The differentiation of neural stem cells (NSCs) into neurons is proposed to be critical in devising potential cell-based therapeutic strategies for central nervous system (CNS) diseases, however, the ...determination and prediction of differentiation is complex and not yet clearly established, especially at the early stage. We hypothesize that deep learning could extract minutiae from large-scale datasets, and present a deep neural network model for predictable reliable identification of NSCs fate. Remarkably, using only bright field images without artificial labelling, our model is surprisingly effective at identifying the differentiated cell types, even as early as 1 day of culture. Moreover, our approach showcases superior precision and robustness in designed independent test scenarios involving various inducers, including neurotrophins, hormones, small molecule compounds and even nanoparticles, suggesting excellent generalizability and applicability. We anticipate that our accurate and robust deep learning-based platform for NSCs differentiation identification will accelerate the progress of NSCs applications.
Terahertz metamaterials for broadband, high modulation depth modulating, and tunable dual-band absorbing are designed based on the similar composite structure of metal and vanadium dioxide film ...arrays. By using external excitation to induce the insulator-metal phase transition of the vanadium dioxide layer, the transmission characteristics of the metamaterial can be manipulated. High modulation depths of more than 80% are achieved in the range of 0.2–0.8 THz, and the bandwidth width with modulation depths exceeding 60% is up to 140%. By increasing the dielectric thickness and adding a metal ground, the initial broadband modulator can be switched to a dual-band absorber when the vanadium dioxide is in the metal phase. Furthermore, the modulation effect and the absorption performance exhibit insensitive characteristics to the polarization angle of incident waves. This work provides potential applications in broadband modulation of terahertz communication as well as dual-band absorption for terahertz detection.
An increasing number of clinical trials require biomarker-driven patient stratification, especially for revolutionary immune checkpoint blockade therapy. Due to the complicated interaction between a ...tumor and its microenvironment, single biomarkers, such as PDL1 protein level, tumor mutational burden (TMB), single gene mutation and expression, are far from satisfactory for response prediction or patient stratification. Recently, combinatorial biomarkers were reported to be more precise and powerful for predicting therapy response and identifying potential target populations with superior survival. However, there is a lack of dedicated tools for such combinatorial biomarker analysis.
Here, we present dualmarker, an R package designed to facilitate the data exploration for dual biomarker combinations. Given two biomarkers, dualmarker comprehensively visualizes their association with drug response and patient survival through 14 types of plots, such as boxplots, scatterplots, ROCs, and Kaplan-Meier plots. Using logistic regression and Cox regression models, dualmarker evaluated the superiority of dual markers over single markers by comparing the data fitness of dual-marker versus single-marker models, which was utilized for de novo searching for new biomarker pairs. We demonstrated this straightforward workflow and comprehensive capability by using public biomarker data from one bladder cancer patient cohort (IMvigor210 study); we confirmed the previously reported biomarker pair TMB/TGF-beta signature and CXCL13 expression/ARID1A mutation for response and survival analyses, respectively. In addition, dualmarker de novo identified new biomarker partners, for example, in overall survival modelling, the model with combination of HMGB1 expression and ARID1A mutation had statistically better goodness-of-fit than the model with either HMGB1 or ARID1A as single marker.
The dualmarker package is an open-source tool for the visualization and identification of combinatorial dual biomarkers. It streamlines the dual marker analysis flow into user-friendly functions and can be used for data exploration and hypothesis generation. Its code is freely available at GitHub at https://github.com/maxiaopeng/dualmarker under MIT license.
Background
In solid tumor Phase 1/2 trials (NCT02407990; NCT04068519), tislelizumab demonstrated clinical benefit, including in advanced gastroesophageal adenocarcinoma (GEA). However, the majority ...of patients with GEA did not respond, highlighting the need to understand mechanisms of resistance and identify predictive biomarkers for response.
