ERK-activated CK-2 triggers blastema formation during appendage regeneration.

Appendage regeneration relies on the formation of blastema, a heterogeneous cellular structure formed at the injury site. However, little is known about the early injury-activated signaling pathways that trigger blastema formation during appendage regeneration. Here, we provide compelling evidence that the extracellular signal-regulated kinase (ERK)-activated casein kinase 2 (CK-2), which has not been previously implicated in appendage regeneration, triggers blastema formation during leg regeneration in the American cockroach, Periplaneta americana. After amputation, CK-2 undergoes rapid activation through ERK-induced phosphorylation within blastema cells. RNAi knockdown of CK-2 severely impairs blastema formation by repressing cell proliferation through down-regulating mitosis-related genes. Evolutionarily, the regenerative role of CK-2 is conserved in zebrafish caudal fin regeneration via promoting blastema cell proliferation. Together, we find and demonstrate that the ERK-activated CK-2 triggers blastema formation in both cockroach and zebrafish, helping explore initiation factors during appendage regeneration.

Two sex pheromone receptors for sexual communication in the American cockroach.

Volatile sex pheromones are vital for sexual communication between males and females. Females of the American cockroach, Periplaneta americana, produce and emit two sex pheromone components, periplanone-A (PA) and periplanone-B (PB). Although PB is the major sex attractant and can attract males, how it interacts with PA in regulating sexual behaviors is still unknown. In this study, we found that in male cockroaches, PA counteracted PB attraction. We identified two odorant receptors (ORs), OR53 and OR100, as PB/PA and PA receptors, respectively. OR53 and OR100 were predominantly expressed in the antennae of sexually mature males, and their expression levels were regulated by the sex differentiation pathway and nutrition-responsive signals. Cellular localization of OR53 and OR100 in male antennae further revealed that two types of sensilla coordinate a complex two-pheromone-two-receptor pathway in regulating cockroach sexual behaviors. These findings indicate distinct functions of the two sex pheromone components, identify their receptors and possible regulatory mechanisms underlying the male-specific and age-dependent sexual behaviors, and can guide novel strategies for pest management.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

Moderate increase of precipitation stimulates CO2 production by regulating soil organic carbon in a saltmarsh.

Saltmarsh is widely recognized as a blue carbon ecosystem with great carbon storage potential. Yet soil respiration with a major contributor of atmospheric CO2 can offset its carbon sink function. Up to date, mechanisms ruling CO2 emissions from saltmarsh soil remain unclear. In particular, the effect of precipitation on soil CO2 emissions is unclear in coastal wetlands, due the lack of outdoor data in real situations. We conducted a 7-year field manipulation experiment in a saltmarsh in the Yellow River Delta, China. Soil respiration in five treatments (-60%, -40%, +0%, +40%, and + 60% of precipitation) was measured in the field. Topsoils from the last 3 years (2019-2021) were analyzed for CO2 production potential by microcosm experiments. Furthermore, quality and quantity of soil organic carbon and microbial function were tested. Results show that only the moderate precipitation rise of +40% induced a 66.2% increase of CO2 production potential for the microcosm experiments, whereas other data showed a weak impact. Consistently, soil respiration was also found to be strongest at +40%. The CO2 production potential is positively correlated with soil organic carbon, including carbon quantity and quality. But microbial diversity did not show any positive response to precipitation sizes. r-/K-strategy seemed to be a plausible explanation for biological factors. Overall, our finding reveal that a moderate precipitation increase, not decrease or a robust increase, in a saltmarsh is likely to improve soil organic carbon quality and quantity, and bacterial oligotroph:copiotroph ratio, ultimately leading to an enhanced CO2 production.

Two transcriptional cascades orchestrate cockroach leg regeneration.

The mystery of appendage regeneration has fascinated humans for centuries, while the underlying regulatory mechanisms remain unclear. In this study, we establish a transcriptional landscape of regenerating leg in the American cockroach, Periplaneta americana, an ideal model in appendage regeneration studies showing remarkable regeneration capacity. Through a large-scale in vivo screening, we identify multiple signaling pathways and transcription factors controlling leg regeneration. Specifically, zfh-2 and bowl contribute to blastema cell proliferation and morphogenesis in two transcriptional cascades: bone morphogenetic protein (BMP)/JAK-STAT-zfh-2-B-H2 and Notch-drm/bowl-bab1. Notably, we find zfh-2 is working as a direct target of BMP signaling to promote cell proliferation in the blastema. These mechanisms might be conserved in the appendage regeneration of vertebrates from an evolutionary perspective. Overall, our findings reveal that two crucial transcriptional cascades orchestrate distinct cockroach leg regeneration processes, significantly advancing the comprehension of molecular mechanism in appendage regeneration.

