Miracle-dz/UniFAR-FTUs huggingface dataset:
PI3K‐p110‐alpha‐subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2

Development of the cerebral cortex is controlled by growth factors among which transforming growth factor beta (TGFβ) and insulin‐like growth factor 1 (IGF1) have a central role. The TGFβ‐ and IGF1‐pathways cross‐talk and share signalling molecules, but in the central nervous system putative points of intersection remain unknown. We studied the biological effects and down‐stream molecules of TGFβ and IGF1 in cells derived from the mouse cerebral cortex at two developmental time points, E13.5 and E16.5. IGF1 induces PI3K, AKT and the mammalian target of rapamycin complexes (mTORC1/mTORC2) primarily in E13.5‐derived cells, resulting in proliferation, survival and neuronal differentiation, but has small impact on E16.5‐derived cells. TGFβ has little effect at E13.5. It does not activate the PI3K‐ and mTOR‐signalling network directly, but requires its activity to mediate neuronal differentiation specifically at E16.5. Our data indicate a central role of mTORC2 in survival, proliferation as well as neuronal differentiation of E16.5‐derived cortical cells. mTORC2 promotes these cellular processes and is under control of PI3K‐p110‐alpha signalling. PI3K‐p110‐beta signalling activates mTORC2 in E16.5‐derived cells but it does not influence cell survival, proliferation and differentiation. This finding indicates that different mTORC2 subtypes may be implicated in cortical development and that these subtypes are under control of different PI3K isoforms.
ABNORMAL STRUCTURAL BRAIN CONNECTOME IN INDIVIDUALS WITH PRECLINICAL ALZHEIMER’S DISEASE

Abstract Alzheimer's disease has a long preclinical phase during which amyloid pathology and neurodegeneration accumulate in the brain without producing overt cognitive deficits. It is currently unclear whether these early disease stages are associated with a progressive disruption in the communication between brain regions that subsequently leads to cognitive decline and dementia. In this study we assessed the organization of structural networks in cognitively normal (CN) individuals harboring amyloid pathology (A+N−), neurodegeneration (A−N+), or both (A+N+) from the prospective and longitudinal Swedish BioFINDER study. We combined graph theory with diffusion tensor imaging to investigate integration, segregation, and centrality measures in the brain connectome in the previous groups. At baseline, our findings revealed a disrupted network topology characterized by longer paths, lower efficiency, increased clustering and modularity in CN A−N+ and CN A+N+, but not in CN A+N−. After 2 years, CN A+N+ showed significant abnormalities in all global network measures, whereas CN A−N+ only showed abnormalities in the global efficiency. Network connectivity and organization were associated with memory in CN A+N+ individuals. Altogether, our findings suggest that amyloid pathology is not sufficient to disrupt structural network topology, whereas neurodegeneration is.
Aggresomes and Russell bodies

All cells are equipped with a proteolytic apparatus that eliminates damaged, misfolded and incorrectly assembled proteins. The principal engine of cytoplasmic proteolysis, the 26S proteasome, requires that substrates be unfolded to gain access to the active site; consequently, it is relatively ineffective at degrading aggregated proteins. Cellular indigestion occurs when the production of aggregation‐prone proteins exceeds the cell's (or organelle's) capacity to eliminate them. Cellular pathways that resolve this indigestion exist, but appear to have limited capacities. Russell bodies and aggresomes are manifestations of cellular indigestion in the endoplasmic reticulum and cytoplasmic compartments, respectively, and are often associated with disease.
Two methods of preparation of xenon-133 saline solution

