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Toxoplasma gondii , the causative parasite of toxoplasmosis, is an apicomplexan parasite that infects warm-blooded mammals. The ability of the calcium-binding proteins (CBPs) to transport large amounts of Ca 2+ appears to be critical for the biological activity of T. gondii . However, the functions of some members of the CBP family have not yet been deciphered. Here, we characterized a putative CBP of T. gondii , TgpCaBP (TGME49_229480), which is composed of four EF-hand motifs with Ca 2+ -binding capability. TgpCaBP was localized in the cytosol and ER of T. gondii , and parasites lacking the TgpCaBP gene exhibited diminished abilities in cell invasion, intracellular growth, egress, and motility. These phenomena were due to the abnormalities in intracellular Ca 2+ efflux and ER Ca 2+ storage, and the reduction in motility was associated with a decrease in the discharge of secretory proteins. Therefore, we propose that TgpCaBP is a Ca 2+ transporter and signaling molecule involved in Ca 2+ regulation and parasitization in the hosts.IMPORTANCECa 2+ signaling is essential in the development of T. gondii . In this study, we identified a calcium-binding protein in T. gondii , named TgpCaBP, which actively regulates intracellular Ca 2+ levels in the parasite. Deletion of the gene coding for TgpCaBP caused serious deficits in the parasite's ability to maintain a stable intracellular calcium environment, which also impaired the secretory protein discharged from the parasite, and its capacity of gliding motility, cell invasion, intracellular growth, and egress from host cells. In summary, we have identified a novel calcium-binding protein, TgpCaBP, in the zoonotic parasite T. gondii , which is a potential therapeutic target for toxoplasmosis.

Background: An accumulating body of research indicates that the pons is related to the occurrence of depression. Si-Ni-San (SNS) is a well-known Chinese herbal formula that is used to treat depression. Chinese herbal formulae have multiple therapeutic characteristics. Although it has been proven that SNS can exert antidepressant effects by improving changes in the limbic system, it is currently unclear whether SNS has therapeutic targets in the pons. This study aimed to explore the therapeutic targets of SNS in the pons for depression treatment., Materials and Methods: Two experiments were conducted. In Experiment 1, 32 rats were divided into four groups: (1) a Control (C) group that received distilled water as a vehicle; (2) a Model (M) group that received the chronic unpredictable mild stress (CUMS) procedure and was administered distilled water; (3) a Stress + SNS (MS) group that received the CUMS procedure and was administered SNS dissolved in distilled water; and (4) a Stress + Fluoxetine (MF) group that received the CUMS procedure and was administered fluoxetine dissolved in distilled water. The open field test (OFT), the sucrose preference test (SPT), and the novel object recognition test (NOR) were performed to test the antidepressant effects of SNS. High-throughput mRNA sequencing (RNA-seq) was used to explore possible gene targets of SNS in the pons, and quantitative real-time PCR was performed to verify the results. High-performance liquid chromatography was used to detect neurotransmitters. Finally, correlation analyses were conducted between behaviors, genes expression, and neurotransmitters. In Experiment 2, 18 rats were divided into the same three groups as in Experiment 1: (1) C, (2) M, and (3) MS. fMRI was used to confirm whether SNS altered the pons in a rat model of depression., Results: SNS significantly improved sucrose preference in the SPT and T N -T O in the NOR compared to the M group ( P < 0.05). RNA-seq filtered 49 differentially expressed genes(DEGs) that SNS could reverse in the pons of the CUMS depression model. Real-time PCR detected six genes, including Complexin2 (Cplx2), Serpinf1, Neuregulin1 (Nrg1), Annexin A1 (Anxa1), β-arrestin 1 (Arrb1) and presenilin 1 (Psen1). SNS significantly reversed changes in the expression of Anxa1, Nrg1, and Psen1 caused by CUMS ( P < 0.05), which is consistent with the DEGs results. Additionally, SNS significantly reversed norepinephrine (NE) changes in the pons. There were 18 noteworthy correlations between behavior, genes, and neurotransmitters ( P < 0.05). fMRI showed that SNS can decrease the amplitude of low-frequency fluctuations (ALFF) in the pons of living depressed rats., Conclusion: The pons is an important target brain region for SNS to exert its antidepressant effects. SNS may improve pontine NE levels by regulating the Anxa1, Nrg1, and Psen1 genes, thereby exerting antidepressant effects and improving cognitive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Zhang, Li, Nie, Qi, Chen, Chen, Liu, Li and Li.)

Bartonella spp. are globally distributed gram-negative facultative intracellular bacteria that infect a wide range of hosts. Rodents are natural reservoirs of many Bartonella species, some of which are also pathogenic to humans. The rapid development of transportation and tourism has highlighted the risk of Bartonella transmission to humans. Thus, it is essential to maintain surveillance of Bartonella spp. infections in rodents. In China, Bartonella spp. infections have been monitored in various areas; however, these have not included the Hulunbuir border regions. In the present study, we monitored the prevalence and genetics of rodent-associated Bartonella spp. in the Hulunbuir border regions. Eleven rodent species were captured at five ports. Eight species were confirmed as Bartonella -positive using quantitative PCR assay, with an overall positivity rate of 20.05 %. Lasiopodomys brandtii was the predominant rodent species captured for Bartonella detection . Sequencing and phylogenetic analysis (using the maximum likelihood method) revealed the presence of three Bartonella species in these rodents, including two pathogenic to humans, namely, Bartonella alsatica and Bartonella grahamii . B. grahamii was the predominant Bartonella species identified in the rodents. Taken together, these results highlight the prevalence and genetic diversity of Bartonella spp. in rodents in the Hulunbuir border regions, indicating the need for risk assessment of human spillover., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 The Authors.)

Ethnopharmacological Relevance: Agrimonia pilosa Ledeb. (Rosaceae, A. pilosa) has been used in traditional medicine in China, Japan, Korea, and other Asian countries for treatment of acute and chronic enteritis and diarrhea. Secondary metabolites have been isolated and tested for biological activities. It remains unclear in terms of its potential components of anti-colorectal cancer properties., Aim of the Study: The study aimed to how extracts from A. pilosa and their components influenced tumor microenvironment and the colorectal tumor growth in vivo on AOM/DSS induced colorectal cancer mice, the metabolites of A. pilosa was also been studied., Materials and Methods: Different methods have been used to extract different parts of A. pilosa. And the anti-proliferation effect of these extracts on colon cancer cells have been tested. The components of A. pilosa and its metabolites in vivo were analyzed by UPLC-QTOF-MS/MS. The anti-colorectal cancer (CRC) effects of A. pilosa and its components in vivo were studied on AOM/DSS induced CRC mice. The effects of constituents of A. pilosa on the composition of immune cells in tumor microenvironment (TME) were analyzed by flow cytometry. 16 S rDNA technology was used to analyze the effect of administration on the composition of intestinal microflora. Pathological section staining was used to compare the morphological changes and molecular expression of intestinal tissue in different groups., Results: The constituent exists in root of A. pilosa showed the strongest anti-proliferation ability on colon cancer cells in vitro. The extract from the root of A. pilosa could attenuate the occurrence of colorectal tumors induced by AOM/DSS in a concentration-dependent manner. Administration of the extract from the root of A. pilosa could affect the proportion of γδT cells, tumor associated macrophages and myeloid derived suppressor cells in TME, increasing the proportion of anti-tumor immune cells and decrease the immunosuppressive cells in the TME to promote the anti-tumor immune response. The administration of the extract adjusted the composition of gut microbiota and its components Agrimoniin and Agrimonolide-6-o-glucoside showed the strongest anti-CRC effect in vivo with adjusting the gut microbiota differently., Conclusions: The extract from root of A. pilosa showed anti-colorectal cancer effects in vivo and in vitro, affecting the composition of gut microbiota and the anti-tumor immune response. Within all components of A. pilosa, Agrimoniin and Agrimonolide-6-o-glucoside showed remarkable anti-CRC efficiency in vivo and in vitro. Besides, the metabolites of extract from root of A. pilosa in gastrointestinal tract mainly composed of two parts: Agrimonolide-related metabolites and Urolithins. The extract from root of A. pilosa could contribute to potential drugs for assisting clinical anti-colon cancer therapy., Competing Interests: Declaration of competing interest The authors have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Recent advancements in nanomaterials have enabled the application of nanotechnology to the development of cutting-edge sensing and actuating devices. For instance, nanostructures' collective and predictable responses to various stimuli can be monitored to determine the physical environment of the nanomaterial, such as temperature or applied pressure. To achieve optimal sensing and actuation capabilities, the nanostructures should be controllable. However, current applications are limited by inherent challenges in controlling nanostructures that counteract many sensing mechanisms that are reliant on their area or spacing. This work presents a technique utilizing the piezo-magnetoelectric properties of nanoparticles to enable strain sensing and actuation in a flexible and wearable patch. The alignment of nanoparticles has been achieved using demagnetization fields with computational simulations confirming device characteristics under various types of deformation followed by experimental demonstrations. The device exhibits favorable piezoelectric performance, hydrophobicity, and body motion-sensing capabilities, as well as machine learning-powered touch-sensing/actuating features.

