eIF3a: A new anticancer drug target in the eIF family

eIF3a is the largest subunit of eIF3, which is a key player in all steps of translation initiation. During the past years, eIF3a is recognized as a proto-oncogene, which is an important discovery in this field. It is widely reported to be correlated with cancer occurrence, metastasis, prognosis, and therapeutic response. Recently, the mechanisms of eIF3a action in the carcinogenesis are unveiled gradually. A number of cellular, physiological, and pathological processes involving eIF3a are identified. Most importantly, it is emerging as a new potential drug target in the eIF family, and some small molecule inhibitors are being developed. Thus, we perform a critical review of recent advances in understanding eIF3a physiological and pathological functions, with specific focus on its role in cancer and anticancer drug targets

eIF3 Regulation of Protein Synthesis, Tumorigenesis, and Therapeutic Response

Translation initiation is the rate-limiting step of protein synthesis and highly regulated. Eukaryotic initiation factor 3 (eIF3) is the largest and most complex initiation factor consisting of 13 putative subunits. A growing number of studies suggest that eIF3 and its subunits may represent a new group of proto- oncogenes and associates with prognosis. They regulate translation of a subset of mRNAs involved in many cellular processes including proliferation, apoptosis, DNA repair, and cell cycle. Therefore, unveiling the mechanisms of eIF3 action in tumorigenesis may help identify attractive targets for cancer therapy. Here, we describe a series of methods used in the study of eIF3 function in regulating protein synthesis, tumorigenesis, and cellular response to therapeutic treatments

The Expression of CD14 +

Blood stasis syndrome (BSS), a comprehensive pathological state, is one of the traditional Chinese medicine syndromes of coronary heart disease (CHD). In our previous study, we investigated that FcγRIIIA (also called CD14+CD16+ monocyte subpopulation) is one of the differentially expressed genes related to CHD patients and its possible role in the atherosclerotic formation and plaque rupture. However, whether or not the deregulation of CD14+CD16+ monocyte subpopulation expression is implicated in the pathogenesis of CHD patients with BSS has not yet been elucidated. In this study, we found that there was no significant difference between CHD patients with BSS and non-BSS in CD14+CD16+ monocyte subpopulation at gene level. Moreover, the protein level of CD14+CD16+ monocyte subpopulation in CHD patients with BSS was increased significantly when compared to the CHD patients with non-BSS. Additionally, the level of inflammatory cytokines downstream of CD14+CD16+ monocyte subpopulation such as TNF-α and IL-1 in sera was much higher in CHD patients with BSS than that in CHD patients with non-BSS. Taken together, these results indicated that CD14+CD16+ monocyte subpopulation was implicated in the pathogenesis of CHD patients with BSS, which may be one of the bases of the essence of BSS investigation

EphB2 represents an independent prognostic marker in patients with gastric cancer and promotes tumour cell aggressiveness

Dysregulated expression of ephrin type-B receptor 2 (EphB2) has been linked with development and progression of solid tumours. In the current study we attempted to investigate the clinical relevance in GC and the effect of EphB2 expression on gastric cancer (GC) cells. EphB2 protein levels in GC and benign gastric tissues were determined using immunohistochemistry. EphB2 transcript expression in a GC cohort with GC tissue samples (n=171) and paired adjacent normal gastric tissues (n=97) was determined using qPCR. The EphB2 expression was over-activated using a CRISPR activator for the investigation of its cellular function. The expression levels of the EphB2 protein in the tumour tissues of tissue arrays were higher than the benign non-cancerous gastric tissues (P<0.05). EphB2 mRNA expression in GC tissues was also significantly elevated when compared with adjacent non-cancerous tissues (P<0.01). EphB2 activation promoted the migration and invasion abilities of the GC cell lines (P<0.01, respectively). In contrast, EphB2 activation significantly decreased the adhesion in GC cells (P<0.0001, respectively). The enrichment analysis of the correlated genes in a GC cohort indicates that EphB2 may function through mediating the cytokine-cytokine interaction, JAK-STAT and TP53 signaling pathways. In conclusion, EphB2 represents as a novel independent prognostic marker in GC. And activation of the EphB2 gene expression elevated the levels of migration and invasion, but suppressed adhesion of GC cells, indicating that EphB2 may act as a tumour promotor in GC. Our findings thus provide fundamental evidence for the consideration of the therapeutic potential of targeting EphB2 in GC

