Miracle-dz/UniFAR-FTUs huggingface dataset:
The neuropilin 2 isoform NRP2b uniquely supports TGFβ-mediated progression in lung cancer

NRP2b connects oncogenic TGFβ to enhanced responsiveness to the promigratory growth factor HGF in non–small cell lung cancer cells. Prometastatic roles for neuropilin 2b Neuropilins are pleiotropic co-receptors for semaphorins and other growth factors, such as TGFβ. In established tumors, TGFβ promotes cell migration and metastasis. Using cell lines, mouse models, and primary patient material, Gemmill et al. found that the roles of the two neuropilin 2 isoforms were distinct in non–small cell lung cancer (NSCLC) cells. Experiments with cultured cells and xenografted tumors with high and low abundance of NRP2a and NRP2b showed that, in contrast to NRP2a, NRP2b inhibited primary tumor growth but mediated TGFβ-induced epithelial-to-mesenchymal transition, cell migration, metastasis, and drug resistance. High amounts of NRP2b in tumors correlated with that of the immunosuppressive ligand PD-L1 and with drug resistance, metastatic disease, and poor prognosis in patients. Selectively targeting this isoform may prevent disease progression and improve drug efficacy in some patients. Neuropilins (NRP1 and NRP2) are co-receptors for heparin-binding growth factors and class 3 semaphorins. Different isoforms of NRP1 and NRP2 are produced by alternative splicing. We found that in non–small cell lung cancer (NSCLC) cell lines, transforming growth factor–β (TGFβ) signaling preferentially increased the abundance of NRP2b. NRP2b and NRP2a differ only in their carboxyl-terminal regions. Although the presence of NRP2b inhibited cultured cell proliferation and primary tumor growth, NRP2b enhanced cellular migration, invasion into Matrigel, and tumorsphere formation in cultured cells in response to TGFβ signaling and promoted metastasis in xenograft mouse models. These effects of overexpressed NRP2b contrast with the effects of overexpressed NRP2a. Hepatocyte growth factor (HGF)–induced phosphorylation of the kinase AKT was specifically promoted by NRP2b, whereas inhibiting the HGF receptor MET attenuated NRP2b-dependent cell migration. Unlike NRP2a, NRP2b did not bind the PDZ domain scaffolding protein GAIP carboxyl terminus–interacting protein (GIPC1) and only weakly recruited phosphatase and tensin homolog (PTEN), potentially explaining the difference between NRP2b-mediated and NRP2a-mediated effects. Analysis of NSCLC patient tumors showed that NRP2b abundance correlated with that of the immune cell checkpoint receptor ligand PD-L1 as well as with epithelial-to-mesenchymal transition (EMT) phenotypes in the tumors, acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, disease progression, and poor survival in patients. NRP2b knockdown attenuated the acquisition of resistance to the EGFR inhibitor gefitinib in cultured NSCLC cells. Thus, in NSCLC, NRP2b contributed to the oncogenic response to TGFβ and correlated with tumor progression in patients.
Identification of Peroxisome Proliferator-responsive Human Genes by Elevated Expression of the Peroxisome Proliferator-activated Receptor α in HepG2 Cells*

In mice and other sensitive species, PPARα mediates the induction of mitochondrial, microsomal, and peroxisomal fatty acid oxidation, peroxisome proliferation, liver enlargement, and tumors by peroxisome proliferators. In order to identify PPARα-responsive human genes, HepG2 cells were engineered to express PPARα at concentrations similar to mouse liver. This resulted in the dramatic induction of mRNAs encoding the mitochondrial HMG-CoA synthase and increases in fatty acyl-CoA synthetase (3–8-fold) and carnitine palmitoyl-CoA transferase IA (2–4-fold) mRNAs that were dependent on PPARα expression and enhanced by exposure to the PPARα agonist Wy14643. A PPAR response element was identified in the proximal promoter of the human HMG-CoA synthase gene that is functional in its native context. These data suggest that humans retain a capacity for PPARα regulation of mitochondrial fatty acid oxidation and ketogenesis. Human liver is refractory to peroxisome proliferation, and increased expression of mRNAs for the peroxisomal fatty acyl-CoA oxidase, bifunctional enzyme, or thiolase, which accompanies peroxisome proliferation in responsive species, was not evident following Wy14643 treatment of cells expressing elevated levels of PPARα. Additionally, no significant differences were seen for the expression of apolipoprotein AI, AII, or CIII; medium chain acyl-CoA dehydrogenase; or stearoyl-CoA desaturase mRNAs.
Injuries in whitewater kayaking