Neutrophils and macrophages confine pathogens by entrapping them in extracellular traps (ETs) through activating TLR9 function. However, plasmodial parasites secreted TatD-like DNases (TatD) to counteract ETs-mediated immune clearance. We found that TLR9 mutant mice increased susceptibility to rodent malaria, suggesting TLR9 is a key protein for host defense. We found that the proportion of neutrophils and macrophages in response to plasmodial parasite infection in the TLR9 mutant mice was significantly reduced compared to that of the WT mice. Importantly, PbTatD can directly bind to the surface TLR9 (sTLR9) on macrophages, which blocking the phosphorylation of mitogen-activated protein kinase and nuclear factor-κB, negatively regulated the signaling of ETs formation by both macrophages and neutrophils. Such, P. berghei TatD is a parasite virulence factor that can inhibit the proliferation of macrophages and neutrophils through directly binding to TLR9 receptors on the cell surface, thereby blocking the activation of the downstream MyD88-NF-kB pathways., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Trypanosoma brucei, a causative agent of human and animal trypanosomiasis, regularly switches its major surface antigen to avoid elimination by the immune system. Toll-like receptor 9 (TLR9) is a key modulator for resistance to host-infective trypanosomes; however, the underlying molecular mechanism remains indistinct. Thus, we first approached the issue using Tlr9-mutant mice that render them non-responsive to TLR9 agonists. After infection, T cells in the spleens of Tlr9-mutant mice were analyzed by flow cytometry and a reduction in CD8 + , CD4 + T, and NKT cells was observed in Tlr9-mutant mice compared to WT mice. We further found that the responses of inflammatory cytokines in the sera were reduced in Tlr9-mutant mice after T. brucei infection. The underlying molecular mechanism was that T. b. brucei DNA activated TLR9, which consequently upregulated the expression of p38 and ERK/MAPK, resulting in host resistance to trypanosome infection. In conclusion, these findings provide novel insights into the TLR9-mediated host responses to trypanosome infection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Host immune responses are tightly controlled by various immune factors during infection, and protozoan parasites also manipulate the immune system to evade surveillance, leading to an evolutionary arms race in host‒pathogen interactions; however, the underlying mechanisms are not fully understood. We observed that the level of superoxide dismutase 3 (SOD3) was significantly elevated in both Plasmodium falciparum malaria patients and mice infected with four parasite species. SOD3-deficient mice had a substantially longer survival time and lower parasitemia than control mice after infection, whereas SOD3-overexpressing mice were much more vulnerable to parasite infection. We revealed that SOD3, secreted from activated neutrophils, bound to T cells, suppressed the interleukin-2 expression and concomitant interferon-gamma responses crucial for parasite clearance. Overall, our findings expose active fronts in the arms race between the parasites and host immune system and provide insights into the roles of SOD3 in shaping host innate immune responses to parasite infection., (© 2024. The Author(s).)

As a safety-critical application, autonomous driving requires high-quality semantic segmentation and real-time performance for deployment. Existing method commonly suffers from information loss and massive computational burden due to high-resolution input-output and multiscale learning scheme, which runs counter to the real-time requirements. In contrast to channelwise information modeling commonly adopted by modern networks, in this article, we propose a novel real-time driving scene parsing framework named NDNet from a novel perspective of spacewise neighbor decoupling (ND) and neighbor coupling (NC). We first define and implement the reversible operations called ND and NC, which realize lossless resolution conversion for complementary thumbnails sampling and collation to facilitate spatial modeling. Based on ND and NC, we further propose three modules, namely, local capturer and global dependence builder (LCGB), spacewise multiscale feature extractor (SMFE), and high-resolution semantic generator (HSG), which form the whole pipeline of NDNet. The LCGB serves as a stem block to preprocess the large-scale input for fast but lossless resolution reduction and extract initial features with global context. Then the SMFE is used for dense feature extraction and can obtain rich multiscale features in spatial dimension with less computational overhead. As for high-resolution semantic output, the HSG is designed for fast resolution reconstruction and adaptive semantic confusion amending. Experiments show the superiority of the proposed method. NDNet achieves the state-of-the-art performance on the Cityscapes dataset which reports 76.47% mIoU at 240+ frames/s and 78.8% mIoU at 150+ frames/s on the benchmark. Codes are available at https://github.com/LiShuTJ/NDNet.

Remodeling the erythrocyte membrane and skeleton by the malarial parasite Plasmodium falciparum is closely associated with intraerythrocytic development. However, the mechanisms underlying this association remain unclear. In this study, we present evidence that erythrocytic α-spectrin, but not β-spectrin, was dynamically ubiquitinated and progressively degraded during the intraerythrocytic development of P. falciparum, from the ring to the schizont stage. We further observed an upregulated expression of P. falciparum phosphatidylinositol 3-kinase (PfPI3K) in the infected red blood cells during the intraerythrocytic development of the parasite. The data indicated that PfPI3K phosphorylated and activated erythrocytic ubiquitin-protein ligase, leading to increased α-spectrin ubiquitination and degradation during P. falciparum development. We further revealed that inhibition of the activity of PfPI3K impaired P. falciparum development in vitro and Plasmodium berghei infectivity in mice. These findings collectively unveil an important mechanism of PfPI3K-ubiquitin-mediated degradation of α-spectrin during the intraerythrocytic development of Plasmodium species. Proteins in the PfPI3K regulatory pathway are novel targets for effective treatment of severe malaria., Importance: Plasmodium falciparum is the causative agent of severe malaria that causes millions of deaths globally. The parasite invades human red blood cells and induces a cascade of alterations in erythrocytes for development and proliferation. Remodeling the host erythrocytic cytoskeleton is a necessary process during parasitization, but its regulatory mechanisms remain to be elucidated. In this study, we observed that erythrocytic α-spectrin is selectively degraded after P. falciparum invasion, while β-spectrin remained intact. We found that the α-spectrin chain was profoundly ubiquitinated by E3 ubiquitin ligase and degraded by the 26S proteasome. E3 ubiquitin ligase activity was regulated by P. falciparum phosphatidylinositol 3-kinase (PfPI3K) signaling. Additionally, blocking the PfPI3K-ubiquitin-proteasome pathway in P. falciparum -infected red blood cells reduced parasite proliferation and infectivity. This study deepens our understanding of the regulatory mechanisms of host and malarial parasite interactions and paves the way for the exploration of novel antimalarial drugs., Competing Interests: The authors declare no conflict of interest.

