Miracle-dz/UniFAR-FTUs huggingface dataset:
Differential regulation of zinc transporter 1, 2, and 4 mRNA expression by dietary zinc in rats.

Zinc metabolism is well regulated over a wide range of dietary intakes to help maintain cellular zinc-dependent functions. Expression of transporter molecules, which influence zinc influx and efflux across the plasma and intracellular membranes, contributes to this regulation. We have examined in rats the comparative response of zinc transporters 1, 2, and 4 (ZnT-1, ZnT-2 and ZnT-4) to dietary zinc. ZnT-1 and ZnT-4 are expressed ubiquitously, whereas ZnT-2 is limited to small intestine, kidney, placenta and, in some cases, the liver. When zinc intake was low (<1 mg Zn/kg), ZnT-2 mRNA was extremely low in small intestine and kidney compared with an adequate intake (30 mg Zn/kg). ZnT-1 and ZnT-2 mRNAs were markedly greater in both tissues when a supplemental zinc intake (180 mg Zn/kg) was provided. ZnT-4 was refractory to changes in zinc intake. When zinc was provided as a single oral dose (70 mg/kg body), ZnT-1 and ZnT-2 mRNA levels were increased many fold in small intestine, liver and kidney, whereas ZnT-4 gene expression was not changed. The expression of ZnT-1 and ZnT-2 is comparable to zinc-induced changes in metallothionein mRNA levels, suggesting a similar mode of regulation for these genes. The relative differential in regulation by zinc is ZnT-2 > ZnT-1 > ZnT-4. These data provide evidence that, in an animal model, zinc transporter expression is responsive to zinc under physiologically relevant conditions.
Basics of a Drug Ontology for Annotations of Clinical Narratives

Although the medication given to a patient during a hospital stay is fundamental for patient safety, quality assessment and economic aspects of health care services, in-patient drug prescriptions are still commonly done on paper in many institutions. In Europe and North America most of the pharmacies are computerized. This does not guarantee, however, that drug prescription information is always available in hospital information systems in a structured way. As long as the only computer-readable sources of medication information are clinical narratives such as dictated or typed discharge or outpatient letters, analysis of drug information depends on natural language processing (NLP). The performance of NLP critically depends on annotated clinical corpora. We are currently developing an annotation schema for mentions of drugs in discharge letters, of which ontological foundations are presented.
Comparison of home and away-from-home physical activity using accelerometers and cellular network-based tracking devices.

BACKGROUND Measuring physical at home and away from home is essential for assessing health and well-being, and could help design interventions to increase physical activity. Here, we describe how physical activity at home and away from home can be quantified by combining information from cellular network-based tracking devices and accelerometers. METHODS Thirty-five working adults wore a cellular network-based tracking device and an accelerometer for 6 consecutive days and logged their travel away from home. Performance of the tracking device was determined using the travel log for reference. Tracking device and accelerometer data were merged to compare physical activity at home and away from home. RESULTS The tracking device detected 98.6% of all away-from-home excursions, accurately measured time away from home and demonstrated few prolonged signal drop-out periods. Most physical activity took place away from home on weekdays, but not on weekends. Subjects were more physically active per unit of time while away from home, particularly on weekends. CONCLUSIONS Cellular network-based tracking devices represent an alternative to global positioning systems for tracking location, and provide information easily integrated with accelerometers to determine where physical activity takes place. Promoting greater time spent away from home may increase physical activity.
Amyloid fibrils from the N-terminal prion protein fragment are infectious

Significance Prion diseases are a group of transmissible neurodegenerative disorders. The protein-only hypothesis asserts that transmission of these diseases does not require nucleic acids and that a misfolded, aggregated form of the prion protein represents a self-perpetuating infectious agent. Even though this model is supported by a large body of experimental data, there is a dispute regarding the role of specific cofactors in prion infectivity as well as the structural basis of prion formation. In this work, we show that structurally well-characterized amyloid fibrils generated from bacterially expressed prion protein fragment 23-144 cause prion disease in transgenic and wild-type mice, demonstrating that cofactors are not obligatory for prion formation and providing insight into the structural basis of prion propagation. Recombinant C-terminally truncated prion protein PrP23-144 (which corresponds to the Y145Stop PrP variant associated with a Gerstmann–Sträussler–Scheinker-like prion disease) spontaneously forms amyloid fibrils with a parallel in-register β-sheet architecture and β-sheet core mapping to residues ∼112–139. Here we report that mice (both tga20 and wild type) inoculated with a murine (moPrP23-144) version of these fibrils develop clinical prion disease with a 100% attack rate. Remarkably, even though fibrils in the inoculum lack the entire C-terminal domain of PrP, brains of clinically sick mice accumulate longer proteinase K-resistant (PrPres) fragments of ∼17–32 kDa, similar to those observed in classical scrapie strains. Shorter, Gerstmann–Sträussler–Scheinker-like PrPres fragments are also present. The evidence that moPrP23-144 amyloid fibrils generated in the absence of any cofactors are bona fide prions provides a strong support for the protein-only hypothesis of prion diseases in its pure form, arguing against the notion that nonproteinaceous cofactors are obligatory structural components of all infectious prions. Furthermore, our finding that a relatively short β-sheet core of PrP23-144 fibrils (residues ∼112–139) with a parallel in-register organization of β-strands is capable of seeding the conversion of full-length prion protein to the infectious form has important implications for the ongoing debate regarding structural aspects of prion protein conversion and molecular architecture of mammalian prions.
Exploitation of Castration-Resistant Prostate Cancer Transcription Factor Dependencies by the Novel BET Inhibitor ABBV-075

