Miracle-dz/UniFAR-FTUs huggingface dataset:
A Pluridimensional View of Biased Agonism

When studying G protein–coupled receptor (GPCR) signaling and ligand-biased agonism, at least three dimensional spaces must be considered, as follows: 1) the distinct conformations that can be stabilized by different ligands promoting the engagement of different signaling effectors and accessory regulators; 2) the distinct subcellular trafficking that can be conferred by different ligands, which results in spatially distinct signals; and 3) the differential binding kinetics that maintain the receptor in specific conformation and/or subcellular localization for different periods of time, allowing for the engagement of distinct signaling effector subsets. These three pluridimensional aspects of signaling contribute to different faces of functional selectivity and provide a complex, interconnected way to define the signaling profile of each individual ligand acting at GPCRs. In this review, we discuss how each of these aspects may contribute to the diversity of signaling, but also how they shed light on the complexity of data analyses and interpretation. The impact of phenotype variability as a source of signaling diversity, and the influence of novel and more sensitive assays in the detection and analysis of signaling pluridimensionality, is also discussed. Finally, we discuss perspectives for the use of the concept of pluridimensional signaling in drug discovery, in which we highlight future predictive tools that may facilitate the identification of compounds with optimal therapeutic and safety properties based on the signaling signatures of drug candidates.
Acyl Chain Specificity of the Acyltransferases LpxA and LpxD and Substrate Availability Contribute to Lipid A Fatty Acid Heterogeneity in Porphyromonas gingivalis

ABSTRACT Porphyromonas gingivalis lipid A is heterogeneous with regard to the number, type, and placement of fatty acids. Analysis of lipid A by matrix-assisted laser desorption ionization-time of flight mass spectrometry reveals clusters of peaks differing by 14 mass units indicative of an altered distribution of the fatty acids generating different lipid A structures. To examine whether the transfer of hydroxy fatty acids with different chain lengths could account for the clustering of lipid A structures, P. gingivalis lpxA (lpxAPg ) and lpxDPg were cloned and expressed in Escherichia coli strains in which the homologous gene was mutated. Lipid A from strains expressing either of the P. gingivalis transferases was found to contain 16-carbon hydroxy fatty acids in addition to the normal E. coli 14-carbon hydroxy fatty acids, demonstrating that these acyltransferases display a relaxed acyl chain length specificity. Both LpxA and LpxD, from either E. coli or P. gingivalis, were also able to incorporate odd-chain fatty acids into lipid A when grown in the presence of 1% propionic acid. This indicates that E. coli lipid A acyltransferases do not have an absolute specificity for 14-carbon hydroxy fatty acids but can transfer fatty acids differing by one carbon unit if the fatty acid substrates are available. We conclude that the relaxed specificity of the P. gingivalis lipid A acyltransferases and the substrate availability account for the lipid A structural clusters that differ by 14 mass units observed in P. gingivalis lipopolysaccharide preparations.
A Dualistic Model of Tourism Seasonality: Approach–Avoidance and Regulatory Focus Theories

Seasonality in tourism is a key but poorly understood issue in the context of the tourism industry. Furthermore, theoretical and conceptual developments regarding seasonality in tourism remain limited. This conceptual study aims to integrate approach–avoidance and regulatory focus theories as frameworks for understanding seasonality in tourism. The study’s purpose is threefold. First, it evaluates current research on seasonality in tourism. Second, it outlines the features of approach–avoidance and regulatory focus theories and their underutilization in the tourism setting. Third, it illustrates the potential of the above theories and frameworks in understanding seasonality in tourism. Also important is our development of a dualistic model to augment policymakers’ understanding of how certain factors, such as fruition-based factors, structural factors, unforeseen factors, and climate-based factors, can influence seasonality in tourism. Implications and suggestions for future research are also discussed.
Catalase (KatA) and Alkyl Hydroperoxide Reductase (AhpC) Have Compensatory Roles in Peroxide Stress Resistance and Are Required for Survival, Persistence, and Nasal Colonization in Staphylococcus aureus