Re-Engineering Therapeutic Anti-Aß Monoclonal Antibody to Target Amyloid Light Chain.

Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and ß-amyloid peptide (Aß) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aß antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aß42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aß42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases.

Identity-Based Matchmaking Encryption with Equality Test.

The identity-based encryption with equality test (IBEET) has become a hot research topic in cloud computing as it provides an equality test for ciphertexts generated under different identities while preserving the confidentiality. Subsequently, for the sake of the confidentiality and authenticity of the data, the identity-based signcryption with equality test (IBSC-ET) has been put forward. Nevertheless, the existing schemes do not consider the anonymity of the sender and the receiver, which leads to the potential leakage of sensitive personal information. How to ensure confidentiality, authenticity, and anonymity in the IBEET setting remains a significant challenge. In this paper, we put forward the concept of the identity-based matchmaking encryption with equality test (IBME-ET) to address this issue. We formalized the system model, the definition, and the security models of the IBME-ET and, then, put forward a concrete scheme. Furthermore, our scheme was confirmed to be secure and practical by proving its security and evaluating its performance.

HNetGO: protein function prediction via heterogeneous network transformer.

Protein function annotation is one of the most important research topics for revealing the essence of life at molecular level in the post-genome era. Current research shows that integrating multisource data can effectively improve the performance of protein function prediction models. However, the heavy reliance on complex feature engineering and model integration methods limits the development of existing methods. Besides, models based on deep learning only use labeled data in a certain dataset to extract sequence features, thus ignoring a large amount of existing unlabeled sequence data. Here, we propose an end-to-end protein function annotation model named HNetGO, which innovatively uses heterogeneous network to integrate protein sequence similarity and protein-protein interaction network information and combines the pretraining model to extract the semantic features of the protein sequence. In addition, we design an attention-based graph neural network model, which can effectively extract node-level features from heterogeneous networks and predict protein function by measuring the similarity between protein nodes and gene ontology term nodes. Comparative experiments on the human dataset show that HNetGO achieves state-of-the-art performance on cellular component and molecular function branches.

ActiveZero++: Mixed Domain Learning Stereo and Confidence-Based Depth Completion With Zero Annotation.

Learning-based stereo methods usually require a large scale dataset with depth, however obtaining accurate depth in the real domain is difficult, but groundtruth depth is readily available in the simulation domain. In this article we propose a new framework, ActiveZero++, which is a mixed domain learning solution for active stereovision systems that requires no real world depth annotation. In the simulation domain, we use a combination of supervised disparity loss and self-supervised loss on a shape primitives dataset. By contrast, in the real domain, we only use self-supervised loss on a dataset that is out-of-distribution from either training simulation data or test real data. To improve the robustness and accuracy of our reprojection loss in hard-to-perceive regions, our method introduces a novel self-supervised loss called temporal IR reprojection. Further, we propose the confidence-based depth completion module, which uses the confidence from the stereo network to identify and improve erroneous areas in depth prediction through depth-normal consistency. Extensive qualitative and quantitative evaluations on real-world data demonstrate state-of-the-art results that can even outperform a commercial depth sensor. Furthermore, our method can significantly narrow the Sim2Real domain gap of depth maps for state-of-the-art learning based 6D pose estimation algorithms.

Highly proliferative and hypodifferentiated CAR-T cells targeting B7-H3 enhance antitumor activity against ovarian and triple-negative breast cancers.

Chimeric antigen receptor (CAR)-T cell immunotherapy is highly effective against hematological neoplasms. However, owing to tumor variability, low antigen specificity, and impermanent viability of CAR-T cells, their use in the treatment of solid tumors is limited. Here, a novel CAR-T cell targeting B7-H3 and incorporating a 4-1BB costimulatory molecule with STAT3-and STAT5-related activation motifs was constructed using lentivirus transduction. B7-H3, a tumor-associated antigen, and its scFv antibody endowed CAR-T cells with tumor-specific targeting capabilities. Moreover, the integration of the trIL2RB and YRHQ motifs stimulated STAT5 and STAT3 in an antigen-dependent manner, inducing a remarkable increase in the proliferation and survival of CAR-T cells via the activation of the JAK-STAT signaling pathway. Besides, the proportion of less-differentiated T cells increased among BB-trIL2RB-z(YRHQ) CAR-T cells. Moreover, BB-trIL2RB-z(YRHQ) effectively inhibited ovarian cancer (OC) and triple-negative breast cancer (TNBC) in vivo at low doses, without high serum levels of inflammatory cytokines and organ toxicity. Therefore, our study proposes a combination of elements for the construction of superior pluripotent CAR-T cells to provide an effective strategy for the treatment of intractable solid tumors.

