Miracle-dz/UniFAR-FTUs huggingface dataset:
New Insights into the Function of M4 Muscarinic Acetylcholine Receptors Gained Using a Novel Allosteric Modulator and a DREADD (Designer Receptor Exclusively Activated by a Designer Drug)

The M4 muscarinic acetylcholine (ACh) receptor (mAChR) is a potential therapeutic target but characterized by a lack of subtype-selective ligands. We recently generated “designer receptors exclusively activated by a designer drug” (DREADDs), which contained mutations of two conserved orthosteric-site residues (Y113C/A203G in the M4 mAChR) that caused a loss of ACh activity but a gain in responsiveness to clozapine-N-oxide (CNO). The current study characterized the interactions of the wild type and the M4 DREADD with a range of agonists, antagonists, and the recently discovered M4 mAChR allosteric potentiator, 3-amino-5-chloro-6-methoxy-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (LY2033298). LY2033298 displayed positive binding cooperativity with ACh, neutral cooperativity with the antagonist, [3H]quinuclidinyl benzilate, and agonism for activation of phosphorylated extracellular signal-regulated kinase (ERK) 1/2 at the wild-type M4 mAChR. LY2033298's cooperativity with clozapine or CNO was weakly positive with respect to binding but profoundly negative with respect to LY2033298 signaling. Although the DREADD mutations increased the binding and function of clozapine-like compounds, all other agonists lost the ability to activate the mutant; for the orthosteric agonists ACh and pilocarpine, this was due partly to a reduced affinity, whereas the affinity of LY2033298 or the atypical agonist 4-I-[3-chlorophenyl]carbamoyloxy)-2-butynyltrimethylammnonium chloride was unaltered. The interaction between LY2033298 and clozapine-like compounds reverted to neutral cooperativity on the DREADD, whereas LY2033298 caused a striking functional rescue of ACh potency and efficacy at the DREADD. These results provide conclusive evidence for the retention of a functional allosteric site on the M4 DREADD and highlight a role for residues Tyr113 and Ala203 in the transmission of cooperativity.
Iron deficiency anaemia in older people: investigation, management and treatment.

Anaemia is the commonest haematological abnormality in the older population. It should never be considered as a normal physiological response to ageing [1]. The overall prevalence of anaemia in older people in the UK is 20.1% in elderly men and 13.7% in elderly women [2]. The causes of anaemia are diverse: the anaemia of chronic disease is probably the commonest in old age [3]. However, iron deficiency anaemia is also common and merits investigation and treatment [1]. In one study, almost a quarter of patients admitted to an acute elderly care ward were found to be anaemic with anaemia of chronic disease (35%) and iron deficiency anaemia (15%) being the commonest causes [4]. The World Health Organisation (WHO) criteria for diagnosing anaemia are a haemoglobin (Hb) level of less than 13 g/dl in men and 12g/dl in women [5]. There is considerable variation regarding this lower cut-off value between studies (Hb-10–11.5 g/dl for women and Hb -12.5–13.8 g/dl for men): perhaps the lower limit of the reference range of haemoglobin concentration for the laboratory performing the test should be used to define anaemia [6]. With advancing age there is a progressive and apparently physiological decrement of marrow haematopoiesis [7]. However, in older patients with haemoglobin levels of less than 12 g/dl or a haematocrit below 36% there can be an underlying cause for the anaemia [8]. In one study, anaemia—as defined by the WHO criteria—was associated with an increased mortality in people aged 85 years and older [9]. In the United States, iron deficiency anaemia occurs in up to 4% of elderly patients [10]. Similarly in the UK 3.5–5.3% of older people admitted in the hospital have iron deficiency anaemia [11]. Iron deficiency typically presents with a microcytic anaemia. Microcytosis is not specific for iron deficiency but may be found in chronic inflammation, sideroblastic anaemia and thalassaemia, and may not be present in combined deficiency with vitamin B12 or folate.
A Cooperative ARQ for Delay-Tolerant Vehicular Networks

