Miracle-dz/UniFAR-FTUs huggingface dataset:
Early Mitochondrial Hyperpolarization and Intracellular Alkalinization in Lactacystin-Induced Apoptosis of Retinal Pigment Epithelial Cells

We investigated the induction and underlying mechanism of apoptosis in retinal pigment epithelial cells by the inhibition of proteasome activity using lactacystin. Rat retinal pigment epithelial cell line retinal pigment epithelial (RPE)-J was used in this study. Apoptosis was evaluated by light and electron microscopies, DNA electrophoresis, and terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. The apoptosis-related proteins were localized in the cells by immunofluorescent microscopy, and the changes of their protein contents and the enzyme activation were monitored by Western blot. Mitochondrial membrane potential was quantified by measuring J aggregate (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazol carbocyanine iodide) fluorescence. To measure changes in intracellular pH, cells were loaded with 2′,7′-bis(carboxyethyl)-5(6′)-carboxyfluorescein and assayed by flow cytometry. To elucidate the type of transport system involving intracellular pH regulation, several transporter inhibitors were used, and their effect on pH and membrane potential was assayed as described above. Lactacystin treatment significantly induced apoptosis in RPE-J cells. During the RPE cell apoptosis, 1) cytochromec and Smac/DIABLO were released into cytosol from mitochondria, 2) translocation of apoptosis-inducing factor to the nucleus was evident, 3) Bax protein seemed to translocate to mitochondria, 4) procaspase-3 and poly(ADP-ribose) polymerase were cleaved, and 5) nuclear condensation and DNA fragmentation were clearly observed. Noticeably, a transient increase of mitochondrial membrane potential was coincidentally detected with the intracellular alkalinization after lactacystin administration. Furthermore, the lactacystin-induced early alkalinization was inhibited by 4-acetamido-4′-isothiocyanostilbene-2,2′-disulfonate, an inhibitor of Cl−/HCO 3 − anion exchanger, which also prevented early mitochondrial hyperpolarization and apoptosis. Lactacystin-induced apoptosis in RPE-J cells is closely associated with an early mitochondrial hyperpolarization induced by intracellular alkalinization.
The Incidence of Vertebral Fractures in Men and Women: The Rotterdam Study

Vertebral fractures are considered the most common fractures in osteoporosis. Nevertheless, little is known about the epidemiology of these fractures, especially in men. Therefore, the incidence of vertebral fractures was studied in 3469 men and women from the Rotterdam Study. Spinal radiographs were obtained at baseline and again after a mean follow‐up of 6.3 years. The follow‐up radiographs were scored for vertebral fractures using the McCloskey‐Kanis assessment method. Whenever a vertebral fracture was detected, the radiograph was compared with the baseline radiograph. If this fracture was not already present at baseline, it was considered an incident fracture. The incidence increased strongly with age, ranging from 7.8/1000 person years (PY) at ages 55‐65 years to 19.6/1000 PY at ages over 75 years for women, and 5.2‐9.3/1000 PY for men, respectively. Analyses repeated in strata of presence or absence of prevalent vertebral fractures showed that both in men and in women, the increase in incidence with age was almost exclusively observed in subjects with one or more prevalent fractures present at baseline. For both genders, the incidence of vertebral fractures doubled per SD decrease in lumbar spine or femoral neck bone mineral density (BMD). This study shows that overall, the incidence of vertebral fractures is higher in women than in men. In both genders, the incidence increases with age. Furthermore, the presence of a prevalent vertebral fracture and a low BMD are strong independent predictors of incident vertebral fractures in men and women.
Granularity of Locks and Degrees of Consistency in a Shared Data Base

The problem of choosing the appropriate Hranularit~ (size) of lockable objects is introduced and the tradeoff between concurrency and overhead is discusseS. A locking protocol which allows simultaneous locking at various granularities by different transactions is presented. It is based on the introduction of additional lock modes besides the conventional share mode an5 exclusive mode. A proof is given of the equivalence of this protocol to a conventional one.
Single-cell paired-end genome sequencing reveals structural variation per cell cycle

