Miracle-dz/UniFAR-FTUs huggingface dataset:
Optknock: A bilevel programming framework for identifying gene knockout strategies for microbial strain optimization

The advent of genome‐scale models of metabolism has laid the foundation for the development of computational procedures for suggesting genetic manipulations that lead to overproduction. In this work, the computational OptKnock framework is introduced for suggesting gene deletion strategies leading to the overproduction of chemicals or biochemicals in E. coli. This is accomplished by ensuring that a drain towards growth resources (i.e., carbon, redox potential, and energy) must be accompanied, due to stoichiometry, by the production of a desired product. Computational results for gene deletions for succinate, lactate, and 1,3‐propanediol (PDO) production are in good agreement with mutant strains published in the literature. While some of the suggested deletion strategies are straightforward and involve eliminating competing reaction pathways, many others suggest complex and nonintuitive mechanisms of compensating for the removed functionalities. Finally, the OptKnock procedure, by coupling biomass formation with chemical production, hints at a growth selection/adaptation system for indirectly evolving overproducing mutants. © 2003 Wiley Periodicals. Biotechnol Bioeng 84: 647–657, 2003.
Survival of the Currently Fittest: Genetics of Rainbow Trout Survival Across Time and Space

As a fitness trait, survival is assumed to exhibit low heritability due to strong selection eroding genetic variation and/or spatio-temporal variation in mortality agents reducing genetic and increasing residual variation. The latter phenomenon in particular may contribute to low heritability in multigeneration data, even if certain cohorts exhibit significant genetic variation. Analysis of survival data from 10 year classes of rainbow trout reared at three test stations showed that treating survival as a single trait across all generations resulted in low heritability (h2 = 0.08–0.17). However, when heritabilities were estimated from homogeneous generation and test station-specific cohorts, a wide range of heritability values was revealed (h2 = 0.04–0.71). Of 64 genetic correlations between different cohorts, 20 were positive, but 16 were significantly negative, confirming that genetic architecture of survival is not stable across generations and environments. These results reveal the existence of hidden genetic variation for survival and demonstrate that treating survival as one trait over several generations may not reveal its true genetic architecture. Negative genetic correlations between cohorts indicate that overall survival has limited potential to predict general resistance, and care should be taken when using it as selection criterion.
Retirement Effects on Health in Europe

What are the health impacts of retirement? As talk of raising retirement ages in pensions and social security schemes continues around the world, it is important to know both the costs and benefits for the individual, as well as the governments' budgets. In this paper we use the Survey of Health, Ageing and Retirement in Europe (SHARE) dataset to address this question in a multi-country setting. We use country-specific early and full retirement ages as instruments for retirement behavior. These statutory retirement ages clearly induce retirement, but are not related to an individual's health. Exploiting the discontinuities in retirement behavior across countries, we find significant evidence that retirement has a health-preserving effect on overall general health. Our estimates indicate that retirement leads to a 35 percent decrease in the probability of reporting to be in fair, bad, or very bad health, and an almost one standard deviation improvement in the health index. While the self-reported health seems to be a temporary impact, the health index indicates there are long-lasting health differences.
Navigation of Magnetic Microrobots With Different User Interaction Levels

Micro-technologies based on wirelessly powered and manoeuvred submillimeter device, i.e.,microrobots, are attracting growing attention. Their application in lab-on-a-chip systems, such as micromanipulation and in vitro cell sorting, is expected to steeply increase. However, the actuation, powering and control of microrobots are challenges that still need concrete solutions. Magnetic fields generally enable wireless navigation of microrobots, but proper control architectures and magnetic navigation systems are needed, depending on the specific task and on the level of interaction required to the user. Here we present a magnetic navigation platform intended for lab-on-a-chip applications and we address its usability with different levels of human involvement by using two control architectures: teleoperated and autonomous. We perform an experimental analysis to demonstrate that both architectures, enrolling different levels of interaction by the user, lead to reliable execution of the microrobotic task. First, we validate the open-loop response of the microrobotic system, and second, we evaluate the performance of the system by testing both control architectures with a standard mobility task. The results show that users can teleoperate the microrobot with 100% success rate, in 14.4±1.9s with a normalized spatial mean error of 0.60±0.13. Moreover, results show a fast decaying learning curve for the users involved in the study. Compared to this, when the navigation task is performed by the autonomous control, 100% success rate, a time of 8.0±0.5s and a normalized spatial mean error of 0.50±0.05 are obtained. Finally, we quantitatively demonstrate how both control methodologies enable very smooth movements of the microrobot, suggesting application for any task where repeatable and dexterous movements in liquid microenvironments are key requirements.
Complexity of Coordinating Autonomous Planning Agents