This study addresses the fault detection (FD) problem in heterogeneous multi-agent systems (HMASs) with unknown system models. A novel data-driven FD scheme is proposed by properly combining hardware and temporal redundant information to accelerate the generation of fault detectors while ensuring detection accuracy. The computational burden associated with the FD scheme is alleviated by applying a two-step order reduction algorithm. Additionally, an optimization problem is formulated, simplified and solved to achieve a compromise between sensitivity to faults and robustness to disturbances, further enhancing the detection performance of agents. Through a series of examples and comparative experiments, the effectiveness and improvements of the proposed approach are demonstrated., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The human sortilin protein is an important drug target and detection marker for cancer research. The sortilin from Toxoplasma gondii transports proteins associated with the apical organelles of the parasite. In this study, we aimed to determine the intracellular localization and structural domains of T. gondii sortilin, which may mediate protein transportation. Approaches to the functional inhibition of sortilin to establish novel treatments for T. gondii infections were explored., Methods: A gene encoding the sortilin protein was identified in the T. gondii genome. Immunoprecipitation and mass spectrometry were performed to identify the protein species transported by T. gondii sortilin. The interaction of each structural domain of sortilin with the transported proteins was investigated using bio-layer interferometry. The binding regions of the transported proteins in sortilin were identified. The effect of the sortilin inhibitor AF38469 on the infectivity of T. gondii was investigated. The binding site of AF38469 on sortilin was determined., Results: The subdomains Vps10, sortilin-C, and sortilin-M of the sortilin were identified as the binding regions for intracellular transportation of the target proteins. The sortilin inhibitor AF38469 bound to the Vps10 structural domain of T. gondii sortilin, which inhibited parasite invasion, replication, and intracellular growth in vitro and was therapeutic in mice infected with T. gondii., Conclusion: The Vps10, sortilin-C, and sortilin-M subdomains of T. gondii sortilin were identified as functional regions for intracellular protein transport. The binding region for the sortilin inhibitor AF38469 was also identified as the Vps10 subdomain. This study establishes sortilin as a promising drug target against T. gondii and provides a valuable reference for the development of anti-T. gondii drug-target studies., (© 2024. The Author(s).)

Aim: Tyrosine decarboxylase (TDC) presented in the gut-associated strain Enterococcus faecalis can convert levodopa (L-dopa) into dopamine (DA), and its increased abundance would potentially minimize the availability and efficacy of L-dopa. However, the known human decarboxylase inhibitors are ineffective in this bacteria-mediated conversion. This study aims to investigate the inhibition of piperine (PIP) on L-dopa bacterial metabolism and evaluates the synergistic effect of PIP combined with L-dopa on Parkinson's disease (PD)., Methods: Metagenomics sequencing was adopted to determine the regulation of PIP on rat intestinal microbiota structure, especially on the relative abundance of E. faecalis. Then, the inhibitory effects of PIP on L-dopa conversion and TDC expression of E. faecalis were tested in vitro. We examined the synergetic effect of the combination of L-dopa and PIP on 6-hydroxydopamine (6-OHDA)-lesioned rats and tested the regulations of L-dopa bioavailability and brain DA level by pharmacokinetics study and MALDI-MS imaging. Finally, we evaluated the microbiota-dependent improvement effect of PIP on L-dopa availability using pseudo-germ-free and E. faecalis-transplanted rats., Results: We found that PIP combined with L-dopa could better ameliorate the move disorders of 6-OHDA-lesioned rats by remarkably improving L-dopa availability and brain DA level than L-dopa alone, which was associated with the effect of PIP on suppressing the bacterial decarboxylation of L-dopa via effectively downregulating the abnormal high abundances of E. faecalis and TDC in 6-OHDA-lesioned rats., Conclusion: Oral administration of L-dopa combined with PIP can improve L-dopa availability and brain DA level in 6-OHDA-lesioned rats by suppressing intestinal bacterial TDC., (© 2023 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

The uncertainty and unknowability of emerging infectious diseases have caused many major public health and security incidents in recent years. As a new tick-borne disease, Dabieshan tick virus (DBTV) necessitate systematic epidemiological and spatial distribution analysis. In this study, tick samples from Liaoning Province were collected and used to evaluate distribution of DBTV in ticks. Outbreak points of DBTV and the records of the vector Haemaphysalis longicornis in China were collected and used to establish a prediction model using niche model combined with environmental factors. We found that H. longicornis and DBTV were widely distributed in Liaoning Province. The risk analysis results showed that the DBTV in the eastern provinces of China has a high risk, and the risk is greatly influenced by elevation, land cover, and meteorological factors. The risk geographical area predicted by the model is significantly larger than the detected positive areas, indicating that the etiological survey is seriously insufficient. This study provided molecular and important epidemiological evidence for etiological ecology of DBTV. The predicted high-risk areas indicated the insufficient monitoring and risk evaluation and the necessity of future monitoring and control work., (© 2024 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

The biology of Toxoplasma gondii, the causative pathogen of one of the most widespread parasitic diseases (toxoplasmosis), remains poorly understood. Lactate, which is derived from glucose metabolism, is not only an energy source in a variety of organisms, including T. gondii, but also a regulatory molecule that participates in gene activation and protein function. Lysine lactylation (Kla) is a type of post-translational modifications (PTMs) that has been recently associated with chromatin remodeling; however, Kla of histone and non-histone proteins has not yet been studied in T. gondii. To examine the prevalence and function of lactylation in T. gondii parasites, we mapped the lactylome of proliferating tachyzoite cells and identified 1964 Kla sites on 955 proteins in the T. gondii RH strain. Lactylated proteins were distributed in multiple subcellular compartments and were closely related to a wide variety of biological processes, including mRNA splicing, glycolysis, aminoacyl-tRNA biosynthesis, RNA transport, and many signaling pathways. We also performed a chromatin immunoprecipitation sequencing (ChIP-seq) analysis using a lactylation-specific antibody and found that the histones H4K12la and H3K14la were enriched in the promoter and exon regions of T. gondii associated with microtubule-based movement and cell invasion. We further confirmed the delactylase activity of histone deacetylases TgHDAC2-4, and found that treatment with anti-histone acetyltransferase (TgMYST-A) antibodies profoundly reduced protein lactylation in T. gondii. This study offers the first dataset of the global lactylation proteome and provides a basis for further dissecting the functional biology of T. gondii., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Colorectal cancer (CRC) is one of the most common tumors in the world. Cholesterol plays an important role in the pathogenesis of tumors. One of the cholesterol transporters, scavenger receptor class B type 1 (SR-B1), a multi-ligand membrane receptor protein, is expressed in the intestines which also highly expressed in various tumors. But the potential mechanism of SR-B1 in CRC development has not been reported., Aims: This study aimed to clarify the importance of SR-B1 in the development and prognosis of CRC as much as possible to provide a possible strategy in CRC treatment., Materials & Methods: In this study, we used SR-B1 gene knockdown mice to study the effect of SR-B1 on colitis-induced or APC min/+ -induced CRC. The expression of related molecules were detected through the immunohistochemistry and hematoxylin-eosin staining, western blot analysis, and Flow cytometry. The gene expression and microbiota in microenvironment of CRC mice were analyzed through eukaryotic mRNA sequencing and 16S rRNA high-throughput sequencing., Results: The results showed that SR-B1 knockdown reduced the tumor load of colitis-induced or APC min/+ -induced CRC. SR-B1 knockdown improved the immune microenvironment by affecting the level of tumor-associated macrophage (TAM), mononuclear myeloid-derived suppressor cells (M-MDSCs), granulocytic myeloid-derived suppressor cells (G-MDSCs), programmed cell death-ligand 1 (PD-L1), and human leukocyte antigen class I-B (HLA-B), and also reduced the level of low-density lipoprotein receptor (LDL-R), and increased the level of ATP binding cassette transporter A1 (ABCA1) to regulate the cholesterol metabolism, and regulated the expression of related genes and intestinal microbiota. SR-B1 knockdown can also trigger the anti-CRC effect of anti-PD 1 in colitis-induced CRC., Discussion: SR-B1 deficiency significantly improved the immunity in tumor microenvironment of colitis-induced or APC min/+ -induced CRC. In addition, the microbiota changes caused by SR-B1 deficiency favor improving the immune response to chemotherapeutic drugs and anti-PD1 therapy. The mechanism of action of SR-B1 deficiency on the development of CRC still needs further in-depth research., Conclusion: This study provides a new treatment strategy for treating CRC by affecting the expression of SR-B1 in intestine., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Polygalae radix (PR) is a well-known traditional Chinese medicine that is used to treat depression, and polygalae radix oligosaccharide esters (PROEs) are the main active ingredient. Although gut microbiota are now believed to play key role in depression, the effects of PROEs on depression via modulation of gut microbiota remain unknown. In this article, we investigate the effect of PROEs on the gut microbiota of a depression rat and the possible mechanism responsible. The depression rat model was induced by solitary rearing combined with chronic unpredictable mild stress (CUMS). The depression-like behavior, the influence on the hypothalamic-pituitary-adrenal (HPA) axis, the contents of monoamine neurotransmitter in the hippocampus, and the quantity of short-chain fatty acids (SCFAs) in the feces were each assessed, and the serum levels of lipopolysaccharide (LPS) and interleukin-6 (IL-6) were measured by ELISA. Additionally, ultrastructural changes of the duodenal and colonic epithelium were observed under transmission electron microscope, and the gut microbiota were profiled by using 16S rRNA sequencing. The results show that PROEs alleviated the depression-like behavior of the depression model rats, increased the level of monoamine neurotransmitters in the brain, and reduced the hyperfunction of the HPA axis. Furthermore, PROEs regulated the imbalance of the gut microbiota in the rats, relieving intestinal mucosal damage by increasing the relative abundance of gut microbiota with intestinal barrier protective functions, and adjusting the level of SCFAs in the feces, as well as the serum levels of LPS and IL-6. Thus, we find that PROEs had an antidepressant effect through the restructuring of gut microbiota that restored the function of the intestinal barrier, reduced the release of intestinal endotoxin, and constrained the inflammatory response.

