The emerging role of deubiquitylating enzyme USP21 as a potential therapeutic target in cancer.

Although certain members of the Ubiquitin-specific peptidases (USPs) have been recognized as promising therapeutic targets for various diseases, research progress regarding USP21 has been relatively sluggish in its early stages. USP21 is a crucial member of the USPs subfamily, involved in diverse cellular processes such as apoptosis, DNA repair, and signal transduction. Research findings from the past decade demonstrate that USP21 mediates the deubiquitination of multiple well-known target proteins associated with critical cellular processes relevant to both disease and homeostasis, particularly in various cancers.This reviewcomprehensively summarizes the structure and biological functions of USP21 with an emphasis on its role in tumorigenesis, and elucidates the advances on the discovery of tens of small-molecule inhibitors targeting USP21, which suggests that targeting USP21 may represent a potential strategy for cancer therapy.

Curriculum vitae of CUG binding protein 1 (CELF1) in homeostasis and diseases: a systematic review.

RNA-binding proteins (RBPs) are kinds of proteins with either singular or multiple RNA-binding domains (RBDs), and they can assembly into ribonucleic acid-protein complexes, which mediate transportation, editing, splicing, stabilization, translational efficiency, or epigenetic modifications of their binding RNA partners, and thereby modulate various physiological and pathological processes. CUG-BP, Elav-like family 1 (CELF1) is a member of the CELF family of RBPs with high affinity to the GU-rich elements in mRNA, and thus exerting control over critical processes including mRNA splicing, translation, and decay. Mounting studies support that CELF1 is correlated with occurrence, genesis and development and represents a potential therapeutical target for these malignant diseases. Herein, we present the structure and function of CELF1, outline its role and regulatory mechanisms in varieties of homeostasis and diseases, summarize the identified CELF1 regulators and their structure-activity relationships, and prospect the current challenges and their solutions during studies on CELF1 functions and corresponding drug discovery, which will facilitate the establishment of a targeted regulatory network for CELF1 in diseases and advance CELF1 as a potential drug target for disease therapy.

An examination of the status, contexts of anatomical body donation, and perspectives in China.

Body donation is a valuable resource in medical education, research, clinical diagnosis, and treatment. Consequently, donors are honored as "Silent Mentors" in Chinese medical schools. This article briefly reviews the history, current status, and strategies to promote body donation in China (excluding data from Hong Kong, Macao, and Taiwan regions) and discusses the problems encountered in body donation work in China. After establishing the People's Republic of China in 1949, the central government issued regulations on the use of dissected bodies. In 2001, the "Shanghai Regulations on Body Donation" were officially implemented and became China's first local legislative regulation on body donation. Subsequently, local legislative regulations and rules on body donation were issued in various regions to promote smooth and orderly body donation. There has been tremendous development in body donation in China for more than 40 years; however, the progress of this partial work has been uneven in various areas owing to the influence of traditional ethical concepts. It is, therefore, imperative to legislate body donations at a national level. Raising the public's scientific literacy and changing the traditional concept of funerals can create a positive social atmosphere for body donation, thus increasing the public's awareness and willingness to donate their bodies. Donating the body at the end of life contributes to life science and medical causes and is a noble act worthy of praise.

Oral vaccination with recombinant Saccharomyces cerevisiae expressing Micropterus salmoides rhabdovirus G protein elicits protective immunity in largemouth bass.

Micropterus salmoides rhabdovirus (MSRV) is one of the main pathogens of largemouth bass, leading to serious economic losses. The G protein, as the only envelope protein present on the surface of MSRV virion, contains immune-related antigenic determinants, thereby becoming the primary target for the design of MSRV vaccines. Here, we displayed the G protein on the surface of yeast cells (named EBY100/pYD1-G) and conducted a preliminary assessment of the protective efficacy of the recombinant yeast vaccine. Upon oral vaccination, a robust immune response was observed in systemic and mucosal tissue. Remarkably, following the MSRV challenge, the relative percent survival of EBY100/pYD1-G treated largemouth bass significantly increased to 66.7 %. In addition, oral administration inhibited viral replication and alleviated the pathological symptoms of MSRV-infected largemouth bass. These results suggest that EBY100/pYD1-G could be used as a potential oral vaccine against MSRV infection.

