Disfunction of dorsal raphe nucleus-hippocampus serotonergic-HTR3 transmission results in anxiety phenotype of Neuroplastin 65-deficient mice.

Anxiety disorders are the most common psychiatric condition, but the etiology of anxiety disorders remains largely unclear. Our previous studies have shown that neuroplastin 65 deficiency (NP65-/-) mice exhibit abnormal social and mental behaviors and decreased expression of tryptophan hydroxylase 2 (TPH2) protein. However, whether a causal relationship between TPH2 reduction and anxiety disorders exists needs to be determined. In present study, we found that replenishment of TPH2 in dorsal raphe nucleus (DRN) enhanced 5-HT level in the hippocampus and alleviated anxiety-like behaviors. In addition, injection of AAV-NP65 in DRN significantly increased TPH2 expression in DRN and hippocampus, and reduced anxiety-like behaviors. Acute administration of exogenous 5-HT or HTR3 agonist SR57227A in hippocampus mitigated anxiety-like behaviors in NP65-/- mice. Moreover, replenishment of TPH2 in DRN partly repaired the impairment of long-term potentiation (LTP) maintenance in hippocampus of NP65-/- mice. Finally, we found that loss of NP65 lowered transcription factors Lmx1b expression in postnatal stage and replenishment of NP65 in DRN reversed the decrease in Lmx1b expression of NP65-/- mice. Together, our findings reveal that NP65 deficiency induces anxiety phenotype by downregulating DRN-hippocampus serotonergic-HTR3 transmission. These studies provide a novel and insightful view about NP65 function, suggesting an attractive potential target for treatment of anxiety disorders.

Metabolism of asparagine in the physiological state and cancer.

Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Suitability of reduced dose glucocorticoids therapy regimen for antibody-associated vasculitis patients with TB: a retrospective study.

INTENTION: Immunosuppressive therapy is the major treatment approach for patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV). Due to impaired cellular immunological function and the use of glucocorticoids and immunosuppressants, AAV patients are predisposed to opportunistic infections, including tuberculosis (TB). This retrospective study aims to analyze the clinical characteristics of patients with AAV and TB and explore suitable glucocorticoid regimens for them. So as to provide a basis for future clinical guidelines and have important value for guiding clinical treatment. METHODS: This study retrospectively reviewed 58 AAV patients (18-80 years old) with TB admitted to Changsha Central Hospital Affiliated with the University of South China from 2016.1 to 2023.4 Patients were divided into standard-dose and reduced-dose glucocorticoid groups before retrospectively analyzing their medical records. RESULTS: A total of 58 AAV patients with TB were enrolled, with 15 dying throughout the monitoring period. Through analysis data, compared with the standard-dose group, the reduced group had less proteinuria and hematuria. In survival analysis, the reduced-dose glucocorticoid group had lower mortality than the standard-dose group (P = 0.03); however, no significant difference was noted in the use of immunoglobulin (P = 0.39), tuberculosis activity (P = 0.64), and age stratification (P = 0.40). The BVAS score before treatment and 6 months post-treatment suggest that the two regimens cause the same risk of ESKD (P > 0.05). CONCLUSION: In conclusion, the reduced glucocorticoid dose group can achieve the same curative effect as the standard dose group and has less damage to the kidney in hematuria and proteinuria. Therefore, the reduced glucocorticoid dose treatment regimen may be more suitable for AAV patients with TB.

Chemiluminescent Conjugated Polymer Nanoparticles for Deep-Tissue Inflammation Imaging and Photodynamic Therapy of Cancer.

