Miracle-dz/UniFAR-FTUs huggingface dataset:
AN APOLIPOPROTEIN E4 FRAGMENT AFFECTS MMP9, TIMP1 AND CYTOKINE LEVELS IN BRAIN CELL LINES

Apolipoprotein (apo) E4 isoform, a major risk factor for Alzheimer’s disease (AD), is more susceptible to proteolysis than apoE2 and apoE3 isoforms. ApoE4 fragments have been found in AD patients’ brain. In the present study, we examined the effect of full-length apoE4 and apoE4 fragments apoE4[ Δ (186-299)] and apoE4[ Δ (166-299)] on inflammation in human neuroblastoma SK-N-SH and human astrocytoma SW-1783 cells. Western blot and zymography analysis showed that treatment of SK-N-SH cells with apoE4[ Δ (186-299)], but not full-length apoE4 or the shorter apoE4[ Δ (166-299)] fragment, leads to increased extracellular levels of matrix metalloproteinase 9 (MMP9) and tissue inhibitor of metalloproteinase 1 (TIMP1). Real-time PCR showed that interleukin (IL)-1 β gene expression is also increased in SK-N-SH cells treated with apoE4[ Δ (186-299)]. Treatment of SK-N-SH cells with IL-1 β leads to increased MMP9 and TIMP1 extracellular levels, suggesting that the induction of IL-1 β may be the mechanism by which apoE4[ Δ (186-299)] regulates MMP9 and TIMP1 levels in these cells. In contrast to SK-N-SH cells, treatment of SW-1783 cells with apoE4[ Δ (186-299)] and to a lesser extent with apoE4, leads to increased TIMP1 extracellular levels without affecting MMP9 levels, Additionally, apoE4[ Δ (186-299)] leads to decreased IL-10 gene expression in SK-N-SH cells, while both apoE4 and apoE4[ Δ (186-299)] lead to decreased TNF α gene expression without affecting IL-1 β and IL-10 gene expression in SW-1783 cells. Overall, our findings indicate that a specific apoE4 fragment (apoE4[ Δ (186-299)]), with molecular mass similar that of apoE4 fragments detected in AD patients’ brain, can influence the level of inflammatory molecules in brain cell lines. It is possible that these phenomena contribute to AD pathogenesis. TNF α gene expression was not affected in SK-N-SH cells treated by apoE4 or apoE4-185, but was decreased in SW-1783 cells treated either by apoE4 or apoE4-185. Additionally, we observed that IL-10 gene expression is decreased in SK-N-SH cells, but not in SW-1783 cells, treated with apoE4-185. Our results indicate that a specific apoE4 fragment can affect the levels of inflammatory molecules in brain cell lines. This finding suggests that fragmented apoE4 may be involved in inflammatory responses in brain, an event that has been associated with AD.
Integrating EGFR Assay with Clinical Parameters Improves Risk Classification for Relapse and Survival in Head and Neck Squamous Cell Carcinoma

PURPOSE— Epidermal growth factor receptor (EGFR) overexpression has been consistently found to be an independent predictor of local-regional relapse (LRR) after radiotherapy. We assessed the extent by which it can refine risk classification for overall survival (OS) and LRR in patients with head and neck squamous cell carcinoma (HNSCC). METHODS AND MATERIALS— EGFR expression in locally advanced HNSCC was measured by immunohistochemistry (IHC) in a series of patients randomized to receive accelerated or conventional radiation regimens in a phase III trial. Subsequently, data of the two series were pooled (N=533) for conducting a recursive partitioning analysis that incorporated clinical parameters (performance status, primary site, T- and N-categories, etc.) and four molecular markers (EGFR, p53, Ki-67, and microvessel density). RESULTS— This study confirmed that patients with higher than median levels of tumor EGFR expression had a lower OS (RR: 1.90, P =0.0010) and a higher LRR (RR: 1.91, P =0.0163). Of the four markers analyzed, only EGFR was found to contribute to refining classification of patients into three risk classes with distinct OS and LRR outcomes. The addition of EGFR to three clinical parameters could identify patients having up to a 5-fold difference in the risk of LRR. CONCLUSIONS— Adding pretreatment EGFR expression data to known robust clinical prognostic variables improved the estimation of the probability for OS and LRR after radiotherapy. Its use for stratifying or selecting patients with defined tumor feature and pattern of relapse for enrollment into clinical trials testing specific therapeutic strategy warrants further investigation.
Differential Expression of VEGF, EG-VEGF, and VEGF Receptors in Human Placentas from Normal and Pre-eclamptic Pregnancies

