Miracle-dz/UniFAR-FTUs huggingface dataset:
Constitutively active mutants of 5‐HT4 receptors are they in unique active states?

Somatic mutations leading to constitutively active G‐protein coupled receptors (GPCRs) are responsible for certain human diseases. A consistent structural description of the molecular change underlying the conversion of GPCRs from an inactive R state to an active R* state is lacking. Here, we show that a series of constitutively active 5‐HT4 receptors (mutated or truncated in the C‐terminal and the third intracellular loop) were characterized by an increase in their denaturation rate at 55°C. The thermal denaturation kinetics were monophasic, suggesting that we were measuring mainly the denaturation rate of R*. Analysis of these kinetics revealed that constitutively active C‐terminal domain mutants, were due to a change in the J constant governing the R/R* equilibrium. However, the constitutive activity of the receptor mutated within the third intracellular loop was the result of both a change in the allosteric J constant and a change in the R* conformation.
Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids.

Tumor cells grown as multicellular spheroids are known to be intrinsically more resistant to a large and diverse array of anticancer chemotherapeutic drugs compared to the same cells grown as dispersed monolayer cell cultures. Some drugs, however, seem relatively insensitive to this multicellular drug resistance, e.g., cisplatinum. Whether the cytotoxic effects of Taxol, an anticancer drug of growing importance in the treatment of breast and ovarian carcinomas, are diminished by multicellular growth conditions is unknown. To study this question, we examined the relative sensitivity of a panel of four different human ovarian carcinoma cell lines to either Taxol or cisplatinum. Upon exposure to Taxol, all the cell lines manifested a relative drug-resistant phenotype when grown as multicellular tumor spheroids, compared to the same cells grown as sparse monolayer cultures. This multicellular-dependent drug-resistant phenotype was not observed when the same cells were exposed to cisplatinum for an equivalent length of time. Monolayer but not spheroid cultures exposed to Taxol demonstrated an accumulation of cells at G2-M and a sub-G1 apoptotic region. In addition, Taxol-induced apoptosis was detected in monolayer conditions but not in the spheroid cultures. The relative sensitivity of the monolayer cell cultures was associated with a decrease in bcl-X(L) protein levels after Taxol exposure, an effect not observed in drug-exposed spheroids. Taken together, these results suggest that some aspects of intrinsic Taxol resistance in ovarian carcinoma may be due to multicellular-dependent or -associated mechanisms. This raises the possibility of using antiadhesive agents to reverse multicellular-dependent Taxol resistance in certain circumstances as a potential means of increasing the initial efficiency of Taxol therapy against ovarian carcinoma.
Variable structure adaptive controller for robot manipulator based on desired trajectory compensation

The paper presents a new controller for robot manipulator with nonlinear friction combing with the slide variable structure control theory. In the paper, the generalized coordinates, its first and second derivatives in the regressor are replaced by its desired value, and the variable structure adaptive controller for robot manipulator based on desired trajectory is formed. The adaptive scheme has best computationally efficient for real-time calculating of the regressor. The simulation research shows that the controller is robust to disturbance of dynamic uncertainty and nonlinear friction.
The biologic window for chimeric l6 radioimmunotherapy

Background. There has been little success in using radioimmunotherapy in patients with adenocarcinoma, partly because of the low tumor uptake of the administered monoclonal antibody (MoAb). The authors recently reported therapeutic response in advanced cancer patients who received131 I chimeric‐L6 MoAb. The L6 MoAb identifies abundant, nonshed antigen that is expressed in many human carcinomas, including carcinomas of the lung, breast, colon, and ovary. In vitro both mouse L6 (L6) and chimeric L6 (ChL6) mediate complement‐dependent tumor cytolysis with human serum, and antibody‐dependent tumor cell cytolysis with normal human peripheral blood mononuclear cells. The authors have used L6 or ChL6 for radioimmunotherapy to exploit their biologic activity to create a “therapeutic window” of increased vascular permeability, allowing more131 I MoAb to reach the tumor. A reactive target is present in the vascular endothelium but can be covered by unlabeled L6 or ChL6.
Maternal depletion of NLRP5 blocks early embryogenesis in rhesus macaque monkeys (Macaca mulatta).

