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Migration can affect reproductive outcomes due to different socioeconomic and cultural contexts before and after migration, to changes in the affective and conjugal status of women and to their life conditions. The aim of this study is to investigate the association between international migration and abortion. The data came from a retrospective life-event survey from sub-Saharan African women living in Île-de-France. Differences in abortion distribution before and after migration were assessed using the Pearson chi-square test, and the association between the predictor and the outcome was investigated using Generalized Estimating Equations. A total of 363 women and 1377 pregnancies were investigated. Among these pregnancies, 15.6% that occurred before and 11.0% that occurred after migration was reported as ended in abortion (p = 0.011). The odds of reporting having had an abortion was lower after migration (OR 0.59, 95% CI 0.42–0.84), even after adjustment. However, after including intendedness of pregnancy in the model, this association lost its significance. The difference in induced abortion occurrence between before and after migration is almost entirely due to a change in the intendedness of pregnancy. Thus, socioeconomic and cultural issues have a greater weight in the decision to abort than the legal interdiction of this practice. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the expression of micro ribonucleic acid (miR)-219- 5p in prostate cancer (PCa), its influences on the biological functions of PCa, and its mechanism. PATIENTS AND METHODS: The expression differences of miR-219-5p and high mobility group protein A2 (HMGA2) in 30 pairs of PCa tissues and para-carcinoma tissues were detected via quantitative Real Time-Polymerase Chain Reaction (qRT-PCR), and the difference in miR-219-5p expression in PCa cell lines and normal prostatic epithelial cells was also determined via qRT-PCR. The human PC-3 cells were divided into negative control group and miR-219-5p overexpression group. Methyl thiazolyl tetrazolium (MTT) and colony formation assays were adopted to detect the cell proliferative ability, and flow cytometry was applied to determine the cell apoptosis. The expression of apoptosis-related proteins was measured via Western blotting, and the invasive and migratory abilities of the cells were examined through wound-healing and transwell assays. Bioinformatics prediction software and luciferase reporter assay were employed to verify the targets that might be controlled by miR-219- 5p. Rescue experiment was conducted to clarify whether the inhibitory effects of miR-219-5p on the growth and metastasis of PC-3 cells depend on the inhibition of HMGA2. RESULTS: It was shown in qRT-PCR results that the expression level of miR-219-5p was downregulated remarkably in PCa tissues and cell lines, but overexpressed miR-219-5p could repress the proliferation and promote the apoptosis of PC-3 cells notably. The results of wound-healing and transwell assays indicated that overexpressed miR-219-5p was able to suppress the invasion and metastasis of PC- 3 cells. According to Western blotting results, overexpressed miR-219-5p could up-regulate the expressions of pro-apoptotic proteins [Bax, cleaved-caspase-3 and cleaved-poly-ADP-ribose- polymerase (PARP)] and reverse the epithelial- mesenchymal transition (EMT) of PCa cells. It was predicted via the bioinformatics software that HMGA2 gene might be a target gene of miR-219-5p. The Dual-Luciferase reporter assay confirmed that there was a direct regulatory relationship between miR-219-5p and HMGA2. The rescue experiment manifested that overexpressed HMGA2 could reverse the inhibition of miR-219-5p on the growth and metastasis of PC-3 cells. CONCLUSIONS: MiR-219-5p suppresses the growth and metastasis abilities of prostate cancer cells by directly repressing the expression of HMGA2. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To investigate the clinical significance of the expression of PSMA (prostate specific membrane antigen), TERT (telomerase reverse transcriptase), and PDEF (prostate derived Ets factor) in malignant tumors of the prostate. PATIENTS AND METHODS: The study was conducted with paraffin slices from 33 specimens of malignant tumors of the prostate and 17 of normal tissue. We found high levels of PSMA, TERT, and PDEF protein by Western blot and immunofluorescence in the malignant tumor of the prostate. We also detected upregulation of PSMA, TERT, and PDEF mRNA in the malignant tumor of the prostate, suggesting complex regulation of these three genes in prostate cancer. RESULTS: Variance analysis showed statistically significant differences comparing the expression of PSMA, TERT, and PDEF in the malignant tumor of the prostate and normal tissues. The high expression of PSMA, TERT, and PDEF in the malignant tumor of the prostate suggests the important roles of these three factors in the occurrence and development of the malignant tumors of the prostate. CONCLUSIONS: PSMA, TERT, and PDEF may serve as a reference for clinical diagnosis and as potential targets for the malignant tumor of the prostate therapeutics. [ABSTRACT FROM AUTHOR]

OBJECTIVE: JAK-STAT3 signaling pathway widely participates in cell proliferation and apoptosis. Suppressor of cytokine signaling 3 (SOCS3) is a negative regulator of JAK-STAT3. SOCS3 downregulation is associated with drug resistance in breast cancer and leukemia. However, its role in bladder cancer drug resistance is still unclear. This study established ADM resistant bladder cancer cell model to investigate the role of SOCS3-JAK/STAT3 signaling pathway ADM resistance. MATERIALS AND METHODS: ADM drug resistant cell line T24/ADM was established. SOCS3, p-JAK2, p-JAK3, and Bcl-2 expressions in T24/ADM, T24, and HBEC cells were compared. Cell proliferation and apoptosis were evaluated by flow cytometry. T24/ADM cells were divided into five groups, including control, pSicoR-blank, pSicoR-SOCS3, FLLL32, and pSicoR-SOCS3 + FLLL32 groups. Cell proliferation was determined by EdU staining. RESULTS: SOCS3 was reduced, while p-JAK2, p-STAT3, and Bcl-2 expressions upregulated in T24 cells compared with HBEC cells. T24/ADM cells exhibited lower SOCS3, higher p-JAK2, p-STAT3, and Bcl-2 levels than T24 cells. Cell apoptosis was higher, whereas cell proliferation was weaker in T24 cells compared with T24/ADM cells. SOCS3 overexpression and/or FLLL32 treatment significantly downregulated p-JAK2, p-STAT3, and Bcl-2 expressions, attenuated cell proliferation, and elevated sensitivity to ADM induced cell apoptosis. CONCLUSIONS: SOCS3 reduction was associated with bladder cancer sensitivity to ADM. SOCS3 overexpression decreased JAK-STAT3 signaling pathway activity, declined Bcl-2 expression, inhibited cell proliferation, elevated cell apoptosis, and enhanced ADM sensitivity in T24 cells. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Clinical significance of PSMA, TERT and PDEF in malignant tumors of the prostate."

