MicroRNA and transcription factor co-regulatory network analysis reveals miR-19 inhibits CYLD in T-cell acute lymphoblastic leukemia

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. The understanding of its gene expression regulation and molecular mechanisms still remains elusive. Started from experimentally verified T-ALL-related miRNAs and genes, we obtained 120 feed-forward loops (FFLs) among T-ALL-related genes, miRNAs and TFs through combining target prediction. Afterwards, a T-ALL miRNA and TF co-regulatory network was constructed, and its significance was tested by statistical methods. Four miRNAs in the miR-17–92 cluster and four important genes (CYLD, HOXA9, BCL2L11 and RUNX1) were found as hubs in the network. Particularly, we found that miR-19 was highly expressed in T-ALL patients and cell lines. Ectopic expression of miR-19 represses CYLD expression, while miR-19 inhibitor treatment induces CYLD protein expression and decreases NF-κB expression in the downstream signaling pathway. Thus, miR-19, CYLD and NF-κB form a regulatory FFL, which provides new clues for sustained activation of NF-κB in T-ALL. Taken together, we provided the first miRNA-TF co-regulatory network in T-ALL and proposed a model to demonstrate the roles of miR-19 and CYLD in the T-cell leukemogenesis. This study may provide potential therapeutic targets for T-ALL and shed light on combining bioinformatics with experiments in the research of complex diseases

Winter hibernation and UCHL1-p34cdc2 association in toad oocyte maturation competence.

Currently, it is believed that toad oocyte maturation is dependent on the physiological conditions of winter hibernation. Previous antibody-blocking experiments have demonstrated that toad ubiquitin carboxyl-terminal hydrolase L1 (tUCHL1) is necessary for germinal vesicle breakdown during toad oocyte maturation. In this paper, we first supply evidence that tUCHL1 is highly evolutionarily conserved. Then, we exclude protein availability and ubiquitin carboxyl-terminal hydrolase enzyme activity as factors in the response of oocytes to winter hibernation. In the context of MPF (maturation promoting factor) controlling oocyte maturation and to further understand the role of UCHL1 in oocyte maturation, we performed adsorption and co-immunoprecipitation experiments using toad oocyte protein extracts and determined that tUCHL1 is associated with MPF in toad oocytes. Recombinant tUCHL1 absorbed p34(cdc2), a component of MPF, in obviously larger quantities from mature oocytes than from immature oocytes, and p13(suc1) was isolated from tUCHL1 with a dependence on the ATP regeneration system, suggesting that still other functions may be involved in their association that require phosphorylation. In oocytes from hibernation-interrupted toads, the p34(cdc2) protein level was significantly lower than in oocytes from toads in artificial hibernation, providing an explanation for the different quantities isolated by recombinant tUCHL1 pull-down and, more importantly, identifying a mechanism involved in the toad oocyte's dependence on a low environmental temperature during winter hibernation. Therefore, in toads, tUCHL1 binds p34(cdc2) and plays a role in oocyte maturation. However, neither tUCHL1 nor cyclin B1 respond to low temperatures to facilitate oocyte maturation competence during winter hibernation

Impact of Anthropogenic Activities and Sea Level Rise on a Lagoon System:Model and Field Observations

The long-term geomorphological evolution of a coastal lagoon is driven by hydrodynamic forcing and is influenced by climate changes and human activities. In this study, a numerical model of the Qilihai lagoon (QL) system was established based on field measurements, previous hydrology data and satellite remote sensing measurements, to simulate the geomorphological evolution of QL from 1900 to 2018. The influences of sea level rise, runoff and human activities on the evolution of geomorphology were investigated. The results of the model show that the construction projects including the tide gate, the bridge, reclamation and the straightening or widening of the tidal channel increased the net deposition within the QL system. Furthermore, the spatial distribution of tidal asymmetry during the natural time period was similar to that of the change in bed thickness. However, bed erosion or deposition was not only dependent on tidal asymmetry but it was also affected by the external sediment supply and the discharge of upstream rivers. Moreover, sea level rise had a significant effect on the tidal asymmetry; therefore, it enhanced the accumulation of sediments in the QL system, while runoff had little effect on the tidal asymmetry or geomorphological changes in the system

Influence Mechanism of Geomorphological Evolution in a Tidal Lagoon with Rising Sea Level

A tidal lagoon system has multiple environmental, societal, and economic implications. To investigate the mechanism of influence of the geomorphological evolution of a tidal lagoon, the effect of critical erosion shear stress, critical deposition shear stress, sediment settling velocity, and initial bed elevation were assessed by applying the MIKE hydro- and morpho-dynamic model to a typical tidal lagoon, Qilihai Lagoon. According to the simulation results, without sediment supply, an increase of critical erosion, deposition shear stress, or sediment settling velocity gives rise to tidal networks with a stable terrain. Such an equilibrium state can be defined as when the change of net erosion has little variation, which can be achieved due to counter actions between the erosion and deposition effect. Moreover, the influence of the initial bed elevation depends on the lowest tidal level. When the initial bed elevation is below the lowest tidal level, the tidal networks tend to be fully developed. A Spearman correlation analysis indicated that the geomorphological evolution is more sensitive to critical erosion or deposition shear stress than sediment settling velocity and initial bed elevation. Exponential sea level rise contributes to more intensive erosion than the linear or the parabolic sea level rise in the long-term evolution of a tidal lagoon

