IRE1α-XBP1 regulates PDK1-dependent induction of epithelial-mesenchymal transition in non-small cell lung cancer cells.

Mounting evidence indicates that activation of unfolded protein response (UPR) and metabolic reprogramming contribute to cancer cell migration and invasion, but the molecular mechanism of pro-EMT program through a coordinated action of UPR with metabolism has not been defined. In this study, we utilized ER stress-inducing reagent, thapsigargin (TG), to induced pharmacologic ER stress in lung cancer cells. Here. We report that the branch of UPR, IRE1α-XBP1 pathway plays a pivotal role in reprogramming lung cancer cell metabolism. At the molecular level, the expression of pyruvate dehydrogenase kinase-1 (PDK-1) is directly induced by XBP1 as a consequence of UPR activation, thus facilitating aerobic glycolysis and lactate production. We also demonstrated that PDK1 serves as a downstream element of UPR activation in induction of Snail and EMT program. In addition, PDK1-induced Snail was dependent on the lactate production derived from metabolic reprogramming. Our findings reveal a critical role of lactate in pro-invasion events and establishes a direct connection between ER-stress and metabolic reprogramming in facilitating cancer cell progression.

Lactate-fueled oxidative metabolism drives DNA methyltransferase 1-mediated transcriptional co-activator with PDZ binding domain protein activation.

Activity of transcriptional co-activator with PDZ binding domain (TAZ) protein is strongly implicated in the pathogenesis of human cancer and is influenced by tumor metabolism. High levels of lactate concentration in the tumor microenvironment as a result of metabolic reprogramming are inversely correlated with patient overall survival. Herein, we investigated the role of lactate in the regulation of the activity of TAZ and showed that glycolysis-derived lactate efficiently increased TAZ expression and activity in lung cancer cells. We showed that the reactive oxygen species (ROS) generated by lactate-fueled oxidative phosphorylation (OXPHOS) in mitochondria activated AKT and thereby inhibited glycogen synthase kinase 3 beta/beta-transducin repeat-containing proteins (GSK-3ß/ß-TrCP)-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1). Upregulation of DNMT1 by lactate caused hypermethylation of TAZ negative regulator of the LATS2 gene promoter, leading to TAZ activation. Moreover, TAZ binds to the promoter of DNMT1 and is necessary for DNMT1 transcription. Our study showed a molecular mechanism of DNMT1 in linking tumor metabolic reprogramming to the Hippo-TAZ pathway and functional significance of the DNMT1-TAZ feedback loop in the migratory and invasive potential of lung cancer cells.

Localized surface plasmon resonance modulation of totally encapsulated VO2/Au/VO2 composite structure.

We design and fabricate a totally encapsulated VO2/Au/VO2 composite structure which is aimed to improve the tunability of the localized surface plasmon resonance (LSPR) peak. In this work, the structure will ensure all the Au NPs' resonant electric field area is filled with VO2. The modulation range of the totally encapsulated structure is larger than that of the semi-coated structure. To further improve the modulation range, we also explore the VO2 thickness dependence of the structure's LSPR modulation. With the increase of the top layer VO2 thin film thickness, the modulation range becomes larger. When the thickness is about 80 nm, the absorption peak achieves a largest shift of 112 nm. FDTD solution and equivalent model of series capacitor are used to explain the phenomenon. These results will contribute to the area of metamaterial electromagnetic wave absorber and other fields.

Technological challenges and future perspectives of plant-based meat analogues: From the viewpoint of proteins.

The global demand for high-quality animal protein faces challenges, prompting a surge in interest in plant-based meat analogues (PBMA). PBMA have emerged as a promising solution, although they encounter technological obstacles. This review discusses the technological challenges faced by PBMA from the viewpoint of plant proteins, emphasizing textural, flavor, color, and nutritional aspects. Texturally, PBMA confront issues, such as deficient fibrous structure, chewiness, and juiciness. Addressing meat flavor and mitigating beany flavor in plant protein are imperative. Furthermore, achieving a distinctive red or pink meat color remains a challenge. Plant proteins exhibit a lower content of essential amino acids. Future research directions encompass (1) shaping myofibril fibrous structures through innovative processing; (2) effectively eliminating the beany flavor; (3) developing biotechnological methodologies for leghemoglobin and plant-derived pigments; (4) optimizing amino acid composition to augment the nutritional profiles. These advancements are crucial for utilization of plant proteins in development of high-quality PBMA.

A Dual-pathway Pyroptosis Inducer Based on Au-Cu2-xSe@ZIF-8 Enhances Tumor Immunotherapy by Disrupting the Zinc Ion Homeostasis.