Two procedures for dissolving /sup 133/Xe gas in isotonic saline simply and economically with reasonably high activity concentrations are described. The first method is a modification of a previously described procedure and introduces a new flow-through mixing system allowing for a more homogeneous preparation. This system can be used with significant cost and time savings in a department with large clinical demand (> 3 patients per week). The second method is a system which can be used economically in a department with a small and/or sporadic clinical demand. This technique involves the preparation of single-patient dose by introducing saline into commercially available /sup 133/Xe gas vials. The solubility of /sup 133/Xe in saline can be significantly increased (> 50%) by introducing saline into a /sup 133/Xe gas vial and incubating the reactive vial at 4 /sup 0/C for 3 hr or more. The suggested modifications are simple and the resultant activity concentrations are relatively high and clinically useful.
Changes in Lognormal Shape Parameter Guide Design of Patient-Specific Radiochemotherapy Cocktails

Uptake of radiopharmaceuticals and chemotherapeutic drugs is nonuniform at the microscopic level. Their distributions are typically lognormal, suggesting that failure in chemotherapy and targeted radionuclide therapy may be attributable, in part, to the characteristics of this biologically ubiquitous distribution. The lognormal problem can be overcome by using cocktails of 2 or more agents, tailored such that at least 1 agent is strongly incorporated by every cell in the target population. Therefore, critical assessment of the tissue uptake of each cocktail component is warranted. Methods: Cellular incorporation of the α-particle–emitting radiochemical (210Po-citrate) and 2 anticancer drugs (daunomycin and doxorubicin) was determined using flow cytometry. The role of their lognormal distribution in clonogenic cell survival was evaluated. Results: The shape parameter of the lognormal distribution was found to be correlated to both intracellular agent concentration and cell survival. Although no difference emerged between the shape parameters for citrate within the first 2 logs of cell kill, those for daunomycin and doxorubicin changed significantly. Conclusion: Changes in the value of the lognormal shape parameter and slope of the cellular drug uptake curves can be used to rapidly screen radiopharmaceuticals and other cytotoxic agents to formulate more effective cocktails for cancer therapy.
Metastatic carcinoma of the pleura.

Pleural secondaries are a frequent finding at necropsy in cases of carcinomatosis, and their presence is of such prognostic significance that much effort has been made in the field of diagnostic cytology as applied to the examination of serous effusions (Foot, 1954; Luse and Reagan, 1954a and b; Papanicolaou, 1954; Leuallen and Carr, 1955; Foot, 1956; Myerson, 1956). The relevant literature has been well reviewed by Spriggs (1957), and a less critical view of the investigation is now accepted (Naylor and Schmidt, 1964) than that adopted by Scadding (1955). In recent years special interest has been shown in the cytological diagnosis of pleural mesotheliomas (Klempman, 1962; Manguikian and Prior, 1963; Naylor, 1963) out of all proportion to the incidence of this condition. The subject of pleural involvement by secondary carcinoma is only briefly mentioned by Spencer (1962), and yet it is of interest since its pathogenesis and the factors influencing the appearance of effusions are poorly understood. It appeared that a study of necropsy material in this department would be worth while, although cytological material obtained during life was available in only a few of the cases.
Fast and Furious

A 65 year old man attended the accident and emergency department complaining of episodic palpitations associated with dizziness. He had a pulse of 250 beats/min with a regular rhythm and a blood pressure of 105/78 mm Hg. Physical examination was otherwise normal. He had a history of paroxysmal atrial fibrillation and was taking flecainide 100 mg twice a day and warfarin. Electrocardiography was performed on admission (fig 1⇓). Subsequently, a 6 mg bolus of adenosine was administered and a continuous two lead rhythm electrocardiogram recorded (fig 2⇓). Fig 1 Electrocardiogram on admission Fig 2 A two lead electrocardiogram recorded during and after administration of an adenosine bolus. (A) Trace from the precordial leads during administration of an adenosine bolus; lead V1 at the top and lead II below. (B) Continuation of the trace from the precordial leads following administration of an adenosine bolus; lead V1 at the top and lead II below ### Short answers
ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response. DOI: http://dx.doi. org/10.7554/eLife.10066. 001
Convex Repeated Games and Fenchel Duality

