining helped in the diagnosis. Though tissue biopsy samples could not be easily acquired in IgG4-RUD patients, tissue pathology was still confirmed as the gold standard diagnostic criterion for IgG4-RUD patients.IgG4-RUD patients showed a satisfactory response to glucocorticoid treatment, with stable kidney function, decreased urine protein and serum IgG4, and rehabilitated radiological findings. For IgG4-TIN patients, SCr declined after the first month of treatment but remained moderately elevated afterwards. For IgG4-GN patients who presented with high baseline proteinuria, urine protein declined to normal ranges after one year of immunosuppressant therapy. IgG4-related renal pelvis/ureter-involved patients seemed to have a better prognosis than those with nephritis and nephropathy. Patients with IgG4-related renal parenchymal disease plus RPF presented with more urgent clinical conditions, but after proper immunosuppressant treatment, creatinine quickly declined after one month even without catheter drainage. While 16 patients had serum IgG4 reelevation during follow-up, only 4 cases of relapses occurred at 15 to 30 months, even without the discontinuance of immunosuppressive treatment. Serum creatinine reelevation seemed to be a specific signal for disease relapse compared with serum IgG4 elevation.In IgG4-RUD patients, the serum IgG4 concentration was much higher than the established cut-off value: the mean initial serum IgG4 concentration was 7920-17900 mg/L. As IgG4-RUD could present only with tumescent lesions, or with individual masses but quiescent clinical manifestations, radiological examinations were noninvasive methods for disease diagnosis and monitoring.Our study had several limitations. This was a single-centre study with a relatively small population. For IgG4-RKD patients, not all underwent renal biopsies. According to inconspicuous initial manifestations, many IgG4-RUD patients had delayed diagnoses; thus, full recovery could not be achieved.In conclusion, primary IgG4-RUD accounts for a significant percentage of IgG4-RD, with diverse clinical presentations and a high frequency of recurrence even under intensive immunosuppressive treatment. If not diagnosed in time, renal dysfunctions are unlikely to completely reverse. Initial serum IgG4 concentration is not valuable for prognosis assessment due to different lengths of disease duration and accompanying involved organs, but close monitoring of IgG4, renal function, and radiology could help in the early recognition of urinary relapse. As the pathogenesis of IgG4-RUD remains confusing, more basic studies are needed for the precise treatment and better prognosis of IgG4-RUD patients.


By using an ensemble-docking strategy, we undertook a large-scale virtual screening campaign in order to identify new putative hits against the MET kinase target. Following a large molecular dynamics sampling of its conformational space, a set of 45 conformers of the kinase was retained as docking targets to take into account the flexibility of the binding site moieties. Our screening funnel started from about 80,000 chemical compounds to be tested in silico for their potential affinities towards the kinase binding site. The top 100 molecules selected—thanks to the molecular docking results—were further analyzed for their interactions, and 25 of the most promising ligands were tested for their ability to inhibit MET activity in cells. F0514-4011 compound was the most efficient and impaired this scattering response to HGF (Hepatocyte Growth Factor) with an IC MET receptor is a multifunctional receptor tyrosine kinase that plays a pivotal role in human development and tumorigenesis. Upon binding of its ligand HGF (Hepatocyte Growth Factor), MET triggers several intracellular signaling cascades, including MAPK and PI3K pathways, leading to various cellular responses, such as survival, proliferation, and migration, among others. MET activation can be driven in cancer by several mechanisms: HGF or MET overexpression, and also mutations .Aberrant activation of MET signaling does not only affect cancer development and progression, but it also contributes to resistance against other cancer drugs ,9,10,11.Even though promising results have been reported, the therapeutic activity of these drugs is still relative and efforts are required to identify new MET inhibitors with physicochemical properties optimized for clinical efficiency ,20. MoreDesigning new putative hits against MET therefore remains a valuable challenge to be tackled. In the present work, we carried out a virtual screening campaign in order to identify innovative compounds able to become new hits for further lead development. As MET plasticity upon ligand binding had been previously highlighted ,23, we tIn previous medicinal chemistry works, we already identified novel MET inhibitors ,31 and cTo use the highest possible chemical diversity, in order to cover a large spectrum of chemical structures ,38,39,40To include kinase-targeted compounds, as such a choice is already proven to be successful ,42;To explore natural products, which are a promising source of anticancer drugs ,44,45;To take into account the repositioning of approved compounds, as drug repurposing presents an increasing interest in cancer research, by removing many costs associated with several steps of drug development ,47,48,49The choice of an appropriated set of compounds to explore the virtual screening space is critical for assuming a good rate of success . Today, According to the criteria listed above concerning the choice of the chemical libraries, we firstly downloaded around 200,000 compounds from the chemical providers listed in In ensemble-based docking calculations, a well-suited choice of the protein target conformational sample is required to reproduce the protein plasticity and the possible induced-fit phenomena ,52.Concerning MET conformational flexibility, our previous exploration by molecular dynamics and normal mode simulations  was limiTo be in accordance with the 26 conformers coming from our previous work , the 19 The ensemble-docking facility proposed in the GOLD docking program was used . This GOWhen docking an ensemble of conformations for a given protein, their binding sites must be defined using a method that is not conformer specific. In the present ensemble-GOLD version, as it was not possible to define the active site by a list of atoms or residues, the only way was to use the centroid of the binding cavity and a sphere radius around this point. Therefore, for each of the 45 aligned protein conformers used here, protein cavities and their center of mass were detected by the LIGSITE program . From thFor each docking run, we used 50 starting poses/molecule for the GOLD generic algorithm. Tested