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This article proposes a wearable system for rapid response during acute hypertension. The system consists of a flexible electrode patch and a signal acquisition module, which is designed for real-time monitoring of photoelectric volume pulse graph (PPG), electrocardiogram (ECG), and bioelectrical impedance (Bio-Z). The flexible patch and miniaturized signal acquisition module provide comfort to the users while maintaining stable contact with human chest skin, and successfully collects three physiological signals, demonstrating its potential application in the healthcare field. In addition, this article introduces a lightweight and effective method based on PPG signal trend components for acute hypertension monitoring, whose effectiveness is verified with animal experiments. As a result, the system reveals a response time of less than 10 s. For the blood pressure rising stage, a mean absolute error (MAE) of 3.34 mmHg between the PPG-based value and the average blood pressure is achieved. For the blood pressure declining stage, an MAE of 2.42 mmHg between the PPG-based value and the average blood pressure is achieved. The results demonstrate a strong correlation between the PPG signal trend components and the blood pressure during acute hypertension monitoring.

The RNA helicase DDX21 is vital for ribosome biogenesis and is upregulated in CRC, but the mechanism by which DDX21 is dysregulated and by which DDX21 promotes tumorigenesis in CRC remains poorly understood. Here, we showed that DDX21 is a direct transcriptional target gene of β-catenin and mediates the protumorigenic function of β-catenin in CRC. DDX21 expression is correlated with the expression and activity of β-catenin, and high DDX21 expression is associated with a poor prognosis in CRC patients. Loss of DDX21 leads to cytoplasmic translocation and decreased transcriptional activity of YAP and suppresses the proliferation and migration of CRC cells, which can be partially rescued by YAP reactivation. Importantly, by using translation elongation inhibitors and DNA intercalators, we showed that ribosomal stress upregulates DDX21 expression and induces the downregulation of LATS and the activation of YAP, probably through the ZAKα-MKK4/7-JNK axis. Overall, our study revealed the transcriptional activation mechanism of DDX21 in CRC and the activation of YAP in the ribosomal stress response, indicating the potential of combination therapy involving the induction of ribosomal stress and YAP inhibition.

ABSTRACTThis study examines the possible consequence of elder mistreatment on resilience and whether social support moderates this posited association, using a rural sample of 432 community-dwelling older Chinese adults aged 60 to 79 years. Elder abuse included verbal abuse, physical abuse, or financial exploitation. Social support was measured by The Multidimensional Scale of Perceived Social Support (MSPSS). Resilience was represented by a seven-item scale. Hierarchical regression models indicated that mistreatment is significantly related to low levels of resilience when confounding factors are adjusted. A significant interaction term (abuse × social support) was also detected. Mistreated respondents who reported higher levels of social support were less likely to experience low resilience compared to those with lower levels of social support. Social support buffers against the undesirable effect of mistreatment on resilience, especially for those who were abused.

IκB kinase (IKK) complex is central regulators of the NF-κB pathway, and dysregulation of IKK phosphorylation leads to hyperactivation of proinflammatory response in various chronic inflammatory diseases, including inflammatory bowel disease (IBD). However, the dynamic modulation of IKK phosphorylation and dephosphorylation in intestinal inflammation remains uncharacterized. Here, we found that autophagy/beclin-1 regulator 1 (AMBRA1) was highly expressed in inflamed colons in a colitis mouse model and in clinical IBD samples. Importantly, AMBRA1 deletion significantly decreased proinflammatory cytokine expression and enhanced the therapeutic effect of infliximab on intestinal inflammation. Mechanistically, the N-term F1 domain of AMBRA1 was required for AMBRA1 to competitively interact with protein phosphatase 4 regulatory subunit 1 (PP4R1) and catalytic protein phosphatase 4 (PP4c) to suppress their interactions with IKK, promote the dissociation of the PP4R1/PP4c complex, and antagonize the dephosphorylation activity of this complex towards the IKK complex. In response to TNF-α stimulation, IKKα phosphorylates AMBRA1 at S1043 to stabilize AMBRA1 expression by impairing its binding to Cullin4A (CUL4A) to decrease its CUL4A-mediated K48-linked ubiquitination. Overall, our study identifies an autophagy-independent function of AMBRA1 as a positive modulator of IKK phosphorylation to promote intestinal inflammation, thus providing a new targeted therapeutic strategy for patients with refractory IBD.

