Bacterial and human peptidylarginine deiminases: targets for inhibiting the autoimmune response in rheumatoid arthritis?

Peptidylarginine deiminases (PADs) convert arginine within a peptide (peptidylarginine) into peptidylcitrulline. Citrullination by human PADs is important in normal physiology and inflammation. Porphyromonas gingivalis, a major pathogen in periodontitis, is the only prokaryote described to possess PAD. P. gingivalis infection may generate citrullinated peptides, which trigger anti-citrullinated peptide antibodies. In susceptible individuals, host protein citrullination by human PADs in the joint probably perpetuates antibody formation, paving the way for the development of chronic arthritis. Blockades of bacterial and human PADs may act as powerful novel therapies by inhibiting the generation of the antigens that trigger and sustain autoimmunity in rheumatoid arthritis

Pathways of airway oxidant formation by house dust mite allergens and viral RNA converge through myosin motors, pannexons and Toll-like receptor 4.

Introduction Intracellular reactive oxidant species (ROS) are generated in human airway epithelial cells by the prothrombinase action of Group 1 house dust mite (HDM) allergens and by ligation of viral RNA sensor Toll‐like receptors (TLRs). We explored signaling convergence between HDM allergens and TLRs in ROS generation because epithelial cells form the primary barrier against inhaled substances and dictate host responses to allergens and viruses. Methods ROS formation by Calu‐3 human airway cells was studied by measuring dihydrorhodamine 123 oxidation after activation by polyinosinic:polycytidylic acid (to activate TLR3), CL097 (to activate TLR7), a natural mixture of HDM allergens, or BzATP. Results TLR4 activation was identified as an indispensable response element for all stimuli, operating downstream from myosin motor activation, pannexon gating for ATP release and the endogenous activation of prothrombin. Exogenous prothrombin activation by HDM allergens was prevented by SGUL 1733, a novel inhibitor of the proteolytic activity of Group 1 HDM allergens, which thus prevented TLR4 from being activated at source. Conclusions Our data identify for the first time that endogenously‐generated prothrombin and TLR4 form a shared effector mechanism essential to intracellular ROS generation activated by a group 1 HDM allergen (itself a prothrombinase) or by ligation of viral RNA‐sensing TLRs. These stimuli operate a confluent signaling pathway in which myosin motors, gating of pannexons, and ADAM 10 lead to prothrombin‐dependent activation of TLR4 with a recycling activation of pannexons

Effect of under-reinforcement on the flexural strength of corroded beams

Reinforced concrete beams are normally designed as under-reinforced to provide ductile behaviour i.e. the tensile moment of resistance, Mt(0) is less than the moment of resistance of the compressive zone, Mc. The degree of under-reinforcement (Mt(0)/Mc ratio) can depend upon the preferences of the designer in complying with design and construction constraints, codes and availability of steel reinforcement diameters and length. Mt(0)/Mc is further influenced during service life by corrosion which decreases Mt(0). The paper investigates the influence of Mt(0)/Mc on the residual flexural strength of corroded beams and determines detailing parameters (e.g. size and percentage of steel reinforcement, cover) on Mt(0)/Mc. Corroded reinforced concrete beams (100 mm · 150 mm deep) with varying Mt(0)/Mc ratios were tested in flexure. The results of the investigation were combined with the results of similar work by other researchers and show that beams with lower Mt(0)/Mc ratios suffer lower flexural strength loss when subjected to tensile reinforcement corrosion. Cover to the main steel does not directly influence Mt(0)/Mc and, thus, the residual flexural strength of corroded beams is not normally affected by increased cover. A simplified expression for estimating the residual strength of corroded beams is also given

TINJAUAN KRIMINOLOGIS TERHADAP TINDAK PIDANA INCEST DENGAN KORBAN ANAK(STUDI KASUS DI LAPAS KLAS IIA BANDA ACEH)