compounds were ranked by the standard goldscore scoring function.Due to the massive calculations needed , and considering the computing time to achieve only one run, we used the Grid5000 facility  providinThe experimental protocols for measuring the potency of MET inhibitors are detailed in previous publications ,62. MDCKThe coordinates of the 45 aligned conformers and of the sphere representing their common binding sites constituted our ensemble-docking protein reference.The first question here concerned the accuracy of this binding site definition compared to ones that are more classical. For that, we compared the docking results for some of the selected 45 MET conformers using three binding site definitions; namely, a residue list, an existing ligand, and the center point of the binding cavity, respectively. For each individual docking target, the three definitions provided almost the same rank and docking score for the associated PDB ligand . MoreoveThe second question was related to the ability of the ensemble-docking process to retrieve a given PDB ligand to its PDB structure among the 45 ones. To evaluate that point, an ensemble-docking calculation was carried out on the 45 protein target conformers using a short chemical library built from their own 45 associated ligands  for further analysis.We started the docking analysis with the Life Chemicals compound F0725-0356 giving the best docking score of 114. A comparison between the X-ray complex 3EFK/MT4 structure and the MD_3EFK/F025-0356 one presented quite similar poses and protein/ligand interactions. Indeed, the most important residues known in MET interactions . The results show that the GOLD docking pose is very stable and still conserved after 10 ns of MD  is not a newcomer in drug design as it has been already tested as a possible activator of E3 ligase (FBW7) and inhibitor of microphthalmia-associated transcription factor (MITF), but was found inactive in both assays. Our study suggests that it could be repositioned for MET inhibition, as evidenced by its biological activity against MET-driven cell scattering. Some drug properties such as solubility and lack of toxicity were already known. With regard to its molecular weight of 650Da, which could be considered as limiting its possible therapeutic action, it should be noted that other inhibitors currently on the market have similar characteristics such as tarloxatinib (679Da), foretinib (632Da), or golvatinib (633Da). Therefore, it should not be a major hurdle if lead optimization provides us with a promising drug in terms of activity and/or selectivity. This will be the topic of future investigations.This virtual screening work presents F0414-4011 as a valuable compound that could be a seed for developing new and innovative leads against MET kinase. Its novelty and originality might be used to overcome the resistance problem found presently for several existing inhibitors.


Late-onset Parkinson’s disease (PD) is dominated clinically and experimentally by a focus on dopamine neuron degeneration and ensuing motor system abnormalities. There are, additionally, a number of non-motor symptoms – including cognitive and psychiatric – that can appear much earlier in the course of the disease and also significantly impair quality of life. The neurobiology of such cognitive and psychiatric non-motor symptoms is poorly understood. The recognition of genetic forms of late-onset PD, which are clinically similar to idiopathic forms in both motor and non-motor symptoms, raises the perspective that brain cells and circuits – and the behaviors they support – differ in significant ways from normal by virtue of the fact that these mutations are carried throughout life, including especially early developmental critical periods where circuit structure and function is particularly susceptible to the influence of experience-dependent activity. In this focused review, we support this central thesis by highlighting studies of LRRK2-G2019S mouse models. We describe work that shows that in G2019S mutants, corticostriatal activity and plasticity are abnormal by P21, the end of a period of excitatory synaptogenesis in striatum. Moreover, by young adulthood, impaired striatal synaptic and non-synaptic forms of plasticity likely underlie altered and variable performance by mutant mice in validated tasks that test for depression-like and anhedonia-like behaviors. Mechanistically, deficits in cellular, synaptic and behavioral plasticity may be unified by mutation-linked defects in trafficking of AMPAR subunits and other membrane channels, which in turn may reflect impairment in the function of the Rab family of GTPases, a major target of LRRK2 phosphorylation. These findings underscore the need to better understand how PD-related mutant proteins influence brain structure and function during an extended period of brain development, and offer new clues for future therapeutic strategies to target non-motor cognitive or psychiatric symptoms of PD. Late-onset Parkinson’s disease (PD) is a movement disorder diagnosed clinically by the appearance in middle age of progressively debilitating motor symptoms, including rigidity, resting tremor, bradykinesia, postural instability, and gait disturbances, among others . Such prLess well understood, both clinically and mechanistically, is a spectrum of prominent non-motor symptoms that appear during a temporally variable prodromal phase occurring prior to onset of the disease-defining motor symptoms . Such noThe clinical management of PD largely focuses on the late-onset motor symptoms, leading in some cases to an almost tacit view that the cellular and synaptic environment in brains of PD patients is normal until the prodromal stage, at which time some pathophysiological process arises to co-opt and disrupt brain circuits and set a course of steady, degenerative decline. Based in part on genetic forms of late-onset PD and the mouse models used to mechanistically interrogate the impact of such mutations on cell and circuit function, there is growing recognition that this view probably does not adequately capture the complexity of the disease process or the cellular/circuit environment in the brain in which the disease manifests . In thisper se – that is, displaying all of the cardinal features of the disease process -pathway SPNs (dSPNs) and indirect (D2R)-pathway SPNs (iSPNs)  , are som (iSPNs) . Develop (iSPNs) . This ea (iSPNs) ; and sec (iSPNs) . This is (iSPNs) . Relatio (iSPNs) . Interes (iSPNs) . These o (iSPNs)  and chan (iSPNs) . These d (iSPNs)  and diff (iSPNs) . Additio (iSPNs) .per se is not normally required for glutamatergic vesicle release at these synapses. Rather, the elevated AP-dependent increase in sEPSC frequency in G2019S slices most