Miracle-dz/UniFAR-FTUs huggingface dataset:
Chemokine Receptors: Attractive Targets for Drug Discovery

Abstract: Studies of two antibodies, efalizumab and natalizumab, have recently demonstrated that the blockade of leukocyte migration is of therapeutic benefit for the treatment of diseases such as psoriasis and multiple sclerosis. The role of chemokines in the control of cell traffic led to their receptors being considered one of the most promising family of targets aimed at disrupting cell recruitment in chronic inflammatory processes. Choosing the appropriate chemokine receptor for each disease was not easy, and the interpretation of target validation studies proved to be extremely difficult. Despite an intense effort in the search for chemokine receptor antagonists in the last decade, no compounds in advanced clinical trials exist as such. The inherent complexity of the family, the differences between the chemokine system in mice and men, and the species selectivity of small‐molecule compounds could account for this fact. Pharmaceutical companies still believe in chemokine receptors as therapeutic targets, as demonstrated by the number of compounds reported to be in development. In the next years, the developmental progression of these compounds will reveal which target within the chemokine family is of real therapeutic value.
Combination approach to score level fusion for Multimodal Biometric system by using face and fingerprint

Biometric System is used for person's recognition and identification for various applications. The Biometric system is unimodal and multimodal biometric system. Unimodal Biometric suffers from Noisy data, Intra class variation, non versality, spoofing etc. These drawbacks can remove by using Multimodal Biometric system. We developed the multimodal Biometric system by using Face and fingerprint Multimodalities. This system takes the advantage of individual Biometric System. This paper presents the fusion of face and fingerprint modalities at score level fusion. The system extracts the features and these features are then used for matching. Euclidean distance matcher is used for Face and Finger print modalities. Fingerprint recognition can be done with the help of minutiae matching and Gabor filter. The Face feature is extracted with the help of PCA (Principle Component Analysis) for dimensionality Reduction. Then the match scores are Normalized and sum score level fusion is used to develop the system. The proposed approach provides the better results. The Recognition Rate is increased and the error rate is decreased by with the help of this system.
Mucosal plexus and electrolyte transport across the rat colonic mucosa.

Histological and functional studies were performed on a preparation of rat colonic mucosa from which the myenteric and submucosal plexus were removed. This preparation, referred to as the mucosa preparation, was used to investigate the potential influence of the mucosal plexus on electrolyte transport. Two neuropharmacologically active agents were used: sea anemone toxin (ATX II) to stimulate the fibres of the mucosal plexus and tetrodotoxin (TTX) to block the fibres of the mucosal plexus. The morphology of the neuronal network of the mucosal plexus was visualized after the epithelium was removed and whole mount preparations of the lamina propria and circular muscle layer of muscularis mucosae were stained histochemically for acetylcholinesterase activity. Several levels of organization within the mucosal plexus were seen. Each crypt is encircled by a thin bundle of fibres near the top. These thin fibres connect with thicker bundles of fibres that encircle groups of two to five crypts in a broad band. These bundles of fibres are in turn connected to larger bundles of fibres which lie in a flat plane just below the crypts along the circular muscle layer of muscularis mucosae. In addition perikarya and ganglia were revealed within the mucosal plexus. The base‐line net transport of Na+ and Cl‐ across the mucosa preparation was completely inhibited by ATX II (10(‐6) M). This effect of ATX II on net Na+ and Cl‐ transport was accompanied with an increase in the short‐circuit current (Isc), transmural conductance, and open‐circuit potential difference across the mucosa preparation. The effect of ATX II on Isc was dose dependent with a half‐maximal effective concentration at 5 X 10(‐8) M‐ATX II and a maximal effective concentration of 10(‐7) M. ATX II was effective only when added to the serosal solution. Net Na+ and Cl‐ transport was restored by TTX (10(‐6) M) to base‐line values in ATX II‐treated tissue. In addition the value of all three electrical parameters rapidly returned to the values measured before the addition of ATX II. TTX was effective in antagonizing the effects of ATX II only when added to the serosal solution. The results suggest that the regulation of electrolyte transport across the epithelium is at least one function of the mucosal plexus. Stimulation of the neurones within the mucosal plexus leads to the inhibition of electrolyte absorption. (ABSTRACT TRUNCATED AT 400 WORDS)
Advanced glycation endproducts: what is their relevance to diabetic complications?

