Miracle-dz/UniFAR-FTUs huggingface dataset:
Stable Brain ATM Message and Residual Kinase-Active ATM Protein in Ataxia-Telangiectasia

The gene that is mutated in ataxia-telangiectasia (A-T), ATM, is catalytically activated in response to DNA damage. Yet a full accounting for the CNS deficits in human A-T or its mouse models remains elusive. We have analyzed the CNS phenotypes of two mouse Atm alleles—Atmtm1Bal (Bal) and Atmtm1Awb (Awb). Neither mutant has detectable mRNA or protein in peripheral tissues. In brain, although Bal/Bal mice have no ATM protein, they have nearly normal amounts of Atm mRNA. Bal/Bal neurons exhibit extensive cell cycle reentry and degeneration in both cortex and cerebellum. Unexpectedly, in Awb/Awb mice a novel mRNA is found in which the engineered mutation is excised. This mRNA is apparently translated and produces a catalytically active ATM protein that responds to DNA damage by phosphorylating p53 and Chk2. Prompted by these results, we examined eight cases of human A-T and found evidence for residual ATM protein in seven of them. These findings offer important new insights into the human disease and the role of brain ATM activity in the severity of the neurological symptoms of A-T.
Tracking Mental Well-Being: Balancing Rich Sensing and Patient Needs

Serious mental illnesses are among the most pressing public healthcare concerns. Continuous and unobtrusive sensing of social and physical functioning has tremendous potential to support lifelong health management by acting as an early warning system to detect changes in mental well-being, delivering context-aware micro-interventions to patients when and where they need them and significantly accelerating patients' understanding of their illness. We have presented a range of techniques from our previous and ongoing work to suggest how technologists can make significant advances in this area. While we are still shaping and evaluating these solutions, there is an opportunity for other researchers in our field to help ease the burden of SMIs by striking a balance between cutting-edge sensing and patient needs. This could empower patients by giving them a hand in their own treatment and ultimately lead to more effective, lower-cost treatment.
Animal escapology I: theoretical issues and emerging trends in escape trajectories

Summary Escape responses are used by many animal species as their main defence against predator attacks. Escape success is determined by a number of variables; important are the directionality (the percentage of responses directed away from the threat) and the escape trajectories (ETs) measured relative to the threat. Although logic would suggest that animals should always turn away from a predator, work on various species shows that these away responses occur only approximately 50–90% of the time. A small proportion of towards responses may introduce some unpredictability and may be an adaptive feature of the escape system. Similar issues apply to ETs. Theoretically, an optimal ET can be modelled on the geometry of predator–prey encounters. However, unpredictability (and hence high variability) in trajectories may be necessary for preventing predators from learning a simple escape pattern. This review discusses the emerging trends in escape trajectories, as well as the modulating key factors, such as the surroundings and body design. The main ET patterns identified are: (1) high ET variability within a limited angular sector (mainly 90–180 deg away from the threat; this variability is in some cases based on multiple peaks of ETs), (2) ETs that allow sensory tracking of the threat and (3) ETs towards a shelter. These characteristic features are observed across various taxa and, therefore, their expression may be mainly related to taxon-independent animal design features and to the environmental context in which prey live – for example whether the immediate surroundings of the prey provide potential refuges.
Lagrangian particle paths and ortho-normal quaternion frames

Experimentalists now measure intense rotations of Lagrangian particles in turbulent flows by tracking their trajectories and Lagrangian-average velocity gradients at high Reynolds numbers. This paper formulates the dynamics of an orthonormal frame attached to each Lagrangian fluid particle undergoing three-axis rotations, by using quaternions in combination with Ertel's theorem for frozen-in vorticity. The method is applicable to a wide range of Lagrangian flows including the three-dimensional Euler equations and its variants such as ideal magneto-hydrodynamics. The applicability of the quaterionic frame description to Lagrangian averaged velocity gradient dynamics is also demonstrated.
Mortality in Diabetes Mellitus: Experience of a Geographically Defined Population