likely represents a gain-of-abnormal function imparted by the mutation, although it remains possible this is an indirect, compensatory effect of the mutation. Other domains of LRRK2 may function in neurotransmitter vesicle release at earlier ages, since mEPSC frequency recorded from SPNs in P15 LRRK2 knockout mice are lower than wildtype  in frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both dSPNs and iSPNs at P21, the height of corticostriatal synaptogenesis. Similar results were observed at P28 in dorsolateral striatum . The magwildtype . The elewildtype .In addition to increased sEPSC frequency – likely presynaptic in origin as discussed above – postsynaptic effects in G2019S dorsomedial SPNs are also evident by P21. Cumulative probability distributions show that dendritic spine-heads are larger in comparison with those on wildtype SPNs. Since generally larger spines are correlated with larger AMPAR currents , predict2R signaling. Repeated stimulation in striatum of G2019S slices produces significantly greater peak levels of DA release and longer DA decay times than wildtype , corticostriatal synapses on dorsomedial G2019S SPNs also exhibit aberrant evoked responses – namely, mutant SPNs are unable to express bidirectional synaptic plasticity . Bidirecwildtype  and sEPSance LTD . Interesance LTD . Finallyance LTD , and an ance LTD . While tTogether, these data raise the question of whether such early changes in striatal circuit structure/function coupled with early and persistent loss of bidirectional striatal synaptic plasticity in G2019S mice would have a lasting impact on striatally based behaviors. Several studies, utilizing different lines of G2019S knockin mice, have reported modest motor-like effects mostly appearing between 3 and 6 months of age or older . GeneralIn behaviorally naive young adult (2–3 month-old) male wildtype and G2019S mice, the mutation alone, in the absence of any particular prior experience, is generally insufficient for altering motor coordination, anxiety, exploratory activity, self-care and anhedonia-like behaviors . AdditioOne interpretation of this behavioral outcome is that this is a type of learning deficit. However, studies testing the social interaction behavior of G2019S mice after only 1-day of social defeat stress (1-day-SDS) complicates this interpretation. G2019S mice subjected to 1-day-SDS are all significantly more socially avoidant compared to 1-day-SDS wildtype mice , anotherper se to include G2019S effects on the peripheral immune system, where LRRK2 is enriched, resulting in aberrant modulatory effects on brain cells and circuits by immune cells  in comparison with wildtype. This is potentially significant, because dynamic trafficking of CP-AMPARs, such as GluA1, into the synaptic membrane is tied mechanistically to both LTP  and the ne cells . It has ne cells .A link between the G2019S mutation and hypothesized deficits in membrane channel trafficking is provided by considering the Rab family of GTPases as a significant target of LRRK2 phosphorylation , 2017 wiCollectively the data support that LRRK2 mutation alters vesicle recycling, trafficking and possibly protein synthesis during development in ways that are sustained, impacting certain cellular behaviors over the lifespan, and in other ways that are transient, but have permanent consequences for the assembly of neural circuits and the eventual behaviors they support. Given the impact of the G2019S mutation on LTP in the dorsal striatum, it is likely that striatal behaviors like action-outcome learning or other forms of goal-directed behaviors will be affected similarly to what has been observed in reward-based circuits modified by social stress paradigms.GH and DB wrote the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs.Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology. IgG4-related kidney disease (IgG4-RKD) is the kidney lesion of IgG4-related disease (IgG4-RD) and its typical manifestation is plasma cell (PC)-rich tubulointerstitial nephritis (TIN) . IgG4-RK+PCs) . At this time, white blood cells 7,100/µL (eosinophil 241/µL), urinary protein (2+), occult blood (-), and urinary sugar (4+) were documented. Urine cytology was negative. Periodic abdominal CT revealed a mass lesion on his right upper ureter and mild right kidney hydronephrosis  50.7 ml/min/1.73 m+PC infiltration [> 100/high power field (HPF)], obliterative phlebitis and storiform fibrosis  and IgG4+PCs surrounded the lymphatic follicle-like structures , hemoglobin A1c 6.5 %, serum IgG 1,674 mg/dL, IgG4 112 mg/dL, anti-nuclear antibody 1:160, rheumatoid factor 47 IU/mL and normal complement levels , although these data would have been somewhat affected by the dexamethasone therapy before operation , urinary glucose (2+), and occult blood (-). Blood examination revealed white blood cells 6,900/µL (eosinophil 511/µL), kidney dysfunction (serum creatinine 2.04 mg/dL, eGFR 26.0 mL/min/1.73 mThe present case showed a ureter mass in the right ureteropelvic junction suggestive of a ureteral malignancy for which ureteronephrectomy was performed. Histopathological analysis showed IgG4-ureteritis and the coexistence of the very early stage of IgG4-TIN with TLT formation in the renal parenchyma.In this case, IgG4-TIN was incidentally detected without any suggestive radiological findings on contrast-enhanced CT. Various radiological abnormalities such as multiple low-density lesions and rim-like lesion on contrast-enhanced CT have been found in IgG4-RKD, each of which reflects the respective pathological findings , 6. On tin situ in IgG4-RD [+PC infiltration. Although TLT could be a potential marker of relapse and resistance to treatment in IgG4-RD [Notably, in the analysis of the scattered kidney lesions in this case, we found that the distribution of the lesions of IgG4-TIN was consistent with the area in which TLT often forms in the kidney, i.e. around perivascular and subcapsular areas. TLT functions as local sites of antigen presentation, clonal expansion, lymphocyte activation and class switching in B cells –17. Alth IgG4-RD . Althoug IgG4-RD , 25, ver IgG4-RD –14. Simi IgG4-RD . TLT for IgG4-RD . In addi IgG4-RD . Conside IgG4-RD , we spec IgG4-RD . Given t IgG4-RD , the dev IgG4-RD , its cliIn conclusion, we report a case of the very early stage of IgG4-TIN containing TLT which was incidentally detected concurrently with IgG4-related ureteritis in the ureteropelvic junction. The distribution of TLT in this case was consistent with that of IgG4-TIN, and IgG4-positive cells infiltrated around TLT, suggesting that IgG4-TIN develops and distributes in tandem with TLT formation. Clarification of the role of TLT in IgG4-TIN lesion formation would facilitate understanding of IgG4-TIN pathophysiology.