We describe an algorithmic framework for an abstract game which we term a convex repeated game. We show that various online learning and boosting algorithms can be all derived as special cases of our algorithmic framework. This unified view explains the properties of existing algorithms and also enables us to derive several new interesting algorithms. Our algorithmic framework stems from a connection that we build between the notions of regret in game theory and weak duality in convex optimization.
Propagation of the fundamental mode in curved graded index multimode fiber and its application in sensor systems

A novel principle of light transmission through very small radius bend in optical fibers is presented. The potential applications of the proposed structure are fiber optic sensors and other fiber optic systems. The design makes use of graded index multimode fiber as transmission medium. However, the feed to the multimode fiber is through a single mode fiber to ensure that only the lowest order spatial mode is launched. Similarly the receiver is also coupled to the sensing element through a single mode fiber. The fundamental mode within graded index multimode fiber proves to be very insensitive to macrobends if bend radius is larger than certain critical value. If bend radius is reduced below critical value the loss increases very rapidly and this allows for construction of relatively sensitive macrobend fiber optic sensor. This work presents a quantitative theoretical model of the proposed structure and a detailed experimental investigation of structure with possibilities for its practical applications.
Vibration control of a nonlinear quarter-car active suspension system by reinforcement learning

This article presents the investigation of performance of a nonlinear quarter-car active suspension system with a stochastic real-valued reinforcement learning control strategy. As an example, a model of a quarter car with a nonlinear suspension spring subjected to excitation from a road profile is considered. The excitation is realised by the roughness of the road. The quarter-car model to be considered here can be approximately described as a nonlinear two degrees of freedom system. The experimental results indicate that the proposed active suspension system suppresses the vibrations greatly. A simulation of a nonlinear quarter-car active suspension system is presented to demonstrate the effectiveness and examine the performance of the learning control algorithm.
Far field radiation from an arbitrarily oriented Hertzian dipole in the presence of a layered anisotropic medium

Far field radiation from an arbitrarily oriented Hertzian dipole for two-layered uniaxially anisotropic medium with a tilted optic axis is treated analytically by using the dyadic Green's function of the problem when the dipole is placed over or embedded in a two-layered uniaxially anisotropic medium. The radiation fields are evaluated using the steepest descent method. Parameter studies including anisotropy, layer thickness and dipole location are performed to investigate the effects of changing different variables on the radiation fields. Results of this work can be applied in microstrip circuits and antennas.
Grazing cow and calf responses to zinc supplementation.

This experiment evaluated weight gain responses to supplemental Zn by cows and calves grazing forage containing less than 20 ppm Zn. One hundred cow-calf pairs in each of 2 years and 120 paird in a third year were pastured together over a 63- to 77-day preliminary period during which cows were exposed to bulls. Each experimental period began in mid-June after bulls were removed and continued for 125 to 154 days. During this period, cattle grazed mature dry forage containing less than 20 ppm Zn and were fed protein supplements with or without added Zn. Estimated Zn intake by each cow-calf pair in the control group ranged from about 140 to 260 mg/pair/day. Daily Zn intake was supplied by forage (100 to 200 mg), basal supplement (32 to 57 mg), water (4 mg), iodized block salt (1 mg) an soil (1 mg). Each cow-calf pair fed the supplement with added Zn received an additional 860 to 900 mg Zn/day. Calves fed Zn gained 6% more (P less than .05) weight (.04 kg/day) between the two groups. Clinical signs of Zn deficiency were not observed in any animals. Conception which occurred before the experimental period, and subsequent calving rates were not affected by Zn supplementation.
Pressure overload causes cardiac hypertrophy in beta1-adrenergic and beta2-adrenergic receptor double knockout mice.