Objective—To provide epidemiological data on whitewater kayaking injuries using a descriptive study. Methods—A retrospective survey was distributed at whitewater events and club meetings, and made available and advertised on the world wide web, through postings and announcements to newsgroups, related sites, and search engines. Data on sex, age, experience, and ability were collected. Injury data collected included mechanism, activity, difficulty of rapid, and self reported severity. Results—Of the 392 kayaking respondents included in the final analysis, 219 suffered 282 distinct injury events. The number of days spent kayaking per season was the only independent predictor of injury. The overwhelming majority of injuries occurred while the kayaker was still in the boat (87%). Striking an object was the most common mechanism of injury (44%), followed by traumatic stress and overuse (25% each). The most common types of injury were abrasion (25%), tendinitis (25%), contusion (22%), and dislocation (17%). The upper extremity, especially the shoulder, was the most commonly injured area of the body. Although half of injured kayakers sought medical care for their injury, and almost one third missed more than one month of kayaking because of the injury, almost all (96%) reported a complete or good recovery. Conclusions—Factors relating to likelihood of injury appear to be connected with exposure, namely the number of days a year that the sport was pursued. Except for class V (extreme) kayakers, reports of injuries paralleled the number of participants. Kayakers reported injuries predominantly on rivers that they assessed to be at a level appropriate to their skills.
Truthful Detection of Selfish Malicious Packet Dropping Nodes in Wireless Ad Hoc Network

: We present a scalable, effective and practical approach for detection of packet-drop attacks in ad hoc networks. In this attack, a malicious network node chooses to selectively drop packets that are supposed to be forwarded, which results in adverse impact on application good-put and network stability. They are responsible for cooperatively shuttling packets amongst themselves in order to provide the illusion of a network with universal point-to-point connectivity. However, this illusion is shattered—as are implicit assumptions of availability, confidentiality, or integrity—when network routers are subverted to act in a malicious fashion. By manipulating, diverting, or dropping packets arriving at a compromised router, an attacker can trivially mount denial-of-service, surveillance, or man-in-the-middle attacks on end host systems. We have tested our protocol in Emulab and have studied its effectiveness in differentiating attacks from legitimate network behavior.
Sport tourism: a framework for research

Sport-based travel has grown dramatically over the past two decades but it has only recently become the focus of concentrated academic inquiry. This paper contributes to the emerging body of literature by conceptualising sport in the context of tourism’s activity, spatial and temporal dimensions. A definition of sport tourism based on these dimensions and featuring a sociological perspective of sporting activity is presented. The distinguishing features of sport as a tourist attraction are then highlighted through the use of Leiper’s systems model of attractions. Finally, the paper proposes a framework which highlights a series of research questions that emerge as the relationships between the fundamental dimensions of sport tourism are systematically explored. Copyright # 2001 John Wiley & Sons, Ltd.
THEMED SECTION: QT SAFETY REVIEW The thorough QT/QTc study 4 years after the implementation of the ICH E14 guidance

The ICH E14 guidance on how to clinically assess a new drug’s liability to prolong the QT interval was adopted in May 2005.A centre-piece of the guidance was the establishment of one single trial, the ‘thorough QT/QTcstudy’, intended to conﬁdentlyidentify drugs that may cause QT prolongation. Initially perceived as a great challenge, this study has rapidly become astandard component of all clinical development programs for new molecular entities. The study is normally conducted inhealthy volunteers, includes both a positive and a negative (placebo) control and is stringently powered to exclude an effecton the QTc interval exceeding 10 ms. The E14 guidance was intentionally not very prescriptive and allowed sponsors andservice providers to explore new methodologies. This has allowed for a rapid development of new methods during the ﬁrstyears after the guidance’s implementation, such as computer-assisted algorithms for QT measurements. Regulators haveworked in close collaboration with pharmaceutical industry to set standards for the design and conduct of the ‘thoroughQT/QTc study’, which therefore has evolved as a key component of cardiac safety assessment of new drugs. This papersummarizes the requirements on the ‘thorough QT/QTc study’ with emphasis on the standard that has evolved based oninteractions between regulators and sponsors and the experience from a large number of completed studies.
A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.
Unifying Program Construction and Modiication 1

We propose a method which integrates program modiication to the reenement calculus style of program development. Given a program developed through stepwise reenement of a speciication, we propose an approach to specify modiications and to derive a new program from the existing reenement steps. This approach is based on the reenement lattice operator meet. A modiication to a speciication is represented by taking the meet of the old speciication and the new feature to add. A solution to the new speciication is constructed by coercing the new feature to match the structure of the existing reenement steps. The method fosters reuse of reenement steps and their proofs. We also show that program construction is streamlined by using coercion.
The effect of technology innovation on mobile communication and mobile products