Over the last two decades, deaths associated with opioids have escalated in number and geographic spread, impacting more and more individuals, families, and communities. Reflecting on the shifting nature of the opioid overdose crisis, Dasgupta, Beletsky, and Ciccarone offer a triphasic framework to explain that opioid overdose deaths (OODs) shifted from prescription opioids for pain (beginning in 2000), to heroin (2010 to 2015), and then to synthetic opioids (beginning in 2013). Given the rapidly shifting nature of OODs, timelier surveillance data are critical to inform strategies that combat the opioid crisis. Using easily accessible and near real-time social media data to improve public health surveillance efforts related to the opioid crisis is a promising area of research.This study explored the potential of using Twitter data to monitor the opioid epidemic. Specifically, this study investigated the extent to which the content of opioid-related tweets corresponds with the triphasic nature of the opioid crisis and correlates with OODs in North Carolina between 2009 and 2017.Opioid-related Twitter posts were obtained using Crimson Hexagon, and were classified as relating to prescription opioids, heroin, and synthetic opioids using natural language processing. This process resulted in a corpus of 100,777 posts consisting of tweets, retweets, mentions, and replies. Using a random sample of 10,000 posts from the corpus, we identified opioid-related terms by analyzing word frequency for each year. OODs were obtained from the Multiple Cause of Death database from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER). Least squares regression and Granger tests compared patterns of opioid-related posts with OODs.P=.01 and P<.001, respectively), as well as in the following year . Moreover, heroin tweets in a given year predicted heroin deaths better than lagged heroin OODs alone (P=.03).The pattern of tweets related to prescription opioids, heroin, and synthetic opioids resembled the triphasic nature of OODs. For prescription opioids, tweet counts and OODs were statistically unrelated. Tweets mentioning heroin and synthetic opioids were significantly associated with heroin OODs and synthetic OODs in the same year (Findings support using Twitter data as a timely indicator of opioid overdose mortality, especially for heroin. Opioid overdose deaths (OODs) constitute a significant public health burden for the United States. In 2018, of the 67,367 drug overdose–related deaths, 70%  were attributed to opioids, with increases across demographic and geographic subgroups. Additionally, OODs involving synthetic opioids  increased 10% from 2017 to 2018 and accounted for two-thirds of opioid-related deaths [Reflecting on the evolving nature of the opioid crisis, Dasgupta, Beletsky, and Ciccarone  present Currently, the monitoring of OODs relies primarily on mortality data that lag between 12 to 18 months behind real time. Given the rapidly shifting nature of OODs, timelier surveillance data are critical to inform strategies that combat the opioid crisis. Over the last several years, there have been over 1000 health-related publications using Twitter to inform health research. This body of science spans a number of disparate areas, including tracking the spread of influenza ,4, oral Regarding opioids specifically, researchers have analyzed Twitter messages and other social media posts from forums such as Reddit to understand their role in recovery from opioid use disorder , and accThis study explored Twitter data to monitor the opioid epidemic. Specifically, this study investigated the extent to which the content of opioid-related tweets corresponds with the triphasic nature of the opioid crisis and correlates with OODs in North Carolina between 2009 and 2017. North Carolina was selected because of its high rates of OODs, which increased notably during the study period.Data collection from Twitter involved retrospectively monitoring the platform using Crimson Hexagon to access all English opioid-related posts from January 1, 2009, through December 31, 2018, in North Carolina. We created queries (opinion monitors) with a set of parameters (search terms) in Crimson Hexagon including commercial  and “street” names  of drugs. We cast a broad net to capture terms referencing both trade and generic names. In order to identify such terms, we searched for common slang words referring to opioids using the Drug Enforcement Administration’s (DEA) Intelligence Report titled “Slang Terms and Code Words: A Reference for Law Enforcement Personnel” . We subsPost location was determined through cross-verification of the geotag, profile information, time zones, content, and image data. This process resulted in a corpus of 100,777 posts consisting of tweets, retweets, mentions, and replies. We made the decision not to exclude retweets with the understanding that retweets signify a unique form of communication through an implied endorsement or agreement with the initial post .Using a random sample of 10,000 posts from the corpus, we identified opioid-related terms by analyzing word frequency for each year. Next, we coded these terms into three tweet categories: prescription opioids , heroin , and synthetic opioids .We obtained annual mortality data from 2009 to 2018 from the Multiple Cause of Death database from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) . Drug ovWe estimated the association between the opioid-related tweet categories and OODs using ordinary least squares regression with either the current tweet count or a 1-year lag of tweet count as the independent variable. We also fit a vector autoregression and used Granger tests  to deterThis study consisted of secondary analyses; no individuals were involved. As data do not include any personally identifiable information, Institutional Review Board approval was not required.The pattern of opioid-related Twitter posts in North Carolina appears in The progression of OODs in North Carolina appears in P=.58) or the no-lag model . In contrast, tweet counts for both heroin and synthetic opioids were significantly associated with OODs. On average, each additional heroin tweet in a given year corresponded to 0.13 additional heroin overdose deaths that same year (P=.01) and 0.13 additional deaths the following year (P=.03). Each additional tweet mentioning synthetic opioids in a given year corresponded to 2.68 additional synthetic opioid overdose deaths that year (P<.001) and 9.24 additional deaths the next year (P=.01).Using the augmented Dickey-Fuller tests, we failed to reject stationarity up to two lags for all variables except for prescription OODs. The association between tweet count and OODs was not significant for prescription opioids in either the one-year lag model  over and above lagged heroin OODs.Granger tests following vector autoregression estimation with one and two lags (only one lag was estimated for prescription OODs) were consistent with the regression results but significant only for heroin tweets; tweets mentioning heroin in a given year significantly predicted subsequent heroin OODs (The pattern of opioid-related Twitter posts in North Carolina resembled the triphasic nature of the opioid crisis as described by Dasgupta et al . Tweets Results from the regression models and Granger tests