A population‐based cohort study identified 915 deaths in 4186 patients with diabetes mellitus over a 5‐year period. Ischaemic heart disease, cerebrovascular disease and malignant neoplasms were the major causes of death and accounted for 40%, 16%, and 14% of deaths, respectively, compared with 27%, 14%, and 25% of deaths in the nondiabetic population. Diabetic patients had a standardized mortality ratio (SMR) of 1.15 (95% CI 1.08–1.22) (p< 0.001). This excess risk of death was largely due to the excess death from ischaemic heart disease (SMR 1.55 (1.40–1.71); p < 0.001) and the impact was greatest in middle‐aged female patients. Stroke mortality was not significantly increased (SMR 1.09 (0.92–1.29)) while cancer mortality was reduced (SMR 0.75 (0.63–0.89); p < 0.01). Death rates in diabetic male patients (SMR 1.04 (0.96–1.13)) did not differ significantly from those in non‐diabetic male patients because the increased risk of ischaemic heart disease deaths (SMR 1.41 (1.22–1.62); p < 0.001) was offset by the reduced risk of deaths from malignant neoplasms (SMR 0.65 (0.51–0.82); p < 0.001). The reduction in cancer mortality did not reach statistical significance in diabetic women (SMR 0.82 (0.64–1.05)). Diabetic nephropathy and metabolic disasters were uncommon as causes of death.
Semiring Programming: A Framework for Search, Inference and Learning

To solve hard problems, AI relies on a variety of disciplines such as logic, probabilistic reasoning, machine learning and mathematical programming. Although it is widely accepted that solving real-world problems requires an integration amongst these, contemporary representation methodologies offer little support for this. In an attempt to alleviate this situation, we introduce a new declarative programming framework that provides abstractions of well-known problems such as SAT, Bayesian inference, generative models, and convex optimization. The semantics of programs is defined in terms of first-order structures with semiring labels, which allows us to freely combine and integrate problems from different AI disciplines.
MOS Scaling: Transistor Challenges for the 21st Century

Conventional scaling of gate oxide thickness, source/drain extension (SDE), junction depths, and gate lengths have enabled MOS gate dimensions to be reduced from 10μm in the 1970’s to a present day size of 0. 1μm. To enable transistor scaling into the 21 century, new solutions such as high dielectric constant materials for gate insulation and shallow, ultra low resistivity junctions need to be developed. In this paper, for the first time, key scaling limits are quantified for MOS transistors (see Table 1). We show that traditional SiO2 gate dielectrics will reach fundamental leakage limits, due to tunneling, for an effective electrical thickness below 2.3 nm. Experimental data and simulations are used to show that although conventional scaling of junction depths is still possible, increased resistance for junction depths below 30 nm results in performance degradation. Because of these limits, it will not be possible to further improve short channel effects. This will result in either unacceptable off-state leakage currents or strongly degraded device performance for gate lengths below 0. 10μm. MOS transistor limits will be reached for 0. 13μm process technologies in production during 2002. Because of these problems, new solutions will need to be developed for continued transistor scaling. We discuss some of the proposed solutions including high dielectric constant gate materials and alternate device architectures.
Malumfashi Endemic Diseases Research Project, XIX. Demographic findings: population structure and fertility.

Population studies were undertaken as part of the Endemic Disease Research Project at Malumfashi northern Nigeria 1974-78. This paper is concerned with population composition and estimates of fertility. Results are based on retrospective enumeration data on 42493 people and on prospective registration data on a subset of 26100 people. The age-sex structure fits the model for developing countries: 45% under age 15 and just 3% aged 65 years and over. The scene for high fertility is set by an early mean age of 1st marriage for women age 15. The crude birth rate was 55% and the general fertility rate 221% (enumeration data). Detailed fertility analyses based on enumeration data suggest consistency particularly when the relationship between the pattern and the level of fertility is examined. The number of live births a woman could expect if she survived to the end of her reproductive period is on the average 6.8. More births were found to occur in the wet season than the dry season. The twinning rate was 1 in 69. (authors)
Effects of prenatal stress on suckling calves.

