Miracle-dz/UniFAR-FTUs huggingface dataset:
Site-Specific Regulation of P2X7 Receptor Function in Microglia Gates Morphine Analgesic Tolerance

Tolerance to the analgesic effects of opioids is a major problem in chronic pain management. Microglia are implicated in opioid tolerance, but the core mechanisms regulating their response to opioids remain obscure. By selectively ablating microglia in the spinal cord using a saporin-conjugated antibody to Mac1, we demonstrate a causal role for microglia in the development, but not maintenance, of morphine tolerance in male rats. Increased P2X7 receptor (P2X7R) activity is a cardinal feature of microglial activation, and in this study we found that morphine potentiates P2X7R-mediated Ca2+ responses in resident spinal microglia acutely isolated from morphine tolerant rats. The increased P2X7R function was blocked in cultured microglia by PP2, a Src family protein tyrosine kinase inhibitor. We identified Src family kinase activation mediated by μ-receptors as a key mechanistic step required for morphine potentiation of P2X7R function. Furthermore, we show by site-directed mutagenesis that tyrosine (Y382–384) within the P2X7R C-terminus is differentially modulated by repeated morphine treatment and has no bearing on normal P2X7R function. Intrathecal administration of a palmitoylated peptide corresponding to the Y382–384 site suppressed morphine-induced microglial reactivity and preserved the antinociceptive effects of morphine in male rats. Thus, site-specific regulation of P2X7R function mediated by Y382–384 is a novel cellular determinant of the microglial response to morphine that critically underlies the development of morphine analgesic tolerance. SIGNIFICANCE STATEMENT Controlling pain is one of the most difficult challenges in medicine and its management is a requirement of a large diversity of illnesses. Although morphine and other opioids offer dramatic and impressive relief of pain, their impact is truncated by loss of efficacy (analgesic tolerance). Understanding why this occurs and how to prevent it are of critical importance in improving pain therapies. We uncovered a novel site (Y382–384) within the P2X7 receptor that can be targeted to blunt the development of morphine analgesic tolerance, without affecting normal P2X7 receptor function. Our findings provide a critical missing mechanistic piece, site-specific modulation by Y382–384, that unifies P2X7R function to the activation of spinal microglia and the development of morphine tolerance.
The cell wall subproteome of Listeria monocytogenes

The surface subproteome of Listeria monocytogenes that includes many proteins already known to be involved in virulence and interaction with host cells has been characterized. A new method for the isolation of a defined surface proteome of low complexity has been established based on serial extraction of proteins by different salts at high concentration, and in all 55 proteins were identified by N‐terminal sequencing and mass spectrometry. About 16% of these proteins are of unknown function and three proteins have no orthologue in the nonpathogenic L. innocua and might be involved in virulence mechanisms. Remarkably, a relatively high number of proteins with a function in the cytoplasmic compartment was identified in this surface proteome. These proteins had neither predicted or detectable signal peptides nor could any modification be observed except removal of the N‐terminal methionine. Enolase (Lmo2455) is one of these proteins. It was shown to be present in the cell wall of the pathogen by immunoelectron microscopy and, along with heat shock factor DnaK (Lmo1473), elongation factor TU (Lmo2653), and glyceraldehyde‐3‐phosphate dehydrogenase (Lmo2459), it was found to be able to bind human plasminogen in overlay blots and surface plasmon resonance (SPR) experiments. The KD values of these interactions were determined by SPR measurements. The data indicate a possible role of these proteins as receptors for human plasminogen on the bacterial cell surface. The potential role of this recruitment of a host protease for extracellular invasion mechanisms is discussed.
[Association between tuberculosis incidence and the Human Development Index in 165 countries of the world].

