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Abstract Brain injury is the leading cause of mortality among patients who survive cardiac arrest (CA). Clinical studies have shown that the presence of post-CA hypoxic hepatitis or pre-CA liver disease is associated with increased mortality and inferior neurological recovery. In our in vivo global cerebral ischemia model, we observed a larger infarct area, elevated tissue injury scores, and increased intravascular CD45+ cell adhesion in reperfused brains with simultaneous hepatic ischemia than in those without it. In the ex vivo brain normothermic machine perfusion (NMP) model, we demonstrated that addition of a functioning liver to the brain NMP circuit significantly reduced post-CA brain injury, increased neuronal viability, and improved electrocortical activity. Furthermore, significant alterations were observed in both the transcriptome and metabolome in the presence or absence of hepatic ischemia. Our study highlights the crucial role of the liver in the pathogenesis of post-CA brain injury.

Abstract African swine fever virus (ASFV) is the causal agent of African swine fever (ASF), which is contagious and highly lethal to domestic pigs and wild boars. The genome of ASFV encodes many proteins important for ASFV life cycle. The functional importance of topoisomerase AsfvTopII has been confirmed by in vivo and in vitro assays, but the structure of AsfvTopII is poorly studied. Here, we report four AsfvTopII complex structures. The ATPase domain structures reveal the detailed basis for ATP binding and hydrolysis, which is shared by AsfvTopII and eukaryotic TopIIs. The DNA-bound structures show that AsfvTopII follows conserved mechanism in G-DNA binding and cleavage. Besides G-DNA, a T-DNA fragment is also captured in one AsfvTopII structure. Mutagenesis and in vitro assays confirm that Pro852 and the T-DNA-binding residue Tyr744 are important for the function of AsfvTopII. Our study not only advances the understanding on the biological function of AsfvTopII, but also provides a solid basis for the development of AsfvTopII-specific inhibitors.

Abstract Mpox virus (MPXV) can cause mpox in humans. Due to its quick and wide spread in the past two years, mpox has turned into a significant public health concern. Helicase E5 is a multi-domain protein; its primer synthesis and DNA unwinding activity are required for genome uncoating and DNA replication of MPXV. However, the in vitro DNA unwinding activity has never been demonstrated. Here, we report the structural and biochemical studies of MPXV E5, showing that the full-length protein adopts an auto-inhibited conformation. Truncation of the N-terminus can recover the in vitro unwinding activity of E5 towards the forked DNA. Further structural analysis reveals that MPXV E5 shares a conserved mechanism in DNA unwinding and primer synthesis with the homologous proteins. These findings not only advance our understanding on the function of MPXV E5, but also provide a solid basis for the development of anti-poxvirus drugs.

Solid-state electrolytes are key ingredients in next-generation devices for energy storage and release. Machine learning molecular dynamics (MLMD) has shown great promise in studying the diffusivity of mobile ions in solid-state electrolytes, with much higher efficiency than conventional ab initio molecular dynamics (AIMD). In this work, we combine an efficient embedded atom neural network (EANN) approach and an uncertainty-driven active learning algorithm that optimally selects data points from high-temperature AIMD trajectories to construct ML potentials for solid-state electrolytes and validate this strategy in a benchmark system, Li3YCl6, for which several controversy theoretical results exist. Through systematic MLMD simulations, we find that a typically used small supercell in AIMD simulations fails to predict the supersonic transition at a critical temperature, leading to a significant overestimation of the Li+ conductivity in Li3YCl6 at room temperature. Fortunately, thanks to the scalability of the EANN potential, extended MLMD simulations in a sufficiently large cell does yield a notable change of temperature-dependence in conductivity at ∼420 K and a much lower room-temperature conductivity in excellent with experiment. Interestingly, our results are all based on a semi-local PBE density functional, which was argued unable to predict the superionic transition. We analyze possible reasons of the seemingly inconsistent MLMD results reported in literature with different ML potentials. This work paves the way of simply using high-temperature AIMD data to generate more reliable MLMD results of low-temperature ionic conductivities in solid-state electrolytes.

Abstract Spiders are representative arthropods of adaptive radiation. The high-quality genomes have only been reported in several web weaver spider species, leaving the wandering spiders’ genomic information scarce. The pond wolf spider, Pardosa pseudoannulata, is a representative species in the retrolateral titial apophysis (RTA) clade. We present a chromosome-level P. pseusoannulata genome assembly of 2.42 Gb in size with a scaffold N50 of 169.99 Mb. Hi-C scaffolding assigns 94.83% of the bases to 15 pseudo-chromosomes. The repeats account for 52.79% of the assembly. The assembly includes 96.2% of the complete arthropod universal single-copy orthologs. Gene annotation predicted 24,530 protein-coding genes with a BUSCO score of 95.8% complete. We identified duplicate clusters of Hox genes and an expanded cuticle protein gene family with 243 genes. The expression patterns of CPR genes change in response to environmental stresses such as coldness and insecticide exposure. The high-quality P. pseudoannulata genome provides valuable information for functional and comparative studies in spiders.