ABSTRACT Oxidative-stress resistance in Staphylococcus aureus is linked to metal ion homeostasis via several interacting regulators. In particular, PerR controls the expression of a regulon of genes, many of which encode antioxidants. Two PerR regulon members, ahpC (alkylhydroperoxide reductase) and katA (catalase), show compensatory regulation, with independent and linked functions. An ahpC mutation leads to increased H2O2 resistance due to greater katA expression via relief of PerR repression. Moreover, AhpC provides residual catalase activity present in a katA mutant. Mutation of both katA and ahpC leads to a severe growth defect under aerobic conditions in defined media (attributable to lack of catalase activity). This results in the inability to scavenge exogenous or endogenously produced H2O2, resulting in accumulation of H2O2 in the medium. This leads to DNA damage, the likely cause of the growth defect. Surprisingly, the katA ahpC mutant is not attenuated in two independent models of infection, which implies reduced oxygen availability during infection. In contrast, both AhpC and KatA are required for environmental persistence (desiccation) and nasal colonization. Thus, oxidative-stress resistance is an important factor in the ability of S. aureus to persist in the hospital environment and so contribute to the spread of human disease.
Occurrence of Impaired Physical Performance in Memory Clinic Patients With Cerebral Small Vessel Disease

Cerebral small vessel disease (CSVD) occurs often in memory clinic patients. Apart from cognitive deficits, these patients can express physical decline, which predicts adverse health outcomes. In this study, we investigated the cooccurrence of clinically relevant impairments in physical performance and CSVD in memory clinic patients. We included 131 patients with vascular brain injury, mild cognitive impairment or Alzheimer disease with available 3T MRI and physical performance scores. CSVD was visually rated according to 3 subtypes and as a total burden score, composed of the presence of white matter hyperintensities (WMH), lacunar infarcts (LI), and cerebral microbleeds (MB). Physical performance was assessed with the Short Physical Performance Battery (SPPB), covering gait speed, balance, and chair stand performance. CSVD markers and impaired physical performance both occurred often. High total CSVD burdens cooccurred with impaired chair stand performances [odds ratio (OR) 2.67; 95% confidence interval (CI) (1.12-6.34)]. WMH cooccurred with impaired SPPB scores (OR, 3.76; 95% CI, 1.68-8.44), impaired gait speeds (OR, 4.11; 95% CI, 1.81-9.31) and impaired chair stand performances (OR, 5.62; 95% CI, 2.29-13.80). In memory clinic patients, high burdens of CSVD, particularly WMH, often cooccur with impairments in physical performance. The presence of WMH should alert clinicians to the presence of these, clinically relevant, physical impairments.
Effectiveness of Depression–Suicidal Behaviour Gatekeeper Training among police officers in three European regions: Outcomes of the Optimising Suicide Prevention Programmes and Their Implementation in Europe (OSPI-Europe) study

Background: Gatekeeper training for community facilitators, to identify and respond to those at risk of suicide, forms an important part of multi-level community-based suicide prevention programmes. Aims: This study examined the effects of gatekeeper training on attitudes, knowledge and confidence of police officers in dealing with persons at risk of suicide. Methods: A total of 828 police officers across three European regions participated in a 4-hour training programme which addressed the epidemiology of depression and suicidal behaviour, symptoms of depression, warning signs and risk factors associated with suicidal behaviour, motivating help-seeking behaviour, dealing with acute suicidal crisis and informing bereaved relatives. Participants completed internationally validated questionnaires assessing stigmatising attitudes, knowledge about depression and confidence in dealing with suicidal persons pre- and post-training. Results: There were significant differences among countries in terms of previous exposure to suicidal persons and extent of previous training. Post-training evaluation demonstrated significant improvements in stigmatising attitudes, knowledge and confidence in all three countries. Conclusion: The consistently positive effects of gatekeeper training of police officers across different regions support inclusion of this type of training as a fundamental part of multi-level community-based suicide prevention programmes and roll-out, nationally and internationally.
Quantitation of antibodies to varicella-zoster virus by immune adherence hemagglutination