Patients with chronic myeloid leukemia and coronavirus disease 2019 in the Omicron era.

To explore the prevalence and severity of COVID-19 and the mental health during the Omicron pandemic in patients with chronic myeloid leukemia (CML), a cross-sectional survey from 2609 respondents with CML was performed. A total of 1725 (66%) reported that they had COVID-19 during this period. Among them, 1621 (94%) were mild; 97 (6%), moderate; 7 (0.4%), severe; and 0, critical or death. Four hundred three (15%), 199 (8%), and 532 (20%) had moderate to severe depression, anxiety, and distress, respectively. Eight hundred ninety (34%), 667 (26%), and 573 (22%), avoidance, intrusion, and hyper-arousal, respectively. In multivariate analyses, longer TKI-therapy duration was significantly associated with a lower prevalence of COVID-19 (odds ratio [OR] = 0.98; 95% confidence interval [CI], 0.95, 0.99; p = 0.043); however, living in urban areas (OR = 1.6 [1.3, 2.0]; p < 0.001) and having family members with COVID-19 (OR = 18.6 [15.1, 22.8]; p < 0.001), a higher prevalence of COVID-19. Increasing age (OR = 1.2 [1.1, 1.4]; p = 0.009), comorbidity(ies) (OR = 1.7 [1.1, 2.7]; p = 0.010), and multi-TKI-resistant patients receiving 3rd-generation TKIs or investigational agents (OR = 2.2 [1.2, 4.2]; p = 0.010) were significantly associated with moderate or severe COVID-19. Female, comorbidity(ies), unvaccinated, and moderate or severe COVID-19 were significantly associated with almost all adverse mental health consequences; increasing age or forced TKI dose reduction because of various restriction during the pandemic, moderate to severe distress, avoidance, or intrusion; however, mild COVID-19, none or mild anxiety, distress, avoidance, or intrusion. In conclusion, shorter TKI-therapy duration, increasing age, comorbidity(ies), or multi-TKI-resistant patients receiving 3rd-generation TKIs or investigational agents had a higher prevalence of COVID-19 or higher risk of moderate or severe disease in patients with CML; increasing age, female, comorbidity(ies), forced TKI dose reduction due to the pandemic, moderate or severe COVID-19, unvaccinated, a higher likelihood of worse mental health.

Physiological and molecular mechanisms of insect appendage regeneration.

Regeneration, as a fascinating scientific field, refers to the ability of animals replacing lost tissue or body parts. Many metazoan organisms have been reported with the regeneration phenomena, but showing evolutionarily variable abilities. As the most diverse metazoan taxon, hundreds of insects show strong appendage regeneration ability. The regeneration process and ability are dependent on many factors, including macroscopic physiological conditions and microscopic molecular mechanisms. This article reviews research progress on the physiological conditions and internal underlying mechanisms controlling appendage regeneration in insects.

Association between autoimmune diseases of the nervous system and schizophrenia: A systematic review and meta-analysis of cohort studies.

INTRODUCTION: Numerous studies have found an association between autoimmune diseases of the nervous system (ADNS) and schizophrenia (SCZ), but the findings remain controversial. We conducted the first meta-analysis to summarize the current evidence from cohort studies that evaluated the association between ADNS and SCZ. METHODS: PubMed, Web of Science, and Embase were comprehensively searched until May 30, 2022 for articles on the association between ADNS and SCZ. Every included study was reported effect size with 95% CIs for the association between ADNS and SCZ. Meta-regression and subgroup analysis were used to assess the heterogeneity. RESULTS: A total of 8 cohort studies with 12 cohorts were included in the meta-analysis. We observed a significant association between ADNS and SCZ (RR = 1.42; 95%CI, 1.18-1.72). Subgroup analysis showed that the risk of SCZ was significantly increased when ADNS were used as exposure factors (RR = 1.48; 95%CI, 1.15-1.89), whereas with SCZ did not observe an increased risk of subsequent ADNS (RR = 1.33; 95%CI, 0.92-1.92); multiple sclerosis (MS) was positively associated with SCZ (RR = 1.36; 95%CI, 1.12-1.66), but no significant association was found between Guillain-Barre syndrome (GBS) and SCZ (RR = 1.90; 95%CI, 0.87-4.17). Meanwhile, we found location was the source of heterogeneity. LIMITATIONS: High heterogeneity was observed (I2 = 92.0%), and only English literature was included in the meta-analysis. CONCLUSIONS: We found a positive association between ADNS and SCZ, and the association was different across the different types of ADNS. The results of the study are helpful for clinicians to carry out targeted preventive measures for ADNS and SCZ.

