Miracle-dz/UniFAR-FTUs huggingface dataset:
A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells

Multiple myeloma (MM) is the paradigmatic proteasome inhibitor (PI) responsive cancer, but many patients fail to respond. An attractive target to enhance sensitivity is (macro)autophagy, recently found essential to bone marrow plasma cells, the normal counterpart of MM. Here, integrating proteomics with hypothesis-driven strategies, we identified the autophagic cargo receptor and adapter protein, SQSTM1/p62 as an essential component of an autophagic reserve that not only synergizes with the proteasome to maintain proteostasis, but also mediates a plastic adaptive response to PIs, and faithfully reports on inherent PI sensitivity. Lentiviral engineering revealed that SQSTM1 is essential for MM cell survival and affords specific PI protection. Under basal conditions, SQSTM1-dependent autophagy alleviates the degradative burden on the proteasome by constitutively disposing of substantial amounts of ubiquitinated proteins. Indeed, its inhibition or stimulation greatly sensitized to, or protected from, PI-induced protein aggregation and cell death. Moreover, under proteasome stress, myeloma cells selectively enhanced SQSTM1 de novo expression and reset its vast endogenous interactome, diverting SQSTM1 from signaling partners to maximize its association with ubiquitinated proteins. Saturation of such autophagic reserve, as indicated by intracellular accumulation of undigested SQSTM1-positive aggregates, specifically discriminated patient-derived myelomas inherently susceptible to PIs from primarily resistant ones. These aggregates correlated with accumulation of the endoplasmic reticulum, which comparative proteomics identified as the main cell compartment targeted by autophagy in MM. Altogether, the data integrate autophagy into our previously established proteasome load-versus-capacity model, and reveal SQSTM1 aggregation as a faithful marker of defective proteostasis, defining a novel prognostic and therapeutic framework for MM.
The Use of Imagery by Portuguese Soccer Goalkeepers

Abstract The purpose of this investigation was to study the extent to which Portuguese soccer goalkeepers used imagery, and to examine if and how athletes of different ages differed in their use of imagery. Seventy soccer goalkeepers playing in the two major Portuguese soccer leagues completed the translated versions of the Sports Inventory of Mental Strategies, the Imagery Use Questionnaire for Soccer Players, the Sport Imagery Training and the Sport Imagery Questionnaire. The results showed that imagery was most used in competition than in training, preferably in its visual dimension and from an internal perspective. The results also demonstrated that athletes used imagery both for motivational and cognitive purposes, but the motivational function, namely its general-mastery component, was slightly more used and with more vivid images. After competition and when injured, under-21 athletes used imagery significantly less than their older counterparts.
A near-infrared survey of Miras and the distance to the Galactic Centre

We report the results of a near-infrared survey for long-period variables in a field of view of 20 arcmin by 30 arcmin towards the Galactic Centre (GC). We have detected 1364 variables, of which 348 are identified with those reported in Glass et al. (2001). We present a catalogue and photometric measurements for the detected variables and discuss their nature. We also establish a method for the simultaneous estimation of distances and extinctions using the period-luminosity relations for the JHKs bands. Our method is applicable to Miras with periods in the range 100--350 d and mean magnitudes available in two or more filter bands. While J-band means are often unavailable for our objects because of the large extinction, we estimated distances and extinctions for 143 Miras whose H- and Ks-band mean magnitudes are obtained. We find that most are located at the same distance to within our accuracy. Assuming that the barycentre of these Miras corresponds to the GC, we estimate its distance modulus to be 14.58+-0.02(stat.)+-0.11(syst.) mag, corresponding to 8.24+-0.08(stat.)+-0.42(syst.) kpc. We have assumed the distance modulus to the LMC to be 18.45 mag, and the uncertainty in this quantity is included in the systematic error above. We also discuss the large and highly variable extinction. Its value ranges from 1.5 mag to larger than 4 mag in A(Ks) except towards the thicker dark nebulae and it varies in a complicated way with the line of sight. We have identified mid-infrared counterparts in the Spitzer/IRAC catalogue of Ramirez et al. (2008) for most of our variables and find that they follow rather narrow period-luminosity relations in the 3.6 to 8.0 micrometre wavelength range.
Lisans Eğitim Programlarının Finansal Okuryazarlık Düzeyine Etkisinin Araştırılması: Türkiye Örneği