Competitive inhibitors of acetyl-lysine binding to the bromodomains of the BET (bromodomain and extra terminal) family are being developed for the treatment of solid and hematologic malignancies. The function of BET family member BRD4 at enhancers/superenhancers has been shown to sustain signal-dependent or pathogenic gene expression programs. Here, the hypothesis was tested that the transcription factor drivers of castration-resistant prostate cancer (CRPC) clinical progression, including the androgen receptor (AR), are critically dependent on BRD4 and thus represent a sensitive solid tumor indication for the BET inhibitor ABBV-075. DHT-stimulated transcription of AR target genes was inhibited by ABBV-075 without significant effect on AR protein expression. Furthermore, ABBV-075 disrupted DHT-stimulated recruitment of BET family member BRD4 to gene-regulatory regions cooccupied by AR, including the well-established PSA and TMPRSS2 enhancers. Persistent BET inhibition disrupted the composition and function of AR-occupied enhancers as measured by a reduction in AR and H3K27Ac ChIP signal and inhibition of enhancer RNA transcription. ABBV-075 displayed potent antiproliferative activity in multiple models of resistance to second-generation antiandrogens and inhibited the activity of the AR splice variant AR-V7 and ligand-binding domain gain-of-function mutations, F877L and L702H. ABBV-075 was also a potent inhibitor of MYC and the TMPRSS2-ETS fusion protein, important parallel transcription factor drivers of CRPC. Implications: The ability of BET family inhibitor ABBV-075 to inhibit transcription activation downstream of the initiating events of transcription factors like AR and TMPRSS2:ETS fusion proteins provides a promising therapeutic option for CRPC patients who have developed resistance to second-generation antiandrogens. Mol Cancer Res; 15(1); 35–44. ©2016 AACR.
Deconstructing trait anxiety: a network perspective

ABSTRACT Background and objectives: For decades, the dominant paradigm in trait anxiety research has regarded the construct as signifying the underlying cause of the thoughts, feelings, and behaviors that supposedly reflect its presence. Recently, a network theory of personality has appeared. According to this perspective, trait anxiety is a formative construct emerging from interactions among its constitutive features (e.g., thought, feelings, behaviors); it is not a latent cause of these features. Design: In this study, we characterized trait anxiety as a network system of interacting elements. Methods: To do so, we estimated a graphical gaussian model via the computation of a regularized partial correlation network in an unselected sample (N = 611). We also implemented modularity-based community detection analysis to test whether the features of trait anxiety cohere as a single network system. Results: We find that trait anxiety can indeed be conceptualized as a single, coherent network system of interacting elements. Conclusions: This radically new approach to visualizing trait anxiety may offer an especially informative view of the interplay between its constitutive features. As prior research has implicated trait anxiety as a risk factor for the development of anxiety-related psychopathology, our findings also set the scene for novel research directions.
Machine vs. Human Translation of SNOMED CT Terms

OBJECTIVE In the context of past and current SNOMED CT translation projects we compare three kinds of SNOMED CT translations from English to German by: (t1) professional medical translators; (t2) a free Web-based machine translation service; (t3) medical students. METHODS 500 SNOMED CT fully specified names from the (English) International release were randomly selected. Based on this, German translations t1, t2, and t3 were generated. A German and an Austrian physician rated the translations for linguistic correctness and content fidelity. RESULTS Kappa for inter-rater reliability was 0.4 for linguistic correctness and 0.23 for content fidelity. Average ratings of linguistic correctness did not differ significantly between human translation scenarios. Content fidelity was rated slightly better for student translators compared to professional translators. Comparing machine to human translation, the linguistic correctness differed about 0.5 scale units in favour of the human translation and about 0.25 regarding content fidelity, equally in favour of the human translation. CONCLUSION The results demonstrate that low-cost translation solutions of medical terms may produce surprisingly good results. Although we would not recommend low-cost translation for producing standardized preferred terms, this approach can be useful for creating additional language-specific entry terms. This may serve several important use cases. We also recommend testing this method to bootstrap a crowdsourcing process, by which term translations are gathered, improved, maintained, and rated by the user community.
The sequential activation of the mitotic microtubule assembly pathways favors bipolar spindle formation

