Efficacy and Safety of Programmed Death 1/Programmed Death-Ligand 1 Plus Cytotoxic T-Lymphocyte-Associated Antigen 4 Inhibitors for Advanced or Metastatic Non-Small Cell Lung Cancer: A Meta-analysis Based on Randomized Controlled Trials.

BACKGROUND: This meta-analysis aims to investigate the efficacy and safety of programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) combined with cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors for patients with advanced or metastatic non-small cell lung cancer (NSCLC). METHODS: Authors conducted a comprehensive search of PubMed, Embase, Cochrane Library, Web of Science, Scopus, and Medline for randomized controlled trials comparing the prognosis and safety of PD-1/PD-L1 plus CTLA-4 inhibitors with other therapies for advanced or metastatic NSCLC. Hazard ratios (HRs) and 95% confidence intervals (CIs) were used as effect sizes. The primary outcomes of this study were overall survival (OS) and progression-free survival. RESULTS: A total of 4943 patients diagnosed with stage III/IV advanced or metastatic NSCLC were included in the analysis of the 6 randomized controlled trials. The results showed that patients receiving dual immunotherapy with PD-1/PD-L1 plus CTLA-4 inhibitors had a longer survival time compared with the control group (HR = 0.88, P = 0.044). However, no statistically significant difference was observed in progression-free survival (HR = 0.95, P = 0.579). Subgroup analysis revealed better OS in the interventional group for patients aged >65 years (HR = 0.88, P = 0.076), smokers (HR = 0.81, P = 0.036), and those with a tumor mutational burden (TMB) ≥20 mut/Mb (HR = 0.66, P < 0.001). Conversely, the control group demonstrated superior OS in patients with TMB <20 mut/Mb (HR = 1.14, P = 0.048). In addition, the statistical results indicated a lower incidence rate of any-grade anemia in the dual immunotherapy group compared with the control group (RR = 0.32, P = 0.04). CONCLUSIONS: This meta-analysis demonstrates the effectiveness and safety of dual immunotherapy with PD-1/PD-L1 plus CTLA-4 inhibitors for treating advanced or metastatic NSCLC. Its efficacy is influenced by certain clinical and pathological factors, such as age, smoking status, and TMB.

The cytokine FAM3B/PANDER is an FGFR ligand that promotes posterior development in Xenopus.

Fibroblast growth factor (FGF)/extracellular signal-regulated kinase (ERK) signaling plays a crucial role in anterior-posterior (A-P) axial patterning of vertebrate embryos by promoting posterior development. In our screens for novel developmental regulators in Xenopus embryos, we identified Fam3b as a secreted factor regulated in ectodermal explants. Family with sequence similarity 3 member B (FAM3B)/PANDER (pancreatic-derived factor) is a cytokine involved in glucose metabolism, type 2 diabetes, and cancer in mammals. However, the molecular mechanism of FAM3B action in these processes remains poorly understood, largely because its receptor is still unidentified. Here we uncover an unexpected role of FAM3B acting as a FGF receptor (FGFR) ligand in Xenopus embryos. fam3b messenger RNA (mRNA) is initially expressed maternally and uniformly in the early Xenopus embryo and then in the epidermis at neurula stages. Overexpression of Xenopus fam3b mRNA inhibited cephalic structures and induced ectopic tail-like structures. Recombinant human FAM3B protein was purified readily from transfected tissue culture cells and, when injected into the blastocoele cavity, also caused outgrowth of tail-like structures at the expense of anterior structures, indicating FGF-like activity. Depletion of fam3b by specific antisense morpholino oligonucleotides in Xenopus resulted in macrocephaly in tailbud tadpoles, rescuable by FAM3B protein. Mechanistically, FAM3B protein bound to FGFR and activated the downstream ERK signaling in an FGFR-dependent manner. In Xenopus embryos, FGFR activity was required epistatically downstream of Fam3b to mediate its promotion of posterior cell fates. Our findings define a FAM3B/FGFR/ERK-signaling pathway that is required for axial patterning in Xenopus embryos and may provide molecular insights into FAM3B-associated human diseases.