Bu calismada lisans egitim program iceriklerinin finansal okuryazarliga etkisi arastirilmistir. Finansal Okuryazarligin egitim programlari ile kazanilabilen yasamsal bir yetenek olmasi calismanin temel varsayimidir. Finansal Kavramlari ve Teknikleri tanima imkâni daha yuksek egitim alan Iktisadi ve Idari Bilimler Fakultesi ogrencilerine karsilik, sayisal analizlerin egitim iceriginde daha buyuk yer aldigi Muhendislik Fakultesi ogrencilerinin finansal okuryazarliklari karsilastirilmistir. 2014 yilinda toplanan verilerle finansal krizin etkilerinin halen devam etmekte oldugu bir donemde, universite ogrencilerinin finansal okuryazarlik duzeyi ayrintili bicimde incelenmistir. Veri, gelismekte olan ulkeler grubunda yer alan Turkiye’den toplanmistir. Turkiye’de son donemde yasanan gelismeler, universite ogrencilerini finansal kararlar almak ve risk yonetimi icin daha da sorumlu hale getirmistir. Bu nedenle bu grubun finansal okuryazarlik duzeyi ile ilgili olarak yapilan calismalarin sonuclari onem kazanmistir. Universite ogrencilerinin finansal okuryazarlik duzeyleri, OECD tarafindan gelistirilen finansal okuryazarlik olcegi kullanilarak belirlenmistir. Calismada universite ogrencilerinin %31,7’ sinin YUKSEK, %30,1’ inin ORTA, %16 sinin ise DUŞUK finansal okuryazarliga sahip oldugu belirlenmistir. Universite Ogrencilerinin egitim alanlari (sayisal: muhendislik fakultesi ve sozel: iktisadi ve idari bilimler fakultesi) ile finansal okuryazarlik duzeyleri arasinda da anlamli iliski tespit edilmistir.
Cycles and the Qualitative Evolution of Chemical Systems

Cycles are abundant in most kinds of networks, especially in biological ones. Here, we investigate their role in the evolution of a chemical reaction system from one self-sustaining composition of molecular species to another and their influence on the stability of these compositions. While it is accepted that, from a topological standpoint, they enhance network robustness, the consequence of cycles to the dynamics are not well understood. In a former study, we developed a necessary criterion for the existence of a fixed point, which is purely based on topological properties of the network. The structures of interest we identified were a generalization of closed autocatalytic sets, called chemical organizations. Here, we show that the existence of these chemical organizations and therefore steady states is linked to the existence of cycles. Importantly, we provide a criterion for a qualitative transition, namely a transition from one self-sustaining set of molecular species to another via the introduction of a cycle. Because results purely based on topology do not yield sufficient conditions for dynamic properties, e.g. stability, other tools must be employed, such as analysis via ordinary differential equations. Hence, we study a special case, namely a particular type of reflexive autocatalytic network. Applications for this can be found in nature, and we give a detailed account of the mitotic spindle assembly and spindle position checkpoints. From our analysis, we conclude that the positive feedback provided by these networks' cycles ensures the existence of a stable positive fixed point. Additionally, we use a genome-scale network model of the Escherichia coli sugar metabolism to illustrate our findings. In summary, our results suggest that the qualitative evolution of chemical systems requires the addition and elimination of cycles.
Randomized Trial and Pharmacokinetic Study of Pegfilgrastim versus Filgrastim after Dose-Intensive Chemotherapy in Young Adults and Children with Sarcomas

Purpose: To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy. Experimental Design: Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c. , daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, ≤500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor–related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4. Results: Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults. Conclusion: A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE. (Clin Cancer Res 2009;15(23):7361–7)
From machu_picchu to "rafting the urubamba river": anticipating information needs via the entity-query graph

We study the problem of anticipating user search needs, based on their browsing activity. Given the current web page p that a user is visiting we want to recommend a small and diverse set of search queries that are relevant to the content of p, but also non-obvious and serendipitous. We introduce a novel method that is based on the content of the page visited, rather than on past browsing patterns as in previous literature. Our content-based approach can be used even for previously unseen pages. We represent the topics of a page by the set of Wikipedia entities extracted from it. To obtain useful query suggestions for these entities, we exploit a novel graph model that we call EQGraph (Entity-Query Graph), containing entities, queries, and transitions between entities, between queries, as well as from entities to queries. We perform Personalized PageRank computation on such a graph to expand the set of entities extracted from a page into a richer set of entities, and to associate these entities with relevant query suggestions. We develop an efficient implementation to deal with large graph instances and suggest queries from a large and diverse pool. We perform a user study that shows that our method produces relevant and interesting recommendations, and outperforms an alternative method based on reverse IR.
Alteration of the load-response mechanism of the knee joint during hemiparetic gait following stroke analyzed by 3-dimensional kinematic.

