148 research outputs found
Analysis of Peptides and Proteins in Their Binding to GroEL
The GroEL-GroES is an essential molecular chaperon system that assists protein folding in cell. Binding of various substrate proteins to GroEL is one of the key aspects in GroEL-assisted protein folding. Small peptides may mimic segments of the substrate proteins in contact with GroEL, and allow detailed structural analysis of the interactions. A model peptide SBP has been shown to bind to a region in GroEL that is important for binding of substrate proteins. Here, we investigated whether the observed GroEL-SBP interaction represented those of GroEL-substrate proteins, and whether SBP was able to mimic various aspects of substrate proteins in GroE- assisted protein folding cycle. We found that SBP competed with substrate proteins, including α-lactalbumin, rhodanese, and malate dehydrogenase, in binding to GroEL. SBP stimulated GroEL ATP hydrolysis rate in a manner similar to that of α-lactalbumin. SBP did not prevent GroES from binding to GroEL, and GroES association reduced the ATPase rates of GroEL/SBP and GroEL/α-lactalbumin to a comparable extent. Binding of both SBP and α-lactalbumin to apo GroEL was dominated by hydrophobic interaction. Interestingly, association of α- lactalbumin to GroEL/GroES was thermodynamically distinct from that to GroEL with reduced affinity and decreased contribution from hydrophobic interaction. However, SBP did not display such differential binding behaviors to apo GroEL and GroEL/GroES, likely due to the lack of a contiguous polypeptide chain that links all of the bound peptide fragments. Nevertheless, studies using peptides provide valuable information on the nature of GroEL-substrate protein interaction, which is central to understand the mechanism of GroEL-assisted protein folding
NQO1 targeting prodrug triggers innate sensing to overcome checkpoint blockade resistance
Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. NAD(P)H:quinone oxidoreductase 1 (NQO1) is highly enriched in multiple tumor types and has emerged as a promising target for direct tumor-killing. Here, we demonstrate that NQO1-targeting prodrug β-lapachone triggers tumor-selective innate sensing leading to T cell-dependent tumor control. β-Lapachone is catalyzed and bioactivated by NQO1 to generate ROS in NQO1high tumor cells triggering oxidative stress and release of the damage signals for innate sensing. β-Lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the tumor. Furthermore, targeting NQO1 is very potent to trigger innate sensing for T cell re-activation to overcome checkpoint blockade resistance in well-established tumors. Our study reveals that targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance
All "Magic Angles" Are "Stable" Topological
We show that the electronic structure of the low-energy bands in the small
angle-twisted bilayer graphene consists of a series of semi-metallic and
topological phases. In particular we are able to prove, using an approximate
low-energy particle-hole symmetry, that the gapped set of bands that exist
around all magic angles has what we conjecture to be a stable topological index
stabilized by a magnetic symmetry and reflected in the odd winding of the
Wilson loop in the Moir\'e BZ. The approximate, emergent particle-hole symmetry
is essential to the topology of graphene: when strongly broken, non-topological
phases can appear. Our paper underpins topology as the crucial ingredient to
the description of low-energy graphene. We provide a -band short range
tight-binding model whose lower bands have the same topology, symmetry, and
flatness as those of the twisted graphene, and which can be used as an
effective low-energy model. We then perform large-scale ( atoms per unit
cell, 40 days per -point computing time) ab-initio calculations of a
series of small angles, from to , which show a more complex
and somewhat qualitatively different evolution of the symmetry of the
low-energy bands than that of the theoretical Moir\'e model, but which confirms
the topological nature of the system. At certain angles, we find no insulating
filling in graphene at electrons per Moir\'e unit cell. The ab-initio
evolution of gaps tends to differ from that of the continuum Moir\'e model.Comment: 7+23 pages, 3+12 figures, 2+3 tables; v2: references added, note
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The p53 Pathway Controls SOX2-Mediated Reprogramming in the Adult Mouse Spinal Cord
Although the adult mammalian spinal cord lacks intrinsic neurogenic capacity, glial cells can be reprogrammed in vivo to generate neurons after spinal cord injury (SCI). How this reprogramming process is molecularly regulated, however, is not clear. Through a series of in vivo screens, we show here that the p53-dependent pathway constitutes a critical checkpoint for SOX2-mediated reprogramming of resident glial cells in the adult mouse spinal cord. While it has no effect on the reprogramming efficiency, the p53 pathway promotes cell-cycle exit of SOX2-induced adult neuroblasts (iANBs). As such, silencing of either p53 or p21 markedly boosts the overall production of iANBs. A neurotrophic milieu supported by BDNF and NOG can robustly enhance maturation of these iANBs into diverse but predominantly glutamatergic neurons. Together, these findings have uncovered critical molecular and cellular checkpoints that may be manipulated to boost neuron regeneration after SCI