Micropterus salmoides rhabdovirus enters cells via clathrin-mediated endocytosis pathway in a pH-, dynamin-, microtubule-, rab5-, and rab7-dependent manner.

IMPORTANCE: Although Micropterus salmoides rhabdovirus (MSRV) causes serious fish epidemics worldwide, the detailed mechanism of MSRV entry into host cells remains unknown. Here, we comprehensively investigated the mechanism of MSRV entry into epithelioma papulosum cyprinid (EPC) cells. This study demonstrated that MSRV enters EPC cells via a low pH, dynamin-dependent, microtubule-dependent, and clathrin-mediated endocytosis. Subsequently, MSRV transports from early endosomes to late endosomes and further into lysosomes in a microtubule-dependent manner. The characterization of MSRV entry will further advance the understanding of rhabdovirus cellular entry pathways and provide novel targets for antiviral drug against MSRV infection.

Lysine-specific demethylase 7A (KDM7A): A potential target for disease therapy.

Histone demethylation is a kind of epigenetic modification mediated by a variety of enzymes and participates in regulating multiple physiological and pathological events. Lysine-specific demethylase 7A is a kind of α-ketoglutarate- and Fe(II)-dependent demethylase belonging to the PHF2/8 subfamily of the JmjC demethylases. KDM7A is mainly localized in the nucleus and contributes to transcriptional activation via removing mono- and di-methyl groups from the lysine residues 9 and 27 of Histone H3. Mounting studies support that KDM7A is not only necessary for normal embryonic, neural, and skeletal development, but also associated with cancer, inflammation, osteoporosis, and other diseases. Herein, the structure of KDM7A is described by comparing the similarities and differences of its amino acid sequences of KDM7A and other Histone demethylases; the functions of KDM7A in homeostasis and dyshomeostasis are summarized via documenting its content and related signaling; the currently known KDM7A-specific inhibitors and their structural relationship are listed based on their structure optimization and pharmacological activities; and the challenges and opportunities in exploring functions and developing targeted agents of KDM7A are also prospected via presenting encountered problems and potential solutions, which will provide an insight in functional exploration and drug discovery for KDM7A-related diseases.

Prevalence of Infectious Hypodermal and Hematopoietic Necrosis Virus (IHHNV) in Farmed Procambarus clarkii of the Middle and Lower Reaches of the Yangtze River in China.

Procambarus clarkii is an important economic aquaculture species worldwide. Infectious hypodermal and hematopoietic necrosis virus (IHHNV) infects numerous crustacean hosts, including P. clarkii. However, there have been few reports on the prevalence of IHHNV in P. clarkii. In this study, 200 farmed P. clarkii were collected from Anhui, Jiangsu, Zhejiang, Hunan, Hubei, and Sichuan provinces in China. PCR detection was employed per the protocol by the World Organization for Animal Health (WOAH) to identify and detect the presence of IHHNV. The positive rate of IHHNV in different provinces ranged from 16.7 to 56.7%, and the overall IHHNV-positive rate was 38.5%. IHHNV strains isolated in this study related closely to infectious IHHNV and split into two major distinct branches. Besides, the IHHNV strains shared a high homology (93.4-99.4%). These findings suggest that a high prevalence of IHHNV was established in farmed P. clarkii in the middle and lower reaches of the Yangtze River.

Oral Vaccination of Recombinant Saccharomyces cerevisiae Expressing ORF132 Induces Protective Immunity against Cyprinid Herpesvirus-2.

