IGFBP-5 regulates muscle cell differentiation by binding to IGF-II and switching on the IGF-II auto-regulation loop

IGF-II stimulates both mitogenesis and myogenesis through its binding and activation of the IGF-I receptor (IGF-IR). How this growth factor pathway promotes these two opposite cellular responses is not well understood. We investigate whether local IGF binding protein-5 (IGFBP-5) promotes the myogenic action of IGF-II. IGFBP-5 is induced before the elevation of IGF-II expression during myogenesis. Knockdown of IGFBP-5 impairs myogenesis and suppresses IGF-II gene expression. IGF-II up-regulates its own gene expression via the PI3K-Akt signaling pathway. Adding IGF-II or constitutively activating Akt rescues the IGFBP-5 knockdown-caused defects. However, an IGF analogue that binds to the IGF-IR but not IGFBP has only a limited effect. When added with low concentrations of IGF-II, IGFBP-5 restores IGF-II expression and myogenic differentiation, whereas an IGF binding–deficient IGFBP-5 mutant has no effect. These findings suggest that IGFBP-5 promotes muscle cell differentiation by binding to and switching on the IGF-II auto-regulation loop

Progesterone Prevents Traumatic Brain Injury-Induced Intestinal Nuclear Factor kappa B Activation and Proinflammatory Cytokines Expression in Male Rats

We have previously shown that traumatic brain injury (TBI) can induce an upregulation of nuclear factor kappa B (NF-κB) and proinflammatory cytokines in the gut, which play an important role in the pathogenesis of acute gut mucosal injury mediated by inflammation. In this work, we investigated whether progesterone administration modulated intestinal NF-κB activity and proinflammatory cytokines expression after TBI in male rats. As a result, we found that administration of progesterone following TBI could decrease NF-κB binding activity, NF-κB p65 protein expression, and concentrations of interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in the gut. TBI-induced damages of gut structure were ameliorated after progesterone injections. The results of the present study suggest that the therapeutic benefit of post-TBI progesterone injections might be due to its inhibitory effects on intestinal NF-κB activation and proinflammatory cytokines expression

Molecular Recognition of Arginine by Supramolecular Complexation with Calixarene Crown Ether Based on Surface Plasmon Resonance

Arginine plays an important role in cell division and the functioning of the immune system. We describe a novel method by which arginine can be identified using an artificial monolayer based on surface plasmon resonance (SPR). The affinity of arginine binding its recognition molecular was compared to that of lysine. In fabrication of an arginine sensing interface, a calix[4]crown ether monolayer was anchored onto a gold surface and then characterized by Fourier Transform infrared reflection absorption spectroscopy, atomic force microscopy, and cyclic voltammetry. The interaction between arginine and its host compound was investigated by SPR. The calix[4]crown ether was found to assemble as a monolayer on the gold surface. Recognition of calix[4]crown monolayer was assessed by the selective binding of arginine. Modification of the SPR chip with the calix[4]crown monolayer provides a reliable and simple experimental platform for investigation of arginine under aqueous conditions

Selectivity of odorant-binding proteins from the southern house mosquito tested against physiologically relevant ligands

As opposed to humans, insects rely heavily on an acute olfactory system for survival and reproduction. Two major types of olfactory proteins, namely, odorant-binding proteins (OBPs) and odorant receptors (ORs), may contribute to the selectivity and sensitivity of the insects' olfactory system. Here, we aimed at addressing the question whether OBPs highly enriched in the antennae of the southern house mosquito, Culex quinquefasciatus, contribute at least in part to the selective reception of physiologically relevant compounds. Using a fluorescence reporter and a panel of 34 compounds, including oviposition attractants, human-derived attractants, and repellents, we measured binding affinities of CquiOBP1, CquiOBP2, and CquiOBP5. Based on dissociation constants, we surmised that CquiOBP2 is a carrier for the oviposition attractant skatole, whereas CquiOBP1 and CquiOBP5 might transport the oviposition pheromone MOP, a human-derived attractant nonanal, and the insect repellent picardin. Binding of these three ligands to CquiOBP1 was further analyzed by examining the influence of pH on apparent affinity as well as by docking these three ligands into CquiOBP1. Our findings suggest that CquiOBP1 might discriminate MOP from nonanal/picaridin on the basis of the midpoint transition of a pH-dependence conformational change, and that MOP is better accommodated in the binding cavity than the other two ligands. These findings, along with previous experimental evidence suggesting that CquiOBP1 does not detect nonanal in vivo, suggest that OBP selectivity may not be clearly manifested in their dissociation constants

Combinatorial administration of insulin and vitamin C alleviates the cerebral vasospasm after experimental subarachnoid hemorrhage in rabbit

