Microenvironment Restruction of Emerging 2D Materials and their Roles in Therapeutic and Diagnostic Nano-Bio-Platforms

Engineering advanced therapeutic and diagnostic nano-bio-platforms (NBPFs) have emerged as rapidly-developed pathways against a wide range of challenges in antitumor, antipathogen, tissue regeneration, bioimaging, and biosensing applications. Emerged 2D materials have attracted extensive scientific interest as fundamental building blocks or nanostructures among material scientists, chemists, biologists, and doctors due to their advantageous physicochemical and biological properties. This timely review provides a comprehensive summary of creating advanced NBPFs via emerging 2D materials (2D-NBPFs) with unique insights into the corresponding molecularly restructured microenvironments and biofunctionalities. First, it is focused on an up-to-date overview of the synthetic strategies for designing 2D-NBPFs with a cross-comparison of their advantages and disadvantages. After that, the recent key achievements are summarized in tuning the biofunctionalities of 2D-NBPFs via molecularly programmed microenvironments, including physiological stability, biocompatibility, bio-adhesiveness, specific binding to pathogens, broad-spectrum pathogen inhibitors, stimuli-responsive systems, and enzyme-mimetics. Moreover, the representative therapeutic and diagnostic applications of 2D-NBPFs are also discussed with detailed disclosure of their critical design principles and parameters. Finally, current challenges and future research directions are also discussed. Overall, this review will provide cutting-edge and multidisciplinary guidance for accelerating future developments and therapeutic/diagnostic applications of 2D-NBPFs

Chronic Ethanol Exposure Enhances the Aggressiveness of Breast Cancer: The Role of p38γ

Both epidemiological and experimental studies suggest that ethanol may enhance aggressiveness of breast cancer. We have previously demonstrated that short term exposure to ethanol (12–48 hours) increased migration/invasion in breast cancer cells overexpressing ErbB2, but not in breast cancer cells with low expression of ErbB2, such as MCF7, BT20 and T47D breast cancer cells. In this study, we showed that chronic ethanol exposure transformed breast cancer cells that were not responsive to short term ethanol treatment to a more aggressive phenotype. Chronic ethanol exposure (10 days - 2 months) at 100 (22 mM) or 200 mg/dl (44 mM) caused the scattering of MCF7, BT20 and T47D cell colonies in a 3-dimension culture system. Chronic ethanol exposure also increased colony formation in an anchorage-independent condition and stimulated cell invasion/migration. Chronic ethanol exposure increased cancer stem-like cell (CSC) population by more than 20 folds. Breast cancer cells exposed to ethanol in vitro displayed a much higher growth rate and metastasis in mice. Ethanol selectively activated p38γ MAPK and RhoC but not p38α/β in a concentration-dependent manner. SP-MCF7 cells, a derivative of MCF7 cells which compose mainly CSC expressed high levels of phosphorylated p38γ MAPK. Knocking-down p38γ MAPK blocked ethanol-induced RhoC activation, cell scattering, invasion/migration and ethanol-increased CSC population. Furthermore, knocking-down p38γ MAPK mitigated ethanol-induced tumor growth and metastasis in mice. These results suggest that chronic ethanol exposure can enhance the aggressiveness of breast cancer by activating p38γ MAPK/RhoC pathway

ErbB2 and p38γ MAPK Mediate Alcohol-Induced Increase in Breast Cancer Stem Cells and Metastasis

