Miracle-dz/UniFAR-FTUs huggingface dataset:
Adaptive-Threshold Region Merging via Path Scanning

Region merging algorithms commonly produce results that are seen to be far below the current commonly accepted state-of-the-art image segmentation techniques. The main challenging problem is the selection of an appropriate and computationally efficient method to control resolution and region homogeneity. In this paper we present a region merging algorithm that includes a semi-greedy criterion and an adaptive threshold to control segmentation resolution. In addition we present a new relative performance indicator that compares algorithm performance across many metrics against the results from human segmentation. Qualitative (visual) comparison demonstrates that our method produces results that outperform existing leading techniques.
Ligand functional selectivity and quantitative pharmacology at G protein-coupled receptors

Introduction: In recent years, it has become clear that individual GPCRs can elicit multiple G-protein-dependent and -independent cellular responses. This has led to the discovery that certain ligands can differentially modulate these responses, a concept known as functional selectivity. Areas covered: In this review, the authors describe the various manifestations of functional selectivity and its potential implication in drug discovery. The authors provide a historical perspective of the observations and methodologies that led to the evolution of this concept. The authors also describe the proposed molecular mechanisms responsible for the engagement of distinct subsets of signaling repertoire by different ligands. The review offers the reader a synthetic view of how functional selectivity could be used in the design of safer and more effective drugs. Expert opinion: Our better understanding of the various ways by which compounds modulate GPCR activity has led to a parallel expansion of the terminology used to describe these phenomena. The authors propose a standardization of this nomenclature as an essential step to both simplify and clarify the language used among researchers to facilitate future collaboration and discovery of these important therapeutic targets. Such clarification of the various aspects of functional selectivity, coupled with the development of tools for effective monitoring, will undoubtedly bring this emerging concept into the general paradigm of drug discovery at GPCRs.
Institutional work in the birth of a carbon accounting profession

PurposeWithin the emergent professional field of carbon accounting, we analyse the institutional work that gives birth to a nascent profession in a multi-actor arena. We therefore contribute to enhancing our understanding of the birth of professions – in their very first steps and infancy.Design/methodology/approachThis study employs a qualitative approach. We collected data from 1999 to 2015 and conducted 15 semi-structured interviews. One of the researchers was active in the field for two years and participated in carbon accounting events in France as a “participant observer”. FindingsOur research contributes to an understanding of the dynamic professionalization process in which the different actors mobilize both creative work and sabotage work. We further theorize how nascent professions structure their project around knowledge, identity and boundary work. At the same time, we develop the notion of sabotage work, which is comprised of two sub-categories of institutional work: counter-work and the absence of work.Originality/valueTo our knowledge, this is one of the first attempts to analyse the birth of an environmental accounting profession. We emphasize both creative work and sabotage work in the professionalization project. We conclude on further research that could be performed on environmental accounting professions.
Somatic frameshift alterations in mononucleotide repeat‐containing genes in different tumor types from an HNPCC family with germline MSH2 mutation

Hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a germline mutation in one of several DNA repair genes, which in the tumors is reflected as microsatellite instability (MSI). MSI+ tumors have been found to carry somatic frameshift mutations in mononucleotide repeats within the coding regions of several genes involved in growth control, apoptosis, and DNA repair, e.g., TGFBRII, BAX, IGFIIR, TCF4, MSH3, and MSH6. We have studied the occurrence of somatic frameshift alterations in these mononucleotide repeat‐containing genes in 24 tumors (15 colorectal cancers, 1 colon adenoma, 4 endometrial cancers, 1 ovarian cancer, 1 gastric cancer, 1 urothelial cancer, and 1 duodenal cancer) from 14 individuals in an HNPCC family with germline hMSH2 mutation. Such somatic frameshift mutations occurred at a variable frequency; the long mononucleotide repeats that characterize intronic MSI markers were mutated in the majority of tumors, 13 of the tumors displayed alterations in the (A)10 tract of TGFBII, eight tumors (all of gastrointestinal origin) had alterations in the (A)9 repeat of TCF4, and one to five tumors had somatic frameshift alterations in the shorter mononucleotide repeats of IGFIIR, BAX, MSH3, and MSH6. Thus, longer mononucleotide repeats were more frequently affected by somatic frameshift mutations. The pattern of alterations varied between the tumors from different family members as well as between different tumors from the same individual. To what extent this variable pattern depends on the widespread mismatch repair deficiency induced by the underlying MSH2 mutation, or represents alternative ways whereby the tumors can achieve a tumorigenic phenotype, is unknown. We suggest, however, that the accumulation of somatic frameshifts, rather than the specific loci in which these occur, drives the development of the tumorigenic phenotype in HNPCC. Genes Chromosomes Cancer 29:33–39, 2000. © 2000 Wiley‐Liss, Inc.
Circulating microRNA expression profile in B-cell acute lymphoblastic leukemia.

