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Metal tolerance protein (MTP) is a cation transporter that plays an important role in tolerance to heavy metal stress. However, thus far, there has been no genome-wide investigation of the MTP gene family in Quercus plants. Quercus dentata is one of the main constructive species of forest in northern China. It has strong tolerance to a variety of heavy metal stresses. In this study, 25 MTPs were identified from the Q. dentata genome and classified into three subfamilies and seven groups according to their sequence characteristics and phylogenetic relationships. Both tandem and segmental duplication events contributed to the expansion of the QdMTP gene family. Interestingly, all 10 tandem duplication events contributed to the expansion of the Mn-CDF subfamily. The expression of Mn-CDF subfamily members in different organs and tissues of Q. dentata was different, and they responded differently to manganese, iron, zinc and cadmium stress treatments. QdMTP10.7, a member of the Mn-CDF subfamily, enhanced yeast growth under manganese, zinc and iron stresses. The subcellular localization in tobacco leaf epidermis cells showed that QdMTP10.7 was located in vacuoles. These data generated from this study provide an important foundation to elucidate the biological roles of QdMTP genes related to heavy metal tolerance in Q. dentata.
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UFMylation is a highly conserved ubiquitin-like post-translational modification that catalyzes the covalent linkage of UFM1 to its target proteins. This modification plays a critical role in the maintenance of endoplasmic reticulum proteostasis, DNA damage response, autophagy, and transcriptional regulation. Mutations in UFM1, as well as in its specific E1 enzyme UBA5 and E2 enzyme UFC1, have been genetically linked to microcephaly. Our previous research unveiled the important role of UFMylation in regulating mitosis. However, the underlying mechanisms have remained unclear due to the limited identification of substrates. In this study, we identified Eg5, a motor protein crucial for mitotic spindle assembly and maintenance, as a novel substrate for UFMylation and identified Lys564 as the crucial UFMylation site. UFMylation did not alter its transcriptional level, phosphorylation level, or protein stability, but affected the mono-ubiquitination of Eg5. During mitosis, Eg5 and UFM1 co-localize at the centrosome and spindle apparatus, and defective UFMylation leads to diminished spindle localization of Eg5. Notably, the UFMylation-defective Eg5 mutant (K564R) exhibited shorter spindles, metaphase arrest, spindle checkpoint activation, and a failure of cell division in HeLa cells. Overall, Eg5 UFMylation is essential for proper spindle organization, mitotic progression, and cell proliferation.
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Cinesinas , Mitose , Fuso Acromático , Ubiquitinação , Humanos , Fuso Acromático/metabolismo , Células HeLa , Cinesinas/metabolismo , Cinesinas/genética , Enzimas Ativadoras de Ubiquitina/metabolismo , Enzimas Ativadoras de Ubiquitina/genética , Células HEK293 , Centrossomo/metabolismo , Processamento de Proteína Pós-Traducional , ProteínasRESUMO
Fragile X syndrome is the leading genetic cause of intellectual disability and autism spectrum disorders. Female premutation carriers exhibit no obvious symptoms during reproductive age, but the premutation allele can expand to full mutation when transmitted to the fetus. Given the relatively low prevalence but large population, the distinct health care system, the middle-income economic status, and low awareness among public and medical professionals, the optimal genetic screening strategy remains unknown. We conducted a pilot study of Fragile X carrier screening in China, involving 22,245 pregnant women and women with childbearing intentions, divided into control and pilot groups. The prevalence of Fragile X carriers in the control group was 1 of 850, similar to East Asian populations. Strikingly, the prevalence of Fragile X carriers in the pilot group was 1 of 356, which can be attributed to extensive medical training, participant education, and rigorous genetic counseling and testing protocols. Cost-effectiveness analyses of four strategies-no screening, population-based screening, targeted screening, and our pilot screening-indicated that our pilot screening was the most cost-effective option. A follow-up survey revealed that 55% of respondents reported undergoing screening because of their family history. We have successfully established a standardized system, addressing the challenges of low prevalence, limited awareness, and genetic testing complexities. Our study provides practical recommendations for implementing Fragile X carrier screening in China.