The nature and pace of genome mutation is largely unknown. Because standard methods sequence DNA from populations of cells, the genetic composition of individual cells is lost, de novo mutations in cells are concealed within the bulk signal and per cell cycle mutation rates and mechanisms remain elusive. Although single-cell genome analyses could resolve these problems, such analyses are error-prone because of whole-genome amplification (WGA) artefacts and are limited in the types of DNA mutation that can be discerned. We developed methods for paired-end sequence analysis of single-cell WGA products that enable (i) detecting multiple classes of DNA mutation, (ii) distinguishing DNA copy number changes from allelic WGA-amplification artefacts by the discovery of matching aberrantly mapping read pairs among the surfeit of paired-end WGA and mapping artefacts and (iii) delineating the break points and architecture of structural variants. By applying the methods, we capture DNA copy number changes acquired over one cell cycle in breast cancer cells and in blastomeres derived from a human zygote after in vitro fertilization. Furthermore, we were able to discover and fine-map a heritable inter-chromosomal rearrangement t(1;16)(p36;p12) by sequencing a single blastomere. The methods will expedite applications in basic genome research and provide a stepping stone to novel approaches for clinical genetic diagnosis.
Factor VIII deficiency does not protect against atherosclerosis

See also Makris M, van Veen JJ. Reduced cardiovascular mortality in hemophilia despite normal atherosclerotic load. This issue, pp 20–2; Zwiers M, Lefrandt JD, Mulder DJ, Smit AJ, Gans ROB, Vliegenthart R, Brands‐Nijenhuis AVM, Kluin‐Nelemans JC, Meijer K. Coronary artery calcification score and carotid intima–media thickness in patients with hemophilia. This issue, pp 23–9.
Nonnegative CCA for Audiovisual Source Separation

We present a method for finding correlated components in audio and video signals. The new technique is applied to the task of identifying sources in video and separating them in audio. The concept of canonical correlation analysis is reformulated such that it incorporates nonnegativity and sparsity constraints on the coefficients of projection directions. Nonnegativity ensures that projections are compatible with an interpretation as energy signals. Sparsity ensures that coefficient weight concentrates on individual sources. By finding multiple conjugate directions we finally obtain a component based decomposition of both data modalities. Experiments effectively demonstrate the potential and benefits of this approach.
Protein Folding Modeling with Neural Cellular Automata Using Rosetta

In this work the temporal and dynamic folding of proteins was modeled with neural cellular automata, on the contrary to the ample research performed on the prediction of the final protein structure. Using the Rosetta environment and its coarse-grained representation, starting from an unfolded or partially folded chain, a connectionist model acts like a cellular automaton to define the moves of the dihedral angles of the protein chain. The process is repeated for all the angles of the amino acids and through several time steps until the protein is folded. The neural cellular automaton uses as input information a partial view of the energy landscape, obtained through the consequences in the energy changes when an angle is moved. The neural model learns to decide the best move in each angle in order to minimize the energy of the final folded conformation. The neural cellular automata are automatically obtained by means of differential evolution. Initial results with short proteins are presented and discussed.
Proportions of diether, macrocyclic diether, and tetraether lipids in Methanococcus jannaschii grown at different temperatures

Growth of Methanococcus jannaschii over a wide temperature range (47 to 75 degrees C) is correlated with an ability to alter dramatically the proportions of three ether lipid cores. These lipids shifted from predominantly diether (2,3-di-O-phytanyl-sn-glycerol) at the lower growth temperatures to macrocyclic diether and tetraether at near optimal growth temperatures. Lipid head groups varied as well, especially with respect to an increase in phosphate at the higher temperatures.
Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy

