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Objective Recurrent spontaneous abortion (RSA) is a major pregnancy complication with unclear pathogenesis. This study aims to investigate the role of miR-20b-5p and its downstream target HIF-1α in trophoblast function and RSA pathogenesis. Methods Placental villous tissues from uRSA patients and healthy pregnant women were collected to assess trophoblast migration, invasion, apoptosis, and placental angiogenesis. The expression levels of miR-20b-5p and HIF-1α were analyzed using qPCR, Western blot, and immunohistochemistry. HTR-8/SVneo cells were transfected with miR-20b-5p mimics, si-miR-20b-5p, and si-HIF-1α to evaluate their effects on trophoblast function. Luciferase reporter assays were performed to confirm the regulatory relationship between miR-20b-5p and HIF-1α. Results Trophoblast cells isolated from uRSA patients exhibited impaired trophoblast invasion and increased trophoblast apoptosis, accompanied by increased trophoblast apoptosis. miR-20b-5p was significantly upregulated, whereas HIF-1α expression was downregulated in uRSA placental tissues. Overexpression of miR-20b-5p inhibited trophoblast migration, invasion, and endothelial-like differentiation, while its knockdown enhanced these functions. HIF-1α was identified as a direct target of miR-20b-5p, and its knockdown partially reversed the effects of miR-20b-5p inhibition. Conclusion miR-20b-5p negatively regulates trophoblast function by targeting HIF-1α, contributing to trophoblast dysfunction and RSA pathogenesis. The miR-20b-5p/HIF-1α axis may serve as a potential therapeutic target for RSA.

Plant volatile organic compounds (VOCs) represent a relatively wide class of secondary metabolites. The VOC profiles of seven seaweeds (Grateloupia filicina, Polysiphonia senticulosa, Callithamnion corymbosum, Sargassum thunbergii, Dictyota dichotoma, Enteromorpha prolifera and Ulva lactuca) from the Yellow Sea of China were investigated using multifiber headspace solid phase microextraction coupled with gas chromatography–mass spectrometry (HS-SPME/GC–MS), among them, the VOCs of three red algae Grateloupia filicina, Polysiphonia senticulosa, and Callithamnion corymbosum were first reported. Principal component analysis (PCA) was used to disclose characteristic categories and molecules of VOCs and network pharmacology was performed to predict potential biomedical utilization of candidate seaweeds. Aldehyde was found to be the most abundant VOC category in the present study and (E)-β-ionone was the only compound found to exist in all seven seaweeds. The chemical diversity of aldehydes in E. prolifera suggest its potential application in chemotaxonomy and hinted that divinylbenzene/carboxen/polydimethylsiloxane (DVB/CAR/PDMS) fiber is more suitable for aldehyde extraction. VOCs in D. dichotoma were characterized as sesquiterpenes and diterpenes and the most relevant pharmacological pathway was the neuroactive ligand–receptor interaction pathway, which suggests that D. dichotoma may have certain preventive and therapeutic values in cancer, especially in lung cancer, in addition to neuropsychiatric diseases.

Intrinsically-photosensitive retinal ganglion cells (ipRGCs) are non-rod/non-cone retinal photoreceptors expressing the visual pigment, melanopsin, to detect ambient irradiance for various non-image-forming visual functions. The M1-subtype, amongst the best studied, mediates primarily circadian photoentrainment and pupillary light reflex. Their intrinsic light responses are more prolonged than those of rods and cones even at the single-photon level, in accordance with the typically slower time course of non-image-forming vision. The short (OPN4S) and long (OPN4L) alternatively-spliced forms of melanopsin proteins are both present in M1-ipRGCs, but their functional difference is unclear. We have examined this point by genetically removing the Opn4 gene ( Opn4 −/− ) in mouse and re-expressing either OPN4S or OPN4L singly in Opn4 −/− mice by using adeno-associated virus, but found no obvious difference in their intrinsic dim-flash responses. Previous studies have indicated that two dominant slow steps in M1-ipRGC phototransduction dictate these cells’ intrinsic dim-flash-response kinetics, with time constants (τ 1 and τ 2 ) at room temperature of ~ 2 s and ~ 20 s, respectively. Here we found that melanopsin inactivation by phosphorylation or by β-arrestins may not be one of these two steps, because their genetic disruptions did not prolong the two time constants or affect the response waveform. Disruption of GAP (GTPase-Activating-Protein) activity on the effector enzyme, PLCβ4, in M1-ipRGC phototransduction to slow down G-protein deactivation also did not prolong the response decay, but caused its rising phase to become slightly sigmoidal by giving rise to a third time constant, τ 3 , of ~ 2 s (room temperature). This last observation suggests that GAP-mediated G-protein deactivation does partake in the flash-response termination, although normally with a time constant too short to be visible in the response waveform.