Jun-Qing Situ,1 Yi-Qing Ye,2 Xiu-Liang Zhu,3 Ri-Sheng Yu,3 Jian You,1 Hong Yuan,1 Fu-Qiang Hu,1 Yong-Zhong Du11College of Pharmaceutical Sciences, 2Women’s Hospital, 3Department of Radiology, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of ChinaAbstract: The delivery of chemotherapeutics into tumor cells is a fundamental knot for tumor-target therapy to improve the curative effect and avoid side effects. Here, A54 peptide-functionalized poly(lactic-co-glycolic acid)-grafted dextran (A54-Dex-PLGA) was synthesized. The synthesized A54-Dex-PLGA self-assembled to form micelles with a low critical micelle concentration of 16.79 µg·mL-1 and diameter of about 50 nm. With doxorubicin (DOX) base as a model antitumor drug, the drug-encapsulation efficiency of DOX-loaded A54-Dex-PLGA micelles (A54-Dex-PLGA/DOX) reached up to 75%. In vitro DOX release from the A54-Dex-PLGA/DOX was prolonged to 72 hours. The A54-Dex-PLGA micelles presented excellent internalization ability into hepatoma cells (BEL-7402 cell line and HepG2 cell line) in vitro, and the cellular uptake of the micelles by the BEL-7402 cell line was specific, which was demonstrated by the blocking experiment. In vitro antitumor activity studies confirmed that A54-Dex-PLGA/DOX micelles suppressed tumor-cell (BEL-7402 cell) growth more effectively than Dex-PLGA micelles. Furthermore, in vivo biodistribution testing demonstrated that the A54-Dex-PLGA micelles had a higher distribution ability to BEL-7402 tumors than that to HepG2 tumors.Keywords: homing peptide, polymeric micelles, doxorubicin, tumor-cell targeting

The article "SOCS3 overexpression enhances ADM resistance in bladder cancer T24 cells, by M.-Z. Li, D.-H. Lai, H.-B. Zhao, Z. Chen, Q.-X. Huang, J. Situ, published in Eur Rev Med Pharmacol Sci 2017; 21 (13): 3005-3011–PMID: 28742207".

Circovirus human is a new viral species that includes the human circovirus (HCirV), which has been linked to hepatitis in immunocompromised persons. We investigated prevalence of HCirV infection in 278 patients with hepatitis and 184 asymptomatic persons using real-time PCR and sequencing assays. HCirV viremia and sequences were found in 8 (2.9%) hepatitis patients and no asymptomatic patients. Alternate causes of hepatitis (hepatitis E and cholangitis) were clearly identifiable in 2 HCirV-infected patients. HCirV could not be ruled out as a contributor to hepatitis in the remaining 6 patients, 4 of whom were immunocompromised. Persistent infections were documented in 3 patients, but only 1 had relapsing hepatitis. One HCirV patient displayed symptoms of an infectious mononucleosis-like syndrome. Isolates clustered with known HCirV strains from France and China. HCirV-derived virus-like particles bound to PLC/PRF/5 and Hep-G2 human hepatoma cells but not to lung epithelial cells, indicating hepatic tropism.

Hepatitis E virus (HEV) variants infecting humans belong to two species: Paslahepevirus balayani (bHEV) and Rocahepevirus ratti (rat hepatitis E virus; rHEV). R. ratti is a ubiquitous rodent pathogen that has recently been recognized to cause hepatitis in humans. Transmission routes of rHEV from rats to humans are currently unknown. In this study, we examined rHEV exposure in cats and dogs to determine if they are potential reservoirs of this emerging human pathogen. Virus-like particle-based IgG enzymatic immunoassays (EIAs) capable of differentiating rHEV & bHEV antibody profiles and rHEV-specific real-time RT-PCR assays were used for this purpose. The EIAs could detect bHEV and rHEV patient-derived IgG spiked in dog and cat sera. Sera from 751 companion dogs and 130 companion cats in Hong Kong were tested with these IgG enzymatic immunoassays (EIAs). Overall, 13/751 (1.7%) dogs and 5/130 (3.8%) cats were sero-reactive to HEV. 9/751 (1.2%) dogs and 2/130 (1.5%) cats tested positive for rHEV IgG, which was further confirmed by rHEV immunoblots. Most rHEV-seropositive animals were from areas in or adjacent to districts reporting human rHEV infection. Neither 881 companion animals nor 652 stray animals carried rHEV RNA in serum or rectal swabs. Therefore, we could not confirm a role for cats and dogs in transmitting rHEV to humans. Further work is required to understand the reasons for low-level seropositivity in these animals.

Classically, all hepatitis E virus (HEV) variants causing human infection belong to the genus Paslahepevirus (HEV-A). However, the increasing cases of rat HEV infection in humans since 2018 challenged this dogma, posing increasing health threats. Herein, we investigated the underlying mechanisms dictating the zoonotic potentials of different HEV species and their possible cross-protection relationships. We found that rat HEV virus-like particles (HEV VLPs ) bound to human liver and intestinal cells/tissues with high efficiency. Moreover, rat HEV VLPs and infectious rat HEV particles penetrated the cell membrane and entered human target cells postbinding. In contrast, ferret HEV VLPs showed marginal cell binding and entry ability, bat HEV VLPs and avian HEV VLPs exhibited no binding and entry potency. Structure-based three-dimensional mapping identified that the surface spike domain of rat HEV is crucial for cell binding. Antigenic cartography indicated that rat HEV exhibited partial cross-reaction with HEV-A. Intriguingly, sera of HEV-A infected patients or human HEV vaccine Hecolin® immunized individuals provided partial cross-protection against the binding of rat HEV VLPs to human target cells. In summary, the interactions between the viral capsid and cellular receptor(s) regulate the distinct zoonotic potentials of different HEV species. The systematic characterization of antigenic cartography and serological cross-reactivity of different HEV species provide valuable insights for the development of species-specific diagnosis and protective vaccines against zoonotic HEV infection., Competing Interests: Competing interests statement:J.S. and S.S. report provisional patent applications for “Hepatitis E virus-like particles and uses thereof” covering the utilization of virus-like particles for serodiagnosis and vaccines (US PTO application no. 63/166,698 and PCT application no. PCT/CN2022/081996). The other authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

MicroRNA-like RNAs (milRNAs) play a significant role in the infection process by plant-pathogenic fungi. However, the specific functions and regulatory mechanisms of fungal milRNAs remain insufficiently elucidated. This study investigated the function of Foc-milR138, an infection-induced milRNA secreted by Fusarium oxysporum f. sp. cubense (Foc), which is the causal agent of Fusarium wilt of banana. Initially, through precursor gene knockout and phenotypic assessments, we confirmed that Foc-milR138 acts as a virulent milRNA prominently upregulated during the early stages of Foc infection. Subsequent bioinformatic analyses and transient expression assays in Nicotiana benthamiana leaves identified a host receptor-like kinase gene, MaLYK3, as the direct target of Foc-milR138. Functional investigations of MaLYK3 revealed its pivotal role in triggering immune responses of N. benthamiana by upregulating a suite of resistance genes, bolstering reactive oxygen species (ROS) accumulation and callose deposition, thereby fortifying disease resistance. This response was markedly subdued upon co-expression with Foc-milR138. Expression pattern analysis further verified the specific suppression of MaLYK3 by Foc-milR138 during the early root infection by Foc. In conclusion, Foc secretes a virulent milRNA (Foc-milR138) to enter the host banana cells and inhibit the expression of the plant surface receptor-like kinase MaLYK3, subverting the disease resistance activated by MaLYK3, and ultimately facilitating pathogen invasion. These findings shed light on the roles of fungal milRNAs and their targets in resistance and pathogenicity, offering promising avenues for the development of disease-resistant banana cultivars., (© 2024 The Author(s). Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)

