Biotextgraph: graphical summarization of functional similarities from textual information.

SUMMARY: Functional interpretation of biological entities such as differentially expressed genes is one of the fundamental analyses in bioinformatics. The task can be addressed by using biological pathway databases with enrichment analysis. However, textual description of biological entities in public databases is less explored and integrated in existing tools and it has a potential to reveal new mechanisms. Here, we present a new R package biotextgraph for graphical summarization of omics' textual description data which enables assessment of functional similarities of the lists of biological entities. We illustrate application examples of annotating gene identifiers in addition to enrichment analysis. The results suggest that the visualization based on words and inspection of biological entities with text can reveal a set of biologically meaningful terms that could not be obtained by using biological pathway databases alone. The results suggest the usefulness of the package in the routine analysis of omics-related data. The package also offers a web-based application for convenient querying. AVAILABILITY AND IMPLEMENTATION: The package, documentation, and web server are available at: https://github.com/noriakis/biotextgraph. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Targeted Quantification of Glutathione/Arginine Redox Metabolism Based on a Novel Paired Mass Spectrometry Probe Approach for the Functional Assessment of Redox Status.

Glutathione (GSH) redox control and arginine metabolism are critical in regulating the physiological response to injury and oxidative stress. Quantification assessment of the GSH/arginine redox metabolism supports monitoring metabolic pathway shifts during pathological processes and their linkages to redox regulation. However, assessing the redox status of organisms with complex matrices is challenging, and single redox molecule analysis may not be accurate for interrogating the redox status in cells and in vivo. Herein, guided by a paired derivatization strategy, we present a new ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS)-based approach for the functional assessment of biological redox status. Two structurally analogous probes, 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) and newly synthesized 2-methyl-6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (MeAQC), were set for paired derivatization. The developed approach was successfully applied to LPS-stimulated RAW 264.7 cells and HDM-induced asthma mice to obtain quantitative information on GSH/arginine redox metabolism. The results suggest that the redox status was remarkably altered upon LPS and HDM stimulation. We expect that this approach will be of good use in a clinical biomarker assay and potential drug screening associated with redox metabolism, oxidative damage, and redox signaling.

Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness.

Perivascular collagen deposition by activated fibroblasts promotes vascular stiffening and drives cardiovascular diseases such as pulmonary hypertension (PH). Whether and how vascular fibroblasts rewire their metabolism to sustain collagen biosynthesis remains unknown. Here, we found that inflammation, hypoxia, and mechanical stress converge on activating the transcriptional coactivators YAP and TAZ (WWTR1) in pulmonary arterial adventitial fibroblasts (PAAFs). Consequently, YAP and TAZ drive glutamine and serine catabolism to sustain proline and glycine anabolism and promote collagen biosynthesis. Pharmacologic or dietary intervention on proline and glycine anabolic demand decreases vascular stiffening and improves cardiovascular function in PH rodent models. By identifying the limiting metabolic pathways for vascular collagen biosynthesis, our findings provide guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.

Perceived overqualification and knowledge sharing: The role of organizational identity and psychological entitlement.

BACKGROUND: Employees' perception of being overqualified is a critical factor in influencing their knowledge sharing behavior. However previous studies have not examined the internal mechanism by which perceived overqualification affects knowledge sharing. OBJECTIVE: Drawing on social exchange theory, the present study aimed to explore the relationship between perceived overqualification and knowledge sharing and to examine the mediating effect of organizational identity and the moderating role of psychological entitlement. METHODS: Participants were 284 full-time employees from different companies in China. They answered self-report questionnaires that assessed perceived overqualification, knowledge sharing, organizational identity, and psychological entitlement. Path analyses were conducted, and the latent moderated structural equations were used to judge the significance of the mediation and moderation. RESULTS: The results revealed that overqualified employees were less willing to share knowledge, and the mediating role of organizational identity was significant. Further, the presence of high psychological entitlement would diminish the beneficial effect of organizational identity on employee knowledge sharing. CONCLUSIONS: The findings of the study enrich and expand our knowledge on the relationship between overqualification and knowledge sharing and have theoretical and practical implications for promoting constructive behavior among overqualified employees.