Glycation is a major cause of spontaneous damage to proteins in physiological systems. This is exacerbated in diabetes as a consequence of the increase in glucose and other saccharides derivatives in plasma and at the sites of vascular complications. Protein damage by the formation of early glycation adducts is limited to lysine side chain and N‐terminal amino groups whereas later stage adducts, advanced glycation endproducts (AGEs), modify these and also arginine and cysteine residues. Metabolic dysfunction in vascular cells leads to the increased formation of methylglyoxal which adds disproportionately to the glycation damage in hyperglycaemia. AGE‐modified proteins undergo cellular proteolysis leading to the formation and urinary excretion of glycation free adducts. AGEs may potentiate the development of diabetic complications by activation of cell responses by AGE‐modified proteins interacting with specific cell surface receptors, activation of cell responses by AGE free adducts, impairment of protein–protein and enzyme–substrate interactions by AGE residue formation, and increasing resistance to proteolysis of extracellular matrix proteins. The formation of AGEs is suppressed by intensive glycaemic control, and may in future be suppressed by thiamine and pyridoxamine supplementation, and several other pharmacological agents. Increasing expression of enzymes of the enzymatic defence against glycation provides a novel and potentially effective future therapeutic strategy to suppress protein glycation.
Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death

Alcohol exposure during development can cause brain malformations and neurobehavioral abnormalities. In view of the teratogenicity of ethanol, identification of molecules that could counteract the neurotoxic effects of alcohol deserves high priority. Here, we report that pituitary adenylate cyclase-activating polypeptide (PACAP) can prevent the deleterious effect of ethanol on neuronal precursors. Exposure of cultured cerebellar granule cells to ethanol inhibited neurite outgrowth and provoked apoptotic cell death. Incubation of granule cells with PACAP prevented ethanol-induced apoptosis, and this effect was not mimicked by vasoactive intestinal polypeptide, suggesting that PAC1 receptors are involved in the neurotrophic activity of PACAP. Ethanol exposure induced a strong increase of caspase-2, -3, -6, -8, and -9 activities, DNA fragmentation, and mitochondrial permeability. Cotreatment of granule cells with PACAP provoked a significant inhibition of all of the apoptotic markers investigated although the neurotrophic activity of PACAP could only be ascribed to inhibition of caspase-3 and -6 activities. These data demonstrate that PACAP is a potent protective agent against ethanol-induced neuronal cell death. The fact that PACAP prevented ethanol toxicity even when added 2 h after alcohol exposure, suggests that selective PACAP agonists could have potential therapeutic value for the treatment of fetal alcohol syndrome.
Sustained-release solid dispersion of pelubiprofen using the blended mixture of aminoclay and pH independent polymers: preparation and in vitro/in vivo characterization

Abstract The present study aimed to develop the sustained-release oral dosage form of pelubiprofen (PEL) by using the blended mixture of 3-aminopropyl functionalized-magnesium phyllosilicate (aminoclay) and pH-independent polymers. The sustained-release solid dispersion (SRSD) was prepared by the solvent evaporation method and the optimal composition of SRSD was determined as the weight ratio of drug: Eudragit® RL PO: Eudragit® RS PO of 1:1:2 in the presence of 1% of aminoclay (SRSD(F6)). The dissolution profiles of SRSD(F6) were examined at different pHs and in the simulated intestinal fluids. The drug release from SRSD(F6) was limited at pH 1.2 and gradually increased at pH 6.8, resulting in the best fit to Higuchi equation. The sustained drug release from SRSD(F6) was also maintained in simulated intestinal fluid at fasted-state (FaSSIF) and fed-state (FeSSIF). The structural characteristics of SRSD(F6) were examined by using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC) and Fourier transform infrared spectroscopy (FT-IR), indicating the change of drug crystallinity to an amorphous form. After oral administration in rats, SRSD(F6) exhibited the prolonged drug exposure in plasma. For both PEL and PEL-transOH (active metabolite), once a day dosing of SRSD(F6) achieved oral exposure (AUC) comparable to those from the multiple dosing (3 times a day) of untreated drug. In addition, the in vivo absorption of SRSD(F6) was well-correlated with the in vitro dissolution data, establishing a good level A in vitro/in vivo correlation. These results suggest that SRSD(F6) should be promising for the sustained-release of PEL, thereby reducing the dosing frequency.
Distinct cellular expression pattern of annexins in Hydra vulgaris