Chimeric antigen receptor (CAR) T cells have been highly successful in treating hematological malignancies, including acute and chronic lymphoblastic leukemia. However, treatment of solid tumors using CAR T cells has been largely unsuccessful to date, partly because of tumor-induced immunosuppressive mechanisms, including adenosine production. Previous studies have shown that adenosine generated by tumor cells potently inhibits endogenous antitumor T cell responses through activation of adenosine 2A receptors (A2ARs). Herein, we have observed that CAR activation resulted in increased A2AR expression and suppression of both murine and human CAR T cells. This was reversible using either A2AR antagonists or genetic targeting of A2AR using shRNA. In 2 syngeneic HER2+ self-antigen tumor models, we found that either genetic or pharmacological targeting of the A2AR profoundly increased CAR T cell efficacy, particularly when combined with PD-1 blockade. Mechanistically, this was associated with increased cytokine production of CD8+ CAR T cells and increased activation of both CD8+ and CD4+ CAR T cells. Given the known clinical relevance of the CD73/adenosine pathway in several solid tumor types, and the initiation of phase I trials for A2AR antagonists in oncology, this approach has high translational potential to enhance CAR T cell efficacy in several cancer types.
Incentivizing electric vehicles to provide regulation while recharging

Electric Vehicles (EV) are drawing tremendous attention, as part of the transition toward environment-friendly transportation. While EV recharging represents a considerable extra load on the grid, they also offer new opportunities in terms of consumption flexibility. In this paper, we use the recharging process of EVs to provide regulation to the grid by varying the instantaneous recharging power. We provide an economic analysis of the incentives at play, including the EV owners point of view (longer recharging durations and impact on battery lifetime versus cheaper energy) and the aggregator point of view (revenues from recharging versus regulation gains). In particular, we analyze the range of regulation rewards such that offering a regulation-oriented recharging benefits both EV owners and the aggregator. Interestingly, we observe that under current market conditions in France, an aggregator could offer regulating EV owners to recharge for 50% cheaper, and still be better off than offering only constant-power recharging.
Expression of Three Cell Adhesion Molecules in Bladder Carcinomas: Correlation with Pathological Features

Recently, independent studies have shown that the expression of two integrin chains, β4 and α2, plus the epithelial cadherin are related to tumour progression in human bladder carcinomas. For the first time, we compare the expression of these three cell adhesion molecules using immunohistochemical analysis of consecutive cryosections from a series of 50 bladder tumours. E‐cadherin, β4, and α2 were strongly expressed in normal urothelium. A majority of non‐invasive bladder cancers stained positively for E‐cadherin (62%), whereas only 29% expressed normal positivity for α2, and only 35% for β4. However, most invasive tumours presented an aberrant expression of α2 (81%), β4 (100%), and E‐cadherin (75%). We studied the correlation of immunoreactivity with histological grade and stage. The α2 pattern was not correlated with stage and grade. In contrast, loss of normal β4 expression was significantly related to increasing tumour grade and deep invasion with a higher correlation for grade. Finally, E‐cadherin expression was highly correlated with stage, but not with grade. Thus our results indicate that, although many invasive bladder tumours presented a disorder in expression of the two integrins α2 and β4, E‐cadherin appeared to be a better marker of invasiveness in bladder carcinomas.
Determination of the effects of pulmonary arterial hypertension and therapy on the cardiovascular system of rats by impedance cardiography