Lysosomal degradation of the maternal dorsal determinant Hwa safeguards dorsal body axis formation.

The Spemann and Mangold Organizer (SMO) is of fundamental importance for dorsal ventral body axis formation during vertebrate embryogenesis. Maternal Huluwa (Hwa) has been identified as the dorsal determinant that is both necessary and sufficient for SMO formation. However, it remains unclear how Hwa is regulated. Here, we report that the E3 ubiquitin ligase zinc and ring finger 3 (ZNRF3) is essential for restricting the spatial activity of Hwa and therefore correct SMO formation in Xenopus laevis. ZNRF3 interacts with and ubiquitinates Hwa, thereby regulating its lysosomal trafficking and protein stability. Perturbation of ZNRF3 leads to the accumulation of Hwa and induction of an ectopic axis in embryos. Ectopic expression of ZNRF3 promotes Hwa degradation and dampens the axis-inducing activity of Hwa. Thus, our findings identify a substrate of ZNRF3, but also highlight the importance of the regulation of Hwa temporospatial activity in body axis formation in vertebrate embryos.

Epigenetic regulation of left-right asymmetry by DNA methylation.

DNA methylation is a major epigenetic modification; however, the precise role of DNA methylation in vertebrate development is still not fully understood. Here, we show that DNA methylation is essential for the establishment of the left-right (LR) asymmetric body plan during vertebrate embryogenesis. Perturbation of DNA methylation by depletion of DNA methyltransferase 1 (dnmt1) or dnmt3bb.1 in zebrafish embryos leads to defects in dorsal forerunner cell (DFC) specification or collective migration, laterality organ malformation, and disruption of LR patterning. Knockdown of dnmt1 in Xenopus embryos also causes similar defects. Mechanistically, loss of dnmt1 function induces hypomethylation of the lefty2 gene enhancer and promotes lefty2 expression, which consequently represses Nodal signaling in zebrafish embryos. We also show that Dnmt3bb.1 regulates collective DFC migration through cadherin 1 (Cdh1). Taken together, our data uncover dynamic DNA methylation as an epigenetic mechanism to control LR determination during early embryogenesis in vertebrates.

The relationship between dairy products intake and breast cancer incidence: a meta-analysis of observational studies.

BACKGROUND: The effect of dairy products intake on breast cancer (BC) is highly controversial. This study aims to investigate the relationship between dairy intake and BC incidence. METHODS: A search was carried out in PubMed, EBSCO, Web of Science, and Cochrane Library databases before January 2021. The primary objective was the risk of BC and intake of dairy products were exposure variables. RESULTS: The meta-analysis comprised 36 articles with 1,019,232 participants. Total dairy products have a protective effect on female population (hazard ratio (HR) =0.95, 95% confidence interval (CI) =0.91-0.99, p = 0.019), especially for estrogen receptor-positive (ER+) (HR = 0.79, p = 0.002) and progesterone receptor-positive (PR+) BC (HR = 0.75, p = 0.027). For ER+/PR+ BC, there is a trend of protection, but it has not reached statistical significance (HR = 0.92, p = 0.075). Fermented dairy products can reduce BC risk in postmenopausal population (HR = 0.96, 95%CI = 0.93-0.99, p = 0.021), but have no protective effect on premenopausal population (HR = 0.98, 95%CI = 0.94-1.03, p = 0.52). Non-fermented dairy products have no significant effect on BC occurrence (p > 0.05). High-fat dairy products are harmful to women, without statistical difference (HR = 1.06, 95%CI = 1.00-1.13, p = 0.066). On the contrary, low-fat dairy products can protect the premenopausal population (HR = 0.94, 95%CI = 0.89-1.00, p = 0.048). CONCLUSION: The intake of dairy products can overall reduce BC risk in the female population, but different dairy products have varying effects on different BC subtypes and menopausal status.

KDM3A-mediated demethylation of histone H3 lysine 9 facilitates the chromatin binding of Neurog2 during neurogenesis.