Cyprinid herpesvirus 2 (CyHV-2) is the etiological agent of herpesviral hematopoietic necrosis (HVHN) disease, which causes serious economic losses in the crucian carp culture industry. In this study, by displaying ORF132 on the surface of Saccharomyces cerevisiae cells (named EBY100/pYD1-ORF132), we evaluated the protective efficacy of oral administration against CyHV-2 infection. Intense innate and adaptive immune responses were evoked in both mucosal and systemic tissues after oral vaccination with EBY100/pYD1-ORF132. Importantly, oral vaccination provided significant protection for crucian carp post CyHV-2 infection, resulting in a relative percent survival (RPS) of 64%. In addition, oral administration suppressed the virus load and relieved histological damage in selected tissues. Our results indicated that surface-displayed ORF132 on S. cerevisiae could be used as potential oral vaccine against CyHV-2 infection.

Lidocaine alleviates inflammation and pruritus in atopic dermatitis by blocking different population of sensory neurons.

BACKGROUND AND PURPOSE: Atopic dermatitis is a common chronic pruritic inflammatory disease of the skin involving neuro-immune communication. Neuronal mechanism-based therapeutic treatments remain lacking. We investigated the efficacy of intravenous lidocaine therapy on atopic dermatitis and the underlying neuro-immune mechanism. EXPERIMENTAL APPROACH: Pharmacological intervention, immunofluorescence, RNA-sequencing, genetic modification and immunoassay were performed to dissect the neuro-immune basis of itch and inflammation in atopic dermatitis-like mouse model and in patients. KEY RESULTS: Lidocaine alleviated skin lesions and itch in both atopic dermatitis patients and calcipotriol (MC903)-induced atopic dermatitis model by blocking subpopulation of sensory neurons. QX-314, a charged NaV blocker that enters through pathologically activated large-pore ion channels and selectivity inhibits a subpopulation of sensory neurons, has the same effects as lidocaine in atopic dermatitis model. Genetic silencing NaV 1.8-expressing sensory neurons was sufficient to restrict cutaneous inflammation and itch in the atopic dermatitis model. However, pharmacological blockade of TRPV1-positive nociceptors only abolished persistent itch but did not affect skin inflammation in the atopic dermatitis model, indicating a difference between sensory neuronal modulation of skin inflammation and itch. Inhibition of activity-dependent release of calcitonin gene-related peptide (CGRP) from sensory neurons by lidocaine largely accounts for the therapeutic effect of lidocaine in the atopic dermatitis model. CONCLUSION AND IMPLICATIONS: NaV 1.8+ sensory neurons play a critical role in pathogenesis of atopic dermatitis and lidocaine is a potential anti-inflammatory and anti-pruritic agent for atopic dermatitis. A dissociable difference for sensory neuronal modulation of skin inflammation and itch contributes to further understanding of pathogenesis in atopic dermatitis.

Gas6 Promotes Microglia Efferocytosis and Suppresses Inflammation Through Activating Axl/Rac1 Signaling in Subarachnoid Hemorrhage Mice.

Early brain injury (EBI) following subarachnoid hemorrhage (SAH) is characterized by rapid development of neuron apoptosis and dysregulated inflammatory response. Microglia efferocytosis plays a critical role in the clearance of apoptotic cells, attenuation of inflammation, and minimizing brain injury in various pathological conditions. Here, using a mouse SAH model, we aim to investigate whether microglia efferocytosis is involved in post-SAH inflammation and to determine the underlying signaling pathway. We hypothesized that TAM receptors and their ligands regulate this process. To prove our hypothesis, the expression and cellular location of TAM (Tyro3, Axl, and Mertk) receptors and their ligands growth arrest-specific 6 (Gas6) and Protein S (ProS1) were examined by PCR, western blots, and fluorescence immunostaining. Thirty minutes after SAH, mice received an intraventricular injection of recombinant Gas6 (rGas6) or recombinant ProS1 (rPros1) and underwent evaluations of inflammatory mediator expression, neurological deficits, and blood-brain barrier integrity at 24 h. Microglia efferocytosis of apoptotic neurons was analyzed in vivo and in vitro. The potential mechanism was determined by inhibiting or knocking down TAM receptors and Rac1 by specific inhibitors or siRNA. SAH induced upregulation of Axl and its ligand Gas6. The administration of rGas6 but not rPros1 promoted microglia efferocytosis, alleviated inflammation, and ameliorated SAH-induced BBB breakdown and neurological deficits. The beneficial effects of rGas6 were arrogated by inhibiting or knocking down Axl and Rac1. We concluded that rGas6 attenuated the development of early brain injury in mice after SAH by facilitating microglia efferocytosis and preventing inflammatory response, which is partly dependent on activation of Axl and Rac1.