The annexins are a structurally related family of Ca2+ and phospholipid binding proteins whose function has not been clearly defined. Further investigations of annexin function may be enhanced by studying simpler organisms that express fewer annexin gene products. We previously characterized annexin XII from the freshwater cnidarian Hydra vulgaris (Schlaepfer, D. D., D. A. Fisher, M. E. Brandt, H. R. Bode, J. Jones, and H. T. Haigler. 1992. J. Biol. Chem. 267:9529-9539). In this report, we detected one other hydra annexin (40 kD) by screening hydra cell extracts with antibodies raised against peptides from highly conserved regions of known annexins. The 40-kD protein was expressed at less than 1% of annexin XII levels. These biochemical studies indicate that hydra contain a very limited number of annexin gene products. The cellular hydra annexin distribution was analyzed by indirect immunofluorescence. Using affinity-purified antibodies to annexin XII, the epithelial battery cells were stained throughout the tentacle. A lower level of annexin XII staining was detected in peduncle region epithelial cells. No other cell types showed detectable annexin XII staining. The anti- peptide antibody that specifically detected the 40-kD hydra annexin, maximally stained the cytoplasm of nematocytes. The immunofluorescent results showed that annexin XII and the 40-kD annexin were not co- expressed in the same cells. Since the hydra annexins localized to specific subsets of the total hydra cell types, it is likely that these proteins perform specialized biological roles, and not general "housekeeping" functions which are part of the essential molecular machinery of all cells.
The carbohydrate recognition domain of collectins

Collectins are effector molecules of the innate immune system that play an important role in the first line of defence against bacteria, viruses and fungi. Most of their interactions with microorganisms are mediated through their carbohydrate recognition domain (CRD), which binds in a Ca2+‐dependent manner to glycoconjugates. This domain is a well‐known structure that is present in a larger group of proteins comprising the C‐type lectin domain family. Collectins form a subgroup within this family based on the presence of a collagen domain and the trimerization of CRDs, which are essential for the ligand‐binding properties of these proteins. The ligand specificity among the nine collectin members is significantly different as a result of both the structural organization of the trimers and specific sequence changes in the binding pocket of the CRD. In addition, some collectin members have additional features, such as N‐linked glycosylation of CRD residues and additional loop structures within the CRD that have a large impact on their interaction with the glycoconjugates present on microorganisms or host cells. The availability of crystal structures of three members of the collectin family (surfactant proteins A and D and mannan‐binding protein) provides an important tool for addressing the impact of these CRD differences on ligand binding. In this review, the structural differences and similarities between the CRDs of collectins are summarized and their relationship with their ligand‐binding characteristics is discussed.
Changes of articular cartilage after immobilization in a rat knee contracture model