Deep-tissue optical imaging and photodynamic therapy (PDT) remain a big challenge for the diagnosis and treatment of cancer. Chemiluminescence (CL) has emerged as a promising tool for biological imaging and in vivo therapy. The development of covalent-binding chemiluminescence agents with high stability and high chemiluminescence resonance energy transfer (CRET) efficiency is urgent. Herein, we design and synthesize an unprecedented chemiluminescent conjugated polymer PFV-Luminol, which consists of conjugated polyfluorene vinylene (PFV) main chains and isoluminol-modified side chains. Notably, isoluminol groups with chemiluminescent ability are covalently linked to main chains by amide bonds, which dramatically narrow their distance, greatly improving the CRET efficiency. In the presence of pathologically high levels of various reactive oxygen species (ROS), especially singlet oxygen (1O2), PFV-Luminol emits strong fluorescence and produces more ROS. Furthermore, we construct the PFV-L@PEG-NPs and PFV-L@PEG-FA-NPs nanoparticles by self-assembly of PFV-Luminol and amphiphilic copolymer DSPE-PEG/DSPE-PEG-FA. The chemiluminescent PFV-L@PEG-NPs nanoparticles exhibit excellent capabilities for in vivo imaging in different inflammatory animal models with great tissue penetration and resolution. In addition, PFV-L@PEG-FA-NPs nanoparticles show both sensitive in vivo chemiluminescence imaging and efficient chemiluminescence-mediated PDT for antitumors. This study paves the way for the design of chemiluminescent probes and their applications in the diagnosis and therapy of diseases.

Risk factors for peripherally inserted central catheter-related venous thrombosis in adult patients with cancer.

PURPOSE: The purpose of this study was to understand and analyze the risk factors of peripherally inserted central catheter (PICC)-related venous thrombosis in adult patients with cancer. METHODS: This observational cohort study included adult patients with cancer who underwent color Doppler ultrasound at the Xiangya Hospital of Central South University, Hunan Provincial Maternal and Child Healthcare Hospital, and Xiangya Changde Hospital, Hunan Province, from January 1, 2017 to December 31, 2021. Univariate and multivariate logistic regression analyses were performed to determine the risk factors of PICC-related venous thrombosis. RESULTS: After risk adjustment, multivariate logistic regression analysis revealed statistically significant associations between PICC-related venous thrombosis and age > 65 years old (OR: 1.791, CI: 1.343-2.389), male sex (OR: 1.398, CI: 1.057-1.849), white blood cell count > 9.5 × 109 /L (OR: 1.422, CI: 1.041-1.942), APTT < 25 s (OR: 2.006, CI: 1.431-2.811), gastrointestinal tumor (OR: 2.191, CI: 1.406-3.414), infection (OR:7.619, CI: 5.783-10.037), the use of cisplatin (OR: 2.374, CI: 1.714-3.214), vincristine (OR: 2.329, CI: 1.447-3.749), the use of polyurethane (OR: 2.449, CI: 1.863-3.219) and open-ended catheters (OR:1.660, CI: 1.131-2.439), keeping time of the catheter (days) (OR: 1.003, CI: 1.001-1.005) were associated with PICC-related venous thrombosis. CONCLUSION: We identified that the presence of age > 65 years old, male sex, white blood cell count > 9.5 × 109 /L, APTT < 25 s, gastrointestinal tumor, infection, the use of cisplatin and vincristine, the use of polyurethane, open-ended catheters and keeping time of the catheter (days), were associated with PICC-related venous thrombosis.

Conjugated Polymer Composite Nanoparticles Augmenting Photosynthesis-Based Light-Triggered Hydrogel Promotes Chronic Wound Healing.