Prediction and screening of circRNA in triple-negative breast cancer.

OBJECTIVE: The purpose of this investigation was to study the expression profile and potential function of circular RNA (circRNA) and long noncoding RNA (lncRNA) in triple-negative breast cancer (TNBC). METHODS: RNA sequencing technology was used to detect differentially expressed circRNAs and lncRNAs between TNBC tissues and the adjacent tissue. The potential functions of these different RNAs were analyzed by GO and KEGG enrichment analysis by bioinformatics tools. We also selected and analyzed these key circRNAs and lncRNAs to verify their important functions in TNBC. RESULTS: A total of 139 differentially expressed circRNAs and 1001 lncRNAs were obtained. The co-expression analysis showed that the hub lncRNAs (OIP5-AS1, DRAIC) were associated with several tumors and mainly enriched in tumor metastasis. We also screened 5 circRNA-hosting genes (NTRK2, FNTA, BAPGEF2, MGST2, ADH1B) that were associated with the brain-derived neurotrophic factor (BDNF) receptor signaling pathway and cerebral cortex development, as well as AMPK and TGF-ß signaling pathway. CONCLUSION: We identified a large number of differentially expressed circRNAs and lncRNAs, which provide useful insight in understanding TNBC carcinogenesis.

Spatial-Temporal Pattern and Convergence Characteristics of Provincial Urban Land Use Efficiency under Environmental Constraints in China.

Revealing the spatial-temporal pattern and convergence characteristics of urban land use efficiency has important guiding significance for adjusting and optimizing the regional urban land use structure. Taking the provincial units in China as the research object, the urban land use efficiency evaluation system considering the unexpected output was constructed, and the slack-based measure (SBA) model was used to quantitatively measure the provincial urban land use efficiency from 2000 to 2020. The exploratory spatial data analysis (ESDA) model and spatial convergence index were combined to reveal the spatial-temporal pattern and convergence characteristics of provincial urban land use efficiency. The results showed that the provincial urban land use efficiency has been continuously improving, with regional differences as shown in eastern region > northeast region > central region > western region. Moran's I of provincial urban land use efficiency was greater than 0, there was a positive spatial correlation, and the clustering feature became increasingly significant. The spatial form of LISA was characterized by "small agglomeration and large dispersion"; the H(High)-H(High) type was clustered in the Yangtze River Delta and Beijing-Tianjin-Hebei, while the L(Low)-L(Low) type was clustered in Xizang, Xinjiang and Qinghai. There was a σ convergence in provincial urban land use efficiency, and there was significant absolute ß convergence and conditional ß convergence of provincial urban land use efficiency. The results showed that the differences in provincial urban land use efficiency were shrinking, showing a "catch-up effect", and converging to their respective stable states over time. Based on the analysis of the spatial-temporal pattern and convergence characteristics of provincial urban land use efficiency in China, we could provide a direction for the optimization of the urban land use structure and efficiency improvement in China, in order to narrow the differences in urban land use efficiency in China's four major regions.

Insular cortical circuits as an executive gateway to decipher threat or extinction memory via distinct subcortical pathways.

