Explore the vast range of titles available.

Lung adenocarcinomas (LUAD) arise from precancerous lesions such as atypical adenomatous hyperplasia, which progress into adenocarcinoma in situ and minimally invasive adenocarcinoma, then finally into invasive adenocarcinoma. The cellular heterogeneity and molecular events underlying this stepwise progression remain unclear. In this study, we perform single-cell RNA sequencing of 268,471 cells collected from 25 patients in four histologic stages of LUAD and compare them to normal cell types. We detect a group of cells closely resembling alveolar type 2 cells (AT2) that emerged during atypical adenomatous hyperplasia and whose transcriptional profile began to diverge from that of AT2 cells as LUAD progressed, taking on feature characteristic of stem-like cells. We identify genes related to energy metabolism and ribosome synthesis that are upregulated in early stages of LUAD and may promote progression. MDK and TIMP1 could be potential biomarkers for understanding LUAD pathogenesis. Our work shed light on the underlying transcriptional signatures of distinct histologic stages of LUAD progression and our findings may facilitate early diagnosis. The origin and progression of lung adenocarcinoma (LUAD) are still poorly understood. Here, the authors analyse LUAD composition and progression in patient samples using single-cell RNA-seq and multiplex imaging, revealing a potential transcriptional divergence from alveolar type 2 cells.

Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy. LUBAC is involved in adding linear ubiquitin chains to important immune signaling proteins. Here the authors show that this mechanism is effective in inhibiting STAT1-mediated interferon signaling, and that the deubiquitinase OTULIN can remove these linear ubiquitins from STAT1 to reactivate this antiviral signaling pathway.

This paper investigates the joint state and fault estimation problem for a class of nonlinear systems subject to both measurement censoring (MC) and random missing measurements (MMs). Recognizing that state estimation for nonlinear systems in complex environments is frequently compromised by MMs, MC phenomena, and actuator faults, a novel joint estimation framework that integrates improved Tobit Kalman filtering and federated fusion is proposed, enabling simultaneous robust estimation of system states and fault signals. Among them, the Tobit measurement model is introduced to characterize the phenomenon of MC, a set of Bernoulli random variables is used to describe the MM phenomenon and common actuator faults (abrupt and ramp faults) are considered. In the fusion estimation stage, each sensor transmits observations to the local estimator for preliminary estimation, then sends the local estimated values to the fusion center for generating fusion estimates. The local filtering error covariance is ensured and the upper bound is minimized by reasonably determining the filter gain, while the fusion center performs fusion estimation based on the federated fusion criterion. In addition, this paper proves the boundedness of the filtering error of the designed estimator under certain conditions. Finally, the effectiveness of the estimation framework is demonstrated through two engineering experiments.

Lactic acid bacteria (LAB) are a phylogenetically diverse group with the ability to convert soluble carbohydrates into lactic acid. Many LAB have a long history of safe use in fermented foods and are recognized as food-grade microorganisms. LAB are also natural inhabitants of the human intestinal tract and have beneficial effects on health. Considering these properties, LAB have potential applications as biotherapeutic vehicles to delivery cytokines, antigens and other medicinal molecules. In this review, we summarize the development of, and advances in, genome manipulation techniques for engineering LAB and the expected future development of such genetic tools. These methods are crucial for us to maximize the value of LAB. We also discuss applications of the genome-editing tools in enhancing probiotic characteristics and therapeutic functionalities of LAB.

Background Lactococcus lactis is one of the most extensively characterized lactic acid bacteria, from physiological traits to industrial exploitation. Since last decade, L . lactis has been developed into cell factories for the production of bioactive compounds such as enzymes, vaccine antigens and natural products. However, its precise and efficient genome editing tools is still required to make L . lactis more suitable candidate for engineered functionality. Results A high active recombinase, RecT of Enterococcus faecalis ATCC14506, was selected from six candidates and mediated homologous recombination between single-stranded DNA (ssDNA) and the L . lactis chromosomal rpoB locus with an efficiency of 100% after rifampin selection. To screen mutants without an externally selectable phenotype, the CRISPR/Cas9 system was used for counterselection, yielding an upp mutant with an efficiency of 46%. By optimization of the copy number of plasmid carrying the CRISPR/Cas9 system and the length of spacer sequence, the off-target efficiency of the recA , galK , hemN and noxD genes were eliminated. The ability of this optimized tool to perform sequential point mutation was demonstrated using the upp and galK gene loci as targets with improved efficiencies > 75%. Moreover, seamless genomic DNA deletions (50/100 bp) or insertion (a loxP site, 34 bp) was efficiently accomplished within 72 h. Conclusions The work provided a rapid, versatile and precise tool for L . lactis genomic engineering by combination of ssDNA recombineering with improved CRISPR/Cas9 counterselection. This tool will simplify the production of isogenic strains for assessment of gene function or construction of biosynthetic host.

