Miracle-dz/UniFAR-FTUs huggingface dataset:
Evidence that Oestradiol Attenuates β‐Adrenoceptor Function in the Hypothalamus of Female Rats by Altering Receptor Phosphorylation and Sequestration

Activation of β‐adrenoceptors in the hypothalamus (HYP) and preoptic area (POA) inhibits both gonadotropin release and reproductive behaviour in female rats. Exposure of female rats for 48 h to physiologically relevant doses of oestrogen attenuates β‐adrenoceptor function in the HYP and POA as indicated by reduced isoproterenol (β‐adrenoceptor agonist) stimulation of adenylyl cyclase activity. Reduced β‐adrenoceptor coupling to G protein in the HYP‐POA from oestrogen‐exposed female rats correlates with attenuation of β‐adrenoceptor function. To examine potential mechanisms underlying receptor‐G protein uncoupling, initial experiments tested the hypothesis that oestrogen attenuation of β‐adrenoceptor function in the HYP and POA involves receptor phosphorylation. Activation of endogenous serine/threonine phosphatases with protamine restores agonist‐stimulated cAMP accumulation in HYP slices from oestrogen‐exposed female rats to control levels. Additional experiments examined whether oestrogen‐induced changes in β‐adrenoceptor binding density and/or subcellular localization correlate with the attenuation of β‐adrenoceptor function in the HYP and POA. Oestrogen treatment does not alter total β‐adrenoceptor binding density in the HYP or POA. However, oestrogen significantly reduces cell surface binding of the hydrophilic β‐adrenoceptor antagonist [3H] CGP 12177 to intact HYP and POA slices. At the same time, oestrogen decreases the fraction of β‐adrenoceptors localized in a light vesicle fraction following sucrose density gradient centrifugation. Therefore, oestrogen attenuates β‐adrenoceptor signalling in the HYP‐POA by uncoupling the β‐adrenoceptor from G protein, perhaps by promoting receptor phosphorylation. Furthermore, a significant fraction of β‐adrenoceptors in the HYP and POA are no longer accessible to hydrophilic ligands, but are not internalized. Thus, physiological doses of oestrogen may facilitate reproductive behaviour and gonadotropin release, in part, by stabilizing β‐adrenoceptor phosphorylation in the HYP and POA, thereby uncoupling the receptors from G protein.
EFFECT OF THE LIGAND IN THE MODELING THE 3 D STRUCTURE OF THE M 3 MUSCARINIC RECEPTOR BAHAREH RASAEIFAR

There are still many question open to completely understand the structure-activity relationships of G-protein coupled receptors. Issues like the actual mapping of the binding site of different subtypes, as well as the mechanism of activation are poorly understood [1]. Accordingly, further studies on the structure-activity relationships are necessary. In this regard, only a few 3D structures are available from X-ray diffraction studies. Computational studies can complement this information through the construction of reliable 3D models. The goal of the present work is to evaluate the effect of using different ligands to obtain reliable models of the three-dimensional structure of a G-protein coupled receptor using a specific template. Specifically, we have constructed in the present work a three dimensional model of the M3 muscarinic receptor by homology modelling, using the Xray structure of M2 muscarinic acetylcholine receptor as template and the sequence analyses of muscarinic acetylcholine receptor family. Furthermore, we have studied the effect of the ligand used in the modelling process. For this purpose three models of the receptor were built, including one without ligand and two models with the selective antagonists tiotropium and N-Methylscopolamine, respectively docked into the orthosteric binding site. The constructed models were refined using molecular dynamic calculations to analyze the effect of ligand refinement process and to derive significant conformational information. Based on the analysis of the refined models done through the calculations of RMSD, RMSF, visualization of the structures and comparison between the refined models and the crystal structure of M3 muscarinic receptor, the addition of a ligand in construction of homology model (and the subsequent refinement process) stabilize the structure. Furthermore, the similarities in the structure conformations of both refined models of M3 muscarinic-ligand complexes and the crystal structure of the M3 muscarinic receptors, suggest that the methodology used in this study can be used in prediction of 3D structure prediction GPCR in the absence of crystal structures. Chapter 1: Introduction
Enzymatic activity profile of a Brazilian culture collection of Candida albicans isolated from diabetics and non‐diabetics with oral candidiasis