In recent years, human motion prediction has become an active research topic in computer vision. However, owing to the complexity and stochastic nature of human motion, it remains a challenging problem. In previous works, human motion prediction has always been treated as a typical inter-sequence problem, and most works have aimed to capture the temporal dependence between successive frames. However, although these approaches focused on the effects of the temporal dimension, they rarely considered the correlation between different joints in space. Thus, the spatio-temporal coupling of human joints is considered, to propose a novel spatio-temporal network based on a transformer and a gragh convolutional network (GCN) (STTG-Net). The temporal transformer is used to capture the global temporal dependencies, and the spatial GCN module is used to establish local spatial correlations between the joints for each frame. To overcome the problems of error accumulation and discontinuity in the motion prediction, a revision method based on fusion strategy is also proposed, in which the current prediction frame is fused with the previous frame. The experimental results show that the proposed prediction method has less prediction error and the prediction motion is smoother than previous prediction methods. The effectiveness of the proposed method is also demonstrated comparing it with the state-of-the-art method on the Human3.6 M dataset.

SignificanceWe describe here a mammalian ciliary phototransduction mechanism in intrinsically photosensitive retinal ganglion cells that uses cAMP as the second messenger. This is highly unusual because cGMP serves as the second messenger in nearly all ciliary phototransduction mechanisms known so far. Even more surprisingly, Gq is the active G protein upstream, which, via its Gβγq released from the active Gαq, directly stimulates adenylyl cyclase to elevate cAMP and open HCN channels, leading to a membrane depolarization. Although such unconventional cross-motif GPCR signaling has previously been described by others in biochemical experiments with heterologously expressed signaling components in cell lines, our finding demonstrates such direct Gq-to-AC signaling in a native cell with a specific function. Nonimage-forming vision in mammals is mediated primarily by melanopsin (OPN4)-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, melanopsin predominantly activates, via Gαq,11,14, phospholipase C-β4 to open transient receptor 6 (TRPC6) and TRPC7 channels. In M2- and M4-ipRGCs, however, a prominent phototransduction mechanism involves the opening of hyperpolarization- and cyclic nucleotide-gated channels via cyclic nucleotide, although the upstream steps remain uncertain. We report here experiments, primarily on M4-ipRGCs, with photo-uncaging of cyclic nucleotides and virally expressed CNGA2 channels to conclude that the second messenger is cyclic adenosine monophosphate (cAMP) – very surprising considering that cyclic guanosine monophosphate (cGMP) is used in almost all cyclic nucleotide-mediated phototransduction mechanisms across the animal kingdom. We further found that the upstream G protein is likewise Gq, which via its Gβγ subunits directly activates adenylyl cyclase (AC). Our findings are a demonstration in a native cell of a cross-motif GPCR signaling pathway from Gq directly to AC with a specific function.

Nonimage-forming vision in mammals is mediated primarily by melanopsin (OPN4)-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, melanopsin predominantly activates, via Gα q,11,14 , phospholipase C-β4 to open transient receptor 6 (TRPC6) and TRPC7 channels. In M2- and M4-ipRGCs, however, a prominent phototransduction mechanism involves the opening of hyperpolarization- and cyclic nucleotide-gated channels via cyclic nucleotide, although the upstream steps remain uncertain. We report here experiments, primarily on M4-ipRGCs, with photo-uncaging of cyclic nucleotides and virally expressed CNGA2 channels to conclude that the second messenger is cyclic adenosine monophosphate (cAMP) – very surprising considering that cyclic guanosine monophosphate (cGMP) is used in almost all cyclic nucleotide-mediated phototransduction mechanisms across the animal kingdom. We further found that the upstream G protein is likewise G q , which via its Gβγ subunits directly activates adenylyl cyclase (AC). Our findings are a demonstration in a native cell of a cross-motif GPCR signaling pathway from G q directly to AC with a specific function.