BACKGROUND Acute lymphoblastic leukemia (ALL) is a highly diverse disease characterized by cytogenetic and molecular abnormalities, including altered microRNA (miRNA) expression signatures. AIM We perform and validate a plasma miRNA expression profiling to identify potential miRNA involved in leukemogenesis METHODS MiRNA expression profiling assay was realized in 39 B-ALL and 7 normal control plasma samples using TaqMan Low Density Array (TLDA) plates on Applied Biosystems 7900 HT Fast Real-Time PCR System. MiRNA validation was done for six miRNA differentially expressed by quantitative real-time PCR. RESULTS Seventy-seven circulating miRNA differentially expressed: hsa-miR-511, -222, and -34a were overexpressed, whereas hsa-miR-199a-3p, -223, -221, and -26a were underexpressed (p values < 0.005 for both sets). According to operating characteristic curve analysis, hsa-miR-511 was the most valuable biomarker for distinguishing B-ALL from normal controls, with an area under curve value of 1 and 100% for sensitivity, and specificity respectively. CONCLUSIONS Measuring circulating levels of specific miRNA implicated in regulation of cell differentiation and/or cell proliferation such as hsa-miRNA-511, offers high sensitivity and specificity in B-ALL detection and may be potentially useful for detection of disease progression, as indicator of therapeutic response, and in the assessment of biological and/or therapeutic targets for patients with B-ALL.
S‐Gal®, A novel 1H MRI reporter for β‐galactosidase

Reporter genes and associated enzyme activity are becoming increasingly significant for research in vivo. The lacZ gene and β‐galactosidase (β‐gal) expression have long been exploited as reporters of biologic manipulation at the molecular level, and a noninvasive detection strategy based on proton MRI is particularly attractive. 3,4‐Cyclohexenoesculetin β‐D‐galactopyranoside (S‐Gal®) is a commercial histologic stain, which forms a black precipitate in the presence of β‐gal and ferric ions, suggesting potential detectability by MRI. Generation of the precipitate is now shown to cause strong T2* relaxation, revealing β‐gal activity. A series of tests with the enzyme in vitro and with tumor cells shows that this approach can be used as an assay for β‐gal activity. Proof of principle is shown in human breast tumor xenografts in mice. Upon direct injection of a mixture of 3,4‐cyclohexenoesculetin β‐D‐galactopyranoside and ferric ammonium citrate, intense contrast was observed immediately in MCF7‐lacZ tumors, but not in wild‐type tumors. 3,4‐Cyclohexenoesculetin β‐D‐galactopyranoside activation in combination with ferric ions introduces a novel approach for assaying enzyme activity by MRI in vivo. Magn Reson Med, 2010. © 2010 Wiley‐Liss, Inc.
Structural basis for the specific inhibition of heterotrimeric Gq protein by a small molecule

Heterotrimeric GTP-binding proteins (G proteins) transmit extracellular stimuli perceived by G protein-coupled receptors (GPCRs) to intracellular signaling cascades. Hundreds of GPCRs exist in humans and are the targets of a large percentage of the pharmaceutical drugs used today. Because G proteins are regulated by GPCRs, small molecules that directly modulate G proteins have the potential to become therapeutic agents. However, strategies to develop modulators have been hampered by a lack of structural knowledge of targeting sites for specific modulator binding. Here we present the mechanism of action of the cyclic depsipeptide YM-254890, which is a recently discovered Gq-selective inhibitor. YM-254890 specifically inhibits the GDP/GTP exchange reaction of α subunit of Gq protein (Gαq) by inhibiting the GDP release from Gαq. X-ray crystal structure analysis of the Gαqβγ–YM-254890 complex shows that YM-254890 binds the hydrophobic cleft between two interdomain linkers connecting the GTPase and helical domains of the Gαq. The binding stabilizes an inactive GDP-bound form through direct interactions with switch I and impairs the linker flexibility. Our studies provide a novel targeting site for the development of small molecules that selectively inhibit each Gα subunit and an insight into the molecular mechanism of G protein activation.
Exogenous Glutamate Concentration Regulates the Metabolic Fate of Glutamate in Astrocytes

