Ligand-engaged TCR is triggered by Lck not associated with CD8 coreceptor

Producción CientíficaThe earliest molecular events in T-cell recognition have not yet been fully described, and the initial T-cell receptor (TCR)-triggering mechanism remains a subject of controversy. Here, using total internal reflection/Forster resonance energy transfer microscopy, we observe a two-stage interaction between TCR, CD8 and major histocompatibility complex (MHC)-peptide. There is an early (within seconds) interaction between CD3ζ and the coreceptor CD8 that is independent of the binding of CD8 to MHC, but that requires CD8 association with Lck. Later (several minutes) CD3ζ–CD8 interactions require CD8–MHC binding. Lck can be found free or bound to the coreceptor. This work indicates that the initial TCR-triggering event is induced by free Lck. The early signalling events that trigger initial T-cell receptor signalling are not clearly defined. Here the authors show that this occurs in two stages, the first between the CD8 coreceptor and CD3 requiring Lck association to CD8, while the second interaction requires binding of major histocompatibility molecules

Roles of MSH2 and MSH6 in cadmium-induced G2/M checkpoint arrest in Arabidopsis roots

DNA mismatch repair (MMR) proteins have been implicated in sensing and correcting DNA damage, and in governing cell cycle progression in the presence of structurally anomalous nucleotide lesions induced by different stresses in mammalian cells. Here, Arabidopsis seedlings were grown hydroponically on 0.5 × MS media containing cadmium (Cd) at 0–4.0 mg L−1 for 5 d. Flow cytometry results indicated that Cd stress induced a G2/M cell cycle arrest both in MLH1-, MSH2-, MSH6-deficient, and in WT roots, associated with marked changes of G2/M regulatory genes, including ATM, ATR, SOG1, BRCA1, WEE1, CYCD4; 1, MAD2, CDKA;1, CYCB1; 2 and CYCB1; 1. However, the Cd-induced G2/M phase arrest was markedly diminished in the MSH2- and MSH6-deficient roots, while a lack of MLH1 had no effect on Cd-induced G2 phase arrest relative to that in the wild type roots under the corresponding Cd stress. Expression of the above G2/M regulatory genes was altered in MLH1, MSH2 and MSH6-deficient roots in response to Cd treatment. Furthermore, Cd elicited endoreplication in MSH2- and MSH6-deficient roots, but not in MLH1-deficient Arabidopsis roots. Results suggest that MSH2 and MSH6 may act as direct sensors of Cd-mediated DNA damage. Taken together, we conclude that MSH2 and MSH6, but not MLH1, components of the MMR system are involved in the G2 phase arrest and endoreplication induced by Cd stress in Arabidopsis roots

Study of brain network alternations in non-lesional epilepsy patients by BOLD-fMRI

ObjectiveTo investigate the changes of brain network in epilepsy patients without intracranial lesions under resting conditions.MethodsTwenty-six non-lesional epileptic patients and 42 normal controls were enrolled for BOLD-fMRI examination. The differences in brain network topological characteristics and functional network connectivity between the epilepsy group and the healthy controls were compared using graph theory analysis and independent component analysis.ResultsThe area under the curve for local efficiency was significantly lower in the epilepsy patients compared with healthy controls, while there were no differences in global indicators. Patients with epilepsy had higher functional connectivity in 4 connected components than healthy controls (orbital superior frontal gyrus and medial superior frontal gyrus, medial superior frontal gyrus and angular gyrus, superior parietal gyrus and paracentral lobule, lingual gyrus, and thalamus). In addition, functional connectivity was enhanced in the default mode network, frontoparietal network, dorsal attention network, sensorimotor network, and auditory network in the epilepsy group.ConclusionThe topological characteristics and functional connectivity of brain networks are changed in in non-lesional epilepsy patients. Abnormal functional connectivity may suggest reduced brain efficiency in epilepsy patients and also may be a compensatory response to brain function early at earlier stages of the disease

Relationship between the Three Laws of Dialectics of Nature and Agricultural Development

Based on the three laws of dialectics of nature-the law of unity of opposites, the law of mutual change of quality and the law of negation of negation, this paper analyzes the relationship between the three laws and agricultural development, and proposes making good use of the three laws to promote the better development of agriculture and realize agricultural modernization

Relationship between the Three Laws of Dialectics of Nature and Agricultural Development

Based on the three laws of dialectics of nature-the law of unity of opposites, the law of mutual change of quality and the law of negation of negation, this paper analyzes the relationship between the three laws and agricultural development, and proposes making good use of the three laws to promote the better development of agriculture and realize agricultural modernization

Operations research models of climate change mitigation and adaptation strategies at diverse scales