Background: The pathogenesis of Crohn's disease involves genetic and environmental factors, with the gut microbiome playing a crucial role. The Crohn's disease-associated variant rs13107325 in the SLC39A8 gene results in an A391T substitution in the ZIP8 metal ion transporter and has previously been linked to alterations in the colonic microbiome in variant carriers. We hypothesized that the A391T substitution alters metal ion homeostasis in the colonic mucosal-luminal interface, thereby inducing dysbiosis which may promote intestinal inflammation., Methods: To evaluate this hypothesis, we generated a SLC39A8 A393T mouse model (matching human A391T). We first examined trace element abundance in the colonic mucosal epithelium and lumen of homozygous A393T and wild-type (WT) mice to determine if the variant affected metal distribution. We also performed 16S rRNA gene sequencing on colon samples at 2 months, 3-4 months, and 12 months of age, and conducted histological scoring of colon tissue collected from 5-month and 10-month old mice., Results: Consistent with an effect of the variant on ZIP8 function, homozygous A393T mice exhibited increased cobalt in the colonic mucosa, but reduced iron, zinc, manganese, cobalt, copper, and cadmium in the colonic lumen. 16S rRNA gene sequencing of colon samples revealed variant-linked effects on microbiome beta diversity in 2-month-, 3-4-month-, and 12-month-old mice. Histological scoring showed spontaneous intestinal inflammation in 10-month but not in 5-month-old mice. Lastly, predicted pathway analysis of the microbiome samples revealed differential enrichment of iron-, zinc-, and cobalt-dependent pathways in A393T mice compared to wild-type controls., Conclusion: These results suggest that the variant in SLC39A8 primarily restricts metal availability to the microbiota, resulting in compositions that can adapt to the environment and that A393T-linked dysbiosis occurs prior to the onset of inflammation. This study paves the way for future studies investigating risk variants as microbiome-disease modifiers., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose: Sentinel node biopsy (SNB) is a common staging tool for breast cancer. Initially, peritumoral (PT) injections were used, however subareolar (SA) injections were later introduced to simplify the technique. Controversy remains regarding whether PT and SA injections map the same sentinel lymph nodes (SLNs). This study aimed to determine whether the regional location of breast SLNs differs when using PT versus SA injections using a large dataset from a single institution., Methods: A total of 1035 patients who underwent breast SNB (PT injections: n = 858 and SA injections: n = 177) with lymphoscintigraphy and SPECT/CT were included. The identified SLN locations using SA injections were compared with those using PT injections. Differences in drainage proportions and odds ratios (ORs) for each clockface breast region and the whole breast were calculated using a two-proportion z-test and Fisher's Exact Test., Results: A higher proportion of internal mammary SLNs were identified using PT injections for the whole breast (0.30 versus 0.09) and for all breast regions, with all regions showing statistical significance except the upper outer quadrant. Similarly, ORs showed identification of internal mammary SLNs was significantly higher when using PT injections (4.35, 95% CI 2.53 to 7.95). There were no significant differences in identifying axillary SLNs between injection sites., Conclusion: This is the largest cohort study to compare the regional location of breast SLNs identified using PT injections versus SA injections. Discordance was shown in the SLNs identified between injection techniques, with PT injections more frequently identifying internal mammary SLNs., (© 2024. The Author(s).)

Toll receptors are involved in the development and innate immunity of insects. BmToll9-1 is an important immune receptor in the Toll pathway. Previous studies have focused on its role as a receptor in immune response. In this study, we aimed to investigate the role of BmToll9-1 as a regulator in the immune response. The expression profiles demonstrated that BmToll9-1 was predominantly expressed in the midgut. RNA interference (RNAi) of BmToll9-1 was found to be effective in the midgut via the injection of dsRNA, which resulted in smaller and lighter larvae and cocoons. Most signaling genes in the Toll pathway and downstream effector genes were downregulated after the RNAi of BmToll9-1 . The hemolymph from BmToll9-1 -silenced larvae showed decreased antibacterial activity against Escherichia coli , either in growth curve or inhibition zone experiments. The above results indicate that BmToll9-1 might be positively involved in the immune pathway of silkworm. As a positive regulator, BmToll9-1 might function mainly in the gut to maintain microbial homeostasis to regulate the growth of silkworms. Silencing of BmToll9-1 downregulates the signaling genes in the Toll pathway and antimicrobial peptide (AMP) production, resulting in decreased antibacterial activity in the hemolymph.

Background: The identification and assessment of sentinel lymph nodes (SLNs) in breast cancer is important for optimised patient management. The aim of this study was to develop an interactive 3D breast SLN atlas and to perform statistical analyses of lymphatic drainage patterns and tumour prevalence., Methods: A total of 861 early-stage breast cancer patients who underwent preoperative lymphoscintigraphy and SPECT/CT were included. Lymphatic drainage and tumour prevalence statistics were computed using Bayesian inference, non-parametric bootstrapping, and regression techniques. Image registration of SPECT/CT to a reference patient CT was carried out on 350 patients, and SLN positions transformed relative to the reference CT. The reference CT was segmented to visualise bones and muscles, and SLN distributions compared with the European Society for Therapeutic Radiology and Oncology (ESTRO) clinical target volumes (CTVs). The SLN atlas and statistical analyses were integrated into a graphical user interface (GUI)., Results: Direct lymphatic drainage to the axilla level I (anterior) node field was most common (77.2%), followed by the internal mammary node field (30.4%). Tumour prevalence was highest in the upper outer breast quadrant (22.9%) followed by the retroareolar region (12.8%). The 3D atlas had 765 SLNs from 335 patients, with 33.3-66.7% of axillary SLNs and 25.4% of internal mammary SLNs covered by ESTRO CTVs., Conclusion: The interactive 3D atlas effectively displays breast SLN distribution and statistics for a large patient cohort. The atlas is freely available to download and is a valuable educational resource that could be used in future to guide treatment., (© 2024. The Author(s).)

Lower selenium levels are observed in Alzheimer's disease (AD) brains, while supplementation shows multiple benefits. Selenoprotein W (SELENOW) is sensitive to selenium changes and binds to tau, reducing tau accumulation. However, whether restoration of SELENOW has any protective effect in AD models and its underlying mechanism remain unknown. Here, we confirm the association between SELENOW downregulation and tau pathology, revealing SELENOW's role in promoting tau degradation through the ubiquitin‒proteasome system. SELENOW competes with Hsp70 to interact with tau, promoting its ubiquitination and inhibiting tau acetylation at K281. SELENOW deficiency leads to synaptic defects, tau dysregulation and impaired long-term potentiation, resulting in memory deficits in mice. Conversely, SELENOW overexpression in the triple transgenic AD mice ameliorates memory impairment and tau-related pathologies, featuring decreased 4-repeat tau isoform, phosphorylation at Ser396 and Ser404, neurofibrillary tangles and neuroinflammation. Thus, SELENOW contributes to the regulation of tau homeostasis and synaptic maintenance, implicating its potential role in AD., (© 2024. The Author(s).)