Abstract Chimeric antigen receptor (CAR)-T therapy requires autologous T lymphocytes from cancer patients, a process that is both costly and complex. Universal CAR-T cell treatment from allogeneic sources can overcome this limitation but is impeded by graft-versus-host disease (GvHD) and host versus-graft rejection (HvGR). Here, we introduce a mutated calcineurin subunit A (CNA) and a CD19-specific CAR into the T cell receptor α constant (TRAC) locus to generate cells that are resistant to the widely used immunosuppressant, cyclosporine A (CsA). These immunosuppressant-resistant universal (IRU) CAR-T cells display improved effector function in vitro and anti-tumour efficacy in a leukemia xenograft mouse model in the presence of CsA, compared with CAR-T cells carrying wild-type CNA. Moreover, IRU CAR-T cells retain effector function in vitro and in vivo in the presence of both allogeneic T cells and CsA. Lastly, CsA withdrawal restores HvGR, acting as a safety switch that can eliminate IRU CAR-T cells. These findings demonstrate the efficacy of CsA-resistant CAR-T cells as a universal, ‘off-the-shelf’ treatment option.

Abstract Background N6-methyladenosine (m6A) mRNA modification plays a critical role in various human biological processes. However, there has been no study reported to elucidate its role in hepatic ischemia-reperfusion injury (IRI). This study was aimed to explore the expression pattern together with the potential functions of m6A regulators in hepatic IRI. Methods The gene expression data (GSE23649) of m6A regulators in human liver tissue samples before cold perfusion and within 2 h after portal vein perfusion from Gene Expression Omnibus database was analyzed. The candidate m6A regulators were screened using random forest (RF) model to predict the risk of hepatic IRI. The evaluation of infiltrating abundance of 23 immune cells was performed using single sample gene set enrichment analysis. Besides, quantitative real time polymerase chain reaction (qRT-PCR) assay was carried out to validate the expression of key m6A regulators in mouse hepatic IRI model. Results The expressions of WTAP, CBLL1, RBM15, and YTHDC1 were found to be increased in liver tissues 2 h after portal vein perfusion; in contrast, the expressions of LRPPRC, FTO, METTL3, and ALKBH5 were decreased. Based on RF model, we identified eight m6A methylation regulators for the prediction of the risk of hepatic IRI. Besides, a nomogram was built to predict the probability of hepatic IRI. In addition, the levels of WTAP, ALKBH5, CBLL1, FTO, RBM15B, LRPPRC and YTHDC1 were correlated with the immune infiltration of activated CD4 T cell, activated dendritic cell (DC), immature DC, mast cell, neutrophil, plasmacytoid DC, T helper (Th) cell (type 1, 2, and 17), gamma delta T cell, T follicular helper (Tfh) cell, myeloid-derived suppressor cell (MDSC), macrophage, natural killer cell, and regulatory Th cell. Among mouse hepatic IRI model, the mRNA level of CBLL1 and YTHDC1 was increased with statistical significance; however, the mRNA level of FTO and METTL3 was decreased among post-reperfusion liver samples compared with those in pre-reperfusion samples with statistical significance. Conclusions The m6A regulators exerted a pivotal impact on hepatic IRI. The m6A patterns that found in this study might provide novel targets and strategies for the alleviation/treatment of hepatic IRI in the future.

Accurately detecting and counting abnormal fish behaviors in aquaculture is essential. Timely detection allows farmers to take swift action to protect fish health and prevent economic losses. This paper proposes an enhanced high-precision detection algorithm based on YOLOv9, named DDEYOLOv9, to facilitate the detection and counting of abnormal fish behavior in industrial aquaculture environments. To address the lack of publicly available datasets on abnormal behavior in fish, we created the “Abnormal Behavior Dataset of Takifugu rubripes”, which includes five categories of fish behaviors. The detection algorithm was further enhanced in several key aspects. Firstly, the DRNELAN4 feature extraction module was introduced to replace the original RepNCSPELAN4 module. This change improves the model’s detection accuracy for high-density and occluded fish in complex water environments while reducing the computational cost. Secondly, the proposed DCNv4-Dyhead detection head enhances the model’s multi-scale feature learning capability, effectively recognizes various abnormal fish behaviors, and improves the computational speed. Lastly, to address the issue of sample imbalance in the abnormal fish behavior dataset, we propose EMA-SlideLoss, which enhances the model’s focus on hard samples, thereby improving the model’s robustness. The experimental results demonstrate that the DDEYOLOv9 model achieves high Precision, Recall, and mean Average Precision (mAP) on the “Abnormal Behavior Dataset of Takifugu rubripes”, with values of 91.7%, 90.4%, and 94.1%, respectively. Compared to the YOLOv9 model, these metrics are improved by 5.4%, 5.5%, and 5.4%, respectively. The model also achieves a running speed of 119 frames per second (FPS), which is 45 FPS faster than YOLOv9. Experimental results show that the DDEYOLOv9 algorithm can accurately and efficiently identify and quantify abnormal fish behaviors in specific complex environments.

This paper presents an innovative three-level direct yaw moment control strategy for distributed drive electric vehicles (DDEV) under emergency conditions. The phase plane analysis is used at the supervisory level to design the stability boundary function taking into account the impact of the road adhesion coefficient. To guarantee the performance of finite-time convergence and singularity-free methods, the adaptive nonsingular fast terminal sliding mode control (ANFTSMC) is developed at the decision level to determine the extra yaw moment for tracking the intended side slip angle and yaw rate. Among this, the unstable domain in the phase plane is further separated into moderately and severely unstable according to the degree of vehicle instability, which is defined by the distance between the state phase point and the stability boundary. Meanwhile, the adaptive weight between the handling and stability is obtained. At the executive level, the quadratic programming algorithm is adopted to allocate four-wheel torque with the objective of optimal tire utilization rate. Finally, the co-simulation test is executed in both closed-loop and open-loop circumstances; according to the simulation results, the presented ANFTSMC method outperforms the SMC, and it can decrease the tracking error and improve the handling and stability.