Threat and extinction memories are crucial for organisms' survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons to be preferentially innervated by intercortical inputs from the orbitofrontal cortex (OFC), specifically enhancing extinction to override fear memory. These results demonstrate that IC serves as an operation node harboring distinct projection neurons that decipher fear or extinction memory under the top-down executive control from OFC.

Meteorin links the bone marrow hypoxic state to hematopoietic stem/progenitor cell mobilization.

Hematopoietic stem/progenitor cells (HSPCs) are supported and regulated by niche cells in the bone marrow with an important characterization of physiological hypoxia. However, how hypoxia regulates HSPCs is still unclear. Here, we find that meteorin (Metrn) from hypoxic macrophages restrains HSPC mobilization. Hypoxia-induced factor 1α and Yin Yang 1 induce the high expression of Metrn in macrophages, and macrophage-specific Metrn knockout increases HSPC mobilization through modulating HSPC proliferation and migration. Mechanistically, Metrn interacts with its receptor 5-hydroxytryptamine receptor 2b (Htr2b) to regulate the reactive oxygen species levels in HSPCs through targeting phospholipase C signaling. The reactive oxygen species levels are reduced in HSPCs of macrophage-specific Metrn knockout mice with activated phospholipase C signaling. Targeting the Metrn/Htr2b axis could therefore be a potential strategy to improve HSPC mobilization for stem cell-based therapy.

A short peptidoglycan recognition protein protects Boleophthalmus pectinirostris against bacterial infection via inhibiting bacterial activity.

Peptidoglycan recognition proteins (PGRPs) belong to a member of pattern-recognition receptors (PRRs), which proposed as antibacterial protein. The present study investigated the antibacterial effect of BpPGRP5 in great blue-spotted mudskipper (Boleophthalmus pectinirostris). BpPGRP5 transcript was detected in all tested tissues with the highest expression level in spleen, and its expression was significantly upregulated in spleen, intestine, and kidney following Aeromonas veronii infection. rBpPGRP5 was found to interact with several polysaccharides and bacteria, including Gram-negative bacteria (Escherichia coli and A. veronii) and Gram-positive bacteria (Listeria monocytogenes and Staphylococcus aureus). rBpPGRP5 inhibited the proliferation of E. coli, S. aureus, L. monocytogenes, and A. veronii in a Zn2+-dependent manner. Furthermore, in vivo studies revealed that intraperitoneal injection of rBpPGRP5 improved the survival rate of A. veronii-infected B. pectinirostris, accompanied by decreased bacterial load in the blood, kidney, intestine, and spleen. Taken together, our results indicated that BpPGRP5 is an antimicrobial protein that protects B. pectinirostris against bacterial infection.

Whole-Transcriptome Analysis Reveals Autophagy Is Involved in Early Senescence of zj-es Mutant Rice.

Senescence is a necessary stage of plant growth and development, and the early senescence of rice will lead to yield reduction and quality decline. However, the mechanisms of rice senescence remain obscure. In this study, we characterized an early-senescence rice mutant, designated zj-es (ZheJing-early senescence), which was derived from the japonica rice cultivar Zhejing22. The mutant zj-es exhibited obvious early-senescence phenotype, such as collapsed chloroplast, lesions in leaves, declined fertility, plant dwarf, and decreased agronomic traits. The ZJ-ES gene was mapped in a 458 kb-interval between the molecular markers RM5992 and RM5813 on Chromosome 3, and analysis suggested that ZJ-ES is a novel gene controlling rice early senescence. Subsequently, whole-transcriptome RNA sequencing was performed on zj-es and its wild-type rice to dissect the underlying molecular mechanism for early senescence. Totally, 10,085 differentially expressed mRNAs (DEmRNAs), 1,253 differentially expressed lncRNAs (DElncRNAs), and 614 differentially expressed miRNAs (DEmiRNAs) were identified, respectively, in different comparison groups. Based on the weighted gene co-expression network analysis (WGCNA), the co-expression turquoise module was found to be the key for the occurrence of rice early senescence. Furthermore, analysis on the competing endogenous RNA (CeRNA) network revealed that 14 lncRNAs possibly regulated 16 co-expressed mRNAs through 8 miRNAs, and enrichment analysis showed that most of the DEmRNAs and the targets of DElncRNAs and DEmiRNAs were involved in reactive oxygen species (ROS)-triggered autophagy-related pathways. Further analysis showed that, in zj-es, ROS-related enzyme activities were markedly changed, ROS were largely accumulated, autophagosomes were obviously observed, cell death was significantly detected, and lesions were notably appeared in leaves. Totally, combining our results here and the remaining research, we infer that ROS-triggered autophagy induces the programmed cell death (PCD) and its coupled early senescence in zj-es mutant rice.