Plant cell death is regulated in plant-pathogen interactions. While some aspartic proteases (APs) participate in regulating programmed cell death or defense responses, the defense functions of most APs remain largely unknown. Here, we report on a virulence factor, PlPeL8, which is a pectate lyase found in the hemibiotrophic pathogen Peronophythora litchii. Through in vivo and in vitro assays, we confirmed the interaction between PlPeL8 and LcAP1 from litchi, and identified LcAP1 as a positive regulator of plant immunity. PlPeL8 induced cell death associated with NbSOBIR1 and NbMEK2. The 11 conserved residues of PlPeL8 were essential for inducing cell death and enhancing plant susceptibility. Twenty-three LcAPs suppressed cell death induced by PlPeL8 in Nicotiana benthamiana depending on their interaction with PlPeL8. The N-terminus of LcAP1 was required for inhibiting PlPeL8-triggered cell death and susceptibility. Furthermore, PlPeL8 led to higher susceptibility in NbAPs-silenced N. benthamiana than the GUS-control. Our results indicate the crucial roles of LcAP1 and its homologs in enhancing plant resistance via suppression of cell death triggered by PlPeL8, and LcAP1 represents a promising target for engineering disease resistance. Our study provides new insights into the role of plant cell death in the arms race between plants and hemibiotrophic pathogens., (© 2024 The Authors New Phytologist © 2024 New Phytologist Foundation.)

Hypoxia in the tumour microenvironment is a major limiting factor in photodynamic therapy. The present study employed a novel O 2 -economised photosensitizer, ACSN, to effectively curtail oxygen consumption by impeding the aerobic respiration of tumour cells, thereby increasing the reactive oxygen species (ROS) production in photodynamic therapy. To enhance the efficacy of photodynamic therapy, the active targeting peptide iRGD was employed to facilitate drug accumulation in the tumour tissue. Therefore, we constructed a targeted drug platform, ACSN/Fe 3 O 4 @MSNs-iRGD, that integrates diagnosis and treatment. The drug exhibited excellent active targeting ability towards gastric cancer MGC-803 cells and can efficiently penetrate the mitochondria upon cellular internalisation. The photosensitizer ACSN, released from the drug, effectively suppressed mitochondrial aerobic respiration to conserve oxygen and exhibited robust ROS production upon laser excitation. The core-shell structure comprises Fe 3 O 4 , which offers excellent T2 dark contrast for real-time tumour monitoring through MRI imaging. By incorporating excellent photodynamic therapy and MRI imaging capabilities, this drug can serve as an effective platform for the integration of tumour diagnosis and treatment, thus addressing the limitations associated with conventional tumour therapies. It is anticipated that this approach will soon be clinically translated., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

During initial stages of microbial invasion, the extracellular space (apoplast) of plant cells is a vital battleground between plants and pathogens. The oomycete plant pathogens secrete an array of apoplastic carbohydrate active enzymes, which are central molecules for understanding the complex plant-oomycete interactions. Among them, pectin acetylesterase (PAE) plays a critical role in the pathogenesis of plant pathogens including bacteria, fungi, and oomycetes. Here, we demonstrated that Peronophythora litchii (syn. Phytophthora litchii) PlPAE5 suppresses litchi (Litchi chinensis) plant immunity by interacting with litchi lipid transfer protein 1 (LcLTP1). The LcLTP1-binding activity and virulence function of PlPAE5 depend on its PAE domain but not on its PAE activity. The high expression of LcLTP1 enhances plant resistance to oomycete and fungal pathogens, and this disease resistance depends on BRASSINOSTEROID INSENSITIVE 1-associated receptor kinase 1 (BAK1) and Suppressor of BIR1 (SOBIR1) in Nicotiana benthamiana. LcLTP1 activates the plant salicylic acid (SA) signaling pathway, while PlPAE5 subverts the LcLTP1-mediated SA signaling pathway by destabilizing LcLTP1. Conclusively, this study reports a virulence mechanism of oomycete PAE suppressing plant LTP-mediated SA immune signaling and will be instrumental for boosting plant resistance breeding., Competing Interests: Conflict of interest statement. None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cell wall degrading enzymes, including pectate lyases (PeLs), released by plant pathogens, break down protective barriers and/or activate host immunity. The direct interactions between PeLs and plant immune-related proteins remain unclear. We identify two PeLs, PlPeL1 and PlPeL1-like, critical for full virulence of Peronophythora litchii on litchi (Litchi chinensis). These proteins enhance plant susceptibility to oomycete pathogens in a PeL enzymatic activity-dependent manner. However, LcPIP1, a plant immune regulator secreted by litchi, binds to PlPeL1/PlPeL1-like, and attenuates PlPeL1/PlPeL1-like induced plant susceptibility to Phytophthora capsici. LcPIP1 also induces cell death and various immune responses in Nicotiana benthamiana. Conserved in plants, LcPIP1 homologs bear a conserved "VDMASG" motif and exhibit immunity-inducing activity. Furthermore, SERK3 interacts with LcPIP1 and is required for LcPIP1-induced cell death. NbPIP1 participates in immune responses triggered by the PAMP protein INF1. In summary, our study reveals the dual roles of PlPeL1/PlPeL1-like in plant-pathogen interactions: enhancing pathogen virulence through PeL enzymatic activity while also being targeted by LcPIP1, thus enhancing plant immunity., (© 2024. The Author(s).)

The emergence of Rocahepevirus ratti [species HEV ratti ( r HEV)] as a causative agent of hepatitis E in humans presents a new potential threat to global public health. The R. ratti genotype 1 ( r -1 HEV) variant only shares 50%-60% genomic identity with Paslahepevirus balayani [species HEV balayani ( b HEV)] variants, which are the main causes of hepatitis E infection in humans. Here, we report antigen diagnoses for r -1 HEV and b HEV using an enzymatic immunoassay (EIA) method. We detected recombinant virus-like particles protein (HEV 239) of r HEV and b HEV using a collection of hepatitis E virus (HEV)-specific monoclonal antibodies. Two optimal candidates, the capture antibody P#1-H4 and the detection antibodies C145 (P#1-H4*/C145 # ) and C158 (P#1-H4*/C158 # ), were selected to detect antigen in infected rat samples and r -1 HEV- or b HEV-infected human clinical samples. The two candidates showed similar diagnostic efficacy to the Wantai HEV antigen kit in b HEV-infected clinical samples. Genomic divergence resulted in low diagnostic efficacy of the Wantai HEV antigen kit (0%, 0 of 10) for detecting r -1 HEV infection. Compared with the P#1-H4*/C145 # candidate (80%, 8 of 10), the P#1-H4*/C158 # candidate had excellent diagnostic efficacy in r -1 HEV-infected clinical samples (100%, 10 of 10). The two candidates bind to a discrete antigenic site that is highly conserved across r HEV and b HEV. P#1-H4*/C145 # and P#1-H4*/C158 # are efficacious candidate antibody combinations for rat HEV antigen detection., Competing Interests: The authors declare no conflict of interest.