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Given the extensive application of dexamethasone in both clinical settings and the livestock industry, human exposure to this drug can occur through various sources and pathways. Prior research has indicated that prenatal exposure to dexamethasone (PDE) heightens the risk of cognitive and emotional disorders in offspring. Axonal development impairment is a frequent pathological underpinning for neuronal dysfunction in these disorders, yet it remains unclear if it plays a role in the neural damage induced by PDE in the offspring. Through RNA-seq and bioinformatics analysis, we found that various signaling pathways related to nervous system development, including axonal development, were altered in the hippocampus of PDE offspring. Among them, the Sonic Hedgehog (SHH) signaling pathway was the most significantly altered and crucial for axonal development. By using miRNA-seq and targeting miRNAs and glucocorticoid receptor (GR) expression, we identified miR-210-3p and miR-362-5p, which can target and suppress SHH expression. Their abnormal high expression was associated with GR activation in PDE fetal rats. Further testing of PDE offspring rats and infant peripheral blood samples exposed to dexamethasone in utero showed that SHH expression was significantly decreased in peripheral blood mononuclear cells (PBMCs) and was positively correlated with SHH expression in the hippocampus and the expression of the axonal development marker growth-associated protein-43. In summary, PDE-induced hippocampal GR-miR-210-3p/miR-362-5p-SHH signaling axis changes lead to axonal developmental damage. SHH expression in PBMCs may reflect axonal developmental damage in PDE offspring and could serve as a warning marker for fetal axonal developmental damage.
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Axônios , Dexametasona , Proteínas Hedgehog , Hipocampo , MicroRNAs , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , MicroRNAs/genética , MicroRNAs/metabolismo , Animais , Dexametasona/toxicidade , Dexametasona/efeitos adversos , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Feminino , Ratos , Gravidez , Axônios/efeitos dos fármacos , Axônios/metabolismo , Axônios/patologia , Masculino , Ratos Sprague-Dawley , Humanos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismoRESUMO
Prenatal caffeine exposure (PCE) is a significant contributor to intrauterine growth retardation (IUGR) in offspring, which has been linked to an increased susceptibility to autism spectrum disorder (ASD) later in life. Additionally, a high-fat diet (HFD) has been shown to exacerbate ASD-like behaviors, but the underlying mechanisms remain unclear. In this study, we first noted in the rat model of IUGR induced by PCE that male PCE offspring exhibited typical ASD-like behaviors post-birth, in contrast to their female counterparts. The female PCE offspring demonstrated only reduced abilities in free exploration and spatial memory. Importantly, both male and female PCE offspring displayed ASD-like behaviors when exposed to HFD. We further observed that PCE + HFD offspring exhibited damaged intestinal mucus barriers and disturbed gut microbiota, resulting in an increased abundance of Escherichia coli (E. coli). The induced differentiation of colonic Th17 cells by E. coli led to an increased secretion of IL-17A, which entered the hippocampus through peripheral circulation and caused synaptic damage in hippocampal neurons, ultimately resulting in ASD development. Our strain transplantation experiment suggested that E. coli-mediated increase of IL-17A may be the core mechanism of ASD with a fetal origin. In conclusion, PCE and HFD are potential risk factors for ASD, and E. coli-mediated IL-17A may play a crucial role in fetal-originated ASD through the gut-brain axis.
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Transtorno do Espectro Autista , Transtorno Autístico , Cafeína , Microbioma Gastrointestinal , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Humanos , Masculino , Gravidez , Ratos , Transtorno do Espectro Autista/induzido quimicamente , Transtorno do Espectro Autista/microbiologia , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/microbiologia , Encéfalo , Eixo Encéfalo-Intestino , Cafeína/efeitos adversos , Cafeína/toxicidade , Dieta Hiperlipídica/efeitos adversos , Escherichia coli , Retardo do Crescimento Fetal/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Interleucina-17/genética , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamenteRESUMO
BACKGROUND: Azithromycin, one of the new-generation macrolides, is an effective medicine for the treatment of mycoplasma infection during pregnancy. Epidemiological studies have reported adverse pregnancy outcomes with prenatal azithromycin exposure (PAzE). However, the effect of PAzE on fetal hippocampal development is unclear. This study aimed to explore the effects and potential mechanism of PAzE-induced fetal hippocampal development at different doses, courses, and time. METHOD: Pregnant mice were administered azithromycin by gavage at different doses (50, 100 or 200 mg/kg.d), different courses (gestational day (GD)15-17 for three consecutive days, or GD17 once a day) and different time (GD10-12, GD15-17). RESULTS: Compared with the control group, morphological development damage of the fetal hippocampus was observed in the PAzE group, with a dysbalance in neuronal proliferation and apoptosis, decreased expression of the neuronal-specific marker Snap25, NeuN, PSD95 and Map2, increased expression of the glial-specific marker Iba1, GFAP, and S-100ß, and decreased expression of P2ry12. The PAzE-induced hippocampal developmental deficiency varied based on different doses, courses, and time, and the developmental toxicity was most significant in the late pregnancy, high dose, multi-course group (AZHT). The significant reduction of SOX2 and Wnt, which were related to regulation of neural progenitor cells (NPCs) proliferation in PAzE fetus compared with the control group indicated that the SOX2/Wnt signaling may be involved in PAzE-induced hippocampal developmental toxicity. CONCLUSION: In this study, PAzE was associated with hippocampal developmental toxicity in a variety of nerve cells. Hippocampal developmental toxicity due to azithromycin was most significant in the late pregnancy, high-dose (equivalent to maximum clinical dose) and multi-course group (AZHT). The findings provide an experimental and theoretical foundation for guiding the sensible use of medications during pregnancy and effectively assessing the risk of fetal hippocampal developmental toxicity.