BACKGROUND Genetic defects in the oocyte can lead to female infertility due to failures in early embryogenesis. NLRP5 (NLR family, Pyrin domain containing 5) is a maternal effect factor required for early embryo development beyond the 2-cell stage in mice. The NLRP5 gene is conserved in mammals. Applying RNA interference (RNAi) technique in the macaque oocyte, we studied the in vitro effect of NLRP5 in preimplantation embryo development in rhesus macaques. METHODS Macaque MII oocytes were collected and subjected to NLRP5 long double-stranded (ds) RNA microinjection, followed by intracytoplasmic sperm injection and in vitro embryo culture. NLRP5 mRNA and protein expression were examined, and the progress of preimplantation embryo development was monitored until the blastocyst stage. RESULT While 46.7 and 41.4% of embryos derived from uninjected and EGFP (Enhanced Green Fluorescence Protein) dsRNA-injected oocytes (control) reached the blastocyst stage within 10 days of culture, respectively, only 7.0% of the NLRP5 knockdown embryos developed to term. The majority of NLRP5 knockdown embryos were arrested between the 8-cell and the 16-cell stages. CONCLUSIONS The work provides the first evidence that long dsRNA-mediated RNAi can be applied to specific gene silencing in rhesus macaque oocytes, and demonstrates that maternal NLRP5 plays an important role in preimplantation embryogenesis in non-human primates.
Reduced cerebral blood flow response and compensation among patients with untreated hypertension

Objective: To determine whether memory performance in hypertensive subjects induces diminished parietal and prefrontal blood flow activation relative to normotensive subjects but compensatory amygdala/hippocampal activation. Methods: Thirty-seven untreated hypertensive subjects and 59 normotensive control subjects performed in two memory and one sensorimotor task while global and regional cerebral blood flow (rCBF) was assessed with [15O]water and PET. Neuropsychological, carotid artery ultrasound, and MRI assessments were obtained. Results: When they were engaged in memory tasks, increases of CBF in hypertensive subjects were less than in normotensive subjects in the posterior parietal area, as expected; blunted responses were also shown within the middle posterior arterial watershed and thalamus. Relative to all other participants, hypertensive subjects that performed relatively well on verbal memory showed an enhanced rCBF response in the right amygdala/hippocampus. Furthermore, hypertensive, but not normotensive, subjects showed task-induced rCBF in the amygdala/hippocampal area that was significantly correlated with task-induced prefrontal rCBF. No confounding influences were identified from carotid artery or MRI measures. Conclusions: Memory performance in hypertensive individuals is related to a blunted regional cerebral blood flow (rCBF) response, particularly in parietal cortex. Potentially compensatory rCBF responses appear to occur in midbrain and correlate with prefrontal rCBF.
Empirical investigations into the characteristics and determinants of the growth of firms

This thesis presents empirical investigations into the growth of firms, using datasets on French and US manufacturing firms. We begin with a lengthy literature review to clearly identify the gaps in the existing literature. We then investigate Gibrat's law and examine the distribution of growth rates. We investigate serial correlation patterns in growth rates and observe that small firms have negative autocorrelation whilst larger firms have positive autocorrelation. In a theoretical discussion we contrast the mainstream 'financial constraints' theory with evolutionary theory, and conclude that neoclassical work may have exaggerated the extent of financial constraints. In our dataset, firm growth is more or less independent from financial performance and we conclude that selection pressures are weak In the final part we consider the relationship between innovation and firm performance Quantile regression techniques reveal that innovation leads to remarkably superior performance in a minority of cases (the 'superstar firms') but has little effect for the 'average firm' .
Integrative analysis of chemo-transcriptomic profiles for drug-feature specific gene expression signatures