indicated that the association with OODs differed by the type of opioid. For prescription opioids, tweet count and OODs were unrelated. The lack of association observed between prescription opioid tweets and overdose deaths may underestimate the true association therein, particularly because some patients who are treated with prescription opioids are chronic pain patients or older individuals , who mayTweets mentioning heroin and synthetic opioids were significantly associated with heroin OODs and synthetic OODs, respectively. Moreover, results from the Granger tests showed that heroin tweets in a given year predicted subsequent heroin deaths better than lagged heroin OODs alone. These predictive results extend recent reports of correlations between opioid-related tweets and opioid overdose rates at the state and county levels ,29.There are a number of limitations to be considered. First, the scope of the terms used in our search parameters was somewhat subjective, in that there are hundreds of terms representing opioids , and we Limitations notwithstanding, to our knowledge, this study is the first to report that the pattern of opioid-related Twitter posts in North Carolina not only resembles the triphasic nature of the opioid crisis , but tha


We explore effects of light dispersion by a wire-grid polarizer (WGP) in imaging polarimetry. The dispersive characteristics of a WGP, combined with off-axis scene incidence, cause significant non-uniformity. The normalized performance measure of contrast due to dispersion of WGP exceeded 0.84 for transmittance and 0.90 for extinction ratio (maximum non-uniformity at 1 and 0 for uniform performance). Dispersion also produces a lateral spread in the imaging plane, which may induce spectral image misregistration. Without higher-order excitation, the misregistration can be at the least a few pixels long in the detector. In the presence of higher-order modes, the dispersive misregistration can be severe and critical for polarized scene extraction. The results emphasize the need for an imaging polarimeter to be designed to manage the dispersive effects. Superb polarimetric performance combined with inherent structural planarity has made a WGP attractive in applications such as spectropolarimetry3 and projection displays4. Effects of a WGP were investigated in conjunction with a rotating platform5 and on the flexible9 and rough surface10. Thermal properties and plasmonic enhancement of a WGP were also studied13. On the other hand, a WGP was implemented using DNA-nanoparticle composites14. For the planarity of the structure, a WGP has been integrated to various electronic and photonic devices including a CMOS and CCD imaging sensor19, contact lens20, fiber-optics21, light-emitting diodes22, liquid crystal26, optical isolators28, a photodiode29, photoelectrochemical solar cells30, and semiconductor laser31.Since 1960s, a wire-grid polarizer (WGP) has been considered as an optical element to discriminate polarization components:38. Many design issues of WGPs have been explored in imaging polarimetry, for example, non-uniformity in the polarimetric performance depending on the incident scene vector39 and effect of finite pixel size40. WGP was integrated into a diffractive optical element41. One of the issues that have not been fully addressed and therefore we intend to address in this work is to understand the dispersive effects on the imaging performance which may appear in addition to typical spherical and chromatic aberration of imaging optics when WGPs are integrated for use in imaging polarimetry. Understanding the dispersive effects is critical to the design of WGPs because the polarimetry like any other imaging applications is performed in a broadband spectrum. More importantly, light dispersion can have an extremely severe and harmful effect on diffractive optical devices including metamaterials as recently reported for far-field applications43, which may limit practical application in imaging. In this sense, this study has a broad implication far greater than mere suggestion of a novel WGP design for imaging polarimetry.Use of a WGP has been particularly beneficial for imaging polarimetry because complete polarization contents of a scene may be measured simply by changing the orientation of wire-grids on a pixelated platform in a flexible ways) and gold (nm) was obtained as ns = 1.5308 and nm = 1.4684 + j1.9530 for λ = 400 nm44. At λ = 700 nm, ns = 1.5131 and nm = 0.1310 + j4.0624. The fill factor ff is defined as the ratio of wire-grid width to the period Λ. Wire-grids are assumed to be rectangular in profile (width ffΛ and thickness h) and infinite along the y axis. Wire-grid periods were varied from Λ = 100 nm ~ 1 μm in a step of 100 nm for a fill factor ff = 0.10, 0.25, 0.50, 0.75, and 0.90. Thickness of wire-grids is fixed at 200 nm.Wire-grids were assumed to be made of gold on a BK7 substrate in air ambience, as shown in the schematic of Fig. f) of an imaging convex lens (f-number f/#). For the convenience of analysis, we have assumed the imaging lens to be cylindrical, as shown in Fig. f-number listed in Table DWGP and DL. For generality, we have assumed that a WGP is not directly integrated into an imaging detector. For this consideration, the thickness of a WGP substrate is set to be ds = 500 μm. The WGP-to-detector distance is s: s = 0 if the WGP operates in contact with the detector. A WGP and a detector are assumed to be aligned at the center in the lateral plane. The diameter of an Airy pattern (DAiry) produced by the aperture is given as:f is the imaging focal length and D is the aperture diameter. DAiry is listed in Table f-#. As is implied in Eq.  by mapping RGB combinations in the CIE 1931 xy chromaticity space. Particle swarm optimization was used to find a specific single RGB combination. Each of the spectral component images was processed with ER(λ) between TE and TM polarization and combined to produce an image acquired by imaging polarimetry. Dispersive artifacts were then applied to the images.Generation of an object and image acquisition were performed on MatlabT) of TM and TE polarized light was measured in the far-field. Extinction ratio (ER) was used as a ratio of reflectance of TM polarization to that of TE polarization, i.e., ER = TTM/TTE. Out of the several factors contributing to non-uniform polarimetric performance of a WGP, we have focused on the angular off-axis and the dispersive effects, which we have quantified with normalized transmittance and extinction ratio. If we consider light rays making minimum and maximum incident angle, L/2 f = 1/2 f/# for on-axis scene incidence. For off-axis incidence, WGP/DL)/2 f/# and WGP/DL)/2 f/#. Insights on the performance non-uniformity due to off-axis imaging of the scene can be obtained by comparing T and ER at NToff) and extinction ratio (NERoff) asWe used rigorous coupled-wave analysis (RCWA) with 60 spatial harmonic orders to calculate optical characteristics of a WGP. For the assessment of polarimetric performance, transmittance (NTλ) and extinction ratio (NERλ) defined asSimilarly, dispersive effects may be evaluated in the visible waveband by wavelength-dependent non-uniformity in transmittance  as well as the wavelength (λ) is varied from θin = 0 ~ 60° in the visible waveband.Before we present diattenuation-based