Mitochondria transplantation/transfer between single cells.

Mitochondrial transplantation/transfer has been increasingly recognized as a potential way for cell and tissue revitalization. In a recent study, Gabelein et al. reported a novel method for single cells mitochondria transplantation using "nanosyringe". This technique combines atomic force microscopy, optical microscopy, and nanofluidics that enable intra- and intercellular organelle micromanipulation and cell-to-cell mitochondria transplantation with up to 95% success rate. The transferred mitochondria fuse to the host mitochondrial network and donor mtDNA incorporate into the recipient mitochondrial genome. The nanosyringe technique provides a novel tool for future mitochondrial research to offer insight into mitochondrial replacement therapy for stroke and fundamental mitochondrial biology.

Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor.

Acidosis is a hallmark of ischemic stroke and a promising neuroprotective target for preventing neuronal injury. Previously, genetic manipulations showed that blockade of acid-sensing ion channel 1a (ASIC1a)-mediated acidotoxicity could dramatically alleviate the volume of brain infarct and restore neurological function after cerebral ischemia. However, few pharmacological candidates have been identified to exhibit efficacy on ischemic stroke through inhibition of ASIC1a. In this work, we examined the ability of a toxin-inspired compound 5b (C5b), previously found to effectively inhibit ASIC1a in vitro, to exert protective effects in animal models of ischemic stroke in vivo. We found that C5b exerts significant neuroprotective effects not only in acid-induced neuronal death in vitro but also ischemic brain injury in vivo, suggesting that ASIC1a is a druggable target for therapeutic development. More importantly, C5b is able to cross the blood brain barrier and significantly reduce brain infarct volume when administered intravenously in the ischemic animal model, highlighting its systemic availability for therapies against neurodegeneration due to acidotoxicity. Together, our data demonstrate that C5b is a promising lead compound for neuroprotection through inhibiting ASIC1a, which warrants further translational studies.

Matrix metalloproteinase-25 from Japanese sea bass (Lateolabrax japonicus) is involved in pro-inflammatory responses.

Matrix metalloproteinases (MMPs) are highly expressed in leukocytes and macrophages, which play a role in the innate immune response. Here, the cDNA sequence of MMP25 from Japanese sea bass (Lateolabrax japonicus) (LjMMP25) was identified. Phylogenetic analysis revealed that LjMMP25 was most closely related to large yellow croaker MMP25. Multiple sequence alignment of LjMMP25 with MMP25 sequences from other teleosts revealed that regions of known functional importance were highly conserved. Expression analysis revealed that LjMMP25 was highly expressed in the head kidney and widely expressed in other tissues including gill, spleen, and liver. LjMMP25 was found to regulate inflammatory cytokine production and promote phagocytosis and bacterial killing in monocytes/macrophages (MO/MФ). Furthermore, LjMMP25 regulated the inflammatory response by modulating NF-κB signaling. These findings reveal new information about the role of LjMMP25 in regulating pro-inflammatory responses in this species.