One of the major challenges in systems biology is to understand the complex responses of a biological system to external perturbations or internal signalling depending on its biological conditions. Genome-wide transcriptomic profiling of cellular systems under various chemical perturbations allows the manifestation of certain features of the chemicals through their transcriptomic expression profiles. The insights obtained may help to establish the connections between human diseases, associated genes and therapeutic drugs. The main objective of this study was to systematically analyse cellular gene expression data under various drug treatments to elucidate drug-feature specific transcriptomic signatures. We first extracted drug-related information (drug features) from the collected textual description of DrugBank entries using text-mining techniques. A novel statistical method employing orthogonal least square learning was proposed to obtain drug-feature-specific signatures by integrating gene expression with DrugBank data. To obtain robust signatures from noisy input datasets, a stringent ensemble approach was applied with the combination of three techniques: resampling, leave-one-out cross validation, and aggregation. The validation experiments showed that the proposed method has the capacity of extracting biologically meaningful drug-feature-specific gene expression signatures. It was also shown that most of signature genes are connected with common hub genes by regulatory network analysis. The common hub genes were further shown to be related to general drug metabolism by Gene Ontology analysis. Each set of genes has relatively few interactions with other sets, indicating the modular nature of each signature and its drug-feature-specificity. Based on Gene Ontology analysis, we also found that each set of drug feature (DF)-specific genes were indeed enriched in biological processes related to the drug feature. The results of these experiments demonstrated the potential of the method for predicting certain features of new drugs using their transcriptomic profiles, providing a useful methodological framework and a valuable resource for drug development and characterization.
Design of Optimized Multilayer PIFA With the EBG Structure for SAR Reduction in Mobile Applications

This paper proposes an optimized multilayer planar inverted-F antenna (PIFA) with an electromagnetic bandgap (EBG) at personal communication services band for specific absorption rate (SAR) reduction. The EBG structure, which has bandgap capability and acts as a perfect magnetic conductor surface, can suppress surface waves and reduce undesired radiation from an antenna. Thus, the EBG structure is capable of preventing electromagnetic (EM) fields being emitted in the direction of the human head. To optimize the multilayer PIFA structure for SAR reduction, the EBG structure between the printed circuit board and antenna layer is designed first. Second, a parameter study about the EBG cell numbers, height, and location of the PIFA with the EBG structure is performed. Finally, the optimized multilayer PIFA with the EBG is investigated and the S-parameters, radiation patterns, total radiated power values, and SAR values are presented. The results demonstrate the reduction of SAR values while maintaining the antenna performance. Thus, the human head can be protected from hazardous EM fields using the EBG structure.
How Effective Is Intensive Nonoperative Initial Treatment of Patients with Diabetes and Charcot Arthropathy of the Feet?

Diabetes mellitus and its related complications are increasing at epidemic rates in the United States. Similarly, Charcot foot and ankle deformities are becoming more prevalent. We did a retrospective review of 115 patients (127 limbs) with diabetes mellitus-associated neuroarthropathy to determine the major clinical outcomes. We hypothesized that an intensive disease-specific protocol would result in low rates of amputations. A single treatment protocol was followed for all subjects treated in a tertiary-based orthopaedic department from 1983-2003. Major outcome variables assessed included rates of below-knee amputation, long-term brace wear, reulceration, reconstructive surgeries, and bilaterality. Survivorship analyses were done during a median followup of 3.8 years. In this cohort, diabetic Charcot arthropathy treated in a structured, intensive, and nonoperative manner was associated with an approximately 2.7% annual rate of amputation, a 23% risk of requiring bracing for more than 18 months, and a 49% risk of recurrent ulceration. Limbs with open ulcers at initial presentation or chronically recurrent ulcers had increased risk for amputation. These results suggest that improved methods of care are needed for patients with diabetes who have Charcot arthropathy. Level of Evidence: Therapeutic study, Level IV (case series-no, or historical control group). See the Guidelines for Authors for a complete description of levels of evidence.
Monoglyceride Lipase Deficiency in Mice Impairs Lipolysis and Attenuates Diet-induced Insulin Resistance*