Neurog2 is a crucial regulator of neuronal fate specification and differentiation in vivo and in vitro However, it remains unclear how Neurog2 transactivates neuronal genes that are silenced by repressive chromatin. Here, we provide evidence that the histone H3 lysine 9 demethylase KDM3A facilitates the Xenopus Neurog2 (formerly known as Xngnr1) chromatin accessibility during neuronal transcription. Loss-of-function analyses reveal that KDM3A is not required for the transition of naive ectoderm to neural progenitor cells but is essential for primary neuron formation. ChIP series followed by qPCR analyses reveal that Neurog2 promotes the removal of the repressive H3K9me2 marks and addition of active histone marks, including H3K27ac and H3K4me3, at the NeuroD1 and Tubb2b promoters; this activity depends on the presence of KDM3A because Neurog2, via its C-terminal domain, interacts with KDM3A. Interestingly, KDM3A is dispensable for the neuronal transcription initiated by Ascl1, a proneural factor related to neurogenin in the bHLH family. In summary, our findings uncover a crucial role for histone H3K9 demethylation during Neurog2-mediated neuronal transcription and help in the understanding of the different activities of Neurog2 and Ascl1 in initiating neuronal development.

Conserved gene regulatory module specifies lateral neural borders across bilaterians.

The lateral neural plate border (NPB), the neural part of the vertebrate neural border, is composed of central nervous system (CNS) progenitors and peripheral nervous system (PNS) progenitors. In invertebrates, PNS progenitors are also juxtaposed to the lateral boundary of the CNS. Whether there are conserved molecular mechanisms determining vertebrate and invertebrate lateral neural borders remains unclear. Using single-cell-resolution gene-expression profiling and genetic analysis, we present evidence that orthologs of the NPB specification module specify the invertebrate lateral neural border, which is composed of CNS and PNS progenitors. First, like in vertebrates, the conserved neuroectoderm lateral border specifier Msx/vab-15 specifies lateral neuroblasts in Caenorhabditis elegans Second, orthologs of the vertebrate NPB specification module (Msx/vab-15, Pax3/7/pax-3, and Zic/ref-2) are significantly enriched in worm lateral neuroblasts. In addition, like in other bilaterians, the expression domain of Msx/vab-15 is more lateral than those of Pax3/7/pax-3 and Zic/ref-2 in C. elegans Third, we show that Msx/vab-15 regulates the development of mechanosensory neurons derived from lateral neural progenitors in multiple invertebrate species, including C. elegans, Drosophila melanogaster, and Ciona intestinalis We also identify a novel lateral neural border specifier, ZNF703/tlp-1, which functions synergistically with Msx/vab-15 in both C. elegans and Xenopus laevis These data suggest a common origin of the molecular mechanism specifying lateral neural borders across bilaterians.

A novel role for Ascl1 in the regulation of mesendoderm formation via HDAC-dependent antagonism of VegT.

Maternally expressed proteins function in vertebrates to establish the major body axes of the embryo and to establish a pre-pattern that sets the stage for later-acting zygotic signals. This pre-patterning drives the propensity of Xenopus animal cap cells to adopt neural fates under various experimental conditions. Previous studies found that the maternally expressed transcription factor, encoded by the Xenopus achaete scute-like gene ascl1, is enriched at the animal pole. Asc1l is a bHLH protein involved in neural development, but its maternal function has not been studied. Here, we performed a series of gain- and loss-of-function experiments on maternal ascl1, and present three novel findings. First, Ascl1 is a repressor of mesendoderm induced by VegT, but not of Nodal-induced mesendoderm. Second, a previously uncharacterized N-terminal domain of Ascl1 interacts with HDAC1 to inhibit mesendoderm gene expression. This N-terminal domain is dispensable for its neurogenic function, indicating that Ascl1 acts by different mechanisms at different times. Ascl1-mediated repression of mesendoderm genes was dependent on HDAC activity and accompanied by histone deacetylation in the promoter regions of VegT targets. Finally, maternal Ascl1 is required for animal cap cells to retain their competence to adopt neural fates. These results establish maternal Asc1l as a key factor in establishing pre-patterning of the early embryo, acting in opposition to VegT and biasing the animal pole to adopt neural fates. The data presented here significantly extend our understanding of early embryonic pattern formation.

