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Highlights Recent advances in the combined delivery platform that integrate nano-/microscale carriers and with 3D hydrogel network for bone regeneration are summarized. The strategies for bioactive molecules delivery involving nanoparticles, nanosheets, and microspheres, along with extra stimuli such as near-infrared light, temperature changes, ultrasonication, and inflammatory conditions, are introduced. The prospects and challenges for the clinical translation and the development of nano-/microscale incorporated hydrogel-based delivery platform are discussed.

Abstract Despite the importance of cellular senescence in human health, how damaged cells undergo senescence remains elusive. We have previously shown that promyelocytic leukemia nuclear body (PML-NBs) translocation of the ciliary FBF1 is essential for senescence induction in stressed cells. Here we discover that an early cellular event occurring in stressed cells is the transient assembly of stress-induced nucleus-to-cilium microtubule arrays (sinc-MTs). The sinc-MTs are distinguished by unusual polyglutamylation and unique polarity, with minus-ends nucleating near the nuclear envelope and plus-ends near the ciliary base. KIFC3, a minus-end-directed kinesin, is recruited to plus-ends of sinc-MTs and interacts with the centrosomal protein CENEXIN1. In damaged cells, CENEXIN1 co-translocates with FBF1 to PML-NBs. Deficiency of KIFC3 abolishes PML-NB translocation of FBF1 and CENEXIN1, as well as senescence initiation in damaged cells. Our study reveals that KIFC3-mediated nuclear transport of FBF1 along polyglutamylated sinc-MTs is a prerequisite for senescence induction in mammalian cells.

Abstract The canonical non-homologous end joining (c-NHEJ) repair pathway, generally viewed as stochastic, has recently been shown to produce predictable outcomes in CRISPR-Cas9 mutagenesis. This predictability, mainly in 1-bp insertions and small deletions, has led to the development of in-silico prediction programs for various animal species. However, the predictability of CRISPR-induced mutation profiles across species remained elusive. Comparing CRISPR-Cas9 repair outcomes between human and plant species reveals significant differences in 1-bp insertion profiles. The high predictability observed in human cells links to the template-dependent activity of human Polλ. Yet plant Polλ exhibits dual activities, generating 1-bp insertions through both templated and non-templated manners. Polλ knockout in plants leads to deletion-only mutations, while its overexpression enhances 1-bp insertion rates. Two conserved motifs are identified to modulate plant Polλ‘s dual activities. These findings unveil the mechanism behind species-specific CRISPR-Cas9-induced insertion profiles and offer strategies for predictable, precise genome editing through c-NHEJ.

Abstract Euxinia, a crucial geological condition, usually signifies more severe extinction events attributed to deoxygenation in Earth's history. Despite extensive exploration of various proxies in paleoredox studies, most are primarily utilized to reconstruct atmospheric pO2, the proportion of anoxic water relative to the entire basin, and broader trends in redox states. Few, however, hold the capacity to precisely delineate local euxinia within confined areas. To address this gap and gain insights into the temporal and spatial extent of benthic euxinia, we propose leveraging the synergistic analysis of total nitrogen isotopes (δ15NTN) and pyrite sulfur isotopes (δ34Spy). Our study focuses on the Triassic Chang 7 Member from the Yanchang Formation, Ordos Basin, North China. Through coupling the δ15NTN and δ34Spy systematics on 11 drill cores within the Ordos Basin, we reconstruct the temporal and spatial distribution of the benthic euxinia zone during the Chang‐7 period. Our results suggest strong spatial heterogeneity of benthic redox conditions, with the euxinia boundary shifting from the central lake to the southwestern sections. Moreover, we identify redox‐controlling factors, including organic carbon loading, water depth, and potential water circulation, and evaluate their interplay with benthic euxinia. Furthermore, the discernment of water circulation patterns may provide an innovative approach to restore the paleowind direction. These findings highlight the effectiveness of coupling δ15NTN and δ34Spy in reconstructing the local benthic redox landscape of benthic environments, and enrich our understanding of biogeochemical processes.