The regulation of intracellular ionic homeostasis to trigger antigen-specific immune responses has attracted extensive interest in tumor therapy. In this study, we developed a dual-pathway nanoreactor, Au-Cu2-xSe@ZIF-8@P18 NPs (ACS-Z-P NPs), which targets danger-associated molecular patterns (DAMPs) and releases Zn2+ and reactive oxygen species (ROS) within the tumor microenvironment (TME). Zn2+ released from the metal-organic frameworks (MOFs) was deposited in the cytoplasm, leading to aberrant transcription levels of intracellular zinc-regulated proteins and DNA damage, thereby inducing pyroptosis and immunogenic cell death (ICD) dependent on caspase1/gasdermin D (GSDMD) pathway. Furthermore, upon laser irradiation, ACS-Z-P NPs could break through the limitations of inherent defects of immunosuppression in TME, enhance ROS generation through a Fenton-like reaction cascade, which subsequently triggered the activation of inflammatory vesicles and the release of damage-associated molecular patterns (DAMPs). This cascade effect led to the amplification of pyroptosis and immunogenic cell death (ICD), thereby remodeling the immunosuppressed TME. Consequently, this process improved dendritic cell (DC) antigen presentation and augmented anti-tumor T-cell responses, effectively initiating antigen-specific immune responses and further enhancing pyroptosis and ICD. This study explores the therapeutic properties of these mechanisms in detail. STATEMENT OF SIGNIFICANCE: : The synthesized Au-Cu2-xSe@ZIF-8@P18 nanoparticles (ACS-Z-Ps) can effectively enhance the body's immune response by regulating zinc ion levels within cells. This regulation leads to abnormal levels of zinc-regulated protein transcription and DNA damage, which induces cellular pyroptosis. As a result, antigen presentation to dendritic cells (DCs) is improved, and anti-tumor T-cell responses are enhanced. The ACS-Z-P NPs overcome the limitations of ROS deficiency and immunosuppression in the tumor microenvironment by using H2O2 in the tumor microenvironment through a Fenton-like reaction. This leads to an increased production of ROS and O2, remodeling of the immunosuppressed tumor microenvironment, and enhanced induction of cell pyroptosis and immunogenic cell death. ACS-Z-P NPs targeted B16 cells using the photosensitizer P18 in combination with PDT treatment. This approach significantly inhibited the proliferation of B16 cells and effectively inhibited tumor growth.

Diversity beyond density: Experienced social mixing of urban streets.

Urban density, in the form of residents' and visitors' concentration, is long considered to foster diverse exchanges of interpersonal knowledge and skills, which are intrinsic to sustainable human settlements. However, with current urban studies primarily devoted to city- and district-level analyses, we cannot unveil the elemental connection between urban density and diversity. Here we use an anonymized and privacy-enhanced mobile dataset of 0.5 million opted-in users from three metropolitan areas in the United States to show that at the scale of urban streets, density is not the only path to diversity. We represent the diversity of each street with the experienced social mixing (ESM), which describes the chances of people meeting diverse income groups throughout their daily experience. We conduct multiple experiments and show that the concentration of visitors only explains 26% of street-level ESM. However, adjacent amenities, residential diversity, and income level account for 44% of the ESM. Moreover, using longitudinal business data, we show that streets with an increased number of food businesses have seen an increased ESM from 2016 to 2018. Lastly, although streets with more visitors are more likely to have crime, diverse streets tend to have fewer crimes. These findings suggest that cities can leverage many tools beyond density to curate a diverse and safe street experience for people.

A Role of Multi-Omics Technologies in Sheep and Goat Meats: Progress and Way Ahead.

Sheep and goat meats are increasingly popular worldwide due to their superior nutritional properties and distinctive flavor profiles. In recent decades, substantial progress in meat science has facilitated in-depth examinations of ovine and caprine muscle development during the antemortem phase, as well as post-mortem changes influencing meat attributes. To elucidate the intrinsic molecular mechanisms and identify potential biomarkers associated with meat quality, the methodologies employed have evolved from traditional physicochemical parameters (such as color, tenderness, water holding capacity, flavor, and pH) to some cutting-edge omics technologies, including transcriptomics, proteomics, and metabolomics approaches. This review provides a comprehensive analysis of multi-omics techniques and their applications in unraveling sheep and goat meat quality attributes. In addition, the challenges and future perspectives associated with implementing multi-omics technologies in this area of study are discussed. Multi-omics tools can contribute to deciphering the molecular mechanism responsible for the altered the meat quality of sheep and goats across transcriptomic, proteomic, and metabolomic dimensions. The application of multi-omics technologies holds great potential in exploring and identifying biomarkers for meat quality and quality control, thereby promoting the optimization of production processes in the sheep and goat meat industry.

Rhythm of the streets: a street classification framework based on street activity patterns.

As the living tissue connecting urban places, streets play significant roles in driving city development, providing essential access, and promoting human interactions. Understanding street activities and how these activities vary across different streets is critical for designing both efficient and livable streets. However, current street classification frameworks primarily focus on either streets' functions in transportation networks or their adjacent land uses rather than actual activity patterns, resulting in coarse classifications. This research proposes an activity-based street classification framework to categorize street segments based on their temporal street activity patterns, which is derived from high-resolution de-identified and privacy-enhanced mobility data. We then apply the proposed framework to 18,023 street segments in the City of Boston and reveal 10 distinct activity-based street types (ASTs). These ASTs highlight dynamic street activities on streets, which complements existing street classification frameworks, which focus on the static or transportation characteristics of the street segments. Our results show that a street classification framework based on temporal street activity patterns can identify street categories at a finer granularity than current methods, which can offer useful implications for state-of-the-art urban management and planning. In particular, we find that our classification distinguishes better those streets where crime is more prevalent than current functional or contextual classifications of streets.