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Nuclear pore complexes (NPCs) on the nuclear membrane surface have a crucial function in controlling the movement of small molecules and macromolecules between the cell nucleus and cytoplasm through their intricate core channel resembling a spiderweb with several layers. Currently, there are few methods available to accurately measure the dynamics of nuclear pores on the nuclear membranes at the nanoscale. The limitation of traditional optical imaging is due to diffraction, which prevents achieving the required resolution for observing a diverse array of organelles and proteins within cells. Super-resolution techniques have effectively addressed this constraint by enabling the observation of subcellular components on the nanoscale. Nevertheless, it is crucial to acknowledge that these methods often need the use of fixed samples. This also raises the question of how closely a static image represents the real intracellular dynamic system. High-speed atomic force microscopy (HS-AFM) is a unique technique used in the field of dynamic structural biology, enabling the study of individual molecules in motion close to their native states. Establishing a reliable and repeatable technique for imaging mammalian tissue at the nanoscale using HS-AFM remains challenging due to inadequate sample preparation. This study presents the rapid strainer microfiltration (RSM) protocol for directly preparing high-quality nuclei from the mouse brain. Subsequently, we promptly utilize HS-AFM real-time imaging and cinematography approaches to record the spatiotemporal of nuclear pore nano-dynamics from the mouse brain. [ABSTRACT FROM AUTHOR]

Sea ice leads play an important role in the heat exchange between the ocean and the overlying atmosphere, particularly narrow leads with widths of less than 100 m. We present a method for detecting sea ice leads in the Arctic using high-resolution infrared images from the Thermal Infrared Spectrometer (TIS) on board the Sustainable Development Science Satellite 1 (SDGSAT-1), with a resolution of 30 m in a swath of 300 km. With the spatial resolution of leads observed by infrared remote sensing increasing to tens of meters, focused on the Beaufort Sea cases in April 2022, the TIS-detected leads achieve good agreement with Sentinel-2 visible images. For the three infrared bands of the TIS, the B2 (10.3–11.3 µm) and B3 (11.5–12.5 µm) bands show similar performance in detecting leads. The B1 band (8.0–10.5 µm) can be usefully complementary to the other two bands, as a result of different temperature measurement sensitivity. Combining the detected results from the three TIS bands, the TIS is able to detect more leads with widths less than hundreds of meters compared to the Moderate Resolution Imaging Spectroradiometer (MODIS). Our results demonstrate that SDGSAT-1 TIS data at 30 m resolution can effectively observe previously unresolvable sea ice leads, providing new insight into the contribution of narrow leads to rapid sea ice changes in the Arctic. [ABSTRACT FROM AUTHOR]

In distributed key-value stores, multiple replica servers are always available for each key-value access operation when the eventual consistency model is employed. Accordingly, the completion times of the key-value access operations generated by an end-user request at different servers may be of great difference, especially when the replica servers are heterogeneous and have time-varying performance. Accordingly, the replica selection algorithm is crucial to cut the response time of end-user requests. The main challenge of making replica selection for each light-weighted key-value access operation is to timely know the status of replica serves. Recently, the adaptive replica selection algorithm C3 suggests guiding the replica selection with the piggybacked information of replica server in the returned “value”. Although C3 has good performance, the poor timeliness of feedback information makes a large performance gap between C3 and the ideal replica selection algorithm. To narrow this gap, the Accelerated Information Dissemination (AID) mechanism is proposed in this paper. Specifically, AID removes the bottleneck of information dissemination at the “slow” servers by letting both “client” and “replica server” store the records about the status of replica servers and both “key” and “value” piggyback multiple records. AID is implemented in Cassandra and evaluated by experiments and large scale simulations. The results show AID can significantly improve the timeliness of feedback information, especially when the number of nodes is large. Accordingly, AID helps C3 to greatly reduce the latency. [ABSTRACT FROM AUTHOR]