Centrosome maturation is the process by which the duplicated centrosomes recruit pericentriolar components and increase their microtubule nucleation activity before mitosis. The role of this process in cells entering mitosis has been mostly related to the separation of the duplicated centrosomes and thereby to the assembly of a bipolar spindle. However, spindles can form without centrosomes. In fact, all cells, whether they have centrosomes or not, rely on chromatin-driven microtubule assembly to form a spindle. To test whether the sequential activation of these microtubule assembly pathways, defined by centrosome maturation and nuclear envelope breakdown, plays any role in spindle assembly, we combined experiments in tissue culture cells and Xenopus laevis egg extracts with a mathematical model. We found that interfering with the sequential activation of the microtubule assembly pathways compromises bipolar spindle assembly in tissue culture cells but not in X. laevis egg extracts. Our data suggest a novel function for centrosome maturation that determines the contribution of the chromosomal microtubule assembly pathway and favors bipolar spindle formation in most animal cells in which tubulin is in limiting amounts.
Embossed Steel Plate-Concrete Composite Member Subjected to Bending and Shear

Two point loading tests of twenty three simply supported open-sandwich beams which consist of concrete and embossed or plain steel plate with headed studs, were carried out. Two types of embossed plates were used, namely checkered and ribbed types. Ultimate loading capacities and failure modes were examined in relation to the types of steel plates, stud spacing and shear span ratios. Methods to predict the shear bond strength of an open-sandwich beam are discussed.
Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A

The lysosomal storage disease cystinosis, caused by cystinosin deficiency, is characterized by cell malfunction, tissue failure, and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R, which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by up-regulation of the transcription factor EB (TFEB), which was down-regulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB up-regulation corrected lysosome distribution and lysosomal LAMP2A localization in Ctns−/− cells but not Rab11 defects. The up-regulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, whereas dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA up-regulation is a potential clinically relevant mechanism to increase cell survival in cystinosis.
Serum uric acid, protein intake and mortality in hemodialysis patients

Background The association between serum uric acid (SUA) and mortality has been conflicting among studies using hemodialysis (HD) patients. Given the close link between purine and protein in foods, we hypothesized that normalized protein catabolic rate (nPCR), a dietary protein intake surrogate, modifies the SUA-mortality association in the HD population. Methods We identified 4298 patients who initiated HD and had one or more SUA measurement in a contemporary cohort of HD patients over 5 years (1 January 2007-31 December 2011), and examined survival probability according to the first uric acid measurement, adjusting for dialysis vintage, case-mix and malnutrition-inflammation complex-related variables. Results Mean SUA concentration was 6.6 ± 1.8 mg/dL. There was a consistent association of higher SUA with better nutritional status and lower all-cause mortality irrespective of adjusted models (Ptrend < 0.001). In the case-mix adjusted model, the highest SUA category (≥8.0 mg/dL) compared with the reference group (>6.0-7.0 mg/dL) showed no significant mortality risk [hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.72-1.13], while the lowest category (<5.0 mg/dL) was associated with higher mortality (HR 1.42, 95% CI 1.16-1.72). The hypouricemia-mortality association was significantly modified by nPCR (Pinteraction = 0.001). Mortality risk of low SUA (<5.0 mg/dL) persisted among patients with low nPCR (<0.9 g/kg/day; HR 1.73, 95% CI 1.42-2.10) but not with high nPCR (≥0.9 g/kg/day; HR 0.99, 95% CI 0.74-1.33). Conclusions SUA may be a nutritional marker in HD patients. Contrary to the general population, low but not high SUA is associated with higher all-cause mortality in HD patients, especially in those with low protein intake. Nutritional features of SUA warrant additional studies.
Asymmetry of movements in CFTR's two ATP sites during pore opening serves their distinct functions