Abstract Background Diabetic nephropathy (DN) and atherosclerosis (AS) are prevalent and severe complications associated with diabetes, exhibiting lesions in the basement membrane, an essential component found within the glomerulus, tubules, and arteries. These lesions contribute significantly to the progression of both diseases, however, the precise underlying mechanisms, as well as any potential shared pathogenic processes between them, remain elusive. Methods Our study analyzed transcriptomic profiles from DN and AS patients, sourced from the Gene Expression Omnibus database. A combination of integrated bioinformatics approaches and machine learning models were deployed to identify crucial genes connected to basement membrane lesions in both conditions. The role of integrin subunit alpha M (ITGAM) was further explored using immune infiltration analysis and genetic correlation studies. Single-cell sequencing analysis was employed to delineate the expression of ITGAM across different cell types within DN and AS tissues. Results Our analyses identified ITGAM as a key gene involved in basement membrane alterations and revealed its primary expression within macrophages in both DN and AS. ITGAM was significantly correlated with tissue immune infiltration within these diseases. Furthermore, the expression of genes encoding core components of the basement membrane was influenced by the expression level of ITGAM. Conclusion Our findings suggest that macrophages may contribute to basement membrane lesions in DN and AS through the action of ITGAM. Moreover, therapeutic strategies that target ITGAM may offer potential avenues to mitigate basement membrane lesions in these two diabetes-related complications.

With the deepening of transit-oriented development (TOD), the construction of high-density, multi-functional urban spatial structures around public transportation stations has become a significant focus in urban development planning. This study is aimed to explore the spatial and temporal cluster patterns and the relationship between taxi passenger flow and land use types around urban rail transit stations. Taking Beijing as an example, this study extracts the time series of pick-up and drop-off points from the taxi GPS track dataset and employs the affinity propagation (AP) method to conduct the spatial and temporal cluster analysis on these taxi pick-up and drop-off points. Then, based on the urban POI dataset, this study classifies these stations into four functional types by adopting the K-means method. Finally, the partial least squares (PLS) method has been used to explore the relationship between the taxi passenger flow and the land use types under different time intervals. The result indicates that: first, there is a regional aggregation effect for the taxi passenger source in the rail transit station area, and the cluster areas are mainly located in Chaoyang and Haidian districts, as well as along the circular metro line. Besides, there is a significant rush hour in the morning and evening for this passenger flow. Second, the commercial, residential, and comprehensive transit stations are mainly located in the central urban districts of Beijing with balanced spatial distribution, while the industrial transit stations are dispersed to the outer suburbs of the city, which conform to Alonso's spatial distribution of land. Third, there is a significant positive correlation between taxi passenger sources in the rail transit station area and land use types containing transportation service, public facility and daily life service. This study analyses the population mobility and land type cluster form around the urban rail transit from the micro-perspective, which verifies and supplements Alonso's transportation location theory. Therefore, this study contributes to the rational planning of urban spatial resource allocation and the construction of the urban rail transit network.

Abstract Serving as the cell's sensory antennae, primary cilia are linked to numerous human genetic diseases when they malfunction. DZIP1L, identified as one of the genetic causes of human autosomal recessive polycystic kidney disease (ARPKD), is an evolutionarily conserved ciliary basal body protein. Although it has been reported that DZIP1L is involved in the ciliary entry of PKD proteins, the underlying mechanism remains elusive. Here, an uncharacterized role of DZIP1L is reported in modulating the architecture and function of transition fibers (TFs), striking ciliary base structures essential for selective cilia gating. Using C. elegans as a model, C01G5.7 (hereafter termed DZIP‐1) is identified as the sole homolog of DZIP1L, which specifically localizes to TFs. While DZIP‐1 or ANKR‐26 (the ortholog of ANKRD26) deficiency shows subtle impact on TFs, co‐depletion of DZIP‐1 and ANKR‐26 disrupts TF assembly and cilia gating for soluble and membrane proteins, including the ortholog of ADPKD protein polycystin‐2. Notably, the synergistic role for DZIP1L and ANKRD26 in the formation and function of TFs is highly conserved in mammalian cilia. Hence, the findings illuminate an evolutionarily conserved role of DZIP1L in TFs architecture and function, highlighting TFs as a vital part of the ciliary gate implicated in ciliopathies ARPKD.

Exposure to irreparable stresses induces transient ciliogenesis, enabling communication with PML-NBs via a FBF1 pathway to trigger senescence in mammalian cells. Fbf1 ablation reduces senescence and associated health decline in mice, highlighting cilia as a promising senotherapy target.