Pregnant Brahman cows (n = 42), bred to either Brahman or Tuli bulls, were randomly assigned to one of three treatments: 1) transported in a stock trailer for 24.2 km, unloaded at a second farm and penned for 1 h, and then returned to the original farm (TRANS); 2) i.v. injection of ACTH, 1 IU/kg BW (ACTH); or 3) walked through the handling facilities (SHAM). Treatments were initiated on d 60 and repeated at 80, 100, 120, and 140 d of gestation. The calves from these cows were subjected to tests to measure their capacity to react to stress. In Test 1, Tuli-sired calves were restrained at 10 and 150 d of age for 3.5 h. In Test 2, Brahman-sired calves were restrained for 3.5 h and given an injection of ACTH (.125 IU ACTH/kg of BW). In Test 3, Test-2 calves were restrained at 180 d of age and hot-iron branded. In Test 4, Test-1 calves were restrained at 180 d of age and given an injection of cortisol (6.7 ng/kg BW) to estimate cortisol clearance rate. During all tests, calves were restrained for 3.5 h, and heart rates were recorded and blood samples were taken at -15, 0, 15, 30, 45, 60, 90, 120, and 180 min. The 10- and 150-d-old TRANS calves maintained greater plasma cortisol in Test 1 (restraint) than the ACTH and SHAM calves (P < .01). The ACTH challenge (Test 2) increased plasma cortisol and ACTH, but cow treatment did not alter the response (P > .4). In response to branding (Test 3), the TRANS, ACTH, and SHAM calves' overall mean plasma cortisol was not affected by treatment (52, 51, and 43 +/- 3 ng/mL, respectively; P > .1), nor was the calves' overall heart rate (91, 94, and 86 +/- 3 beats/min, respectively; P > . 1). In Test 4, TRANS calves cleared plasma of cortisol at a slower rate than did the SHAM calves (P < .01), but not the ACTH calves (261, 374, and 473 +/- 50 mL/min, respectively; P > .1). The TRANS calves had an overall greater heart rate than did the ACTH or the SHAM calves (91, 79, and 77 +/- 2 beats/min, respectively; P < .001). Exposing cows to repeated transportation stress during gestation altered their calf's physiological response to stress, and these alterations could have a profound influence on the calfs ability to adapt to stress, thereby influencing its welfare. Further research should examine the growth, immune function, and reproductive function of prenatally stressed calves to determine whether these changes in plasma cortisol are beneficial or deleterious.
Hystereses in dwarf nova outbursts and low-mass X-ray binaries

Context. The disc instability model (DIM) successfully explains why many accreting compact binary systems exhibit outbursts, during which their luminosity increases by orders of magnitude. The DIM correctly predicts which systems should be transient and works regardless of whether the accretor is a black hole, a neutron star or a white dwarf. However, it has been known for some time that the outbursts of X-ray binaries (which contain neutron-star or black-hole accretors) exhibit hysteresis in the X-ray hardness-intensity diagram (HID). More recently, it has been shown that the outbursts of accreting white dwarfs also show hysteresis, but in a diagram combining optical, EUV and X-ray fluxes. Aims. We examine here the nature of the hysteresis observed in cataclysmic variables and low-mass X-ray binaries. Methods. We use the Hameury et al. (1998) code for modelling dwarf nova outbursts, and construct the hardness intensity diagram as predicted by the disc instability model. Results. We show explicitly that the standard DIM - modified only to account for disc truncation - can explain the hysteresis observed in accreting white dwarfs, but cannot explain that observed in X-ray binaries. Conclusions. The spectral evidence for the existence of different accretion regimes / components (disc, corona, jets, etc.) should be based only on wavebands that are specific to the innermost parts of the discs, i.e. EUV and X-rays, which is a difficult task because of interstellar absorption. The existing data, however, indicate that an EUV/X-ray hysteresis is present in SS Cyg.
Affichage de publicités sur des portails web

Nous nous interessons au probleme de l'affichage de publicites sur le web. De plus en plus d'annonceurs souhaitent maintenant payer uniquement lorsque quelqu'un clique sur leurs publicites. Dans ce modele, l'operateur du portail a interet a identifier les publicites les plus cliquees, selon ses categories de visiteurs. Comme les probabilites de clic sont inconnues a priori, il s'agit d'un dilemme exploration/exploitation. Ce probleme a souvent ete traite en ne tenant pas compte de contraintes provenant du monde reel : les campagnes de publicites ont une duree de vie et possedent un nombre de clics a assurer et ne pas depasser. Pour cela, nous introduisons une approche hybride (MAB+LP) entre la program- mation lineaire et les bandits. Nos algorithmes sont testes sur des modeles crees avec un important acteur du web commercial. Ces experiences montrent que ces approches atteignent une performance tres proche de l'optimum et mettent en evidence des aspects cles du probleme.
Model-based testing in practice