Expression of the hormonal FGF co-receptor Klotho beta in the Xenopus laevis model.

Klotho beta (Klb), a single-pass transmembrane protein, has been described as a co-receptor for endocrine FGFs, such as FGF15/19 and FGF21, to regulate critical metabolic processes in multiple organs and tissues in adult mice. However, its function during early embryonic development remains largely unknown. In this paper, we evaluated for the first time the expression of klb mRNA during early development of Xenopus laevis by RT-PCR and whole mount in situ hybridization. RT-PCR experiments showed that the expression of klb was initially detected at late gastrula stage followed by a quick increasing and continued expression throughout embryonic development. Whole mount in situ hybridization detected specific expression of klb in many primordial organs at tailbud stage such as liver primordium and pancreatic buds, implying that the hormonal FGF signaling may play a role in the foregut development. The dynamic and specific expression patterns of klb also suggest that Xenopus laevis can serve a convenient model for the function of the hormonal FGF signaling in organogenesis and metabolism regulation during embryonic development.

Compound C induces protective autophagy in human cholangiocarcinoma cells via Akt/mTOR-independent pathway.

Compound C, a well-known inhibitor of AMP-activated protein kinase (AMPK), has been reported to exert antitumor activities in some types of cells. Whether compound C can exert antitumor effects in human cholangiocarcinoma (CCA) remains unknown. Here, we demonstrated that compound C is a potent inducer of cell death and autophagy in human CCA cells. Autophagy inhibitors increased the cytotoxicity of compound C towards human CCA cells, as confirmed by increased LDH release, and PARP cleavage. It is notable that compound C treatment increased phosphorylated Akt, sustained high levels of phosphorylated p70S6K, and decreased mTOR regulated p-ULK1 (ser757). Based on the data that blocking PI3K/Akt or mTOR had no apparent influence on autophagic response, we suggest that compound C induces autophagy independent of Akt/mTOR signaling in human CCA cells. Further study demonstrated that compound C inhibited the phosphorylation of JNK and its target c-Jun. Blocking JNK by SP600125 or siRNA suppressed autophagy induction upon compound C treatment. Moreover, compound C induced p38 MAPK activation, and its inhibition promoted autophagy induction via JNK activation. In addition, compound C induced p53 expression, and its inhibition attenuated compound C-induced autophagic response. Thus, compound C triggers autophagy, at least in part, via the JNK and p53 pathways in human CCA cells. In conclusion, suppresses autophagy could increase compound C sensitivity in human CCA.

Small C-terminal Domain Phosphatase 3 Dephosphorylates the Linker Sites of Receptor-regulated Smads (R-Smads) to Ensure Transforming Growth Factor ß (TGFß)-mediated Germ Layer Induction in Xenopus Embryos.

Germ layer induction is one of the earliest events shortly after fertilization that initiates body formation of vertebrate embryos. In Xenopus, the maternally deposited transcriptional factor VegT promotes the expression of zygotic Nodal/Activin ligands that further form a morphogen gradient along the vegetal-animal axis and trigger the induction of the three germ layers. Here we found that SCP3 (small C-terminal domain phosphatase 3) is maternally expressed and vegetally enriched in Xenopus embryos and is essential for the timely induction of germ layers. SCP3 is required for the full activation of Nodal/Activin and bone morphogenetic protein signals and functions via dephosphorylation in the linker regions of receptor-regulated Smads. Consistently, the linker regions of receptor-regulated Smads are heavily phosphorylated in fertilized eggs, and this phosphorylation is gradually removed when embryos approach the midblastula transition. Knockdown of maternal SCP3 attenuates these dephosphorylation events and the activation of Nodal/Activin and bone morphogenetic protein signals after midblastula transition. This study thus suggested that the maternal SCP3 serves as a vegetally enriched, intrinsic factor to ensure a prepared status of Smads for their activation by the upcoming ligands during germ layer induction of Xenopus embryos.

