Miracle-dz/UniFAR-FTUs huggingface dataset:
Rapamycins: Mechanisms of Action and Cellular Resistance

Rapamycins are macrocyclic lactones that possess immunosuppressive, antifungal and antitumor properties. The parent compound, rapamycin, is approved as an immunosuppressive agent for preventing rejection in patients receiving organ transplantation. Two analogues, CCI-779 and RAD001 are currently being investigated as anticancer agents. Rapamycins first bind a cyclophilin FKBP12, and this complex binds and inhibits the function of mTOR (mammalian target of rapamycin) a serine/threonine (Ser/Thr) kinase with homology to phosphatidylinositol 3’ kinase. Currently, as mTOR is the only identified target, this places rapamycins in a unique position of being the most selective kinase inhibitor known. Consequently these agents have been powerful tools in elucidating the role of mTOR in cellular growth, proliferation, survival and tumorigenesis. Increasing evidence suggests that mTOR acts as a central controller sensing cellular environment (nutritional status or mitogenic stimulation) and regulating translation initiation through the eukaryotic initiation factor 4E, and ribosomal p70 S6 kinase pathways. Here we review the conserved TOR signaling pathways, conceptual basis for tumor selectivity, and the mechanisms of resistance to this class of antitumor agent.
An Overview Of SID and TIM

In this series of articles we hope to shed useful light on the high-frequency performace of amplifiers. Modern operational amplifiers and cir­ cuits of similar topology have an inherent Slew Rate (SR) lim­ it, and they will produce dis­ tortion as the output Signal Slope (SS) approaches this lim­ it. We refer to this distortion as Slew Induced Distortion (SID). If an amplifier is driven into slew-rate limiting gross distor­ tion will be produced. This is analogus to driving an amplifier into amplitude clipping, which also produces gross distortion. The distortion pro­ duced by driving an amplifier towards slew-rate limiting has also been described as Transient Intermodulation distortion (TIM) [3,8,9,17,18,51,56], Until recently [33,34] there has not been a thorough study of this distortion. Therefore, this series is intended to be a comprehensive overview and explanation of SID. We will explain how and when SID is produced by an amplifier, and measurement techniques for and typical measurements of this distortion will be described. The results of a listening test for SID will be discussed, and the results of a theoretical calculation of SID in a 741 op amp will be shown and com­ pared with measurements. Some reasonable design criteria will also be reviewed. Above all, we will attempt to give a good overall perspective of this subject so that the reader will be able to judge its relevance to his or her own situation. Before discussing how SID occurs within amplifiers, it is necessary and appropriate to first consider how the slew rate itself is related to an audio signal. A sine-wave audio signal has definite and measurable parameters, namely its ampli­ tude and frequency. However, a somewhat more subtle parameter (and one germane to this issue) is the slope of the signal, as is determined by its amplitude and frequency. A simple relationship which defines the signal slope (SS) of a sine wave is the equation SS = 2 tt V p f (1) where Vp is the peak signal voltage, and f its frequency.
Sexual Selection in the Water Spider: Female Choice and Male-Male Competition

The water spider Argyroneta aquatica is the only spider spending its whole life under water, and one of the few spider species in which males are larger than females. Previous studies indicated that males can cannibalize females, which is uncommon among spiders. Here we aimed to further test for a potential influence of sexual selection on male body size. We examined the importance of female choice by testing whether females prefer the larger of two simultaneously presented males as mating partners. Further, we examined the influence of male–male competition by comparing the fighting behaviour between large and small males when alone or when together with a female, and we determined the outcome of fights. We found that females approach and choose large males as mating partners, despite the risk of male cannibalism. Additionally, males intensively compete for females, and large males clearly win against smaller ones. Hence sexual selection seems to be important for the evolution of the peculiar sexual size dimorphism of water spiders, as large size is beneficial for males in both the intra- and intersexual context. Previous studies have suggested an important role of natural selection in the sex-specific body size of water spiders, but natural and sexual selection mechanisms apparently work in the same direction, favouring large male size.
SUBARACHNOID HEMORRHAGE TREATED WITH CLIPPING: LONG‐TERM EFFECTS ON EMPLOYMENT, RELATIONSHIPS, PERSONALITY, AND MOOD