Mega-TTS: Zero-Shot Text-to-Speech at Scale with Intrinsic Inductive Bias

Scaling text-to-speech to a large and wild dataset has been proven to be highly effective in achieving timbre and speech style generalization, particularly in zero-shot TTS. However, previous works usually encode speech into latent using audio codec and use autoregressive language models or diffusion models to generate it, which ignores the intrinsic nature of speech and may lead to inferior or uncontrollable results. We argue that speech can be decomposed into several attributes (e.g., content, timbre, prosody, and phase) and each of them should be modeled using a module with appropriate inductive biases. From this perspective, we carefully design a novel and large zero-shot TTS system called Mega-TTS, which is trained with large-scale wild data and models different attributes in different ways: 1) Instead of using latent encoded by audio codec as the intermediate feature, we still choose spectrogram as it separates the phase and other attributes very well. Phase can be appropriately constructed by the GAN-based vocoder and does not need to be modeled by the language model. 2) We model the timbre using global vectors since timbre is a global attribute that changes slowly over time. 3) We further use a VQGAN-based acoustic model to generate the spectrogram and a latent code language model to fit the distribution of prosody, since prosody changes quickly over time in a sentence, and language models can capture both local and long-range dependencies. We scale Mega-TTS to multi-domain datasets with 20K hours of speech and evaluate its performance on unseen speakers. Experimental results demonstrate that Mega-TTS surpasses state-of-the-art TTS systems on zero-shot TTS, speech editing, and cross-lingual TTS tasks, with superior naturalness, robustness, and speaker similarity due to the proper inductive bias of each module. Audio samples are available at https://mega-tts.github.io/demo-page

Intra-annual carbon fluxes and resource use efficiency of subtropical urban forests: insights from Chongming Island ecological observatory

Understanding the carbon budget within cities is crucial in the context of carbon peaking and carbon neutrality. This study investigates the carbon source-sink dynamics of urban forest ecosystems using carbon flux observations from the Chongming Island Ecological Observatory in Shanghai. The study aims to reveal the intra-annual variations of carbon fluxes and explore the changes in resource use efficiency of urban forest ecosystems within the framework of the big-leaf model. The results reveal distinct patterns in temperature (Tair), relative humidity (RH), radiation, and vapor pressure deficit (VPD). Diurnal cycles of net ecosystem exchange (NEE), gross primary production (GPP), and ecosystem respiration (Reco) exhibit seasonal variations, with higher amplitudes observed from April to September. The observed forest ecosystem acts as a moderate carbon sink (318.47 gC m−2 year−1), with the highest carbon uptake occurring in May and the highest carbon emission in February. During the growing season, the total carbon sink was 225.37 gC m−2, composed of GPP 1337.01 gC m−2 and Reco 1111.64 gC m−2. Water-use efficiency (WUE) and light-use efficiency (LUE) exhibit seasonal variations, while carbon-use efficiency (CUE) declines after May. These findings contribute to our understanding of urban forest carbon dynamics and their potential role in carbon management strategies