OBJECTIVES Assess relationship between the Human Development Index (HDI) and the incidence of tuberculosis (TB) in 165 countries in the World in the period 2005-2011. MATERIALS AND METHODS An ecological study was done, using HDI data that were obtained from the United Nations Development Program (UNDP), and the incidence rates from the Stop TB Program of the World Health Organization (WHO). The annual variation of the variables was assessed and non-linear regression models (Exponential), were done. RESULTS At the non-linear regression models, it was observed that the relationship between epidemiological and HDI was significant, those countries with higher rates presented lower values of HDI (p<0.01). Additionally the variation in time was significantly associated with HDI variation. CONCLUSIONS This information reflect the significant influence of socioeconomical indicators such as the HDI on the TB incidence rates in the World, particularly in endemic countries, being an inverse relationship between both types of variables; with an increase or improvement in the HDI, the disease incidence rate decreased or it is found lower.
Combining variance and process research approaches to understand system use

System use is a key concept in information systems (IS) research. Understanding and predicting the use of IS has significant implications for realising the benefits of IS investments. This is because a system that is underutilised, misused or avoided altogether will not achieve the aspirations of its designers or those who have procured the system. Given the centrality of the use concept it is important that the ways in which researchers choose to represent and examine use are understood. There are two approaches often used to examine use: variance and process. The central knowledge claim of this paper is that combining variance and process research approaches will contribute to richer representations and understanding of use. An illustrative case study that employed both approaches demonstrates how variance and process approaches shed light on use. This research highlights how a combined research approach yields a more holistic understanding of the phenomena of interest.
Genetic screening of Hrp type III‐related pathogenicity genes controlled by the HrpB transcriptional activator in Ralstonia solanacearum

As in many other Gram‐negative phytopathogenic bacteria, the Hrp type III secretion system is essential for the pathogenicity of Ralstonia solanacearum on host plants. The expression of most of the type III effector genes previously isolated from R. solanacearum is co‐regulated with those of hrp genes by an AraC‐type transcriptional activator, HrpB. In order to isolate type III‐related pathogenicity genes, we screened hrpB‐regulated genes in R. solanacearum. Using a transposon‐based system, we isolated 30 novel hpx (hrpB‐dependent expression) genes outside the hrp gene cluster. Most of the hpx genes contain a PIP (plant‐inducible promoter) box‐like motif in their putative promoter regions. Seven hpx genes encoded homologues of known type III effectors and type III‐related proteins found in other animal and plant pathogens. Four encoded known enzymes, namely, glyoxalase I, Nudix hydrolase, spermidine synthase and transposase. Interestingly, six hpx genes encoded two types of leucine‐rich repeat (LRR) protein. Products of the remaining genes did not show any significant homology to known proteins. We also identified two novel hrpB‐regulated genes, hpaZ and hpaB, downstream of hrpY in the hrp cluster. The hpaB gene of R. solanacearum, but not hpaZ, was required for both the pathogenicity and ability to induce hypersensitive reaction on plants. We show that a hpaB null mutant still produces Hrp pili on the cell surface although it shows a typical Hrp‐defective phenotype on plants.
Metabolic Regulator βKlotho Interacts with Fibroblast Growth Factor Receptor 4 (FGFR4) to Induce Apoptosis and Inhibit Tumor Cell Proliferation*

In organs involved in metabolic homeostasis, transmembrane α and βklothos direct FGFR signaling to control of metabolic pathways. Coordinate expression of βklotho and FGFR4 is a property of mature hepatocytes. Genetic deletion of FGFR4 or βklotho in mice disrupts hepatic cholesterol/bile acid and lipid metabolism. The deletion of FGFR4 has no effect on the proliferative response of hepatocytes after liver injury. However, its absence results in accelerated progression of dimethynitrosamine-initiated hepatocellular carcinomas, indicating that FGFR4 suppresses hepatoma proliferation. The mechanism underlying the FGFR4-mediated hepatoma suppression has not been addressed. Here we show that βklotho expression is more consistently down-regulated in human and mouse hepatomas than FGFR4. Co-expression and activation by either endocrine FGF19 or cellular FGF1 of the FGFR4 kinase in a complex with βklotho restricts cell population growth through induction of apoptotic cell death in both hepatic and nonhepatic cells. The βklotho-FGFR4 partnership caused a depression of activated AKT and mammalian target of rapamycin while activating ERK1/2 that may underlie the pro-apoptotic effect. Our results show that βklotho not only interacts with heparan sulfate-FGFR4 to form a complex with high affinity for endocrine FGF19 but also impacts the quality of downstream signaling and biological end points activated by either FGF19 or canonical FGF1. Thus the same βklotho-heparan sulfate-FGFR4 partnership that mediates endocrine control of hepatic metabolism plays a role in cellular homeostasis and hepatoma suppression through negative control of cell population growth mediated by pro-apoptotic signaling.
Construct Validation Using Computer-Aided Text Analysis (CATA)