Identifications of novel host cell factors that interact with the receptor binding domain of the SARS-CoV-2 spike protein.

SARS-CoV-2 entry into host cells is facilitated by the interaction between the receptor binding domain of its spike protein (CoV2-RBD) and host cell receptor, ACE2, promoting viral membrane fusion. The virus also uses endocytic pathways for entry, but the mediating host factors remain largely unknown. It is also unknown whether mutations in the RBD of SARS-CoV-2 variants promote interactions with additional host factors to promote viral entry. Here, we used the GST pull-down approach to identify novel surface-located host factors that bind to CoV2-RBD. One of these factors, SH3BP4, regulates internalization of CoV2-RBD in an ACE2-independent, but integrin- and clathrin-dependent manner, and mediates SARS-CoV-2 pseudovirus entry, suggesting that SH3BP4 promotes viral entry via the endocytic route. Many of the identified factors, including SH3BP4, ADAM9 and TMEM2, show stronger affinity to CoV2-RBD than to RBD of the less infective SARS-CoV, suggesting SARS-CoV-2-specific utilization. We also found factors preferentially binding to the RBD of the SARS-CoV-2 Delta variant, potentially enhancing its entry. These data identify the repertoire of host cell surface factors that function in the events leading to entry of SARS-CoV-2.

Enhanced Complement Expression in the Tumor Microenvironment Following Neoadjuvant Therapy: Implications for Immunomodulation and Survival in Pancreatic Ductal Adenocarcinoma.

Background: Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its specific effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study aims to investigate how NAT differentially impacts PDAC's carcinoma cells and TME. Methods: Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME between 23 NAT-treated and 13 NAT-naïve PDAC patients, correlating with their clinicopathologic features. Analysis of an online single-nucleus RNA sequencing (snRNA-seq) dataset was performed for validation of the specific cell types responsible for NAT-induced gene expression alterations. Results: NAT not only induces apoptosis and inhibits proliferation in carcinoma cells but also significantly remodels the TME. Notably, NAT induces a coordinated upregulation of multiple key complement genes (C3, C1S, C1R, C4B and C7) in the TME, making the complement pathway one of the most significantly affected pathways by NAT. Patients with higher TME complement expression following NAT exhibit improved overall survival. These patients also exhibit increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells, monocytes, and mast cells; and reduced immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement was specifically upregulated in CAFs but not in other stroma cell types. Conclusions: NAT can enhance complement production and signaling within the TME, which is associated with reduced immunosuppression in PDAC. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients.

Fe(III)/peroxymonosulfate oxidation system for the degradation of rhein, a toxic component abundance in rhubarb residue.

Rhubarb is widely used in health care, but causing a great amount of rhein-containing herbal residue. Rhein with several toxicities might pollute environment, damage ecology and even hazard human health if left untreated. In this study, the degradation effects of bisulfite- (BS) and peroxymonosulfate- (PMS) based oxidation systems on rhein in rhubarb residue were compared and investigated. The effects of BS and PMS with two valence states of ferric ion (Fe) on the degradation of rhein in rhubarb residue were optimized for the selection of optimal oxidation system. The influences of reaction temperature, reaction time and initial pH on the removal of rhein under the optimal oxidation system were evaluated. The chemical profiles of rhubarb residue with and without oxidation process were compared by UPLC-QTOF-MS/MS, and the degradation effects were investigated by PLS-DA and S plot/OPLS-DA analysis. The results manifested that PMS showed relative higher efficiency than BS on the degradation of rhein. Moreover, Fe(III) promoted the degradation effect of PMS, demonstrated that Fe(III)/PMS is the optimal oxidation system to degrade rhein in rhubarb residue. Further studies indicated that the degradation of rhein by the Fe(III)/PMS oxidation system was accelerated with the prolong of reaction time and the elevation of reaction temperature, and also affected by the initial pH. More importantly, Fe(III)/PMS oxidation system could degrade rhein in rhubarb residue completely under the optimal conditions. In conclusion, Fe(III)/PMS oxidation system is a feasible method to treat rhein in rhubarb residue.