Abstract: The metabolic fate of glutamate in astrocytes has been controversial since several studies reported >80% of glutamate was metabolized to glutamine; however, other studies have shown that half of the glutamate was metabolized via the tricarboxylic acid (TCA) cycle and half converted to glutamine. Studies were initiated to determine the metabolic fate of increasing concentrations of [U‐13C]glutamate in primary cultures of cerebral cortical astrocytes from rat brain. When astrocytes from rat brain were incubated with 0.1 mM [U‐13C]glutamate 85% of the 13C metabolized was converted to glutamine. The formation of [1,2,3‐13C3]glutamate demonstrated metabolism of the labeled glutamate via the TCA cycle. When astrocytes were incubated with 0.2–0.5 mM glutamate, 13C from glutamate was also incorporated into intracellular aspartate and into lactate that was released into the media. The amount of [13C]lactate was essentially unchanged within the range of 0.2–0.5 mM glutamate, whereas the amount of [13C]aspartate continued to increase in parallel with the increase in glutamate concentration. The amount of glutamate metabolized via the TCA cycle progressively increased from 15.3 to 42.7% as the extracellular glutamate concentration increased from 0.1 to 0.5 mM, suggesting that the concentration of glutamate is a major factor determining the metabolic fate of glutamate in astrocytes. Previous studies using glutamate concentrations from 0.01 to 0.5 mM and astrocytes from both rat and mouse brain are consistent with these findings.
Classical and emergent cardiovascular disease risk factors in type 2 diabetics from the Vallecas area (DICARIVA study).

BACKGROUND Type 2 diabetes mellitus (T2DM) is a major independent risk factor for cardiovascular disease (CVD) and a highly prevalent disease with a wide variety of associated metabolic disorders. OBJECTIVES To describe features and prevalence of altered CVD risk factors in a T2DM population: DIabetes CArdiovascular RIsk of VAllecas (DICARIVA) study. PATIENTS AND METHODS 735 adult Spanish patients of the Vallecas area with T2DM from the Infanta Leonor Hospital (Madrid, Spain) were included in the study. Age, disease time-evolution, anthropometric measurements, glycemia, glucated haemoglobin A1c (HbA1c), lipid/lipoprotein profile, total cholesterol/high density lipoprotein cholesterol (HDL-cholesterol), low density lipoprotein cholesterol (LDL-cholesterol)/HDL-cholesterol and triglycerides/HDL-cholesterol ratios, triglycerides-glucose index (TyG), fibrinogen, high sensitivity-c reactive protein (hs-CRP) and microalbuminuria were assessed. RESULTS Mean, standard deviations, and percentile distributions were obtained in males, females and the whole T2DM population for classical and emergent CVD risk markers. Obesity was found in 45% of patients, while 60% had high cardiovascular risk according to waist circumference and conicity index. Total and LDL-cholesterol were at desirable and optimum levels, respectively, in 60% of patients. One third showed the conjoint presence of low HDL-cholesterol, high triglycerides and small and dense LDL. Increased levels of hs-CRP, hyperfibrinogenia and microalbuminuria were detected in 40%, 50% and 30% of patients, respectively. Age, body mass index, total cholesterol, hs-CRP and fibrinogen were higher while weight, conicity index, total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol and triglycerides/HDL-cholesterol ratios, and microalbuminuria lower in women. According to TyG values 62% of patients suffered metabolic syndrome. CONCLUSIONS Altered anthropometric and metabolic CVD risk factors were highly prevalent in the DICARIVA study. The CVD marker cut-off points obtained in some emergent markers seems relevant and would be employed for future early T2DM diagnoses strategy in order to reduce its high morbidity and mortality impact.
Functional evaluation of peripheral nerve regeneration and target reinnervation in animal models: a critical overview