This paper proposes a Cooperative ARQ protocol to be used in delay-tolerant vehicular networks. The proposed scheme has been implemented and evaluated through an experimental testbed, showing that packet losses in transmissions from an access point to cars can be reduced to the half without any cost as long as cooperation takes place on areas where connectivity with access points is not present. In these areas, cars in a platoon recover from other cars packets that they have failed to receive from the access point.
Changes in Wind Speed under Heat Waves Enhance Urban Heat Islands in the Beijing Metropolitan Area

The interaction between urban heat islands (UHIs) and heat waves (HWs) is studied using measurements collected at two towers in the Beijing, China, metropolitan area and an analytical model. Measurements show that 1) the positive interaction between UHIs and HWs not only exists at the surface but also persists to higher levels (up to ~70 m) and 2) the urban wind speed is enhanced by HWs during daytime but reduced during nighttime as compared with its rural counterpart. A steady-state advection–diffusion model coupled to the surface energy balance equation is then employed to understand the implication of changes in wind speed on UHIs, which reveals that the observed changes in wind speed positively contribute to the interaction between UHIs and HWs in both daytime and nighttime. The vertical structure of the positive interaction between UHIs and HWs is thus likely an outcome resulting from a combination of changes in the surface energy balance and wind profile.
Role of radiosurgery in craniopharyngiomas: a preliminary report.

PURPOSE The purpose of this retrospective review is to evaluate our experience using radiosurgery in the management of craniopharyngiomas. MATERIALS AND METHODS Fourteen patients, 6 males and 8 females, ages ranging from 3 to 44 years of age, were treated with radiosurgery from February 1994 through December 2000 for primary or recurrent craniopharyngioma. There were two adults and 12 children. All patients were treated with the Leksell Gamma units Model U or C. The mean minimum dose was 14 Gy ranging from 11 to 20 Gy and the mean maximum dose was 29 Gy ranging from 24 to 40 Gy. Volume of treatment ranged from 0.1 to 26.5 cm(3). The dose to critical structures was below 8 Gy to the optic chiasm and below 14 Gy to the brain stem. One of the 14 patients had previous conventional radiation therapy. RESULTS All patients are alive and with out evidence of recurrent disease 6-86 months after treatment. Only two patients required retreatment. CONCLUSIONS Although craniopharyngioma is a benign tumor, its location makes even advanced microsurgical techniques difficult to perform. Radiosurgery obviates the shortcomings of surgical resection near the hypothalamic-pituitary axis without the morbidity of open surgery.
A Dollar from 15 Cents: Cross-Platform Management for Internet Services

As Internet services become ubiquitous, the selection and management of diverse server platforms now affects the bottom line of almost every firm in every industry. Ideally, such cross-platform management would yield high performance at low cost, but in practice, the performance consequences of such decisions are often hard to predict. In this paper, we present an approach to guide cross-platform management for real-world Internet services. Our approach is driven by a novel performance model that predicts application-level performance across changes in platform parameters, such as processor cache sizes, processor speeds, etc., and can be calibrated with data commonly available in today's production environments. Our model is structured as a composition of several empirically observed, parsimonious sub-models. These sub-models have few free parameters and can be calibrated with lightweight passive observations on a current production platform. We demonstrate the usefulness of our cross-platform model in two management problems. First, our model provides accurate performance predictions when selecting the next generation of processors to enter a server farm. Second, our model can guide platform-aware load balancing across heterogeneous server farms.
Deep Free-Form Deformation Network for Object-Mask Registration

This paper addresses the problem of object-mask registration, which aligns a shape mask to a target object instance. Prior work typically formulate the problem as an object segmentation task with mask prior, which is challenging to solve. In this work, we take a transformation based approach that predicts a 2D non-rigid spatial transform and warps the shape mask onto the target object. In particular, we propose a deep spatial transformer network that learns free-form deformations (FFDs) to non-rigidly warp the shape mask based on a multi-level dual mask feature pooling strategy. The FFD transforms are based on B-splines and parameterized by the offsets of predefined control points, which are differentiable. Therefore, we are able to train the entire network in an end-to-end manner based on L2 matching loss. We evaluate our FFD network on a challenging object-mask alignment task, which aims to refine a set of object segment proposals, and our approach achieves the state-of-the-art performance on the Cityscapes, the PASCAL VOC and the MSCOCO datasets.
Comparison of Naive Bayes smoothing methods for Twitter sentiment analysis