Clinical characteristics and antibiotic treatment of peritoneal dialysis-associated peritonitis caused by Pseudomonas species: a review of 15 years' experience from southern China.

Pseudomonas can lead to peritoneal dialysis-associated peritonitis, which is characterized by a poor prognosis, such as a substantial failure rate and a high death rate. This study aimed to provide an overview of Pseudomonas peritonitis's clinical features, the regimens of antibiotic, antibiotic resistance, and outcomes in peritoneal dialysis (PD) patients. This study observed patients with Pseudomonas peritonitis in two large PD centers in South China from January 2008 to December 2022. The demographics, symptomatology, antibiotics regimens, resistance to common antibiotics, and clinical outcomes of all included patients were reviewed. A total of 3,459 PD patients were included, among them 57 cases of peritonitis caused by Pseudomonas, including 48 cases (84.2%) of Pseudomonas aeruginosa. The incidence rate of Pseudomonas peritonitis was 0.0041 episode per patient-year. Of them, 28.1% (16 cases) of the patients were accompanied by exit site infection (ESI), and all had abdominal pain and turbid ascites at the time of onset. The most commonly used antibiotic combination was ceftazidime combined with amikacin. Approximately 89% of Pseudomonas species were sensitive to ceftazidime, and 88% were sensitive to amikacin. The overall primary response rate was 28.1% (16 patients), and the complete cure rate was 40.4% (23 patients). There was no significant difference in the complete cure rate of peritonitis using three and other antibiotic treatment regimens (44.8% vs 46.4%; P = 0.9). The successful treatment group had higher baseline albumin level (35.9 ± 6.2; P = 0.008) and residual urine volume (650.7 ± 375.5; P = 0.04). Although the incidence of peritonitis caused by Pseudomonas was low, the symptoms were serious, and prognosis was very poor. Pseudomonas was still highly susceptible to first-line antibiotics currently in use against Gram-negative bacteria. Patients with successful treatment had higher albumin levels and higher urine output. IMPORTANCE: Although the incidence of peritoneal dialysis-associated peritonitis caused by Pseudomonas is very low, it seriously affects the technique survival of peritoneal dialysis patients. However, there are few studies and reports on Pseudomonas peritonitis in the Chinese mainland area. Therefore, the purpose of this study is to describe the clinical characteristics, the regimens of antibiotic, drug resistance, and outcome of peritoneal dialysis patients in southern China in the past 15 years and summarize the clinical experience in the treatment of Pseudomonas peritonitis.

Targeting the molecular chaperone CCT2 inhibits GBM progression by influencing KRAS stability.

Proper protein folding relies on the assistance of molecular chaperones post-translation. Dysfunctions in chaperones can cause diseases associated with protein misfolding, including cancer. While previous studies have identified CCT2 as a chaperone subunit and an autophagy receptor, its specific involvement in glioblastoma remains unknown. Here, we identified CCT2 promote glioblastoma progression. Using approaches of coimmunoprecipitation, mass spectrometry and surface plasmon resonance, we found CCT2 directly bound to KRAS leading to increased stability and upregulated downstream signaling of KRAS. Interestingly, we found that dihydroartemisinin, a derivative of artemisinin, exhibited therapeutic effects in a glioblastoma animal model. We further demonstrated direct binding between dihydroartemisinin and CCT2. Treatment with dihydroartemisinin resulted in decreased KRAS expression and downstream signaling. Highlighting the significance of CCT2, CCT2 overexpression rescued the inhibitory effect of dihydroartemisinin on glioblastoma. In conclusion, the study demonstrates that CCT2 promotes glioblastoma progression by directly binding to and enhancing the stability of the KRAS protein. Additionally, dihydroartemisinin inhibits glioblastoma by targeting the CCT2 and the following KRAS signaling. Our findings overcome the challenge posed by the undruggable nature of KRAS and offer potential therapeutic strategies for glioblastoma treatment.

