Protein tyrosine phosphatase PTPN22 regulates LFA-1 dependent Th1 responses

A missense C1858T single nucleotide polymorphism within PTPN22 is a strong genetic risk factor for the development of multiple autoimmune diseases. PTPN22 encodes a protein tyrosine phosphatase that negatively regulates immuno-receptor proximal Src and Syk family kinases. Notably, PTPN22 negatively regulates kinases downstream of T-cell receptor (TCR) and LFA-1, thereby setting thresholds for T-cell activation. Alterations to the quality of TCR and LFA-1 engagement at the immune synapse and the regulation of downstream signals can have profound effects on the type of effector T-cell response induced. Here we describe how IFNγ+ Th1 responses are potentiated in Ptpn22−/− T-cells and in T-cells from mice expressing Ptpn22R619W (the mouse orthologue of the human genetic variant) as they age, or following repeated immune challenge, and explore the mechanisms contributing to the expansion of Th1 cells. Specifically, we uncover two LFA-1-ICAM dependent mechanisms; one T-cell intrinsic, and one T-cell extrinsic. Firstly, we found that in vitro anti-CD3/LFA-1 induced Th1 responses were enhanced in Ptpn22−/− T-cells compared to WT, whereas anti-CD3/anti-CD28 induced IFNy responses were similar. These data were associated with an enhanced ability of Ptpn22−/− T-cells to engage ICAM-1 at the immune synapse when incubated on planar lipid bilayers, and to form conjugates with dendritic cells. Secondly, we observed a T-cell extrinsic mechanism whereby repeated stimulation of WT OT-II T-cells with LPS and OVA323-339 pulsed Ptpn22−/− bone marrow derived dendritic cells (BMDCs) was sufficient to enhance Th1 cell development compared to WT BMDCs. Furthermore, this response could be reversed by LFA-1 blockade. Our data point to two related but distinct mechanisms by which PTPN22 regulates LFA-1 dependent signals to enhance Th1 development, highlighting how perturbations to PTPN22 function over time to regulate the balance of the immune response

Critical role for Gimap5 in the survival of mouse hematopoietic stem and progenitor cells

HSCs lacking the guanosine nucleotide-binding protein Gimap5, which stabilizes expression of the Mcl-1 Bcl2 family protein, exhibit impaired survival and long-term repopulation capacity

PaLM: Scaling Language Modeling with Pathways

Large language models have been shown to achieve remarkable performance across a variety of natural language tasks using few-shot learning, which drastically reduces the number of task-specific training examples needed to adapt the model to a particular application. To further our understanding of the impact of scale on few-shot learning, we trained a 540-billion parameter, densely activated, Transformer language model, which we call Pathways Language Model PaLM. We trained PaLM on 6144 TPU v4 chips using Pathways, a new ML system which enables highly efficient training across multiple TPU Pods. We demonstrate continued benefits of scaling by achieving state-of-the-art few-shot learning results on hundreds of language understanding and generation benchmarks. On a number of these tasks, PaLM 540B achieves breakthrough performance, outperforming the finetuned state-of-the-art on a suite of multi-step reasoning tasks, and outperforming average human performance on the recently released BIG-bench benchmark. A significant number of BIG-bench tasks showed discontinuous improvements from model scale, meaning that performance steeply increased as we scaled to our largest model. PaLM also has strong capabilities in multilingual tasks and source code generation, which we demonstrate on a wide array of benchmarks. We additionally provide a comprehensive analysis on bias and toxicity, and study the extent of training data memorization with respect to model scale. Finally, we discuss the ethical considerations related to large language models and discuss potential mitigation strategies

PaLM 2 Technical Report

We introduce PaLM 2, a new state-of-the-art language model that has better multilingual and reasoning capabilities and is more compute-efficient than its predecessor PaLM. PaLM 2 is a Transformer-based model trained using a mixture of objectives. Through extensive evaluations on English and multilingual language, and reasoning tasks, we demonstrate that PaLM 2 has significantly improved quality on downstream tasks across different model sizes, while simultaneously exhibiting faster and more efficient inference compared to PaLM. This improved efficiency enables broader deployment while also allowing the model to respond faster, for a more natural pace of interaction. PaLM 2 demonstrates robust reasoning capabilities exemplified by large improvements over PaLM on BIG-Bench and other reasoning tasks. PaLM 2 exhibits stable performance on a suite of responsible AI evaluations, and enables inference-time control over toxicity without additional overhead or impact on other capabilities. Overall, PaLM 2 achieves state-of-the-art performance across a diverse set of tasks and capabilities. When discussing the PaLM 2 family, it is important to distinguish between pre-trained models (of various sizes), fine-tuned variants of these models, and the user-facing products that use these models. In particular, user-facing products typically include additional pre- and post-processing steps. Additionally, the underlying models may evolve over time. Therefore, one should not expect the performance of user-facing products to exactly match the results reported in this report