Background: Malaria caused by Plasmodium species is a prominent public health concern worldwide, and the infection of a malarial parasite is transmitted to humans through the saliva of female Anopheles mosquitoes. Plasmodium invasion is a rapid and complex process. A critical step in the blood-stage infection of malarial parasites is the adhesion of merozoites to red blood cells (RBCs), which involves interactions between parasite ligands and receptors. The present study aimed to investigate a previously uncharacterized protein, PbMAP1 (encoded by PBANKA&#95;1425900), which facilitates Plasmodium berghei ANKA (PbANKA) merozoite attachment and invasion via the heparan sulfate receptor., Methods: PbMAP1 protein expression was investigated at the asexual blood stage, and its specific binding activity to both heparan sulfate and RBCs was analyzed using western blotting, immunofluorescence, and flow cytometry. Furthermore, a PbMAP1-knockout parasitic strain was established using the double-crossover method to investigate its pathogenicity in mice., Results: The PbMAP1 protein, primarily localized to the P. berghei membrane at the merozoite stage, is involved in binding to heparan sulfate-like receptor on RBC surface of during merozoite invasion. Furthermore, mice immunized with the PbMAP1 protein or passively immunized with sera from PbMAP1-immunized mice exhibited increased immunity against lethal challenge. The PbMAP1-knockout parasite exhibited reduced pathogenicity., Conclusions: PbMAP1 is involved in the binding of P. berghei to heparan sulfate-like receptors on RBC surface during merozoite invasion., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Ticks are vectors and reservoirs of a variety of pathogens including protozoa, bacteria and viruses which cause tick-borne diseases (TBDs) in humans and livestock. TBDs pose serious constraints to the improvement of livestock production in tropical and subtropical regions of the world. Despite their wide distribution, information on the tick and pathogen relationship is scarce in Tanzania. We used nested PCR and sequencing to screen pathogens of public and veterinary health importance in ticks collected by flagging from four districts of Tanzania. In total, 2021 ticks comprising nine species were identified. DNA from ticks was pooled according to tick species, developmental stage, and location, then screened for Babesia bigemina, Babesia bovis, Theileria parva and Coxiella burnetii. Out of 377 pools, 34.7% were positive for at least one pathogen. Theileria parva was the most abundant with a minimum infection rate (MIR) of 2.8%, followed by B. bigemina (MIR = 1.8%) and B. bovis (MIR = 0.8%). Multiple pathogens detection was observed in 7.2% of the tested pools. However, PCR screening of individual tick DNA revealed that only 0.3% of the examined pools had co-infection. DNA of C. burnetii was never detected in any tick DNA pool. The MIR of tick-borne pathogens (TBPs) differed significantly among districts, seasons, tick species, and tick developmental stages. Sequence analysis showed that B. bigemina RAP-1a, B. bovis SBP-4, and T. parva p104 genes were conserved among pathogens in the four districts. Despite the absence of C. burnetii in ticks, considering its pathogenic potential, it is essential to continue monitoring for its possible recurrence in ticks. This information adds to the knowledge of TBPs epidemiology and will contribute to the scientific basis for planning future control strategies., (© 2023. The Author(s).)

Identification of promising schistosome antigen targets is crucial for the development of anti-schistosomal strategies. Schistosomes rely on their neuromuscular systems to coordinate important locomotory behaviors. Tyrosine hydroxylase (TH) is critical in the initial rate-limiting step in biosynthesis of catecholamine, the important neuroactive agents, which promote the lengthening of the worm through muscular relaxation and are therefore of great importance to the movement of the organism both within and between its hosts. THs from both Schistosoma mansoni and Schistosoma japonicum and their enzyme activities have been discovered; however, the role of these proteins during infection have not been explored. Herein, a recombinant protein of the nonconserved fragment of S. japonicum TH (SjTH) was produced and the corresponding polyclonal antibody was generated. The expression and antigenicity of SjTH were detected by qRT-PCR, western blotting, immunofluorescence assays, and ELISA. Mice immunized with the recombinant SjTH were challenged with cercariae to evaluate the immunoprotective value of this protein. Our results showed SjTH not only distributed in the head associated with the central nervous system, but also expressed along the tegument and the intestinal intima, which are involved in the movement, coupling and digestion of the parasites and associated with the peripheral nervous system. This protein can effectively stimulate humoral immune responses in mammalian hosts and has high potential as a biomarker for schistosomiasis immunodiagnosis. Furthermore, immunization with recombinant SjTH showed to reduce the worm and egg burden of challenged mice, and to contribute to the systemic balance of the Th1/Th2 responses. Taken together, these results suggest that SjTH is an important pathogenic molecule in S. japonicum and may be a possible target for anti-schistosomal approaches., Competing Interests: All authors report no competing interests., (Copyright: © 2023 Piao et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

For biped robots, the ability to maintain balance under external forces is an essential requirement. Inspired by human beings' behaviors to resist external forces, a compliant-resistant balance-control method is proposed to keep the biped robot balance subjected to an external force. A model-free trajectory generator is designed based on the central pattern generator (CPG) to generate compliant-resistant human-like behavior. The CPG pattern generator generates the desired pulse signal utilizing Matsuoka's CPG. The signal modulator applies the defined signal to the robot's center of mass (CoM) to generate the workspace trajectory when standing on double feet. Moreover, when standing on single foot, the output signal of the CPG will directly act on the hip joint of the robot to generate the joint space trajectory. Furthermore, the motion engine calculates the workspace trajectory into joint sequence values. The proposed control strategy can generate defined pulse signals to realize compliant-resistant balance control for biped robots. The control strategy proposed in this paper is verified in the NAO simulation environment.

