Miracle-dz/UniFAR-FTUs huggingface dataset:
Identification of Intracellular Domains in the Growth Hormone Receptor Involved in Signal Transduction

Abstract The growth hormone (GH) receptor belongs to the GH/prolactin/cytokine super-family of receptors. The signal transduction mechanism utilized by this class of receptors remains largely unknown. In order to identify functional domains in the intracellular region of the GH receptor we generated a number of GH receptor mutants and analyzed their function after transfection into various cell lines. A truncated GH receptor missing 184 amino acids at the C-terminus was unable to mediate GH effects on transcription of the Spi 2.1 and insulin genes. However, this mutant was fully active in mediating GH-stimulated metabolic effects such as protein synthesis and lipolysis. Furthermore, this mutant GH receptor internalized rapidly following GH binding. Another truncated GH receptor lacking all but five amino acids of the cytoplasmic domain could not mediate any effects of GH nor did it internalize. Deletion of the prolinerich region or changing the four prolines to alanines also resulted in a GH receptor deficient in signaling. Mutation of phenylalanine 346 to alanine resulted in a GH receptor which did not internalize rapidly; however, this mutant GH receptor was capable of mediating GH-stimulated transcription as well as metabolic effects. These results indicate that the intracellular part of the GH receptor can be divided into at least three functional domains: (i) for transcriptional activity, two domains are involved, one located in the C-terminal 184 amino acids and the other in the prolinerich domain; (ii) for metabolic effects, a domain located in or near the proline-rich region is of importance; and (iii) for internalization, phenylalanine 346 is necessary.
Mental Disorders, Comorbidity, and Postrunaway Arrests Among Homeless and Runaway Adolescents

This study examined the associations between lifetime mental disorder, comorbidity, and self-reported postrunaway arrests among 428 (187 males, 241 females) homeless and runaway youth. The analysis examined the pattern of arrests across five lifetime mental disorders (alcohol abuse, drug abuse, conduct disorder, major depressive episode, and posttraumatic stress disorder). The adolescents, ranging from 16 to 19 years old, were interviewed directly on the streets and in shelters in four Midwestern states using computer-assisted personal interviewing. Extensive self-reports of early life history, behaviors since running away from home, and diagnostic interviewing (UM-CIDI and DISC-R) were used to estimate possible disorders. There was a high level of postrunaway arrests reported by the youth; more than half were arrested at least once after the initial runaway, with the average of 4.4 times. Consistent with the hypotheses, there were differential associations between individual mental disorders and involvement with the criminal justice system. Only externalizing disorders such as substance abuse and conduct disorder were related to arrest. Street youth with multiple externalizing and internalizing disorders were more likely to be arrested than nondisordered youths.
Leptonic CP violation studies at MiniBooNE in the (3+2) sterile neutrino oscillation hypothesis

We investigate the extent to which leptonic CP-violation in (3+2) sterile neutrino models leads to different oscillation probabilities for {nu}{sub {mu}}{yields}{nu}{sub e} and {nu}{sub {mu}}{yields}{nu}{sub e} oscillations at MiniBooNE. We are using a combined analysis of short-baseline (SBL) oscillation results, including the LSND and null SBL results, to which we impose additional constraints from atmospheric oscillation data. We obtain the favored regions in MiniBooNE oscillation probability space for both (3+2) CP-conserving and (3+2) CP-violating models. We further investigate the allowed CP-violation phase values and the MiniBooNE reach for such a CP violation measurement. The analysis shows that the oscillation probabilities in MiniBooNE neutrino and antineutrino running modes can differ significantly, with the latter possibly being as much as 3 times larger than the first. In addition, we also show that all possible values of the single CP-violation phase measurable at short baselines in (3+2) models are allowed within 99% CL by existing data.
Seasonality Affects the Diversity and Composition of Bacterioplankton Communities in Dongjiang River, a Drinking Water Source of Hong Kong