While grinding has been employed as an important machining method to meet the workpiece quality requirement, the machined surface integrity of nickel based superalloy with/without coolants applied and under different cooling pressure has not been studied in detail regarding the subsurface microstructure and mechanical properties variation. This study gives a comprehensive investigation on the surface and subsurface characterization of workpieces machined with selected grinding conditions (dry, flood cooling and high pressure cooling), focusing on the in-depth exploration of the thermal influence on surface morphology generation, subsurface microstructure alteration, crystal orientation variation, and mechanical properties formation. The dry grinding process leads to significant subsurface material alternation in respect of both microstructure and mechanical properties. An obvious recrystallization and white layer are observed at the same time, which is an uncommon phenomenon in the former investigation of the ground surface. In addition, evident material soft is identified in the subsurface area of the workpiece acquired from the dry grinding scenario (hardness reduced to only half of the bulk materials in a large depth location). Interestingly, a plate-like ηphase is observed inside the grains, which is influenced by the extreme thermal load. As a comparison, the introduced coolant not only improves the surface morphology (Ra value reduced 3.8 % and 13.2 % with flood cooling and high pressure cooling, respectively) but also alters the subsurface properties to a more industrial and machining preferable state. Smooth surface, no recrystallization, less hardness variation (microhardness variation depths are 1400 μm, 800 μm, and 600 μm under dry, flood cooling, high pressure cooling conditions, respectively), and compressive residual stress are obviously found from the present study. It is found that high pressure cooling can sufficiently carry away the grinding generated heat in time and deliver the coolant into the grinding region, which improves the ground workpiece quality. These findings could be of help for choosing suitable cooling methods in the industry and help understand the obtained part/components quality.

Harvesting vibration energy during riding for powering on-board appliances has been demanded. However, few vibration energy harvesters on bicycle have been reported and the output power can hardly satisfy the requirement. A vibration energy harvester for bicycle is proposed based on a directional variable inertia flywheel and coaxial mechanical motion rectifier, in order to improve the output power and stability via improving the ratio of inertia and damping. The coaxial mechanical motion rectifier is designed to convert reciprocating rotation to unidirectional rotation, and the directional variable inertia flywheel is designed to extend the overrunning phase. Dynamic modeling with two-degree-of-freedom is proposed with the consideration of the nonlinear velocity response in the overrunning phase. The input force and output voltage are simulated with different input signals and external resistances. Lab tests demonstrate that the directional variable inertia flywheel is beneficial to increasing the output power, and maximum output power of 1.73 W is achieved. Finally, road tests of applying the vibration energy harvester on a bicycle are carried out, and average output power of 2.11 W and maximum power of 9.77 W are achieved.

Chatter vibration is apt to occur when machining thin-walled parts with insufficient rigidity. The harmful excitation of periodical cutting forces can be mitigated by enhancing the dynamic stiffness or increasing the damping of the part. A composite viscous damper including air damping and eddy current damping is designed, which can be attached on the thin-walled part by the vacuum. Based on the formulations of air damping and eddy current damping, the optimal equivalent viscous damping is derived for achieving the maximum critical depth of cut. Furthermore, the geometries of the damper are determined for damping a specific thin-walled part after investigating its relationship with viscous damping. The modal test indicates that the damper can suppress multiple modes of the cylindrical thin-walled part, and the amplitude of the first mode of the frequency response function (FRF) is reduced by 57%. The composite viscous damper is applied to suppress the chatter and resonant vibration of the thin-walled part during machining. Milling tests demonstrate that the machining vibration is reduced by 55% and 76% after employing single damper and four dampers, respectively.