ABSTRAKTRI KARUNIA PUTRI AMELIA,TINJAUAN KRIMINOLOGIS TERHADAP 2015 TINDAK PIDANA INCEST DENGAN KORBAN ANAK (STUDI KASUS DI LAPAS KLAS IIA BANDA ACEH)Fakultas Hukum Universitas Syiah Kuala(v,54),pp.,bibl(Dr. DAHLAN ALI., S.H., M.Hum., M.Kn.,)Salah satu kejahatan yang sering terjadi adalah tindak pidana perkosaan. Tindak pidana perkosaan merupakan salah satu dari tindak pidana terhadap kesusilaan. Dalam Bab XIV dalam Buku II KUHP memuat kejahatan terhadap kesusilaan yang tersebar pada pasal 281 hingga 303 KUHP. Di dalamnya yang dimaksud dengan kesusilaan sebagian besar berkaitan dengan seksualitas. Salah satu jenis kelainan seksual adalah hubungan seks yang dilakukan secara paksa bersama seseorang yang masih ada hubungan darah yaitu incest, dan yang biasanya menjadi korban ialah anak-anak. Incest sebagaimana dirumuskan dalam kamus besar bahasa Indonesia adalah hubungan seksual antara orang-orang yang bersaudara dekat yang dianggap melanggar adat, hukum dan agama. Sanksi mengenai incest dengan korban anak dapat dilihat dalam Pasal 81 dan Pasal 82 Undang-Undang No. 23 Tahun 2002 Tentang Perlindungan Anak.Penelitian ini bertujuan untuk menjelaskan faktor penyebab terjadinya tindak pidana incest, dan untuk mengetahui upaya yang perlu dilakukan untuk menanggulangi tindak pidana incest di provinsi Aceh.Untuk memperoleh data dalam penelitian skripsi ini, dilakukan penelitian pustaka (library research) dan penelitian lapangan (field research) yang dilaksanakan di Banda Aceh dengan lokasi penelitian pada Lembaga Pemasyarakatan Klas IIA dengan tipe penelitian deskriptif yaitu menganalisis data yang diperoleh dari studi lapangan dan kepustakaan dengan cara menjelaskan dan menggambarkan kenyataan objek. Hasil penelitian menunjukkan bahwa faktor-faktor penyebab terjadinya tindak pidana incest adalah: Faktor rendahnya pendidikan dan ekonomi, Faktor lingkungan atau tempat tinggal, Faktor alkohol, Faktor kurangnya pemahaman terhadap agama, dan Peranan korban. Penanggulangan tindak pidana incest dapat dilakukan dengan cara mengadakan pelayanan emergency call kepada masyarakat, mengadakan pengedukasian bagi para orang tua, dan juga pembinaan mental kepada pelaku dan korban tindak pidana incest.Disarankan kepada pemerintah agar hendaknya memperbanyak wadah tempat pengaduan untuk masyarakat, serta diadakan penyuluhan hukum agar dapat menumbuhkan kesadaran masyarakat untuk benar-benar mentaati hukum. Selain itu disarankan agar sistem pembuktian dalam kasus perkosaan dapat lebih permudah, khususnya incest.Banda Ace

Harnessing the Therapeutic Potential of Th17 Cells

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases

PS J1721+8842: A gravitationally lensed dual AGN system at redshift 2.37 with two radio components

Dual-Active Galactic Nuclei (AGN) are a natural consequence of the hierarchical structure formation scenario, and can provide an important test of various models for black hole growth. However, due to their rarity and difficulty to find at high redshift, very few confirmed dual-AGN are known at the epoch where galaxy formation peaks. Here we report the discovery of a gravitationally lensed dual-AGN system at redshift 2.37 comprising two optical/IR quasars separated by 6.5 ± 0.6 kpc, and a third compact (Reff = 0.45 ± 0.02 kpc) red galaxy that is offset from one of the quasars by 1.7 ± 0.1 kpc. From Very Large Array imaging at 3 GHz, we detect 600 and 340 pc-scale radio emission that is associated with both quasars. The 1.4 GHz luminosity densities of the radio sources are about 1024.35 W Hz−1, which is consistent with weak jets. However, the low brightness temperature of the emission is also consistent with star-formation at the level of 850 to 1150 M⊙ yr−1. Although this supports the scenario where the AGN and/or star-formation is being triggered through an ongoing triple-merger, a post-merger scenario where two black holes are recoiling is also possible, given that neither has a detected host galaxy

Analysis of interfacial shrinkage stresses in patch repairs

This paper presents simple analytical expressions that predict the interfacial shrinkage stresses in a repair patch over time. Four repair materials (L2, L3, L4 and G1) were applied by spraying (gunite) to unpropped compression members of two highway structures, and their performance was monitored to approximately six months' age. The elastic moduli of all the repair materials, E rm , were greater than the elastic moduli of the substrate concrete, E sub . The mechanics of patch repair interaction with the substrate were established, and analytical models, based on an analogy of the bimetallic strip undergoing a drop in temperature, were developed. Basic properties of the repair material (elastic modulus, shrinkage and tensile creep) and substrate concrete (elastic modulus), and geometrical details of the repair patch, are required to analyse the interfacial stresses in the repair patch. Verification of the analytical procedures is based on the field data, and the results show a satisfactory correlation between the actual and predicted stress redistribution.</p

A simplified design approach to prevent shrinkage cracking in patch repairs

This paper outlines two procedures for determining the interfacial shrinkage stresses in a repair patch. The first is an analytical approach based on the analogy of a bimetallic strip undergoing contraction (shrinkage). The second is a semi-empirical procedure based on strain monitoring of in situ repairs to in-service bridges. The procedures determine conversion factors to relate the specified properties of the repair materials to their in situ properties in a field repair patch. For example, the shrinkage of a repair patch is influenced by the volume–surface effect, site temperature and relative humidity which are not considered in repair material specification. Creep is initiated in situ by differential shrinkage stresses in the repair material and is determined by adopting an effective elastic modulus approach. Both procedures require the basic material properties (elastic modulus, shrinkage, creep) and geometrical details (width, depth) of the repair patch. The analytical approach incorporates the repair material creep coefficient to predict the interfacial tensile stresses. Alternatively, it uses a less rigorous, elastic approach that omits creep. The creep approach provides higher accuracy whereas the elastic approach overestimates stresses since relaxation by creep is neglected. The elastic approach is recommended for design due to its simplicity and the in-built factor of safety provided by the overestimation of tensile stress. The semi-empirical approach uses an expression derived from long-term field data to determine the strain (and consequently stresses) at the interface of the repair patch and the substrate concrete. The procedures predict the maximum interfacial tensile stress during the service life of a repair patch. They can be used to design crack-free repair patches and optimise repair material selection through a better understanding of the interaction between the repair patch and substrate concrete.</p