Peripheral nerve injuries usually lead to severe loss of motor, sensory and autonomic functions in the patients. Due to the complex requirements for adequate axonal regeneration, functional recovery is often poorly achieved. Experimental models are useful to investigate the mechanisms related to axonal regeneration and tissue reinnervation, and to test new therapeutic strategies to improve functional recovery. Therefore, objective and reliable evaluation methods should be applied for the assessment of regeneration and function restitution after nerve injury in animal models. This review gives an overview of the most useful methods to assess nerve regeneration, target reinnervation and recovery of complex sensory and motor functions, their values and limitations. The selection of methods has to be adequate to the main objective of the research study, either enhancement of axonal regeneration, improving regeneration and reinnervation of target organs by different types of nerve fibres, or increasing recovery of complex sensory and motor functions. It is generally recommended to use more than one functional method for each purpose, and also to perform morphological studies of the injured nerve and the reinnervated targets.
Designing passive MRI-safe implantable conducting leads with electrodes.

PURPOSE The presence of implanted electronic devices with conducting leads and electrodes are contraindicated for magnetic resonance imaging (MRI), denying many patients its potential benefits. The prime concern is MRI's radio frequency (RF) fields, which can cause elevated local specific absorption rates (SARs) and potential heat injury. The purpose of this article is to develop and compare a range of passive implantable "MRI-safe" lead designs. METHODS Conducting leads incorporating different lengths (3-75 cm), insulation thicknesses (0-105 microm), resistances (100-3000 omega), coiled conductors (inner diameter < or = 1.2 mm), high-impedance (135-2700 omega) RF traps, and single-coiled and triple-coiled coaxial-wound "billabong" leads with reversed coil sections that oppose and reduce the induced current, are investigated both experimentally using local temperature measurements, and by numerical full-wave electromagnetic field analysis of the local SAR, in three different-sized bioanalogous model saline-gel phantoms at 1.5 T MRI and 4 W/kg exposure. RESULTS In all designs, the maximum computed 1 g average SAR and experimental temperature rise occur at the bare electrodes. Electrode heating increases with lead insulation thickness and peaks for uncoiled leads 25-50 cm long. A reasonable match between computed SAR and the point SAR estimated from thermal sensors obtained by approximating the computation volume to that of the thermal probes. Factors that maximize the impedance of leads with resistive, coiled, RF trap and billabong elements can effectively limit heating below 1-2 degrees, but folded lead configurations can be a concern. The RF trap and billabong designs can both support multiple conductors and electrodes, with billabong prototype leads also heating <1 degrees C when tested for 3 T MRI. CONCLUSIONS Lead insulation and length strongly affect implanted lead safety to RF exposure during MRI. Lead designs employing impedance and reversed winding sections offer hope for the development of passive, MRI-safe, implantable conducting leads for future human use.
Analysis of gadobenate dimeglumine-enhanced MR findings for characterizing small (1-2-cm) hepatic nodules in patients at high risk for hepatocellular carcinoma.

PURPOSE To retrospectively identify magnetic resonance (MR) imaging findings that are associated with hepatocellular carcinoma (HCC) in 1-2-cm nodules detected at surveillance ultrasonography (US) and to propose newer MR imaging diagnostic criteria. MATERIALS AND METHODS Institutional research ethics board approval was obtained, and informed patient consent was waived. Among 145 consecutive patients who had 1-2-cm nodules that were newly detected at surveillance US, 108 patients underwent gadobenate dimeglumine-enhanced MR imaging. After excluding hemangiomas and unconfirmed nodules, the study sample comprised 96 patients with 116 nodules, including 43 HCCs and 73 benign nodules. MR imaging findings were assessed for signal intensity at each sequence. On the basis of the results of univariate and multivariable logistic regression analyses, several diagnostic criteria were developed by using combinations of MR imaging findings, which were then compared with the American Association for the Study of Liver Diseases (AASLD) practice guideline. RESULTS Univariate analysis revealed four imaging findings associated with HCC, including arterial phase hyperintensity, portal or delayed phase hypointensity (washout), hyperintensity on T2-weighted images, and hepatobiliary phase hypointensity (P < .001 for each). In the multivariable analysis, arterial phase hyperintensity (adjusted odds ratio [OR], 17.1; P = .003) and washout (adjusted OR, 11.7; P = .007) were associated with HCC. Of the developed criteria, the criteria including nodules fitting the AASLD practice guideline (arterial phase hyperintensity and washout) or nodules having three or more findings were considered most reasonable, showing improved sensitivity (77% [33 of 43] versus 67% [29 of 43], P = .048) and comparable specificity (95% [69 of 73] versus 99% [72 of 73], P = .09), as compared with AASLD practice guideline. CONCLUSION Alternative MR imaging criteria for diagnosing HCC in 1-2-cm nodules detected at surveillance US that can improve sensitivity compared with the AASLD practice guideline were proposed. A larger study is needed to verify the preliminary criteria in this study. SUPPLEMENTAL MATERIAL http://radiology.rsna. org/lookup/suppl/doi:10.1148/radiol.11101549/-/DC1.
Effects of stimulation of hindlimb flexor group II afferents during fictive locomotion in the cat.