EL-VIT: Probing Vision Transformer with Interactive Visualization
Nowadays, Vision Transformer (ViT) is widely utilized in various computer
vision tasks, owing to its unique self-attention mechanism. However, the model
architecture of ViT is complex and often challenging to comprehend, leading to
a steep learning curve. ViT developers and users frequently encounter
difficulties in interpreting its inner workings. Therefore, a visualization
system is needed to assist ViT users in understanding its functionality. This
paper introduces EL-VIT, an interactive visual analytics system designed to
probe the Vision Transformer and facilitate a better understanding of its
operations. The system consists of four layers of visualization views. The
first three layers include model overview, knowledge background graph, and
model detail view. These three layers elucidate the operation process of ViT
from three perspectives: the overall model architecture, detailed explanation,
and mathematical operations, enabling users to understand the underlying
principles and the transition process between layers. The fourth interpretation
view helps ViT users and experts gain a deeper understanding by calculating the
cosine similarity between patches. Our two usage scenarios demonstrate the
effectiveness and usability of EL-VIT in helping ViT users understand the
working mechanism of ViT.Comment: 10 pages, 7 figures, conferenc
Reactive Astrocytes in Glial Scar Attract Olfactory Ensheathing Cells Migration by Secreted TNF-α in Spinal Cord Lesion of Rat
BACKGROUND:After spinal cord injury (SCI), the formation of glial scar contributes to the failure of injured adult axons to regenerate past the lesion. Increasing evidence indicates that olfactory ensheathing cells (OECs) implanted into spinal cord are found to migrate into the lesion site and induce axons regeneration beyond glial scar and resumption of functions. However, little is known about the mechanisms of OECs migrating from injection site to glial scar/lesion site. METHODS AND FINDINGS:In the present study, we identified a link between OECs migration and reactive astrocytes in glial scar that was mediated by the tumor necrosis factor-alpha (TNF-alpha). Initially, the Boyden chamber migration assay showed that both glial scar tissue and reactive astrocyte-conditioned medium promoted OECs migration in vitro. Reactive astrocyte-derived TNF-alpha and its type 1 receptor TNFR1 expressed on OECs were identified to be responsible for the promoting effect on OECs migration. TNF-alpha-induced OECs migration was demonstrated depending on activation of the extracellular signal-regulated kinase (ERK) signaling cascades. Furthermore, TNF-alpha secreted by reactive astrocytes in glial scar was also showed to attract OECs migration in a spinal cord hemisection injury model of rat. CONCLUSIONS:These findings showed that TNF-alpha was released by reactive astrocytes in glial scar and attracted OECs migration by interacting with TNFR1 expressed on OECs via regulation of ERK signaling. This migration-attracting effect of reactive astrocytes on OECs may suggest a mechanism for guiding OECs migration into glial scar, which is crucial for OECs-mediated axons regrowth beyond the spinal cord lesion site
Amplifying the Music Listening Experience through Song Comments on Music Streaming Platforms
Music streaming services are increasingly popular among younger generations
who seek social experiences through personal expression and sharing of
subjective feelings in comments. However, such emotional aspects are often
ignored by current platforms, which affects the listeners' ability to find
music that triggers specific personal feelings. To address this gap, this study
proposes a novel approach that leverages deep learning methods to capture
contextual keywords, sentiments, and induced mechanisms from song comments. The
study augments a current music app with two features, including the
presentation of tags that best represent song comments and a novel map metaphor
that reorganizes song comments based on chronological order, content, and
sentiment. The effectiveness of the proposed approach is validated through a
usage scenario and a user study that demonstrate its capability to improve the
user experience of exploring songs and browsing comments of interest. This
study contributes to the advancement of music streaming services by providing a
more personalized and emotionally rich music experience for younger
generations.Comment: In the Proceedings of ChinaVis 202
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