<p>Abstract</p> <p>Background</p> <p>Cerebral vasospasm (CVS) is a common serious complication after the spontaneous subarachnoid hemorrhage (SAH). Despite recent advances in medical and surgical treatments, the 30-day mortality rate of SAH remains high, and there is lack of especially effective clinical treatment to alleviate and improve CVS. The present study has investigated the therapeutic effect of insulin and vitamin C on CVS after SAH.</p> <p>Results</p> <p>Five days after SAH, there is obvious basilar artery spasm in SAH group, whose average vascular cross-sectional area (233,099 ± 16,750 μm²) is significantly smaller than that in control group (462,128 ± 74,756 μm²), which is also significantly different from those in SAH + insulin group (221,114 ± 43,457 μm²) and SAH + vitamin C group (237,820 ± 21,703 μm²). SAH + insulin + vitamin C group shows no evident vasospasm and maintains a vascular cross-sectional area of 425,530 ± 45,503 μm², which is significantly different from that in SAH group. Insulin receptor α (InRα) expression is significantly downregulated in the vascular endothelial cells of SAH, SAH + insulin, and SAH + vitamin C groups (<it>P </it>< 0.01) but remains unchanged in vascular endothelial cells of SAH + insulin + vitamin C group (<it>P </it>> 0.05). Five days after SAH, serum and cerebrospinal fluid NO levels in SAH, SAH + insulin, and SAH + vitamin C groups decrease significantly (<it>P </it>< 0.01) compared to that in control group, whereas the reduction is not evident in SAH + insulin + vitamin C group (<it>P </it>> 0.05).</p> <p>Conclusion</p> <p>Combinatorial treatment with insulin and vitamin C has effectively relieved the CVS after SAH in rabbit, possibly through increasing the InRα expression and NO level, whereas treatment with insulin or vitamin C alone fails to do so.</p

A case report of atypical chronic myeloid leukemia with complete hematological and major molecular response to Venetoclax/Azacitidine treatment

Atypical Chronic Myeloid Leukemia (aCML), a myeloproliferative neoplasm with poor prognosis, was reclassified as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the WHO 2022 classification. Due to the heterogeneity of its clinical features and the lack of unique biomarkers, as well as limited treatment options, aCML currently lacks a standardized treatment protocol. In this case report, we reviewed a young man diagnosed with aCML who achieved complete clinical and hematologic remission subsequent to receiving a therapeutic regimen combining Venetoclax and Azacitidine

OAG-BERT: Pre-train Heterogeneous Entity-augmented Academic Language Models

To enrich language models with domain knowledge is crucial but difficult. Based on the world's largest public academic graph Open Academic Graph (OAG), we pre-train an academic language model, namely OAG-BERT, which integrates massive heterogeneous entities including paper, author, concept, venue, and affiliation. To better endow OAG-BERT with the ability to capture entity information, we develop novel pre-training strategies including heterogeneous entity type embedding, entity-aware 2D positional encoding, and span-aware entity masking. For zero-shot inference, we design a special decoding strategy to allow OAG-BERT to generate entity names from scratch. We evaluate the OAG-BERT on various downstream academic tasks, including NLP benchmarks, zero-shot entity inference, heterogeneous graph link prediction, and author name disambiguation. Results demonstrate the effectiveness of the proposed pre-training approach to both comprehending academic texts and modeling knowledge from heterogeneous entities. OAG-BERT has been deployed to multiple real-world applications, such as reviewer recommendations and paper tagging in the AMiner system. It is also available to the public through the CogDL package

Toward targeted therapy in chemotherapy-resistant pancreatic cancer with a smart triptolide nanomedicine

Chemoresistance is the major impediment for treating pancreatic cancer. Herb-derived compound triptolide (TP) can inhibit proliferation of chemo-resistant pancreatic cancer (CPC) cell lines through multiple mechanisms, which exhibited superior anticancer efficacy compared with gemcitabine. However, toxicity due to non-specific exposure to healthy tissues hindered its clinical translation. Herein we successfully achieved targeting CPC cells and avoiding exposure to healthy tissues for TP by nucleolin-specific aptamer (AS1411) mediated polymeric nanocarrier. We conjugated AS1411 aptamer to carboxy terminated poly(ethylene glycol)–block–poly(d, l-lactide) (HOOC-PEG-PDLLA), then prepared AS1411-PEG-PDLLA micelle loading TP (AS-PPT) through solid dispersion technique. AS-PPT showed more antitumor activity than TP and equivalent specific binding ability with gemcitabine-resistant human pancreatic cancer cell (MIA PaCa-2) to AS1411 aptamer in vitro. Furthermore, we studied the distribution of AS-PPT (Cy3-labed TP) at tissue and cellular levels using biophotonic imaging technology. The results showed AS1411 facilitated TP selectively accumulating in tumor tissues and targeting CPC cells. The lifetime of the MIA PaCa-2 cell-bearing mice administrated with AS-PPT was efficiently prolonged than that of the mice subjected to the clinical anticancer drug Gemzar®in vivo. Such work provides a new strategy for overcoming the drug resistance of pancreatic cancer

Generative AI for Controllable Protein Sequence Design: A Survey

The design of novel protein sequences with targeted functionalities underpins a central theme in protein engineering, impacting diverse fields such as drug discovery and enzymatic engineering. However, navigating this vast combinatorial search space remains a severe challenge due to time and financial constraints. This scenario is rapidly evolving as the transformative advancements in AI, particularly in the realm of generative models and optimization algorithms, have been propelling the protein design field towards an unprecedented revolution. In this survey, we systematically review recent advances in generative AI for controllable protein sequence design. To set the stage, we first outline the foundational tasks in protein sequence design in terms of the constraints involved and present key generative models and optimization algorithms. We then offer in-depth reviews of each design task and discuss the pertinent applications. Finally, we identify the unresolved challenges and highlight research opportunities that merit deeper exploration.Comment: 9 page