Vascular Endothelial Growth Factor (VEGF) is a potent regulator of placental vascular function. Endothelial dysfunction is a key factor associated with pre-eclampsia. In this study, we examined expression of VEGF, endocrine-gland-derived VEGF (EG-VEGF), and VEGF receptors (VEGF receptor-1 [VEGFR-1] and -2 [VEGFR-2], and neuropilin-1 [NP-1] and -2 [NP-2]) in human placentas from women with normal and pre-eclamptic (PE) pregnancies using quantitative or semi-quantitative PCR. We found that total VEGF mRNA expression was increased 2.8 fold ( p < 0.05), along with increases in mRNA expression of VEGF121, 165, and 189 ( p < 0.05; 1.7, 1.9, and 1.8 fold, respectively) in PE vs normal placentas. Expression of VEGFR-1 mRNA, but not EG-VEGF and the other three VEGF receptors studied, was elevated ( p < 0.05) 2.7 fold in PE vs normal placentas. Protein expression of VEGF and its four receptors was determined using Western blot analysis. For VEGF, two major isoforms (VEGF165 and 189) were detected. For VEGFR-1, VEGFR-2, NP-1, and NP-2, one major band was observed at 180, 235, 130 and 130 kD, respectively. All of these bands were corresponding to their positive controls. Of these five proteins studied, only VEGFR-1 levels were increased ( p < 0.05; 1.7 fold) in PE placentas. The expression of VEGF and the four VEGF receptors was confirmed using immunohistochemistry. They were primarily present in syncytiotrophoblasts and endothelial cells of villous capillaries and large vessels. Thus, together with the previous reports that VEGFR-1 mediates trophoblast function and inhibits VEGF-induced angiogenesis and endothelium-dependent vasodilation, these data suggest that the increased VEGFR-1 expression may alter VEGF-mediated function on trophoblast and endothelial cells in PE placentas.
Cerebellar Cortical Layer-Specific Control of Neuronal Migration by PACAP

Migration of immature neurons is essential for forming the cortical layers and nuclei. Impairment of migration results in aberrant neuronal cytoarchitecture, which leads to various neurological disorders. Neurons alter the mode, tempo and rate of migration when they translocate through different cortical layers, but little is known about the mechanisms underlying this process. Here we show that endogenous pituitary adenylate cyclase-activating polypeptide (PACAP) has short-term and cortical layer-specific effects on granule cell migration in the early postnatal mouse cerebellum. Application of exogenous PACAP significantly slowed the migration of isolated granule cells and shortened the leading process in the microexplant cultures of the P0-3 cerebella. Interestingly, in the cerebellar slices of P10 mice, application of exogenous PACAP significantly inhibited granule cell migration in the EGL and ML, but failed to alter the movement in the PCL and IGL. In contrast, application of PACAP antagonist accelerated granule cell migration in the PCL, but did not change the movement in the EGL, ML and IGL. Inhibition of the cAMP signaling and the activity of phospholipase C significantly reduced the effects of exogenous PACAP on granule cell migration. The PACAP action on granule cell migration was transient, and lasted for approximately 2 hours. The duration of PACAP action on granule cell migration was determined by the desensitization of its receptors and prolonged by inhibiting the PKC. Endogenous PACAP was present sporadically in the bottom of the ML, intensively in the PCL, and throughout the IGL. Collectively, these results indicated that PACAP acts on granule cell migration as “a brake (stop signal) for cell movement”. Furthermore, these results suggest that endogenous PACAP slows granule cell migration when the cells enter the PACAP-rich PCL, and 2 hours later the desensitization of PACAP receptors allows the cells to accelerate the rate of migration and to actively move within the PACAP-rich IGL. Therefore, endogenous PACAP may provide a cue that regulates granule cell migration in a cerebellar cortical layer-specific manner.
Differential requirement of PKC- θ in the development and function of Natural Regulatory T cells

CD4+CD25+ natural Treg cells, which are developed in the thymus, migrate to the periphery to actively maintain self-tolerance. Similar to conventional T cells, TCR signals are critical for the development and activation of Treg cell inhibitory function. While PKC- θ -mediated TCR signals are required for the activation of peripheral naïve T cells, they are dispensable for their thymic development. Here, we show that mice deficient in PKC- θ had a greatly reduced number of CD4 +Foxp3+ Treg cells, which was independent of PKC- θ -regulated survival, as transgenic Bcl-x L could not restore the Treg cell population in PKC- θ − / − mice. Active and WT PKC- θ markedly stimulated, whereas inactive PKC- θ and dominant negative NFAT inhibited Foxp3 promoter activity. In addition, mice-deficient in calcineurin A β had a decreased Treg cell population, similar to that observed in PKC- θ deficient mice. It is likely that PKC- θ promoted the development of Treg cells by enhancing Foxp3 expression via activation of the calcineurin/NFAT pathway. Finally, Treg cells deficient in PKC- θ were as potent as WT Treg cells in inhibiting T cell activation, indicating that PKC- θ was not required for Treg cell-mediated inhibitory function. Our data highlight the contrasting roles PKC- θ plays in conventional T cell and natural Treg cell during in vitro culture, to an extent similar to what was observed in WT control Tregs. One of the effector mechanisms for Treg cell-mediated inhibition is the production of cytokine TGF- β . We did not observe differences in the production of TGF- β by Treg cells compared to WT and PKC- θ − / − mice. These data confirmed PKC- θ was required for Treg cell development, as well as for the activation of conventional T cells, but was not required for Treg cell-mediated inhibition.
and Reviews Chiamydial Infections