Purpose In order to understand the influence of technology innovation on market demand diffusion in the ICT service market, the purpose of this paper is to examine technology innovation in the mobile product market, which keeps a complementary relationship with the mobile communication market. Design/methodology/approach This study collected mobile communication user information of four leading countries in the ICT market – the USA, the UK, Korea, and Japan from 1981 to 2014. This study applies the Bass diffusion model to analyze the form of market demand diffusion and conducts white noise test to verify the hypotheses. Findings Technology innovation of mobile communication leads to an increase in innovation effect and a decrease in imitation effect. Thus, technology innovation of mobile communication needs to be promoted continuously for the purpose of increasing adopters in the early stage. Besides, mobile product’s technology innovation leads to an increase in imitation effect and a decrease in innovation effect, because individuals were aware of the usefulness of the products and services. Hence, the increase in the number of imitators caused a higher increase in imitation effect than in the mobile communication’s innovation effect. Originality/value Based on the results of this study, the role that product and service technology innovation plays in renewing the form of market demand diffusion in the ICT service market was defined. Also, since the strategies and plans to acquire competitive advantage of business were understood, it may help both companies and policy decision makers.
Yellow Fever Outbreak, Imatong, Southern Sudan

In May 2003, the World Health Organization received reports about a possible outbreak of a hemorrhagic disease of unknown cause in the Imatong Mountains of southern Sudan. Laboratory investigations were conducted on 28 serum samples collected from patients in the Imatong region. Serum samples from 13 patients were positive for immunoglobulin M antibody to flavivirus, and serum samples from 5 patients were positive by reverse transcription–polymerase chain reaction with both the genus Flavivirus–reactive primers and yellow fever virus–specific primers. Nucleotide sequencing of the amplicons obtained with the genus Flavivirus oligonucleotide primers confirmed yellow fever virus as the etiologic agent. Isolation attempts in newborn mice and Vero cells from the samples yielded virus isolates from five patients. Rapid and accurate laboratory diagnosis enabled an interagency emergency task force to initiate a targeted vaccination campaign to control the outbreak.
Distribution of Blood Flow within the Skin of the Rabbit with Particular Reference to Hair Growth

Previous work using a Kr85 clearance technique demonstrated the existence in rabbit thigh skin of a bimodal distribution of blood flow which was consistent with the presence of two distinct vascular compartments with markedly different flow rates. These observations on the rabbit thigh have been extended to compare flow patterns during the inactive phase of the hair growth cycle and during active hair growth. Resting areas and hair-growing areas of rabbit skin have been examined histologically and the vascular pattern has been demonstrated after perfusion of the vessels with India ink. The results provide an anatomical basis for the two-compartment model derived from analysis of the clearance curves. The mean rate of blood flow for the fast compartment during the inactive phase was 29.7 ml/100 g tissue/min and 4.3 ml/100 g tissue/min for the slow compartment; these did not change significantly with active hair growth. However the relative size of the fast compartment altered markedly with active hair growth, the relative size of the fast compartment increasing from 21 to 67% of the tissue mass. The mean cutaneous blood flow was more than doubled during the active phase. Histological studies demonstrated a marked increase in the size of the follicles during the active phase and a concomitant increase in the extent of the vascular bed around the follicles. This would indicate that the fast compartment represents the follicular tissue and its associated blood supply; its flow rate was a measure of nutrient blood flow to the hair follicle. The flow rate of the slow compartment was then a measure of nutrient blood flow in the rest of the skin. These conclusions were supported by observations in areas of skin with sparse hair growth. The effect of body heating and cooling on cutaneous blood flow distribution was also noted.
protein ArhGAP 44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons

In the vertebrate central nervous system, exploratory filopodia transiently form on dendritic branches to sample the neuronal environment and initiate new trans-neuronal contacts. While much is known about the molecules that control filopodia extension and subsequent maturation into functional synapses, the mechanisms that regulate initiation of these dynamic, actin-rich structures have remained elusive. Here, we find that filopodia initiation is suppressed by recruitment of ArhGAP44 to actin-patches that seed filopodia. Recruitment is mediated by binding of a membrane curvature-sensing ArhGAP44 N-BAR domain to plasma membrane sections that were deformed inward by acto-myosin mediated contractile forces. A GAP domain in ArhGAP44 triggers local Rac-GTP hydrolysis, thus reducing actin polymerization required for filopodia formation. Additionally, ArhGAP44 expression increases during neuronal development, concurrent with a decrease in the rate of filopodia formation. Together, our data reveals a local auto-regulatory mechanism that limits initiation of filopodia via protein recruitment to nanoscale membrane deformations. DOI: 10.7554/eLife.03116. 001
Identification of stress‐inducible proteins in Lactobacillus delbrueckii subsp. bulgaricus

Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus) is a homofermentative bacterium that produces lactic acid during growth. We adapted the two‐dimensional electrophoresis (2‐DE) technique to study the response of this bacterium to acidity. De novo protein synthesis was monitoried by [35S]methionine labeling of exponentially growing cultures under standard (pH 6) and acidic (pH 4.75) conditions. After 2‐DE separation, the protein patterns were compared. The protein spots showing increased radioactivity levels under acid conditions were considered acid‐induced. We determined the N‐terminal amino acid sequence of three highly induced proteins; comparing these proteins to databases we identified them to be the well‐known heat shock proteins GroES, GroEL, and DnaK. Their induction levels were measured and compared. This is the first study by 2‐DE of stress response in L. bulgaricus. We established the method and present a protein map which will be useful for future studies.
Rabbit anti‐thymocyte globulin in liver transplantation: All that glitters is not gold, but 1000 patients are so many to dazzle

Marina Berenguer and Jos e-Antonio Pons Liver Transplantation and Hepatology Unit, La Fe Hospital, Valencia, Spain; Network Center for Biomedical Research in Hepatic and Digestive Diseases, Valencia, Spain; Faculty of Medicine, University of Valencia, Valencia, Spain; Virgen de la Arrixaca Hospital, Murcia, Spain; Network Center for Biomedical Research in Hepatic and Digestive Diseases, Murcia, Spain; and Faculty of Medicine, University of Murcia, Murcia, Spain
International and Development Economics Simple Monetary Growth Model with Variable Rates of Time Preference

This paper constructs a simple optimal monetary growth model in which an endogenous and variable rate of time preference provides a rational foundation for a Tobin-effect in a system where otherwise strong neoclassical assumptions (e.g., perfect foresight, an infinite planning horizon, and continuous marketclearing) are maintained. Changes in the proportional rate of growth of the nominal money supply affect both the rate of time preference (ñ) and the equilibrium capital—labour ratio. The impact effect of a fall in ñ (less impatience), and the induced capital accumulation that goes with it, drives the result. Proper transformation rules for two-state variable control problems and curvature and simulation results for the rate of time preference function are also established. The latter in particular provides a reasonable and easily understood foundation for simple systems in which the rate of time preference depends on an index of future consumption, and provides a counter-argument to well-known criticisms (e.g., Blanchard and Fischer (1989) and Barro and Sali-i-Martin (1995)) of Epstein—Uzawa rate of time preference functions. All results are obtained in an analytically simple way, using standard techniques. Asia Pacific School of Economics and Government THE AUSTRALIAN NATIONAL UNIVERSITY http://apseg.anu.edu.au International and Development Economics Working Paper 01-10 A Simple Monetary Growth Model with Variable Rates of Time Preference Tom Kompas National Centre for Development Studies Australian National University Canberra, ACT Australia 0200 e-mail address: tom.kompas@anu.edu.au Omar Abdel-Razeq Department of Economics An-Najah National University Nablus, Palestine
Pilot-Scale Anaerobic Co-Digestion of the OFMSW: Improving Biogas Production and Startup

This paper presents experimental results regarding anaerobic co-digestion of the organic fraction of municipal solid waste and fruit and vegetable waste in order to establish the efficiency of a 2 m3 volume pilot plant in terms of biogas and methane yield and stability of the process. The research study presents the feasibility of developing anaerobic digestion as an effective method for municipal solid waste management. The experiments were conducted in mesophilic conditions (35 °C). Domestic waste water was used as inoculum. The results showed that the inoculum presence, temperature, and pH control, were essential in order to improve biogas production and its composition. Using liquid inoculum, the CH4 percentage in the biogas oscillated between 44% and 51%, and the biogas production from 0.504 and 0.6 m3/day. Compared to domestic waste water, animal manure increased the CH4 concentration in biogas (up to 63%), while the daily biogas production increased by 26% and varied from 0.693 to 0.786 m3. The cumulative biogas production at the end of the experiments were 11.7 m3 and 15.89 m3, respectively. Using inoculum and co-digestion, the plant startup time was significantly reduced, the total solids content decreased from 22.7% to 19.8%, while the volatile solids decreased from 37.6% to 31.2%.
The effect of financial market development on income distribution in OPEC (2000- 2012)

This paper examines the relations and financ ial market dev elopment on income distribution in OPEC 2000-2012. The intended type in this article is Data Panel. Then, the reliability evaluation of the variables has been prec eded using Lin, Lev in and C hu (LLC ) and Philips-Proun (PP) Test. The experimental results of this study is confirmed the significant and positive relationship the v ariable of income inequality financ ial dev elopment in OPEC and also, square of financial dev elopment is negative. The adequate ev idence is being to confirm the existenc e of Greenwood and Jovanov ic h (1990) inv erted-U-shaped non-linear relationship between financ ial dev elopment and income inequality in these c ountries. Also, human capital has negative effect and inflation has positive effec t on income distribution in the studied c ountries.