Albuminuria and podocyte injury are the key cellular events in the progression of diabetic nephropathy (DN). Acetyl-CoA synthetase 2 (ACSS2) is a nucleocytosolic enzyme responsible for the regulation of metabolic homeostasis in mammalian cells. This study aimed to investigate the possible roles of ACSS2 in kidney injury in DN. We constructed an ACSS2-deleted mouse model to investigate the role of ACSS2 in podocyte dysfunction and kidney injury in diabetic mouse models. In vitro, podocytes were chosen and transfected with ACSS2 siRNA and ACSS2 inhibitor and treated with high glucose. We found that ACSS2 expression was significantly elevated in the podocytes of patients with DN and diabetic mice. ACSS2 upregulation promoted phenotype transformation and inflammatory cytokine expression while inhibiting podocytes’ autophagy. Conversely, ACSS2 inhibition improved autophagy and alleviated podocyte injury. Furthermore, ACSS2 epigenetically activated raptor expression by histone H3K9 acetylation, promoting activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway. Pharmacological inhibition or genetic depletion of ACSS2 in the streptozotocin-induced diabetic mouse model greatly ameliorated kidney injury and podocyte dysfunction. To conclude, ACSS2 activation promoted podocyte injury in DN by raptor/mTORC1-mediated autophagy inhibition.

BackgroundHeart failure (HF) is a life-threatening complication of cardiovascular disease. HF patients are more likely to progress to acute kidney injury (AKI) with a poor prognosis. However, it is difficult for doctors to distinguish which patients will develop AKI accurately. This study aimed to construct a machine learning (ML) model to predict AKI occurrence in HF patients.Materials and methodsThe data of HF patients from the Medical Information Mart for Intensive Care-IV (MIMIC-IV) database was retrospectively analyzed. A ML model was established to predict AKI development using decision tree, random forest (RF), support vector machine (SVM), K-nearest neighbor (KNN), and logistic regression (LR) algorithms. Thirty-nine demographic, clinical, and treatment features were used for model establishment. Accuracy, sensitivity, specificity, and the area under the receiver operating characteristic curve (AUROC) were used to evaluate the performance of the ML algorithms.ResultsA total of 2,678 HF patients were engaged in this study, of whom 919 developed AKI. Among 5 ML algorithms, the RF algorithm exhibited the highest performance with the AUROC of 0.96. In addition, the Gini index showed that the sequential organ function assessment (SOFA) score, partial pressure of oxygen (PaO2), and estimated glomerular filtration rate (eGFR) were highly relevant to AKI development. Finally, to facilitate clinical application, a simple model was constructed using the 10 features screened by the Gini index. The RF algorithm also exhibited the highest performance with the AUROC of 0.95.ConclusionUsing the ML model could accurately predict the development of AKI in HF patients.

The zircon U-Pb chronology database provides a good opportunity to obtain important zircon growth peak periods in the Earth's history so as to study the origin and evolution of the crust. It should be noted that research preference affects the objectivity of zircon sampling, leading to hot data in the database and age statistics. To evaluate the influence of hot data on statistical results, the W and Y indexes are introduced. Using a Gaussian model of multipeak fitting of zircon U-Pb age frequencies, we identify seven major growth peaks in zircons from the Chinese continental crust, which are 2498.95, 1855.82, 828.88, 444.29, 249.46, 131.96, and 58.21 Ma. Due to differences in the time scales of zircon growth peaks, these peaks can be divided into two categories: first-order zircon growth peaks (I) and second-order zircon growth peaks (II), which represent longer and shorter time scales, perhaps due to different kinds of geological dynamics, respectively. In addition, there are clear correspondences between these ages and various geological events recognized by most scholars, namely, the Wutai orogeny, Lvliang orogeny, Jinning orogeny, Caledonian orogeny, Indosinian orogeny, Yanshanian orogeny, and Himalayan orogeny, respectively.

Most cells possess sensory cilia, which need to be gated properly. Here the authors show that the C. elegans proteins TALP-3 and ANKR-26 coordinate cilia gating in the context of transition fibers and that this mechanism is conserved in mammalian cells and likely implicated in certain ciliopathies.