In sentiment analysis, the absence of sample features in the training data will lead to misclassification. Smoothing is used to overcome this problem. Previous studies show that there are differences in performance obtained by the various smoothing techniques against various types of data. In this paper, we compare the performance of Naive Bayes smoothing methods in improving the performance of sentiment analysis of tweets. The results indicated that Laplace smoothing is superior to Dirichlet smoothing and Absolute Discounting with the micro-average value of F1-Score 0.7234 and macro-average F1-Score 0.7182.
Journal of Graph Algorithms and Applications Embedding, Clustering and Coloring for Dynamic Maps 78 Hu Et Al. Embedding, Clustering and Coloring for Dynamic Maps

We describe a practical approach for visualizing multiple relationships defined on the same dataset using a geographic map metaphor, where clusters of nodes form countries and neighboring countries correspond to nearby clusters. Our aim is to provide a visualization that allows us to compare two or more such maps (showing an evolving dynamic process, or obtained using different relationships). In the case where we are considering multiple relationships, e.g., different similarity metrics, we also provide an interactive tool to visually explore the effect of combining two or more such relationships. Our method ensures good readability and mental map preservation, based on dynamic node placement with node stability , dynamic clustering with cluster stability, and dynamic coloring with color stability. A preliminary version of this paper appeared in the 5th IEEE PacificVis Symposium (2012). The current expanded version applies the proposed technique to new application domains (e.g., TV landscape that evolves over time), including a purely geographic one (clustering of regions in the US based on social interaction metrics).
A randomized placebo-controlled trial of methotrexate in psoriatic arthritis

Objective. MTX is widely used to treat synovitis in PsA without supporting trial evidence. The aim of our study was to test the value of MTX in the first large randomized placebo-controlled trial (RCT) in PsA. Methods. A 6-month double-blind RCT compared MTX (15 mg/week) with placebo in active PsA. The primary outcome was PsA response criteria (PsARC). Other outcomes included ACR20, DAS-28 and their individual components. Missing data were imputed using multiple imputation methods. Treatments were compared using logistic regression analysis (adjusted for age, sex, disease duration and, where appropriate, individual baseline scores). Results. Four hundred and sixty-two patients were screened and 221 recruited. One hundred and nine patients received MTX and 112 received placebo. Forty-four patients were lost to follow-up (21 MTX, 23 placebo). Twenty-six patients discontinued treatment (14 MTX, 12 placebo). Comparing MTX with placebo in all randomized patients at 6 months showed no significant effect on PsARC [odds ratio (OR) 1.77, 95% CI 0.97, 3.23], ACR20 (OR 2.00, 95% CI 0.65, 6.22) or DAS-28 (OR 1.70, 95% CI 0.90, 3.17). There were also no significant treatment effects on tender and swollen joint counts, ESR, CRP, HAQ and pain. The only benefits of MTX were reductions in patient and assessor global scores and skin scores at 6 months (P = 0.03, P < 0.001 and P = 0.02, respectively). There were no unexpected adverse events. Conclusions. This trial of active PsA found no evidence for MTX improving synovitis and consequently raises questions about its classification as a disease-modifying drug in PsA. Trial registration. Current Controlled Trials, www.controlled-trials.com, ISRCTN:54376151.
Expression, mutagenesis and kinetic analysis of recombinant K1E endosialidase to define the site of proteolytic processing and requirements for catalysis