Autoantibodies against angiotensin-converting enzyme 2 (ACE2) are frequently reported in patients during coronavirus disease 2019 (COVID-19) with evidence for a pathogenic role in severe infection. However, little is known of the prevalence or clinical significance of ACE2 autoantibodies in late convalescence or following COVID-19 vaccination. In this study, we measured ACE2 autoantibodies in a cohort of 182 COVID-19 convalescent patients, 186 COVID-19 vaccine recipients, and 43 adolescents with post-mRNA vaccine myopericarditis using two ACE2 enzymatic immunoassays (EIAs). ACE2 IgM autoantibody EIA median optical densities (ODs) were lower in convalescent patients than pre-COVID-19 control samples with only 2/182 (1.1%) convalescents testing positive. Similarly, only 3/182 (1.6%) convalescent patients tested positive for ACE2 IgG, but patients with history of moderate-severe COVID-19 tended to have significantly higher median ODs than controls and mild COVID-19 patients. In contrast, ACE2 IgG antibodies were detected in 10/186 (5.4%) COVID-19 vaccine recipients after two doses of vaccination. Median ACE2 IgG EIA ODs of vaccine recipients were higher than controls irrespective of the vaccine platform used (inactivated or mRNA). ACE2 IgG ODs were not correlated with surrogate neutralizing antibody levels in vaccine recipients. ACE2 IgG levels peaked at day 56 post-first dose and declined within 12 months to baseline levels in vaccine recipients. Presence of ACE2 antibodies was not associated with adverse events following immunization including myopericarditis. One convalescent patient with ACE2 IgG developed Guillain-Barre syndrome, but causality was not established. ACE2 autoantibodies are observed in COVID-19 vaccine recipients and convalescent patients, but are likely innocuous., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Osteoarthritis (OA) is the most common irreversible chronic joint dysfunction disease, which is pathologically characterized by disturbance of articular cartilage homeostasis leading to subsequent inflammatory response and cartilage extracellular matrix (ECM) degradation. Increasing evidence has demonstrated the dysregulation of transcription factors play crucial roles in the occurrence and development of osteoarthritis (OA), but the potential functions and mechanism of most transcription factors in OA has not been completely illuminated. In this study, we identified that transcription factor V-ets erythroblastosis virus E26 oncogene homolog 2 (ETS2) was significantly down-regulated in OA cartilage and IL-1β-induced OA chondrocytes. Functional experiments in vitro demonstrated that the overexpressed ETS2 strikingly enhanced proliferation, outstandingly suppressed apoptosis, and dramatically reduced inflammation and ECM degradation in IL-1β-induced OA chondrocytes, whereas the knockdown of ETS2 led to the opposite effects. Further in vivo studies have shown that up-regulated ETS2 dramatically ameliorates cartilage injury in DMM-induced OA mice. Mechanical studies have disclosed that DNMT1-mediated downregulation of ETS2 dramatically promotes STAT1 by inhibiting miR-155 transcription, and increased STAT1 initiates a feedback loop that may enhance DNMT1-mediated hypermethylation of ETS2 to inhibit ETS2 expression, thus forming a DNMT1/ETS2/miR-155/STAT1 feedback loop that inhibits MAPK signaling pathways and aggravates OA cartilage injury. In all, our results revealed that overexpression of ETS2 markedly ameliorated OA cartilage injury through the ETS2/miR-155/STAT1/DNMT1 feedback loop, providing a new perspective on the pathogenesis and therapeutic strategies for OA., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Uncovering how host metal(loid)s mediate the immune response against invading pathogens is critical for better understanding the pathogenesis mechanism of infectious disease. Clinical data show that imbalance of host metal(loid)s is closely associated with the severity and mortality of COVID-19. However, it remains elusive how metal(loid)s, which are essential elements for all forms of life and closely associated with multiple diseases if dysregulated, are involved in COVID-19 pathophysiology and immunopathology. Herein, we built up a metal-coding assisted multiplexed serological metallome and immunoproteome profiling system to characterize the links of metallome with COVID-19 pathogenesis and immunity. We found distinct metallome features in COVID-19 patients compared with non-infected control subjects, which may serve as a biomarker for disease diagnosis. Moreover, we generated the first correlation network between the host metallome and immunity mediators, and unbiasedly uncovered a strong association of selenium with interleukin-10 (IL-10). Supplementation of selenium to immune cells resulted in enhanced IL-10 expression in B cells and reduced induction of proinflammatory cytokines in B and CD4 + T cells. The selenium-enhanced IL-10 production in B cells was confirmed to be attributable to the activation of ERK and Akt pathways. We further validated our cellular data in SARS-CoV-2-infected K18-hACE2 mice, and found that selenium supplementation alleviated SARS-CoV-2-induced lung damage characterized by decreased alveolar inflammatory infiltrates through restoration of virus-repressed selenoproteins to alleviate oxidative stress. Our approach can be readily extended to other diseases to understand how the host defends against invading pathogens through regulation of metallome., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Oomycete pathogens can secrete hundreds of effectors into plant cells to interfere with the plant immune system during infection. Here, we identified a Arg-X-Leu-Arg (RXLR) effector protein from the most destructive pathogen of litchi (Litchi chinensis Sonn.), Peronophythora litchii, and named it P. litchii avirulence homolog 202 (PlAvh202). PlAvh202 could suppress cell death triggered by infestin 1 or avirulence protein 3a/resistance protein 3a in Nicotiana benthamiana and was essential for P. litchii virulence. In addition, PlAvh202 suppressed plant immune responses and promoted the susceptibility of N. benthamiana to Phytophthora capsici. Further research revealed that PlAvh202 could suppress ethylene (ET) production by targeting and destabilizing plant S-adenosyl-L-methionine synthetase (SAMS), a key enzyme in the ET biosynthesis pathway, in a 26S proteasome-dependent manner without affecting its expression. Transient expression of LcSAMS3 induced ET production and enhanced plant resistance, whereas inhibition of ET biosynthesis promoted P. litchii infection, supporting that litchi SAMS (LcSAMS) and ET positively regulate litchi immunity toward P. litchii. Overall, these findings highlight that SAMS can be targeted by the oomycete RXLR effector to manipulate ET-mediated plant immunity., Competing Interests: Conflict of interest statement. The authors declare that they have no conflict of interest., (© American Society of Plant Biologists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recent studies involving transplantation of feces from schizophrenia (SCZ) patients and their healthy controls into germ-free mice have demonstrated that the gut microbiome plays a critical role in mediating SCZ-linked physiology and behavior. To date, only one animal model (a metabotropic glutamate receptor 5 knockout) of SCZ has been reported to recapitulate SCZ-linked gut dysbiosis. Since human 22q11.2 microdeletion syndrome is associated with increased risk of SCZ, we investigated whether the 22q11.2 microdeletion ("Q22") mouse model of SCZ exhibits both SCZ-linked behaviors and intestinal dysbiosis. We demonstrated that Q22 mice display increased acoustic startle response and ileal (but not colonic) dysbiosis, which may be due to the role of the ileum as an intestinal region with high immune and neuroimmune activity. We additionally identified a negative correlation between the abundance of a Streptococcus species in the ilea of Q22 mice and their acoustic startle response, providing early evidence of a gut-brain relationship in these mice. Given the translational relevance of this mouse model, our work suggests that Q22 mice could have considerable utility in preclinical research probing the relationship between gut dysbiosis and the gut-brain axis in the pathogenesis of SCZ.