dispersive effects in imaging polarimetry, it is also of interest to explore the effect on more general Stokes polarimetry. For convenience, we assume single-point acquisition in the far-field with unpolarized light incidence. The results are shown in Fig. 49. If we quantify the variation of polarization states with a sum of arc lengths (Lp) measured between points on the Poincaré sphere , dLp/dθin = 0.5795 and dLp/dλ = 1.185. More importantly, we emphasize that the polarization state varies with light wavelength and may thus be affected significantly by the spectral content of an incident scene. The scene-based variation of polarization states may be additive to the dispersive effects that were presented previously. For more explicit understanding of dispersive effects in imaging polarimetry, however, we only consider diattenuation properties of a WGP in the following section.It is quite clear that the polarization states may vary drastically due to light dispersion. Interestingly, the spectral variation of polarization tends to increase with a high angle of incidence due both to the difference in phase change that TE or TM polarization undergoes with respect to the incidence angle and also to the changes in the relative amount between the components polarized in parallel and orthogonal to the wire-gridsER. Now, performance non-uniformity and image misregistration due to light dispersion degrades overall polarimetric content in a pixel. Figure Λ) greater than light wavelength. For the simulation of dispersive effects, therefore, the wire-grid period of WGP and incident angle were assumed to be Λ = 1000 nm and θin = 60° as the worst case. The baboon image as an object was acquired through a WGP as 50:50 TM and TE component. A TM image was obtained as transmitted through a WGP, while TE image intensity was proportionately reduced with ER(λ). The TM and TE component images were then combined to form a final ideal image without dispersion in Fig. st TM image. In this illustration of an example, the detector sensitivity was assumed to be independent of wavelengths. With wavelength dependence, the contrast between ideal and dispersive images can be even starker.Under the conditions without dispersive artifacts, polarimetric performance is represented by 52. For example, higher-order diffraction modes need to be strictly suppressed, e.g., using a WGP with sufficiently fine wire-grids or employing filters in the light paths. To remove or reduce zeroth-order dispersive effects, a WGP is best integrated directly with a detector or in the closest proximity. A WGP mounted in an optical plane that is relayed in a 4 f imaging system to an image plane would cause more severe artifacts because of the distance between a WGP and a detector. This may be compensated using dispersive devices, e.g., gratings, in the optical path.The comparison of the magnified images laden with dispersive artifacts in the inset of Fig. In summary, we have investigated effects of dispersion in imaging polarimetry based on WGPs. Mainly, there are mainly two effects: dispersion aggravates performance non-uniformity, which is less severe than one that is caused by off-axis imaging. In addition, dispersive lateral spread produces image misregistration in the detector. The spread is expected to be smaller than or on the order of 10 μm in typical imaging conditions. This may be significantly worse when higher-order diffraction components are excited and can add systemic noise to the acquired images. The results therefore emphasize the need to consider dispersive artifacts for the design of WGP-based imaging polarimetry.


Concrete has become the most common construction material, showing, among other advantages, good behaviour when subjected to high temperatures. Nevertheless, concrete is usually reinforced with elements of other materials such as steel in the form of rebars or fibres. Thus, the behaviour under high temperatures of these other materials can be critical for structural elements. In addition, concrete spalling occurs when concrete is subjected to high temperature due to internal pressures. Micro polypropylene fibres (PP) have shown to be effective for reducing such spalling, although this type of fibres barely improves any of the mechanical properties of the element. Hence, a combination of PP with steel rebars or fibres can be effective for the structural design of elements exposed to high temperatures. New polyolefin fibres (PF) have become an alternative to steel fibres. PF meet the requirements of the standards to consider the contributions of the fibres in the structural design. However, there is a lack of evidence about the behaviour of PF and elements made of polyolefin fibre reinforced concrete (PFRC) subjected to high temperatures. Given that these polymer fibres would be melt above 250 °C, the behaviour in the intermediate temperatures was assessed in this study. Uni-axial tests on individual fibres and three-point bending tests of PFRC specimens were performed. The results have shown that the residual load-bearing capacity of the material is gradually lost up to 200 °C, though the PFRC showed structural performance up to 185 °C. One of the most relevant advantages of concrete as a construction and building material, compared with other structural materials such as steel or wood, is its behaviour when subjected to fire and high temperatures. In the 1970s, an extensive experimental campaign initiated to analyse and investigate the behaviour of concrete subjected to high temperatures, due to the growth of the nuclear industry that uses this material as confinement in reactors and for cooling towers [Given that fire remains as one of the most relevant potential risks for structures, research dealing with the response of reinforced concrete and fibre reinforced concrete under this circumstance has been conducted, showing that some micro polypropylene fibres (PP) can be used to control the risk of explosive spalling . CertainSeveral types of synthetic fibres such as PP, polyvinyl alcohol (PVA), nylon (Ny), polyethylene (PE) have shown several advantages and have been used mainly in combination with SF and specially for high strength concrete . Steel fThe significance of this research relies on the assessment of the behaviour of PFRC exposed to high temperature. To the authors’ best knowledge, this is the first time that polyolefin fibres have been studied under such conditions. Moreover, the fracture properties and the residual strengths were obtained by three-point bending tests on notched specimens previously exposed to the referred a range of temperature from 20 °C to 200 °C. The results have shown that the residual load-bearing capacity of the material is gradually lost up to 200 °C, though the PFRC showed structural performance up to 185 °C. In addition, in this research, the variation of the mechanical properties of isolated PF exposed to a range of temperature from 20 °C to 160 °C was studied.The experimental campaign encompassed two main research aims: characterisation of the properties of isolated fibres subjected to high temperatures and characterisation of the residual properties of fibre reinforced concrete specimens after being exposed to high temperatures. The specimens were subjected to heat in a Memmet UFB-500 stove  capable of reaching temperatures