Water quality ranks the most vital criterion for rivers serving as drinking water sources, which periodically changes over seasons. Such fluctuation is believed associated with the state shifts of bacterial community within. To date, seasonality effects on bacterioplankton community patterns in large rivers serving as drinking water sources however, are still poorly understood. Here we investigated the intra-annual bacterial community structure in the Dongjiang River, a drinking water source of Hong Kong, using high-throughput pyrosequencing in concert with geochemical property measurements during dry, and wet seasons. Our results showed that Proteobacteria, Actinobacteria, and Bacteroidetes were the dominant phyla of bacterioplankton communities, which varied in composition, and distribution from dry to wet seasons, and exhibited profound seasonal changes. Actinobacteria, Bacteroidetes, and Cyanobacteria seemed to be more associated with seasonality that the relative abundances of Actinobacteria, and Bacteroidetes were significantly higher in the dry season than those in the wet season (p < 0.01), while the relative abundance of Cyanobacteria was about 10-fold higher in the wet season than in the dry season. Temperature and NO3--N concentration represented key contributing factors to the observed seasonal variations. These findings help understand the roles of various bacterioplankton and their interactions with the biogeochemical processes in the river ecosystem.
Dental Amalgam and Psychosocial Status: The New England Children’s Amalgam Trial

High-dose exposures to elemental mercury vapor cause emotional dysfunction, but it is uncertain whether the levels of exposure that result from having dental amalgam restorations do so. As part of the New England Children’s Amalgam Trial, a randomized trial involving 6- to 10-year-old children, we evaluated the hypothesis that restoration of caries using dental amalgam resulted in worse psychosocial outcomes than restoration using mercury-free composite resin. The primary outcome was the parent-completed Child Behavior Checklist. The secondary outcome was children’s self-reports using the Behavior Assessment System for Children. Children’s psychosocial status was evaluated in relation to three indices of mercury exposure: treatment assignment, surface-years of amalgam, and urinary mercury excretion. All significant associations favored the amalgam group. No evidence was found that exposure to mercury from dental amalgams was associated with adverse psychosocial outcomes over the five-year period following initial placement of amalgams.
Nutrient balancing in grasshoppers: behavioural and physiological correlates of dietary breadth

SUMMARY We examined correlates of nutrient balancing with dietary range by comparing diet selection and ingestive, post-ingestive and performance-related responses to macronutrient imbalance in two species of grasshopper. One of the two species, Locusta migratoria (the African migratory locust), is a specialist grass-feeder, while the other, Schistocerca gregaria (the desert locust), is a generalist herbivore that includes both grasses and forbs in its diet. In ad libitum conditions, both species composed a balanced intake of the two macronutrients protein and carbohydrate from nutritionally complementary synthetic foods, but the composition of the selected diet differed, with the generalist selecting more protein, but not carbohydrate, than the grass-specialist. The grass-specialist, by contrast, retained ingested nitrogen more efficiently on the ad libitum diets. When confined to nutritionally imbalanced foods, both species regulated ingestion in such a way as to mitigate excesses as well as deficits of the two nutrients. The responses were, however, distinct in the two species, with the generalist feeder ingesting greater excesses of protein than the specialist. The species also differed in their post-ingestive responses to ingested excesses of nutrient, with the generalist but not the specialist using protein-derived carbon as an energy source when fed carbohydrate-deficient foods. The generalist also retained a higher level of body protein when confined to protein-deficient diets. The data suggested one functional reason why the generalist species selected a diet with higher protein content in the ad libitum treatment because, when confined to the nutritionally imbalanced foods, development rate peaked on higher protein foods for the generalist compared with the specialist. Many aspects of these data agree with the prediction that generalist-feeding animals should show greater behavioural and physiological flexibility in their responses to nutrient imbalance than do specialists.
A Reliable Screening Procedure for Coeliac Disease in Clinical Practice