The impacts of climate change are beyond the observable effects on the environment and it requires extensive efforts in all aspects of society to take actions and ensure a sustainable future. Therefore, it is crucial for policymakers to understand the associated risks, plan for the adverse impacts brought by climate change and make informed decisions. To assist this, through a variety of operations research models and case studies from three projects, this dissertation examines climate change mitigation and adaptation strategies and explores relevant policy implications at three different scales: the urban city level, the individual project level, and the national level. Chapter 2 focuses on vehicle fuel efficiency policies at the urban scale. Given the large and rapidly increasing share of global energy consumption taking place in cities, it becomes crucial to understand the interactions between urban form and energy consumption and avoid unintended policy consequences. By extending the classic monocentric city model to incorporate endogenous investment in vehicle fuel efficiency by households, we investigate the systemic impacts of vehicle fuel efficiency on urban form and urban form feedbacks for energy consumption in cities. We prove analytically that raising vehicle fuel efficiency induces a more compact urban form if households are underinvesting in efficiency, but a more sprawling urban form if efficiency is increased beyond the rational household optimum. In the former case, the urban form adjustment further reduces energy use in the transportation and residential sectors. In the latter case, the urban form adjustment increases vehicle travel, which offsets at least some of the direct reduction in transportation energy use stemming from the efficiency improvement (direct rebound). Additionally, its larger homes demand more energy in the residential sector (indirect rebound). Numerical illustrations are included to confirm the analytical findings for a stylized city. Chapter 3 addresses decision-making under uncertainty on infrastructure resilience upgrade programs. As climate change threatens to cause increasingly frequent and severe natural disasters, decision-makers must consider costly investments to enhance the resilience of critical infrastructures. Evaluating these potential resilience improvements using traditional cost-benefit analysis (CBA) approaches is often problematic because disasters are stochastic and can destroy even hardened infrastructure, meaning that the lifetimes of investments are themselves uncertain. In this work, we develop a novel Markov decision process (MDP) model for CBA of infrastructure resilience upgrades that offer prevention (reduce the probability of a disaster) and/or protection (mitigate the cost of a disaster) benefits. Stochastic features of the model include disaster occurrences and whether or not a disaster terminates the effective life of an earlier resilience upgrade. From our MDP model, we derive analytical expressions for the decision-maker’s willingness to pay (WTP) to enhance infrastructure resilience and conduct a comparative static analysis to investigate how the WTP varies with the fundamental parameters of the problem. The applicability of this MDP framework is demonstrated by two case studies of electric utility infrastructure hardening programs. The first case study considers elevating a flood-prone substation and the second evaluates upgrading transmission structures to withstand high winds. Results from these two case studies show that assumptions about the value of lost load during power outages and the distribution of customer types significantly influence the WTP for the resilience upgrades and are material to the decisions of whether or not to implement them. In Chapter 4, we use the US-TIMES model to explore the decarbonization pathways in the U.S. by modeling portfolios of granular sectoral mitigation policies in the electricity, transportation and buildings sectors. By combining the complementary dimensions of techno-economic and political-organizational feasibilities, we design three different policy scenarios based on portfolios of sectoral mitigation policies that would be politically feasible under Low Alignment, Medium Alignment and High Alignment scenarios of the federal government’s commitment to reducing GHG emissions. We compare these three scenarios with the business-as-usual (BAU) scenario and a stylized 80% system-wide decarbonization scenario. This work contributes to the literature by incorporating granular sectoral climate policies in an energy system optimization to enhance policy realism. Our findings highlight the significance of decarbonizing the electricity sector and electrifying the other sectors such as transportation to cost-effectively reduce GHG emissions. Given the complexity of the energy system, the effectiveness of sectoral policies should be evaluated from a systems level. Our findings also reveal that the GHG emissions reduction relative to 2010’s emissions in Low Alignment, Medium Alignment and High Alignment scenarios are 24.4%, 36.5%, and 44.3%, respectively. The average abatement costs of employing these portfolios of policies are $16.2,$15.8 and $12.8/tCO2e, which are 4.1, 2.1, 1.6 times as high as the average abatement costs obtained through the optimal (least system-wide cost) decarbonization pathways. The AACs that we obtain in this study is lower than mainstream estimates of Social Cost of Carbon (Interagency Working Group on Social Cost of Greenhouse Gases, 2015; Nordhaus, 2017). This suggests that even if political considerations mean that we do not necessarily follow the most cost-effective approach to decarbonize the economy, there are still likely to be net benefits. Each of these three projects, on its scale, captures the underlying characteristics of climate change mitigation or adaptation strategies. While the focus of each project varies, they serve the common goal of providing system-wide and high-level insights on decision-making for cost-effectively reducing GHG emissions or adapting to the impacts of climate change.Mechanical Engineerin

Salivary gland tumours: a combined morphometric, flow cytometric and immunohistochemical analysis

published_or_final_versionAnatomyDoctoralDoctor of Philosoph