Monoglyceride lipase (MGL) influences energy metabolism by at least two mechanisms. First, it hydrolyzes monoacylglycerols (MG) into fatty acids and glycerol. These products can be used for energy production or synthetic reactions. Second, MGL degrades 2-arachidonoyl glycerol (2-AG), the most abundant endogenous ligand of cannabinoid receptors (CBR). Activation of CBR affects energy homeostasis by central orexigenic stimuli, by promoting lipid storage, and by reducing energy expenditure. To characterize the metabolic role of MGL in vivo, we generated an MGL-deficient mouse model (MGL-ko). These mice exhibit a reduction in MG hydrolase activity and a concomitant increase in MG levels in adipose tissue, brain, and liver. In adipose tissue, the lack of MGL activity is partially compensated by hormone-sensitive lipase. Nonetheless, fasted MGL-ko mice exhibit reduced plasma glycerol and triacylglycerol, as well as liver triacylglycerol levels indicative for impaired lipolysis. Despite a strong elevation of 2-AG levels, MGL-ko mice exhibit normal food intake, fat mass, and energy expenditure. Yet mice lacking MGL show a pharmacological tolerance to the CBR agonist CP 55,940 suggesting that the elevated 2-AG levels are functionally antagonized by desensitization of CBR. Interestingly, however, MGL-ko mice receiving a high fat diet exhibit significantly improved glucose tolerance and insulin sensitivity in comparison with wild-type controls despite equal weight gain. In conclusion, our observations implicate that MGL deficiency impairs lipolysis and attenuates diet-induced insulin resistance. Defective degradation of 2-AG does not provoke cannabinoid-like effects on feeding behavior, lipid storage, and energy expenditure, which may be explained by desensitization of CBR.
Contiguous spread of Mycobacterium ulcerans in Buruli ulcer lesions analysed by histopathology and real‐time PCR quantification of mycobacterial DNA

The distribution of M. ulcerans in Buruli ulcer lesions was analysed by IS2404 real‐time PCR quantification of M. ulcerans DNA and by semi‐quantitative microscopic assessment of the number of acid‐fast bacilli (AFB). Mycobacterial burden was compared with histopathological changes. Focal distribution of tissue destruction extending into areas with high and low mycobacterial burden was a feature in all lesions analysed. Even where most of the mycobacteria were washed out of ulcerative lesions, peaks of mycobacterial DNA and AFB in the necrotic base of the ulcers still marked the position of the primary infection focus. Significant amounts of mycobacterial DNA and microcolonies were also present in samples from more peripheral regions and occasionally in excised margins of macroscopically and histologically healthy‐appearing excised tissue margins. Additional peaks of mycobacterial DNA clearly marked sites where satellite lesions were developing. Even when granulomas provided evidence for the development of cell‐mediated immunity, development of satellite lesions by contiguous spreading was not completely prevented. Areas free of mycobacterial DNA were found between primary and secondary infection foci and around scarring tissue of healing lesions. These results demonstrate that IS2404 real‐time PCR analysis is a better tool than the less sensitive and only semi‐quantitative microscopic enumeration of AFB for studying the dynamics of M. ulcerans infection in situ. Copyright © 2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Current Concepts in Intrauterine Growth Restriction