Ascl1 represses the mesendoderm induction in Xenopus.

Ascl1 is a multi-functional regulator of neural development in invertebrates and vertebrates. Ectopic expression of Ascl1 can generate functional neurons from non-neural somatic cells. The abnormal expression of ASCL1 has been reported in several types of carcinomas. We have previously identified Ascl1 as a crucial maternal regulator of the germ layer pattern formation in Xenopus Functional studies have indicated that the maternally-supplied Ascl1 renders embryonic cells a propensity to adopt neural fates on one hand, and represses the mesendoderm formation on the other. However, it remains unclear how Ascl1 achieves its repressor function during the activation of mesendoderm genes by VegT. Here, we performed series of gain- and loss-of-function experiments and found that: (i) VegT, the maternal mesendoderm determinant in Xenopus, is required for the deposition of H3K27ac and H3K9ac at its target gene loci during mesendoderm induction; (ii) Ascl1 and VegT antagonistically modulate the deposition of acetylated histone marks at mesendoderm gene loci; (iii) Ascl1 overexpression reduces the VegT-occupancy at mesendoderm gene loci; (iv) Ascl1 but not Neurog2 possesses a repressive activity during mesendoderm induction. These findings reveal a novel repressive function for Ascl1 in inhibiting non-neural fates during early Xenopus embryogenesis.

Sebox regulates mesoderm formation in early amphibian embryos.

BACKGROUND: Mix/Bix genes are important regulators of mesendoderm formation during vertebrate embryogenesis. Sebox, an additional member of this gene family, has been implicated in endoderm formation during early embryogenesis in zebrafish. However, it remains unclear whether Sebox plays a unique role in early Xenopus embryos. RESULTS: In this study, we provide evidence that Sebox is uniquely required for the formation of mesoderm during early Xenopus embryogenesis. Sebox is dynamically expressed in the involuted mesoderm during gastrulation. It is activated by Nodal/Activin signaling and modulated by zygotic Wnt/ß-catenin signaling. Overexpression of Sebox perturbs movements during convergent extension and inhibits the expression of mesodermal, but not endodermal, genes induced by Nodal/Activin signaling. Depletion of Sebox using a specific morpholino increases the expression of noncanonical wnt5a, wnt5b, and wnt11b. Depletion of Sebox also up-regulates the expression of pcdh8.2, a paraxial mesoderm-specific protocadherin, in a Wnt11B-dependent manner. Sebox morphants display reduced development of the head and notochord. CONCLUSIONS: Our findings illustrate that Sebox, a unique member of the Mix/Bix gene family, functions downstream of Nodal/Activin signaling and is required for the proper expression of noncanonical Wnt ligands and the normal development of mesoderm in Xenopus.

NEDD4L regulates convergent extension movements in Xenopus embryos via Disheveled-mediated non-canonical Wnt signaling.

During the early vertebrate body plan formation, convergent extension (CE) of dorsal mesoderm and neurectoderm is coordinated by the evolutionarily conserved non-canonical Wnt/PCP signaling. Disheveled (Dvl), a key mediator of Wnt/PCP signaling, is essential for the medial-lateral polarity formation in the cells undergoing convergent extension movements. NEDD4L, a highly conserved HECT type E3 ligase, has been reported to regulate the stability of multiple substrates including Dvl2. Here we demonstrate that NEDD4L is required for the cellular polarity formation and convergent extension in the early Xenopus embryos. Depletion of NEDD4L in early Xenopus embryos results in the loss of mediolateral polarity of the convergent-extending mesoderm cells and the shortened body axis, resembling those defects caused by the disruption of non-canonical Wnt signaling. Depletion of xNEDD4L also blocks the elongation of the animal explants in response to endogenous mesoderm inducing signals and partially compromises the expression of Brachyury. Importantly, reducing Dvl2 expression can largely rescue the cellular polarity and convergent extension defects in NEDD4L-depleted embryos and explants. Together with the data that NEDD4L reduces Dvl2 protein expression in the frog embryos, our findings suggest that regulation of Dvl protein levels by NEDD4L is essential for convergent extension during early Xenopus embryogenesis.