Research on Adsorption, Permeation and Filtration Kinetics in Chemical Protection Technology

The dynamic research status of three processes in chemical protection technology, namely, adsorption of steam by activated carbon, permeation of solvent by polymer film and filtering aerosol by cigarette paper were studied in this paper. The advantages and disadvantages of each model were analyzed, and the dynamic behaviors of the three processes were fully understood, which can effectively guide the research and development of chemical defense equipment and chemical defense of troops. It provides a reference for the study of the dynamic theory of the three processes

Study on Hydrolysis Reaction Rate of Several Chemical Warfare Agents

According to the first-order kinetic reaction equation, the hydrolysis rate constants of homogeneous and heterogeneous phase of eight poisons under different conditions were calculated, and the relationship between hydrolysis rate constants and temperature was obtained according to the arrhenius formula, and the activation energy of hydrolysis reaction of some poisons was calculated. The evolution curve of homogeneous hydrolysis rate of 0.5 g/L HD with time was collected by T-135 method, and the hydrolysis rate was 0.1 min-1 and the half-life was 7 min. Poison concentration, pH of system, environmental temperature and structural composition of soil all affect the hydrolysis rate of Chemical Warfare Agents

Study on the Application of New Materials in Chemical Protective Clothing

It is necessary to protect the safety of people in certain occupations where they might be exposed to hazardous chemicals. This review provided an overview of chemical protective clothing, along with its necessity during industrial and military operations as well as in response to acts of terror. Moreover, chemical protection or barrier suits are illustrated and explained including their types, selection processes based on chemical hazards, working environments, and various materials available for the fabrication of effective barrier clothing. Additionally, the current research gaps were elucidated in this review, so as the challenges facing recently developed chemical protective clothing, and relevant research are compiled onto a single platform. Moreover, the future development trend of chemical protective equipment based on new materials and technologies was also explored and analyzed

Government regulation and associated innovations in building energy-efficiency supervisory systems for large-scale public buildings in a market economy

The supervision of energy efficiency in government office buildings and large-scale public buildings is the main embodiment for government implementation of Public Administration in the fields of resource saving and environmental protection. Aimed at improving the current situation of lack of government administration in building energy efficiency, this paper proposes the concept of "change and redesign of governmental supervision in building energy efficiency", repositioning the role of government supervision. Based on this theory and other related theories in regulation economic and modern management, this paper analyzes and researches the action and function of all level governments in execution of the supervisory system of building energy efficiency in government office buildings and large-scale public buildings. This paper also defines the importance of government supervision in energy-efficiency system. Finally, this paper analyzes and researches the interaction mechanism between government and owners of different type buildings, government and energy-efficiency service institution with gambling as main features. This paper also presents some measurements to achieve a common benefit community in implementation of building energy-efficiency supervisory system.Energy efficiency supervision Government regulation Common benefit community

Titanium Dioxide: From Engineering to Applications

Titanium dioxide (TiO2) nanomaterials have garnered extensive scientific interest since 1972 and have been widely used in many areas, such as sustainable energy generation and the removal of environmental pollutants. Although TiO2 possesses the desired performance in utilizing ultraviolet light, its overall solar activity is still very limited because of a wide bandgap (3.0⁻3.2 eV) that cannot make use of visible light or light of longer wavelength. This phenomenon is a deficiency for TiO2 with respect to its potential application in visible light photocatalysis and photoelectrochemical devices, as well as photovoltaics and sensors. The high overpotential, sluggish migration, and rapid recombination of photogenerated electron/hole pairs are crucial factors that restrict further application of TiO2. Recently, a broad range of research efforts has been devoted to enhancing the optical and electrical properties of TiO2, resulting in improved photocatalytic activity. This review mainly outlines state-of-the-art modification strategies in optimizing the photocatalytic performance of TiO2, including the introduction of intrinsic defects and foreign species into the TiO2 lattice, morphology and crystal facet control, and the development of unique mesocrystal structures. The band structures, electronic properties, and chemical features of the modified TiO2 nanomaterials are clarified in detail along with details regarding their photocatalytic performance and various applications