Activation of protein arginine methyltransferase 1 and subsequent extension of moth lifespan is effected by the ROS/JNK/CREB signaling axis.

Previous studies have demonstrated that high physiological levels of reactive oxygen species induce pupal diapause and extend lifespan in the moth Helicoverpa armigera. This has been shown to occur via protein arginine methyltransferase 1 (PRMT1) blockade of Akt-mediated phosphorylation of the transcription factor FoxO, after which activated FoxO promotes the initiation of diapause. However, it is unclear how PRMT1 is activated upstream of FoxO activity. Here, we show that high reactive oxygen species levels in the brains of H. armigera diapause-destined pupae activate the expression of c-Jun N-terminal kinase, which subsequently activates the transcription factor cAMP-response element binding protein. We show that cAMP-response element binding protein then directly binds to the PRMT1 promoter and upregulates its expression to prevent Akt-mediated FoxO phosphorylation and downstream FoxO nuclear localization. This novel finding that c-Jun N-terminal kinase promotes FoxO nuclear localization in a PRMT1-dependent manner to regulate pupal diapause reveals a complex regulatory mechanism in extending the healthspan of H. armigera.

CBR1 decreases protein carbonyl levels via the ROS/Akt/CREB pathway to extend lifespan in the cotton bollworm, Helicoverpa armigera.

Reactive oxygen species (ROS) are considered a major cause of ageing and ageing-related diseases through protein carbonylation. Little is known about the molecular mechanisms that confer protection against ROS. Here, we observed that, compared with nondiapause-destined pupae, high protein carbonyl levels are present in the brains of diapause-destined pupae, which is a 'non-ageing' phase in the moth Helicoverpa armigera. Protein carbonyl levels respond to ROS and decrease metabolic activity to induce diapause in order to extend lifespan. However, protein carbonylation in the brains of diapause-destined pupae still occurs at a physiological level compared to young adult brains. We find that ROS activate Akt, and Akt then phosphorylates the transcription factor CREB to facilitate its nuclear import. CREB binds to the promoter of carbonyl reductase 1 (CBR1) and regulates its expression. High CBR1 levels reduce protein carbonyl levels to maintain physiological levels. This is the first report showing that the moth brain can naturally control protein carbonyl levels through a distinct ROS-Akt-CREB-CBR1 pathway to extend lifespan.

Prot2GO: Predicting GO Annotations From Protein Sequences and Interactions.

Protein is the main material basis of living organisms and plays crucial role in life activities. Understanding the function of protein is of great significance for new drug discovery, disease treatment and vaccine development. In recent years, with the widespread application of deep learning in bioinformatics, researchers have proposed many deep learning models to predict protein functions. However, the existing deep learning methods usually only consider protein sequences, and thus cannot effectively integrate multi-source data to annotate protein functions. In this article, we propose the Prot2GO model, which can integrate protein sequence and PPI network data to predict protein functions. We utilize an improved biased random walk algorithm to extract the features of PPI network. For sequence data, we use a convolutional neural network to obtain the local features of the sequence and a recurrent neural network to capture the long-range associations between amino acid residues in protein sequence. Moreover, Prot2GO adopts the attention mechanism to identify protein motifs and structural domains. Experiments show that Prot2GO model achieves the state-of-the-art performance on multiple metrics.

FoxO induces pupal diapause by decreasing TGFß signaling.

Diapause is a form of dormancy used widely by insects to survive adverse seasons. Previous studies have demonstrated that forkhead box O (FoxO) is activated during pupal diapause initiation in the moth Helicoverpa armigera. However, it is unclear how FoxO induces diapause. Here, we show that knockout of FoxO causes H. armigera diapause-destined pupae to channel into nondiapause, indicating that FoxO is a master regulator that induces insect diapause. FoxO activates the ubiquitin-proteasome system (UPS) by promoting ubiquitin c (Ubc) expression via directly binding to the Ubc promoter. Activated UPS decreases transforming growth factor beta (TGFß) receptor signaling via ubiquitination to block developmental signaling to induce diapause. This study significantly advances the understanding of insect diapause by uncovering the detailed molecular mechanism of FoxO.