Diabetic chronic wounds are characterized by local hypoxia, impaired angiogenesis, and bacterial infection. In situ, self-supply of dissolved oxygen combined with the elimination of bacteria is urgent and challenging for chronic nonhealing wound treatment. Herein, an oxygen-generating system named HA-L-NB/PFE@cp involving biological photosynthetic chloroplasts (cp)/conjugated polymer composite nanoparticles (PFE-1-NPs@cp) and light-triggered hyaluronic acid-based (HA-L-NB) hydrogel for promoting diabetic wound healing is introduced. Briefly, conjugated polymer nanoparticles (PFE-1-NPs) possess unique light harvesting ability, which accelerates the electron transport rates in photosystem II (PS II) by energy transfer, elevating photosynthesis beyond natural chloroplasts. The enhanced release of oxygen can greatly relieve hypoxia, promote cell migration, and favor antibacterial photodynamic therapy. Additionally, the injectable hydrogel precursors are employed as a carrier to deliver PFE-1-NPs@cp into the wound. Under light irradiation, they quickly form a gel by S-nitrosylation coupling reaction and in situ anchor on tissues through amine-aldehyde condensation. Both in vitro and in vivo assays demonstrate that the oxygen-generating system can simultaneously relieve wound hypoxia, eliminate bacteria, and promote cell migration, leading to the acceleration of wound healing. This study provides a facile approach to develop an enhanced oxygen self-sufficient system for promoting hypoxic tissue, especially diabetic wound healing.

Bioactive Conjugated Polymer-Based Biodegradable 3D Bionic Scaffolds for Facilitating Bone Defect Repair.

Bone defect regeneration is one of the great clinical challenges. Suitable bioactive composite scaffolds with high biocompatibility, robust new-bone formation capability and degradability are still required. This work designs and synthesizes an unprecedented bioactive conjugated polymer PT-C3 -NH2 , demonstrating low cytotoxicity, cell proliferation/migration-promoting effect, as well as inducing cell differentiation, namely regulating angiogenesis and osteogenesis to MC3T3-E1 cells. PT-C3 -NH2 is incorporated into polylactic acid-glycolic acid (PLGA) scaffolds, which is decorated with caffeic acid (CA)-modified gelatin (Gel), aiming to improve the surface water-wettability of PLGA and also facilitate to the linkage of conjugated polymer through catechol chemistry. A 3D composite scaffold PLGA@GC-PT is then generated. This scaffold demonstrates excellent bionic structures with pore size of 50-300 µm and feasible biodegradation ability. Moreover, it also exhibites robust osteogenic effect to promote osteoblast proliferation and differentiation in vitro, thus enabling the rapid regeneration of bone defects in vivo. Overall, this study provides a new bioactive factor and feasible fabrication approach of biomimetic scaffold for bone regeneration.

The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages.

Breast cancer is the most common cancer affecting women worldwide. Investigating metabolism in breast cancer may accelerate the exploitation of new therapeutic options for immunotherapies. Metabolic reprogramming can confer breast cancer cells (BCCs) with a survival advantage in the tumor microenvironment (TME) and metabolic alterations in breast cancer, and the corresponding metabolic byproducts can affect the function of tumor-associated macrophages (TAMs). Additionally, TAMs undergo metabolic reprogramming in response to signals present in the TME, which can affect their function and breast cancer progression. Here, we review the metabolic crosstalk between BCCs and TAMs in terms of glucose, lipids, amino acids, iron, and adenosine metabolism. Summaries of inhibitors that target metabolism-related processes in BCCs or TAMs within breast cancer have also served as valuable inspiration for novel therapeutic approaches in the fight against this disease. This review provides new perspectives on targeted anticancer therapies for breast cancer that combine immunity with metabolism.

Nanocarriers for gene delivery to the cardiovascular system.

Cardiovascular diseases have posed a great threat to human health. Fortunately, gene therapy holds great promise in the fight against cardiovascular disease (CVD). In gene therapy, it is necessary to select the appropriate carriers to deliver the genes to the target cells of the target organs. There are usually two types of carriers, viral carriers and non-viral carriers. However, problems such as high immunogenicity, inflammatory response, and limited loading capacity have arisen with the use of viral carriers. Therefore, scholars turned their attention to non-viral carriers. Among them, nanocarriers are highly valued because of their easy modification, targeting, and low toxicity. Despite the many successes of gene therapy in the treatment of human diseases, it is worth noting that there are still many problems to be solved in the field of gene therapy for the treatment of cardiovascular diseases. In this review, we give a brief introduction to the common nanocarriers and several common cardiovascular diseases (arteriosclerosis, myocardial infarction, myocardial hypertrophy). On this basis, the application of gene delivery nanocarriers in the treatment of these diseases is introduced in detail.