The secretion of hydrolytic enzymes is a fundamental virulence factor of Candida albicans to develop disease. The objective of this study was to characterise the virulence of 148 clinical isolates of C. albicans from oral candidiasis by assessing the expression of phospholipase (PL) and secreted aspartyl proteinase (SAP). Isolates were obtained from healthy subjects (HS) and diabetics (DOC) and non‐diabetics with oral candidiasis (NDOC). An aliquot (5 μl) of each cell suspension was inoculated on PL and SAP agar plates and incubated. Enzymes secretion was detected by the formation of an opaque halo around the colonies and enzymatic activity (PZ) was determined by the ratio between colony diameter and colony diameter plus the halo zone. Statistical comparisons were made by a one‐way anova followed by Tukey's post hoc test (α = 0.05). The clinical sources of C. albicans had significant effect (P < 0.001) on the PZ values of both enzymes. For PL, clinical isolates from NDOC and DOC had highest enzymatic activity than those from HS (P < 0.05), with no significant differences between them (P = 0.506). For SAP, C. albicans from NDOC showed the lower enzymatic activity (P < 0.001). There were no significant differences between isolates from HS and DOC (P = 0.7051). C. albicans isolates from NDOC and DOC patients showed an increased production of PL.
Bargaining Between Rebel Groups and the Outside Option of Violence

Although military cooperation among rebel groups in multi-party civil wars could help rebels defeat or extract concessions from an incumbent government, violent conflict among rebel groups is empirically prevalent. Why do rebel groups in multi-party civil wars choose to fight one another? This article models the strategic dilemma facing rebel groups in multi-party civil wars as an alternating-offer bargaining game of incomplete information with an outside option. The game-theoretic model explores the relationship between the status quo distribution of power among rebel groups, the costs of fighting, and the likelihood that one rebel group will opt to unilaterally end bargaining over a set of goods, such as access to supply routes, natural resources, and control over civilian populations. We show that the likelihood of violent conflict between rebel groups is lowest when the status quo distribution of benefits reflects the existing distribution of power.
Sensitivity and integration in a visual pathway for circadian entrainment in the hamster (Mesocricetus auratus).

1. Light‐induced phase shifts of the circadian rhythm of wheel‐running activity were used to measure the photic sensitivity of a circadian pacemaker and the visual pathway that conveys light information to it in the golden hamster (Mesocricetus auratus). The sensitivity to stimulus irradiance and duration was assessed by measuring the magnitude of phase‐shift responses to photic stimuli of different irradiance and duration. The visual sensitivity was also measured at three different phases of the circadian rhythm. 2. The stimulus‐response curves measured at different circadian phases suggest that the maximum phase‐shift is the only aspect of visual responsivity to change as a function of the circadian day. The half‐saturation constants (sigma) for the stimulus‐response curves are not significantly different over the three circadian phases tested. The photic sensitivity to irradiance (1/sigma) appears to remain constant over the circadian day. 3. The hamster circadian pacemaker and the photoreceptive system that subserves it are more sensitive to the irradiance of longer‐duration stimuli than to irradiance of briefer stimuli. The system is maximally sensitive to the irradiance of stimuli of 300 s and longer in duration. A quantitative model is presented to explain the changes that occur in the stimulus‐response curves as a function of photic stimulus duration. 4. The threshold for photic stimulation of the hamster circadian pacemaker is also quite high. The threshold irradiance (the minimum irradiance necessary to induce statistically significant responses) is approximately 10(11) photons cm‐2 s‐1 for optimal stimulus durations. This threshold is equivalent to a luminance at the cornea of 0.1 cd m‐2. 5. We also measured the sensitivity of this visual pathway to the total number of photons in a stimulus. This system is maximally sensitive to photons in stimuli between 30 and 3600 s in duration. The maximum quantum efficiency of photic integration occurs in 300 s stimuli. 6. These results suggest that the visual pathways that convey light information to the mammalian circadian pacemaker possess several unique characteristics. These pathways are relatively insensitive to light irradiance and also integrate light inputs over relatively long durations. This visual system, therefore, possesses an optimal sensitivity of ‘tuning’ to total photons delivered in stimuli of several minutes in duration. Together these characteristics may make this visual system unresponsive to environmental ‘noise’ that would interfere with the entrainment of circadian rhythms to light‐dark cycles.
Obsessive–compulsive disorder, tics and anxiety in 6-year-old twins