Catalytically active, recombinant fusion proteins of bacteriophage E endosialidase were expressed and purified from Escherichia coli. Constructs with different fusion partners added to the amino terminus of the endosialidase were enzymatically active. A post‐translational proteolytic cleavage was shown to occur between serine 706 and aspartate 707 to generate the 76 kDa mature enzyme from the 90 kDa translation product. Endosialidase truncated at the C‐terminus from aspartate 707 was observed to have the same 76 kDa molecular weight as wild‐type enzyme using denaturing SDS–PAGE but, under native PAGE conditions, was not observed to form the ≈250 kDa trimeric wild‐type enzyme, implying that the C‐terminus of the enzyme may be required for correct assembly of active trimer, rather than as part of the active site as has been previously suggested. Mutagenesis of aspartate 138 to alanine greatly reduced enzyme activity whereas conversion of other selected aspartate residues to alanine had less effect, consistent with similarities between the structure and cata‐lytic mechanism of bacteriophage E endosialidase and those of exosialidases.
THE RELATIONSHIP BETWEEN INSTITUTIONS, BANKING REGULATION AND BANKING DEVELOPMENT IN THE MENA REGION

The purpose of the paper is to check, on the one hand, the nature of the relationship existing between institutional development (measured by the corruption level, quality of bureaucracy, rule and law, law enforcement…), banking regulation and banking development. On the other hand, we test the relationship that exists between banking development and economic growth. We used the GMM (General Method of Moments) system on dynamic panel data for 19 countries of the MENA region, in the 2 estimations (Algeria, Bahrain, Egypt, Iran, Israel, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, Sudan, Syria, Tunisia, Turkey, United Arab Emirates, Yemen). The main results are: (i) the existence of a positive and statistically significant effect of the economic development on the banking development, (ii) banking regulation affects positively and in a significant manner, the banking development, (iii) the non existence of a significant statistically relationship between institutional quality and banking development, (iv) and finally, our findings also suggest that economic growth is enhanced by banking development. The absence of a significant relationship between institutional environment quality and banking development can be explained by the nature of the institutional indicators, which vary very slowly through time. That’s why, may be, banking development level reached by MENA region countries, cannot be explained by institutional development. We have chosen to assimilate the financial development to just banking development, given the relative importance of the banking sector, in comparison to the size and importance of the financial markets in these countries.
Collaborative Care Management of Major Depression Among Low-Income, Predominantly Hispanic Subjects With Diabetes

OBJECTIVE To determine whether evidence-based socioculturally adapted collaborative depression care improves receipt of depression care and depression and diabetes outcomes in low-income Hispanic subjects. RESEARCH DESIGN AND METHODS This was a randomized controlled trial of 387 diabetic patients (96.5% Hispanic) with clinically significant depression recruited from two public safety-net clinics from August 2005 to July 2007 and followed over 18 months. Intervention (INT group) included problem-solving therapy and/or antidepressant medication based on a stepped-care algorithm; first-line treatment choice; telephone treatment response, adherence, and relapse prevention follow-up over 12 months; plus systems navigation assistance. Enhanced usual care (EUC group) included standard clinic care plus patient receipt of depression educational pamphlets and a community resource list. RESULTS INT patients had significantly greater depression improvement (≥50% reduction in Symptom Checklist-20 depression score from baseline; 57, 62, and 62% vs. the EUC group's 36, 42, and 44% at 6, 12, and 18 months, respectively; odds ratio 2.46–2.57; P < 0.001). Mixed-effects linear regression models showed a significant study group–by–time interaction over 18 months in diabetes symptoms; anxiety; Medical Outcomes Study Short-Form Health Survey (SF-12) emotional, physical, and pain-related functioning; Sheehan disability; financial situation; and number of social stressors (P = 0.04 for disability and SF-12 physical functioning, P < 0.001 for all others) but no study group–by–time interaction in A1C, diabetes complications, self-care management, or BMI. CONCLUSIONS Socioculturally adapted collaborative depression care improved depression, functional outcomes, and receipt of depression treatment in predominantly Hispanic patients in safety-net clinics.
Assessing quality experience and learning outcomes: Part II: findings and discussion

