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In the age of artificial intelligence, the best approach to handling huge amounts of data is a tremendously motivating and hard problem. Among machine learning models, stochastic gradient descent (SGD) is not only simple but also very effective. This study provides a detailed analysis of contemporary state-of-the-art deep learning applications, such as natural language processing (NLP), visual data processing, and voice and audio processing. Following that, this study introduces several versions of SGD and its variant, which are already in the PyTorch optimizer, including SGD, Adagrad, adadelta, RMSprop, Adam, AdamW, and so on. Finally, we propose theoretical conditions under which these methods are applicable and discover that there is still a gap between theoretical conditions under which the algorithms converge and practical applications, and how to bridge this gap is a question for the future.

Cigarette smokers often use e-cigarettes to quit smoking. The outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) in 2019 summer sparked discussions about vaping. However, there is a gap in exploring EVALI's impact on discussions related to smoking cessation and vaping in smoking cessation on social media. This study examines trends, sentiments, and topics in smoking cessation discussions before, during, and after EVALI. English tweets from September 1, 2018, to January 31, 2020, were collected using snscrape, filtered for smoking-cessation-related keywords. Sentiments were assessed with Valence Aware Dictionary and sEentiment Reasoner (VADER), categorizing tweets as positive, negative, or neutral. Topics were identified via Latent Semantic Analysis, and LexRank was used to extract representative sentences for qualitative insights into the discussions. Among 397,528 smoking cessation-related tweets, discussions significantly increased in September 2019, accompanied by a decline in sentiment scores. Five topic groups-\"Vaping\", \"Cannabis\", \"Stop Smoking\", \"Gum\", and \"Tobacco\"-were identified. \"Vaping\" dominated the entire timespan, surpassing other topics in volume. Sentiment scores decreased for \"Vaping\", \"Stop Smoking\", and \"Cannabis\" in September 2019, while remaining stable for \"Gum\" and \"Tobacco\". Representative sentences showed that despite the EVALI outbreak, many individuals still perceived vaping as an effective smoking cessation tool and oppose tobacco control policies targeting e-cigarette flavors. The results deepen our comprehension of how perceptions regarding smoking cessation evolve during EVALI, offering insights for refining public health communication strategies in future health crises.

Effective reprogramming of chronic wound healing remains challenging due to the limited drug delivery efficacy hindered by physiological barriers, as well as the inappropriate dosing timing in distinct healing stages. Herein, a core-shell structured microneedle array patch with programmed functions (PF-MNs) is designed to dynamically modulate the wound immune microenvironment according to the varied healing phases. Specifically, PF-MNs combat multidrug-resistant bacterial biofilm at the early stage via generating reactive oxygen species (ROS) under laser irradiation. Subsequently, the ROS-sensitive MN shell gradually degrades to expose the MN core component, which neutralizes various inflammatory factors and promotes the phase transition from inflammation to proliferation. In addition, the released verteporfin inhibits scar formation by blocking Engrailed-1 ( En1 ) activation in fibroblasts. Our experiments demonstrate that PF-MNs promote scarless wound repair in mouse models of both acute and chronic wounds, and inhibit the formation of hypertrophic scar in rabbit ear models. Effective reprogramming of chronic wound healing remains challenging due to the limited drug delivery efficacy hindered by physiological barriers, as well as the inappropriate dosing timing in distinct healing stages. Here, the authors report a core-shell structured microneedle array patch with programmed functions which dynamically modulates the wound immune microenvironment according to the varied healing phases

The cation channel of sperm (CatSper) is essential for sperm motility and fertility 1 , 2 . CatSper comprises the pore-forming proteins CATSPER1–4 and multiple auxiliary subunits, including CATSPERβ, γ, δ, ε, ζ, and EFCAB9 1 , 3 – 9 . Here we report the cryo-electron microscopy (cryo-EM) structure of the CatSper complex isolated from mouse sperm. In the extracellular view, CATSPER1–4 conform to the conventional domain-swapped voltage-gated ion channel fold 10 , following a counterclockwise arrangement. The auxiliary subunits CATSPERβ, γ, δ and ε—each of which contains a single transmembrane segment and a large extracellular domain—constitute a pavilion-like structure that stabilizes the entire complex through interactions with CATSPER4, 1, 3 and 2, respectively. Our EM map reveals several previously uncharacterized components, exemplified by the organic anion transporter SLCO6C1. We name this channel–transporter ultracomplex the CatSpermasome. The assembly and organization details of the CatSpermasome presented here lay the foundation for the development of CatSpermasome-related treatments for male infertility and non-hormonal contraceptives. A structure of the sperm-specific CatSper complex features a number of additional components; together, these components and the CatSper complex are termed the CatSpermasome.