Chronic obstructive pulmonary disease (COPD) and lung cancer, closely related to smoking, are major lung diseases affecting millions of individuals worldwide. The generated gas mixture of smoking is proved to contain about 4,500 components such as carbon monoxide, nicotine, oxidants, fine particulate matter, and aldehydes. These components were considered to be the principle factor driving the pathogenesis and progression of pulmonary disease. A large proportion of lung cancer patients showed a history of COPD, which demonstrated that there might be a close relationship between COPD and lung cancer. In the early stages of smoking, lung barrier provoked protective response and DNA repair are likely to suppress these changes to a certain extent. In the presence of long-term smoking exposure, these mechanisms seem to be malfunctioned and lead to disease progression. The infiltration of inflammatory cells to mucosa, submucosa, and glandular tissue caused by inhaled cigarette smoke is responsible for the destruction of matrix, blood supply shortage, and epithelial cell death. Conversely, cancer cells have the capacity to modulate the proliferation of epithelial cells and produce of new vascular networks. Comprehension understanding of mechanisms responsible for both pathologies is necessary for the prevention and treatment of COPD and lung cancer. In this review, we will summarize related articles and give a glance of possible mechanism between cigarette smoking induced COPD and lung cancer.

The dual challenges of global population explosion and environmental deterioration represent major hurdles for 21 st Century agriculture culminating in an unprecedented demand for food security. In this Review, we revisit historical concepts of plasticity and canalization before integrating them with contemporary studies of genotype-environment interactions (G×E) that are currently being carried out at the genome-wide level. In doing so we address both fundamental questions regarding G×E and potential strategies to best secure yields in both current and future climate scenarios. Breeding environmental adaptive crop cultivars under the climate changing scenario is anything but easy. Here, the authors review the concepts of plasticity and canalization and their integration with contemporary studies of genotype-environmental interactions with the objective to facilitate crop breeding.

•This study addresses the cognitive neural bases of how semantics affects reinforcement learning.•Rule learning in L2 is less responsive to reward and punishment compared to L1.•Color-rule learning updates responses based on the outcome of any single trial.•Semantic-rule learning relies more on previous information.•The STG serves rule-learning when the carrier of information involves language semantics. In real-life communication, individuals use language that carries evident rewarding and punishing elements, such as praise and criticism. A common trend is to seek more praise while avoiding criticism. Furthermore, semantics is crucial for conveying information, but such semantic access to native and foreign languages is subtly distinct. To investigate how rule learning occurs in different languages and to highlight the importance of semantics in this process, we investigated both verbal and non-verbal rule learning in first (L1) and second (L2) languages using a reinforcement learning framework, including a semantic rule and a color rule. Our computational modeling on behavioral and brain imaging data revealed that individuals may be more motivated to learn and adhere to rules in an L1 compared to L2, with greater striatum activation during the outcome phase in the L1. Additionally, results on the learning rates and inverse temperature in the two rule learning tasks showed that individuals tend to be conservative and are reluctant to change their judgments regarding rule learning of semantic information. Moreover, the greater the prediction errors, the greater activation of the right superior temporal gyrus in the semantic-rule learning condition, demonstrating that such learning has differential neural correlates than symbolic rule learning. Overall, the findings provide insight into the neural mechanisms underlying rule learning in different languages, and indicate that rule learning involving verbal semantics is not a general symbolic learning that resembles a conditioned stimulus-response, but rather has its own specific characteristics.

Liquorice is a traditional medicine. Triterpenoids such as glycyrrhizin and glycyrrhetinic acid are the main active constituents of liquorice. Studies have revealed that these compounds exert inhibitory effects on several viruses, including SARS-CoV-2. The main mechanisms of action of these compounds include inhibition of virus replication, direct inactivation of viruses, inhibition of inflammation mediated by HMGB1/TLR4, inhibition of β-chemokines, reduction in the binding of HMGB1 to DNA to weaken the activity of viruses, and inhibition of reactive oxygen species formation. We herein review the research progress on the antiviral effects of glycyrrhizin and its derivatives. In addition, we emphasise the significance of exploring unknown antiviral mechanisms, structural modifications, and drug combinations in future studies.

In the present study, we investigated the relationship between tDCS dosage and the effects of single-site and dual-site tDCS. In Experiment 1, two types of stimulation intensities (1 mA or 1.5 mA) were applied while participants performed a Flanker task. In Experiment 2, two different stimulation durations were manipulated while participants conducted the same task. Behavioural performance under different dosages was evaluated in the framework of both traditional reaction time measures and the drift diffusion model (DDM), respectively. Conventional reaction time analyses did not reveal any significant effect of stimulation intensity and stimulation duration on cognitive control task. In contrast, DDM analyses revealed that the detrimental effects of high-intensity tDCS diminished as tDCS continued. Additionally, these results showed that high-intensity tDCS in the single-site condition led to longer non-decision time, indicating an interruption to the perceptual and motor processes, while for dual-site tDCS, both the perceptual process and evidence accumulation process were interrupted with longer non-decision time and slower drift rates. This study underscores the importance of understanding the effects of tDCS from a temporal perspective, providing important implications for optimizing tDCS parameters and understanding the underlying mechanisms of using tDCS to enhance cognitive control.