Background: Both epidemiological and experimental studies suggest that excessive alcohol exposure increases the risk for breast cancer and enhances metastasis/recurrence. We have previously demonstrated that alcohol enhanced the migration/invasion of breast cancer cells and cancer cells overexpressing ErbB2/HER2 were more sensitive to alcohol exposure. However, the underlying mechanisms remain unclear. This study was designed to investigate the mechanisms underlying alcohol-enhanced aggressiveness of breast cancer. Cancer stem cells (CSCs) play a critical role in cancer metastasis and recurrence. Methods: We evaluated the effect of chronic alcohol exposure on mammary tumor development/metastasis in MMTV-neu transgenic mice and investigated the cell signaling in response to alcohol exposure in breast cancer cells overexpressing ErbB2/HER2. Results and discussion: Chronic alcohol exposure increased breast cancer stem cell-like CSC population and enhanced the lung and colon metastasis in MMTV-neu transgenic mice. Alcohol exposure caused a drastic increase in CSC population and mammosphere formation in breast cancer cells overexpressing ErbB2/HER2. Alcohol exposure stimulated the phosphorylation of p38γ MAPK (p-p38γ) which was co-localized with phosphorylated ErbB2 and CSCs in the mammary tumor tissues. In vitro results confirmed that alcohol activated ErbB2/HER2 and selectively increased p-p38γ MAPK as well as the interaction between p38γ MAPK and its substrate, SAP97. However, alcohol did not affect the expression/phosphorylation of p38α/β MAPKs. In breast cancer cell lines, high expression of ErbB2 and p-p38γ MAPK was generally correlated with more CSC population. Blocking ErbB2 signaling abolished heregulin β1- and alcohol-stimulated p-p38γ MAPK and its association with SAP97. More importantly, p38γ MAPK siRNA significantly inhibited an alcohol-induced increase in CSC population, mammosphere formation and migration/invasion of breast cancer cells overexpressing ErbB2. Conclusions: p38γ MAPK is downstream of ErbB2 and plays an important role in alcohol-enhanced aggressiveness of breast cancer. Therefore, in addition to ErbB2/HER2, p38γ MAPK may be a potential target for the treatment of alcohol-enhanced cancer aggressiveness

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

An Optimization Method for Non-IID Federated Learning Based on Deep Reinforcement Learning

Federated learning (FL) is a distributed machine learning paradigm that enables a large number of clients to collaboratively train models without sharing data. However, when the private dataset between clients is not independent and identically distributed (non-IID), the local training objective is inconsistent with the global training objective, which possibly causes the convergence speed of FL to slow down, or even not converge. In this paper, we design a novel FL framework based on deep reinforcement learning (DRL), named FedRLCS. In FedRLCS, we primarily improved the greedy strategy and action space of the double DQN (DDQN) algorithm, enabling the server to select the optimal subset of clients from a non-IID dataset to participate in training, thereby accelerating model convergence and reaching the target accuracy in fewer communication epochs. In simulation experiments, we partition multiple datasets with different strategies to simulate non-IID on local clients. We adopt four models (LeNet-5, MobileNetV2, ResNet-18, ResNet-34) on the four datasets (CIFAR-10, CIFAR-100, NICO, Tiny ImageNet), respectively, and conduct comparative experiments with five state-of-the-art non-IID FL methods. Experimental results show that FedRLCS reduces the number of communication rounds required by 10–70% with the same target accuracy without increasing the computation and storage costs for all clients

Worldwide consequences of a mid-Holocene cooling in the Nordic Seas

The Earth's climate, marked by long-term shifts and punctuated events, shapes terrestrial and marine ecosystems. Despite the present interglacial period's warmth and stability compared to preceding glaciations, the Holocene has witnessed significant cooling events with worldwide consequences. Leveraging marine records from the Nordic Seas, we provide the first detailed account of a cooling event centered around 6.8 ka BP. Utilizing paleoceanographic proxies and advanced modelling, we unveil a distinct subsurface water cooling, associated with a stepwise increase in sea-ice cover in the eastern Fram Strait. Our findings emphasize the role of Greenland Sea deep convection onset and the subsequent westward shift in Atlantic Water flow, enabling sea-ice advection from the Barents Sea. The heightened sea-ice cover weakens Atlantic Water advection, perturbing overturning circulation in the eastern Nordic Seas. These perturbations propagate worldwide, affecting North Atlantic deep-water circulation, inducing widespread hemispheric cooling, shifting the Intertropical Convergence Zone southward, and weakening the East Asian monsoon. Incorporating rigorous modelling supports and augments proxy-based paleoreconstructions, underscoring sea-ice dynamics and ocean circulation's critical influence. This study highlights the potential for localized cooling events within ostensibly stable climatic intervals, underscoring the need to comprehend their mechanisms for precise climate predictions and informed policymaking toward a sustainable future