Application of New COF Materials in Secondary Battery Anode Materials.

Covalent organic framework materials (COFs), as a new type of organic porous material, not only have the characteristics of flexible structure, abundant resources, environmental friendliness, etc., but also have the characteristics of a regular structure and uniform pore channels, so they have broad application prospects in secondary batteries. Their functional group structure, type, and number of active sites play a crucial role in the performance of different kinds of batteries. Therefore, this article starts from these aspects, summarizes the application and research progress of the COF anode materials used in lithium-ion batteries, sodium-ion batteries, and potassium-ion batteries in recent years, discusses the energy storage mechanism of COF materials, and expounds the application prospects of COF electrodes in the field of energy storage.

Leukocyte-Specific Morrbid Promotes Leukocyte Differentiation and Atherogenesis.

Monocyte-to-M0/M1 macrophage differentiation with unclear molecular mechanisms is a pivotal cellular event in many cardiovascular diseases including atherosclerosis. Long non-coding RNAs (lncRNAs) are a group of protein expression regulators; however, the roles of monocyte-lncRNAs in macrophage differentiation and its related vascular diseases are still unclear. The study aims to investigate whether the novel leukocyte-specific lncRNA Morrbid could regulate macrophage differentiation and atherogenesis. We identified that Morrbid was increased in monocytes and arterial walls from atherosclerotic mouse and from patients with atherosclerosis. In cultured monocytes, Morrbid expression was markedly increased during monocyte to M0 macrophage differentiation with an additional increase during M0 macrophage-to-M1 macrophage differentiation. The differentiation stimuli-induced monocyte-macrophage differentiation and the macrophage activity were inhibited by Morrbid knockdown. Moreover, overexpression of Morrbid alone was sufficient to elicit the monocyte-macrophage differentiation. The role of Morrbid in monocyte-macrophage differentiation was also identified in vivo in atherosclerotic mice and was verified in Morrbid knockout mice. We identified that PI3-kinase/Akt was involved in the up-regulation of Morrbid expression, whereas s100a10 was involved in Morrbid-mediated effect on macrophage differentiation. To provide a proof of concept of Morrbid in pathogenesis of monocyte/macrophage-related vascular disease, we applied an acute atherosclerosis model in mice. The results revealed that overexpression of Morrbid enhanced but monocyte/macrophage-specific Morrbid knockout inhibited the monocytes/macrophages recruitment and atherosclerotic lesion formation in mice. The results suggest that Morrbid is a novel biomarker and a modulator of monocyte-macrophage phenotypes, which is involved in atherogenesis.

Yttrium chloride induces ferroptosis in cardiomyocytes via iron accumulation and triggers cardiac lipid peroxidation and inflammation that cause heart adverse events in mice.

The growing presence of yttrium (Y) in the environment raises concern regarding its safety and toxicity. However, limited toxicological data are available to determine cardiotoxicity of Y and its underlying mechanisms. In the present study, yttrium chloride (YCl3) intervention with different doses was performed in male Kunming mice for the toxicological evaluation of Y in the heart. After 28 days of intragastric administration, 500 mg/kg·bw YCl3 induces iron accumulation in cardiomyocytes, and triggers ferroptosis through the glutathione peroxidase 4 (GPX4)/glutathione (GSH)/system Xc- axis via the inhibition of Nrf2 signaling pathway. This process led to cardiac lipid peroxidation and inflammatory response. Further RNA sequencing transcriptome analysis found that many genes involved in ferroptosis and lipid metabolism-related pathways were enriched. The ferroptosis induced by YCl3 in cardiomyocytes ultimately caused cardiac injury and dysfunction in mice. Our findings assist in the elucidation of the potential subacute cardiotoxicity of Y3+ and its underlying mechanisms.