Background. Previous reports of genetic influences on obsessive–compulsive disorder (OCD) symptoms have suggested moderate heritability. Family history studies of co-morbidity have found familial aggregation with tics, especially for early-onset OCD, and familial aggregation with anxiety disorders. Method. Heritability of OCD and familial aggregation of OCD, tics and anxiety disorders were investigated in a community sample of 6-year-old twins using a two-phase design in which 4662 twin pairs were sampled and 854 pairs were assessed in the second phase by maternal-informant diagnostic interview using DSM-IV criteria. Results. In the multivariate model combined additive genetic and common environmental effects were estimated as 47% for sub-threshold OCD, and the model was unable to distinguish these sources of familial aggregation. There were strong familial aggregations between sub-threshold OCD and tics and between sub-threshold OCD and other anxiety disorders (80% and 97% respectively), although again specific sources could not be distinguished. Conclusions. The findings are consistent with the hypothesis of a tic-related early-onset OCD phenotype, but also with the hypothesis of an anxiety-related early-onset OCD phenotype.
Generalized Hyperpigmentation of the Skin due to Vitamin B12 Deficiency

A 49‐year‐old man presented with neurosis, hyperpigmentation of the skin, and depigmentation of the hair. On examination, hyperpigmentation was observed on the oral mucosa and the skin of the forearms, elbows, palmar creases and periunguinal area, knees, and feet. He had megaloblastic anemia with a low serum level of vitamin B12 due to malabsorption resulting from a gastrectomy 10 years previously. His hyperpigmentation was resolved with vitamin B12 supplementation. Histology showed an increase of melanin in the basal layer. In electron microscopic study, many melanosomes were observed in melanocytes and surrounding keratinocytes. We consider that the dominant mechanism of hyperpigmentation due to vitamin B12 deficiency is not a defect in melanin transport but is rather an increase in melanin synthesis.
Evaluation of a Phenology-Dependent Response Method for Estimating Leaf Area Index of Rice Across Climate Gradients

Accurate estimate of the seasonal leaf area index (LAI) in croplands is required for understanding not only intra- and inter-annual crop development, but also crop management. Lack of consideration in different growth phases in the relationship between LAI and vegetation indices (VI) often results in unsatisfactory estimation in the seasonal course of LAI. In this study, we partitioned the growing season into two phases separated by maximum VI ( VI max ) and applied the general regression model to the data gained from two phases. As an alternative method to capture the influence of seasonal phenological development on the LAI-VI relationship, we developed a consistent development curve method and compared its performance with the general regression approaches. We used the Normalized Difference VI (NDVI) and the Enhanced VI (EVI) from the rice paddy sites in Asia (South Korea and Japan) and Europe (Spain) to examine its applicability across different climate conditions and management cycles. When the general regression method was used, separating the season into two phases resulted in no better estimation than the estimation obtained with the entire season observation due to an abrupt change in seasonal LAI occurring during the transition between the before and after VI max . The consistent development curve method reproduced the seasonal patterns of LAI from both NDVI and EVI across all sites better than the general regression method. Despite less than satisfactory estimation of a local LAI max , the consistent development curve method demonstrates improvement in estimating the seasonal course of LAI. The method can aid in providing accurate seasonal LAI as an input into ecological process-based models.
Assessment of liver fibrosis with elastography point quantification technique in chronic hepatitis B virus patients: A comparison with liver pathological results

Elastography point quantification (ElastPQ) was a newly non‐invasive method for the assessment of liver fibrosis by measuring liver stiffness. We aimed at evaluating the reproducibility of ElastPQ technology in the determination of liver stiffness and to investigate the value of ElastPQ in liver fibrosis staging among chronic hepatitis B patients.
Chinese Yellow Wine Could Inhibit Production of Matrixmetalloproteinase-2 Induced by Homocysteine in Cultured Rat Vascular Endothelial Cells