BackgroundT cell-mediated acute rejection(AR) after heart transplantation(HT) ultimately results in graft failure and is a common indication for secondary transplantation. It’s a serious threat to heart transplant recipients. This study aimed to explore the novel lncRNA-miRNA-mRNA networks that contributed to AR in a mouse heart transplantation model.MethodsThe donor heart from Babl/C mice was transplanted to C57BL/6 mice with heterotopic implantation to the abdominal cavity. The control group was syngeneic heart transplantation with the same kind of mice donor. The whole-transcriptome sequencing was performed to obtain differentially expressed mRNAs (DEmRNAs), miRNAs (DEmiRNAs) and lncRNAs (DElncRNAs) in mouse heart allograft. The biological functions of ceRNA networks was analyzed by GO and KEGG enrichment. Differentially expressed ceRNA involved in programmed cell death were further verified with qRT-PCR testing.ResultsLots of DEmRNAs, DEmiRNAs and DElncRNAs were identified in acute rejection and control after heart transplantation, including up-regulated 4754 DEmRNAs, 1634 DElncRNAs, 182 DEmiRNAs, and down-regulated 4365 DEmRNAs, 1761 DElncRNAs, 132 DEmiRNAs. Based on the ceRNA theory, lncRNA-miRNA-mRNA regulatory networks were constructed in allograft acute rejection response. The functional enrichment analysis indicate that the down-regulated mRNAs are mainly involved in cardiac muscle cell contraction, potassium channel activity, etc. and the up-regulated mRNAs are mainly involved in T cell differentiation and mononuclear cell migration, etc. The KEGG pathway enrichment analysis showed that the down-regulated DEmRNAs were mainly enriched in adrenergic signaling, axon guidance, calcium signaling pathway, etc. The up-regulated DEmRNAs were enriched in the adhesion function, chemokine signaling pathway, apoptosis, etc. Four lncRNA-mediated ceRNA regulatory pathways, Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox, 1700071M16Rik/miR-145a-3p/Themis2, were finally validated. In addition, increased expression of PVT1, 1700071M16Rik, Tox and Themis2 may be considered as potential diagnostic gene biomarkers in AR.ConclusionWe speculated that Pvt1/miR-30c-5p/Pdgfc, 1700071M16Rik/miR-145a-3p/Pdgfc, 1700071M16Rik/miR-145a-3p/Tox and 1700071M16Rik/miR-145a-3p/Themis2 interaction pairs may serve as potential biomarkers in AR after HT.

Abstract Dynamic and heterogeneous interaction between tumor cells and the surrounding microenvironment fuels the occurrence, progression, invasion, and metastasis of solid tumors. In this process, the tumor microenvironment (TME) fractures cellular and matrix architecture normality through biochemical and mechanical means, abetting tumorigenesis and treatment resistance. Tumor cells sense and respond to the strength, direction, and duration of mechanical cues in the TME by various mechanotransduction pathways. However, far less understood is the comprehensive perspective of the functions and mechanisms of mechanotransduction. Due to the great therapeutic difficulties brought by the mechanical changes in the TME, emerging studies have focused on targeting the adverse mechanical factors in the TME to attenuate disease rather than conventionally targeting tumor cells themselves, which has been proven to be a potential therapeutic approach. In this review, we discussed the origins and roles of mechanical factors in the TME, cell sensing, mechano‐biological coupling and signal transduction, in vitro construction of the tumor mechanical microenvironment, applications and clinical significance in the TME.

HARP are member of protein-only RNase P, which catalyzes pre-tRNA 5’-end processing and maturation. Here, the authors present crystal structure and provide mechanistic insights into pre-tRNA binding and cleavage by HARP proteins.

Abstract Owing to its great threat to human health and environment, Pb2+ pollution has been recognized as a major public problem by the World Health Organization (WHO). Many DNA aptamers have been utilized in the development of Pb2+-detection sensors, but the underlying mechanisms remain elusive. Here, we report three Pb2+-complexed structures of the thrombin binding aptamer (TBA). These high-resolution crystal structures showed that TBA forms intramolecular G-quadruplex and Pb2+ is bound by the two G-tetrads in the center. Compared to K+-stabilized G-quadruplexes, the coordinating distance between Pb2+ and the G-tetrads are much shorter. The T3T4 and T12T13 linkers play important roles in dimerization and crystallization of TBA, but they are changeable for Pb2+-binding. In combination with mutagenesis and CD spectra, the G8C mutant structure unraveled that the T7G8T9 linker of TBA is also variable. In addition to expansion of the Pb2+-binding aptamer sequences, our study also set up one great example for quick and rational development of other aptamers with similar or optimized binding activity.

Infection of human parvovirus B19 (B19V) can cause a variety of diseases, such as hydrops fetalis, erythema infectiosum in children and acute arthropathy in women. Although B19V infection mainly occurs during childhood, about 50 % of adults are still susceptible to B19V infection. As the major replication protein of B19V, deletion of NS1 completely abolishes the infectivity of the virus. The nuclease domain of NS1 (NS1_Nuc) is responsible for DNA Ori binding and nicking that is critical for B19V viral DNA replication. NS1 has various variants, the structure and function for the majority of the variants are poorly studied. Here, we report two high-resolution crystal structures of NS1_Nuc, revealed the detailed conformations of many key residues. Structural comparison indicates that these residues are important for ssDNA or dsDNA binding by NS1. NS1 belongs to the HUH-endonuclease superfamily and it shares conserved ssDNA cleavage mechanism with other HUH-endonuclease members. However, our structural analyses, mutagenesis and in vitro assay results all suggested that NS1_Nuc utilizes one unique model in ssDNA binding.