Regulation of fetal growth is multifactorial and complex. Diverse factors, including intrinsic fetal conditions as well as maternal and environmental factors, can lead to intrauterine growth restriction (IUGR). The interaction of these factors governs the partitioning of nutrients and rate of fetal cellular proliferation and maturation. Although IUGR is probably a physiologic adaptive response to various stimuli, it is associated with distinct short- and long-term morbidities. Immediate morbidities include those associated with prematurity and inadequate nutrient reserve, while childhood morbidities relate to impaired maturation and disrupted organ development. Potential long-term effects of IUGR are debated and explained by the fetal programming hypothesis. In formulating a comprehensive approach to the management and follow-up of the growth-restricted fetus and infant, physicians should take into consideration the etiology, timing, and severity of IUGR. In addition, they should be cognizant of the immediate perinatal response of the growth-restricted infant as well as the childhood and long-term associated morbidities. A multi disciplinary approach is imperative, including early recognition and obstetrical management of IUGR, assessment of the growth-restricted newborn in the delivery room, possible monitoring in the neonatal intensive care unit, and appropriate pediatric follow-up. Future research is necessary to establish effective preventive, diagnostic, and therapeutic strategies for IUGR, perhaps affecting the health of future generations.
Psychological characteristics of individuals high and low in their ability to cope with tinnitus.

&NA; Seventy‐seven individuals with tinnitus were assessed with a variety of standardized psychological tests and scales assessing subjective loudness, annoyance, and ability to cope with the tinnitus. Significant correlations were found between coping ability and psychological test scores. Based on their responses on the coping scale, subjects were classified as “high copers” (N = 45) or “low copers” (N = 32). For comparison purposes, the two tinnitus groups were also compared to a group of chronic pain (headache) patients (N = 34) and to a group of nonheadache/non‐tinnitus controls (N = 65). Results revealed the low coping tinnitus subjects to be significantly more psychologically distressed than the high copers. Of interest, the low copers were very similar in their psychological profiles to the chronic pain patients, while the high copers were similar to the non‐patient control subjects. Implications of these results are discussed.
The Walking Environment in Lima, Peru and Pedestrian–Motor Vehicle Collisions: An Exploratory Analysis

Objective: Pedestrians comprise 78% of the road fatalities in Peru. The objective of this study was to explore the relationship between the walking environment and pedestrian–motor vehicle collisions. Methods: A matched case-control study was used to detect the odds of a pedestrian–motor vehicle collision at a pedestrian crossing location. Data were collected from 11 sampled police commissaries in Lima, Peru. Results: In a multivariable model adjusting for vehicle and pedestrian flow, pedestrian collisions were less likely in the presence of a curb and sidewalk on both roadway sides (odds ratio [OR] = 0.19, 95% confidence interval [CI], 0.11–0.33) or a pedestrian barricade (OR = 0.11, 95% CI, 0.01–0.81). There was a greater risk of collisions for each street vendor present (OR = 2.82, 95% CI, 1.59–5.00) or whether any parked vehicles (OR = 3.67, 95% CI, 1.18–11.4) were present. Conclusions: Improving or addressing these potentially modifiable features of the walking environment could improve pedestrian safety in Lima and in similar urban settings in low- and middle-income countries.
How narrowly should anti-poverty programs be targeted? Simulation evidence from Bolivia and Indonesia

A key question in the design of anti-poverty programs is to what extent they should be targeted. Empirical evaluations of targeted transfer schemes and simulation exercises often point to further gains that can be had from targeted transfers vis-a-vis universal transfers or from more narrow targeting. Theoretical work, on the other hand, has identified hidden costs associated with targeting - including politico-economic constraints on budgets - but these are frequently ignored in empirical work. In this paper we first argue that common targeting measures can be interpreted as preferences that attach specific weights to true and false positive rates. Based on data from Bolivia and Indonesia, we show that targeting based on an imperfect poverty classifier based on proxy means tests results in very distinct 'optimal' beneficiary shares when these measures are used as a decision criterion. Implications from poverty simulations are sensitive to assumptions about the political economy relationship between the beneficiary share and the available budget. In fact, in many situations, optimizing targeting measures will be misleading when the actual goal is to maximize the effect on poverty.