HECT domain-containing E3 ubiquitin ligase NEDD4L negatively regulates Wnt signaling by targeting dishevelled for proteasomal degradation.

Wnt signaling plays a pivotal role in embryogenesis and tissue homeostasis. Dishevelled (Dvl) is a central mediator for both Wnt/ß-catenin and Wnt/planar cell polarity pathways. NEDD4L, an E3 ubiquitin ligase, has been shown to regulate ion channel activity, cell signaling, and cell polarity. Here, we report a novel role of NEDD4L in the regulation of Wnt signaling. NEDD4L induces Dvl2 polyubiquitination and targets Dvl2 for proteasomal degradation. Interestingly, the NEDD4L-mediated ubiquitination of Dvl2 is Lys-6, Lys-27, and Lys-29 linked but not typical Lys-48-linked ubiquitination. Consistent with the role of Dvl in both Wnt/ß-catenin and Wnt/planar cell polarity signaling, NEDD4L regulates the cellular ß-catenin level and Rac1, RhoA, and JNK activities. We have further identified a hierarchical regulation that Wnt5a induces JNK-mediated phosphorylation of NEDD4L, which in turn promotes its ability to degrade Dvl2. Finally, we show that NEDD4L inhibits Dvl2-induced axis duplication in Xenopus embryos. Our work thus demonstrates that NEDD4L is a negative feedback regulator of Wnt signaling.

Deep Kernel Principal Component Analysis for multi-level feature learning.

Principal Component Analysis (PCA) and its nonlinear extension Kernel PCA (KPCA) are widely used across science and industry for data analysis and dimensionality reduction. Modern deep learning tools have achieved great empirical success, but a framework for deep principal component analysis is still lacking. Here we develop a deep kernel PCA methodology (DKPCA) to extract multiple levels of the most informative components of the data. Our scheme can effectively identify new hierarchical variables, called deep principal components, capturing the main characteristics of high-dimensional data through a simple and interpretable numerical optimization. We couple the principal components of multiple KPCA levels, theoretically showing that DKPCA creates both forward and backward dependency across levels, which has not been explored in kernel methods and yet is crucial to extract more informative features. Various experimental evaluations on multiple data types show that DKPCA finds more efficient and disentangled representations with higher explained variance in fewer principal components, compared to the shallow KPCA. We demonstrate that our method allows for effective hierarchical data exploration, with the ability to separate the key generative factors of the input data both for large datasets and when few training samples are available. Overall, DKPCA can facilitate the extraction of useful patterns from high-dimensional data by learning more informative features organized in different levels, giving diversified aspects to explore the variation factors in the data, while maintaining a simple mathematical formulation.

Tree growth and density enhanced, while diversity and spatial clustering reduced soil mycorrhizal C and N sequestration: Strong interaction with soil properties in northeastern China.

In this paper, the effects of species diversity, tree growth, and spatial clustering on mycorrhizal carbon and nitrogen sequestration and the interaction of soil physicochemical properties in Northeast China were investigated. Based on 720 10 m ∗ 10 m plots in Harbin Experimental Forest Farm of Northeast Forestry University, we determined mycorrhizal biomarkers of easily extractable Glomalin-related soil protein (EEG) and total Glomalin-related soil protein (TG). Four plant diversity indices, seven structural metrics, and five soil properties were also measured. We found that: 1) The low tree diversity plots had 1.08-1.23 times higher TG, EEG, TG-N/TN (proportion of N in TG to TN), and TG-C/SOC (proportion of C in TG to SOC) than the high plots. 2) Tree diameter was negatively correlated with EEG and TG, but positively correlated with the EEG and TG contribution to soil TN and SOC. Soil EEG and TG were positively correlated with under-branch height and tree density. W (Uniform Angle Index, higher W indicates more clustering of tree distribution in the plot) was negatively correlated with the above four ratios and positively correlated with EEG/TG. 3) pH was the most powerful explainer for the GRSP variations (6.8 %, strongest negative association with GRSP/TN, R2 > 0.13), followed by soil electrical conductance (6.5 %, positive relation with TG, p < 0.05), AP (3.2 %). 4) Plant diversity mainly affected GRSP traits through the interaction with soils (0.07), tree growth and density directly increased TG, TG-N/TN, and TG-C/SOC, while tree spatial distribution directly reduced TG-N/TN. Our finding highlighted the important effects of tree diversity and forest structural traits on GRSP amount, carbon sequestration, and nutrient retentions, and could support glomalin-related forest soil management of temperate forests in the high-latitude northern hemisphere.