BackgroundLipid metabolism disorder, as one major complication in patients with chronic kidney disease (CKD), is tied to an increased risk for cardiovascular disease (CVD). Traditional lipid-lowering statins have been found to have limited benefit for the final CVD outcome of CKD patients. Therefore, the purpose of this study was to investigate the effect of microinflammation on CVD in statin-treated CKD patients.MethodsWe retrospectively analysed statin-treated CKD patients from January 2013 to September 2020. Machine learning algorithms were employed to develop models of low-density lipoprotein (LDL) levels and CVD indices. A fivefold cross-validation method was employed against the problem of overfitting. The accuracy and area under the receiver operating characteristic (ROC) curve (AUC) were acquired for evaluation. The Gini impurity index of the predictors for the random forest (RF) model was ranked to perform an analysis of importance.ResultsThe RF algorithm performed best for both the LDL and CVD models, with accuracies of 82.27% and 74.15%, respectively, and is therefore the most suitable method for clinical data processing. The Gini impurity ranking of the LDL model revealed that hypersensitive C-reactive protein (hs-CRP) was highly relevant, whereas statin use and sex had the least important effects on the outcomes of both the LDL and CVD models. hs-CRP was the strongest predictor of CVD events.ConclusionMicroinflammation is closely associated with potential CVD events in CKD patients, suggesting that therapeutic strategies against microinflammation should be implemented to prevent CVD events in CKD patients treated by statin.

Abstract. Accumulating evidence has revealed that the composition of gut microbiota in patients with diabetes mellitus (DM) varies compared to those with healthy controls. The abnormal production and releases of metabolites derived from microbiota into the blood circulation contribute to the development of DM through the activation of multiple metabolic pathways, including trimethylamine N-oxide, short-chain fatty acids, lipopolysaccharide, aromatic amino acids, and their related metabolites. Therefore, the modulation of gut microbiota through dietary intervention, probiotics, broad-spectrum antibiotics, and fecal microbiota transplantation could be a potential therapeutic approach for DM. This review mainly summarized the complicated interactions of gut microbiota through its metabolites with DM.

Abstract Background New non-invasive biomarkers are demanded to identify renal damage in various autoimmune-associated kidney diseases. Glomerular podocyte damage mediated by systemic lupus erythematosus (SLE) plays an important role in the pathogenesis and progression of lupus nephritis (LN). This study evaluated whether the podocyte-derived microparticles (MPs) were novel biomarkers of clinical and histological features in SLE patients with LN. Methods A cross-sectional study, including 34 SLE patients and 16 healthy controls, was designed. Urinary annexin V+ podocalyxin+ MPs of all participants were quantified by flow cytometry. The correlation of podocyte-derived MPs with clinical and histological parameters of SLE patients was analysed. Results The number of annexin V+ podocalyxin+ MPs from urine samples were markly increased in patients with SLE. Furthermore, the level of urinary podocyte-derived MPs was positively correlated with the SLE Disease Activity Index (SLEDAI) score, anti-dsDNA antibody titre, erythrocyte sedimentation rate, and proteinuria. Conversely, it was negatively correlated with the level of complement C3 and serum albumin. The number of urinary podocyte-derived MPs was significantly increased in SLE patients with high activity indices. Receiver operating characteristic (ROC) curves were calculated to assess the power for podocyte-derived MP levels in differentiating between SLE patients with and without LN. Podocyte-derived MP levels were able to differentiate between SLE patients with mild disease activity, as well as those with moderate and above disease activity. SLE patients showed increased podocyte-derived MP excretion into the urine. Conclusions These findings suggest that the change in urinary podocyte-derived MP levels could be useful for evaluating and monitoring SLE disease activity.

Primary cilia are microtube-based organelles that extend from the cell surface and function as biochemical and mechanical extracellular signal sensors. Primary cilia coordinate a series of signaling pathways during development. Cilia dysfunction leads to a pleiotropic group of developmental disorders, termed ciliopathy. Phosphoinositides (PIs), a group of signaling phospholipids, play a crucial role in development and tissue homeostasis by regulating membrane trafficking, cytoskeleton reorganization, and organelle identity. Accumulating evidence implicates the involvement of PI species in ciliary defects and ciliopathies. The abundance and localization of PIs in the cell are tightly regulated by the opposing actions of kinases and phosphatases, some of which are recently discovered in the context of primary cilia. Here, we review several cilium-associated PI kinases and phosphatases, including their localization along cilia, function in regulating the ciliary biology under normal conditions, as well as the connection of their disease-associated mutations with ciliopathies.