PURPOSE The aims of this study were to evaluate the variables found in the alteration of the load-response mechanism on 3-dimensional kinematic analysis of the knee joint during hemiparetic gait following stroke. METHODS We evaluated 66 adult patients (33 men and 33 women), aged 45.4 +/- 8.5 years (mean +/- SD), with a diagnosis of ischemic cerebrovascular accident either right or left hemiparesis and brachial prevalence. All the participants underwent 3-dimensional gait evaluation with a Vicon 370, and the values of the angular kinematics of the knee joint were selected for analysis. RESULTS There were no statistically significant differences (by the Kruskal-Wallis test) between the subjects regarding the following variables: angular knee position at initial contact and time of peak knee flexion in the stance. The clinically relevant characteristics found were: an increase in knee joint flexion during the initial contact and a movement amplitude below that anticipated in this phase of the walking cycle. These should be taken into account when choosing the best treatment, because they are the ones which exhibit the most important alteration in the load-response mechanism in all patients. CONCLUSION There is still no consensus among the different specialists regarding the variations in kinematics during the hemiparetic gait. One of the most frequently discussed joints is the knee--the way the main changes take place during the gait cycle and whether the gait velocity changes the patterns of joint mobility.
A Theory of Socioeconomic Disparities in Health over the Life Cycle

Understanding of the substantial disparity in health between low and high socioeconomic status (SES) groups is hampered by the lack of a sufficiently comprehensive theoretical framework to interpret empirical facts and to predict yet untested relations. We present a life-cycle model that incorporates multiple mechanisms explaining (jointly) a large part of the observed disparities in health by SES. In our model, lifestyle factors, working conditions, retirement, living conditions and curative care are mechanisms through which SES, health and mortality are related. Our model predicts a widening and possibly a subsequent narrowing with age of the gradient in health by SES.
Cognitive dimensions of notations

classificatory schemes need to be justified in concrete terms. The dimensions concept can be justified by pointing to areas where progress is slow, as I have done above; or by criticising existing systems; or by raising design issues in relation to present growth areas. Let’s take the last, and look at OOPS. Object-oriented systems have been praised as resolving some cognitive problems (Rosson & Alpert 1988), at least in principle. I take no issue with that, but are they adequately usable yet? A fundamental claim in this paper is that system = notation + environment. Research papers on OOPS, however, offer a myriad new languages, with different ideas about the semantics of inheritance, etc., but say very little about environments. Here are some questions arising from the preceding discussion, with remarks relating to one OOPS, Smalltalk-80. I shall take the five dimensions I have described in order. 1. Are there hidden dependencies and one-way links in the structure? Smalltalk-80 scores fairly well here; most relationships can be browsed in both directions, although there are times when it would nice to make dependencies more immediately visible without having to search for them, so that they could at as reminders. However, there is little support in searching for ill-specified targets. “I want something that handles a bitmap, what can I find? ” Nor is it easy to find out what kind of object can fill an instance variable slot in a method. 2. If the inheritance hierarchy viscous, or is it easy to reconstruct in a different fashion? The inheritance structure lends to be viscous. For instance, given a class Animal with many sub-classes Trout, Herring, Minnow, etc. inserting a new class Fish between Animal and its subclasses requires many operations (add a new subclass, Fish, to Animal; move Trout to Animal, etc.) Moreover, changing the inheritance hierarchy normally means changing the pattern of class and instance variables in the hierarchy — our new class, Fish, will contain information relevant to all its subclasses, and this information will have to he extracted from its previous position in the hierarchy and brought together under the new heading. 3. Is the generative order adequately decoupled? Not in Smalltalk-80, where inheritance hierarchies must be created top-down. We lack at present any published evidence on how Smalltalk programmers work, but experts have criticised this aspect in precisely the terms I would expect, namely that when designing the inheritance hierarchy the mental order in which steps are generated is not top-down, so that the effect of the environment’s insistence on top-down working is constrictive (Goldstein & Bobrow 1981; LaLonde 1987). LaLonde’s description is that the expert first designs a specific data type, by focussing on a useful set of operations, and then that data type is positioned in a logical hierarchy. 4. Is it role-expressive? Again, not adequately; although the purpose of object-oriented programming is to clarify relations between parts of programs, one finds that relationships between methods are obscure. The only browsers provided operate on
A Prostacyclin-sparing Effect of Indobufen vs. Aspirin