CFTR, the chloride channel mutated in cystic fibrosis (CF) patients, is opened by ATP binding to two cytosolic nucleotide binding domains (NBDs), but pore-domain mutations may also impair gating. ATP-bound NBDs dimerize occluding two nucleotides at interfacial binding sites; one site hydrolyzes ATP, the other is inactive. The pore opens upon tightening, and closes upon disengagement, of the catalytic site following ATP hydrolysis. Extent, timing, and role of non-catalytic-site movements are unknown. Here we exploit equilibrium gating of a hydrolysis-deficient mutant and apply Φ value analysis to compare timing of opening-associated movements at multiple locations, from the cytoplasmic ATP sites to the extracellular surface. Marked asynchrony of motion in the two ATP sites reveals their distinct roles in channel gating. The results clarify the molecular mechanisms of functional cross-talk between canonical and degenerate ATP sites in asymmetric ABC proteins, and of the gating defects caused by two common CF mutations.
Bone mass is recovered from lactation to postweaning in adolescent mothers with low calcium intakes.

BACKGROUND Adolescent mothers may be at increased risk of irreversible bone loss during pregnancy and lactation, particularly when calcium intake is low. OBJECTIVE Longitudinal changes in bone mass from lactation to postweaning were evaluated in 10 adolescent mothers aged 15-18 y who habitually consumed <500 mg Ca/d. DESIGN Total-body bone mineral content (TBBMC), total-body bone mineral density (TBBMD), and lumbar spine bone mineral density (LSBMD) were measured at lactation (6-24 wk postpartum) and after weaning (12-30 mo postpartum). Serum hormones (intact parathyroid hormone, estradiol, and prolactin), serum calcium, and markers of bone turnover [urinary N-telopeptide cross-linking region of type I collagen (NTx) and plasma activity of bone alkaline phosphatase] were measured at lactation. RESULTS TBBMC, total calcium content, TBBMD, and LSBMD increased from lactation to postweaning (P < 0.01). TBBMD and LSBMD were, respectively, 3.6% and 9.7% lower than predicted at lactation and 0.3% and 4.8% lower than predicted in the postweaning period. The increase in age-matched TBBMD adequacy was correlated with the time after resumption of menses (r = 0.86, P < 0.01). Calcium accretion from lactation to postweaning correlated negatively with estradiol (r = -0.86) and prolactin (r = -0.69) and positively with intact parathyroid hormone (r = 0.72) and NTx (r = 0.84) measured at lactation (P < 0.05). CONCLUSIONS It appears that adolescent mothers with habitually low calcium intakes recover from lactation-associated bone loss after weaning. The rate of bone accretion, however, may not be sufficient to attain peak bone mass at maturity. Hormones regulating bone turnover during lactation may influence bone recovery in adolescent mothers.
Keldysh field theory for driven open quantum systems

Recent experimental developments in diverse areas—ranging from cold atomic gases to light-driven semiconductors to microcavity arrays—move systems into the focus which are located on the interface of quantum optics, many-body physics and statistical mechanics. They share in common that coherent and driven–dissipative quantum dynamics occur on an equal footing, creating genuine non-equilibrium scenarios without immediate counterpart in equilibrium condensed matter physics. This concerns both their non-thermal stationary states and their many-body time evolution. It is a challenge to theory to identify novel instances of universal emergent macroscopic phenomena, which are tied unambiguously and in an observable way to the microscopic drive conditions. In this review, we discuss some recent results in this direction. Moreover, we provide a systematic introduction to the open system Keldysh functional integral approach, which is the proper technical tool to accomplish a merger of quantum optics and many-body physics, and leverages the power of modern quantum field theory to driven open quantum systems.
Detecting Malware Domains at the Upper DNS Hierarchy

In recent years Internet miscreants have been leveraging the DNS to build malicious network infrastructures for malware command and control. In this paper we propose a novel detection system called Kopis for detecting malware-related domain names. Kopis passively monitors DNS traffic at the upper levels of the DNS hierarchy, and is able to accurately detect malware domains by analyzing global DNS query resolution patterns. Compared to previous DNS reputation systems such as Notos [3] and Exposure [4], which rely on monitoring traffic from local recursive DNS servers, Kopis offers a new vantage point and introduces new traffic features specifically chosen to leverage the global visibility obtained by monitoring network traffic at the upper DNS hierarchy. Unlike previous work Kopis enables DNS operators to independently (i.e., without the need of data from other networks) detect malware domains within their authority, so that action can be taken to stop the abuse. Moreover, unlike previous work, Kopis can detect malware domains even when no IP reputation information is available. We developed a proof-of-concept version of Kopis, and experimented with eight months of real-world data. Our experimental results show that Kopis can achieve high detection rates (e.g., 98.4%) and low false positive rates (e.g., 0.3% or 0.5%). In addition Kopis is able to detect new malware domains days or even weeks before they appear in public blacklists and security forums, and allowed us to discover the rise of a previously unknown DDoS botnet based in China.