Chlamydiae are among the most common human bacterial pathogens. Chlamydia trachomatis has long been known as the causative agent of trachoma, the world's leading cause of preventable blindness. ' Only in the past two decades have we realized that this organism is an important cause of genital tract disease. These infections are important not only because of their incidence but also because the infections result in long-term consequences such as tubal factor infertility and ectopic pregnancy. Cpsittaci is recognized as the cause of psittacosis, a relatively uncommon human infection acquired through exposure to infected birds. In recent years what was thought to be a variant of C psittaci, with no known avian reservoir, was recognized as a cause of atypical pneumonia in humans. This variant, originally called the TWAR agent, has now been placed in its
Fluorodeoxyglucose-Positron Emission Tomography / Computed Tomography Predicts Preinvasive Endobronchial Lesion Progression to Invasive Cancer

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RED IN TRANSLATION Breaking Barriers New Insights into Airway Epithelial Barrier Function in Health and Disease

Epithelial permeability is a hallmark of mucosal in ﬂ ammation, but the molecular mechanisms involved remain poorly understood. A key component of the epithelial barrier is the apical junctional complex that forms between neighboring cells. Apical junctional complexes are made of tight junctions and adherens junctions and link to the cellular cytoskeleton via numerous adaptor proteins. Although the existence of tight and adherens junctions between epithelial cells has long been recognized, in recent years there have been signi ﬁ cant advances in our understanding of the molecular regulation of junctional complex assembly and disassembly. Here we review the current thinking about the structure and function of the apical junctional complex in airway epithelial cells, emphasizing the translational aspects of relevance to cystic ﬁ brosis and asthma. Most work to date has been conducted using cell culture models, but technical advancements in imaging techniques suggest that we are on the verge of important new breakthroughs in this area in physiological models of airway diseases.
Investigating the Influence of Bridge Officer Experience on Ice Management Effectiveness Using a Marine Simulator Experiment

The research investigates the influence of human expertise on the effectiveness of ice management operations. The key contribution is an experimental method for investigating human factor issues in an operational setting. Ice management is defined as a systematic operation that enables a marine operation to proceed safely in the presence of sea ice. In this study, the effectiveness of ice management operations was assessed in terms of ability to modify the presence of pack ice around an offshore structure. This was accomplished in a full-mission marine simulator as the venue for a systematic investigation. In the simulator, volunteer participants from a range of seafaring experience levels were tasked with individually completing ice management tasks. Recorded from 36 individuals' simulations, we compared ice management effectiveness metrics against two independent variables: (i) experience level of the participant, categorized as either cadet or seafarer and (ii) ice severity, measured in ice concentration. The results showed a significant difference in ice management effectiveness between experience categories. We examined what the seafarers did that made them more effective and characterized their operational tactics. The research provides insight into the relative importance of vessel operator skills in contributing to effective ice management, as well as how this relative importance changes as ice conditions vary from mild to severe. This may have implications for training in the nautical sciences and could help to inform good practices in ice management.
Assembly with the Na,K-ATPase α 1 Subunit Is Required for Export of β 1 and β 2 Subunits from the Endoplasmic Reticulum

The level of the heterodimeric Na,K-ATPase is tightly controlled in epithelia to maintain appropriate transport function. The catalytic Na,K-ATPase α subunit is not able to exit the ER or catalyze ion transport unless assembled with the β subunit. However, requirements for the ER exit of the Na,K-ATPase β subunit that plays an additional, ion-transport-independent, role in intercellular adhesion are not clear. Exogenous β 1 or β 2 subunits expressed in renal MDCK cells replace endogenous β 1 subunits in the α – β complexes in the ER, resulting in a decrease in the amount of the α 1 -bound endogenous β 1 subunits by 47–61% with no change in the amount of α 1 subunits. Disruption of the α 1 – β association by mutations in defined α 1 -interacting regions of either β 1 or β 2 subunits results in the ER retention and rapid degradation of unassembled mutants. Hence, the ER quality control system allows export only of assembled α – β complexes to the Golgi, thereby maintaining an equimolar ratio of α and β subunits in the plasma membrane, whereas the number of α 1 subunits in the ER determines the amount of the α – β complexes.
Gustatory insular cortex lesions disrupt drug-, but not LiCl-, induced suppression of CS intake