Hypothalamic Control of Conspecific Self-Defense

Summary: Active defense against a conspecific aggressor is essential for survival. Previous studies revealed strong c-Fos expression in the ventrolateral part of the ventromedial hypothalamus (VMHvl) in defeated animals. Here, we examined the functional relevance and in vivo responses of the VMHvl during conspecific defense. We found that VMHvl cells expressing estrogen receptor α (Esr1) are acutely excited during active conspecific defense. Optogenetic inhibition of the cells compromised an animal’s ability to actively defend against an aggressor, whereas activating the cells elicited defense-like behaviors. Furthermore, the VMHvl is known for its role in aggression. In vivo recording and c-Fos mapping revealed differential organization of the defense and aggression-responsive cells in the VMHvl. Specifically, defense-activated cells are concentrated in the anterior part of the VMHvl, which preferentially targets the periaqueductal gray (PAG). Thus, our study identified an essential neural substrate for active conspecific defense and expanded the function of the VMHvl. : Active defense against conspecific aggressors is essential for survival, but its underlying neural substrates remain largely unknown. Through a series of in vivo recordings and functional manipulations, Wang et al. demonstrate that cells expressing estrogen receptor α in a small medial hypothalamic nucleus are essential for defense against a bully. Keywords: ventromedial hypothalamus, self-defense, aggression, estrogen receptor alpha, neural circui

Downregulation of SPARC expression inhibits the invasion of human trophoblast cells in vitro.

Successful pregnancy depends on the precise regulation of extravilloustrophoblast (EVT) invasion into the uterine decidua. SPARC (secreted protein acidic and rich in cysteine) is a matricellular glycoprotein that plays critical roles in the pathologies associated with obesity and diabetes, as well as tumorigenesis. The objective of this study was to investigate the role of SPARC in the process of trophoblast invasion which shares many similarities with tumor cell invasion. By Western blot, higher expression of SPARC was observed in mouse brain, ovary and uterus compared to other mouse tissues. Immunohistochemistry analysis revealed a spatio-temporal expression of SPARC in mouse uterus in the periimplantation period. At the implantation site of d8 pregnancy, SPARC mainly accumulated in the secondary decidua zone (SDZ), trophoblast cells and blastocyst. The expression of SPARC was also detected in human placental villi and trophoblast cell lines. In a Matrigel invasion assay, we found SPARC-specific RNA interference significantly reduced the invasion of human extravilloustrophoblast HTR8/SVneo cells. Microarray analysis revealed that SPARC depletion upregulated the expression of interleukin 11 (IL11), KISS1, insulin-like growth factor binding protein 4 (IGFBP4), collagen type I alpha 1 (COLIA1), matrix metallopeptidase 9 (MMP9), and downregulated the expression of the alpha polypeptide of chorionic gonadotropin (CGA), MMP1, gap junction protein alpha 1 (GJA1), et al. The gene array result was further validated by qRT-PCR and Western blot. The present data indicate that SPARC may play an important role in the regulation of normal placentation by promoting the invasion of trophoblast cells into the uterine decidua

CoreRec: A Counterfactual Correlation Inference for Next Set Recommendation

Next set recommendation aims to predict the items that are likely to be bought in the next purchase. Central to this endeavor is the task of capturing intra-set and cross-set correlations among items. However, the modeling of cross-set correlations poses challenges due to specific issues. Primarily, these correlations are often implicit, and the prevailing approach of establishing an indiscriminate link across the entire set of objects neglects factors like purchase frequency and correlations between purchased items. Such hastily formed connections across sets introduce substantial noise. Additionally, the preeminence of high-frequency items in numerous sets could potentially overshadow and distort correlation modeling with respect to low-frequency items. Thus, we devoted to mitigating misleading inter-set correlations. With a fresh perspective rooted in causality, we delve into the question of whether correlations between a particular item and items from other sets should be relied upon for item representation learning and set prediction. Technically, we introduce the Counterfactual Correlation Inference framework for next set recommendation, denoted as CoreRec. This framework establishes a counterfactual scenario in which the recommendation model impedes cross-set correlations to generate intervened predictions. By contrasting these intervened predictions with the original ones, we gauge the causal impact of inter-set neighbors on set prediction—essentially assessing whether they contribute to spurious correlations. During testing, we introduce a post-trained switch module that selects between set-aware item representations derived from either the original or the counterfactual scenarios. To validate our approach, we extensively experiment using three real-world datasets, affirming both the effectiveness of CoreRec and the cogency of our analytical approach