OBJECTIVEOnly one-third of patients regain functional independence after aneurysmal subarachnoid hemorrhage (SAH). Despite this recovery, many of these patients experience psychosocial problems. We assessed the long-term effects of SAH on employment, relationships, personality, and mood. METHODSWe included patients who had been treated by clipping after SAH between 1985 and 2001 and who resumed independent living. Patients underwent structured interviews regarding employment, relationships, and personality before and after the SAH. Anxiety and depression were assessed by the Hospital Anxiety and Depression Scale, and scores were compared between the study group and a control population. RESULTSSix hundred and ten patients were interviewed (mean follow-up after SAH, 8.9 yr). Of the employed patients, 26% stopped working and 24% worked shorter hours or had a position with less responsibility. On average, patients returned to work 9.4 months after discharge (range, 0–96 mo). Seven percent of patients were divorced because of SAH-related problems. Fifty-nine percent of the patients reported changes in personality, with the most commonly noted changes being increased irritability (37%) or emotionality (29%). Patients with SAH had a statistically significant higher mean depression score than the control population. Approximately 10% of the patients had a Hospital Anxiety and Depression Scale score in the range of a probable depressive or anxious state. Only 25% reported a complete recovery without psychosocial or neurological problems. CONCLUSIONThe long-term psychosocial effects of SAH are considerable, even in patients who regain functional independence. Treating physicians should be aware of these long-term effects of SAH when discussing prognosis and reintegration to work after initial recovery with patients and family.
A Novel Fractionally Spaced Frequency Domain Equalization Scheme for Single Carrier Cyclic Prefix Assisted MIMO-CDMA Systems

In this paper, we propose a novel fractionally spaced frequency domain equalization scheme for the downlink of single carrier cyclic prefix assisted MIMO-CDMA system over frequency selective channels. This scheme combines the fractionally spaced frequency domain equalizer with parallel interference cancellation (PIC) in the frequency domain to cancel the inter chip interference (ICI), inter antenna interference (IAI) and multiple access interference (MAI). It is shown that our proposed scheme significantly outperforms the conventional frequency domain equalization algorithms with low complexity.
Revised life tables for Finland 1881-1990.

This publication contains the revised life tables by estimating the old age populations by the method of extinct cohorts and offers to users the resulting life tables which cover a period of 110 years. In comparison with previous life tables for Finland significant upward corrections were made to old-age death rates for the earlier part of the twentieth century. After 1945 however any differences were negligible. (EXCERPT)
One-year results of a durable polymer everolimus-eluting stent in de novo coronary narrowings (The SPIRIT FIRST Trial).

AIM Short-term results of durable polymer everolimus-eluting stents have shown significant improvements in clinical and angiographic outcomes. This report presents the 1-year clinical and angiographic data from the SPIRIT FIRST Trial. METHODS AND RESULTS This first-in-man single blind multi-centre randomized controlled trial assessed the safety and efficacy of everolimus and a durable polymer on a cobalt chromium stent in patients with de novo native coronary artery lesions. Of the 60 patients enrolled, a total of 56 patients (27 everolimus arm and 29 bare stent arm) were qualified to per-treatment analyses at 1 year. Quantitative angiographic and intravascular ultrasound (IVUS) analyses were performed. Angiographic late loss, IVUS neointimal volume obstruction and major adverse cardiac events (MACE) at 1 year were assessed as the study endpoints. At 1 year, the in-stent late loss and diameter stenosis of patients were 0.24 mm and 18% in the everolimus arm (n=20), as compared with 0.84 mm and 37% in the bare stent arm (n=25, p < 0.001). Significantly less neointimal hyperplasia was observed in the everolimus arm compared to the bare stent arm (neointimal volume, 13+/-9 mm3 vs. 37+/-17 mm3, p < 0.001; volume obstruction, 10+/-7% vs. 28+/-12%, p < 0.001). The overall MACE rate was 15.4% in the everolimus arm and 21.4% in the bare stent arm. CONCLUSION The safety and efficacy of everolimus-eluting stent with a durable polymer observed at 6 months was sustained at 1 year.
Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina* 210

Retinoids are chromophores involved in vision, transcriptional regulation, and cellular differentiation. Members of the short chain alcohol dehydrogenase/reductase superfamily catalyze the transformation of retinol to retinal. Here, we describe the identification and properties of three enzymes from a novel subfamily of four retinol dehydrogenases (RDH11–14) that display dual-substrate specificity, uniquely metabolizing all-trans- andcis-retinols with C15 pro-Rspecificity. RDH11–14 could be involved in the first step of all-trans- and 9-cis-retinoic acid production in many tissues. RDH11–14 fill the gap in our understanding of 11-cis-retinal and all-trans-retinal transformations in photoreceptor (RDH12) and retinal pigment epithelial cells (RDH11). The dual-substrate specificity of RDH11 explains the minor phenotype associated with mutations in 11-cis-retinol dehydrogenase (RDH5) causing fundus albipunctatus in humans and engineered mice lacking RDH5. Furthermore, photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments. These newly identified enzymes add new elements to important retinoid metabolic pathways that have not been explained by previous genetic and biochemical studies.
Flowering Phenology and Genetic Similarity among Local and Recently Introduced Populations of Andropogon gerardii in Ohio