Methods
All tislelizumab-treated patients with GEA from the Phase 1/2 trials were included (
N
= 105). Programmed death-ligand 1 (PD-L1) expression (Tumor Area Positivity TAP ≥ 5%), interferon gamma (IFN
γ
)-related gene signature, gene expression profile, tumor mutational burden (TMB), and gene hyperamplification (HA) were analyzed for correlation with tislelizumab.
Results
A moderate association was observed between PD-L1 TAP ≥ 5%, IFN
γ
gene signature, TMB-high and efficacy. A potential correlation between hyperamplification (HA +) and worse outcomes with programmed cell death protein 1 (PD-1) inhibition was identified. Hyperamplified genes were mainly enriched in cancer progression pathways, including cell cycle and RTK-RAS-PI3K pathways. Joint PD-L1 TAP ≥ 5% and lack of hyperamplification showed the most favorable benefit with an objective response rate of 29.4%, and median progression-free survival and overall survival of 4.1 and 14.7 months, respectively. Tumors with TAP ≥ 5% and HA − had inflamed immune signatures with increased immune cell infiltration, enhanced anti-tumor cytotoxic activity and antigen presentation signatures. Findings were validated in two independent gastric and gastrointestinal cancer cohorts treated with immune checkpoint inhibitors.
Conclusions
In GEA, PD-L1 positivity, IFN
γ
-related gene signature and TMB-high status were positively associated with tislelizumab clinical benefit, whereas HA was associated with worse clinical outcomes. Combining PD-L1 positivity and HA − may help identify patients more likely to benefit from PD-1 blockade.
Convergent evolution is a process that has occurred throughout the tree of life, but the historical genetic and biochemical context promoting the repeated independent origins of a trait is rarely ...understood. The well-known stimulant caffeine, and its xanthine alkaloid precursors, has evolved multiple times in flowering plant history for various roles in plant defense and pollination. We have shown that convergent caffeine production, surprisingly, has evolved by two previously unknown biochemical pathways in chocolate, citrus, and guaraná plants using either caffeine synthase- or xanthine methyltransferase-like enzymes. However, the pathway and enzyme lineage used by any given plant species is not predictable from phylogenetic relatedness alone. Ancestral sequence resurrection reveals that this convergence was facilitated by co-option of genes maintained over 100 million y for alternative biochemical roles. The ancient enzymes of the Citrus lineage were exapted for reactions currently used for various steps of caffeine biosynthesis and required very few mutations to acquire modern-day enzymatic characteristics, allowing for the evolution of a complete pathway. Future studies aimed at manipulating caffeine content of plants will require the use of different approaches given the metabolic and genetic diversity revealed by this study.
One-dimensional chain-like VS
4
possesses an ultra-high specific capacity and good diffusion kinetics for sodium storage. However, the big volume fluctuation upon cycling and the dissolution of ...polysulfides should be addressed. Herein, the polydopamine-coated hierarchical VS
4
sub-microspheres (VS
4
@PDA) have been rationally synthesized via facile solvothermal and subsequent polymerization processes. The surface PDA layer not only suppresses the big volume changes, but also maintains the structural stability. Thus, as the anode materials, VS
4
@PDA shows a relatively high reversible capacity (782 mAh g
−1
for 150 cycles at 0.5 A g
−1
), excellent cyclic stability (289.5 mAh g
−1
for 300 cycles at 2 A g
−1
), and good rate performance (209.6 mAh g
−1
at 2 A g
−1
, 173.2 mAh g
−1
at 5 A g
−1
), obviously superior to those of VS
4
and V
3
S
4
@NC. Besides, the assembled full cell with VS
4
@PDA as an anode and Na
3
V
2
(PO
4
)
3
/rGO as a cathode shows good cyclic stability. Moreover, the capacity fading and charge storage mechanism of VS
4
@PDA have been investigated via a series of ex situ testing methods in detail. The remarkable sodium storage features of VS
4
@PDA indicate promising applications in sodium storage fields.