Coordination of neurite extension with surrounding glia development is critical for neuronal function, but the underlying molecular mechanisms remain poorly understood. Through a genome-wide mutagenesis screen in C. elegans, we identified dyf-4 and daf-6 as two mutants sharing similar defects in dendrite extension. DAF-6 encodes a glia-specific patched-related membrane protein that plays vital roles in glial morphogenesis. We cloned dyf-4 and found that DYF-4 encodes a glia-secreted protein. Further investigations revealed that DYF-4 interacts with DAF-6 and functions in a same pathway as DAF-6 to regulate sensory compartment formation. Furthermore, we demonstrated that reported glial suppressors of daf-6 could also restore dendrite elongation and ciliogenesis in both dyf-4 and daf-6 mutants. Collectively, our data reveal that DYF-4 is a regulator for DAF-6 which promotes the proper formation of the glial channel and indirectly affects neurite extension and ciliogenesis.

Although the immune checkpoint role of programmed death ligand 1 (PD-L1) has been established and targeted in cancer immunotherapy, the tumor-intrinsic role of PD-L1 is less appreciated in tumor biology and therapeutics development, partly because of the incomplete mechanistic understanding. Here we demonstrate a potentially novel mechanism by which PD-L1 promotes the epithelial-mesenchymal transition (EMT) in triple-negative breast cancer (TNBC) cells by suppressing the destruction of the EMT transcription factor Snail. PD-L1 directly binds to and inhibits the tyrosine phosphatase PTP1B, thus preserving p38-MAPK activity that phosphorylates and inhibits glycogen synthase kinase 3β (GSK3β). Via this mechanism, PD-L1 prevents the GSK3β-mediated phosphorylation, ubiquitination, and degradation of Snail and consequently promotes the EMT and metastatic potential of TNBC. Significantly, PD-L1 antibodies that confine the tumor-intrinsic PD-L1/Snail pathway restricted TNBC progression in immunodeficient mice. More importantly, targeting both tumor-intrinsic and tumor-extrinsic functions of PD-L1 showed strong synergistic tumor suppression effect in an immunocompetent TNBC mouse model. Our findings support that PD-L1 intrinsically facilitates TNBC progression by promoting the EMT, and this potentially novel PD-L1 signaling pathway could be targeted for better clinical management of PD-L1–overexpressing TNBCs.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. Methods: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+⁣/- cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. Results: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. Conclusions: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

Cilia, which either generate coordinated motion or sense environmental cues and transmit corresponding signals to the cell body, are highly conserved hair-like structures that protrude from the cell surface among diverse species. Disruption of ciliary functions leads to numerous human disorders, collectively referred to as ciliopathies. Cilia are mechanically supported by axonemes, which are composed of microtubule doublets. It has been recognized for several decades that tubulins in axonemes undergo glutamylation, a post-translational polymodification, that conjugates glutamic acid chains onto the C-terminal tail of tubulins. However, the physiological roles of axonemal glutamylation were not uncovered until recently. This review will focus on how cells modulate glutamylation on ciliary axonemes and how axonemal glutamylation regulates cilia architecture and functions, as well as its physiological importance in human health. We will also discuss the conventional and emerging new strategies used to manipulate glutamylation in cilia.

The amount of zircon U-Pb geochronological data for China has grown rapidly in recent years. Nearly 410,000 items of zircon U-Pb geochronological data, representing more than 7,000 relevant articles in the Elsevier Science Database, have been collected to a database in this research. Statistics on the ages and absolute errors of these collated data, yielded smallest standard errors for (206Pb/238U), (207Pb/235U), and (207Pb/206Pb) ages within respective time intervals of < 1388.96 Ma, 1388.96–3282.52 Ma, and > 3282.52 Ma. The ages and their absolute errors were determined using three main geochronology methods, based on laser ablation inductively coupled mass spectrometer (LA-ICP-MS), sensitive high-resolution ion microprobe (SHRIMP), and secondary ion mass spectrometer (SIMS) measurements. We compared the influence of these different methods on errors for each age interval. In addition, using a Gaussian model of multi-peak fitting of zircon U-Pb age frequencies, we identified seven growth peaks in zircons from the Chinese continental crust, which are 48.60 Ma, 131.49 Ma, 249.91 Ma, 444.27 Ma, 835.95 Ma, 1860.65 Ma, and 2505.54 Ma. It is clear that there are correspondences between these ages and various geological events, namely, the Wutai movement, Lvliang movement, Jinning movement, Caledonian movement, Indo-China movement, Yanshan movement, and Himalayaorogeny movement, respectively. The time and spatial distributions of these zircons correspond to distinct geological events on the Chinese continent, reflecting its crustal evolution.