In this study, we summarize recent advances in the synthesis of magnetic catalysts utilized for biodiesel production, particularly focusing on the physicochemical properties, activity, and reusability of magnetic mixed metal oxides, supported magnetic catalysts, ionic acid-functionalized magnetic catalysts, heteropolyacid-based magnetic catalysts, and metal–organic framework-based magnetic catalysts. The prevailing reaction conditions in the production of biodiesel are also discussed. Lastly, the current limitations and challenges for future research needs in the magnetic catalyst field are presented.

Acetylcholinesterase (AChE) is an essential neurotransmitter hydrolase in nervous systems of animals and its number varies among species. So far, five AChEs have been identified in the natural enemy Pardosa pseudoannulata. Here we found that Ppace1, Ppace2 and Ppace5 were highly expressed in the spider brain, among which the mRNA level of Ppace5, but not Ppace1 and Ppace2, could be up-regulated by organophosphorus insecticides at their sublethal concentrations. In spider brain, the treatment by organophosphorus insecticides at the sublethal concentrations could increase total AChE activity, although high concentrations inhibited the activity. The activity that increased from the sublethal concentration pretreatment could compensate for the activity inhibition due to subsequent application of organophosphorus insecticides at lethal concentrations, and consequently reduce the mortality of spiders. PpAChE1 and PpAChE2 were highly sensitive to organophosphorus insecticides, and their activities would be strongly inhibited by the insecticides. In contrast, PpAChE5 displayed relative insensitivity towards organophosphorus insecticides, but with the highest catalytic efficiency for ACh. That meant the up-regulation of Ppace5 under insecticide exposure was important for maintaining AChE activity in spider brain, when PpAChE1 and PpAChE2 were inhibited by organophosphorus insecticides. The study demonstrated that multiple AChEs in the spider brain worked collaboratively, with part members for maintaining AChE activity and other members responding to organophosphorus inhibition, to provide protection from organophosphorus insecticides. In fields, high concentration insecticides are often applied when ineffective controls of insect pests occur due to relative-low concentration of insecticides in last round application. This application pattern of organophosphorus insecticides provides more chances for P. pseudoannulata to survive and controlling insect pests as a natural enemy.

Cycloxaprid, an oxabridged cis-nitromethylene neonicotinoid, showed high insecticidal activity in Hemipteran insect pests. In this study, the action of cycloxaprid was characterized by recombinant receptor Nlα1/rβ2 and cockroach neurons. On Nlα1/β2 in Xenopus oocytes, cycloxaprid acted as a full agonist. The imidacloprid resistance-associated mutation Y151S reduced the Imax of cycloxaprid by 37.0% and increased EC50 values by 1.9-fold, while the Imax of imidacloprid was reduced by 72.0%, and EC50 values increased by 2.3-fold. On cockroach neurons, the maximum currents elicited by cycloxaprid were only 55% of that of acetylcholine, a full agonist, but with close EC50 values of that of trans-neonicotinoids. In addition, cycloxaprid inhibited acetylcholine-evoked currents on insect neurons in a concentration-dependent manner when co-applied with acetylcholine. Cycloxaprid at low concentrations significantly inhibited the activation of nAChRs by acetylcholine, and its inhibition potency at 1 µM was higher than its activation potency on insect neurons. Two action potencies, activation, and inhibition, by cycloxaprid on insect neurons provided an explanation for its high toxicity to insect pests. In summary, as a cis-nitromethylene neonicotinoid, cycloxaprid showed high potency on both recombinant nAChR Nlα1/β2 and cockroach neurons, which guaranteed its high control effects on a variety of insect pests.

Adoptive cell therapy (ACT) with engineered T cells has emerged as a promising strategy for the treatment of malignant tumors. Among them, there is great interest in engineered γδ T cells for ACT. With both adaptive and innate immune characteristics, γδ T cells can be activated by γδ TCRs to recognize antigens in a MHC-independent manner, or by NK receptors to recognize stress-induced molecules. The dual recognition system enables γδ T cells with unique activation and cytotoxicity profiles, which should be considered for the design of engineered γδ T cells. However, the current designs of engineered γδ T cells mostly follow the strategies that used in αβ T cells, but not making good use of the specific characteristics of γδ T cells. Therefore, it is no surprising that current engineered γδ T cells in preclinical or clinical trials have limited efficacy. In this review, we summarized the patterns of antigen recognition of γδ T cells and the features of signaling pathways for the functions of γδ T cells. This review will additionally discuss current progress in engineered γδ T cells and provide insights in the design of engineered γδ T cells based on their specific characteristics.