Model-based testing is a new and evolving technique for generating a suite of test cases from requirements. Testers using this approach concentrate on a data model and generation infrastructure instead of hand-crafting individual tests. Several relatively small studies have demonstrated how combinatorial test generation techniques allow testers to achieve broad coverage of the input domain with a small number of tests. We have conducted several relatively large projects in which we applied these techniques to systems with millions of lines of code. Given the complexity of testing, the model-based testing approach was used in conjunction with test automation harnesses. Since no large empirical study has been conducted to measure efficacy of this new approach, we report on our experience with developing tools and methods in support of model-based testing. The four case studies presented here offer details and results of applying combinatorial test-generation techniques on a large scale to diverse applications. Based on the four projects, we offer our insights into what works in practice and our thoughts about obstacles to transferring this technology into testing organizations.
Modulation of Chlamydomonas reinhardtii flagellar motility by redox poise

Redox-based regulatory systems are essential for many cellular activities. Chlamydomonas reinhardtii exhibits alterations in motile behavior in response to different light conditions (photokinesis). We hypothesized that photokinesis is signaled by variations in cytoplasmic redox poise resulting from changes in chloroplast activity. We found that this effect requires photosystem I, which generates reduced NADPH. We also observed that photokinetic changes in beat frequency and duration of the photophobic response could be obtained by altering oxidative/reductive stress. Analysis of reactivated cell models revealed that this redox poise effect is mediated through the outer dynein arms (ODAs). Although the global redox state of the thioredoxin-related ODA light chains LC3 and LC5 and the redox-sensitive Ca2+-binding subunit of the docking complex DC3 did not change upon light/dark transitions, we did observe significant alterations in their interactions with other flagellar components via mixed disulfides. These data indicate that redox poise directly affects ODAs and suggest that it may act in the control of flagellar motility.
On the Impossibility of Dimension Reduction for Doubling Subsets of ℓp

A major open problem in the field of metric embedding is the existence of dimension reduction for n-point subsets of Euclidean space, such that both distortion and dimension depend only on the doubling constant of the pointset, and not on its cardinality. In this paper, we negate this possibility for ℓp spaces with p > 2. In particular, we introduce an n-point subset of ℓp with doubling constant O(1), and demonstrate that any embedding of the set into ℓdp with distortion D must have D ≥ Ω ((c log n/d)1/2−1/p).
Varied pathological and therapeutic response effects associated with CHCHD2 mutant and risk variants

Mutations and polymorphic risk variant of coiled‐coil‐helix‐coiled‐coil‐helix domain containing 2 (CHCHD2) have been associated with late‐onset Parkinson disease. In vivo pathological evidence of CHCHD2 mutations is currently lacking. Utilizing transgenic Drosophila model, we examined the relative pathophysiologic effect of the pathogenic (c.182C>T, p.Thr61Ile and c.434G>A, p.Arg145Gln) and the risk (c.5C>T, p.Pro2Leu) CHCHD2 variants. All the transgenic models exhibited locomotor dysfunction that could be exacerbated by rotenone exposure, dopaminergic neuron degeneration, reduction in lifespan, mitochondrial dysfunction, oxidative stress, and impairment in synaptic transmission. However, both mutants showed more severe early motor dysfunction, dopaminergic neuronal loss, and higher hydrogen peroxide production compared with the risk variant. p.Thr61Ile (co‐segregated in three independent PD families) displayed the most severe phenotype followed by p.Arg145Gln (present only in index patient). We treated the transgenic flies with Ebselen, a mitochondrial hydrogen peroxide scavenger compound; Ebselen appears to be more effective in ameliorating motor function in the mutant than the risk variant models. We provide the first in vivo evidence of the pathological effects associated with CHCHD2 mutations. There was a difference in the pathological and drug response effects between the pathogenic and the risk variants. Ebselen may be a useful neuroprotective drug for carriers of CHCHD2 mutations.
Promyelocytic Leukemia Activates Chk2 by Mediating Chk2 Autophosphorylation*