Ranunculusjiguanshanicus (Ranunculaceae), a new species from Sichuan, China.

Ranunculusjiguanshanicus (Ranunculaceae), a new species from Chongzhou in Sichuan province, China, is here described and illustrated. The new species is easily distinguishable from other Chinese members of the genus by an array of characters, including small stature, glabrous and prostrate stems, 3-foliolate leaves with obvious petiolules (3-5 mm long), unequally 3-sected leaflets, lanceolate to linear ultimate leaflet segments, small flowers (5.2-6 mm in diameter), and long styles in the carpels and achenes (ca. 0.8 mm long). A distribution map of this new species is also provided.

Ranunculusmaoxianensis (Ranunculaceae), a new species from northwestern Sichuan, China, with an emended description of R.chongzhouensis, the putative closest ally of the new species.

Ranunculusmaoxianensis (Ranunculaceae), a new species from Jiuding Shan in Maoxian county, northwestern Sichuan province, China, is here illustrated and described. The species is morphologically similar to R.chongzhouensis, a species also occurring in Sichuan, in having reniform leaves and puberulous receptacles, carpels and achenes, but differs by having leaves adaxially puberulous with shorter appressed hairs 0.16‒0.28 mm long (vs. longer appressed hairs 0.55‒0.85 mm long), larger flowers (1.8‒2 cm vs. 1.4‒1.6 cm in diameter), larger (8‒10 × 5.5‒6.5 mm vs. 6‒7 × 4.5‒5 mm) and widely obovate petals (vs. obovate), more numerous stamens (35‒55 vs. 12‒18), and subglobose gynoecium and aggregate fruit (vs. ellipsoid). The two species are also different in chromosome number and chromosome morphology. Ranunculuschongzhouensis has a karyotype of 2n = 2x = 16 = 10m + 6sm while R.maoxianensis has a karyotype of 2n = 4x = 32 = 16m + 16sm. An emended description of R.chongzhouensis is provided, and its geographical distribution is largely extended.

An SSL-PUF Based Access Authentication and Key Distribution Scheme for the Space-Air-Ground Integrated Network.

The Space-Air-Ground Integrated Network (SAGIN) expands cyberspace greatly. Dynamic network architecture, complex communication links, limited resources, and diverse environments make SAGIN's authentication and key distribution much more difficult. Public key cryptography is a better choice for terminals to access SAGIN dynamically, but it is time-consuming. The semiconductor superlattice (SSL) is a strong Physical Unclonable Function (PUF) to be the hardware root of security, and the matched SSL pairs can achieve full entropy key distribution through an insecure public channel. Thus, an access authentication and key distribution scheme is proposed. The inherent security of SSL makes the authentication and key distribution spontaneously achieved without a key management burden and solves the assumption that excellent performance is based on pre-shared symmetric keys. The proposed scheme achieves the intended authentication, confidentiality, integrity, and forward security, which can defend against masquerade attacks, replay attacks, and man-in-the-middle attacks. The formal security analysis substantiates the security goal. The performance evaluation results confirm that the proposed protocols have an obvious advantage over the elliptic curve or bilinear pairings-based protocols. Compared with the protocols based on the pre-distributed symmetric key, our scheme shows unconditional security and dynamic key management with the same level performance.

Ranunculusluanchuanensis (Ranunculaceae), a new species from Henan, China.