In Ohio and elsewhere, recent grassland plantings in the federal Conservation Reserve Program (CRP) have become much more extensive than native prairie remnants. The seed source for CRP grasslands in Ohio often comes from as far away as Missouri or Texas, which may be undesirable from the standpoint of conservation genetics. The goal of this study was to examine the potential for gene flow from large, recently introduced populations of Big bluestem (Andropogon gerardii, Poaceae) to small local populations of this outcrossing perennial species. We examined the potential for cross‐pollination between three local populations and three introduced CRP populations by comparing flowering phenologies. Flowering times overlapped extensively, indicating that cross‐pollination is possible where local and introduced genotypes co‐occur. To compare genetic variation in local and CRP populations, we analyzed variation at 68 RAPD loci in six populations of each type. Somewhat surprisingly, we found no significant differences in the genetic diversity or composition between the two groups (local vs. CRP). In summary, we found that local and introduced populations of Big bluestem have the potential to interbreed, based on their flowering periods, but further research is needed to determine whether local genotypes harbor unique genetic variation that could be jeopardized by hybridization with introduced genotypes.
Looking to the Future of Work and Family Theory and Research: Some Reflections

Maureen Perry-Jenkins and Shelley MacDermid Wadsworth (2017) have provided a thought-provoking review of some of the topics and theoretical themes that have inspired researchers in the area of work and family research from the start of the 21st century. They had the interesting idea of presenting an overview of nominations for the Kanter Award since the year 2000, seen through a specific theoretical lens—the ecological perspective. I should state from the outset that, belonging to a different disciplinary context, I am not overly familiar with the ecological perspective. What follows is a series of reflections, from the perspective of a European sociologist, that relate in direct or less direct ways to the arguments presented in the final section of the article, “Looking to the Future of Work and Family Theory and Research. ” I say more below, however, about our disciplinary differences, because it seems to me that there may be some interesting interdisciplinary connections between approaches that I am more familiar with and the perspective taken by the authors.
The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy*

Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes. The etiology of this characteristic clinical syndrome remains unknown. We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner (63% inhibition observed with 100 μm indinavir). Indinavir treatment did not affect early insulin signaling events or the translocation of intracellular Glut1 or Glut4 glucose transporters to the cell surface. To determine whether indinavir may be directly affecting the intrinsic transport activity of glucose transporters, the Glut1 and Glut4 isoforms were heterologously expressed and analyzed inXenopus laevis oocytes. Indinavir at 100 μmhad no effect on Glut1 transport activity in Xenopusoocytes, whereas Glut4 activity was significantly inhibited (45% inhibition). Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients.
Wear.x: Developing Wearables that Embody Felt Experience

Physical discomfort can be highly personal, difficult to discern from the outside, challenging to effectively communicate. Yet communicating discomfort can be of great value. We present a method for developing wearables that transfer one person's discomfort to another: a modified fashion ideation process that enables a person to bring their hidden embodied experiences into wearable form. Using five complementary foci, the method seeks to simulate rather than replicate; to support people to find abstracted expressions for their lived experiences of discomfort, with which to negotiate shared understanding. The resulting wearables support empathic engagement with how another person might feel. Physical discomfort can be highly personal, difficult to discern from the outside, challenging to effectively communicate. Yet communicating discomfort can be of great value. We present a method for developing wearables that transfer one person's discomfort to another: a modified fashion ideation process that enables a person to bring their hidden embodied experiences into wearable form. Using five complementary foci, the method seeks to simulate rather than replicate; to support people to find abstracted expressions for their lived experiences of discomfort, with which to negotiate shared understanding. The resulting wearables support empathic engagement with how another person might feel.
[Radical prostatectomy as monotherapy for locally advanced prostate cancer (T3a): 12 years follow-up].