Background: The main autoantigen recognized by the sera of patients with coeliac disease (CD) is tissue transglutaminase (tTG). A human-recombinant form of tTG was used to develop an ELISA to measure anti-tTG serum antibodies for the diagnosis of CD. Preliminary retrospective reports suggest that the human tTG-based ELISA could identify coeliac patients missed by the IgA-anti-endomysium antibody test (AEA). Whether the human recombinant tTG ELISA is sufficiently accurate to become the main diagnostic CD tool in everyday clinical practice is unknown. The objective was to determine, in a prospective study, the sensitivity and specificity of an ELISA test based on the use of human tTG compared with AEA, to analyse the discordant cases for HLA DQ2-8 and for clinical and intestinal biopsy characteristics. Methods: 1106 patients referred to a gastrointestinal outpatient clinic for symptoms attributable to CD, 52 first-degree relatives of CD patients and 200 healthy controls were tested for both anti-human tTG and AEA antibodies. Results: Out of 1158 subjects, 146 were tested positive for anti-tTG antibodies and 140 were biopsy-proven coeliacs. The AEA test identified 126/1158 coeliacs who also tested positive for anti-tTG antibodies. The 14 patients missed by the AEA test carried the typical HLA-DQ for CD; they had normal levels of total serum IgA and had milder pathology than those with both anti-tTG and AEA positivity ( P < 0001). Conclusions: These results prove that human tTG-based ELISA is an excellent diagnostic tool for CD, for mass screening by both the specialist and the general clinic.
Crystal structure of the GINS complex and functional insights into its role in DNA replication

The GINS complex, which contains the four subunits Sld5, Psf1, Psf2, and Psf3, is essential for both the initiation and progression of DNA replication in eukaryotes. GINS associates with the MCM2-7 complex and Cdc45 to activate the eukaryotic minichromosome maintenance helicase. It also appears to interact with and stimulate the polymerase activities of DNA polymerase ε and the DNA polymerase α-primase complex. To further understand the functional role of GINS, we determined the crystal structure of the full-length human GINS heterotetramer. Each of the four subunits has a major domain composed of an α-helical bundle-like structure. With the exception of Psf1, each of the other subunits has a small domain containing a three-stranded β-sheet core. Each full-length protein in the crystal has unstructured regions that are all located on the surface of GINS and are probably involved in its interaction with other replication factors. The four subunits contact each other mainly through α-helices to form a ring-like tetramer with a central pore. This pore is partially plugged by a 16-residue peptide from the Psf3 N terminus, which is unique to some eukaryotic Psf3 proteins and is not required for tetramer formation. Removal of these N-terminal 16 residues of Psf3 from the GINS tetramer increases the opening of the pore by 80%, suggesting a mechanism by which accessibility to the pore may be regulated. The structural data presented here indicate that the GINS tetramer is a highly stable complex with multiple flexible surface regions.
SOST Is a Ligand for LRP5/LRP6 and a Wnt Signaling Inhibitor*

Sclerosteosis is an autosomal recessive disease that is characterized by overgrowth of bone tissue and is linked to mutations in the gene encoding the secreted protein SOST. Sclerosteosis shares remarkable similarities with “high bone mass” diseases caused by “gain-of-function” mutations in the LRP5 gene, which encodes a coreceptor for Wnt signaling proteins. We show here that SOST antagonizes Wnt signaling in Xenopus embryos and mammalian cells by binding to the extracellular domain of the Wnt coreceptors LRP5 and LRP6 and disrupting Wnt-induced Frizzled-LRP complex formation. Our findings suggest that SOST is an antagonist for Wnt signaling and that the loss of SOST function likely leads to the hyperactivation of Wnt signaling that underlies bone overgrowth seen in sclerosteosis patients.
E2F1, a Novel Regulator of Metabolism

In the past years, several lines of evidence have shown that cell cycle regulatory proteins also can modulate metabolic processes. The transcription factor E2F1 is a central player involved in cell cycle progression, DNA-damage response, and apoptosis. Its crucial role in the control of cell fate has been extensively studied and reviewed before; however, here, we focus on the participation of E2F1 in the regulation of metabolism. We summarize recent findings about the cell cycle-independent roles of E2F1 in various tissues that contribute to global metabolic homeostasis and highlight that E2F1 activity is increased during obesity. Finally, coming back to the pivotal role of E2F1 in cancer development, we discuss how E2F1 links cell cycle progression with different metabolic adaptations required for cell growth and survival.
Influence of institutional pressures on performance measurement systems