Graphical Abstract
Abstract
The Kv1.3 potassium channel is expressed abundantly on activated T cells and mediates the cellular immune response. This role has made the channel a target for therapeutic immunomodulation ...to block its activity and suppress T cell activation. Here, we report structures of human Kv1.3 alone, with a nanobody inhibitor, and with an antibody-toxin fusion blocker. Rather than block the channel directly, four copies of the nanobody bind the tetramer’s voltage sensing domains and the pore domain to induce an inactive pore conformation. In contrast, the antibody-toxin fusion docks its toxin domain at the extracellular mouth of the channel to insert a critical lysine into the pore. The lysine stabilizes an active conformation of the pore yet blocks ion permeation. This study visualizes Kv1.3 pore dynamics, defines two distinct mechanisms to suppress Kv1.3 channel activity with exogenous inhibitors, and provides a framework to aid development of emerging T cell immunotherapies.
Apelin, a novel endogenous ligand of the G-protein-coupled receptor APJ, is encoded by the
gene and can be hydrolyzed into multiple subtypes, with Apelin-13 being one of the most active subtypes of ...the Apelin family. Recent studies have revealed that Apelin-13 functions as an adipokine that participates in the regulation of different biological processes, such as oxidative stress, inflammation, apoptosis, and energy metabolism, thereby playing an important role in the prevention and treatment of various metabolic diseases. However, the results of recent studies on the association between Apelin-13 and various metabolic states remain controversial. Furthermore, Apelin-13 is regulated or influenced by various forms of exercise and could therefore be categorized as a new type of exercise-sensitive factor that attenuates metabolic diseases. Thus, in this review, our purpose was to focus on the relationship between Apelin-13 and related metabolic diseases and the regulation of response movements, with particular reference to the establishment of a theoretical basis for improving and treating metabolic diseases.
Dynamic regulation of transcription is crucial for the cellular responses to various environmental or developmental cues. Gdown1 is a ubiquitously expressed, RNA polymerase II (Pol II) interacting ...protein, essential for the embryonic development of metazoan. It tightly binds Pol II
and competitively blocks the binding of TFIIF and possibly other transcriptional regulatory factors, yet its cellular functions and regulatory circuits remain unclear. Here, we show that human GDOWN1 strictly localizes in the cytoplasm of various types of somatic cells and exhibits a potent resistance to the imposed driving force for its nuclear localization. Combined with the genetic and microscope-based approaches, two types of the functionally coupled and evolutionally conserved localization regulatory motifs are identified, including the CRM1-dependent nucleus export signal (NES) and a novel Cytoplasmic Anchoring Signal (CAS) that mediates its retention outside of the nuclear pore complexes (NPC). Mutagenesis of CAS alleviates GDOWN1's cytoplasmic retention, thus unlocks its nucleocytoplasmic shuttling properties, and the increased nuclear import and accumulation of GDOWN1 results in a drastic reduction of both Pol II and its associated global transcription levels. Importantly, the nuclear translocation of GDOWN1 occurs in response to the oxidative stresses, and the ablation of
significantly weakens the cellular tolerance. Collectively, our work uncovers the molecular basis of GDOWN1's subcellular localization and a novel cellular strategy of modulating global transcription and stress-adaptation via controlling the nuclear translocation of GDOWN1.
The analysis of glyphosate is essential to agricultural production, environment protection and public health. Herein, we proposed a fast and convenient “on-off-on” fluorescence platform for sensitive ...detection of glyphosate
via
Cu
2+
modulated g-C
3
N
4
nanosheets. The fluorescence of the system was quenched by Cu
2+
. With the presence of glyphosate, the fluorescence could be restored due to the formation of Cu
2+
- glyphosate complex. The proposed method was cost-effective with label-free and enzyme-free. Moreover, it exhibits high sensitivity with a low detection limit of 0.01 μg/ml. Furthermore, the proposed method has been successfully monitored glyphosate in real samples.
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