OBJECTIVES To evaluate the oncological and functional results of radical prostatectomy as monotherapy for stage T3a prostate cancer. METHODS We include our initial and consecutive series of 83 patients with prostate cancer (studied by digital rectal examination and transrectal ultrasound) who had not received neoadjuvant treatment undergoing radical prostatectomy from July 1988 to December 2003. No patient received adjuvant treatment, and deferred intermittent androgen blockade was used when patients with biochemical progression exceeded a PSA of 4ng/ml. Up RESULTS After a mean follow-up of 68.7 (1-139) months: overall and specific survival 97.6% and 100% respectively; biochemical progression 36.1% (22 pT2 (0%), 41 p T3a (36.6%), 13 pT3b (61.5%) and 7pT4a (100%)). Positive margins 61.4% (41.2% unifocal with a progression rate of 23.8%). 96.4% achieved continence and 39.6% recovered potency. Among 30 patients with biochemical progression, 19 required treatment with deferred intermittent androgen blockade (one cycle in 10 patients, two cycles in six, and three cycles in the remaining three). CONCLUSIONS Our results support the indication of radical prostatectomy as single therapy without neoadjuvant treatment as a curative indication for locally advanced prostate cancer (T3a) whenever complete excision is expected: Gleason 7 T3 tumors without diffuse extension on ultrasound. 26.5% of these T3a patients were overstaged and resulted to be organ-confined (pT2). Ten-year probability of biochemical progression-free survival was 100% for pT2 and 81.9% for the lower risk pT3a (well or moderately-differentiated with negative surgical margins or unifocal). Functional results for T3a were similar to the ones of the clinically-localized (T2) series for both retropubic and perineal approaches. 30 patients had developed biochemical progression at the time of study closure and were free of hormonal treatment during 81.6% of the total follow-up time with our deferred intermittent androgen blockade treatment line, so that we consider we can offer it as the first treatment option for progression providing a maximal quality of life and allowing ulterior second line therapies. Patients who mainly benefited were those on progression who have recovered sexual function: 41.7% of potent patients after radical prostatectomy recovered potency again over the second phase (no treatment) of the deferred intermittent androgen blockade.
Role of PI3‐kinase in the development of interstitial cells and pacemaking in murine gastrointestinal smooth muscle

1 Development of the pacemaker system in the small intestine depends upon signalling via tyrosine kinase (Kit) receptors. The downstream pathways initiated by Kit in interstitial cells of Cajal (ICC) have not been investigated. Wortmannin and 2‐(4‐morpholinyl)‐8‐phenyl‐4H‐1‐benzopyran‐4‐one (LY 294002), inhibitors of phosphatidylinositol 3′‐kinase (PI3‐kinase), were used to test the involvement of this pathway in the development and maintenance of ICC and electrical rhythmicity in the murine small intestine. 2 ICC and electrical slow waves were present in the murine jejunum at birth. ICC and electrical rhythmicity continued to develop in neonates such that adult activity was recorded after 1 week. Development of ICC and rhythmicity were maintained in organ culture. 3 Wortmannin or LY 294002 inhibited the development of slow waves and blocked rhythmicity within 2‐4 days. Loss of slow waves was preceded by disappearance of Kit‐positive cells from the myenteric (IC‐MY) and deep muscular plexus (IC‐DMP) regions. Wortmannin or LY 294002 had no acute effect on slow waves. 4 Muscles from older animals (day 10‐day 30) developed resistance to wortmannin treatment, but when the exposure to wortmannin was increased to 35 days, damage to ICC networks and electrical dysrhythmias were observed. 5 PI3‐kinase appears to be a critical downstream signalling element linking Kit receptors to ICC development and maintenance of phenotype. ICC are more sensitive to Kit or PI3‐kinase blockade at birth, but the importance of the PI3‐kinase signalling in the maintenance of ICC persists into adulthood. Interference with PI3‐kinase signalling in immature or adult animals could result in disruption of ICC and gastrointestinal dysrhythmias.
Functional diversity in biters: the evolutionary morphology of the oral jaw system in pacus, piranhas and relatives (Teleostei: Serrasalmidae)

Serrasalmid fishes form a highly specialized group of biters that show a large trophic diversity, ranging from pacus able to crush seeds to piranhas capable of cutting flesh. Their oral jaw system has been hypothesized to be forceful, but variation in bite performance and morphology with respect to diet has not previously been investigated. We tested whether herbivorous species have higher bite forces, larger jaw muscles and more robust jaws than carnivorous species. We measured in vivo and theoretical bite forces in 27 serrasalmid species. We compared the size of the adductor mandibulae muscle, the jaw mechanical advantages, the type of jaw occlusion, and the size and shape of the lower jaw. We also examined the association between bite performance and functional morphological traits of the oral jaw system. Contrary to our predictions, carnivorous piranhas deliver stronger bites than their herbivorous counterparts. The size of the adductor mandibulae muscle varies with bite force and muscles are larger in carnivorous species. Our study highlights an underestimated level of functional morphological diversity in a fish group of exclusive biters. We provide evidence that the trophic specialization towards carnivory in piranhas results from changes in the configuration of the adductor mandibulae muscle and the lower jaw shape, which have major effects on bite performance and bite strategy.