The objective was to determine the changes of articular cartilage of the knee joint during immobilization in a rat model. The knee joints of adult male rats were immobilized at 150° of flexion using an internal fixator for 3 days, and 1, 2, 4, 8, and 16 weeks. The articular cartilage from the medial midcondylar region of the knee was obtained, divided into three areas (non‐contact area, transitional area, contact area), and in each area, a degree of degeneration was evaluated by gross observation, histomorphometric grading, and measurements of thickness and number of chondrocytes. Elasticity of the articular cartilage was estimated by measuring the sound speed with use of scanning acoustic microscopy. Degeneration of the articular cartilage was mainly observed in the contact and transitional areas. Matrix staining intensity by safranin‐O and number of chondrocytes were decreased in these two areas. The thickness of the articular cartilage in the non‐contact and contact areas was unchanged, but it was increased in the transitional area. Decrease in sound speed was observed in the transitional area of both the femoral and tibial cartilage, indicating the softening of the articular cartilage. The changes of articular cartilage became obvious as early as 1 week after immobilization. These changes may be due to a lack of mechanical stress or a lack of joint fluid circulation during immobilization. Although we do not know the reversibility of these changes of articular cartilage, early mobilization is preferable to avoid these cartilage changes. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:236–242, 2009
Low Body Mass Index: A Risk Factor for Superior Mesenteric Artery Syndrome in Adolescents Undergoing Spinal Fusion for Scoliosis

Study Design Five cases of superior mesenteric artery (SMA) syndrome occurred at our institution over a 4-year period in adolescents undergoing spinal fusion surgery for scoliosis. All patients had in common a very slender body habitus. The measurement of body mass index (BMI) was low in all patients and an age-matched control group of patients undergoing similar surgery without this complication was assessed with this Index to determine its utility as a screening tool for this postoperative condition. Objective The goal was to determine if BMI is a useful parameter to assess the relative risk of patients undergoing spinal fusion surgery for developing the complication of SMA syndrome. Background Data SMA syndrome is a serious and potentially fatal complication of spinal fusion surgery for scoliosis. Significant curve correction and slender body habitus have been cited in the literature as potential risk factors for this disorder. Methods BMI and the amount of scoliosis curve correction in the 5 patients developing SMA syndrome after spinal fusion were calculated and compared with those values in a group of 18 age-matched patients undergoing spinal fusion during the same time period. Results Absolute curve correction was comparable between the 2 groups. All 5 patients who developed SMA syndrome had a BMI of less than 18. Conclusions Patients undergoing spinal fusion surgery for scoliosis with a BMI of less than 18 are at risk to develop SMA syndrome postoperatively.
Delicate conformational changes of a protein in the CRP family lead to dramatic functional changes via binding of an alternate secondary messenger molecule

CLP (c-AMP receptor protein like protein) from the plant pathogen Xanthomonas campestris (Xc) is a moderately strong c-di-GMP binder. After binding with c-di-GMP, XcCLP is dissociated from DNA, thus changing the expression profile of approximately 300 downstream genes, many of which are involved in the pathogenicity of Xc. To better understand the intricacies of this interesting regulation mechanism, a crystal structure of XcCLP has been determined to a resolution of 2.28 Å. This, in conjunction with an abundance of biochemical studies of mutants based on this structure, has illuminated a better understanding of c-di-GMP receptor. In this addendum, the following aspects of this unique protein shall be described from a more structural perspective: 1) Why c-di-GMP cannot bind to the c-NMP domain of XcCLP; 2) Why XcCLP can intrinsically bind to cognate DNA in the absence of any ligand; and 3) How c-di-GMP inhibits the DNA-binding capability of XcCLP, thus releasing XcCLP from DNA. Interestingly, the aforementioned questions are related by the subtle side-chain flipping of several key signature amino acids. In particular, through mutant studies and sequence alignments of proteins in the CRP family, four key signature amino acid residues have been identified that may allow one to distinguish whether a member in the CRP-FNR family is a c-AMP or a c-di-GMP responsive protein. In conclusion, a possible evolutionary pathway from EcCRP to XcCLP will be described
Effects of 14‐deoxyandrographolide and 14‐deoxy‐11,12‐didehydroandrographolide on nitric oxide production in cultured human endothelial cells