Abstract Background Increased plasma level of lipoprotein(a) (Lpa) is a risk factor of cardiovascular diseases. This study aimed to explore the role of Lpa in the progression of atherosclerosis in patients with end-stage renal disease (ESRD) and to investigate whether its potential mechanism is mediated by CXC chemokine ligand 16 (CXCL16) and low-density lipoprotein receptor (LDLr). Methods This is a retrospective clinical study. From January 2015 to April 2016, forty-six ESRD patients from Danyang First People’s Hospital were investigated. The patients were grouped according to their plasma Lpa levels: control group (Lpa

The small GTPase ARL13B is mutated in the human ciliopathy Joubert syndrome. Here the authors show that ARL13B and the RAB11 effector FIP5 promote import of tubulin glutamylase into cilia and as such axoneme polyglutamylation, which is demonstrated to be required for cilia signaling.

Abstract Background Evidence from quantitative studies suggest that Tai Chi produces a variety of health-related benefits, but few qualitative studies have investigated how older adults perceive the benefit of Tai Chi. The objective of the current study was to qualitatively evaluate the perceived benefits of Tai Chi practice among community older population. Methods This study was conducted with participants from a trial examining the effects of a 12-week Tai Chi training on ischemic stroke risk in community older adults (n = 170). A total of 20 participants were randomly selected from a convenience sample of participants who had completed 12-week Tai Chi training (n = 68) were interviewed regarding their perceived benefit on physical and mental health and whether Tai Chi exercise was suitable for the elderly. Results All participants agreed that Tai Chi training could relax their body and make them comfortable. Most of them thought Tai Chi training could promote physical health, including relieving pain, enhancing digestion, strengthening immunity, enhancing energy and improving sleep quality, enhancing their mental and emotional state (e.g. improving mood and reducing anxiety, improving concentration and promoting interpersonal relationship). Most of participants also agreed that Tai Chi exercise was appropriate for community older people. Three primary themes emerged from content analysis: Improving physical health; Enhancing mental and emotional state; Conforming with the request of the elderly. Conclusion The findings indicate that regular Tai Chi exercise may have positive benefits in terms of improved physical health and mental state among community elderly population, and may be useful and feasible body-mind exercise to community elderly population for its positive effects and advantages. Trial registration ChiCTR ChiCTR-TRC-13003601 . Registered 23 July 2014.

Developing ultralong organic phosphorescence (UOP) materials with smart response to external stimuli is of great interest in photonics applications, whereas the manipulation of molecular stacking on tuning such dynamic UOP is still a formidable challenge. Herein, we have reported two polymorphs with distinct photoactivated dynamic UOP behavior based on a pyridine derivative for the first time. Our experiment revealed that the dynamic UOP behavior including photoactivation and deactivation feature is highly dependent on irradiation intensity and environmental atmosphere. Additionally, given the unique dynamic UOP feature, these phosphors have been successfully applied to phosphorescence-dependent molecular logic gate and timing data storage. This result not only paves a way to design smart functional materials but also expands the scope of the applications on organic phosphorescence materials.

Transition fibres (TFs) and the transition zone (TZ) are basal ciliary structures thought to act as a gate to regulate protein transport. Here the authors show that the C. elegansorthologue of hydrolethalus protein 1, HYLS-1, disrupts both structures and compromises the trafficking of cargo through the ciliary gate.