Colorectal cancer has risen to the third occurring cancer in the world. Fluorouracil (5-Fu), oxaliplatin, and cisplatin are the most effective chemotherapeutic agents for clinical chemotherapy. Nevertheless, due to chemotherapeutic drug resistance, the survival rate of patients with CRC remains very low. In this study, we used the inflammation-induced or mutation-family-inherited murine CRC models to study the anticancer and immunotherapy effects of urolithin B (UB), the final metabolite of polyphenols in the gastrointestinal tract. The label-free proteomics analysis and the gene ontology (GO) classifications were used to test and analyze the proteins affected by UB. And 16S rDNA sequencing and flow cytometry were utilized to uncover gut microbiome composition and immune defense improved by UB administration. The results indicated that urolithin B prevents colorectal carcinogenesis by remodeling gut microbial and tumor immune microenvironments, such as HLA-B, NK cells, regulatory T cells, and γδ TCR cells, and decreasing the PD-L1. The combination of urolithin B with first-line therapeutic drugs improved the colorectal intestinal hematochezia by shaping gut microbiota, providing a strategy for the treatment of immunotherapy treatment for CRC treatments. UB combined with anti-PD-1 antibody could inhibit the growth of colon cancer. Urolithin B may thus contribute to anticancer treatments and provide a high immune response microenvironment for CRC patients' further immunotherapy., Competing Interests: All authors declare no competing interests., (Copyright © 2023 Lixue Wang et al.)

Background: Perivascular epithelioid cell tumor (PEComa) occurring in the female genital tract are rare, and typically found in the uterine corpus. PEComa occurring in the cervix is extremely rare, and very few cases have been reported till now. Cytological diagnosis of cervical PEComa is even rarer. So far, only two cases of PEComa diagnosed by conventional cervical smears have been reported., Case Presentation: A 55-year-old postmenopausal woman presented with abnormal vagina discharge for 3 months. A liquid-based cytology test was performed. Microscopically, some loosely cohesive epithelioid cells were uniform with abundant clear cytoplasm, showing predominantly round or oval nuclei with finely stippled chromatin. Distinct round nucleoli were visible in some cells, notably with numerous melanin pigments in the cytoplasm. The cytopathological features were well correlated with cell block and histopathological findings. Upon immunohistochemistry (IHC), the tumor cells were positive for HMB45 and TFE3, focally positive for MelanA, while negative for muscle marker. Fluorescence in situ hybridization (FISH) confirmed TFE3 gene rearrangement. The final pathological diagnosis was PEComa identified by the liquid-based cytology, cell block, cervical biopsy, IHC and FISH result. The patient underwent a total hysterectomy with bilateral salpingo-oophorectomy and was followed up for 2 years with no evidence of disease., Conclusion: The cytologic characteristics of the tumor can provide sufficient clues for PEComa diagnosis, which includes loosely cohesive, epithelioid morphology with abundant clear or eosinophilic cytoplasm, low-grade nuclear atypia, cytoplasmic melanin pigments. This will help cytopathologists to recognize this rare tumor that occurred in the cervix, and the combination of predictive morphology evaluation, immunophenotype, and molecular testing can achieve the definitive diagnosis of PEComa., (© 2023. The Author(s).)

Dihydroartemisinin (DHA), a potent antimalarial drug, also exhibits distinct property in modulation on T reg and B cells, which has been recognized for decades, but the underlying mechanisms remain understood. Herein we revealed that DHA could promote T reg proliferation, meanwhile, suppress B cell expansion in germinal centers, and consequently decrease the number of circulating plasma cells and the content of serum immunoglobulins. Further, DHA-activated T reg significantly mitigated lipopolysaccharide-induced and malaria-associated inflammation. All these scenarios were attributed to the upregulation of c-Fos expression by DHA and enhancement of its interaction with target genes in both T reg and circulating plasma cells with bilateral cell fates. In T reg , the c-Fos-DHA complex upregulated cell proliferation-associated genes and promoted cell expansion; whereas in plasma cells, it upregulated the apoptosis-related genes resulting in decreased circulating plasma cells. Thus, the bilateral immunoregulatory mechanism of DHA was elucidated and its application in the treatment of autoimmune diseases is further justified., (© 2023. The Author(s).)

Scavenger receptor class B type 1 (SR-B1), a multiligand membrane receptor, is expressed in a gradient along the gastrocolic axis. SR-B1 deficiency enhances lymphocyte proliferation and elevates inflammatory cytokine production in macrophages. However, whether SR-B1 affects intestinal metabolites is unclear. In this study, we detected metabolite changes in the intestinal tissue of SR-B1 -/- mice, including amino acids and neurotransmitters, by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) and HPLC. We found that SR-B1 -/- mice exhibited changes in intestinal lipid metabolites and metabolic pathways, including the glycerophospholipid, sphingolipid, linoleic acid, taurine, and hypotaurine metabolic pathways. SR-B1 deficiency influenced the contents of amino acids and neurotransmitters in all parts of the intestine; the contents of leucine (LEU), phenylalanine (PHE), tryptophan (TRP), and tyrosine (TYR) were affected in all parts of the intestine; and the contents of 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) were significantly decreased in both the colon and rectum. In summary, SR-B1 deficiency regulated intestinal lipids, amino acids, and neurotransmitter metabolism in mice.

The salt overly sensitive (SOS) pathway is essential for maintaining sodium ion homeostasis in plants. This conserved pathway is activated by a calcium signaling-dependent phosphorylation cascade. However, the identity of the phosphatases and their regulatory mechanisms that would deactivate the SOS pathway remain unclear. In this study, we demonstrate that PP2C.D6 and PP2C.D7, which belong to clade D of the protein phosphatase 2C (PP2C) subfamily in Arabidopsis thaliana, directly interact with SOS1 and inhibit its Na+/H+ antiporter activity under non-salt-stress conditions. Upon salt stress, SOS3-LIKE CALCIUM-BINDING PROTEIN8 (SCaBP8), a member of the SOS pathway, interacts with the PP2Cs and suppresses their phosphatase activity; simultaneously, SCaBP8 regulates the subcellular localization of PP2C.D6 by releasing it from the plasma membrane. Thus, we identified two negative regulators of the SOS pathway that repress SOS1 activity under nonstress conditions. These processes set the stage for the activation of SOS1 by the kinase SOS2 to achieve plant salt tolerance. Our results suggest that reversible phosphorylation/dephosphorylation is crucial for the regulation of the SOS pathway, and that calcium sensors play dual roles in activating/deactivating SOS2 and PP2C phosphatases under salt stress., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background & Aims: Dyskeratosis congenita (DC) is a telomere biology disorder caused primarily by mutations in the DKC1 gene. Patients with DC and related telomeropathies resulting from premature telomere dysfunction experience multiorgan failure. In the liver, DC patients present with nodular hyperplasia, steatosis, inflammation, and cirrhosis. However, the mechanism responsible for telomere dysfunction-induced liver disease remains unclear., Methods: We used isogenic human induced pluripotent stem cells (iPSCs) harboring a causal DC mutation in DKC1 or a CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/Cas9)-corrected control allele to model DC liver pathologies. We differentiated these iPSCs into hepatocytes (HEPs) or hepatic stellate cells (HSCs) followed by generation of genotype-admixed hepatostellate organoids. Single-cell transcriptomics were applied to hepatostellate organoids to understand cell type-specific genotype-phenotype relationships., Results: Directed differentiation of iPSCs into HEPs and stellate cells and subsequent hepatostellate organoid formation revealed a dominant phenotype in the parenchyma, with DC HEPs becoming hyperplastic and also eliciting a pathogenic hyperplastic, proinflammatory response in stellate cells independent of stellate cell genotype. Pathogenic phenotypes in DKC1-mutant HEPs and hepatostellate organoids could be rescued via suppression of serine/threonine kinase AKT (protein kinase B) activity, a central regulator of MYC-driven hyperplasia downstream of DKC1 mutation., Conclusions: Isogenic iPSC-derived admixed hepatostellate organoids offer insight into the liver pathologies in telomeropathies and provide a framework for evaluating emerging therapies., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Trypanosoma brucei , the pathogen causing African sleeping sickness (trypanosomiasis) in humans, causes debilitating diseases in many regions of the world, but mainly in African countries with tropical and subtropical climates. Enormous efforts have been devoted to controlling trypanosomiasis, including expanding vector control programs, searching for novel anti-trypanosomial agents, and developing vaccines, but with limited success. In this study, we systematically investigated the effect of graphene quantum dots (GQDs) on trypanosomal parasites and their underlying mechanisms. Ultrasmall-sized GQDs can be efficiently endocytosed by T. brucei and with no toxicity to mammalian-derived cells, triggering a cascade of apoptotic reactions, including mitochondrial disorder, intracellular reactive oxygen species (ROS) elevation, Ca 2+ accumulation, DNA fragmentation, adenosine triphosphate (ATP) synthesis impairment, and cell cycle arrest. All of these were caused by the direct interaction between GQDs and the proteins associated with cell apoptosis and anti-oxidation responses, such as trypanothione reductase (TryR), a key protein in anti-oxidation. GQDs specifically inhibited the enzymatic activity of TryR, leading to a reduction in the antioxidant capacity and, ultimately, parasite apoptotic death. These data, for the first time, provide a basis for the exploration of GQDs in the development of anti-trypanosomials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xie, Liang, Jiang, Liu, Zhang, Li, Zhang, Sang, Feng, Chen, Zhang and Chen.)