14‐deoxyandrographolide (DA) and 14‐deoxy‐11,12‐didehydroandrographolide (DDA) are two diterpenoids isolated from A. paniculata, a popular folk medicine used as an antihypertensive drug in Malaysia. We have previously reported that DDA exhibited a greater hypotensive effect in anaesthetized rats and a vasorelaxant activity in isolated rat aorta, compared with DA. Their vasorelaxant activities were mediated through the activation of the enzymes, nitric oxide synthase (NOS) and guanylyl cyclase. The present study demonstrated that both DA and DDA stimulated nitric oxide (NO) release from human endothelial cells. DDA compared with DA caused a greater production of NO; this is in line with the finding of the earlier study that the vasorelaxant effect of DDA was more dependent on endothelium than DA. Copyright © 1999 John Wiley & Sons, Ltd.
The antihypoxia–adenosinergic pathogenesis as a result of collateral damage by overactive immune cells

Here, we attract attention to the possibility of iatrogenic exacerbation of immune–mediated tissue damage as a result of the unintended weakening of the tissue–protecting, hypoxia–adenosinergic pathway. These immunosuppressive, anti–inflammatory pathways play a critical and nonredundant role in the protection of normal tissues from collateral damage during an inflammatory response. We believe that it is the tissue hypoxia associated with inflammatory damage that leads to local inhibition of overactive immune cells by activating A2AR and A2BR and stabilizing HIF–1α. We show in an animal model of acute lung injury that oxygenation (i.e., inspiring supplemental oxygen) reverses tissue hypoxia and exacerbates ongoing inflammatory lung tissue damage. However, little has been done to carefully investigate and prevent this in a clinical setting. Similarly, the consumption of caffeine antagonizes A2ARs, resulting in exacerbation of ongoing acute inflammation. It is suggested that although the elimination of hypoxia–adenosinergic immunosuppression is desirable to improve vaccines, it is important to take into account the unintentional effects of supplemental oxygen and caffeine, which may increase collateral, inflammatory tissue damage.
Australian adults use complementary and alternative medicine in the treatment of chronic illness: a national study

Objectives: The objectives of this study were to identify the prevalence of the use of vitamin/mineral supplements or natural/herbal remedies, concurrent use of pharmaceutical medication, and to profile those most likely to use these complementary and alternative medicines (CAM) in the treatment of five chronic conditions identified as national health priorities (asthma, diabetes, arthritis, osteoporosis, heart or circulatory condition) within the Australian adult population.
Exploitation et diffusion des silex de la région du Grand-Pressigny au Paléolithique

La region du Grand-Pressigny (Indre-et-Loire, France), notamment connue pour son silex brun d'excellente qualite, est en fait riche d'une grande diversite de ressources lithiques. Certains de ces materiaux, particulierement types et dont les gites sont bien localises dans le paysage, ont ete exploites et diffuses durant tout le Paleolithique par les populations de chasseurs-collecteurs nomades qui ont frequente ce secteur du sud-ouest du Bassin parisien. L'etude du deplacement de ces materiaux, sous des formes tres diverses (blocs, eclats, lames, outils. . . ), a permis d'appre��hender la variabilite des territoires d'exploitation paleolithiques, les modalites d'occupation de ces territoires et, plus largement, de demontrer des contacts entre des regions eloignees de plus de 250 kilometres.
Serum levels of vitamin D, vitamin D‐binding protein and vitamin D receptor in migraine patients from central Anatolia region

Inflammation is proposed to be involved in the pathogenesis of both vitamin D deficiency and migraine. However, the data examining the relation of vitamin D with migraine are limited. We aimed to investigate the serum levels of vitamin D, vitamin D‐binding protein (VDBP) and vitamin D receptor (VDR) in combination, in migraine patients from central Anatolia region.
Results and reliability of protein quantification for two‐dimensional gel electrophoresis strongly depend on the type of protein sample and the method employed

We investigated the effects of tissue samples taken from rat brain on the reliability of three protein quantification kits: the Bradford assay, the 2‐D Quant Kit, and the EZQ Protein Quantitation Kit. All three assays measured significantly smaller amounts of protein after extraction than the reference values before extraction. Only small effects were seen in homogenates, but very pronounced differences in membrane‐enriched and highly lipophilic subcellular fractions. Researchers should evaluate which method of protein quantification is best qualified for their specific experimental design.