Introduction: Therapeutic monoclonal antibodies (mAbs) against the SARS-CoV-2 spike protein have been shown to improve the outcome of severe COVID-19 patients in clinical trials. However, novel variants with spike protein mutations can render many currently available mAbs ineffective., Methods: We produced mAbs by using hybridoma cells that generated from mice immunized with spike protein trimer and receptor binding domain (RBD). The panel of mAbs were screened for binding and neutralizing activity against different SARS-CoV-2 variants. The in vivo effectiveness of WKS13 was evaluated in a hamster model., Results: Out of 960 clones, we identified 18 mAbs that could bind spike protein. Ten of the mAbs could attach to RBD, among which five had neutralizing activity against the ancestral strain and could block the binding between the spike protein and human ACE2. One of these mAbs, WKS13, had broad neutralizing activity against all Variants of Concern (VOCs), including the Omicron variant. Both murine or humanized versions of WKS13 could reduce the lung viral load in hamsters infected with the Delta variant., Conclusions: Our data showed that broad-spectrum high potency mAbs can be produced from immunized mice, which can be used in humans after humanization of the Fc region. Our method represents a versatile and rapid strategy for generating therapeutic mAbs for upcoming novel variants., Competing Interests: Authors JF-WC, SY, K-YY, and KK-WT were affiliated with company Centre for Virology, Vaccinology and Therapeutics. The remaining 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 © 2023 Wen, Cai, Fan, Zhang, Luo, Tang, Shuai, Chen, Zhang, Situ, Tsoi, Wang, Chan, Yuan, Yuen, Zhou and To.)

Neutralising monoclonal antibody (mAb) is an important weapon in our arsenal for combating respiratory viral infections. However, the effectiveness of neutralising mAb has been impeded by the rapid emergence of mutant variants. Early administration of broad-spectrum mAb with improved delivery efficiency can potentially enhance efficacy and patient outcomes. WKS13 is a humanised mAb which was previously demonstrated to exhibit broad-spectrum activity against SARS-CoV-2 variants. In this study, a dual targeting formulation strategy was designed to deliver WKS13 to both the nasal cavity and lower airways, the two critical sites of infection caused by SARS-CoV-2. Dry powders of WKS13 were first prepared by spray drying, with cyclodextrin used as stabiliser excipient. Two-fluid nozzle (TFN) was used to produce particles below 5 μm for lung deposition (C-TFN formulation) and ultrasonic nozzle (USN) was used to produce particles above 10 μm for nasal deposition (C-USN formulation). Gel electrophoresis and size exclusion chromatography studies showed that the structural integrity of mAb was successfully preserved with no sign of aggregation after spray drying. To achieve dual targeting property, C-TFN and C-USN were mixed at various ratios. The aerosolisation property of the mixed formulations dispersed from a nasal powder device was examined using a Next Generation Impactor (NGI) coupled with a glass expansion chamber. When the ratio of C-TFN in the mixed formulation increased, the fraction of particles deposited in the lung increased proportionally while the fraction of particles deposited in the nasal cavity decreased correspondingly. A customisable aerosol deposition profile could therefore be achieved by manipulating the mixing ratio between C-TFN and C-USN. Dual administration of C-TFN and C-USN powders to the lung and nasal cavity of hamsters, respectively, was effective in offering prophylactic protection against SARS-CoV-2 Delta variant. Viral loads in both the lung tissues and nasal wash were significantly reduced, and the efficacy was comparable to systemic administration of unformulated WKS13. Overall, dual targeting powder formulation of neutralising mAb is a promising approach for prophylaxis of respiratory viral infections. The ease and non-invasive administration of dual targeting nasal powder may facilitate the widespread distribution of neutralising mAb during the early stage of unpredictable outbreaks., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background & Aims: Rat hepatitis E virus ( Rocahepevirus ratti ; HEV-C1) is an emerging cause of hepatitis E that is divergent from conventional human-infecting HEV variants ( Paslahepevirus balayani ; HEV-A). Validated serological assays for HEV-C1 are lacking. We aimed to develop a parallel enzymatic immunoassay (EIA) system that identifies individuals with HEV-C1 exposure. We also aimed to conduct the first HEV-C1 seroprevalence study in humans using this validated EIA system., Methods: Expressed HEV-A (HEV-A4 p239) and HEV-C1 (HEV-C1 p241) peptides were characterised. Blood samples were simultaneously tested in HEV-A4 p239 and HEV-C1 p241 IgG EIAs. An optical density (OD) cut-off-based interpretation algorithm for identifying samples seropositive for HEV-A or HEV-C1 was validated using RT-PCR-positive infection sera. This algorithm was used to measure HEV-C1 seroprevalence in 599 solid organ transplant recipients and 599 age-matched immunocompetent individuals., Results: Both peptides formed virus-like particles. When run in HEV-A4 p239 and HEV-C1 p241 EIAs, HEV-A and HEV-C1 RT-PCR-positive samples formed distinct clusters with minimal overlap in a two-dimensional plot of optical density values. The final EIA interpretation algorithm showed high agreement with RT-PCR results (Cohen's κ = 0.959) and was able to differentiate HEV-A and HEV-C1 infection sera with an accuracy of 94.2% (95% CI: 85.8-98.4%). HEV-C1 IgG seroprevalence was 7/599 (1.2%) among solid organ transplant recipients and 4/599 (0.7%) among immunocompetent individuals. Five of 11 (45.5%) of these patients had history of transient hepatitis of unknown cause., Conclusions: HEV-C1 exposure was identified in 11/1198 (0.92%) individuals in Hong Kong indicating endemic exposure. This is the first estimate of HEV-C1 seroprevalence in humans. The parallel IgG EIA algorithm is a valuable tool for investigating epidemiology and risk factors for HEV-C1 infection., Impact and Implications: Rat hepatitis E virus has recently been discovered to infect humans, but antibody tests for this infection are lacking, making it difficult to gauge how common this infection is. We developed an antibody test algorithm that can identify individuals with past rat hepatitis E virus exposure. We used this algorithm to estimate rat hepatitis E exposure rates in humans in Hong Kong and found that approximately 1% of all tested people had been exposed to this virus previously., Competing Interests: SS reports provisional patent applications for ‘Hepatitis E virus-like particles and uses thereof’ covering the utilisation of virus-like particles described in this paper for serodiagnosis and vaccines (US PTO application no. 63/166,698 and PCT application no. PCT/CN2022/081996). The other authors declare no conflicts of interest. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

This study investigates the synthesis of a new compound, PYR26, and the multi-target mechanism of PYR26 inhibiting the proliferation of HepG2 human hepatocellular carcinoma cells. PYR26 significantly inhibits the growth of HepG2 cells ( p < 0.0001) and this inhibition has a concentration effect. There was no significant change in ROS release from HepG2 cells after PYR26 treatment. The mRNA expressions of CDK4 , c-Met and Bak genes in HepG2 cells were significantly inhibited ( p < 0.05), while mRNA expression of pro-apoptotic factors such as caspase-3 and Cyt c was significantly increased ( p < 0.01). The expression of PI3K, CDK4 and pERK proteins decreased. The expression level of caspase-3 protein was increased. PI3K is a kind of intracellular phosphatidylinositol kinase. PI3K signaling pathway is involved in signal transduction of a variety of growth factors, cytokines and extracellular matrix and plays an important role in preventing cell apoptosis, promoting cell survival and influencing cell glucose metabolism. CDK4 is a catalytic subunit of the protein kinase complex and is important for G1 phase progression of the cell cycle. PERK refers to phosphorylated activated ERK, which is translocated from cytoplasm to the nucleus after activation, and then participates in various biological reactions such as cell proliferation and differentiation, cell morphology maintenance, cytoskeleton construction, cell apoptosis and cell canceration. Compared with the model group and the positive control group, the tumor volume of the nude mice in the low-concentration PYR26 group, the medium-concentration group and the high-concentration group was smaller, and the organ volume was smaller than that in the model group and the positive control group. The tumor inhibition rates of low-concentration group PYR26, medium-concentration group and high-concentration group reached 50.46%, 80.66% and 74.59%, respectively. The results showed that PYR26 inhibited the proliferation of HepG2 cells and induced apoptosis of HepG2 cells by down-regulating c-Met , CDK4 and Bak , up-regulating the mRNA expression of caspase-3 and Cyt c genes, down-regulating PI3K, pERK and CDK4 proteins and up-regulating the protein level of caspase-3. In a certain range, with the increase in PYR26 concentration, the tumor growth was slower and the tumor volume was smaller. Preliminary results showed that PYR26 also had an inhibitory effect on the tumors of Hepa1-6 tumor-bearing mice. These results suggest that PYR26 has an inhibitory effect on the growth of liver cancer cells, therefore it has potential to be developed into a new anti-liver cancer drug.