The rapid decline of Arctic sea ice has been reminding us the significant impacts caused by global warming. However, the other side of the coin is that this opens a window to utilize the Arctic sea routes in the summer seasons, bringing remarkable economic benefits for ocean transportation between Asia and Europe. However, commercial vessels with low ice classes must tackle substantial environmental challenges in the Arctic sea routes, particularly those caused by variable sea ice, even in the melting seasons. Therefore, the science-based support for shipping safety in the Arctic sea routes is being given more prominence. Emerging satellite remote sensing technology plays a critical role in environmental monitoring in the Arctic. This paper reviews state-of-the-art satellite observations on monitoring sea ice and potential applications on supporting shipping activities in the Arctic Ocean. Moreover, we introduced a recently developed system based on satellite observations to support the safe transportation of Chinese cargo vessels in the Arctic northern sea route, demonstrating the efforts by both the science and business communities to promote the development of the polar silk road. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis is a progressive and age‐related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL‐2 and BCL‐XL, leading to BAX inactivation. We further showed that high levels of inactive BAX‐mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl‐valyl‐O‐methylaspartyl‐[2,6‐difluorophenoxy]‐methyl ketone (QVD‐OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1‐activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment. [ABSTRACT FROM AUTHOR]

AbstractObjectivesMethodResultsConclusionThe prevalence of the co-occurrence of depressive and anxious symptoms (CO) and their influence on perceived overall health were not clear in community dwelling Chinese older adults. The aims of the study were to investigate the prevalence of CO and to explore its influence on self-rated health (SRH).This study included 12301 individuals aged ≥65 years from the 2018 wave of the Chinese Longitudinal Healthy Longevity Survey (CLHLS), a nationally representative survey of older adults in mainland China. Participants received face-to-face interviews and assessments of depressive symptoms and anxious symptoms via 10-item of the Center for Epidemiologic Studies Depression Scale (CES-D-10) and 7-item Generalized Anxiety Disorder Questionnaire (GAD-7), respectively. SRH was measured by self-reported. A logistic regression model was used to examine the association between CO and SRH after adjusting for confounding variables.The average age was 83.4 (SD: 11.0) years and there were 6576 (53.5%) females. The age- and sex-standardized prevalence of depressive symptoms only (DSO) was 38.6%, anxious symptoms only (ASO) was 1.5%, and CO was 10.8%. Compared with those without depressive and anxious symptoms, the older adults with DSO or ASO were more likely to have significant influence on SRH. And particularly, CO was likely to produce the greatest decrement in the level of SRH.CO was not rare in Chinese older adults nationwide. The older adults having CO had increased risk for lower level of SRH than having DSO or ASO. More attention should be given to CO among the older adults. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by extensive extracellular matrix (ECM) deposition by activated myofibroblasts, which are specialized hyper-contractile cells that promote ECM remodeling and matrix stiffening. New insights on therapeutic strategies aimed at reversing fibrosis by targeting myofibroblast fate are showing promise in promoting fibrosis resolution. Previously, we showed that a novel adipocytokine, omentin-1, attenuated bleomycin (BLM)-induced lung fibrosis by reducing the number of myofibroblasts. Apoptosis, deactivation, and reprogramming of myofibroblasts are important processes in the resolution of fibrosis. Here we report that omentin-1 reverses established lung fibrosis by promoting mechanically activated myofibroblasts dedifferentiation into lipofibroblasts. Omentin-1 promotes myofibroblasts lipogenic differentiation by inhibiting dimerization and nuclear translocation of glycolytic enzymes pyruvate kinase isoform M2 (PKM2) and activation of the downstream Yes-associated protein (YAP) by increasing the cofactor fructose-1,6-bisphosphate (F1, 6BP, FBP). Moreover, omentin-1 activates proliferator-activated receptor gamma (PPARγ) signaling, the master regulator of lipogenesis, and promotes the upregulation of the lipogenic differentiation-related protein perilipin 2 (PLIN2) by suppressing the PKM2-YAP pathway. Ultimately, omentin-1 facilitates myofibroblasts transformation into the lipofibroblast phenotype, with reduced collagen synthesis and enhanced degradation properties, which are crucial mechanisms to clear the ECM deposition in fibrotic tissue, leading to fibrosis resolution. Our results indicate that omentin-1 targets mechanical signal accelerates fibrosis resolution and reverses established lung fibrosis by promoting myofibroblasts lipogenic differentiation, which is closely associated with ECM clearance in fibrotic tissue. These findings suggest that targeting mechanical force to promote myofibroblast lipogenic differentiation is a promising therapeutic strategy against persistent lung fibrosis. [ABSTRACT FROM AUTHOR]