Drug Repositioning of Inflammatory Bowel Disease Based on Co-Target Gene Expression Signature of Glucocorticoid Receptor and TET2

The glucocorticoid receptor (GR) and ten-eleven translocation 2 (TET2), respectively, play a crucial role in regulating immunity and inflammation, and GR interacts with TET2. However, their synergetic roles in inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), remain unclear. This study aimed to investigate the co-target gene signatures of GR and TET2 in IBD and provide potential therapeutic interventions for IBD. By integrating public data, we identified 179 GR- and TET2-targeted differentially expressed genes (DEGs) in CD and 401 in UC. These genes were found to be closely associated with immunometabolism, inflammatory responses, and cell stress pathways. In vitro inflammatory cellular models were constructed using LPS-treated HT29 and HCT116 cells, respectively. Drug repositioning based on the co-target gene signatures of GR and TET2 derived from transcriptomic data of UC, CD, and the in vitro model was performed using the Connectivity Map (CMap). BMS-536924 emerged as a top therapeutic candidate, and its validation experiment within the in vitro inflammatory model confirmed its efficacy in mitigating the LPS-induced inflammatory response. This study sheds light on the pathogenesis of IBD from a new perspective and may accelerate the development of novel therapeutic agents for inflammatory diseases including IBD

The Pacific Decadal Oscillation modulated marine heatwaves in the Northeast Pacific during past decades

Abstract The Pacific Decadal Oscillation has been suggested to play an important role in driving marine heatwaves in the Northeast Pacific during recent decades. Here we combine observations and climate model simulations to show that marine heatwaves became longer, stronger and more frequent off the Northeast Pacific coast under a positive Pacific Decadal Oscillation scenario, unlike what is found during a negative Pacific Decadal Oscillation scenario. This primarily results from the different mean-state sea surface temperatures between the two Pacific Decadal Oscillation phases. Compared to the cool (negative) phase of the Pacific Decadal Oscillation, warmer coastal sea surface temperatures occur during the positive Pacific Decadal Oscillation phase due to reduced coastal cold upwelling and increased net downward surface heat flux. Model results show that, relative to the background anthropogenic global warming, the positive Pacific Decadal Oscillation in the period 2013–2022 prolongs marine heatwaves duration by up to 43% and acts to increase marine heatwaves annual frequency by up to 32% off the Northeast Pacific coast

Reserve Demand Determination Method Considering the Different Time Periods Uncertainty of Wind and Solar

With the gradual realization of China’s 14th Five-Year Plan, the proportion of installed renewable energy capacity in all regions has increased significantly. The access of a high proportion of renewable energy has brought serious challenges to the safe and stable operation of the power system. The uncertainty of wind power and photovoltaic output makes it difficult for the traditional reserve demand determination method to economically and effectively calculate the reserve capacity required by the system, so it is urgent to propose a reasonable reserve capacity demand determination method. On the one hand, it ensures that the deserve capacity needed by the system is sufficient to cope with real-time active fluctuations, and on the other hand, it improves the economy of the reserve capacity. The reserve demand determination method considering the different time periods uncertainty of wind and solar in this paper is able to meet the reserve demand of new power system. At last, the article proves the benefits of Reserve Demand Determination Method through a numerical example

Reserve Demand Determination Method Considering the Different Time Periods Uncertainty of Wind and Solar

With the gradual realization of China’s 14th Five-Year Plan, the proportion of installed renewable energy capacity in all regions has increased significantly. The access of a high proportion of renewable energy has brought serious challenges to the safe and stable operation of the power system. The uncertainty of wind power and photovoltaic output makes it difficult for the traditional reserve demand determination method to economically and effectively calculate the reserve capacity required by the system, so it is urgent to propose a reasonable reserve capacity demand determination method. On the one hand, it ensures that the deserve capacity needed by the system is sufficient to cope with real-time active fluctuations, and on the other hand, it improves the economy of the reserve capacity. The reserve demand determination method considering the different time periods uncertainty of wind and solar in this paper is able to meet the reserve demand of new power system. At last, the article proves the benefits of Reserve Demand Determination Method through a numerical example