BILIARY HAPTOGLOBIN, A POTENT PROMOTER OF CHOLESTEROL CRYSTALLIZATION AT PHYSIOLOGICAL CONCENTRATIONS

Background/Aims: Several proteins present in human bile have been reported to promote cholesterol crystallization and thus are potentially important in the formation of cholesterol crystals as the initial stage in gallstone pathogenesis. To be physiologically relevant, such proteins must either be present in high concentration in bile or have a potent promoting activity. The current study explored several of the more abundant but unexamined biliary proteins based upon their also having sufficiently high serum concentrations that antibodies were available for both their isolation and quantitation. Methods: Protein purification was accomplished by immunoaffinity chromatography of bile followed by delipidation. Con A affinity chromatography of bile was used to obtain the bound fraction, a portion of which was delipidated. Crystallization-promoting activity of both the purified proteins and Con A-bound glycoprotein fractions (CABG) was measured by a photometric crystal growth assay. A competitive antibody-capture ELISA assay was developed to measure concentrations of alpha(1)-antitrypsin, transferrin, and haptoglobin in native bile. Results: At their relevant physiological concentrations, biliary haptoglobin (15 mu g/ml) had a crystallization-promoting activity twice that of the biliary IgM (75 mu g/ml) used as a reference standard (P < 0.05). Biliary transferrin (20 mu g/ml) had only modest promoting activity (P < 0.05). Biliary alpha(1)-antitrypsin (50 mu g/ml), by contrast, showed no promoting activity. Delipidation of the CABG fraction decreased its promoting activity by 75%. Biliary haptoglobin accounts for about 30% of delipidated total CABG-promoting activity. Conclusions: Biliary haptoglobin at its physiological concentration has a highly potent crystallization-promoting activity and thus becomes a candidate for major attention in understanding gallstone pathogenesis. Biliary lipids associated with CABG account for a major portion of the cholesterol-crystallization-promoting activity of this fraction

A Horizon Scan of research priorities to inform policies aimed at reducing the harm of plastic pollution to biota

Plastic pollution in the oceans is a priority environmental issue. The recent increase in research on the topic, coupled with growing public awareness, has catalyzed policymakers around the world to identify and implement solutions that minimize the harm caused by plastic pollution. To aid and coordinate these efforts, we surveyed experts with scientific experience identified through their peer-reviewed publications. We asked experts about the most pressing research questions relating to how biota interact with plastic pollution that in turn can inform policy decisions and research agendas to best contribute to understanding and reducing the harm of plastic pollution to biota. We used a modified Horizon Scan method that first used a subgroup of experts to generate 46 research questions on aquatic biota and plastics, and then conducted an online survey of researchers globally to prioritize questions in terms of their importance to inform policy development. One hundred and fifteen experts from 29 countries ranked research questions in six themes. The questions were ranked by urgency, indicating which research should be addressed immediately, which can be addressed later, and which are of limited relevance to inform action on plastics as an environmental pollutant. We found that questions relating to the following four themes were the most commonly top-ranked research priorities: (i) sources, circulation and distribution of plastics, (ii) type of harm from plastics, (iii) detection of ingested plastics and the associated problems, and (iv) related economies and policy to ingested plastics. While there are many research questions on the topic of impacts of plastic pollution on biota that could be funded and investigated, our results focus collective priorities in terms of research that experts believe will inform effective policy and on-the-ground conservation.© 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/

Neurodegeneration and inflammation crosstalk: therapeutic targets and perspectives

Glia, which was formerly considered to exist just to connect neurons, now plays a key function in a wide range of physiological events, including formation of memory, learning, neuroplasticity, synaptic plasticity, energy consumption, and homeostasis of ions. Glial cells regulate the brain's immune responses and confers nutritional and structural aid to neurons, making them an important player in a broad range of neurological disorders. Alzheimer's, ALS, Parkinson's, frontotemporal dementia (FTD), and epilepsy are a few of the neurodegenerative diseases that have been linked to microglia and astroglia cells, in particular. Synapse growth is aided by glial cell activity, and this activity has an effect on neuronal signalling. Each glial malfunction in diverse neurodegenerative diseases is distinct, and we will discuss its significance in the progression of the illness, as well as its potential for future treatmen

Reusable photocatalytic optical fibers for underground, deep-sea, and turbid water remediation

An approach for underground, deep, and turbid water remediation is presented based on optical fibers with a photocatalytic coating. Thus, photocatalytic TiO2 P25 nanoparticles immobilized in a poly(vinylidene difluoride) (PVDF) matrix are coated on polymeric optical fibers (POFs) and the photocatalytic performance of the system is assessed under artificial sunlight. To the best of our knowledge, poly(methyl methacrylate)-POF coated with TiO2/PVDF and the reusability of any type of POF for photocatalytic applications are not previously reported. The photocatalytic efficiency of the hybrid material in the degradation of ciprofloxacin (CIP) and its reusability are evaluated here. It is shown that 50 w/w% of TiO2 P25 achieves a degradation of 95% after 72 h under artificial sunlight and a reusability of three times leads to a loss of activity inferior to 11%. The efficient removal of ciprofloxacin and the stability of the POF coated with TiO2 P25 successfully demonstrate its suitability in the degradation of pollutants with potential application in regions with low light illumination, as in underground and deep water.Peer ReviewedPostprint (published version