Plexin-B1 silencing inhibits ovarian cancer cell migration and invasion

BACKGROUND: Elevated Plexin-B1 expression has been found in diverse human cancers and in non-neoplastic tissues, and it mediates diverse biological and pathological activities. However, whether or not Plexin-B1 expression is involved in human ovarian tumors remains unclear. In the present study, Plexin-B1 expression was explored in benign and malignant human ovarian tumor tissues. In addition, the impact of Plexin-B1 expression on ovarian cancer cell proliferation, migration and invasion were investigated in vitro. METHODS: Plexin-B1 expression was analyzed in normal and benign ovarian tissues and serous ovarian tumors (both borderline and malignant) by immunohistochemical staining, as well as in four human ovarian cancer cell lines (A2780, C13*, SKOV3, and OV2008) by RT-PCR and western blot analyses. Furthermore, endogenous Plexin-B1 expression was suppressed by Plexin-B1 siRNA in SKOV3 cells, which overexpress Plexin-B1. Protein levels of Plexin-B1, AKT and AKT(Ser473 )were examined by western blot analysis. Cell proliferation, migration and invasion were measured with MTT, wound healing and boyden chamber assays, respectively, and the cytoskeleton was monitored via F-actin staining. RESULTS: Expression levels of Plexin-B1 protein were significantly higher in serous ovarian carcinomas than in normal ovaries or benign ovarian neoplasms, and in the former, Plexin-B1 expression was positively correlated with lymphatic metastasis, and the membrane and cytoplasm of cancer cells stained positively. SKOV3 cells displayed the highest Plexin-B1 expression at both the mRNA and protein levels among the four tested human ovarian cancer cell lines and was selected as a cell model for further in vitro experiments. Plexin-B1 siRNA significantly suppressed phosphorylation of AKT at Ser473 in SKOV3 cells, but it did not alter total AKT expression. In addition, silencing of Plexin-B1 in SKOV3 cells inhibited cell migration and invasion and reorganized the cytoskeleton, whereas cell proliferation was not affected. CONCLUSION: Plexin-B1 expression correlates with malignant phenotypes of serous ovarian tumors, probably via phosphorylation of AKT at Ser473, suggesting that Plexin-B1 might be a useful biomarker and/or a novel therapeutic target

Differences in regional homogeneity between patients with Crohn's disease with and without abdominal pain revealed by resting-state functional magnetic resonance imaging

Abnormal pain processing in the central nervous system may be related to abdominal pain in patients with Crohn's disease (CD). The purpose of this study was to investigate changes in resting-state brain activity in patients with CD in remission and its relationship with the presence of abdominal pain. Twenty-five patients with CD and with abdominal pain, 25 patients with CD and without abdominal pain, and 32 healthy subjects were scanned using a 3.0-T functional magnetic resonance imaging scanner. Regional homogeneity (ReHo) was used to assess resting-state brain activity. Daily pain scores were collected 1 week before functional magnetic resonance imaging. We found that patients with abdominal pain exhibited lower ReHo values in the insula, middle cingulate cortex (MCC), and supplementary motor area and higher ReHo values in the temporal pole. In contrast, patients without abdominal pain exhibited lower ReHo values in the hippocampal/parahippocampal cortex and higher ReHo values in the dorsomedial prefrontal cortex (all P < 0.05, corrected). The ReHo values of the insula and MCC were significantly negatively correlated with daily pain scores for patients with abdominal pain (r = -0.53, P = 0.008 and r = -0.61, P = 0.002, respectively). These findings suggest that resting-state brain activities are different between remissive patients with CD with and without abdominal pain and that abnormal activities in insula and MCC are closely related to the severity of abdominal pain

Discovery of charge density wave in a correlated kagome lattice antiferromagnet

A hallmark of strongly correlated quantum materials is the rich phase diagram resulting from competing and intertwined phases with nearly degenerate ground state energies. A well-known example is the copper oxides, where a charge density wave (CDW) is ordered well above and strongly coupled to the magnetic order to form spin-charge separated stripes that compete with superconductivity. Recently, such rich phase diagrams have also been revealed in correlated topological materials. In two-dimensional kagome lattice metals consisting of corner-sharing triangles, the geometry of the lattice can produce flat bands with localized electrons, non-trivial topology, chiral magnetic order, superconductivity and CDW order. While CDW has been found in weakly electron correlated nonmagnetic AV3Sb5 (A = K, Rb, Cs), it has not yet been observed in correlated magnetic ordered kagome lattice metals. Here we report the discovery of CDW within the antiferromagnetic (AFM) ordered phase of kagome lattice FeGe. The CDW in FeGe occurs at wavevectors identical to that of AV3Sb5, enhances the AFM ordered moment, and induces an emergent anomalous Hall effect. Our findings suggest that CDW in FeGe arises from the combination of electron correlations-driven AFM order and van Hove singularities-driven instability possibly associated with a chiral flux phase, in stark contrast to strongly correlated copper oxides and nickelates, where the CDW precedes or accompanies the magnetic order.Comment: 36 pages, 4 figures in main tex