OBJECTIVE Cardiac hypertrophy arises as an adaptive response to increased afterload. Studies in knockout mice have shown that catecholamines, but not alpha1-adrenergic receptors, are necessary for such an adaptation to occur. However, whether beta-adrenergic receptors are critical for the development of cardiac hypertrophy in response to pressure overload is not known at this time. METHODS AND RESULTS Pressure overload was induced by transverse aortic banding in beta1-adrenergic and beta2-adrenergic receptor double knockout (DbetaKO) mice, in which the predominant cardiac beta-adrenergic receptor subtypes are lacking. Chronic pressure overload for 4 weeks induced cardiac hypertrophy in both DbetaKO and wild-type mice. There were no significant differences between banded mice in left ventricular weight to body weight ratio, in the left ventricular wall thickness, in the cardiomyocyte size or in the expression levels of the load-sensitive cardiac genes such as ANF and beta-MHC. Additionally, the left ventricular systolic pressure, an index of afterload, and cardiac contractility, evaluated as dp/dtmax, the maximal slope of systolic pressure increment, and Ees, end-systolic elastance, were increased at a similar level in both wild-type and DbetaKO banded mice, and were significantly greater than in sham controls. CONCLUSION Despite chronic activation of the cardiac beta-adrenergic system being sufficient to induce a pathological hypertrophy, we show that beta1-adrenergic and beta2-adrenergic receptors are not an obligatory component of the signaling pathway that links the increased afterload to the development of cardiac hypertrophy.
Economic Evaluation of the 80% Baccalaureate Nurse Workforce Recommendation: A Patient-level Analysis

Background:Higher proportions of BSN-educated nurses were associated with improved outcomes in hospital-level studies. A recent Institute of Medicine report calls for increasing the proportion of BSN-educated nurses to 80% by 2020. Patient-level evidence of cost and quality implications of the 80% BSN threshold is needed for a business case to support these efforts. Objectives:To conduct the economic analysis of meeting the 80% BSN threshold on patient outcomes and costs, using linked patient-nurse data. Research Design:Retrospective observational patient-level analysis of electronic data. Linear and logistic regression modeling with patient controls and diagnosis and unit fixed effects. Subjects:A total of 8526 adult medical-surgical patients matched with 1477 direct care nurses from an Eastern US academic medical center, during June 1, 2011–December 31, 2011. Measures:Outcomes include hospital mortality, all-cause same-facility 30-day readmission, length-of-stay, and total hospitalization cost. BSN proportion is a continuous measure for the proportion of nurse assessment inputs into the patient’s electronic medical record made by BSN-educated nurses; a dichotomous indicator for BSN proportion is 0.8–1.0. Results:Continuous BSN proportion was associated with lower mortality (OR=0.891, P<0.01). Compared with patients with <80% BSN care, patients receiving ≥80% of care from BSN nurses had lower odds of readmission (OR=0.813, P=0.04) and 1.9% shorter length-of-stay (P=0.03). Economic simulations support a strong business case for increasing the proportion of BSN-educated nurses to 80%. Conclusions:A combined approach of increasing the hospital-level BSN proportion to 80% and assuring a high BSN dose through individual patient-level staffing assignments is needed to achieve projected quality and costs benefits.
TorsinA and the TorsinA-Interacting Protein Printor Have No Impact on Endoplasmic Reticulum Stress or Protein Trafficking in Yeast

Early-onset torsion dystonia is a severe, life-long disease that leads to loss of motor control and involuntary muscle contractions. While the molecular etiology of the disease is not fully understood, a mutation in an AAA+ ATPase, torsinA, has been linked to disease onset. Previous work on torsinA has shown that it localizes to the endoplasmic reticulum, where there is evidence that it plays roles in protein trafficking, and potentially also protein folding. Given the high level of evolutionary conservation among proteins involved in these processes, the ability of human such proteins to function effectively in yeast, as well as the previous successes achieved in examining other proteins involved in complex human diseases in yeast, we hypothesized that Saccharomyces cerevisiae might represent a useful model system for studying torsinA function and the effects of its mutants. Since torsinA is proposed to function in protein homeostasis, we tested cells for their ability to respond to various stressors, using a fluorescent reporter to measure the unfolded protein response, as well as their rate of protein secretion. TorsinA did not impact these processes, even after co-expression of its recently identified interacting partner, printor. In light of these findings, we propose that yeast may lack an additional cofactor necessary for torsinA function or proteins required for essential post-translational modifications of torsinA. Alternatively, torsinA may not function in endoplasmic reticulum protein homeostasis. The strains and assays we describe may provide useful tools for identifying and investigating these possibilities and are freely available.
Systematic review and meta-analysis of surgical ablation for atrial fibrillation during mitral valve surgery.