Vaccenic acid suppresses intestinal inflammation by increasing anandamide and related N-acylethanolamines in the JCR:LA-cp rat

Vaccenic acid (VA), the predominant ruminantderived trans fat in the food chain, ameliorates hyperlipidemia, yet mechanisms remain elusive. We investigated whether VA could influence tissue endocannabinoids (ECs) by altering the availability of their biosynthetic precursor, arachidonic acid (AA), in membrane phospholipids (PLs). JCR:LA-cp rats were assigned to a control diet with or without VA (1% w/w), cis-9, trans-11 conjugated linoleic acid (CLA) (1% w/w) or VA+CLA (1% + 0.5% w/w) for 8 weeks. VA reduced the EC, 2-arachidonoylglycerol (2-AG), in the liver and visceral adipose tissue (VAT) relative to control diet (P 0.05). Interestingly, VA increased jejunal concentrations of anandamide and those of the noncannabinoid signaling molecules, oleoylethanolamide and palmitoylethanolamide, relative to control diet (P < 0.05). This was consistent with a lower jejunal protein abundance (but not activity) of their degrading enzyme, fatty acid amide hydrolase, as well as the mRNA expression of TNFα and interleukin 1β (P < 0.05). The ability of VA to reduce 2-AG in the liver and VAT provides a potential mechanistic explanation to alleviate ectopic lipid accumulation. The opposing regulation of ECs and other noncannabinoid lipid signaling molecules by VA suggests an activation of benefit via the EC system in the intestine

Appropriate Use of CT Perfusion following Aneurysmal Subarachnoid Hemorrhage: A Bayesian Analysis Approach

These investigators evaluated the test characteristics of CTP in patients with SAH for detection of delayed cerebral ischemia. Ninety-seven patients were assessed with CTP for ischemia and with DSA for vasospasm. The authors concluded that positive CTP findings identified patients who should be carefully considered for induced hypertension, hypervolemia, and hemodilution and/or intra-arterial therapy while negative CTP findings are useful in guiding a no-treatment decision. BACKGROUND AND PURPOSE: In recent years CTP has been used as a complementary diagnostic tool in the evaluation of delayed cerebral ischemia and vasospasm. Our aim was to determine the test characteristics of CTP for detecting delayed cerebral ischemia and vasospasm in SAH, and then to apply Bayesian analysis to identify subgroups for its appropriate use. MATERIALS AND METHODS: Our retrospective cohort comprised consecutive patients with SAH and CTP performed between days 6 and 8 following aneurysm rupture. Delayed cerebral ischemia was determined according to primary outcome measures of infarction and/or permanent neurologic deficits. Vasospasm was determined by using DSA. The test characteristics of CTP and its 95% CIs were calculated. Graphs of conditional probabilities were constructed by using Bayesian techniques. Local treatment thresholds (posttest probability of delayed cerebral ischemia needed to initiate induced hypertension, hypervolemia, and hemodilution or intra-arterial therapy) were determined via a survey of 6 independent neurologists. RESULTS: Ninety-seven patients with SAH were included in the study; 39% (38/97) developed delayed cerebral ischemia. Qualitative CTP deficits were seen in 49% (48/97), occurring in 84% (32/38) with delayed cerebral ischemia and 27% (16/59) without. The sensitivity, specificity, and positive and negative predictive values (95% CI) for CTP were 0.84 (0.73-0.96), 0.73 (0.62-0.84), 0.67 (0.51-0.79), and 0.88 (0.74-0.94), respectively. A subgroup of 57 patients underwent DSA; 63% (36/57) developed vasospasm. Qualitative CTP deficits were seen in 70% (40/57), occurring in 97% (35/36) with vasospasm and 23% (5/21) without. The sensitivity, specificity, and positive and negative predictive values (95% CI) for CTP were 0.97 (0.92-1.0), 0.76 (0.58-0.94), 0.88 (0.72-0.95), and 0.94 (0.69-0.99), respectively. Treatment thresholds were determined as 30% for induced hypertension, hypervolemia, and hemodilution and 70% for intra-arterial therapy. CONCLUSIONS: Positive CTP findings identify patients who should be carefully considered for induced hypertension, hypervolemia, and hemodilution and/or intra-arterial therapy while negative CTP findings are useful in guiding a no-treatment decision