Milky disease caused by Metschnikowia bicuspidata fungus has significantly harmed the Chinese mitten crab Eriocheir sinensis aquaculture industry. However, the effect of M. bicuspidata infection on the metabolism and intestinal flora of the crab remains unclear. In this study, we aimed to explore the changes in the metabolism and intestinal flora E. sinensis after 48 h of infection with M. bicuspidata , using metabolomic and metagenomic analyses. Metabolomic analysis results revealed 420 significantly different metabolites between the infected and control groups, and these metabolites were enriched in 58 metabolic pathways. M. bicuspidata infection decreased the levels of metabolites related to amino acid biosynthesis, the tricarboxylic acid cycle, as well as lysine, histidine, linolenic, arachidonic, and linoleic acid metabolism. These results indicated that M. bicuspidata infection significantly affected the energy metabolism, growth, and immunity of E. sinensis . The results of metagenomic analysis showed that the anaerobes and ascomycetes populations significantly increased and decreased, respectively, after M. bicuspidata infection. These changes in intestinal flora significantly upregulated metabolic and synthetic pathways while downregulating immunity-related pathways. The results of integrated metabolomic and metagenomic analyses showed that 55 differentially expressed genes and 28 operational taxonomic units were correlated with 420 differential metabolites. Thus, the intestinal flora changes caused by M. bicuspidata infection also affected the metabolites. This study provides novel insights into the metabolic-and intestinal microflora-based effects of M. bicuspidata infection in E. sinensis , as well as a theoretical basis for the interaction between fungi and crustaceans., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Bao, Xing, Cao, Li and Chen.)

Background: Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking., Methods: Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort., Results: Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p < 0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p = 0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78-24.51, p = 0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06-13.4, p = 0.94)., Conclusion: Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD., Competing Interests: Declaration of competing interest None to report. Specifically, JGN, JFB, QC, NS, TDM, PR, GMT, BCS, TRM, and FBJ and have no relevant conflicts of interest. BRE has received consulting fees from Boehringer Ingelheim unrelated to this project. SMK has received consulting fees from Acceleron Pharma, United Therapeutics Corporation, and VIVUS unrelated to this project and holds stock in AbbVie., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Ethnopharmacological Relevance: Penthorum chinense Pursh. (PCP) is commonly used as a Miao ethnomedicine and health food for liver protection in China. Gansukeli (WS3-B-2526-97) is made from the extract of PCP (PCPE) for the treatment of viral hepatitis. In recent years, PCPE has been reported in the treatment of non-alcoholic fatty liver disease (NAFLD), however its potential mechanism is not fully elucidated., Aim of the Study: To investigate the ameliorating effect of PCPE on high-fat diet (HFD)-induced NAFLD mice and demonstrate whether its protective effect is gut microbiota dependent and associated with bile acid (BA) metabolism., Materials and Methods: The alleviating effect of PCPE on NAFLD was conducted on male C57BL/6J mice fed an HFD for 16 weeks, and this effect associated with gut microbiota dependent was demonstrated by pseudo-germfree mice treated with antibiotics and fecal microbiota transplantation (FMT). The composition of the gut microbiota in the cecum contents was analyzed by 16S rRNA sequencing, and the levels of BAs in liver and fecal samples were determined by UPLC/MS-MS., Results: The results showed that administration of PCPE for 8 weeks could potently ameliorate HFD-induced NAFLD and alleviate dyslipidemia and insulin resistance. Moreover, PCPE treatment alleviated gut dysbiosis, especially reducing the relative abundance of bile salt hydrolase (BSH)-producing bacteria. Furthermore, PCPE significantly increased the levels of taurine-conjugated BAs in feces, such as tauro-β-muricholic acid (T-βMCA), tauroursodesoxycholic acid (TUDCA), and taurochenodeoxycholic acid (TCDCA), and increased hepatic chenodeoxycholic acid (CDCA). The protein and mRNA expression of farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15) were decreased in intestine, increased taurine-conjugated BAs inhibited the intestinal signaling pathway, which was associated with increased genes expression of enzymes in the alternative BA synthesis pathway that reduced the levels of cholesterol. The increased CDCA produced via the alternative BA synthesis pathway promoted hepatic FXR activation and BA excretion., Conclusion: Our study is the first time to demonstrate that PCPE could ameliorate NAFLD in HFD-induced mice by regulating the gut microbiota and BA metabolism, and from a novel perspective, to clarify the mechanism of PCPE in NAFLD., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The immunomodulatory potential of dihydroartemisinin (DHA) has recently been highlighted; however, the potential mechanism remains to be clarified. Single-cell RNA sequencing was explored in combination with cellular and biochemical approaches to elucidate the immunomodulatory mechanisms of DHA. In this study, we found that DHA induced both spleen enlargement and rearrangement of splenic immune cell subsets in mice. It was revealed that DHA promoted the reversible expansion of effective regulatory T cells and interferon-γ + cytotoxic CD8 + T cells in the spleen via induction of superoxide dismutase 3 (SOD3) expression and increased phosphorylation of c-Jun N-terminal kinases (JNK) and its downstream activator protein 1 (AP-1) transcription factors. Further, SOD3 knockout mice were resistant to the regulatory effect of DHA. Thus, DHA, through the activation of the SOD3-JNK-AP-1 axis, beneficially regulated immune cell heterogeneity and splenic immune cell homeostasis to treat autoimmune diseases., (© 2022. Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature.)

Artemisinin (ART) and dihydroartemisinin (DHA), apart from their profound anti-malaria effect, can also beneficially modulate the host immune system; however, the underlying molecular mechanisms remain unclear. Here, we report that DHA selectively induced T-cell activation, with an increased proportion of Ki67 + CD4 + T cells, CD25 + CD4 + T cells, interferon (IFN)-γ-producing CD8 + T cells, Brdu + CD8 + T cells and neutrophils, which was found to enhance cellular immunity to experimental malaria and overcome immunosuppression in mice. We further revealed that DHA upregulated the expression of cell proliferation-associated proteins by promoting the phosphorylation of mitogen-activated protein kinase (MAPK), cyclin-dependent kinases (CDKs), and activator protein 1 in the spleen. This study is the first to provide robust evidence that DHA selectively induced the expansion of subsets of splenic T cells through phosphorylated CDKs and MAPK to enhance cellular immune responses under non-pathological or pathological conditions. The data significantly deepened our knowledge in the mechanism underlying DHA-mediated immunomodulation., (© 2022. The Author(s).)