above 200 °C with an accuracy of ±0.5 °CIsolated polyolefin-based macro fibres were introduced in an oven at various temperatures in order to assess the influence of temperature on the mechanical properties. In order to evaluate such mechanical properties, uniaxial tensile tests were performed supplying values of load and displacements. Digital image techniques (DIC) were implemented to obtain the longitudinal deformation. With such results and with a previous meticulous measurement of the fibre cross section and the initial length, it was possible to compute the ultimate residual strength for each temperature. With the stress–strain curve, the residual modulus of elasticity was calculated as the slope of the fitting curve in the quasi-straight stretch. The fibres tested were Sika-fiber T-60   and theiThe fibres were introduced in the oven when it had reached the target temperature for an hour. Then, the fibres were kept in the oven for 24 h. This timing was chosen following the rationale found in references . Before The uniaxial tensile tests of the fibres were performed according to UNE-EN 6892-1: 2017  assumed The video recorded one image per second by use of a high-definition IDS UI-1480SE camera . This device has a five-megapixel sensor with a resolution of 2560 × 1920 pixels. The application of a two-dimensional image analysis can be obtained by synchronising mechanical testing and video recording.The temperatures studied were 100 °C, 125 °C, 150 °C and 160 °C. This set of temperatures permitted assessing the progressive modification of their properties. Higher temperatures would not allow performing the test because of the melting of the fibres. For each one, five specimens were tested, and stress–strain curves were recorded. Given that this type of test in polyolefins may show high degrees of scattering of the experimental results, such number of valid tests was chosen for each temperature. A representative average curve was interpolated for each temperature. 3, with a water/cement ratio of 0.5, were employed. The mix proportioning can be seen in The experimental campaign was performed with concrete elements manufactured with the concrete mix design of the reference . Thus, s3 of polyolefin fibres). The third temperature was the room temperature in order to compare the residual properties with the original ones. After exposed to those temperatures, the properties evaluated in concrete specimens were pulse velocity and residual elasticity modulus by ultrasound, compressive strength, fracture energy and residual flexural strength. These properties were assessed in prismatic specimens, cast for three-point bending tests (TPB). Given that the concrete with 10 kg/m3 (HF10) was considered as structural material , sev3 (height × depth × length). In order to assess compressive strength tests, cubic specimens of side 10 mm were obtained by sawing them from the reaming halves of the prismatic specimens tested. For each temperature, a pair of cubic pieces were tested. The tests were performed according to EN 12390-3 [The fracture tests were performed following RILEM TC-187-SOC [ 12390-3 . Table 4The heating process of specimens was carried out by means of convection heat in an oven, at an approximate heating rate of 2.80 °C/min. When the specimens reached the maximum temperature of analysis, they remained for 3 h at such temperature. The oven turned on and off using programmers during the night before the test day. The test specimens cooled on the stove for a period of 7 h.3 by using thermocouples, showing that the heating times chosen were adequate.The heating time of the concrete specimens was chosen based on references ,21 that Ultrasound pulse velocity test may allow the evaluation of porosity and internal damage of concrete. The tests were performed before and after exposing the specimens to the heating process. In the case of the measurements after heating, they were performed when the specimen reached 30 °C in order to avoid wrong lectures during the test .Vp) and residual modulus of elasticity (E) at 20 °C have been labelled in the tables as Vp20 and E20 respectively.For all the specimens, pulse velocity was assessed according to the methodology proposed by standard UNE-EN 12504-4: 2006 . The pulD (300 mm) and the length of the notch D/3 (33.3 mm), where D is the height of the specimen. a0 being the length of the notch, sph the ligament length and P the applied load. In addition to the residual strengths, the maximum load that corresponds to the limit of proportionality (LOPF), the deflection and crack opening were obtained by means of two Linear Variable Differential Transformer (LVDT) (to measure deflection in the midspan) and one Crack Mouth Opening Displacement (CMOD) resistive transducer (to measure the crack mouth opening), respectively. The two LVDTs were placed at each side of the specimen in the midspan and the deflection was considered the average value. The CMOD was placed in the lips of the notch in order to measure the opening of the notch.In order to obtain the residual flexural tensile strengths of PFRC, tests were carried out according to RILEM TC-187-SOC recommendation . This prWith the results of the tests, the curves stress vs. crack opening (FL-CMOD) were obtained in order to determine the residual flexural tensile strengths for crack openings of 0.5, 1.5, 2.5 and 3.5 mm. The fracture energy was calculated with the load vs. deflection curves .It is worth noting that the careful manufacturing process, being of key importance in this study, in addition to the accuracy of the equipment and measuring devices permitted the reduction of the experimental scatter. The specimen positioning was carefully made by means of laser devices. The notch was machined with a water-cooled low-speed diamond cutting disc. The concrete specimens rested on two rigid steel cylinders laid on two ground supports, which allowed free rotation out of the plane of the beam and guarantee negligible friction rolling in the longitudinal direction of the beam. Thus, the results of the fracture tests showed a remarkably low degree of scatter that can be verified for the specimens exposed to 20 °C by previous works on references ,9. For tLOPF) was reached in all cases for CMOD below 0.1 mm. The first post-cracking branch of the curve after LOPF followed the typical shape of the concrete softening behaviour up to CMOD values close to 0.5 mm (MINF) at which a new reloading branch initiated. Such reloading branch was constantly increasing up to the crack opening (CMOD) at which the fibres collapse by any of the failure mechanisms (mainly sliding or breaking). Such point of the curve was named maximum residual remaining load (REMF). This can be better understood by seeing FG) and coefficient of variation for plain concrete as a function of temperature are shown in Fracture energy was analysed for both plain and PFRC specimens. The load at the proportionality limit  assessed for HF3 and HF10 can be seen in Conversely, load–deflection curve was different for 200 °C. Such a curve showed residual values for Rf1 (strength at CMOD 0.5 mm) should be superior to 40% of LOPf and Rf3 (strength at CMOD 2.5 mm) shall not be less than 20% of LOPf. Thus, the analysis of residual flexural tensile strengths Rf1, Rf2, Rf3, Rf4 were considered with respect to the increase