Abstract Background Ischemia‐reperfusion injury (IRI) is considered an inherent component of organ transplantation that compromises transplant outcomes and organ availability. The ischemia‐free liver transplantation (IFLT) procedure has been developed to avoid interruption of blood supply to liver grafts. It is unknown how IFLT might change the characteristics of graft IRI. Methods Serum and liver biopsy samples were collected from IFLT and conventional liver transplantation (CLT) recipients. Pathological, metabolomics, transcriptomics, and proteomics analyses were performed to identify the characteristic changes in graft IRI in IFLT. Results Peak aspartate aminotransferase (539.59 ± 661.76 U/L versus 2622.28 ± 3291.57 U/L) and alanine aminotransferase (297.64 ± 549.50 U/L versus 1184.16 ± 1502.76 U/L) levels within the first 7 days and total bilirubin levels by day 7 (3.27 ± 2.82 mg/dl versus 8.33 ± 8.76 mg/dl) were lower in the IFLT versus CLT group (all p values

Abstract Background Hepatitis B virus (HBV) infection is a global health problem and interferon-alpha (IFN-α) is one of the effective therapies. However, little is known about the genetic background of the HBV infection or the genetic determinants of the IFN-α treatment response. Thus, we aim to explore the possible molecular mechanisms of HBV infection and its response to the IFN-α therapy with a comprehensive bioinformatics analysis. Methods The Gene Expression Omnibus datasets (GSE83148, GSE84044 and GSE66698) were collected and the differentially expressed genes (DEGs), key biological processes and intersecting pathways were analyzed. The expression of the co-expressed DEGs in the clinical samples was verified by quantitative real time polymerase chain reaction (qRT-PCR). Results Analysis of all the 3 datasets revealed that there were eight up-regulated and one down-regulated co-expressed DEGs following the HBV infection and after IFN-α treatment. In clinical samples, the mRNA level of HKDC1, EPCAM, GSN, ZWINT and PLD3 were significantly increased, while, the mRNA level of PLEKHA2 was significantly decreased in HBV infected liver tissues compared to normal liver tissues. PI3K-Akt signaling pathway, focal adhesion, HTLV-I infection, cytokine-cytokine receptor interaction, metabolic pathways, NF-κB signaling pathway were important pathways associated with the HBV infection and the response of IFN-α treatment. Conclusions The co-expressed genes, common biological processes and intersecting pathways identified in the study might play an important role in HBV infection and response of IFN-α treatment. The dysregulated genes may act as novel biomarkers and therapeutic targets for HBV.

Transplant rejection remains a major barrier to graft survival and involves a diversity of cell types. However, the heterogeneity of each cell type in the allograft remains poorly defined. In the present study, we used single-cell RNA sequencing technology to analyze graft-infiltrating cells to describe cell types and states associated with acute rejection in a mouse heart transplant model. Unsupervised clustering analysis revealed 21 distinct cell populations. Macrophages formed five cell clusters: two resident macrophage groups, two infiltrating macrophage groups and one dendritic cell-like monocyte group. Infiltrating macrophages were predominantly from allogeneic grafts. Nevertheless, only one infiltrating macrophage cluster was in an active state with the upregulation of CD40, Fam26f and Pira2, while the other was metabolically silent. Re-clustering of endothelial cells identified five subclusters. Interestingly, one of the endothelial cell populations was almost exclusively from allogeneic grafts. Further analysis of this population showed activation of antigen processing and presentation pathway and upregulation of MHC class II molecules. In addition, Ubiquitin D was specifically expressed in such endothelial cell population. The upregulation of Ubiquitin D in rejection was validated by staining of mouse heart grafts and human kidney biopsy specimens. Our findings present a comprehensive analysis of intra-graft cell heterogeneity, describe specific macrophage and endothelial cell populations which mediate rejection, and provide a potential predictive biomarker for rejection in the clinic.

Changes and challenges in employment are inevitable under the measures enacted to contain the COVID-19 pandemic. Early evidence suggests that the pandemic would disproportionately affect women compared to men. Focussing on women workforce in construction, this exploratory study examines the challenges associated with changes in their job situations, the adopted strategies in addressing the challenges and their opinions on employment situation of women workforce during the pandemic. Results of a content analysis show that the top ranked challenges are: (i) overworked; (ii) working space; (iii) social interactions; (iv) collaboration; and (v) parenting. The most cited strategies in addressing these challenges are: (i) increased visual communication; (ii) a dedicated workspace; (iii) self-scheduling; (iv) flexible working arrangements; and (v) breaking out work time and personal time. The evidence is suggestive that most challenges are interrelated, and the strategies adopted by the respondents are multi-level and interdependent. The results also show that the most mentioned opinion is the increased caring and domestic responsibilities among women workforce. Under the uncertainty about the duration of the pandemic and future contagion waves, these findings are critical in informing employing organizations’ human resource management challenges to better support their female employees during pandemic time and beyond.

The fall armyworm (FAW) Spodoptera frugiperda is a notorious pest, causing severe crop damage worldwide and prompting effective prevention and control. Over-reliance on and intensive use of insecticides are prone to leading to the rapid evolution of insecticide resistance, urging rational insecticide application. One effective way of rational insecticide application is to apply insecticides of different modes of action in combination or supplemented with adjuvants. In this study, we assessed the efficacies of two individual insecticides, emamectin benzoate (EB) and chlorantraniliprole (CT), and their mixture, supplemented with and without the oil adjuvant Jijian® to control FAW in laboratory bioassays and a field trial. Both EB and CT showed high toxicities to FAW. The EB × CT mixture at a mass ratio of 9:1 yielded a remarkable synergistic effect, with the co-toxicity coefficient (CTC) being 239.38 and the median lethal concentration (LC50) being 0.177 mg/L. In leaf-spray bioassays, the addition of the adjuvant reduced the LC50 values of both the individual insecticides and the EB × CT mixture by more than 59%, significantly improving the efficacies. The field trial confirmed the synergistic effects of the adjuvant, which reduced the amount of EB × CT mixture by 80%. This study provides an effective and promising insecticide–adjuvant mixture to control S. frugiperda.