We consider the problem of coordinating autonomous agents that have to perform a joint task. This joint task consists of a set of elementary tasks, partially ordered by a set of precedence constraints. Each agent is assigned (using some given task allocation protocol) a subset of the available tasks. We assume that agents wish to be fully independent during the planning process, yet they are dependent on each other because of the precedences between tasks allocated to different agents. In this paper we concentrate on the following coordination problem: how to offer complete autonomy for the participating agents in planning their part of the tasks, while at the same time guaranteeing that the individually constructed feasible plans (whatever they may be) are fully respected in constructing the joint plan. As we will see, this problem comes down to finding a minimal set of additional constraints (a coordination set) such that after adding these constraints a combined plan for executing all tasks can be achieved by simply joining whatever plans have been developed by the individual agents. We show that this problem can be decomposed into two subproblems: verifying that a given set of additional constraints is a coordination set, i.e., allows agents to plan independently (the coordination verification problem), and finding out whether a coordination set is of minimal size (the minimal coordination problem). We will show that the coordination verification problem alone is co-NPcomplete. In the general case, if the only dependencies are precedence constraints between tasks, the coordination problem is Σp2-complete; if we also allow simultaneity constraints between tasks (i.e., constraints specifying that tasks may not be performed simultaneously), then the coordination problem is Πp3-complete. Even rather simple cases of the coordination problem turn out to be intractable and we show that it is very unlikely that constant-ratio approximation algorithms for this problem exist even if each agent has only a trivial planning task to perform.
Cellular Neuroscience

former preferentially synthesizes GABA for vesicular release, the latter for cytoplasmic stores (Soghomonian and Martin, 1998). Indeed, ratio of GAD 65 to GAD 67 is higher in synaptic vesicle fractions than in cytosol (Solimena et al., 1993). GAD 65 may be anchored to synaptic vesicles by forming a complex that includes the vesicular GABA transporter VGAT, an integral membrane protein of synaptic vesicles responsible for their filling (McIntire et al., 1997). This may provide a structural and functional coupling between synthesis and vesicular packaging of GABA (Hsu et al., 2000; Jin et al., 2003). Interestingly, [ 3 H]GABA newly synthesized from [ 3 H]Glu by synaptic vesicle-associated GAD is taken up preferentially into vesicles over cytosolic GABA (Jin et al., 2003). Minor sources of GABA, such as putrescine, spermine, spermidine, and ornithine, offer a negligible contribution to releasable GABA. Glu used for GABA synthesis may originate from diverse sources. Glu–GABA/glutamine cycle Glutamate derived from glutamine (Gln) is an important GABA precursor (Bradford et al., 1983; Sonnewald et al., 1993). Released GABA is taken up by astrocytic transporters (i.e., GAT-3; Minelli et al., 1996), and catabolized to the tricarboxylic acid (TCA) cycle intermediate succinate by GABA transaminase and succinate semialdehyde dehy-drogenase; the resulting α-ketoglutarate is then transformed to Glu which is converted to Gln by Gln synthetase (Martinez-Hernandez et al., 1977). Gln is then extruded from astrocytes by SNAT3, a system N transporter (Chaudry et al., 1999, 2002; Boulland et al., 2002), and taken up by axon terminals. Gln influx into neurons is thought to be mediated by SNAT1 and/or SNAT2, two system A transporters (Fricke et al., 2007); this view is compatible with expression of
Iron isomaltoside 1000: a new intravenous iron for treating iron deficiency in chronic kidney disease.

BACKGROUND Patients with chronic kidney disease (CKD) often suffer from iron deficiency anemia necessitating treatment with intravenous iron. This study was designed to assess the safety of iron isomaltoside 1000 (Monofer) in CKD patients. The secondary objective was to assess its effect on iron deficiency anemia. METHODS This open-label, noncomparative, multicenter trial assigned 182 patients with CKD (n=161 in dialysis and n=21 in predialysis) to iron isomaltoside 1000 either as 4 intravenous bolus injections of 100-200 mg iron per dose or as a fast high-dose infusion at baseline. Patients were generally undergoing erythropoiesis-stimulating agent (ESA) treatment (82%), and the dosage was to be kept constant during the trial. They were either switched from an existing parenteral maintenance therapy (n=144) or were not currently being treated with parenteral iron (n=38). Frequency of adverse events (AEs) and changes in markers of iron deficiency anemia were measured during 8 weeks from baseline. RESULTS Nineteen treatment-related AEs occurred in 13 patients (7.1%) and after 584 treatments (3.3%). No anaphylactic or delayed allergic reactions were observed. There were no clinically significant changes in routine clinical laboratory tests or vital signs. Hemoglobin increased from 99.2 g/L (SD=9.0) at baseline to 111.2 g/L (SD=14.7) at week 8 in patients not currently treated with parenteral iron (p<0.001) and increased slightly or stabilized in patients in maintenance therapy. S-Ferritin, s-iron and transferrin saturation increased significantly at all visits. CONCLUSIONS Iron isomaltoside 1000 was clinically well tolerated, safe and effective. This new intravenous iron may offer a further valuable choice in treating the anemia of CKD.
Evaluation of Indigenous Grass Species Suitability for Rehabilitation of Degraded Semi-arid Rangeland in Suswa, Kenya