Rats suppress intake of a normally preferred 0.15% saccharin conditioned stimulus (CS) when it is paired with an aversive agent like lithium chloride (LiCl) or a preferred substances such as sucrose or a drug of abuse. The reward comparison hypothesis suggests that rats avoid intake of a saccharin cue following pairings with a drug of abuse because the rats are anticipating the availability of the rewarding properties of the drug. The present study used bilateral ibotenic acid lesions to examine the role of the gustatory cortex in the suppression of CS intake induced by cocaine, morphine, and LiCl. The results show that bilateral lesions of the insular gustatory cortex (1) fully prevent the suppressive effects of both a 15- and a 30-mg/kg dose of morphine, (2) attenuate the suppressive effect of a 10 mg/kg dose of cocaine, but (3) are overridden by a 20 mg/ kg dose of the drug. Finally, these same cortical lesions had no impact on LiCl-induced conditioned taste aversion. The current data show that the insular taste cortex plays an integral role in drug-induced avoidance of a gustatory CS.
SECOND-ORDER SCHEDULES AND THE PROBLEM OF CONDITIONED REINFORCEMENT

Thirteen pigeons were exposed to a variety of second-order schedules in which responding under a component schedule was reinforced according to a schedule of reinforcement. Under different conditions, completion of each component resulted in either (1) the brief presentation of a stimulus also present during reinforcement (pairing operation), (2) the brief presentation of a stimulus not present during reinforcement (nonpairing operation), or (3) no brief stimulus presentation (tandem). Brief-stimulus presentations engendered a pattern of responding within components similar to that engendered by food. Pattern- ing was observed when fixed-interval and fixed-ratio components were maintained under fixed- and variable-ratio and fixed- and variable-interval schedules. There were no apparent differences in performance under pairing and nonpairing conditions in any study. The properties of the stimuli presented in brief-stimulus operations produced different effects on response patterning. In one study, similar effects on performance were found whether brief-stimulus presentations were response-produced or delivered independently of re- sponding. Response patterning did not occur when the component schedule under which a nonpaired stimulus was produced occurred independently of the food schedule. The results suggest a reevaluation of the role of conditioned reinforcement in second-order schedule performance. The similarity of behavior under pairing and nonpairing operations is consistent with two hypotheses: (1) the major effect is due to the discriminative properties of the brief stimulus; (2) the scheduling operation under which the paired or non- paired stimulus is presented can establish it as a reinforcer. responses are reinforced ac- cording to some schedule. Although these ways of speaking make explicit the reinforcement of responses, they produce greater difficulties, in that the expres-sions "component performance" and "component re- sponses" are vague and may be misleading. "Reinforce-ment of component performance," for example, needs clarification as to whether "performance" implies a pattern of responding. "Reinforcement of component responses" needs clarification that not any component response may produce the reinforcer, but only the response that completes a component.
Cardiac autonomic control in Brugada patients during sleep: the effects of sleep disordered breathing

Aims— Brugada syndrome is characterized by typical ECG features, ventricular arrhythmias and sudden cardiac death (SCD), more frequent during nighttime. Autonomic cardiovascular control has been implicated in triggering the ventricular arrhythmias. Sleep-disordered breathing (SDB) elicits marked autonomic changes during sleep and it is associated with an increased risk of nighttime SCD. Brugada patients may have a higher likelihood of SDB compared to controls. However, no data are available on cardiac autonomic control in Brugada patients, particularly with regard to the comorbidity of SDB. Methods— We evaluated autonomic cardiovascular control in Brugada patients with SDB (BRU-SDB, n=9), without SDB (BRU, n= 9), in controls (CON, n=8) and in non-Brugada patients with SDB (n=6), during wakefulness and sleep (N2, N3 and REM). Linear spectral and entropy-derived measures of heart rate variability (HRV) were performed during apnea-free stable breathing epochs. Results— Total HRV was attenuated in BRU-SDB compared to CON and BRU. During N2 and REM, in BRU-SDB patients sympathetic modulation decreased compared to BRU and CON, while during REM, they showed an increased parasympathetic modulation, compared to the other two groups. BRU-SDB and SDB were similar in terms of spectral components. Entropy-derived indices showed preserved dynamic changes in Brugada patients compared to controls through the different sleep stages. Conclusion— Brugada syndrome per se does not appear associated with an altered autonomic cardiovascular control during wakefulness and sleep. The comorbidity with SDB may contribute to disrupted autonomic cardiovascular regulation during sleep, possibly predisposing to the increased likelihood of sleep-related ventricular tachyarrhythmias and SCD.