Summary: Background Ischaemia-reperfusion injury is considered an inevitable component of organ transplantation, compromising organ quality and outcomes. Although several treatments have been proposed, none has avoided graft ischaemia and its detrimental consequences.Methods Ischaemia-free liver transplantation (IFLT) comprises surgical techniques enabling continuous oxygenated blood supply to the liver of brain-dead donor during procurement, preservation, and implantation using normothermic machine perfusion technology. In this non-randomised study, 38 donor livers were transplanted using IFLT and compared to 130 conventional liver transplants (CLT).Findings Two recipients (5•3%) in the IFLT group experienced early allograft dysfunction, compared to 50•0% in patients receiving conventional transplants (absolute risk difference, 44•8%; 95% confidence interval, 33•6-55•9%). Recipients of IFLT had significantly reduced median (IQR) peak aspartate aminotransferase levels within the first week compared to CLT recipients (365, 238-697 vs 1445, 791-3244 U/L, p

(1) Background: This study aimed to develop a comprehensive understanding of the treatment-related adverse events when using PD-1 or PD-L1 inhibitors in triple-negative breast cancer (TNBC). (2) Methods: We conducted a meta-analysis of Phase II/III randomized clinical trials. Studies were searched for using PubMed, Embase, and Cochrane Library from 1 March 1980 till 30 June 2022. Data on adverse events were mainly extracted from ClinicalTrials.gov and published articles. A generalized linear mixed model with the logit transformation was employed to obtain the overall incidence of adverse events across all studies. For serious adverse events with low incidences, the Peto method was used to calculate the odds ratio (OR) and 95% confidence interval (95%CI) in the PD-1 or PD-L1 inhibitors groups compared to the control groups. (3) Results: Nine studies were included in the meta-analysis, including a total of 2941 TNBC patients treated with PD-1 or PD-L1 inhibitors (including atezolizumab, pembrolizumab and durvalumab) and 2339 patients in the control groups. Chemotherapy alone was the control group in all studies. The average incidences of all serious immune-related adverse events of interest (hypothyroidism, hyperthyroidism, pneumonitis, pruritus, rash) were less than 1%, except for adrenal insufficiency (1.70%, 95%CI: 0.50–5.61%) in the PD-1 or PD-L1 groups. PD-1 or PD-L1 inhibitors significantly increased the risk of serious pneumonitis (OR = 2.52, 95%CI: 1.02–6.26), hypothyroidism (OR = 5.92, 95%CI: 1.22–28.86), alanine aminotransferase (ALT) elevation (OR = 1.66, 95%CI: 1.12–2.45), and adrenal insufficiency (OR = 18.81, 95%CI: 3.42–103.40). For non-serious adverse events, the patients treated with PD-1 or PD-L1 inhibitors had higher risk of aspartate aminotransferase (AST) elevation (OR =1.26, 95%CI: 1.02–1.57), hypothyroidism (OR = 3.63, 95%CI: 2.92–4.51), pruritus (OR = 1.84, 95%CI: 1.30–2.59), rash (OR = 1.29, 95%CI: 1.08–1.55), and fever (OR = 1.77, 95%CI: 1.13–2.77), compared with chemotherapy alone. (4) Conclusions: The incidence of serious immune-related adverse events in PD-1 or PD-L1 inhibitors groups is low but significantly higher than in chemotherapy groups. When using PD-1 or PD-L1 inhibitors for the treatment of TNBC, serious pneumonitis, hypothyroidism, ALT elevation, and adrenal insufficiency should be considered. Non-serious adverse events, such as AST elevation, rash, and fever, should also be taken into consideration.

Abstract Background MicroRNAs (miRNAs) play a pivotal role in hepatocellular carcinoma (HCC) progression and have been confirmed to participate in the carcinogenesis and development of HCC. However, the relationship between miR-497-5p and HCC remains unclear. Methods Kaplan–Meier curve analysis and the log-rank test were used to investigate the efficacy of miR-497-5p on overall survival (OS) and disease-free survival (DFS) in patients with HCC. According to in vitro experiments, programmed cell death 4 (PDCD4) was a target of miR-497-5p by the dual-luciferase activity assay. The efficacy of PDCD4 on cell proliferation and metastasis in HCC was examined by transwell assays, CCK-8 assays and reverse transcription quantitative PCR (RT-qPCR). Additionally, we conducted a luciferase activity reporter assay to confirm the interaction between lncRNA XIST and miR-49-5p. Then, to evaluate the relationship between lncRNA XIST and miR-497-5p, several mechanistic experiments, including qRT-PCR, Western blotting, transwell assays and tumor xenograft assays, were performed. Results miR-497-5p was upregulated in HCC tissues, and high expression of miR-497-5p resulted in increases in tumor size and tumor number and a higher tumor-node-metastasis (TNM) stage and Edmondson grade in patients with HCC. Silencing miR-497-5p inhibited the proliferation and migration of HCC cells. PDCD4, which was downregulated in HCC tissues, was shown to be a target of miR-497-5p and was negatively correlated with the expression of miR-497-5p. lncRNA XIST was found to act as a miR-497-5p sponge and to regulate the level of PDCD4, which is targeted by miR-497-5p. lncRNA XIST was observed to be downregulated in the HCC tissues and positively correlated with the expression of PDCD4. Conclusions Our findings reveal that the XIST/miR-497-5p/PDCD4 axis participates in HCC development and that XIST could be used as a biomarker of HCC.