Construct validity continues to pose challenges in the organizational sciences. To capture difficult-to-measure constructs of interest, researchers have often relied on content analysis. One content analysis technique, computer-aided text analysis (CATA), is particularly attractive because of the ability to process large samples with high speeds and reliabilities. Unfortunately, inconsistent guidance exists to guide researchers through the use of this tool in a manner compatible with accepted methods used to validate constructs in a rigorous manner. The authors review research using content analysis to examine the extent to which such studies integrate methods for assessing content, external, discriminant, and predictive validity. To provide direction for organizational researchers interested in using CATA to measure theoretically based constructs relevant to the management field, they suggest a number of possible procedures to enhance construct validity. They illustrate these procedures using the construct of entrepreneurial orientation.
The effect of topically applied secretory leukocyte protease inhibitor on the eosinophil response in the late phase of allergic conjunctivitis

Purpose. This study examined the effects of secretory leukocyte protease inhibitor (SLPI), a protease inhibitor in tears, in allergic conjunctivitis. Methods. Conjunctiva of male Hartley guinea pigs sensitized with ovalbumin were treated with SLPI or the vehicle 10min before antigen challenge or simultaneously. The animals were sacrificed after antigen challenges of 0-24 h duration, and the inhibition of eosinophil conjunctival migration and degranulation by SLPI was analyzed histochemically. The effects of SLPI on mast cell chymase and tryptase were also examined. Results. Treatment of sensitized guinea pigs with SLPI suppressed the conjunctival recruitment and degranulation of eosinophils after antigen challenge for 6 h, inhibiting the development of allergic conjunctivitis. The effects of SLPI were observed at concentrations =0. 1µM, with a peak at 5µM. SLPI inhibited chymase in a dose-dependent manner, but had no effect on tryptase. Conclusion. The topical SLPI application may be therapeutic in allergic conjunctivitis.
Adenovirus E4orf3 Targets Transcriptional Intermediary Factor 1γ for Proteasome-Dependent Degradation during Infection

ABSTRACT The ability of adenovirus early region proteins, E1B-55K and E4orf6, to usurp control of cellular ubiquitin ligases and target proteins for proteasome-dependent degradation during infection is well established. Here we show that the E4 gene product, E4orf3 can, independently of E1B-55K and E4orf6, target the transcriptional corepressor transcriptional intermediary factor 1γ (TIF1γ) for proteasome-mediated degradation during infection. Initial mass spectrometric studies identified TIF1 family members—TIF1α, TIF1β, and TIF1γ—as E1B-55K-binding proteins in both transformed and infected cells, but analyses revealed that, akin to TIF1α, TIF1γ is reorganized in an E4orf3-dependent manner to promyelocytic leukemia protein-containing nuclear tracks during infection. The use of a number of different adenovirus early region mutants identified the specific and sole requirement for E4orf3 in mediating TIF1γ degradation. Further analyses revealed that TIF1γ is targeted for degradation by a number of divergent human adenoviruses, suggesting that the ability of E4orf3 to regulate TIF1γ expression is evolutionarily conserved. We also determined that E4orf3 does not utilize the Cullin-based ubiquitin ligases, CRL2 and CRL5, or the TIF1α ubiquitin ligase in order to promote TIF1γ degradation. Further studies suggested that TIF1γ possesses antiviral activity and limits adenovirus early and late gene product expression during infection. Indeed, TIF1γ knockdown accelerates the adenovirus-mediated degradation of MRE11, while TIF1γ overexpression delays the adenovirus-mediated degradation of MRE11. Taken together, these studies have identified novel adenovirus targets and have established a new role for the E4orf3 protein during infection.
Distress Levels in Patients with Premenstrual Dysphoric Disorder

score dropped to 83. However, following generalized tonic-clonic seizures at clozapine 450 mg daily, the drug was reduced to 200 mg daily. Valproate was added and titrated to 1000 mg daily. After a normal EEG, his clozapine was increased, but owing to marked sedation, the drug was again reduced to 200 mg daily. Because the patient’s psychopathology had worsened (his PANSS score increased to 102), risperidone was subsequently added and titrated to 6 mg daily. Simultaneously, Mr C underwent CBT with 2 procedures: 1) belief modification by way of verbal challenge and reality testing for delusions (4) and 2) normalizing his rationale for auditory hallucinations and somatic passivity (5). Sessions were weekly and lasted 20 to 40 minutes.
Effect of Progressive Self-Focus Meditation on Attention, Anxiety, and Depression Scores