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Efeitos Tardios da Exposição Pré-Natal , Feminino , Humanos , Gravidez , Animais , Camundongos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Azitromicina/toxicidade , Feto , Neurônios , HipocampoRESUMO
BACKGROUND: Autism spectrum disorder (ASD) has been associated with intrauterine growth restriction (IUGR), but the underlying mechanisms are unclear. RESULTS: We found that the IUGR rat model induced by prenatal caffeine exposure (PCE) showed ASD-like symptoms, accompanied by altered gut microbiota and reduced production of indole 3-propionic acid (IPA), a microbiota-specific metabolite and a ligand of aryl hydrocarbon receptor (AHR). IUGR children also had a reduced serum IPA level consistent with the animal model. We demonstrated that the dysregulated IPA/AHR/NF-κB signaling caused by disturbed gut microbiota mediated the hippocampal microglia hyperactivation and neuronal synapse over-pruning in the PCE-induced IUGR rats. Moreover, postnatal IPA supplementation restored the ASD-like symptoms and the underlying hippocampal lesions in the IUGR rats. CONCLUSIONS: This study suggests that the microbiota-IPA-brain axis regulates ASD susceptibility in PCE-induced IUGR offspring, and supplementation of microbiota-derived IPA might be a promising interventional strategy for ASD with a fetal origin. Video Abstract.
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Transtorno do Espectro Autista , Microbioma Gastrointestinal , Animais , Feminino , Gravidez , Ratos , Encéfalo , Cafeína/toxicidade , Retardo do Crescimento Fetal/induzido quimicamente , Microbioma Gastrointestinal/fisiologia , Hipocampo , Microglia , Plasticidade NeuronalRESUMO
NgBR is the Nogo-B receptor, encoded by NUS1 gene. As NgBR contains a C-terminal domain that is similar to cis-isoprenyltransferase (cis-IPTase), NgBR was speculated to stabilize nascent Niemann-Pick type C 2 (NPC2) to facilitate cholesterol transport out of lysosomes. Mutations in the NUS1 were known as risk factors for Parkinson's disease (PD). In our previous study, it was shown that knockdown of Drosophila NUS1 orthologous gene tango14 causes decreased climbing ability, loss of dopaminergic neurons, and decreased dopamine contents. In this study, tango14 mutant flies were generated with a mutation in the C-terminal enzyme activity region using CRISPR/Cas9. Tango14 mutant showed a reduced lifespan with locomotive defects and cholesterol accumulation in Malpighian tubules and brains, especially in dopaminergic neurons. Multilamellar bodies were found in tango14 mutants using electron microscopy. Neurodegenerative-related brain vacuolization was also detected in tango14 knockdown flies in an age-dependent manner. In addition, tango14 knockdown increased α-synuclein (α-syn) neurotoxicity in α-syn-overexpressing flies, with decreased locomotive activities, dopamine contents, and the numbers of dopaminergic neurons in aging flies. Thus, these observations suggest a role of NUS1, the ortholog of tango14, in PD-related pathogenesis.