Ranunculusluanchuanensis (Ranunculaceae), a new species from Laojun Shan in Luanchuan county, Henan province, central China, is here illustrated and described. It is morphologically similar to R.limprichtii in having 3-lobed and subreniform basal leaves, 3-lobed cauline leaves, and small flowers with reflexed and caducous sepals, but differs by having slender and basally slightly thickened roots (vs. fusiform), prostrate stems (vs. erect), obliquely ovoid and glabrous carpels and achenes (vs. widely ovoid and puberulous), longer styles in the carpels (ca. 1.2 mm vs. 0.6-0.8 mm) and achenes (ca. 1.8 mm vs. 0.6-0.8 mm), and glabrous receptacles (vs. sparsely puberulous). Ranunculusluanchuanensis, currently known only from its type locality, is geographically isolated from R.limprichtii, a species widely distributed in Gansu, Qinghai, Sichuan, Xizang (Tibet) and Yunnan, China. The distribution map of this new species and its putative closest ally, R.limprichtii, is also provided.

Neuroplastin 65 deficiency reduces amyloid plaque formation and cognitive deficits in an Alzheimer's disease mouse model.

Introduction: Alzheimer's disease (AD) is characterized by increasing cognitive dysfunction, progressive cerebral amyloid beta (Aß) deposition, and neurofibrillary tangle aggregation. However, the molecular mechanisms of AD pathologies have not been completely understood. As synaptic glycoprotein neuroplastin 65 (NP65) is related with synaptic plasticity and complex molecular events underlying learning and memory, we hypothesized that NP65 would be involved in cognitive dysfunction and Aß plaque formation of AD. For this purpose, we examined the role of NP65 in the transgenic amyloid precursor protein (APP)/presenilin 1 (PS1) mouse model of AD. Methods: Neuroplastin 65-knockout (NP65-/-) mice crossed with APP/PS1 mice to get the NP65-deficient APP/PS1 mice. In the present study, a separate cohort of NP65-deficient APP/PS1 mice were used. First, the cognitive behaviors of NP65-deficient APP/PS1 mice were assessed. Then, Aß plaque burden and Aß levels in NP65-deficient APP/PS1 mice were measured by immunostaining and western blot as well as ELISA. Thirdly, immunostaining and western blot were used to evaluate the glial response and neuroinflammation. Finally, protein levels of 5-hydroxytryptamin (serotonin) receptor 3A and synaptic proteins and neurons were measured. Results: We found that loss of NP65 alleviated the cognitive deficits of APP/PS1 mice. In addition, Aß plaque burden and Aß levels were significantly reduced in NP65-deficient APP/PS1 mice compared with control animals. NP65-loss in APP/PS1 mice resulted in a decrease in glial activation and the levels of pro- and anti-inflammatory cytokines (IL-1ß, TNF-α, and IL-4) as well as protective matrix YM-1 and Arg-1, but had no effect on microglial phenotype. Moreover, NP65 deficiency significantly reversed the increase in 5-hydroxytryptamine (serotonin) receptor 3A (Htr3A) expression levels in the hippocampus of APP/PS1 mice. Discussion: These findings identify a previously unrecognized role of NP65 in cognitive deficits and Aß formation of APP/PS1 mice, and suggest that NP65 may serve as a potential therapeutic target for AD.

CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes.

In this study, we identified that a conserved circular RNA (circRNA) DICAR, which was downregulated in diabetic mouse hearts. DICAR had an inhibitory effect on diabetic cardiomyopathy (DCM), as the spontaneous cardiac dysfunction, cardiac cell hypertrophy, and cardiac fibrosis occurred in DICAR deficiency (DICAR+/-) mice, whereas the DCM was alleviated in DICAR-overexpressed DICARTg mice. At the cellular level, we found that overexpression of DICAR inhibited, but knockdown of DICAR enhanced the diabetic cardiomyocyte pyroptosis. At the molecular level, we identified that DICAR-VCP-Med12 degradation could be the underlying molecular mechanism in DICAR-mediated effects. The synthesized DICAR junction part (DICAR-JP) exhibited a similar effect to the entire DICAR. In addition, the expression of DICAR in circulating blood cells and plasma from diabetic patients was lower than that from health controls, which was consistent with the decreased DICAR expression in diabetic hearts. DICAR and the synthesized DICAR-JP may be drug candidates for DCM.