Malignant perivascular epithelioid cell tumor of the uterus

Perivascular epithelioid cell tumors (PEComas) are a rare collection of tumors arising in a wide array of anatomic locations and characterized by a myomelanocytic phenotype. PEComas which occur in non-classic anatomic distributions are known as perivascular epithelioid cell tumor-not otherwise specified (PEComa-NOS), and one of the most common primary sites for PEComa-NOS is the uterus. The risk of aggressive behavior of these tumors has been linked to a number of factors evaluable on pathologic review following initial surgical resection. We report a case of PEComa-NOS of the uterus with multiple high-risk features, including frank vascular invasion, with no evidence of recurrent disease 18 months following initial surgical resection

Exposure to depleted uranium does not alter the co-expression of HER-2/neu and p53 in breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Amongst the extensive literature on immunohistochemical profile of breast cancer, very little is found on populations exposed to a potential risk factor such as depleted uranium. This study looked at the immunohistochemical expression of HER-2/neu (c-erbB2) and p53 in different histological types of breast cancer found in the middle Euphrates region of Iraq, where the population has been exposed to high levels of depleted uranium.</p> <p>Findings</p> <p>The present investigation was performed over a period starting from September 2008 to April 2009. Formalin-fixed, paraffin-embedded blocks from 70 patients with breast cancer (62 ductal and 8 lobular carcinoma) were included in this study. A group of 25 patients with fibroadenoma was included as a comparative group, and 20 samples of normal breast tissue sections were used as controls. Labeled streptavidin-biotin (LSAB+) complex method was employed for immunohistochemical detection of HER-2/neu and p53.</p> <p>The detection rate of HER-2/neu and p53 immunohistochemical expression were 47.14% and 35.71% respectively in malignant tumors; expression was negative in the comparative and control groups (p < 0.05).</p> <p>HER-2/neu immunostaining was significantly associated with histological type, tumor size, nodal involvement, and recurrence of breast carcinoma (<it>p </it>< 0.05), p53 immunostaining was significantly associated with tumor size, nodal involvement and recurrence of breast cancer (<it>p </it>< 0.05). There was greater immunoexpression of HER-2/neu in breast cancer in this population, compared with findings in other populations.</p> <p>Both biomarkers were positively correlated with each other. Furthermore, all the cases that co-expressed both HER-2/neu and p53 showed the most unfavorable biopathological profile.</p> <p>Conclusion</p> <p>P53 and HER-2/neu over-expression play an important role in pathogenesis of breast carcinoma. The findings indicate that in regions exposed to high levels of depleted uranium, although p53 and HER-2/neu overexpression are both high, correlation of their expression with age, grade, tumor size, recurrence and lymph node involvement is similar to studies that have been conducted on populations not exposed to depleted uranium. HER-2/neu expression in breast cancer was higher in this population, compared with results on non-exposed populations.</p

Probucol Release from Novel Multicompartmental Microcapsules for the Oral Targeted Delivery in Type 2 Diabetes

In previous studies, we developed and characterised multicompartmental microcapsules as a platform for the targeted oral delivery of lipophilic drugs in type 2 diabetes (T2D). We also designed a new microencapsulated formulation of probucol-sodium alginate (PB-SA), with good structural properties and excipient compatibility. The aim of this study was to examine the stability and pH-dependent targeted release of the microcapsules at various pH values and different temperatures. Microencapsulation was carried out using a Büchi-based microencapsulating system developed in our laboratory. Using SA polymer, two formulations were prepared: empty SA microcapsules (SA, control) and loaded SA microcapsules (PB-SA, test), at a constant ratio (1:30), respectively. Microcapsules were examined for drug content, zeta potential, size, morphology and swelling characteristics and PB release characteristics at pH 1.5, 3, 6 and 7.8. The production yield and microencapsulation efficiency were also determined. PB-SA microcapsules had 2.6 ± 0.25% PB content, and zeta potential of −66 ± 1.6%, suggesting good stability. They showed spherical and uniform morphology and significantly higher swelling at pH 7.8 at both 25 and 37°C (p < 0.05). The microcapsules showed multiphasic release properties at pH 7.8. The production yield and microencapsulation efficiency were high (85 ± 5 and 92 ± 2%, respectively). The PB-SA microcapsules exhibited distal gastrointestinal tract targeted delivery with a multiphasic release pattern and with good stability and uniformity. However, the release of PB from the microcapsules was not controlled, suggesting uneven distribution of the drug within the microcapsules

Structural insights into Clostridium perfringens delta toxin pore formation

Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus β-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 Å crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal α-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins

Clinical Application of Computer-Aided Diagnostic System for Harmonious Introduction of Complementary Dialysis Therapy

In chronic peritoneal dialysis (PD) therapy, peritoneal permeability is gradually enhanced over the duration of the therapeutic course, leading to a grave decline in the therapeutic efficiency. In recent years, a novel therapy (CD therapy), which integrates PD therapy with hemodialysis therapy, is being applied to end-stage PD patients to complement the decline of therapeutic efficiency caused by the grave degeneration of the peritoneal tissue. To realize a harmonious introduction of the CD therapy, this study developed a useful index (KAu/c), which evaluates both therapeutic efficiency and degeneration of peritoneal tissue. Using a mathematical model and KAu/c, we were able to validate the therapeutic efficiency in the PD patients, and, in one case, propose a better prescription for the patient by employing the CD therapy. The clinical implementation of this methodology is indispensable with regard to expanding the therapeutic monitoring system for renal replacement therapy