Background: The effects of Chinese yellow wine on the production of homocysteine (Hcy) induced intracellular MMP-2 in cultured rats vascular endothelial cells (VECs) has not been investigated. Methods: Isolation, cultivation, purification and identification of vascular endothelial cells of rat thoracic aorta in vitro were conducted. The VECs in passages 3 to 4 were used in all studies. HCY was used to induce VECs to over expressing MMP-2. Cells were divided into 5 groups: Control, Hcy, Hcy+yellow wine, Hcy+red wine, Hcy+ethanol and the cells were given different treatment for 48 h. The mRNA expression of MMP-2 was detected by FQ-PCR. The western blotting and gelatin zymography were applied to test the protein levels and the enzymatic activity of MMP-2. Results: Hcy could significantly increase the expression and activity of MMP-2 compared with the control group, and could reach the maximum at 500 μ mol/L, cultured for 48 h. Compared with those in Hcy group, the expression and activity of MMP-2 in yellow wine and red wine groups was significantly decreased. No significant difference was shown as between the ethanol group and the Hcy group and no significant discrepancy between the yellow wine and red wine group was found. Conclusions: The result suggest that Hcy promotes the expression and activity of MMP-2, which may play an important role in pathogenesis of atherosclerosis (AS). Treatment with yellow wine or red wine decreases Hcy-induced MMP-2 production in VECs. The attenuation of MMP-2 activation by yellow wine and red wine might contribute to their beneficial effects on the cardiovascular system.
Competitive edge of laparoscopic appendectomy versus open appendectomy: a subgroup comparison analysis.

BACKGROUND With the advances in laparoscopic instruments and surgical techniques, the use of laparoscopic appendectomy (LA) has been increasing rapidly in recent years. In this retrospective analysis, we aimed to determine the competitive edge of LA versus open appendectomy (OA) in different settings of disease complexity, gender, and age difference. METHODS A retrospective analysis of the patients diagnosed with acute appendicitis at Changhua and Chang-Bing Show-Chwan Memorial Hospitals from January 1, 2004 to December 31, 2009 was conducted. Trend and indication of OA and LA were recorded, combined with a comparison of medical costs, complication rates, wound infection rates, and hospital stays in different settings of disease complexity, gender, and age group. RESULTS A total of 1366 appendicitis patients were enrolled, and the rate of LA use increased rapidly, from 8.1% in 2004 to 90.3% in 2009. The increased use of LA was seen in both the uncomplicated and complicated appendicitis patients and in both gender and age groups (pediatric, adult, and elderly). Compared with OA, LA was associated with a lower complication rate (9.5% versus 5.8%; P = .013), a lower wound infection rate (8.6% versus 4.2%; P = .001), and a shorter hospital stay (4.60 ± 3.64 versus 4.06 ± 1.84 days; P = .001), but a higher mean cost (32,670 ± 28,568 versus 37,567 ± 12,064 New Taiwan dollars). In the subgroup analysis, the patients with complicated appendicitis, female patients, and pediatric and elderly patients benefited from a reduced hospital stay. LA is about 15% more expensive than OA. CONCLUSIONS LA is as safe and effective as OA in many settings of appendicitis and may be selectively advantageous in patients with complicated appendicitis and in elderly subgroups.
Vaccinia-related Kinase 1 (VRK1) Is an Upstream Nucleosomal Kinase Required for the Assembly of 53BP1 Foci in Response to Ionizing Radiation-induced DNA Damage*