BACKGROUND Surgical ablation has emerged as an acceptable treatment modality for patients with atrial fibrillation (AF) undertaking concomitant cardiac surgery. However, the efficacy of surgical ablation in patient populations undergoing mitral valve surgery is not well established. The present meta-analysis aims to establish the current randomized evidence on clinical outcomes of surgical ablation versus no ablative treatment in patients with AF undergoing mitral valve surgery. METHODS Electronic searches were performed using six databases from their inception to September 2013, identifying all relevant randomized controlled trials (RCTs) comparing surgical ablation versus no ablation in AF patients undergoing mitral valve surgery. Data were extracted and analyzed according to predefined clinical endpoints. RESULTS Nine relevant RCTs were identified for inclusion in the present analysis. The number of patients in sinus rhythm (SR) was significantly improved in the surgical ablation group compared to the non-ablation group at discharge. This effect on SR remained at all follow-up periods until >1 year. Results indicated that there was no significant difference between surgical ablation and no ablation in terms of 30-day mortality, all-cause mortality, pacemaker implantation, stroke, thromboembolism, cardiac tamponade, reoperation for bleeding and myocardial infarction. CONCLUSIONS Results from the present meta-analysis demonstrate that the addition of surgical ablation for AF leads to a significantly higher rate of sinus rhythm in mitral valve surgical patients, with no increase in the rates of mortality, pacemaker implantation, stroke and thromboembolism. Further research should be directed at correlating different surgical ablation subtypes to cardiac and cerebrovascular events at long-term follow-up.
Association between plasma cholesterol and prostate cancer in the PSA era

We previously found that statin users had a lower risk of advanced and possibly high‐grade prostate cancer compared with nonusers. We hypothesize that statins' effects on cholesterol synthesis may explain those findings because prostate cancer cells exhibit cholesterol dysregulation. Thus, we investigated whether low plasma cholesterol is associated with prostate cancer overall and by stage and grade. Participants were drawn from the 18,018 members of the Health Professionals Follow‐Up Study who provided blood in 1993–1995. We ascertained 698 incident cases through January 2000. Controls were 698 men who had a PSA test and were matched to cases. Plasma cholesterol was measured enzymatically. Conditional logistic regression was used to estimate multivariable ORs and 95% CIs of total, clinically organ‐confined (n = 518), advanced (T3b or worse; n = 61), low‐grade (Gleason sum < 7; n = 386) and high‐grade (Gleason sum ≥ 7, n = 247) disease. Low cholesterol (<25th percentile vs. ≥25th percentile) was not associated with total (OR = 0.93, 95% CI: 0.72–1.20), organ‐confined (OR = 0.87, 95% CI: 0.64–1.18) or low‐grade (OR = 1.06, 95% CI: 0.75–1.51) disease. However, men with low cholesterol had a lower risk of high‐grade disease (OR = 0.61, 95% CI: 0.39–0.98), especially if organ‐confined (OR = 0.54, 95% CI: 0.29–0.99). The association for advanced disease appeared inverse, but number of cases was small (OR = 0.42, 95% CI: 0.13–1.36). Associations remained after excluding cholesterol‐lowering drug users. These results coupled with prior statin findings suggest that mechanistic studies on cholesterol metabolism should be pursued to understand a possible target for preventing poorly differentiated prostate cancers. © 2008 Wiley‐Liss, Inc.