Objective: This work aims to systematically identify, describe, and appraise all prognostic models for cervical cancer and provide a reference for clinical practice and future research.Methods: We systematically searched PubMed, EMBASE, and Cochrane library databases up to December 2020 and included studies developing, validating, or updating a prognostic model for cervical cancer. Two reviewers extracted information based on the CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modeling Studies checklist and assessed the risk of bias using the Prediction model Risk Of Bias ASsessment Tool.Results: Fifty-six eligible articles were identified, describing the development of 77 prognostic models and 27 external validation efforts. The 77 prognostic models focused on three types of cervical cancer patients at different stages, i.e., patients with early-stage cervical cancer (n = 29; 38%), patients with locally advanced cervical cancer (n = 27; 35%), and all-stage cervical cancer patients (n = 21; 27%). Among the 77 models, the most frequently used predictors were lymph node status (n = 57; 74%), the International Federation of Gynecology and Obstetrics stage (n = 42; 55%), histological types (n = 38; 49%), and tumor size (n = 37; 48%). The number of models that applied internal validation, presented a full equation, and assessed model calibration was 52 (68%), 16 (21%), and 45 (58%), respectively. Twenty-four models were externally validated, among which three were validated twice. None of the models were assessed with an overall low risk of bias. The Prediction Model of Failure in Locally Advanced Cervical Cancer model was externally validated twice, with acceptable performance, and seemed to be the most reliable.Conclusions: Methodological details including internal validation, sample size, and handling of missing data need to be emphasized on, and external validation is needed to facilitate the application and generalization of models for cervical cancer.

γδ T cells are distributed in various lymphoid and nonlymphoid tissues, and act as early responders in many conditions. Previous studies have proven their significant roles in infection, cancer, autoimmune diseases and tissue maintenance. Recently, accumulating researches have highlighted the crosstalk between γδ T cells and nervous systems. In these reports, γδ T cells maintain some physiological functions of central nervous system by secreting interleukin (IL) 17, and neurons like nociceptors can in turn regulate the activity of γδ T cells. Moreover, γδ T cells are involved in neuroinflammation such as stroke and multiple sclerosis. This review illustrates the relationship between γδ T cells and nervous systems in physiological and pathological conditions.

Chimeric antigen receptor (CAR) therapy has been proved effective in a stream of clinical trials, especially in hematologic malignancies. However, current CAR therapy is highly personalized as cells used are derived from patients themselves, which can be costly, time-consuming, and sometimes fails to achieve optimal therapeutic results due to poor quality/quantity of patient-derived cells. On the contrary, universal CAR therapy, which is based on healthy individuals’ cells, circumvents several limitations of current autologous CAR therapy. To achieve the universality of CAR therapy, the allogeneic cell transplantation related issues, such as graft-versus-host disease (GVHD) and host-versus-graft activities (HVGA), must be addressed. In this review, we focus on current progress regarding GVHD and HVGA in the universal CAR therapy, followed by a universal CAR design that may be applied to allogeneic cells and a summary of key clinical trials in this field. This review may provide valuable insights into the future design of universal CAR products.

Objective: to evaluate the risk of treatment-related adverse events of different severity and different system with PD-1 or PD-L1 inhibitors. Methods: randomized controlled trials (RCTs) that using PD-1/PD-L1 for cancer treatment were searched in the PubMed, Embase, Cochrane Library, and Web of Science from 1 January 2019 to 31 May 2021. Adverse events data were extracted from clinical trials website or original article by two authors separately. Meta-analysis was used to determine risk ratio (RR) and 95% confidence interval (95% CI) of adverse events in PD-1/PD-L1 inhibitors groups compared to that of control groups. Subgroup analyses were also performed. Results: a total of 5,807 studies were initially identified and after exclusion, 41 studies were included in meta-analysis. All the trials were international multicenter, randomized, phase II/III clinical trials, with the median follow-up of 27.5 months on average. Analysis of all grade adverse events showed that PD-1/PD-L1 inhibitors treatment significantly increased the risk of immune-related adverse events, including pruritus (RR: 2.34, 95% CI: 1.85–2.96), rash (RR: 1.53, 95% CI: 1.25–1.87), ALT elevation (RR 1.54, 95% CI 1.23–1.92), AST elevation (AST: RR 1.49, 95% CI 1.20–1.85), hepatitis (RR: 3.54, 95% CI: 1.96–6.38) and hypothyroid (RR: 5.29, 95% CI: 4.00–6.99) compared with that of control group. Besides that, PD-1/PD-L1 inhibitors were associated with higher risk of adverse events related to respiratory system including cough (RR: 1.33, 95% CI: 1.21–1.48), dyspnea (RR:1.23, 95% CI: 1.12–1.35) and chest pain (RR: 1.26, 95% CI: 1.07–1.47) compared with that of control groups in our meta-analysis and the dyspnea was taken high risk both in all grade and grade 3 or higher (RR: 1.55, 95% CI: 1.13–2.12). The risk of arthralgia was increased with PD-1/PD-L1 inhibitors (RR: 1.27, 95% CI: 1.10–1.47). Although the risk of myalgia was similar with PD-1/PD-L1 inhibitors and control groups, under subgroup analysis, PD-1/PD-L1 inhibitors decreased the risk of myalgia (RR: 0.56, 95% CI: 0.45–0.70) compared with that of chemotherapy. Conclusions: our results provide clear evidence that the risk of treatment-related adverse events in PD-1 or PD-L1 varies widely in different system. In particular, when using PD-1/PD-L1 inhibitors for oncology treatment, besides the common immune-related adverse events like pruritus, rash, hepatitis, and hypothyroid, the respiratory disorders and musculoskeletal disorders, such as cough, dyspnea, arthralgia, and myalgia, should also be taken into consideration.