Summary Indobufen ((±)-2-[p-(l-oxo-2-insoindolinyl)-phenyI]-butyric acid, indo) is a drug inhibiting platelet function by a reversible block of the arachidonic acid metabolism at the level of cyclooxygenase. Since tolerability profile of such drugs is mostly linked to extra-platelet cyclooxygenase inhibition, we prospectively evaluated the extent of platelet and extra-platelet cyclooxygenase inhibition by in vivo administration of indo in comparison with ASA. We assessed the effects of the two drugs on the ex vivo generation of TXB2 and 6-keto-PGFlΑ in whole blood, as indices of the production of TXA2 and PGI2 (prostacyclin), respectively, either after spontaneous clotting at 37° C for 1 h (Study 1) or after the addition of 2 Μg/ml collagen (Study 2). Generation of 6-keto-PGFlΑ in whole blood is a mixed index of platelet and extra-platelet cyclooxygenase activity, deriving from both platelet and white blood cell arachidonic acid metabolization. Fifteen patients with ischemic heart disease and baseline serum TXB2 levels > 300 ng/ml were allocated to receiving one single administration of either indobufen 200 mg (n = 6) or aspirin 500 mg (n = 9). Whole blood prostanoid generation was assessed at 0,1,2,4,6, 8,12 and 24 h after drug administration (Study 1). Ten healthy male volunteers were allocated to a double-blind, randomized crossover comparison of indo 200 mg b.i. d. vs. ASA 300 mg/d for 7 days (Study 2). Prostanoid generation and whole blood platelet aggregation were performed before and at the end of each study period (Day 0 and Day 7). At each time-point after single dose administration (Study 1), indobufen caused less % inhibition of whole blood 6-keto-PGFlΑ than of TXB2. At 2 h, TXB2 was reduced to a similar extent after ASA (98 ± 4%) and indo (97 ± 6%) (p = N.S.), while inhibition of 6-keto-PGFla was clearly different (> 98% after ASA, 81 ± 2.5% after indo, p < 0.01). After one week of ASA or indo (Study 2) the maximum extent of whole blood platelet aggregation was similarly inhibited (from 17.2 ± 1.4 ohms to 3.6 ± 1.3 ohms with ASA; from 18.3 ± 1.0 ohms to 1.6 ± 0.7 ohms with indo (p ASA vs. indo = N. S.). Despite equal inhibition of whole blood TX production after collagen (from 49.0 ± 4.3 ng/ml to 1.1 ± 0.6 ng/ml with ASA, from 49.8 ± 1.3 ng/ml to 1.4 ± 0.6 ng/ml with indo), again, however, 6-keto-PGFlΑ production was less affected by indo than by ASA (from 409 ± 30 pg/ml to 37 ± 13 pg/ml with ASA, inhibition = 91%; from 396 ± 35 to 318 ± 40 with indo, inhibition = 20%). These differential effects of indo and ASA might lead to a better platelet selectivity, tolerability and benefit/risk profile of indo vs. ASA, which are worthy of further assessment.
Structural change and change advocacy: a study in becoming a software engineering organization

Most organizations desire higher-quality, lower-cost IS projects. To achieve this goal, many organizations are moving to formal project management and software engineering practices. Two tools that are used to formalize processes and practices are structured development and maintenance methodologies (SDMM), and the Software Engineering Institute's Capability Maturity Model (SEI CMM). While SDMMs and the CMM are excellent tools to instill project discipline in IS organizations, they are not silver bullets. A great deal of cultural and structural change must first occur. Other changes include reward systems, online shared services and knowledge reuse. This longitudinal study examines one 500-person IS organization over a four-year time period. The results of this study confirm previous literature on change advocacy, and yield rich insight into how to change a typical ad-hoc IS organization into a software engineering organization.
Glutathione Depletion in PC12 Results in Selective Inhibition of Mitochondrial Complex I Activity

Oxidative stress appears to play an important role in degeneration of dopaminergic neurons of the substantia nigra (SN) associated with Parkinson's disease (PD). The SN of early PD patients have dramatically decreased levels of the thiol tripeptide glutathione (GSH). GSH plays multiple roles in the nervous system both as an antioxidant and a redox modulator. We have generated dopaminergic PC12 cell lines in which levels of GSH can be inducibly down-regulated via doxycycline induction of antisense messages against both the heavy and light subunits of γ-glutamyl-cysteine synthetase, the rate-limiting enzyme in glutathione synthesis. Down-regulation of glutamyl-cysteine synthetase results in reduction in mitochondrial GSH levels, increased oxidative stress, and decreased mitochondrial function. Interestingly, decreases in mitochondrial activities in GSH-depleted PC12 cells appears to be because of a selective inhibition of complex I activity as a result of thiol oxidation. These results suggest that the early observed GSH losses in the SN may be directly responsible for the noted decreases in complex I activity and the subsequent mitochondrial dysfunction, which ultimately leads to dopaminergic cell death associated with PD.