Background: The cellular response to DNA damage requires multiple signaling pathways to guarantee genomic stability. Results: Vaccinia-related kinase 1 (VRK1) is activated by ionizing radiation and required for formation of 53BP1 foci in response to DNA damage. Conclusion: Human VRK1 is an early step in the cellular response to DNA damage induced by ionizing radiation. Significance: VRK1 forms part of a novel pathway for DNA protection. Cellular responses to DNA damage require the formation of protein complexes in a highly organized fashion. The complete molecular components that participate in the sequential signaling response to DNA damage remain unknown. Here we demonstrate that vaccinia-related kinase 1 (VRK1) in resting cells plays an important role in the formation of ionizing radiation-induced foci that assemble on the 53BP1 scaffold protein during the DNA damage response. The kinase VRK1 is activated by DNA double strand breaks induced by ionizing radiation (IR) and specifically phosphorylates 53BP1 in serum-starved cells. VRK1 knockdown resulted in the defective formation of 53BP1 foci in response to IR both in number and size. This observed effect on 53BP1 foci is p53- and ataxia-telangiectasia mutated (ATM)-independent and can be rescued with VRK1 mutants resistant to siRNA. VRK1 knockdown also prevented the activating phosphorylation of ATM, CHK2, and DNA-dependent protein kinase in response to IR. VRK1 activation in response to DNA damage is a novel and early step in the signaling of mammalian DNA damage responses.
Epidermolysis Bullosa Acquisita following Bullous Pemphigoid, Successfully Treated with the Anti-CD20 Monoclonal Antibody Rituximab

Epidermolysis bullosa acquisita is a rare autoimmune subepidermal blistering disease, often resisting current treatments, especially systemic corticosteroids. We report a patient having a bullous pemphigoid who relapsed with clinical and immunological features of inflammatory epidermolysis bullosa acquisita. An anti-CD20 monoclonal antibody (rituximab) was proposed because of resistance to high-dose steroids and other immunosuppressive agents. The disease dramatically improved within a few weeks following rituximab infusion allowing the decrease in steroid therapy. Our case illustrates also the possible evolution from bullous pemphigoid to epidermolysis bullosa acquisita that should be suspected when clinical atypia occurs or in case of corticosteroid resistance.
Immunohistochemical Expression of Estrogen Receptor in Adenocarcinomas of the Lung: The Antibody Factor

BackgroundImmunohistochemistry for estrogen receptor may be used to distinguish metastatic breast cancers from adenocarcinomas of other sites, including those of the lung. The estrogen receptor exists as 2 subtypes, α and β. Estrogen receptor α is the predominant subtype expressed by more than two-thirds of human breast cancers. Adenocarcinomas of lung origin may also express estrogen receptor, primarily the β subtype. Human estrogen receptor α is highly homologous to estrogen receptor β and consequently, antibodies used to detect estrogen receptor α in breast carcinomas may detect estrogen receptor β in pulmonary adenocarcinomas. We investigated the immunohistochemical expression of estrogen receptor in proven primary lung adenocarcinomas using 3 anti-estrogen receptor α antibodies: mouse monoclonal 1D5, 6F11, and rabbit monoclonal SP1. DesignNinety-two pulmonary adenocarcinomas (53 women and 39 men) confirmed by clinical presentation and positive immunohistochemistry for thyroid transcription factor-1 (TTF-1) were included in this study. There were 19 incisional biopsies and 73 excisional specimens. Immunohistochemistry for estrogen receptor using antibodies 1D5, 6F11, and SP1 was performed on formalin-fixed, paraffin-embedded tissue following antigen retrieval. Any nuclear reactivity for estrogen receptor was considered a positive result. ResultFocal positive nuclear reaction for estrogen receptor was detected in 7 (7.6%) cases of primary pulmonary adenocarcinoma using antibody 1D5, 13 (14.1%) using 6F11, and 25 (27.2%) using SP1. The differences in reactivity for estrogen receptor in pulmonary adenocarcinomas between SP1 and 1D5, and between SP1 and 6F11 were statistically significant (P<0.001). Positive cases showed only a focal pattern of staining with each of the 3 antibodies. There was no significant difference in reactivity for estrogen receptor in pulmonary adenocarcinomas of men and women. Positive staining was highest in nonmucinous bronchioloalveolar adenocarcinomas for all of the antibodies, and for SP1, variation by histologic subtype was significant (P<0.001). ConclusionsSP1 has a significantly higher detection rate for the expression of estrogen receptor in pulmonary adenocarcinomas when compared with either 1D5 or 6F11. Caution should therefore be exercised in the use of this antibody alone in distinguishing a metastatic breast from a primary pulmonary adenocarcinoma.