This study evaluated the effects of Progressive Self-focus Meditation with 42 volunteers (M age = 46.0 yr., SD = 14.1) allocated to two groups: one that had weekly 1-hr. training sessions in the practice for 5 wk. and one waiting-list group. Participants were evaluated before and after 5 wk. on the Beck Anxiety Inventory, Beck Depression Inventory, the Digit Symbol subtest of the Wechsler Adult Intelligence Scale, and the Mindfulness Attention Awareness Scale. After 5 wk. , a significant reduction in scores on depression was found in the Meditation group as well as an increase in attention in comparison with the waiting-list Control group.
The desmopressin test as a predictive factor of outcome after pituitary surgery for Cushing's disease.

OBJECTIVE Taking advantage of the over-expression of V3 receptors in adenomatous corticotroph cells, we evaluated the response to the vasopressin agonist desmopressin in 22 patients operated on for Cushing's disease, with a mean follow-up of 4.5 years. SUBJECTS AND METHODS Twenty-two patients (17 women) operated on for Cushing's disease with a follow-up >2 years (median, 48; range, 24-141 months) underwent one desmopressin test (10 microg i.v. bolus) 3-6 months postoperatively. Twelve were in remission (R group), five had immediate failure (IF) after surgery and five had late recurrence (LR). RESULTS Both ACTH and cortisol peaks after desmopressin were significantly lower in the R group than in the LR group (P=0.003 and P=0.013 respectively). The receiver operator characteristic curve method defined an ACTH peak threshold > or =22 pg/ml or ACTH rise > or =35%; cortisol peak > or =350 nmol/l or cortisol rise > or =14%. None of twelve patients in remission had ACTH or cortisol peaks above these thresholds vs three of five patients from the LR group and five of five in the IF group. DISCUSSION On the basis of ACTH or cortisol peaks respectively, the desmopressin test was predictive of a later recurrence with a positive predictive value of 100% or 80% respectively, and a negative predictive value of 92%. Sensitivity and specificity were 80% and 100% respectively based on ACTH peak, and 80% and 92% respectively based on cortisol peak. CONCLUSION In this first long-term study, a marked response of ACTH or cortisol to desmopressin was predictive of a later recurrence with good specificity and sensitivity.
Complete Genome Sequence of the Circulatory Foot-and-Mouth Disease Virus Serotype Asia1 in Bangladesh

ABSTRACT The complete genome sequence of foot-and-mouth disease virus (FMDV) serotype Asia1 isolated from Bangladesh is reported here. Genome analysis revealed amino acid substitutions in the VP1 antigenic region and deletions in both the 5′ and 3′ untranslated regions (UTRs) compared to the genome of the existing vaccine strain (GenBank accession no. AY304994).
Self-disclosure as a function of reward-cost outcomes.

Fifty-six sailors individually participated in a lengthy interaction session, ostensibly with another sailor (an experimenter confederate). They were subjected to one of four reward/cost interaction histories (Continuous Positive, Later Positive, Continuous Negative, and Later Negative). In addition, Ss expected to be in either a long-term or short-term relationship with their partner (Non-Withdrawal or Withdrawal). Disclosure measures included average time talked, breadth and depth of interpersonal exchange. Results confirmed earlier studies to the effect that (1) more disclosure occurred in nonintimate versus intimate areas, (2) disclosure varied directly as a function of interpersonal reward/cost factors, and (3) the impact of reward/cost factors was primarily in intimate topical areas. An extension of past findings indicated a "contrast effect" that is, shifts in reinforcement which were inconsistent with prior established expectations produced exaggerated behaviors. This happened in the NonWithdrawal condition, and only partially in the Withdrawal condition. These results were seen as consistent with findings from the gain-loss model and earlier studies on social penetration processes.
Distinct Receptor Tyrosine Kinase Subsets Mediate Anti-HER2 Drug Resistance in Breast Cancer*