Immobilization of Thermomyces lanuginosus lipase in a novel polysaccharide-based hydrogel by a two-step crosslinking method and its use in the lauroylation of α-arbutin.

The Thermomyces lanuginosus lipase (TLLs) was successfully immobilized within a novel hydrogel matrix through a two-step crosslinking method. TLLs were initially crosslinked through the Schiff base reaction by oxidized carboxymethyl cellulose (OCMC). The water-soluble OCMC@TLLs complex was subsequently crosslinked by carboxymethyl chitosan (CMCSH) in a microfluidic apparatus to form the CMCHS/OCMC@TLLs microspheres. The CD (Circular Dichroism, CD) and FT-IR (Fourier Transform infrared spectroscopy, FT-IR) spectra demonstrated that the crosslinking of TLLs with OCMC resulted in a less significant impact on their structure compared to that with glutaraldehyde. CMCHS/OCMC@TLLs showed decreased catalytic performance due to the mass transfer resistance, while its thermal stability was greatly improved. The CMCHS/OCMC@TLLs were used to catalyze the lauroylation of arbutin in tetrahydrofuran. After 12 h of reaction under optimal conditions, the yield of 6'-O-lauryl arbutin reached an impressive 92.12%. The prepared 6'-O-lauryl arbutin has high lipophilicity and exhibits similar tyrosinase inhibitory activity and higher antioxidant activity compared to its parent compound.

SCFFBXW11 Complex Targets Interleukin-17 Receptor A for Ubiquitin-Proteasome-Mediated Degradation.

Interleukin-17 (IL-17) is a pro-inflammatory cytokine that participates in innate and adaptive immune responses and plays an important role in host defense, autoimmune diseases, tissue regeneration, metabolic regulation, and tumor progression. Post-translational modifications (PTMs) are crucial for protein function, stability, cellular localization, cellular transduction, and cell death. However, PTMs of IL-17 receptor A (IL-17RA) have not been investigated. Here, we show that human IL-17RA was targeted by F-box and WD repeat domain-containing 11 (FBXW11) for ubiquitination, followed by proteasome-mediated degradation. We used bioinformatics tools and biochemical techniques to determine that FBXW11 ubiquitinated IL-17RA through a lysine 27-linked polyubiquitin chain, targeting IL-17RA for proteasomal degradation. Domain 665-804 of IL-17RA was critical for interaction with FBXW11 and subsequent ubiquitination. Our study demonstrates that FBXW11 regulates IL-17 signaling pathways at the IL-17RA level.

Stability and integrity of self-assembled bovine parvovirus virus­like particles (BPV­VLPs) of VP2 and combination of VP1VP2 assisted by baculovirus-insect cell expression: a potential logistical platform for vaccine deployment.

BACKGROUND: Bovine parvovirus (BPV) is an autonomous DNA virus with a smaller molecular size and subtle differences in its structural proteins, unlike other animal parvoviruses. More importantly, this virus has the potential to produce visible to silent economic catastrophes in the livestock business, despite receiving very little attention. Parvoviral virus-like particles (VLPs) as vaccines and as logistical platforms for vaccine deployment are well studied. However, no single experimental report on the role of VP1 in the assembly and stability of BPV-VLPs is available. Furthermore, the self-assembly, integrity and stability of the VLPs of recombinant BPV VP2 in comparison to VP1 VP2 Cap proteins using any expression method has not been studied previously. In this study, we experimentally evaluated the self-assembling ability with which BPV virus-like particles (VLPs) could be synthesized from a single structural protein (VP2) and by integrating both VP2 and VP1 amino acid sequences. METHODS: In silico and experimental cloning methods were carried out. His-tagged and without-His-tag VP2 and V1VP2-encoding amino acid sequences were cloned and inserted into pFastbacdual, and insect cell-generated recombinant protein was evaluated by SDS‒PAGE and western blot. Period of infectivity and expression level were determined by IFA. The integrity and stability of the BPV VLPs were evaluated by transmission electron microscopy. The secondary structure of the BPV VLPs from both VP2 and V1VP2 was analyzed by circular dichroism. RESULTS: Our findings show that VP2 alone was equally expressed and purified into detectable proteins, and the stability at different temperatures and pH values was not appreciably different between the two kinds of VLPs. Furthermore, BPV-VP2 VLPs were praised for their greater purity and integrity than BPV-VP1VP2 VLPs, as indicated by SDS‒PAGE. Therefore, our research demonstrates that the function of VP1 has no bearing on the stability or integrity of BPV-VLPs. CONCLUSIONS: In summary, incredible physiochemically stable BPV VP2-derived VLPs have been found to be promising candidates for the development of multivalent vaccines and immunodiagnostic kits against enteric viruses and to carry heterogeneous epitopes for various economically important livestock diseases.