Development of resistance to chemotherapy is a major obstacle in extending the survival of patients with cancer. Although originally defined as an immune checkpoint molecule, B7-H1 (also named as PD-L1 or CD274) was found to play a role in cancer chemoresistance; however, the underlying mechanism of action of B7-H1 in regulation of chemotherapy sensitivity remains unclear in cancer cells. Here we show that development of chemoresistance depends on an increased activation of ERK in cancer cells overexpressing B7-H1. Conversely, B7-H1 knockout (KO) by CRISPR/Cas9 renders human cancer cells susceptible to chemotherapy in a cell-context dependent manner through a reduced activation of p38 MAPK. B7-H1 was found to associate with the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) and this association promoted or maintained the activation of ERK or p38 MAPK in cancer cells. Importantly, we found that targeting B7-H1 by anti-B7-H1 monoclonal antibody (H1A) increased the sensitivity of human triple negative breast cancer cells to cisplatin therapy in vivo. Our results suggest that targeting B7-H1 by an antibody capable of disrupting B7-H1 signals may be a new approach to sensitize cancer cells to chemotherapy.

The primary cilium is essential for embryonic development and tissue pattern formation. Here the authors show that PIPKIγ localizes to the basal body of the primary cilium and cooperates with the Joubert Syndrome associated protein INPP5E to regulate the initiation of ciliogenesis.

To investigate the effectiveness and safety of Tai Chi Chuan (TCC) on physical and psychological health of college students.Two hundred six college students were recruited and randomly allocated to a control group or a TCC exercise group in an equal ratio. Participants in the control group were instructed to maintain their original activity level and those in the TCC exercise group received 12 weeks of TCC exercise training based on their original activity level. Physical and psychological outcomes were evaluated at baseline, 13 weeks and 25 weeks. Intention-to-treat analysis was performed for the above outcomes.Compared with the control group, the TCC exercise group showed significant improvements at the end of the 12-week intervention period for flexibility (length of Sit and Reach (cm): TCC group 14.09±7.40 versus control 12.88±6.57, P = 0.039 adjusted for its baseline measures using a general linear model) and balance ability (open eyes perimeter: TCC group 235.6(191~314) versus control 261(216~300); closed eyes perimeter: TCC group 370.5 (284~454) versus control 367 (293~483); P = 0.0414, 0.008, respectively, adjusted for corresponding baseline measures using a general linear model). No significant changes in other physical and mental outcomes were found between the two groups. No adverse events were reported during the study period.TCC exercise was beneficial in college students for improving flexibility and balance capability to some extent, compared with usual exercise.Chinese Clinical Trial Registry ChiCTR-TRC-13003328.

BACKGROUND: Chronic inflammation plays a crucial role in the progression of vascular calcification (VC). This study was designed to investigate whether the low-density lipoprotein receptor (LDLr) pathway is involved in the progression of VC in patients with end-stage renal disease (ESRD) during inflammation. METHODS AND RESULTS: Twenty-eight ESRD patients were divided into control and inflamed groups according to plasma C-reactive protein (CRP) level. Surgically removed tissues from the radial arteries of patients receiving arteriovenostomy were used in the experiments. The expression of tumour necrosis factor-α (TNF-α) and monocyte chemotactic protein-1 (MCP-1) of the radial artery were increased in the inflamed group. Hematoxylin-eosin and alizarin red S staining revealed parallel increases in foam cell formation and calcium deposit formation in continuous cross-sections of radial arteries in the inflamed group compared to the control, which were closely correlated with increased LDLr, sterol regulatory element binding protein-2 (SREBP-2), bone morphogenetic proteins-2 (BMP-2), and collagen I protein expression, as shown by immunohistochemical and immunofluorescent staining. Confocal microscopy confirmed that inflammation enhanced the translocation of the SREBP cleavage-activating protein (SCAP)/SREBP-2 complex from the endoplasmic reticulum to the Golgi, thereby activating LDLr gene transcription. Inflammation increased alkaline phosphatase protein expression and reduced α-smooth muscle actin protein expression, contributing to the conversion of the vascular smooth muscle cells in calcified vessels from the fibroblastic to the osteogenic phenotype; osteogenic cells are the main cellular components involved in VC. Further analysis showed that the inflammation-induced disruption of the LDLr pathway was significantly associated with enhanced BMP-2 and collagen I expression. CONCLUSIONS: Inflammation accelerated the progression of VC in ESRD patients by disrupting the LDLr pathway, which may represent a novel mechanism involved in the progression of both VC and atherosclerosis.