Immune adherence hemagglutination was compared with the complement fixation test as a means of measuring antibodies to varicella-zoster virus. Analysis of acute- and convalescent-phase sera from patients infected with varicella-zoster or with herpes simplex virus showed the immune adherence hemagglutination test to be more sensitive than the complement fixation test, and greater cross-reactivity between the two viruses appeared to be associated with the increased sensitivity. The two assay methods were used to measure antibodies to varicella-zoster virus in 265 sera obtained from patients of different ages as well as sera from 26 patients with leukemia. There were 35 cases where antibodies were detected by immune adherence hemagglutination but not by complement fixation, whereas in five cases the converse was found. Our findings support the contention that immune adherence hemagglutination is the method of choice for detecting antibodies to varicella-zoster virus.
Specific insulin sensitivity and leptin responses to a nutritional treatment of obesity via a combination of energy restriction and fatty fish intake.

BACKGROUND Nutritional strategies to treat obesity often influence neuroendocrine factors related to body weight control. The present study aimed to investigate whether the inclusion of three fatty fish servings per week within a hypocaloric diet may have specific healthy effects on insulin and leptin functions. METHODS Thirty-two subjects (body mass index = 31.6 +/- 3.5 kg m(-2)) aged 36 +/- 7 years, were assigned to a control or fish-based energy-restricted diet over an 8-week period. Anthropometry, body composition, lipid profile, leptin and insulin values were measured at the start and at the end of the dietary intervention. RESULTS Both experimental diets resulted in a similar mean weight loss (control = 5.3 +/- 2.6% versus fish-based = 5.5 +/- 2.5%; P = 0.783). A significant reduction in insulin resistance, as determined by the homeostatic model assessment index (HOMA-IR = insulin x glucose/22.5), was observed after the fish-based intervention. The change in circulating leptin was higher in the fish-based diet compared to the control group. Sixteen percent of the variability in the change of adjusted-leptin could be explained (P = 0.034) by the HOMA index change and the type of diet. CONCLUSIONS Three servings a week of fatty fish included in an energy-restricted diet appears to be a valid strategy for specifically improving insulin sensitivity and leptin levels in obese subjects, which could involve a better body weight regulation after a nutritional intervention period.
Separation of reboxetine enantiomers by means of capillary electrophoresis

The novel antidepressant reboxetine, a selective norepinephrine reuptake inhibitor, is increasingly used in the treatment of different forms of major depression. Reboxetine is a chiral compound, and is marketed as a racemic mixture of (R,R)‐ and (S,S)‐reboxetine; however, the pharmacokinetic and toxicological profiles of the two enantiomers are rather different. For this reason, a simple capillary electrophoretic method for the separation of reboxetine enantiomers has been developed. Sulfobutyl ether‐β‐cyclodextrin was chosen as the chiral selector, and several parameters, such as cyclodextrin and buffer concentration, buffer pH and capillary temperature were investigated in order to obtain good separation and acceptable run times. Using an uncoated, fused‐silica capillary (internal diameter 50 νm, total length 48.5 cm, effective length 40.0 cm) and a background electrolyte consisting of a pH 3.0, 100 mM phosphate buffer containing 1.25 mM cyclodextrin, reboxetine enantiomers were baseline separated (resolution > 4) with a voltage of 20 kV in less than 16 min. Since pure enantiomers of reboxetine were not available, they were obtained from the racemic powder by means of direct‐phase, high‐performance liquid chromatography and their identity confirmed by circular dichroism spectra.
Mos10 (Vps60) is required for normal filament maturation in Saccharomyces cerevisiae