Ultra-high photoelectric conversion efficiency and obvious carrier separation in photovoltaic ZnIn2X4 (X = S, Se, and Te) van der Waals heterostructures.

The need for low-carbon solar electricity production has become increasingly urgent for energy security and climate change mitigation. However, the bandgap and carrier separation critical requirements of high-efficiency solar cells are difficult to satisfy simultaneously in a single material. In this work, several van der Waals ZnIn2X4 (X = S, Se, and Te) heterostructures were designed based on density functional theory. Our results suggest that both ZnIn2S4/ZnIn2Se4 and ZnIn2Se4/ZnIn2Te4 heterostructures are direct bandgap semiconductors at the Γ point. Besides, obvious carrier spatial separations were observed in the ZnIn2S4/ZnIn2Se4 and ZnIn2Se4/ZnIn2Te4 heterostructures. Interestingly, the ZnIn2S4/ZnIn2Se4 heterostructure has a suitable bandgap of 1.43 eV with good optical absorption in the visible light range. The calculated maximum theoretical photoelectric conversion efficiency of ZnIn2S4/ZnIn2Se4 heterostructure was 32.1%, and it can be further enhanced to 32.9% under 2% tensile strain. Compared to single-layer ZnIn2X4 materials, the electron effective mass of the ZnIn2S4/ZnIn2Se4 heterostructure is relatively low, which results in high electron mobility in the heterostructure. The suitable bandgap, obvious carrier separation, high electron mobility, and excellent theoretical photoelectric conversion efficiency of the ZnIn2S4/ZnIn2Se4 heterostructure make it a promising candidate for novel 2D-based photoelectronic devices and solar cells.

Separation, purification and structural characterization of marine oligosaccharides: A comprehensive and systematic review of chromatographic methods.

Marine oligosaccharides have now been applied in a wide range of industry due to various kinds of physiological activities. However, the oligosaccharides with different polymeric degrees (Dps) differed in physiological activities and applicable fields. So it is promising and essential to separate, purify and structurally characterize these oligosaccharides for understanding their structure-function relationship. This review will summarize the lasted developments in the separation, purification and structural characterization of marine oligosaccharides, including the alginate oligosaccharides, carrageenan oligosaccharides, agar oligosaccharides, chitin oligosaccharides and chitosan oligosaccharides, emphasizing the successful examples of methods for separation and purification. Furthermore, an outlook for preparation of functional oligosaccharides in food biotechnology and agriculture fields is also included. This comprehensive review could definitely promote the utilization of marine functional polysaccharides for food and agriculture.

Phosphorylation of PP2Ac by PKC is a key regulatory step in the PP2A-switch-dependent AKT dephosphorylation that leads to apoptosis.