Tick-borne diseases including East Coast fever, anaplasmosis and babesiosis constitute a major constraint to improving livestock production worldwide, including Tanzania. Determination of the prevalence and factors associated with the occurrence of pathogens in cattle is important for informed decision making on the control and prevention of these diseases. However, little is known about the epidemiology of these pathogens in cattle in some regions of Tanzania. Therefore, this study aimed at establishing the prevalence of Anaplasma marginale, Babesia bigemina, Babesia bovis and Theileria parva in cattle, determine the risk factors associated with infection with these pathogens and also to assess tick control practices in Gairo and Monduli districts of Tanzania. Out of the 520 cattle sampled, the majority (82.9%) were infested with ticks of different species, predominated by Rhipicephalus decoloratus (42.7%), Amblyomma variegatum (31.3%), Rhipicephalus pulchellus (23.1%) and Rhipicephalus appendiculatus (17.7%). Other ticks that were found on cattle included Rhipicephalus microplus (15.8%), Amblyomma gema (13.8%), Rhipicephalus evertsi (12.9%), Amblyomma lepidum (8.1%), Hyalomma truncatum (2.9%) and Hyalomma albiparmatum (2.1%). On microscopy 23 (4.4%) of 520 cattle were positive for hemoparasites. Of the 23 positive cattle, 13 (2.5%), 6 (1.2%) and 3 (0.6%) were monolithically infected with A. marginale, T. parva, and B. bovis respectively, while one (0.2% %) had co-infections of T. parva and A. marginale. The number of positive cattle increased to 184 (35.4%), when they were subjected to detection with PCR. This included the 23 samples that were positive on microscopy. Based on PCR, the overall prevalence of the pathogens from the two districts was 11.5%, 11.2%, 6.2% and 2.5% for B. bigemina, A. marginale, T. parva and B. bovis, respectively. Hemoparasite co-infection occurred in 6.9% of the cattle examined. The prevalence of co-infections was 2.7%, 4%, and 0.02% for T. parva/A. marginale, B. bigemina/A. marginale and B. bigemina/A. marginale/T. parva, respectively. Cattle with co-infections had significantly lower (p < 0.005) mean packed cell volume as compared to cattle with mono-infections. The majority (96%) of cattle examined were subjected to different methods of tick control. A number of risk factors were shown to be associated with the occurrence of tick-borne pathogens in cattle. Higher prevalence of A. marginale may be due to its wide range of biological and mechanical transmission. These findings could be used to strengthen future control programs for ticks and tick-borne diseases in the study areas., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Metschnikowia bicuspidata is a globally distributed pathogenic yeast with a wide range of aquatic hosts. A new strain, M. bicuspidata LNES0119, isolated from the Chinese mitten crab Eriocheir sinensis , has caused a serious reduction in production and marked economic loss for the aquaculture industry in China. Therefore, the whole-genome sequence of M. bicuspidata LNES0119 was sequenced using Illumina and Oxford Nanopore technology; whole-genome annotation and comparative genomic analyses of this pathogen were performed as well. A high-quality genome of M. bicuspidata LNES0119 was 16.13 Mb in size, with six scaffolds and six contigs, and encoded 5,567 putative predicted genes. Of these, 1,467 genes shared substantial homology with genes in the pathogen-host interactions database. Comparative genomic analyses of three M. bicuspidata strains and one non-pathogenic yeast, M. aff. pulcherrima , showed 331 unique genes in M. bicuspidata LNES0119, 30 of which were putatively related to pathogenicity. Overall, we identified several meaningful characteristics related to pathogenicity and virulence that may play essential roles in the infection and pathogenicity of M. bicuspidata LNES0119. Our study will aid in identifying potential targets for further exploration of the molecular basis of the pathogenicity of M. bicuspidata as well as the therapeutic intervention of M. bicuspidata infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Bao, Xing, Li and Chen.)

Background: Antigens of migrating schistosomula are promising candidates as schistosomiasis vaccine targets, since immune attack on hepatic schistosomula would interrupt the parasites life cycle and reduce egg burden on the host., Methods: In this study, we report a collection of Schistosoma japonicum schistosomula proteins (SjScPs) that are highly expressed in hepatic schistosomula. The expression characteristics, antigenicity and immune protection of these proteins were studied by western blot, ELISA, immunofluorescence and challenge assays., Results: We found that several of these SjScPs were highly antigenic and could effectively stimulate humoral immune responses in both human and other mammalian hosts. In particular, SjScP25, SjScP37, SjScP41, SjScP80, and SjScP88 showed high potential as biomarkers for schistosomiasis immunodiagnosis. Furthermore, we demonstrated that immunization with several of the recombinant SjScPs were able to protect mice from S japonicum challenge infection, with SjScP25 generating the most protective results., Conclusions: Our work represents a group of novel schistosome immunogens, which may be promising schistosomiasis japonica diagnosis and vaccine candidates., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Dyskeratosis congenita (DC) is a rare genetic disorder characterized by deficiencies in telomere maintenance leading to very short telomeres and the premature onset of certain age-related diseases, including pulmonary fibrosis (PF). PF is thought to derive from epithelial failure, particularly that of type II alveolar epithelial (AT2) cells, which are highly dependent on Wnt signaling during development and adult regeneration. We use human induced pluripotent stem cell-derived AT2 (iAT2) cells to model how short telomeres affect AT2 cells. Cultured DC mutant iAT2 cells accumulate shortened, uncapped telomeres and manifest defects in the growth of alveolospheres, hallmarks of senescence, and apparent defects in Wnt signaling. The GSK3 inhibitor, CHIR99021, which mimics the output of canonical Wnt signaling, enhances telomerase activity and rescues the defects. These findings support further investigation of Wnt agonists as potential therapies for DC-related pathologies., Competing Interests: RF, ZG, KS, DL, KE, WY, QC, GS, JP, SR, RB, JT, AB, MM, DF, CL, FJ No competing interests declared, EM Reviewing editor, eLife, (© 2022, Fernandez et al.)

Cherry tomato ( Solanum lycopersicum ) is popular with consumers over the world due to its special flavor. Soluble solids content (SSC) and firmness are two key metrics for evaluating the product qualities. In this work, we develop non-destructive testing techniques for SSC and fruit firmness based on hyperspectral images and the corresponding deep learning regression model. Hyperspectral reflectance images of over 200 tomato fruits are derived with the spectrum ranging from 400 to 1,000 nm. The acquired hyperspectral images are corrected and the spectral information are extracted. A novel one-dimensional (1D) convolutional ResNet (Con1dResNet) based regression model is proposed and compared with the state of art techniques. Experimental results show that, with a relatively large number of samples our technique is 26.4% better than state of art technique for SSC and 33.7% for firmness. The results of this study indicate the application potential of hyperspectral imaging technique in the SSC and firmness detection, which provides a new option for non-destructive testing of cherry tomato fruit quality in the future., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xiang, Chen, Su, Zhang, Chen, Zhou, Yao, Xuan and Cheng.)