Laser speckle contrast imaging (LSCI) can generate retinal blood flow maps inexpensively and non-invasively. These flow maps can be used to identify various eye disorders associated with reduced blood flow. Despite early success, one of the major obstacles to clinical adoption of LSCI is poor repeatability of the modality. Here, we propose an LSCI registration pipeline that registers contrast maps to correct for rigid movements. Post-registration, intra(same)-day and inter(next)-day repeatability are studied using various quantitative metrics. We have studied LSCI repeatability intra-day by using the coefficient of variation. Using the processing pipelines and custom hardware developed, similar repeatability was observed when compared to previously reported values in the literature. Inter-day repeatability analysis indicates no statistical evidence (p = 0.09) of a difference between flow measurements performed on two independent days. Further improvements to hardware, environmental controls, and participant control must be made to provide higher confidence in the repeatability of blood flow. However, this is the first time that repeatability across two different days (inter-day) using multiple exposure speckle imaging (MESI) has been analyzed and reported., Competing Interests: The authors declare no conflicts of interest, (© 2022 Optica Publishing Group under the terms of the Optica Open Access Publishing Agreement.)

Circular RNAs (circRNAs) are widely expressed in eukaryotes. However, only a subset has been functionally characterized. We identify and validate a collection of circRNAs in Drosophila, and show that depletion of the brain-enriched circRNA Edis (circ&#95;Ect4) causes hyperactivation of antibacterial innate immunity both in cultured cells and in vivo. Notably, Edis depleted flies display heightened resistance to bacterial infection and enhanced pathogen clearance. Conversely, ectopic Edis expression blocks innate immunity signaling. In addition, inactivation of Edis in vivo leads to impaired locomotor activity and shortened lifespan. Remarkably, these phenotypes can be recapitulated with neuron-specific depletion of Edis, accompanied by defective neurodevelopment. Furthermore, inactivation of Relish suppresses the innate immunity hyperactivation phenotype in the fly brain. Moreover, we provide evidence that Edis encodes a functional protein that associates with and compromises the processing and activation of the immune transcription factor Relish. Importantly, restoring Edis expression or ectopic expression of Edis-encoded protein suppresses both innate immunity and neurodevelopment phenotypes elicited by Edis depletion. Thus, our study establishes Edis as a key regulator of neurodevelopment and innate immunity., Competing Interests: The authors have declared that no competing interests exist.

Oomycetes cause hundreds of destructive plant diseases, threatening agricultural production and food security. These fungus-like eukaryotes show multiple sporulation pattern including the production of sporangium, zoospore, chlamydospore and oospore, which are critical for their survival, dispersal and infection on hosts. Recently, genomic and genetic technologies have greatly promoted the study of molecular mechanism of sporulation in the genus Phytophthora and Peronophythora . In this paper, we characterize the types of asexual and sexual spores and review latest progress of these two genera. We summarize the genes encoding G protein, mitogen-activated protein kinase (MAPK) cascade, transcription factors, RNA-binding protein, autophagy-related proteins and so on, which function in the processes of sporangium production and cleavage, zoospore behaviors and oospore formation. Meanwhile, various molecular, chemical and electrical stimuli in zoospore behaviors are also discussed. Finally, with the molecular mechanism of sporulation in Phytophthora and Peronophythora is gradually being revealed, we propose some thoughts for the further research and provide the alternative strategy for plant protection against phytopathogenic oomycetes., 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 Situ, Xi, Lin, Huang, Song, Jiang and Kong.)

Background: Hepatitis E virus (HEV) variants belonging to Orthohepevirus species A (HEV-A) are the primary cause of human hepatitis E. However, we previously reported that Orthohepevirus species C genotype 1 (HEV-C1), a divergent HEV variant commonly found in rats, also causes hepatitis in humans. Here, we present a clinical-epidemiological investigation of human HEV-C1 infections detected in Hong Kong, with an emphasis on outcomes in immunocompromised individuals., Methods: A surveillance system for detecting human HEV-C1 infections was established in Hong Kong. Epidemiological and clinical characteristics of HEV-C1 cases identified via this system between 1 August 2019 and 31 December 2020 were retrieved. Phylogenetic analysis of HEV-C1 strain sequences was performed. Infection outcomes of immunocompromised individuals with HEV-A and HEV-C1 infections were analyzed., Results: HEV-C1 accounted for 8 of 53 (15.1%) reverse-transcription polymerase chain reaction (RT-PCR)-confirmed HEV infections in Hong Kong during the study period, raising the total number of HEV-C1 infections detected in the city to 16. Two distinct HEV-C1 strain groups caused human infections. Patients were elderly and/or immunocompromised; half tested negative for HEV immunoglobulin M. Cumulatively, HEV-C1 accounted for 9 of 21 (42.9%) cases of hepatitis E recorded in immunocompromised patients in Hong Kong. Immunocompromised HEV-C1 patients progressed to persistent hepatitis at similar rates (7/9 [77.8%]) as HEV-A patients (10/12 [75%]). HEV-C1 patients responded to oral ribavirin, although response to first course was sometimes poor or delayed., Conclusions: Dedicated RT-PCR-based surveillance detected human HEV-C1 cases that evade conventional hepatitis E diagnostic testing. Immunosuppressed HEV-C1-infected patients frequently progress to persistent HEV-C1 infection, for which ribavirin is a suitable treatment option., Competing Interests: Potential conflicts of interest. S. S. has received speaker’s honoraria from Abbott Laboratories Ltd. All other authors report no potential conflicts of interest. The authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background & Aims: HEV variants such as swine genotypes within Paslahepevirus species balayani (HEV-A) and rat HEV ( Rocahepevirus ratti ; HEV-C1) cause chronic hepatitis E in immunocompromised individuals. There are few reliable and accessible small animal models that accurately reflect chronic HEV infection. We aimed to develop an immunocompromised rat model of chronic hepatitis E infection., Methods: In this animal model infection study, rats were immunosuppressed with a drug combination (prednisolone, tacrolimus, and mycophenolate mofetil) commonly taken by transplant recipients. Rats were challenged with human- and rat-derived HEV-C1 strains or a human-derived HEV-A strain. Viral load, liver function, liver histology, humoural, and cellular immune responses were monitored., Results: A high-dose (HD) immunosuppressive regimen consistently prolonged human- and rat-derived HEV-C1 infection in rats (up to 12 weeks post infection) compared with transient infections in low-dose (LD) immunosuppressant-treated and immunocompetent (IC) rats. Mean HEV-C1 viral loads in stool, serum, and liver tissue were higher in HD regimen-treated rats than in LD or IC rats ( p <0.05). Alanine aminotransferase elevation was observed in chronically infected rats, which was consistent with histological hepatitis and HEV-C1 antigen expression in liver tissue. None (0/6) of the HD regimen-treated, 5/6 LD regimen-treated, and 6/6 IC rats developed antibodies to HEV-C1 in species-specific immunoblots. Reversal of immunosuppression was associated with clearance of viraemia and restoration of HEV-C1-specific humoural and cellular immune responses in HD regimen-treated rats, mimicking patterns in treated patients with chronic hepatitis E. Viral load suppression was observed with i.p. ribavirin treatment. HD regimen-treated rats remained unsusceptible to HEV-A infection., Conclusions: We developed a scalable immunosuppressed rat model of chronic hepatitis E that closely mimics this infection phenotype in transplant recipients., Lay Summary: Convenient small animal models are required for the study of chronic hepatitis E in humans. We developed an animal model of chronic hepatitis E by suppressing immune responses of rats with drugs commonly taken by humans as organ transplant rejection prophylaxis. This model closely mimicked features of chronic hepatitis E in humans., Competing Interests: SS has received speaker’s honoraria from Abbott Medical Laboratories. The other authors report that there are no competing interests to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2022 The Author(s).)