BACKGROUND: Although GqPCR activation often leads to cell survival by activating the PI3K/AKT pathway, it was previously shown that in several cell types AKT activity is reduced and leads to JNK activation and apoptosis. The mechanism of AKT inactivation in these cells involves an IGBP1-coupled PP2Ac switch that induces the dephosphorylation and inactivation of both PI3K and AKT. However, the machinery involved in the initiation of PP2A switch is not known. METHODS: We used phospho-mass spectrometry to identify the phosphorylation site of PP2Ac, and raised specific antibodies to follow the regulation of this phosphorylation. Other phosphorylations were monitored by commercial antibodies. In addition, we used coimmunoprecipitation and proximity ligation assays to follow protein-protein interactions. Apoptosis was detected by a TUNEL assay as well as PARP1 cleavage using SDS-PAGE and Western blotting. RESULTS: We identified Ser24 as a phosphorylation site in PP2Ac. The phosphorylation is mediated mainly by classical PKCs (PKCα and PKCß) but not by novel PKCs (PKCδ and PKCε). By replacing the phosphorylated residue with either unphosphorylatable or phosphomimetic residues (S24A and S24E), we found that this phosphorylation event is necessary and sufficient to mediate the PP2A switch, which ultimately induces AKT inactivation, and a robust JNK-dependent apoptosis. CONCLUSION: Our results show that the PP2A switch is induced by PKC-mediated phosphorylation of Ser24-PP2Ac and that this phosphorylation leads to apoptosis upon GqPCR induction of various cells. We propose that this mechanism may provide an unexpected way to treat some cancer types or problems in the endocrine machinery.

Excited state properties of 5-fluoro-4-thiouridine derivative†.

The excited state properties of thionated 5-fluorouridine (2',3',5'-tri-O-acetyl-5-fluoro-4-thiouridine; ta5F4TUrd), synthesized with Lawesson's reagent, have been intensively investigated with nanosecond transient absorption spectroscopy, time-resolved thermal lensing, near-infrared emission, and quantum chemical calculation. The intrinsic triplet lifetime of ta5F4TUrd was determined to be 4.2 ± 0.7 µs in acetonitrile, and the formation quantum yield of the excited triplet state was as large as 0.79 ± 0.01 . The quenching rate constants of the triplet ta5F4TUrd by the dissolved oxygen molecule and by the self-quenching process were found to be nearly equal to the diffusion-controlled rate of acetonitrile. The quantum yield of the singlet molecular oxygen produced through energy transfer between the triplet ta5F4TUrd and the dissolved oxygen, Φ Δ , was successfully determined to be 0.61 ± 0.02 under the oxygen-saturated condition. From the oxygen concentration dependence of the Φ Δ value, the fraction of triplet ta5F4TUrd quenched by dissolved oxygen which gives rise to the 1 O2 * formation, S Δ , was successfully obtained to be 0.78 ± 0.01 , which was the largest among the thionucleobases and the thionucleosides reported so far. This could be due to the lower energy and/or the ππ* character of the triplet state.

A Biomimetic Lignocellulose Aerogel-Based Membrane for Efficient Phenol Extraction from Water.

Rapid extraction and concentration systems based on green materials such as cellulose or lignin are promising. However, there is still a need to optimize the material properties and production processes. Unlike conventional cellulose or lignin sorbent materials, aquatic reed root cells can concentrate external organic pollutants in the water and accumulate them in the plant. Inspired by this, a new nanocellulose-lignin aerogel (NLAG) was designed, in which nanocellulose was used as a substrate and lignin and polyamide epoxy chloropropane were used to crosslink cellulose in order to enhance the strength of the NLGA, resulting in good mechanical stability and water-oil amphiphilic properties. In practical applications, the organic membrane on the NLAG can transport organic pollutants from water to the NLAG, where they are immobilized. This is evidenced by the fact that the aerogel can remove more than 93% of exogenous phenol within a few minutes, highly enriching it inside. In addition, the aerogel facilitates filtration and shape recovery for reuse. This work establishes a novel biopolymer-aerogel-based extraction system with the advantages of sustainability, high efficiency, stability, and easy detachability, which are hard for the traditional adsorbent materials to attain.

Predicting cell types with supervised contrastive learning on cells and their types.