Stretchable conductive fibers are key building blocks for constructing textile electronics. In this Preview, we highlight the scalable production of stretchable conductive fibers based on multimaterial thermal drawing and chemical deposition. The resulting fibers exhibit initial electrical conductivities up to 4,415 S/cm while retaining more than 500% stretchability. They can be further made into multifilaments, driving the development of textile electronics toward real-world applications.

Implantable sensors, especially ion sensors, facilitate the progress of scientific research and personalized healthcare. However, the permanent retention of implants induces health risks after sensors fulfill their mission of chronic sensing. Biodegradation is highly anticipated; while; biodegradable chemical sensors are rare due to concerns about the leakage of harmful active molecules after degradation, such as ionophores. Here, a novel biodegradable fiber calcium ion sensor is introduced, wherein ionophores are covalently bonded with bioinert nanoparticles to replace the classical ion‐selective membrane. The fiber sensor demonstrates comparable sensing performance to classical ion sensors and good flexibility. It can monitor the fluctuations of Ca2+in a 4‐day lifespan in vivo and biodegrade in 4 weeks. Benefiting from the stable bonding between ionophores and nanoparticles, the biodegradable sensor exhibits a good biocompatibility after degradation. Moreover, this approach of bonding active molecules on bioinert nanoparticles can serve as an effective methodology for minimizing health concerns about biodegradable chemical sensors. A biodegradable fiber calcium ion sensor is developed by covalently bonding ionophores on bioinert nanoparticles to replace the plasticized ion‐selective membrane. The sensor can monitor the fluctuation of Ca2+in vivo and completely degrade with good biocompatibility.

The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+ hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and it plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+ HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intraaortic hematopoietic cluster (IAHC) cells. The inflammatory mediators lipopolysaccharide and interferon-γ increase RUNX1+ HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.

The hematopoietic stem cells (HSCs) that produce blood for the lifetime of an animal arise from RUNX1+hemogenic endothelial cells (HECs) in the embryonic vasculature through a process of endothelial-to-hematopoietic transition (EHT). Studies have identified inflammatory mediators and fluid shear forces as critical environmental stimuli for EHT, raising the question of how such diverse inputs are integrated to drive HEC specification. Endothelial cell MEKK3-KLF2/4 signaling can be activated by both fluid shear forces and inflammatory mediators, and it plays roles in cardiovascular development and disease that have been linked to both stimuli. Here we demonstrate that MEKK3 and KLF2/4 are required in endothelial cells for the specification of RUNX1+HECs in both the yolk sac and dorsal aorta of the mouse embryo and for their transition to intraaortic hematopoietic cluster (IAHC) cells. The inflammatory mediators lipopolysaccharide and interferon-γ increase RUNX1+HECs in an MEKK3-dependent manner. Maternal administration of catecholamines that stimulate embryo cardiac function and accelerate yolk sac vascular remodeling increases EHT by wild-type but not MEKK3-deficient endothelium. These findings identify MEKK-KLF2/4 signaling as an essential pathway for EHT and provide a molecular basis for the integration of diverse environmental inputs, such as inflammatory mediators and hemodynamic forces, during definitive hematopoiesis.