Hepatitis E virus (HEV) infection in humans is primarily caused by genotypes within Paslahepevirus species balayani (HEV-A). Rocahepevirus species ratti (HEV-C1, otherwise known as rat HEV) can also infect humans. HEV grows poorly in cell culture. Recent studies have reported that hyper-confluent cell layers, amphotericin B, MgCl 2 , progesterone, and dimethyl sulfoxide (DMSO) increase HEV yield in vitro. Here, we describe an independent evaluation of the effectiveness of these modifications in improving the yield of HEV-A genotype 4 (HEV-A4) and HEV-C1 from clinical samples in PLC/PRF/5 cells. We found that amphotericin B, MgCl 2 , and DMSO increased HEV yield from high-viral-load patient stool samples, while progesterone was not effective. Yield of HEV-C1 was lower than HEV-A4 across all medium conditions, but was boosted by DMSO. HEV-A4 could be maintained for over 18 months in amphotericin B- and MgCl 2 -containing medium, with the demonstration of viral antigen in supernatants and infected cells. We also evaluated various protocols to remove pseudo-envelopes from cell culture-derived HEV. Treating cell culture supernatant with NP-40 was the most effective. Our findings identify key modifications that boost HEV growth in vitro and illustrate the importance of independent verification of such studies using diverse HEV variants and cell lines.

The essential trace element selenium plays an important role in maintaining brain function. Selenoprotein W (SELENOW), the smallest selenoprotein that has been identified in mammals, is sensitive to selenium levels and abundantly expressed in the brain. However, its biological role in the brain remains to be clarified. Here, we studied the morphological and functional changes in the brain caused by SELENOW deficiency using its gene knockout (KO) mouse models. Histomorphological alterations of the amygdala and hippocampus, specifically in the female SELENOW KO mice, were observed, ultimately resulting in less anxiety-like behavior and impaired contextual fear memory. Fear conditioning (FC) provokes rapidly intricate responses involving neuroplasticity and oligodendrogenesis. During this process, the females generally show stronger contextual FC than males. To characterize the effect of SELENOW deletion on FC, specifically in the female mice, a Tandem mass tag (TMT)-based comparative proteomic approach was applied. Notably, compared to the wildtype (WT) no shock (NS) mice, the female SELENOW KO NS mice shared lots of common differentially expressed proteins (DEPs) with the WT FC mice in the hippocampus, enriched in the biological process of ensheathment and oligodendrocyte differentiation. Immunostaining and Western blotting analyses further confirmed the proteomic results. Our work may provide a holistic perspective of gender-specific SELENOW function in the brain and highlighted its role in oligodendrogenesis during fear memory.

Background: While artificial intelligence (AI) offers possibilities of advanced clinical prediction and decision-making in healthcare, models trained on relatively homogeneous datasets, and populations poorly-representative of underlying diversity, limits generalisability and risks biased AI-based decisions. Here, we describe the landscape of AI in clinical medicine to delineate population and data-source disparities., Methods: We performed a scoping review of clinical papers published in PubMed in 2019 using AI techniques. We assessed differences in dataset country source, clinical specialty, and author nationality, sex, and expertise. A manually tagged subsample of PubMed articles was used to train a model, leveraging transfer-learning techniques (building upon an existing BioBERT model) to predict eligibility for inclusion (original, human, clinical AI literature). Of all eligible articles, database country source and clinical specialty were manually labelled. A BioBERT-based model predicted first/last author expertise. Author nationality was determined using corresponding affiliated institution information using Entrez Direct. And first/last author sex was evaluated using the Gendarize.io API., Results: Our search yielded 30,576 articles, of which 7,314 (23.9%) were eligible for further analysis. Most databases came from the US (40.8%) and China (13.7%). Radiology was the most represented clinical specialty (40.4%), followed by pathology (9.1%). Authors were primarily from either China (24.0%) or the US (18.4%). First and last authors were predominately data experts (i.e., statisticians) (59.6% and 53.9% respectively) rather than clinicians. And the majority of first/last authors were male (74.1%)., Interpretation: U.S. and Chinese datasets and authors were disproportionately overrepresented in clinical AI, and almost all of the top 10 databases and author nationalities were from high income countries (HICs). AI techniques were most commonly employed for image-rich specialties, and authors were predominantly male, with non-clinical backgrounds. Development of technological infrastructure in data-poor regions, and diligence in external validation and model re-calibration prior to clinical implementation in the short-term, are crucial in ensuring clinical AI is meaningful for broader populations, and to avoid perpetuating global health inequity., Competing Interests: Leo Anthony Celi is the Editor-in Chief of PLOS Digital Health and Judy Gichoya Wawira is a Section Editor for PLOS Digital Health., (Copyright: © 2022 Celi 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.)

C 2 H 2 zinc finger is one of the most common motifs found in the transcription factors (TFs) in eukaryotes organisms, which have a broad range of functions, such as regulation of growth and development, stress tolerance and pathogenicity. Here, PlCZF1 was identified to encode a C 2 H 2 zinc finger in the litchi downy blight pathogen Peronophythora litchii . PlCZF1 is conserved in P. litchii and Phytophthora species. In P. litchii , PlCZF1 is highly expressed in sexual developmental and early infection stages. We generated Δplczf1 mutants using the CRISPR/Cas9 method. Compared with the wild type, the Δplczf1 mutants showed no significant difference in vegetative growth and asexual reproduction, but were defective in oospore development and virulence. Further experiments revealed that the transcription of PlM90 , PlLLP and three laccase encoding genes were down-regulated in the Δplczf1 mutant. Our results demonstrated that PlCZF1 is a vital regulator for sexual development and pathogenesis in P. litchii.