Aim To evaluate the effects of bosentan, sildenafil, and combined therapy on the cardiovascular system using impedance cardiography (ICG) in rats with monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH). Methods Seventy male Wistar-albino rats were randomized into five groups. A single dose of MCT was given to all rats, except to the control group. After 4 weeks, bosentan, sildenafil, and combined treatment was started and lasted for 3 weeks. The last group that developed PAH did not receive any medication. Echocardiographic evaluation was performed to determine the PAH development. Thoracic fluid content index (TFCI), stroke volume index (SI), heart rate (HR), cardiac index (CI), and myocardial contractility index (IC) were determined. All procedures were performed at the baseline and after 4 and 7 weeks. Results Echocardiographic parameters showed that the all MCT-injected rats developed PAH. There were no significant inter- and intra-group differences in TFCI, SI, and IC (P > 0.05), but at the 7th week, CI value in the sildenafil-treated PAH rats was significantly higher than in other groups and HR of PAH rats with combined therapy was significantly lower than in other groups. Conclusion PAH did not have an effect on LV function of rats, or if it did, the effect was compensated by physiological processes. Also, sildenafil treatment deteriorated the LV cardiac index.
Effects of forest harvesting on summer stream temperatures in New Brunswick, Canada: an inter-catchment, multiple-year comparison

Abstract. This paper presents a pre- and post-harvest comparison of stream temperatures collected in five neighbouring streams (sub-catchments) over a period of five years (1994-1998). The aim of the study was to determine whether land cover changes from clear cutting in areas outside forest buffer zones (applied to streams >0.5 m wide) might contribute to an increase in summer mean stream temperatures in buffered streams downslope by infusion of warmed surface and sub-surface water into the streams. Specific relationships were observed in all five forest streams investigated. To assist in the analysis, several spatially-relevant variables, such as land cover change, mid-summer potential solar radiation, flow accumulation, stream location and slope of the land were determined, in part, from existing aerial photographs, GIS-archived forest inventory data and a digital terrain model of the study area. Spatial calculations of insolation levels for July 15th were used as an index of mid-summer solar heating across sub-catchments. Analysis indicated that prior to the 1995 harvest, differences in stream temperature could be attributed to (i) topographic position and catchment-to-sun orientation, (ii) the level of cutting that occurred in the upper catchment prior to the start of the study, and (iii) the average slope within harvested areas. Compared to the pre-harvest mean stream temperatures in 1994, mean temperatures in the three streams downslope from the 1995 harvest areas increased by 0.3 to 0.7°C (representing a 4-8% increase; p-value of normalised temperatures Keywords: terrain attributes, solar radiation, land cover, forest buffers, New Brunswick regulations, spatial modelling, DEM, forest covertypes
Caspase-1 is active since the early phase of rheumatoid arthritis

Background We have previously reported an increase in interleukin (IL)-1β levels in very recent onset arthritis. Therefore, molecular mechanisms that regulate IL-1β secretion, such as caspase-1 activation, might play a relevant role in arthritis onset and progression. Objectives Our main goal was to evaluate caspase-1 state of activation in early polyarthritis and established rheumatoid arthritis (RA) patients. Materials and methods Blood samples were collected from 12 untreated early polyarthritis patients, 12 established RA patients and 10 healthy controls. Caspase-1 activity was assessed using a carboxyfluorescein FLICA detection kit. Results We found that both early polyarthritis and established RA patients have higher active caspase-1 levels. Surprisingly, caspase-1 activation levels in patient cells remain unchanged when cells were stimulated with Escherichia coli and ATP, whereas in control cells caspase-1 levels increased after stimulation. We observed no significant differences when comparing early polyarthritis with established RA samples. However, in RA patients with higher disease activity the proportion of active caspase-1 is higher. Conclusions Our results suggest that leucocytes in both early polyarthritis and established RA patients have high baseline levels of activated caspase-1, which cannot be significantly increased after stimulation. Altogether, our data supports the hypothesis that caspase-1 is activated in early arthritis.
No bad local minima: Data independent training error guarantees for multilayer neural networks

We use smoothed analysis techniques to provide guarantees on the training loss of Multilayer Neural Networks (MNNs) at differentiable local minima. Specifically, we examine MNNs with piecewise linear activation functions, quadratic loss and a single output, under mild over-parametrization. We prove that for a MNN with one hidden layer, the training error is zero at every differentiable local minimum, for almost every dataset and dropout-like noise realization. We then extend these results to the case of more than one hidden layer. Our theoretical guarantees assume essentially nothing on the training data, and are verified numerically. These results suggest why the highly non-convex loss of such MNNs can be easily optimized using local updates (e.g., stochastic gradient descent), as observed empirically.
Appropriate Timing for Thyroidectomy Scar Treatment Using a 1,550‐nm Fractional Erbium‐Glass Laser