Targeted inhibitors of the human epidermal growth factor receptor 2 (HER2), such as trastuzumab and lapatinib, are among the first examples of molecularly targeted cancer therapy and have proven largely effective for the treatment of HER2-positive breast cancers. However, approximately half of those patients either do not respond to these therapies or develop secondary resistance. Although a few signaling pathways have been implicated, a comprehensive understanding of mechanisms underlying HER2 inhibitor drug resistance is still lacking. To address this critical question, we undertook a concerted approach using patient expression data sets, HER2-positive cell lines, and tumor samples biopsied both before and after trastuzumab treatment. Together, these methods revealed that high expression and activation of a specific subset of receptor tyrosine kinases (RTKs) was strongly associated with poor clinical prognosis and the development of resistance. Mechanistically, these RTKs are capable of maintaining downstream signal transduction to promote tumor growth via the suppression of cellular senescence. Consequently, these findings provide the rationale for the design of therapeutic strategies for overcoming drug resistance in breast cancer via combinational inhibition of the limited number of targets from this specific subset of RTKs.
Mammary tumors in ruminants

The frequency of mammary neoplasia in different species varies tremendously. Among women, breast cancer features as one of the most frequent types of cancer globally. Breast cancer is the cause of almost half a million deaths worldwide each year. Of these deaths, more than 58 % are occurring in developing countries. Mammary tumors are rare in cows, mares, goats, ewes, and sows as evident by few cases reported in literature. In dairy cattle and milking goats the udders are inspected daily by palpation when milking and the tumors would be detected soon. The morphological features of bovine mammary gland are more similar to those in human than in rodents, the latter being commonly used for cancerogenic studies. There are several factors that might affect the high rate of tumor development in women and attenuate the development of tumors in ruminants. Besides diet, life style, reproductive history, stress load, the general physiology and metabolism might have an influence. Translational research using different mammary gland cell populations from several species may lead to comparative studies and may help reduce the risk and contribute to discovery of new therapeutic targets to treat breast cancer. In present work the zero occurrence of mammary gland tumors in ruminants will be reviewed focusing on literature records and mechanisms underlying the resistance.
Pharmacodynamic evaluation of 4 angiotensin-converting enzyme inhibitors in healthy adult horses.

BACKGROUND Angiotensin-converting enzyme (ACE) inhibitors are used in horses with cardiovascular disorders despite the paucity of available data regarding their efficacy. HYPOTHESIS The degree of serum ACE inhibition varies considerably between drugs. ANIMALS Eight healthy adult horses. METHODS Randomized prospective study. Horses were fasted overnight prior to receiving one of 4 ACE inhibitors intragastrically, administered at one of 2 dosages, using a randomized Latin square design (benazepril: 0.5 and 0.25 mg/kg; ramipril: 0.3 and 0.1 mg/kg; quinapril: 0.25 and 0.125 mg/kg; perindopril: 0.1 and 0.05 mg/kg). Serum ACE activity was measured using a kinetic spectrophotometric method. RESULTS There was a significant effect of drug and dosage on maximum ACE inhibition (I(max)), ACE inhibition 24 hours after administration (I(24h)), and area under the curve (AUC(0-48h)). Benazepril at 0.5 mg/kg resulted in significantly higher I(max) (86.9 ± 7.0%) and I(24h) (60.3 ± 7.9%) compared to the other drugs. There was a significant decrease in indirect blood pressure (BP) over time after administration of each drug, but differences in BP were not significantly different between drugs. Pharmacodynamic variables measured after administration of benazepril to horses with free access to hay were not significantly different from those obtained after fasting. Administration of benazepril orally once daily for 7 days did not result in a cumulative effect on ACE inhibition. CONCLUSIONS AND CLINICAL IMPORTANCE Of the ACE inhibitors tested, oral benazepril (0.5 mg/kg) is the most effective at inhibiting serum ACE activity in healthy horses.