The cockroach, Periplaneta americana, is an obnoxious and notorious pest of the world, with a strong ability to adapt to a variety of complex environments. However, the molecular mechanism of this adaptability is mostly unknown. In this study, the genes and microbiota composition associated with the adaptation mechanism were studied by analyzing the transcriptome and 16S rDNA pyrosequencing of the P. americana midgut, respectively. Midgut transcriptome analysis identified 82,905 unigenes, among which 64 genes putatively involved in digestion (11 genes), detoxification (37 genes) and oxidative stress response (16 genes) were found. Evaluation of gene expression following treatment with cycloxaprid further revealed that the selected genes (CYP6J1, CYP4C1, CYP6K1, Delta GST, alpha-amylase, beta-glucosidase and aminopeptidase) were upregulated at least 2.0-fold at the transcriptional level, and four genes were upregulated more than 10.0-fold. An interesting finding was that three digestive enzymes positively responded to cycloxaprid application. Tissue expression profiles further showed that most of the selected genes were midgut-biased, with the exception of CYP6K1. The midgut microbiota composition was obtained via 16S rDNA pyrosequencing and was found to be mainly dominated by organisms from the Firmicutes phylum, among which Clostridiales, Lactobacillales and Burkholderiales were the main orders which might assist the host in the food digestion or detoxification of noxious compounds. The preponderant species, Clostridium cellulovorans, was previously reported to degrade lignocellulose efficiently in insects. The abundance of genes involved in digestion, detoxification and response to oxidative stress, and the diversity of microbiota in the midgut might provide P. americana high capacity to adapt to complex environments.

Acetylcholinesterase (AChE), an important neurotransmitter hydrolase in both invertebrates and vertebrates, is targeted by organophosphorus and carbamate insecticides. In this study, two new AChEs were identified in the pond wolf spider Pardosa pseudoannulata, an important predatory natural enemy of several insect pests. In total, four AChEs were found in P. pseudoannulata (including two AChEs previously identified in our laboratory). The new putative AChEs PpAChE3 and PpAChE4 contain most of the common features of the AChE family, including cysteine residues, choline binding sites, the conserved sequence 'FGESAG' and conserved aromatic residues but with a catalytic triad of 'SDH' rather than 'SEH'. Recombinant enzymes expressed in Sf9 cells showed significant differences in biochemical properties compared to other AChEs, such as the optimal pH, substrate specificity, and catalytic efficiency. Among three test substrates, PpAChE1, PpAChE3 and PpAChE4 showed the highest catalytic efficiency (Vmax/KM) for ATC (acetylthiocholine iodide), with PpAChE3 exhibiting a clear preference for ATC based on the VmaxATC/VmaxBTC ratio. In addition, the four PpAChEs were more sensitive to the AChE-specific inhibitor BW284C51, which acts against ATC hydrolysis, than to the BChE-specific inhibitor ISO-OMPA, which acts against BTC hydrolysis, with at least a 8.5-fold difference in IC50 values for each PpAChE. PpAChE3, PpAChE4, and PpAChE1 were more sensitive than PpAChE2 to the tested Carb insecticides, and PpAChE3 was more sensitive than the other three AChEs to the tested OP insecticides. Based on all the results, two new functional AChEs were identified from P. pseudoannulata. The differences in AChE sequence between this spider and insects enrich our knowledge of invertebrate AChE diversity, and our findings will be helpful for understanding the selectivity of insecticides between insects and natural enemy spiders.

The pond wolf spider Pardosa pseudoannulata, an important natural predatory enemy of rice planthoppers, is found widely distributed in paddy fields. However, data on the genes involved in insecticide action, detoxification, and response are very limited for P. pseudoannulata, which inhibits the development and appropriate use of selective insecticides to control insect pests on rice. We used transcriptome construction from adult spider cephalothoraxes to analyze and manually identify genes enconding metabolic enzymes and target receptors related to insecticide action and detoxification, including 90 cytochrome P450s, 14 glutathione S-transferases (GSTs), 17 acetylcholinesterases (AChEs), 17 nicotinic acetylcholine receptors (nAChRs), and 17 gamma-aminobutyric acid (GABA) receptors, as well as 12 glutamate-gated chloride channel (GluCl) unigenes. Sequence alignment and phylogenetic analysis revealed the different subclassifications of P450s and GSTs, some important sequence diversities in nAChRs and GABA receptors, polymorphism in AChEs, and high similarities in GluCls. For P450s in P. pseudoannulata, the number of unigenes belonging to the CYP2 clade was much higher than that in CYP3 and CYP4 clades. The results differed from insects in which most P450 genes were in CYP3 and CYP4 clades. For GSTs, most unigenes belonged to the delta and sigma classes, and no epsilon GST class gene was found, which differed from the findings for insects and acarina. Our results will be useful for studies on insecticide action, selectivity, and detoxification in the spider and other related animals, and the sequence differences in target genes between the spider and insects will provide important information for the design of selective insecticides.