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Doença de Parkinson , Animais , Colesterol , Dopamina , Neurônios Dopaminérgicos/patologia , Drosophila/genética , Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína/genéticaRESUMO
Media streaming, with an edge-cloud setting, has been adopted for a variety of applications such as entertainment, visualization, and design. Unlike video/audio streaming where the content is usually consumed passively, virtual reality applications require 3D assets stored on the edge to facilitate frequent edge-side interactions such as object manipulation and viewpoint movement. Compared to audio and video streaming, 3D asset streaming often requires larger data sizes and yet lower latency to ensure sufficient rendering quality, resolution, and latency for perceptual comfort. Thus, streaming 3D assets faces remarkably additional than streaming audios/videos, and existing solutions often suffer from long loading time or limited quality. To address this challenge, we propose a perceptually-optimized progressive 3D streaming method for spatial quality and temporal consistency in immersive interactions. On the cloud-side, our main idea is to estimate perceptual importance in 2D image space based on user gaze behaviors, including where they are looking and how their eyes move. The estimated importance is then mapped to 3D object space for scheduling the streaming priorities for edge-side rendering. Since this computational pipeline could be heavy, we also develop a simple neural network to accelerate the cloud-side scheduling process. We evaluate our method via subjective studies and objective analysis under varying network conditions (from 3G to 5G) and edge devices (HMD and traditional displays), and demonstrate better visual quality and temporal consistency than alternative solutions.
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Gráficos por Computador , Realidade Virtual , Redes Neurais de ComputaçãoRESUMO
Videos are an accessible form of media for analyzing sports postures and providing feedback to athletes. Existing sport-specific systems embed bespoke human pose attributes and thus can be hard to scale for new attributes, especially for users without programming experiences. Some systems retain scalability by directly showing the differences between two poses, but they might not clearly visualize the key differences that viewers would like to pursue. Besides, video-based coaching systems often present feedback on the correctness of poses by augmenting videos with visual markers or reference poses. However, previewing and augmenting videos limit the analysis and visualization of human poses due to the fixed viewpoints in videos, which confine the observation of captured human movements and cause ambiguity in the augmented feedback. To address these issues, we study customizable human pose data analysis and visualization in the context of running pose attributes, such as joint angles and step distances. Based on existing literature and a formative study, we have designed and implemented a system, PoseCoach, to provide feedback on running poses for amateurs by comparing the running poses between a novice and an expert. PoseCoach adopts a customizable data analysis model to allow users' controllability in defining pose attributes of their interests through our interface. To avoid the influence of viewpoint differences and provide intuitive feedback, PoseCoach visualizes the pose differences as part-based 3D animations on a human model to imitate the demonstration of a human coach. We conduct a user study to verify our design components and conduct expert interviews to evaluate the usefulness of the system.
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Foveation and (de)focus are two important visual factors in designing near eye displays. Foveation can reduce computational load by lowering display details towards the visual periphery, while focal cues can reduce vergence-accommodation conflict thereby lessening visual discomfort in using near eye displays. We performed two psychophysical experiments to investigate the relationship between foveation and focus cues. The first study measured blur discrimination sensitivity as a function of visual eccentricity, where we found discrimination thresholds significantly lower than previously reported. The second study measured depth discrimination threshold where we found a clear dependency on visual eccentricity. We discuss the study results and suggest further investigation.
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Percepção de Profundidade/fisiologia , Percepção Visual/fisiologia , Adulto , Humanos , Pessoa de Meia-Idade , Estimulação Luminosa , Limiar Sensorial , Adulto JovemRESUMO
Design of time-varying vector fields, i.e., vector fields that can change over time, has a wide variety of important applications in computer graphics. Existing vector field design techniques do not address time-varying vector fields. In this paper, we present a framework for the design of time-varying vector fields, both for planar domains as well as manifold surfaces. Our system supports the creation and modification of various time-varying vector fields with desired spatial and temporal characteristics through several design metaphors, including streamlines, pathlines, singularity paths, and bifurcations. These design metaphors are integrated into an element-based design to generate the time-varying vector fields via a sequence of basis field summations or spatial constrained optimizations at the sampled times. The key-frame design and field deformation are also introduced to support other user design scenarios. Accordingly, a spatial-temporal constrained optimization and the time-varying transformation are employed to generate the desired fields for these two design scenarios, respectively. We apply the time-varying vector fields generated using our design system to a number of important computer graphics applications that require controllable dynamic effects, such as evolving surface appearance, dynamic scene design, steerable crowd movement, and painterly animation. Many of these are difficult or impossible to achieve via prior simulation-based methods. In these applications, the time-varying vector fields have been applied as either orientation fields or advection fields to control the instantaneous appearance or evolving trajectories of the dynamic effects.