in temperature. Such residual strengths are those obtained through Equation (2) at CMOD values of 0.5 mm, 1.5 mm, 2.5 mm and 3.5 mm, respectively.The structural capacity of PFRC was assessed according to UNE-EN 14561:2007 , EHE-08 Given the low fibre dosage of HF3, the specimens did not meet the requirements of the standards even when exposed to ambient temperature. At least until temperatures of 150 °C the specimens behaved similarly to those only exposed to ambient temperature. In the case of the HF3 specimens exposed to 200 °C, the fibres that seemed to be closest to the surface reaching their melting point and the residual properties were strongly affected. The residual flexural tensile strengths of HF3 exposed to various temperatures are shown in LOPf decreased with a value of 5.94 MPa in the control test to 4.22 MPa at 150 °C, a decrease of 29%. Regarding Rf1 and Rf3 the specimens met the structural requirements of the standards up to those exposed to 165 °C, with values 42% and 71% for Rf1 and Rf3 respectively. From 175 °C to 200 °C, only Rf3 met the requirements. This is worth mentioning because such is the requirement for ultimate limit state in design. The tests conducted on HF10 specimens showed that as the temperature of exposure increased, The variation of the compressive strength was assessed by testing at least three specimens, rejecting highly dispersed values and considering repeatability or reproducibility specified in EN 12390-3 . The resAs can be seen in Specimens subjected to 150 °C and 160 °C showed residual values of the modulus of elasticity 33% and 9% lower respectively. Thus, after exposed to such temperatures the degradation was noticeable which could be attributed to the proximity to the crystalline melting temperature (175 °C) . The symThe percentage of reduction of maximum tensile strength with increase of temperature was lower than in the case of the modulus of elasticity. The residual strengths for specimens subjected up to 150 °C maintained 78% of the value for the control specimens. The residual tensile strength for the specimens exposed to 160 °C was still 50% of the control specimens.The polyolefin is a partially crystalline polymer, having in general greater mechanical strength than a polymer with an amorphous structure . The fibThe deformation increased with temperature: at 100 °C and 125 °C the growth in deformation was about 1.06 and 1.32 times superior in reference to fibres only exposed to room temperature. These values increased sharply for fibres exposed to 150 °C and 160 °C, being 2.45 and 4.92, respectively. The elongation capacity of fibre is not affected by being exposed to increasing temperatures. According to the results obtained, the minimum and maximum elongation varies between 14.55 mm for 20 °C and 17.45 mm for 125 °C, oscillating between these values for the rest of temperatures.This sudden increase of the strain could be attributed to the fact that the fibre diminishes its length although maintains its capacity of elongation in the tests. The fibre reduced its length down to 48% of its initial magnitude for 160 °C. The residual pulse velocity for all the concrete types according to In all cases, values between 88% and 91% of pulse velocity at room temperature were obtained. These results were comparable with those evaluated by K.K. Sideris  for highIn reference to the static modulus of elasticity, it can be appreciated a similar behaviour to the previous results as shown in 3).In the case of HF10, specimens were exposed to several increasing steps of temperature between 150 °C and 200 °C, as can be seen in TI) could be computed by expression (1), being FRCA the area under the load–deflection curve for HF3 and HF10 and HFA the area under the load–deflection curve for HF at 0.5 mm.Toughness index was computed by dividing the area under load deflection curve for concrete HF3 and HF10 by the reference value of the energy absorption of the concrete without fibres (HF), obtained from the area under the Load–LVDT curve at 0.5 mm of deflection. The toughness index  was assessed. At 185 °C, 81% of the fracture energy was kept and at 200 °C a residual value of 17% was found, attributed to the change in the state of the fibres. When they reach their melting point, the effective number of fibres in the fracture surface decreased, with a reduction of 50%. MINF) and the maximum remaining post-cracking load (REMF). These values are the reference values to be used in the analysis of the fracture behaviour of PFRC [To assess the fracture properties of the specimens manufactured with fibre reinforced concrete, a fracture surface analysis was performed following previously published research and models ,34,35. T of PFRC ,13. FiguRf1) and 2.5 mm (Rf3) are the parameters associated with structural design. Therefore, the evolution of such parameters when PFRC is exposed to high temperature is directly related with the residual strengths that could be considered for structural design at each temperature step.The fracture behaviour of fibre reinforced concrete was assessed. This analysis is of key relevance in order to assess the structural contribution of the fibres to Service Limit State and Ultimate Limit State . According to annex 14 of EHE-08 , residuaRf1 and Rf3 of the specimens exposed only to room temperature were about 15% of the strength at limit of proportionality (LOPf) and are detailed in Rf1) and 1% (Rf3).The residual strengths of HF3 were below the required by the standards at any of the temperatures tested. The fracture curves can be seen in Rf1) and 56% at 2.5 mm of CMOD (Rf3) with respect to a value of 5.94 MPa of LOPf. This behaviour, considered by the standards as structural, is even more noticeable for the specimens exposed to 150 °C and 165 °C. Such specimens reached 52% and 42% in Rf1, and for Rf3 the percentages reached 66% and 71% respectively.The behaviour of HF10 specimens is shown in Rf1 was lower than 40%), being 32% of LOPf for 175 °C, although the material maintained the main characteristics of structural fibre reinforced concrete with 57% of LOPf in the case of Rf3 . As shown in the results, the performance for ULS was still acceptable at 175 °C and 185 °C with residual strengths of 2.55 MPa and 2.66 MPa, respectively. Nevertheless, a strong reduction was found for specimens subjected to 200 °C, with absence of any structural behaviour although still showing structural integrity as compared with plain concrete.For higher steps of temperature, the SLS requirement is not met . Conversely, specimens exposed to 200 °C showed absence of any structural capacity, though the specimens still did not collapse or show brittle failure.PFRC specimens with 10 kg/mBased on this study, it is suggested to perform an evaluation of spalling behaviour, and mechanical properties of reinforced concrete with polyolefin fibres at temperatures above 200 °C, so the possibilities of PF could be explored for temperatures beyond such a temperature.Both mechanical and physical properties  of the fibres studied individually exposed to high temperatures showed a bilinear behaviour, with a negative slope for all of them except in the case of deformation, which was positive. The influence of temperature was visible from 100 °C and showed and abrupt increase in the deterioration of the properties from 150 °C.