BACKGROUND Surgical scarring is a common cosmetic problem that occurs in various surgical fields, including dermatology. Many trials have been conducted to determine how to prevent this distressing scar formation. A 1,550‐nm fractional erbium‐glass laser has been used to improve the appearance of surgical scars, but an appropriate treatment time has not been established. OBJECTIVES To determine the appropriate time to apply 1,550‐nm fractional erbium‐glass laser treatment for thyroidectomy scars. MATERIALS AND METHODS Korean patients with linear surgical suture lines after thyroidectomy (N = 65) were treated using a 1,550‐nm fractional erbium‐glass laser. Patients were divided into three groups according to postoperative treatment time. Laser treatment was started in 40, 15, and 10 patients 3 weeks, 3 months, and 6 months postoperatively, respectively. Each patient was treated three times at 1‐month intervals using the same parameters (14 mJ, 100 spots/cm2, 2 passes). RESULTS Mean Vancouver Scar Scale scores were significantly lower after laser treatment (p < .01), with the greatest difference in the group that began treatment 3 weeks postoperatively. Global assessment also indicated better cosmetic outcomes in the 3‐week postoperative treatment group. CONCLUSION Early postoperative 1,550‐nm fractional erbium‐glass laser treatment of thyroidectomy scars is more effective than later treatment.
Agency and Corporate Purchase of Insurance

Consistent with the agency cost rational, this paper documents that managers having larger private benefits of control purchase more insurance to reduce their own exposure to the probability of left-tail outcomes and hence the volatility of the firm's cash flows. Private benefits of control are estimated by the market value of the right to vote (measured as the difference between the price of the stock and an equivalent synthetic stock that is constructed with options). Our results hold when we control for the probability of a control contest. We also find that firms with larger private benefits of control tend to use more debt.
Reducing the number of embryos transferred in Sweden-impact on delivery and multiple birth rates.

BACKGROUND Reduction of the number of embryos transferred has been introduced to decrease the multiple birth rates (MBRs) after IVF and the associated risks for the children. The aim of this report is to present the effect of two steps in reduction of the number of embryos transferred, when applied in the majority of the patients, on national data for delivery and MBR after IVF in Sweden. METHODS This observational study is based on annual reports from all IVF clinics in Sweden to the National Board of Health and Welfare for the time period 1991-2004. RESULTS The main finding is that despite a successive reduction in the number of embryos transferred, delivery rates were maintained at around 26% while MBR decreased dramatically, from about 35% to around 5%. The same pattern was noticed, independent of age, for all women below 40. In comparison with the USA, lower delivery and MBR were noted for Sweden whereas a higher 'birth per embryo transferred' was found. CONCLUSIONS Single embryo transfer (SET) results in satisfactory delivery rates and a dramatic decrease in the MBRs, also when applied on a broad scale. The experience from Sweden ought to encourage other countries to introduce SET more widely.
Path vs. subpath vs. link restoration for fault management in IP-over-WDM networks: performance comparisons using GMPLS control signaling

We investigate three restoration techniques (path, subpath, and link restoration) for fault management in an IP-over-WDM network. We have implemented all of these techniques on the ns-2 simulation platform using generalized multiprotocol label switching (GMPLS) control signaling. These techniques can handle practical situations such as simultaneous multiple fiber failures, which are difficult to design for and recover from by nonrestoration techniques. We then present performance measurement results for the three restoration techniques by applying them to a typical nationwide mesh network running IP over WDM. We investigate interesting trade-offs in the performance of the restoration techniques on restoration success rate, average restoration time, availability, and blocking probability.