The Chinese mitten crab, Eriocheir sinensis , is an important farmed crustacean species in China, outranking other farmed crabs in yield and economic importance. An infection called "milky disease", caused by the yeast, Metschnikowia bicuspidata , has emerged in E. sinensis farms in northeast China and has caused progressive economic losses. The diseased crabs present with opaque, whitish muscles and milky hemolymph. Currently, there are no effective drugs to treat the infection. Clarifying the transmission route of M. bicuspidata would help to treat and prevent the disease. We investigated the effects of three different M. bicuspidata infection methods (feeding, immersion, and cohabitation) on E. sinensis . All three infection methods led to a high infection rate in healthy crabs. After 35 d, the infection rate was 76.7%, 66.7%, and 53.3% in the feeding, immersion, and cohabitation groups, respectively. Diseased crabs exhibited the typical symptom of hemolymph emulsification, with a high pathogen load of M. bicuspidata . The yeast was not detected in the oocytes of infected crabs. Fertilized embryos, zoea larvae, and megalopae of infected ovigerous crabs tested negative for yeast, indicating that direct transmission from mother to offspring does not occur. Our results highlight avenues for the prevention and control of this yeast.

Babesiosis poses a serious threat to immunocompromised individuals and the major etiological species of Babesia for human babesiosis is Babesia microti . Merozoites are a critical stage in the life cycle of Babesia microti . Several merozoite proteins have been demonstrated to play important roles in this process; however, most of the merozoite proteins of B. microti remain unknown. In the present study, we identified a novel merozoite protein of B. microti with similar structure to the thioredoxin (Trx)-like domain of the Trx family, which was named as B. microti Trx-like protein ( Bm TLP). Western blot assays demonstrated that this protein was expressed by B. microti during the erythrocytic infection process, and its expression peaked on day 7 post-infection in vivo . Immunofluorescence assay further showed that this protein is mainly expressed in B. microti merozoites. Bm TLP hold both heparin- and erythrocyte-binding properties, which are critical functions of invasion-related proteins. Immunization with recombinant Bm TLP imparted significant protection against B. microti infection in mice. Taken together, these results suggest that the novel merozoite protein, Bm TLP, is an important pathogenic molecule of B. microti and may be a possible target for the design of babesiosis control strategy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Piao, Ma, Liu, Hou and Chen.)

Recently, robotic sensor systems have gained more attention annually in complex system sense strategies. The robotic sensors sense the information from itself and the environment, and fuse information for the use of perception, decision, planning, and control. As an important supplement to traditional industrial robots, co-bots (short for co-working robots) play an increasingly vital role in helping small and medium-sized enterprises realize intelligent manufacturing. They have high flexibility and safety so that they can assist humans to complete highly repetitive and high-precision work. In order to maintain robot safe operation in the increasing complex working environment and human-computer intelligent interactive control, this paper is concerned with the problem of applicant accuracy analysis and singularity avoidance for co-bots. Based on the dynamic model with load and torque sensors, which is used to detect the external force at the end of the robot, this paper systematically analyzes the causes of singularity phenomenon in the robot motion control. The inverse solution is obtained by analytical method and numerical method, respectively. In order to ensure the smooth and safe operation in the whole workspace, it is necessary for a robot to avoid singularity. Singularity avoidance schemes are utilized for different control tasks, including point-to-point control and continuous path control. Corresponding simulation experiments are designed to verify the effectiveness of different evasion schemes, in which the advantages and disadvantages are compared and analyzed.

The development of malaria vaccines and medicines depends on the discovery of novel malaria protein targets, but the functions of more than 40% of P. falciparum genes remain unknown. Asexual parasites are the critical stage that leads to serious clinical symptoms and that can be modulated by malaria treatments and vaccines. To identify critical genes involved in the development of Plasmodium parasites within erythrocytes, the expression profile of more than 5,000 genes distributed across the 14 chromosomes of the PF3D7 strain during its six critical developmental stages (merozoite, early-ring, late-ring, early trophozoite, late-trophozoite, and middle-schizont) was evaluated. Hence, a qRT-PCR-based transcriptome of the erythrocytic developmental process of P. falciparum was revealed. Weighted gene coexpression network analyses revealed that a large number of genes are upregulated during the merozoite release process. Further gene ontology analysis revealed that a cluster of genes is associated with merozoite and may be apical complex components. Among these genes, 135 were comprised within chromosome 14, and 80% of them were previously unknown in functions. Western blot and immunofluorescence assays using newly developed corresponding antibodies showed that some of these newly discovered proteins are highly expressed in merozoites. Further invasion inhibition assays revealed that specific antibodies against several novel merozoite proteins can interfere with parasite invasion. Taken together, our study provides a developmental transcriptome of the asexual parasites of P. falciparum and identifies a group of previously unknown merozoite proteins that may play important roles in the process of merozoite invasion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hou, Li, Jiang, Piao, Ma, Liu and Chen.)

It is desired to develop self-healing gel electrolytes for flexible electrochromic devices (ECDs) due to the demand of healing damages caused during operations. We here report a hydrogel electrolyte with remarkable self-healing capability, excellent stretchability, and ionic conductivity. The hydrogel electrolyte was synthesized via one-step copolymerization of glycerol monomethacrylate (GMA) and acrylamide (AAm) in the presence of borate. Within the hydrogel electrolyte, dynamic cross-linking is expected to be formed due to the borate-didiol complexation and hydrogen-bonding interactions. As a result, the hydrogel electrolyte demonstrates an excellent self-healing efficiency of up to 97%, a fracture strain of 1155%, a fracture toughness of 136.6 kJ m -3 , and a fracture stress of 13.0 kPa. Additionally, a flexible ECD based on the hydrogel electrolyte and an electrochromic layer of poly(3,4-(2,2-dimethyl-propylenedioxy)thiophene) (PProDOT-Me 2 ) was assembled and evaluated. The device is found to be stable in both mechanical and optical properties over 1000 operation cycles. This study may provide a promising way for self-healing electrolyte gels to be utilized in a variety of flexible electrochemical devices, including ECDs, supercapacitors, and batteries.

Lysine lactylation has been recognized as a novel post-translational modification occurring on histones. However, lactylation in non-histone proteins, especially in proteins of early branching organisms, is not well understood. Energy metabolism and the histone repertoire in the early diverging protozoan parasite Trypanosoma brucei , the causative agent of African trypanosomiasis, markedly diverge from those of conventional eukaryotes. Here, we present the first exhaustive proteome-wide investigation of lactylated sites in T. brucei . We identified 387 lysine-lactylated sites in 257 proteins of various cellular localizations and biological functions. Further, we revealed that glucose metabolism critically regulates protein lactylation in T. brucei although the parasite lacks lactate dehydrogenase. However, unlike mammals, increasing the glucose concentration reduced the level of lactate, and protein lactylation decreased in T. brucei via a unique lactate production pathway. In addition to providing a valuable resource, these foregoing data reveal the regulatory roles of protein lactylation of trypanosomes in energy metabolism and gene expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Zhang, Jiang, Yu, Guan, Sang, Feng, Chen and Chen.)

Tachaea chinensis, a parasitic isopod, negatively affects the production of several commercially important shrimp species. To better understand the interaction between shrimp immunity and isopod infection, we performed a transcriptome analysis of the hepatopancreas of Palaemonetes sinensis challenged with T. chinensis. After assembly and annotation, 75,980 high-quality unigenes were obtained using RNA-seq data. Differential gene expression analysis revealed 896 significantly differently expressed genes (DEGs) after infection, with 452 and 444 upregulated and downregulated genes, respectively. Specifically, expression levels of genes involved in detoxification, such as the interferon regulatory factor, venom carboxylesterase-6, serine proteinase inhibitor, and cytochrome P450, were upregulated. Furthermore, expression levels of genes corresponding to retinol dehydrogenase, triosephosphate isomerase, variant ionotropic glutamate receptor, and phosphoenolpyruvate carboxykinase were significantly upregulated after isopod parasitization, indicating that the shrimp's visual system was influenced by isopod parasitization. Moreover, quantitative real-time PCR of 10 DEGs helped validate the RNA-seq findings. These results provide a valuable basis for future studies on the elucidation of immune responses of P. sinensis to T. chinensis infection., (Copyright © 2021 Elsevier Ltd. All rights reserved.)