Objective: To determine whether adverse childhood experiences (ACEs) of children of alcoholics (COA) in male were associated with their current "risky drinking". Methods: This case–control study used the Alcohol Use Disorder Identification Test (AUDIT, cutoff is 7) to divide the participants into two groups, a "risky drinking" group (N = 53) and a "non-risky drinking" group (N = 97). Demographic data, Adverse Childhood Experiences-International Questionnaire (ACE-IQ), the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale (HAMD) and the Mini-International Neuropsychiatric Interview (MINI) were used for assessment. The specific relationships between ACEs and "risky drinking" were explored. Results: Respondents ranged in age from 29.70 ± 6.72 years; 74.5% were females; 94.7% were of Han nationality; 56.7% had a level of education above high school; 12% had no formal or stable job. There was difference in attitude to self-drinking between two groups (P < 0.001). The "risky drinking" group was more likely to have experienced a major depressive episode (P < 0.05), nonalcohol psychoactive substance use disorder (P < 0.01) and bulimia nervosa (P < 0.05), and they also experienced more physical abuse (P < 0.05), community violence (P < 0.001) and collective violence (P < 0.01). In a single factor logistic regression, physical abuse, community violence and collective violence were associated with a two to 11- fold increase in "risky drinking" in the adult COA, and in multiple factor logistic regression, community violence showed a graded relationship with "risky drinking". Conclusion: The childhood adverse experiences contribute to "risky drinking" in COA. This finding in the Chinese context have significant implications for prevention not only in China but in other cultures. There must be greater awareness of the role of ACEs in the perpetuation of alcoholism. [ABSTRACT FROM AUTHOR]

Objective: To determine whether adverse childhood experiences (ACEs) of children of alcoholics (COA) in male were associated with their current "risky drinking". Methods: This case–control study used the Alcohol Use Disorder Identification Test (AUDIT, cutoff is 7) to divide the participants into two groups, a "risky drinking" group (N = 53) and a "non-risky drinking" group (N = 97). Demographic data, Adverse Childhood Experiences-International Questionnaire (ACE-IQ), the Hamilton Anxiety Rating Scale (HAMA), the Hamilton Depression Rating Scale (HAMD) and the Mini-International Neuropsychiatric Interview (MINI) were used for assessment. The specific relationships between ACEs and "risky drinking" were explored. Results: Respondents ranged in age from 29.70 ± 6.72 years; 74.5% were females; 94.7% were of Han nationality; 56.7% had a level of education above high school; 12% had no formal or stable job. There was difference in attitude to self-drinking between two groups (P < 0.001). The "risky drinking" group was more likely to have experienced a major depressive episode (P < 0.05), nonalcohol psychoactive substance use disorder (P < 0.01) and bulimia nervosa (P < 0.05), and they also experienced more physical abuse (P < 0.05), community violence (P < 0.001) and collective violence (P < 0.01). In a single factor logistic regression, physical abuse, community violence and collective violence were associated with a two to 11- fold increase in "risky drinking" in the adult COA, and in multiple factor logistic regression, community violence showed a graded relationship with "risky drinking". Conclusion: The childhood adverse experiences contribute to "risky drinking" in COA. This finding in the Chinese context have significant implications for prevention not only in China but in other cultures. There must be greater awareness of the role of ACEs in the perpetuation of alcoholism. [ABSTRACT FROM AUTHOR]