Early pseudohyphal growth of Saccharomyces cerevisiae is well described, and is known to be subject to a complex web of developmental regulation. In maturing filaments, young cells differ significantly from their pseudohyphal progenitors, in their shape, and in their timing and direction of cell division. The changes that occur during filament maturation result in round and oval cells surrounding and covering the pseudohyphal filament. In a screen for mutants that affect this process, a vacuolar protein sorting gene, MOS10 (VPS60), and a gene encoding an α subunit of the proteasome core, PRE9, were isolated. Characterization of the mos10/mos10 phenotype showed that the process of filament maturation is regulated differently from early filamentous growth, and that the requirement for Mos10 is limited to the maturation stage of pseudohyphal development. The mos10/mos10 phenotype is unlikely to be an unspecific effect of disruption of endocytosis or vacuolar protein sorting, because it is not recapitulated by mutants in other genes required for these processes. Disruption of homologues of MOS10, which act as components of the ESCRT‐III complex in targeting proteins for vacuolar degradation, results in abnormal early pseudohyphal growth, not in the filament maturation defect seen in mos10/mos10. Thus, Mos10 may function in targeting of specific cargo proteins for degradation, under conditions particular to maturing filaments.
Synchronized walking cadence for TUG in perturbed environments: Using Earcon or Tacton cues?

Audio and haptic cueing have proven their usability to assist gait for patients with Parkinson's disease. These cueings are used when a gait issue is classified in real-time by an artificial intelligent algorithm using wearable IMU signals located at the lower limb. Such gait issue could be freezing of gait (FOG) and Bradykinesia symptoms. This system detects freezing periods and plays a rhythmic pattern such as Tacton or Earcon in haptic or audio respectively. When prior training is done with an appropriate serious game, cueing could help to recover gait cadence and then help to avoid fall. Both types of cueing were used in different research works without prior analysis on the best stimulation to use in a perturbed environment. Since rhythmic auditory sound could be an issue in a real outdoor environment, this paper suggests evaluating rhythmic stimulation cueing with the Time Up and Go clinical assessment test used for mobility evaluation.
Development of a serum‐free system to expand dental‐derived stem cells: PDLSCs and SHEDs

Recently, extracted teeth have been identified as a viable source of stem cells for tissue regenerative approaches. Current expansion of these cells requires incorporation of animal sera; yet, a fundamental issue underlying cell cultivation methods for cell therapy regards concerns in using animal sera. In this study, we investigated the development of a chemically defined, serum‐free media (K‐M) for the expansion of human periodontal ligament stem cells (PDLSCs) and human stem cells from exfoliated deciduous teeth (SHEDs). Proliferation assays were performed comparing cells in serum‐containing media (FBS‐M) with cells cultured in four different serum‐free medium and these demonstrated that in these medium, the cell proliferation of both cell types was significantly less than the proliferation of cells in FBS‐M. Additional proliferation assays were performed using pre‐coated fibronectin (FN) tissue culture plates and of the four serum‐free medium, only K‐M enabled PDLSCs and SHEDs to proliferate at higher rates than cells cultured in FBS‐M. Next, alkaline phosphatase activity showed that PDLSCs and SHEDs exhibited similar osteogenic potential whether cultured in K‐M or FBS‐M, and, additionally, cells retained their multipotency in K‐M as seen by expression of chondrogenic and adipogenic genes, and positive Von Kossa, Alcian blue, and Oil Red O staining. Finally, differential expression of 84 stem cell associated genes revealed that for most genes, PDLSCs and SHEDs did not differ in their expression regardless of whether cultured in K‐M or FBS‐M. Taken together, the data suggest that K‐M can support the expansion of PDLSCs and SHEDs and maintenance of their multipotency. J. Cell. Physiol. 226: 66–73, 2010. © 2010 Wiley‐Liss, Inc.
Quantitative assessment of lung cancer perfusion using MDCT: does measurement reproducibility improve with greater tumor volume coverage?