Objective Recurrent spontaneous abortion (RSA) is a major pregnancy complication with unclear pathogenesis. This study aims to investigate the role of miR-20b-5p and its downstream target HIF-1[alpha] in trophoblast function and RSA pathogenesis. Methods Placental villous tissues from uRSA patients and healthy pregnant women were collected to assess trophoblast migration, invasion, apoptosis, and placental angiogenesis. The expression levels of miR-20b-5p and HIF-1[alpha] were analyzed using qPCR, Western blot, and immunohistochemistry. HTR-8/SVneo cells were transfected with miR-20b-5p mimics, si-miR-20b-5p, and si-HIF-1[alpha] to evaluate their effects on trophoblast function. Luciferase reporter assays were performed to confirm the regulatory relationship between miR-20b-5p and HIF-1[alpha]. Results Trophoblast cells isolated from uRSA patients exhibited impaired trophoblast invasion and increased trophoblast apoptosis, accompanied by increased trophoblast apoptosis. miR-20b-5p was significantly upregulated, whereas HIF-1[alpha] expression was downregulated in uRSA placental tissues. Overexpression of miR-20b-5p inhibited trophoblast migration, invasion, and endothelial-like differentiation, while its knockdown enhanced these functions. HIF-1[alpha] was identified as a direct target of miR-20b-5p, and its knockdown partially reversed the effects of miR-20b-5p inhibition. Conclusion miR-20b-5p negatively regulates trophoblast function by targeting HIF-1[alpha], contributing to trophoblast dysfunction and RSA pathogenesis. The miR-20b-5p/HIF-1[alpha] axis may serve as a potential therapeutic target for RSA. Keywords: Recurrent spontaneous abortion, Trophoblast, MiR-20b-5p, HIF-1[alpha]

Nonimage-forming vision in mammals is mediated primarily by melanopsin (OPN4)- expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs). In mouse M1-ipRGCs, melanopsin predominantly activates, via Gαq,11,14, phospholipase C-β4 to open transient receptor 6 (TRPC6) and TRPC7 channels. In M2- and M4-ipRGCs, however, a prominent phototransduction mechanism involves the opening of hyperpolarization- and cyclic nucleotide-gated channels via cyclic nucleotide, although the upstream steps remain uncertain. We report here experiments, primarily on M4-ipRGCs, with photo-uncaging of cyclic nucleotides and virally expressed CNGA2 channels to conclude that the second messenger is cyclic adenosine monophosphate (cAMP) – very surprising considering that cyclic guanosine monophosphate (cGMP) is used in almost all cyclic nucleotide-mediated phototransduction mechanisms across the animal kingdom. We further found that the upstream G protein is likewise Gq, which via its Gβγ subunits directly activates adenylyl cyclase (AC). Our findings are a demonstration in a native cell of a cross-motif GPCR signaling pathway from Gq directly to AC with a specific function.

China's economy has been rapidly growing over the past few decades; however, increasingly more modern cities are facing problems caused by poor city planning, such as traffic networks, resource distribution and routine management. Optimization methods are urgently needed during city development. From location planning perspective, the residential area issue is discussed in this paper. Based on this issue, a numerical-analysis-based method is proposed for selecting proper residential areas in grid transportation networks. First, a grid layout is introduced to formalize a real traffic network. Furthermore, to guarantee its approximation, a considerable amount of data are obtained from real-world scenarios based on the shortest routes to demonstrate the problem of traffic jams. Then, a quantitative evaluation system is proposed, which quantitatively evaluates the specified location with the traffic flow distribution index, traffic congestion index and infrastructure convenience index. Each index reflects the attitude of citizens from a unique perspective, which affects the final location planning and selection. Finally, an analytic hierarchy process is designed to analyse all these indices together for a comprehensive analysis, and case studies and experiments are conducted to demonstrate the effectiveness of the proposed method. The generated residential location can be considered as a technical reference for further city planning and development decisions.

Macrophages play pivotal roles in development, homeostasis, tissue repair and immunity. Macrophage prolifera tion is promoted by macrophage colonystimulating factor （MCSF）induced Akt signaling; yet, how this process is terminated remains unclear. Here, we identify casein kinase 2interacting protein1 （CKIP1） as a novel inhibitor of macrophage proliferation. In resting macrophages, CKIP1 was phosphorylated at Serine 342 by constitutively active GSK3β, the downstream target of Akt. This phosphorylation triggers the polyubiquitination and proteasomal degra dation of CKIP1. Upon MCSF stimulation, Akt is activated by CSF1RPI3K and then inactivates GSIOp, leading to the stabilization of CKIP1 and β-catenin proteins, pcatenin promotes the expression of proliferation genes in cluding cyclin D and cMyc. CKIP1 interacts with TRAF6, a ubiquitin ligase required for K631inked ubiquitination and plasma membrane recruitment of Akt, and terminates TRAF6mediated Akt activation. By this means, CKIP1 inhibits macrophage proliferation specifically at the late stage after MCSF stimulation. Furthermore, CKIP1 defi ciency results in increased proliferation and decreased apoptosis of macrophages in vitro and CKIP-1/ mice sponta neously develop a macrophagedominated splenomegaly and myeloproliferation. Together, these data demonstrate that CKIP-1 plays a critical role in the regulation of macrophage homeostasis by inhibiting TRAF6-mediated Akt activation.