Single-cell RNA-sequencing (scRNA-seq) is a powerful technique that provides high-resolution expression profiling of individual cells. It significantly advances our understanding of cellular diversity and function. Despite its potential, the analysis of scRNA-seq data poses considerable challenges related to multicollinearity, data imbalance, and batch effect. One of the pivotal tasks in single-cell data analysis is cell type annotation, which classifies cells into discrete types based on their gene expression profiles. In this work, we propose a novel modeling formalism for cell type annotation with a supervised contrastive learning method, named SCLSC (Supervised Contrastive Learning for Single Cell). Different from the previous usage of contrastive learning in single cell data analysis, we employed the contrastive learning for instance-type pairs instead of instance-instance pairs. More specifically, in the cell type annotation task, the contrastive learning is applied to learn cell and cell type representation that render cells of the same type to be clustered in the new embedding space. Through this approach, the knowledge derived from annotated cells is transferred to the feature representation for scRNA-seq data. The whole training process becomes more efficient when conducting contrastive learning for cell and their types. Our experiment results demonstrate that the proposed SCLSC method consistently achieves superior accuracy in predicting cell types compared to five state-of-the-art methods. SCLSC also performs well in identifying cell types in different batch groups. The simplicity of our method allows for scalability, making it suitable for analyzing datasets with a large number of cells. In a real-world application of SCLSC to monitor the dynamics of immune cell subpopulations over time, SCLSC demonstrates a capability to discriminate cell subtypes of CD19+ B cells that were not present in the training dataset.

Dominant mechanism in spinal cord injury-induced immunodeficiency syndrome (SCI-IDS): sympathetic hyperreflexia.

Clinical studies have shown that individuals with spinal cord injury (SCI) are particularly susceptible to infectious diseases, resulting in a syndrome called SCI-induced immunodeficiency syndrome (SCI-IDS), which is the leading cause of death after SCI. It is believed that SCI-IDS is associated with exaggerated activation of sympathetic preganglionic neurons (SPNs). After SCI, disruption of bulbospinal projections from the medulla oblongata C1 neurons to the SPNs results in the loss of sympathetic inhibitory modulation from the brain and brainstem and the occurrence of abnormally high levels of spinal sympathetic reflexes (SSR), named sympathetic hyperreflexia. As the post-injury survival time lengthens, mass recruitment and anomalous sprouting of excitatory interneurons within the spinal cord result in increased SSR excitability, resulting in an excess sympathetic output that disrupts the immune response. Therefore, we first analyze the structural underpinnings of the spinal cord-sympathetic nervous system-immune system after SCI, then demonstrate the progress in highlighting mechanisms of SCI-IDS focusing on norepinephrine (NE)/Beta 2-adrenergic receptor (ß2-AR) signal pathways, and summarize recent preclinical studies examining potential means such as regulating SSR and inhibiting ß2-AR signal pathways to improve immune function after SCI. Finally, we present research perspectives such as to promote the effective regeneration of C1 neurons to rebuild the connection of C1 neurons with SPNs, to regulate excitable or inhibitory interneurons, and specifically to target ß2-AR signal pathways to re-establish neuroimmune balance. These will help us design effective strategies to reverse post-SCI sympathetic hyperreflexia and improve the overall quality of life for individuals with SCI.

APR-246 increases tumor antigenicity independent of p53.

We previously reported that activation of p53 by APR-246 reprograms tumor-associated macrophages to overcome immune checkpoint blockade resistance. Here, we demonstrate that APR-246 and its active moiety, methylene quinuclidinone (MQ) can enhance the immunogenicity of tumor cells directly. MQ treatment of murine B16F10 melanoma cells promoted activation of melanoma-specific CD8+ T cells and increased the efficacy of a tumor cell vaccine using MQ-treated cells even when the B16F10 cells lacked p53. We then designed a novel combination of APR-246 with the TLR-4 agonist, monophosphoryl lipid A, and a CD40 agonist to further enhance these immunogenic effects and demonstrated a significant antitumor response. We propose that the immunogenic effect of MQ can be linked to its thiol-reactive alkylating ability as we observed similar immunogenic effects with the broad-spectrum cysteine-reactive compound, iodoacetamide. Our results thus indicate that combination of APR-246 with immunomodulatory agents may elicit effective antitumor immune response irrespective of the tumor's p53 mutation status.