Low Dimensional Trajectory Hypothesis is True: DNNs Can Be Trained in Tiny Subspaces.

Deep neural networks (DNNs) usually contain massive parameters, but there is redundancy such that it is guessed that they could be trained in low-dimensional subspaces. In this paper, we propose a Dynamic Linear Dimensionality Reduction (DLDR) based on the low-dimensional properties of the training trajectory. The reduction method is efficient, supported by comprehensive experiments: optimizing DNNs in 40-dimensional spaces can achieve comparable performance as regular training over thousands or even millions of parameters. Since there are only a few variables to optimize, we develop an efficient quasi-Newton-based algorithm, obtain robustness to label noise, and improve the performance of well-trained models, which are three follow-up experiments that can show the advantages of finding such low-dimensional subspaces. The code is released (Pytorch: https://github.com/nblt/DLDR and Mindspore: https://gitee.com/mindspore/docs/tree/r1.6/docs/sample_code/dimension_reduce_training).

Maternal Mga is required for Wnt signaling and organizer formation in the early Xenopus embryo.

Maternal Wnt11 is both necessary and sufficient for the formation of Spemann organizer in Xenopus embryo. Xnr3 and Siamois have been identified as the direct target genes of maternal Wnt11/ß-catenin during organizer induction. The depletion of maternal XTcf3 resulted in the ectopic expression of Xnr3 and Siamois, suggesting the activity of ß-catenin/XTcf3 is strictly regulated in the early Xenopus embryos. Here, we show that Xenopus mga (Xmga) is a maternal gene required for dorsal axis formation. Overexpression experiments indicate that mouse Mga potentiates the activity of ß-catenin in the induction of organizer-specific genes. Depletion of maternal Xmga results in the dramatic decrease of the expression of organizer genes and ventralization phenotype, indicating that Xmga is required for ß-catenin function and organizer formation. Depletion of XTcf3 cannot rescue organizer gene expression and axis formation in Xmga-depleted embryos, suggesting Xmga is downstream of XTcf3 during organizer induction. We conclude that maternal Xmga is critical for the function of ß-catenin during organizer formation and dorsal development of Xenopus embryo. To our knowledge, this is a report for the first time to implicate Mga in regulating Wnt signaling.

Center-Aware Adversarial Autoencoder for Anomaly Detection.

Anomaly detection based on subspace learning has attracted much attention, in which the compactness of subspace is commonly considered as the core concern. Most related studies directly optimize the distance from the subspace representation to the fixed center, and the influence of the anomaly level of each normal sample is not considered to adjust the normal concentrated areas. In such cases, it is difficult to isolate the normal areas from the anomaly ones by making the subspace compact. To this end, we propose a center-aware adversarial autoencoder (CA-AAE) method, which detects anomaly samples by acquiring more compact and discriminative subspace representations. To fully exploit the subspace information to improve the compactness, anomaly-level description and feature learning are novelly integrated herein by dividing the output space of the encoder into presubspace and postsubspace. In presubspace, the toward-center prior distribution is imposed by the adversarial learning mechanism, and the anomaly level of normal samples can be described from a probabilistic perspective. In postsubspace, a novel center-aware strategy is established to enhance the compactness of the postsubspace, which achieves adaptive adjustment of the normal areas by constructing a weighted center based on the anomaly level. Then, a flexible anomaly score function is constructed in the testing stage, in which both the toward-center loss and the reconstruction loss are combined to balance the information in the learned subspace and the original space. Compared to other related methods, the proposed CA-AAE shows the effectiveness and advantages in numerical experiments.