Chk2 is a kinase critical for DNA damage-induced apoptosis and is considered a tumor suppressor. Chk2 is essential for p53 transcriptional and apoptotic activities. Although mutations of p53 are present in more than half of all tumors, mutations of Chk2 in cancers are rare, suggesting that Chk2 may be inactivated by unknown alternative mechanisms. Here we elucidate one such alternative mechanism regulated by PML (promyelocytic leukemia) that is involved in acute promyelocytic leukemia (APL). Although p53-inactivating mutations are extremely rare in APL, t(15;17) chromosomal translocation which fuses retinoic acid receptor (RARα) to PML is almost always present in APL, while the other PML allele is intact. We demonstrate that PML interacts with Chk2 and activates Chk2 by mediating its autophosphorylation step, an essential step for Chk2 activity that occurs after phosphorylation by the upstream kinase ATM (ataxia telangiectasia-mutated). PML/RARα in APL suppresses Chk2 by dominantly inhibiting the auto-phosphorylation step, but inactivation of PML/RARα with alltrans retinoic acid (ATRA) restores Chk2 autophosphorylation and activity. Thus, by fusing PML with RARα, the APL cells appear to have achieved functional suppression of Chk2 compromising the Chk2-p53 apoptotic pathway.
Stability Analysis of a Turbocharger Rotor System Supported on Floating Ring Bearings

The stability of a turbocharger rotor is governed by the coupling of rotor dynamics and fluid dynamics because the high speed rotor system is supported on a pair of hydrodynamic floating ring bearings which comprise of inner and outer fluid films in series. In order to investigate the stability, this paper has developed a finite element model of the rotor system with consideration of such exciting forces as rotor imbalance, hydrodynamic fluid forces, lubricant feed pressure and dead weight. The dimensionless analytical expression of nonlinear oil film forces in floating ring bearings have been derived on the basis of short bearing theory. Based on numerical simulation, the effects of rotor imbalance, lubricant viscosity, lubricant feed pressure and bearing clearances on the stability of turbocharger rotor system have been studied. The disciplines of the stability of two films and dynamic performances of rotor system have been provided.
Aerobic Exercise Training Increases Muscle Water Content in Obese Middle-Age Men.

PURPOSE The objective of this study is to determine whether muscle water content (H2Omuscle) expands with training in deconditioned middle-age men and the effects of this expansion in other muscle metabolites. METHODS Eighteen obese (BMI = 33 ± 3 kg⁻¹·m⁻²) untrained (V˙O2peak = 29 ± 7 mL⁻¹·kg⁻¹·min⁻¹) metabolic syndrome men completed a 4-month aerobic cycling training program. Vastus lateralis muscle biopsies were collected before and 72 h after the completion of the last training bout. Water content, total protein, glycogen concentration, and citrate synthase activity were measured in biopsy tissue. Body composition was assessed using dual-energy X-ray absorptiometry, and cardiometabolic fitness was measured during an incremental cycling test. RESULTS Body weight and fat mass were reduced -1.9% and -5.4%, respectively (P < 0.05), whereas leg fat free mass increased with training (1.8%, P = 0.023). Cardiorespiratory fitness (i.e., V˙O2peak), exercise maximal fat oxidation (i.e., FOmax), and maximal cycling power (i.e., Wmax) improved with training (11%, 33%, and 10%, respectively; P < 0.05). After 4 months of training, H2Omuscle increased from 783 ± 18 to 799 ± 24 g·kg⁻¹ wet weight (ww) (2%, P = 0.011), whereas muscle protein concentration decreased 11% (145 ± 15 to 129 ± 13 g·kg⁻¹ ww, P = 0.007). Citrate synthase activity (proxy for mitochondrial density) increased by 31% (17 ± 5 to 22 ± 5 mmol·min⁻¹·kg⁻¹ ww, P = 0.024). Muscle glycogen concentration increased by 14% (22 ± 7 to 25 ± 7 g·kg⁻¹ ww) although without reaching statistical significance when expressed as per kilogram of wet weight (P = 0.15). CONCLUSIONS Our findings suggest that aerobic cycling training increases quadriceps muscle water although reduces muscle protein concentration in obese metabolic syndrome men. Reduced protein concentration coexists with increased leg lean mass suggestive of a water dilution effect that however does not impair increased cycling leg power with training.