OBJECTIVE To date, quantitative assessment of tumor vascularity using perfusion CT has been limited to a single tumor level, with the potential for measurement error in heterogeneous tumors. We aimed to determine if greater z-axis tumor coverage improves the reproducibility of perfusion CT measurements in lung cancer. SUBJECTS AND METHODS Paired perfusion studies were performed on 10 patients who had histologically confirmed advanced non-small cell lung cancer. Using 16-MDCT, multiple sequential volumetric acquisitions encompassing the entire tumor were acquired after infusion of i.v. contrast material. Using Patlak analysis, median values of tumor permeability (mL/100 mL/min) and blood volume (mL/100 mL) were measured for 10-mm z-axis coverage, and for 40-mm z-axis coverage in each of the paired perfusion studies. Measurement reproducibility was evaluated using Bland-Altman statistics. RESULTS Mean difference (95% limits of agreement) for tumor permeability was 1.4 (-4.0 to 6.8) for 10-mm coverage and 0.8 (-3.6 to 5.2) for 40-mm coverage. Mean difference (95% limits of agreement) for blood volume was 1.9 (-5.1 to 8.9) for 10-mm coverage and 1.4 (-3.7 to 6.6) for 40-mm coverage. The coefficient of variation for permeability was 18.7% for 10-mm coverage, improving to 11.9% for 40-mm coverage. The coefficient of variation for blood volume was 41.7% for 10-mm coverage, improving to 32.6% for 40-mm coverage. CONCLUSION Our results show that an improvement in tumor perfusion measurement reproducibility may be achieved with greater z-axis coverage.
A New Pyrimidine-Specific Reporter Gene: A Mutated Human Deoxycytidine Kinase Suitable for PET During Treatment with Acycloguanosine-Based Cytotoxic Drugs

In this article, we describe a series of new human-derived reporter genes based on human deoxycytidine kinase (dCK) suitable for clinical PET. Methods: Native dCK and its mutant reporter genes were tested in vitro and in vivo for their phosphorylation of pyrimidine- and acycloguanosine-based radiotracers including 2′-deoxy-2′-fluoroarabinofuranosylcytosine, 2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil (FEAU), penciclovir, and 9-[4-fluoro-3-(hydroxymethyl)butyl]guanine (FHBG) and clinically applied antiviral and anticancer drugs. Results: Cells transduced with dCK mutant reporter genes showed high in vitro and in vivo uptake of pyrimidine-based radiopharmaceuticals (18F-FEAU) comparable to that of herpes simplex virus type-1 thymidine kinase (HSV1-tk)–transduced cells. These mutants did not phosphorylate acycloguanosine-based radiotracers (18F-FHBG) or antiviral drugs (ganciclovir). Furthermore, the mutants displayed suicidal activation of clinically used pyrimidine-based prodrugs (cytarabine, gemcitabine). Conclusion: The mutants of human dCK can be used as pyrimidine-specific PET reporter genes for imaging with 18F-FEAU during treatment with acycloguanosine-based antiviral drugs. Additionally, the prosuicidal activity of these reporters with pyrimidine-based analogs will allow for the safe elimination of transduced cells.
Macroeconomic Indicators and Economic Performance in Selected Sub Sahara African Countries: Panel Generalized Method of Moment Approach

This study empirically examined the effect of macroeconomic indicators on economic performance of selected sub Sahara African Countries between 1990 and 2017. The study employed four variables: GDP growth rate, Inflation rate, Monetary policy rate and Exchange rate and panel unit root test using two criteria to test for stationarity, panel cointegration test was also conducted to test for long run cointegration between the variables employed and Generalized Method of Moment method of estimation was employed to check the relationships between the variables. The results of the panel unit root test result from the LLC and IPS methods shows that the order of integrations mixed with some of the variables being stationary at levels (GDPgr and INFL) and first difference (MPR and EXHR) at the same time. The result of Pedroni cointegration test indicated the bivariate long-run cointegration equation between the variables employed. The GMM result revealed that all explanatory variables accounted for 23% variation of Economic performance in SSA. However, the study made the following policy implications: More balanced but flexible approach towards the MPR should be embraced to allow more room for impressive economic growth in these countries. Macroeconomic policy decision is not enough to stimulate growth in the economy of any nation. The interplay of fiscal instruments and monetary instruments backed with political will of the government on genuine implementation of well-thought out programmes can be employed as the antidote to ensure that the macroeconomic objectives are achieved both in the short and long-run.