Purpose Grounded in DiMaggio and Powell’s (1983) institutional isomorphism perspective of institutional theory, the purpose of this study is to examine the influence of institutional pressures on the performance measurement system (PMS) within banks and financial institutions. Design/methodology/approach A survey was used to collect data from 71 banks and financial institutions operating in Australia. Findings Four institutional pressures, the normative pressure “corporate change” and the coercive pressures “economic and financial legislation”, “socio-economic political pressures” and “banking regulations” were found to be associated with the use of multi-dimensional performance measures. In addition, the coercive pressure “economic and financial legislation” and the normative pressure “corporate change” were associated with the use of financial, internal and learning and growth performance measures. Finally, the use of internal and learning and growth measures was positively associated with the coercive force “socioeconomic-political pressures”, and the use of financial measures was associated with the coercive pressure “banking regulations”. Research limitations/implications Given the recent global financial crisis, the study offers a reference within the contemporary performance measurement literature in relation to the influence of institutional pressures on the PMS within banks and financial institutions. Originality/value While prior research has focused on manufacturing organisations, this study deepens our understanding of the institutional environment of banks and financial institutions and how specific coercive, mimetic and normative forces influence the PMS.
Influence of anti-TNF-alpha infliximab therapy on adhesion molecules associated with atherogenesis in patients with rheumatoid arthritis.

OBJECTIVE Chronic systemic inflammation plays a pivotal role in the development of atherosclerosis in rheumatoid arthritis (RA). Soluble (s) adhesion molecules were found significantly increased in RA patients with active disease. Since increased levels of some adhesion molecules were closely linked to the development of endothelial dysfunction and atherosclerosis and administration of anti-TNF-alpha-infliximab resulted in a rapid and dramatic improvement of endothelial function in long-term infliximab treated RA patients, we assessed whether infusion of the chimeric anti-TNF-alpha infliximab might also yield a rapid and favorable effect on serum levels of soluble adhesion molecules in RA patients periodically treated with this drug because of severe disease. METHODS We recruited patients with RA refractory to conventional therapy seen over a period of 2 months at Hospital Xeral-Calde, Lugo, Spain, who were on periodical treatment with infliximab for at least 14 weeks. Blood samples for determination of sICAM-1, sICAM-3, sVCAM-1, sE-selectin, and sP-selectin levels by ELISA were taken immediately before and after infliximab infusion. RESULTS Thirty-four RA patients (25 women; mean age: 55.4 years; mean DAS28: 4.27) fulfilled the inclusion criteria. Following infliximab infusion a reduction of the overall mean values of the five adhesion molecules was observed. However, when a Wilcoxon signed-rank test was used, only significant differences for sICAM-3 and sP-selectin were observed. In this regard, sICAM-3 and sP-selectin levels fell in 26 (77%) and 28 (82%) of the 34 patients. CONCLUSION Our study confirms a rapid and beneficial effect of infliximab infusion on expression of some adhesion molecules in RA patients treated periodically with this anti-TNF-alpha monoclonal antibody because of severe disease.
A review of proximal inputs to the near response

Maddox proposed that the perceived nearness of a target could influence the ocular vergence response. Proximal inputs have been used to refer to all static and dynamic cues to depth other than disparity and blur. In this paper, we review a number of studies in which proximal influences have been assessed. While general agreement exists that proximal contributions are significant when blur and disparity cues are absent (open‐loop conditions), there are conflicting reports on the role of proximal vergence and accommodation under closed‐loop conditions.
Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers.