Land degradation is a major problem facing rangelands globally leading to diminished production capacity of these fragile ecosystems. This reduces their potential to provide ecosystem services such as provision of feed and food increasing communities’ vulnerability to droughts and other effects of climate change. Land degradation can be reversed by planting and protecting grasses to provide soil cover and enhance soil physical and chemical properties aimed at controlling soil erosion. Different grass species are used for land rehabilitation for varied reasons among communities. These vary with location, communities’ needs and priorities, preferences and type of livestock species reared. There is a need therefore for site-specific studies, to take into account the unique indigenous knowledge pool and livelihood preferences to inform rehabilitation efforts using grasses among rangeland communities. This study investigated grass species preferences for rangeland rehabilitation among pastoral community in Suswa, southern Kenya and the reasons underlying these preferences. Household surveys, focus group discussions and key informant interviews were used to assess community’s perceptions of the existing grass species and their suitability for range rehabilitation. Descriptive analysis revealed that Cynodon plectostachyus (76%), Chloris gayana (73%), Pennisetum clandestinum (69%), Cymbopogon citratus (46%) and Themeda triandra (42%) were the most preferred species for range rehabilitation. Additionally, grasses perceived to be suitable for range rehabilitation were those with high grazing value to the livestock. This study shows that the
A Dynamic Multisectoral Analysis of Jordan's Trade Liberalisation

This paper aims at assessing the impact on the Jordanian economy of the implementation of the Association Agreement (AA) with the European Union (EU). The Agreement between Jordan and the EU entered into force in 2002. It eliminates progressively tariffs on industrial goods imported by Jordan from the EU, and leads eventually to the creation of a free-trade area between Jordan and the EU in 2014. Custom duties on agricultural products imported by Jordan from the EU are subject to a gradual, but partial reduction. Given the negative impact of trade liberalisation on government revenue, counteracting fiscal measures are required in order to offset the loss in government revenue. In order to capture intertemporal and intersectoral effects brought about by trade liberalisation on the domestic economy, a multisectoral and dynamic CGE model is specified and calibrated to simulate the implementation of the preferential trade agreement with the EU and non-discriminatory trade liberalisation.
Low-cost accurate skeleton tracking based on fusion of kinect and wearable inertial sensors

In this paper, we present a novel multi-sensor fusion method to build a human skeleton. We propose to fuse the joint position information obtained from the popular Kinect sensor with more precise estimation of body segment orientations provided by a small number of wearable inertial sensors. The use of inertial sensors can help to address many of the well known limitations of the Kinect sensor. The precise calculation of joint angles potentially allows the quantification of movement errors in technique training, thus facilitating the use of the low-cost Kinect sensor for accurate biomechanical purposes e.g. the improved human skeleton could be used in visual feedback-guided motor learning, for example. We compare our system to the gold standard Vicon optical motion capture system, proving that the fused skeleton achieves a very high level of accuracy.
Synthesizing checkers for on-line verification of System-on-Chip designs

In modern System-on-Chip (SoC) designs verification becomes the major bottleneck. Since by using state-of-the-art techniques complete designs cannot be fully formally verified, it becomes more and more important to check the correct behaviour during operation. This becomes even more significant in systems that are changed during lifetime, like re-configurable systems. In this paper we present a hardware extension that allows to efficiently synthesize checkers and properties that have been used in the verification process. This allows for an on-line verification of SoC designs. For the verification hardware a regular layout is discussed that can easily be synthesized and has a very low area overhead. The on-line check has (nearly) no effect on the delay of the considered chip.
Dynamics of Dynamin during Clathrin Mediated Endocytosis in PC12 Cells

Background Members of the dynamin super-family of GTPases are involved in disparate cellular pathways. Dynamin1 and dynamin2 have been implicated in clathrin-mediated endocytosis. While some models suggest that dynamin functions specifically at the point of vesicle fission, evidence also exists for a role prior to fission during vesicle formation and it is unknown if there is a role for dynamin after vesicle fission. Although dynamin2 is ubiquitously expressed, dynamin1 is restricted to the nervous system. These two structurally similar endocytic accessory proteins have not been studied in cells that endogenously express both. Methodology/Principal Findings The present study quantitatively assesses the dynamics of dynamin1 and dynamin2 during clathrin-mediated endocytosis in PC12 cells, which endogenously express both proteins. Both dynamin isoforms co-localized with clathrin and showed sharp increases in fluorescence intensity immediately prior to internalization of the nascent clathrin-coated vesicle. The fluorescence intensity of both proteins then decreased with two time constants. The slower time constant closely matched the time constant for the decrease of clathrin intensity and likely represents vesicle movement away from the membrane. The faster rate may reflect release of dynamin at the neck of nascent vesicle following GTP hydrolysis. Conclusions/Significance This study analyses the role of dynamin in clathrin-mediated endocytosis in a model for cellular neuroscience and these results may provide direct evidence for the existence of two populations of dynamin associated with nascent clathrin-coated vesicles.
Electro–magneto-encephalography for a three-shell model: distributed current in arbitrary, spherical and ellipsoidal geometries