Traditional photonic sensing based on the change of balanced reflection of photonic structures can hardly distinguish chemical species with similar refractive indices. Here a sensing method based on the dynamic reflection spectra (DRS) of photonic crystal gel has been developed to distinguish even homologues, isomers and solvents with similar structures and physical properties. There are inherent relationships between solvent properties, diffusion behaviour and evolution of reflection signals, so that the geometric characteristics of DRS pattern including ascending/descending, colour changes, splitting/merging and curvature of reflection band can be utilized to recognize different organic solvents. With adequate solvents being tested, a database of DRS patterns can be established, which provide a standard to identify an unknown solvent. Photonic sensing is a method for detecting individual chemical species, but can fail when they are sufficiently similar in physical properties. Here, the authors report a method that can distinguish even very closely related species, such as homologues and chemical isomers.

Background Lipid metabolism reprogramming is a hallmark for tumor which contributes to tumorigenesis and progression, but the commonality and difference of lipid metabolism among pan-cancer is not fully investigated. Increasing evidences suggest that the alterations in tumor metabolism, including metabolite abundance and accumulation of metabolic products, lead to local immunosuppression in the tumor microenvironment. An integrated analysis of lipid metabolism in cancers from different tissues using multiple omics data may provide novel insight into the understanding of tumorigenesis and progression. Results Through systematic analysis of the multiple omics data from TCGA, we found that the most-widely altered lipid metabolism pathways in pan-cancer are fatty acid metabolism, arachidonic acid metabolism, cholesterol metabolism and PPAR signaling. Gene expression profiles of fatty acid metabolism show commonalities across pan-cancer, while the alteration in cholesterol metabolism and arachidonic acid metabolism differ with tissue origin, suggesting tissue specific lipid metabolism features in different tumor types. An integrated analysis of gene expression, DNA methylation and mutations revealed factors that regulate gene expression, including the differentially methylated sites and mutations of the lipid genes, as well as mutation and differential expression of the up-stream transcription factors for the lipid metabolism pathways. Correlation analysis of the proportion of immune cells in the tumor microenvironment and the expression of lipid metabolism genes revealed immune-related differentially expressed lipid metabolic genes, indicating the potential crosstalk between lipid metabolism and immune response. Genes related to lipid metabolism and immune response that are associated with poor prognosis were discovered including HMGCS2, GPX2 and CD36, which may provide clues for tumor biomarkers or therapeutic targets. Conclusions Our study provides an integrated analysis of lipid metabolism in pan-cancer, highlights the perturbation of key metabolism processes in tumorigenesis and clarificates the regulation mechanism of abnormal lipid metabolism and effects of lipid metabolism on tumor immune microenvironment. This study also provides new clues for biomarkers or therapeutic targets of lipid metabolism in tumors.

Hydrogen sulfide (H 2 S) as an important biological gasotransmitter plays a pivotal role in many physiological and pathological processes. The sensitive and quantitative detection of H 2 S level is therefore crucial for precise diagnosis and prognosis evaluation of various diseases but remains a huge challenge due to the lack of accurate and reliable analytical methods in vivo. In this work, we report a smart, H 2 S-responsive and depleting nanoplatform (ZNNPs) for quantitative and real-time imaging of endogenous H 2 S for early diagnosis and treatment of H 2 S-associated diseases. We show that ZNNPs exhibit unexpected NIR conversion (F 1070  → F 720 ) and ratiometric photoacoustic (PA 680 /PA 900 ) signal responsiveness towards H 2 S, allowing for sensitive and quantitative visualization of H 2 S in acute hepatotoxicity, cerebral hemorrhage model as well as colorectal tumors in living mice. ZNNPs@FA simultaneously scavenges the mitochondrial H 2 S in tumors leading to significant ATP reduction and severe mitochondrial damage, together with the activated photodynamic effect, resulting in efficient suppression of colorectal tumor growth in mice. We believe that this platform may provide a powerful tool for studying the vital impacts of H 2 S in related diseases. Abnormal levels of intracellular hydrogen sulphide (H2S) have been associated with different pathological conditions, including cancer. Here the authors report the design of a H2S-responsive and -depleting nanoplatform that, combined with NIR-II photodynamic properties, can be used for H2S imaging and cancer therapy.

A glucose-responsive “closed-loop” insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (“smart insulin patch”) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GO ₓ) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy.

Cells respond to physical stimuli, such as stiffness 1 , fluid shear stress 2 and hydraulic pressure 3 , 4 . Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer 5 . However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na + /H + exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology. Elevated viscosity counterintuitively increases the motility of various cell types in vitro and imprints mechanical memory to tumour cells, which enables them to disseminate more efficiently in vivo.

Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.