CONTEXT Genetic alterations in receptor tyrosine kinases (RTKs) and phosphatidylinositol 3-kinase (PI3K)/Akt and MAPK pathways have not been fully defined in anaplastic and follicular thyroid cancers [anaplastic thyroid cancer (ATC), follicular thyroid cancer (FTC)]. OBJECTIVE The objective of the study was to explore a wide-range genetic basis for the involvement of these pathways in ATC. DESIGN We examined mutations and copy number gains of a large panel of genes in these pathways and corresponding phosphorylation of ERK (p-ERK) and Akt. RESULTS We found frequent copy gains of RTK genes, including EGFR, PDGFRalpha and -beta, VEGFR1 and 2, KIT, and MET and in PIK3Ca, PIK3Cb, and PDK1 genes in the PI3K/Akt pathway. Mutations of Ras, PIK3Ca, PTEN, and BRAF genes and RET/PTC rearrangements were common, whereas mutations in PDK1, Akt1, Akt2, and RTK genes were uncommon in ATC. Overall, 46 of 48 ATC (95.8%) harbored at least one genetic alteration, and coexistence of two or more was seen in 37 of 48 ATC (77.1%). These genetic alterations were somewhat less common in FTC. Genetic alterations that could activate both the PI3K/Akt and MAPK pathways were found in 39 of 48 ATC (81.3%). RTK gene copy gains were preferentially associated with p-Akt, suggesting their dominant role in activating the PI3K/Akt pathway. The phosphorylation of Akt was far more common than p-ERK in FTC, and both were relatively common and often coexisted in ATC. CONCLUSIONS Genetic alterations in the RTKs and PI3K/Akt and MAPK pathways are extremely prevalent in ATC and FTC, providing a strong genetic basis for an extensive role of these signaling pathways and the development of therapies targeting these pathways for ATC and FTC, particularly the former.
Target Specificities of DrosophilaEnhancer of split Basic Helix-Loop-Helix Proteins

ABSTRACT Seven Enhancer of split genes in Drosophila melanogaster encode basic-helix-loop-helix transcription factors which are components of the Notch signalling pathway. They are expressed in response to Notch activation and mediate some effects of the pathway by regulating the expression of target genes. Here we have determined that the optimal DNA binding site for the Enhancer of split proteins is a palindromic 12-bp sequence, 5′-TGGCACGTG(C/T)(C/T)A-3′, which contains an E-box core (CACGTG). This site is recognized by all of the individual Enhancer of split basic helix-loop-helix proteins, consistent with their ability to regulate similar target genes in vivo. We demonstrate that the 3 bp flanking the E-box core are intrinsic to DNA recognition by these proteins and that the Enhancer of split and proneural proteins can compete for binding on specific DNA sequences. Furthermore, the regulation conferred on a reporter gene in Drosophila by three closely related sequences demonstrates that even subtle sequence changes within an E box or flanking bases have dramatic consequences on the overall repertoire of proteins that can bind in vivo.
Oxaliplatin-induced hepatocellular injury and ototoxicity: A review of the literature and report of unusual side effects of a commonly used chemotherapeutic agent

After extensive literature review utilizing PubMed and Medline searches, we present a rare case of oxaliplatin-induced grade 3/4 hepatocellular injury and ototoxicity. The patient is a 46-year-old female diagnosed with stage IIIC (pT3N2bM0) adenocarcinoma of the sigmoid colon. PET/CT prior to surgery and chemotherapy was negative for distant metastatic disease and baseline liver-associated enzymes were within normal limits. Following sigmoidectomy, patient began adjuvant chemotherapy with 5-florouracil, leucovorin, and oxaliplatin (mFOLFOX-6). Cycle 1 was complicated only by refractory nausea. However, cycle 2 was complicated by vertigo with refractory nausea, tinnitus, and marked elevation in liver enzymes in a hepatocellular pattern. Extensive workup was negative and the etiology of her symptoms and grade 3/4 hepatocellular injury was hypothesized to be the result of oxaliplatin. Aspartate aminotransferase and alanine aminotransferase decreased after two additional weeks off therapy and during cycle 3 in which oxaliplatin was held. She had no evidence of 5-florouracil toxicity. On cycle 4, oxaliplatin was restarted at 50% dose; symptoms and liver-associated enzymes remained stable. However, oxaliplatin was increased up to 75% full dose for cycle 5 with reported vertigo, tinnitus, nausea, and return of elevation in liver-associated enzymes. Oxaliplatin is a chemotherapy agent widely used in the treatment of many malignancies including colon cancer. Side effects include peripheral neuropathy, gastrointestinal toxicity, neutropenia, grade 1/2 hepatocellular injury, and hepatic vascular lesions. However, grade 3/4 hepatocellular injury and ototoxicity are extremely rare with the administration of oxaliplatin. Therefore, we present the unusual chemotherapy side effects.