The problem of determining a continuously distributed neuronal current inside the brain under the assumption of a three-shell model is analysed. It is shown that for an arbitrary geometry, electroencephalography (EEG) provides information about one of the three functions specifying the three components of the current, whereas magnetoencephalography (MEG) provides information about a combination of this function and of one of the remaining two functions. Hence, the simultaneous use of EEG and MEG yields information about two of the three functions needed for the reconstruction of the current. In particular, for spherical and ellipsoidal geometries, it is possible to determine the angular parts of these two functions as well as to obtain an explicit constraint satisfied by their radial parts. The complete determination of the radial parts, as well as the determination of the third function, requires some additional a priori assumption about the current. One such assumption involving harmonicity is briefly discussed.
Changes in Weight and Glucose Can Protect Against Progression in Early Diabetes Independent of Improvements in β-Cell Function.

CONTEXT Evidence-based strategies to prevent progression of dysglycemia in newly diagnosed type 2 diabetes are needed. OBJECTIVE To undertake a secondary analysis of the Early Diabetes Intervention Program (EDIP) in order to understand the features that were protective against worsening glycemia. DESIGN EDIP was a randomized, placebo-controlled trial. SETTING Two university diabetes centers. PATIENTS A total of 219 overweight individuals with fasting glucose < 7.8 mmol/L and 2-hour oral glucose tolerance test (OGTT) glucose > 11.1 mmol/L. INTERVENTIONS Acarbose versus placebo, on a background of dietary recommendations, with quarterly visits to assess glycemia and intervention adherence for up to 5 years. MAIN OUTCOME MEASURES Progression of fasting glucose ≥ 7.8 mmol/L on two consecutive quarterly visits. Cox proportional hazards modeling and ANOVA were performed to evaluate determinants of progression. RESULTS Progression-free status was associated with reductions in weight, fasting glucose, 2-hour OGTT glucose, and increases in the high-density lipoprotein/triglyceride ratio. The reduction in fasting glucose was the only effect that remained significantly associated with progression-free status in multivariable Cox modeling. The reduction in fasting glucose was in turn primarily associated with reductions in weight and in 2-hour OGTT glucose. Acarbose treatment did not explain these changes. CONCLUSIONS In early diabetes, reductions in glucose, driven by reductions in weight, can delay progressive metabolic worsening. These observations underscore the importance of lifestyle management including weight loss as a tool to mitigate worsening of glycemia in newly diagnosed diabetes.
Design and crystal structure of a native-like HIV-1 envelope trimer that engages multiple broadly neutralizing antibody precursors in vivo

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4. 1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.
Activating transcription factor 2 controls Bcl‐2 promoter activity in growth plate chondrocytes

Activating transcription factor 2 (ATF‐2) is expressed ubiquitously in mammals. Mice deficient in ATF‐2 (ATF‐2 m/m) are slightly smaller than their normal littermates at birth. Approximately 50% of mice born mutant in both alleles die within the first month. Those that survive develop a hypochondroplasia‐like dwarfism, characterized by shortened growth plates and kyphosis. Expression of ATF‐2 within the growth plate is limited to the resting and proliferating zones. We have previously shown that ATF‐2 targets the cyclic AMP response element (CRE) in the promoters of cyclin A and cyclin D1 in growth plate chondrocytes to activate their expression. Here, we demonstrate that Bcl‐2, a cell death inhibitor that regulates apoptosis, is expressed within the growth plate in proliferative and prehypertrophic chondrocytes. However, Bcl‐2 expression declines in hypertrophic chondrocytes. The Bcl‐2 promoter contains a CRE at −1,552 bp upstream of the translation start. Mutations within this CRE cause reduced Bcl‐2 promoter activity. We show here that the absence of ATF‐2 in growth plate chondrocytes corresponds to a decline in Bcl‐2 promoter activity, as well as a reduction in Bcl‐2 protein levels. In addition, we show that ATF‐2 as well as CREB, a transcription factor that can heterodimerize with ATF‐2, bind to the CRE within the Bcl‐2 promoter. These data identify the Bcl‐2 gene as a novel target of ATF‐2 and CREB in growth plate chondrocytes. J. Cell. Biochem. 101: 477–487, 2007. © 2007 Wiley‐Liss, Inc.