1. This study examines the effects of electrical stimulation of hindlimb flexor nerves on the fictive locomotion pattern. Locomotion was initiated by stimulation of the mesencephalic locomotor region in the decerebrate paralysed cat and monitored by recording the electroneurogram from selected hindlimb flexor and extensor muscle nerves. Flexor nerves were stimulated using short trains (20‐50 stimuli at 100 Hz) during either the flexor or the extensor phase of the fictive locomotor cycle. 2. Stimulation of tibialis anterior (TA), posterior biceps and semitendinosus (PBSt) or sartorius (Sart) nerves at 5 times threshold (T) during the flexor phase of the fictive locomotor cycle terminated on‐going activity in flexor nerves and initiated activity in extensors. Thus, flexor nerve stimulation during flexion shortened the locomotor cycle by resetting to extension. The failure of lower intensity (2T) stimulation of PBSt or Sart nerves to reset the step cycle to extension suggests that group II afferents are responsible for these actions. Resetting evoked by 2T stimulation of the TA nerve may be due to a high proportion of group II afferents with low electrical threshold. 3. During extension, stimulation of TA and PBSt nerves at 5T did not perturb the locomotor rhythm whereas Sart stimulation prolonged the locomotor cycle. 4. Stimulation of cutaneous or knee joint afferents failed to produce effects similar to those evoked by stimulation of flexor muscle nerves at group II strength. These findings are at odds with those obtained elsewhere in the acute spinal, DOPA fictive locomotion preparation. The possibility that group II resetting during fictive locomotion is not mediated by flexion reflex pathways but by previously unknown pathways released in the present preparation is discussed. 5. Since many of the flexor afferents recruited by 5T electrical stimulation are the length‐sensitive group II fibres, spindle secondaries may act to regulate the duration and onset of flexor and extensor activity during real locomotion. The resetting from flexion to extension also suggests that unexpected or enhanced activity of flexor secondaries during swing would promote a switch of the step cycle to stance.
Safety and immunogenicity of nonadjuvanted and MF59-adjuvanted influenza A/H9N2 vaccine preparations.

BACKGROUND Influenza A/H9N2 viruses can infect humans and are considered to be a pandemic threat. Effective vaccines are needed for these and other avian influenza viruses. METHODS We performed a phase I, randomized, double-blind trial to evaluate the safety and immunogenicity of a 2-dose schedule (administered on days 0 and 28) of 4 dose levels (3.75, 7.5, 15, and 30 microg of hemagglutinin) of inactivated influenza A/chicken/Hong Kong/G9/97 (H9N2) vaccine with and without MF59 adjuvant. Vaccine safety was assessed with a diary and selected blood tests. Immunogenicity was measured using serum hemagglutination inhibition (HAI) and microneutralization (MNt) antibody assays. RESULTS. Ninety-six healthy adults (age, 18-34 years) were enrolled in the study. Arm discomfort was more common in groups that received adjuvant, but adverse effects of the vaccination were generally mild. Geometric mean serum HAI and MNt antibody titers to the influenza A/chicken/Hong Kong/G9/97 (H9N2) virus strain for all vaccine groups were similar on day 0 but were significantly higher (P<.001) on both days 28 and 56 for the MF59-adjuvanted vaccine groups than for groups given nonadjuvanted vaccine. Other measures of immunogenicity were also higher in the adjuvanted vaccine groups. HAI and MNt geometric mean titers measured after the administration of a single dose of MF59-adjuvanted vaccine were similar to those measured after 2 doses of nonadjuvanted vaccine. CONCLUSIONS The combination of MF59 adjuvant with a subunit vaccine was associated with improved immune responses to an influenza A/H9N2 virus. The adjuvanted vaccine was immunogenic even after a single dose, raising the possibility that a 1-dose vaccination strategy may be attainable with the use of adjuvanted vaccine.