Small extracellular vesicles (sEVs) play a crucial role in local and distant cell communication. The intrinsic properties of sEVs make them compatible biomaterials for drug delivery, vaccines, and theranostic nanoparticles. Although sEV proteomics have been robustly studied, a direct instantaneous assessment of sEV structure dynamics remains difficult. Here, we use the high‐speed atomic force microscopy (HS‐AFM) to evaluate nanotopological changes of sEVs with respect to different physicochemical stresses including thermal stress, pH, and osmotic stress. The sEV structure is severely altered at high‐temperature, high‐pH, or hypertonic conditions. Surprisingly, the spherical shape of the sEVs is maintained in acidic or hypotonic environments. Real‐time observation by HS‐AFM imaging reveals an irreversible structural change in the sEVs during transition of pH or osmolarity. HS‐AFM imaging provides both qualitative and quantitative data at high spatiotemporal resolution (nanoscopic and millisecond levels). In summary, our study demonstrates the feasibility of HS‐AFM for structural characterization and assessment of nanoparticles. [ABSTRACT FROM AUTHOR]

Master transcription factors such as TP63 establish super-enhancers (SEs) to drive core transcriptional networks in cancer cells, yet the spatiotemporal regulation of SEs within the nucleus remains unknown. The nuclear pore complex (NPC) may tether SEs to the nuclear pore where RNA export rates are maximal. Here, we report that NUP153, a component of the NPC, anchors SEs to the NPC and enhances TP63 expression by maximizing mRNA export. This anchoring is mediated through protein-protein interaction between the intrinsically disordered regions (IDRs) of NUP153 and the coactivator BRD4. Silencing of NUP153 excludes SEs from the nuclear periphery, decreases TP63 expression, impairs cellular growth, and induces epidermal differentiation of squamous cell carcinoma. Overall, this work reveals the critical roles of NUP153 IDRs in the regulation of SE localization, thus providing insights into a new layer of gene regulation at the epigenomic and spatial level. [Display omitted] • NUP153 regulates the localization of BRD4 condensates relevant to SEs • The intrinsically disordered regions of NUP153 are responsible for trapping SEs • The tethering of SEs to NUP153 drives TP63 oncogene expression via mRNA export Hazawa et al. demonstrate that protein-protein interaction between the intrinsically disordered regions of NUP153 and the coactivator BRD4 regulates the localization of phase-separated super-enhancer at nuclear periphery. This spatial organization drives TP63 oncogene expression by ensuring effective mRNA export. [ABSTRACT FROM AUTHOR]

Epigenetic deregulation plays an essential role in colorectal cancer progression. Bromodomains are epigenetic "readers" of histone acetylation. Bromodomain-containing protein 4 (BRD4) plays a pivotal role in transcriptional regulation and is a feasible drug target in cancer cells. Disease-specific elevation of nucleoporin, a component of the nuclear pore complex (NPC), is a determinant of cancer malignancy, but BRD4-driven changes of NPC composition remain poorly understood. Here, we developed novel aminocyclopropenones and investigated their biological effects on cancer cell growth and BRD4 functions. Among 21 compounds developed here, we identified aminocyclopropenone 1n (ACP-1n) with the strongest inhibitory effects on the growth of the cancer cell line HCT116. ACP-1n blocked BRD4 functions by preventing its phase separation ability both in vitro and in vivo, attenuating the expression levels of BRD4-driven MYC. Notably, ACP-1n significantly reduced the nuclear size with concomitant suppression of the level of the NPC protein nucleoporin NUP210. Furthermore, NUP210 is in a BRD4-dependent manner and silencing of NUP210 was sufficient to decrease nucleus size and cellular growth. In conclusion, our findings highlighted an aminocyclopropenone compound as a novel therapeutic drug blocking BRD4 assembly, thereby preventing BRD4-driven oncogenic functions in cancer cells. This study facilitates the development of the next generation of effective and potent inhibitors of epigenetic bromodomains and extra-terminal (BET) protein family. [ABSTRACT FROM AUTHOR]