Purpose – This paper is the first part of a comprehensive report about a research study that aims to assess the relationship between the university experience and student outcomes as a means of determining a university's success in meeting its educational goals.Design/methodology/approach – It focuses on the research methodology deployed. Underlying the methodology are four research questions that determine the empirical design, the process, the selection, and the adaptation of an appropriate measurement instrument.Findings – While this paper, the first part of a research report, focuses primarily on the research methodology, the second part (to be published as a separate paper) will report on the findings, discussions and implications for assessing universities based on student experiences and learning outcomes.Research limitations/implications – This paper will interrogate the various methods of analysis and identify the limitations that are inherent in the overall design.Practical implications – An alt.
Programming strategies for rapid aiming movements under simple and choice reaction time conditions

Increases in reaction time (RT) as a function of response complexity have been shown to differ between simple and choice RT tasks. Of interest in the present study was whether the influence of response complexity on RT depends on the extent to which movements are programmed in advance of movement initiation versus during execution (i.e., online). The task consisted of manual aiming movements to one or two targets (one- vs. two-element responses) under simple and choice RT conditions. The probe RT technique was employed to assess attention demands during RT and movement execution. Simple RT was greater for the two- than for the single-target responses but choice RT was not influenced by the number of elements. In both RT tasks, reaction times to the probe increased as a function of number of elements when the probe occurred during movement execution. The presence of the probe also caused an increase in aiming errors in the simple but not choice RT task. These findings indicated that online programming was occurring in both RT tasks. In the simple RT task, increased executive control mediated the integration between response elements through the utilization of visual feedback to facilitate the implementation of the second element.
Spatial Distributions of HIV Infection in an Endemic Area of Western Kenya: Guiding Information for Localized HIV Control and Prevention

HIV is still a major health problem in developing countries. Even though high HIV-risk-taking behaviors have been reported in African fishing villages, local distribution patterns of HIV infection in the communities surrounding these villages have not been thoroughly analyzed. The objective of this study was to investigate the geographical distribution patterns of HIV infection in communities surrounding African fishing villages. In 2011, we applied age- and sex-stratified random sampling to collect 1,957 blood samples from 42,617 individuals registered in the Health and Demographic Surveillance System in Mbita, which is located on the shore of Lake Victoria in western Kenya. We used these samples to evaluate existing antibody detection assays for several infectious diseases, including HIV antibody titers. Based on the results of the assays, we evaluated the prevalence of HIV infection according to sex, age, and altitude of participating households. We also used Kulldorff’s spatial scan statistic to test for HIV clustering in the study area. The prevalence of HIV at our study site was 25.3%. Compared with the younger age group (15–19 years), adults aged 30–34 years were 6.71 times more likely to be HIV-positive, and the estimated HIV-positive population among women was 1.43 times larger than among men. Kulldorff’s spatial scan statistic detected one marginally significant (P = 0.055) HIV-positive and one significant HIV-negative cluster (P = 0.047) in the study area. These results suggest a homogeneous HIV distribution in the communities surrounding fishing villages. In addition to individual behavior, more complex and diverse factors related to the social and cultural environment can contribute to a homogeneous distribution pattern of HIV infection outside of African fishing villages. To reduce rates of transmission in HIV-endemic areas, HIV prevention and control programs optimized for the local environment need to be developed.
Ultrastructure of the cell envelope of the archaebacteria Thermoproteus tenax and Thermoproteus neutrophilus

The ultrastructures of the regular surface layers (S-layers) of the extremely thermophilic archaebacteria Thermoproteus tenax and Thermoproteus neutrophilus were examined by freeze-etching, freeze-drying, and negative staining methods combined with optical and digital image enhancement. In both strains, a monolayer of macromolecules arranged in hexagonal arrays with center-to-center spacings of approximately 30 nm was the only component of the cell wall. The gross morphologies of the S-layer lattices of the two organisms were similar and showed the same handedness in the arrangement of the protomers of the morphological units. Striking differences were found in the anionic charge distributions on the surfaces of the two S-layer proteins as determined by labeling with polycationic ferritin. Analysis of the lattice orientation, together with the number and distribution of lattice faults on intact cells, provided a strong indication that the S-layers of both organisms have a shape-determining function.