Cancer metabolic reprogramming enhances its malignant behaviors and drug resistance, which is regulated by POU domain transcription factors. This study explored the effect of POU domain class 2 transcription factor 1 (POU2F1) on metabolic reprogramming in colon cancer. The POU2F1 expression was analyzed in GEO dataset, TCGA cohorts and human colon cancer tissues by bioinformatics and immunohistochemistry. The effects of altered POU2F1 expression on proliferation, glucose metabolism and oxaliplatin sensitivity of colon cancer cells were tested. The impacts of POU2F1 on aldolase A (ALDOA) expression and malignant behaviors of colon cancer cells were examined. We found that up-regulated POU2F1 expression was associated with worse prognosis and oxaliplatin resistance in colon cancer. POU2F1 enhanced the proliferation, aerobic glycolysis and the pentose phosphate pathway (PPP) activity, but reduced oxidative stress and apoptosis in colon cancer cells, dependent on up-regulating ALDOA expression. Mechanistically, POU2F1 directly bound to the ALDOA promoter to enhance the ALDOA promoter activity in colon cancer cells. Moreover, activation of the POU2F1-ALDOA axis decreased the sensitivity to oxaliplatin in colon cancer cells. These data indicate that the POU2F1-ALDOA axis promotes the progression and oxaliplatin resistance by enhancing metabolic reprogramming in colon cancer. Our findings suggest that the POU2F1-ALDOA axis may be new therapeutic targets to overcome oxaliplatin resistance in colon cancer.

Nonlinearities have been evidenced during the chatter vibration of milling. Machinability of the thin-walled part is feed rate and position-dependent, and is subject to process damping at low cutting speed. Therefore, chatter stability prediction of milling considering nonlinear cutting force, nonlinear structural stiffness and process damping is investigated. The cutting force and stiffness are established based on the polynomial model and the process damping is investigated based on the dissipated energy. The dynamic cutting force and stability lobes are solved in the time domain with coefficients updated at each iteration. By formulating the displacement as an expanded form via the perturbation method, the time-consuming solution of delay differential equations is avoided. After formulating the identification of the nonlinear model via cutting tests and modal tests, numerical simulations considering nonlinearities are carried out and compared with the analytical method. The proposed method attains high accuracy of classic time-domain solution, but with an improved computational efficiency. Finally, cutting tests are conducted to verify the prediction of cutting force and stability lobes.

The BCR–ABL fusion oncoprotein causes chronic myeloid leukemia or acute lymphoblastic leukemia in Ph+patients because the ABL kinase is constitutively activated. However, current clinical treatment with ABL inhibitors is seriously limited by drug resistance and adverse effects. Although the emerging proteolysis-targeting chimeras (PROTACs) have been introduced to degrade BCR–ABL, most of them showed limited activity and could not overcome the common drug-resistant mutants, especially for T315I mutant. Herein, we systematically designed a set of unique PROTACs by globally targeting all the three binding sites of BCR–ABL, including dasatinib-, ponatinib-, and asciminib-based PROTACs. Our ponatinib-based PROTACs showed practical activity as dasatinib-based PROTACs, while no reported ponatinib-based PROTACs could degrade BCR–ABL before. As a proof of concept, some additional dasatinib-based PROTACs were then designed to degrade T315I mutant too. We provided a global PROTAC toolbox for degrading both wild-type and T315I-mutated BCR–ABL from each binding site. More importantly, these PROTACs showed better selectivity and less adverse effects than the inhibitors, indicating that PROTACs had great potential for overcoming clinical drug resistance and safety issues.

3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) is an eight-pass transmembrane protein in the endoplasmic reticulum (ER) and a classical drug target to treat dyslipidemia. Statins including the well-known atorvastatin (Lipitor; Pfizer) have been widely used for the prevention and treatment of cardiovascular disease for decades. However, statins can elicit a compensatory upregulation of HMGCR protein and cause adverse effects including skeletal muscle damage. They are ineffective for patients with statin intolerance. Inspired by the recently emerging proteolysis-targeting chimeras (PROTACs), we set out to eliminate HMGCR protein using PROTAC-mediated degradation. One PROTAC designated as P22A was found to reduce HMGCR protein level and block cholesterol biosynthesis potently with less compensatory upregulation of HMGCR. To the best of our knowledge, HMGCR is the first ER-localized, polytopic transmembrane protein successfully degraded by the PROTAC technique. This finding may provide a new strategy to lower cholesterol levels and treat the associated diseases.

The vibration absorber has been effective in vibration control. From the demand of manufacturing structural parts with a deep hole, the design of a turning cutting tool with large length–diameter ratio is presented. An analytical approach of acquiring frequency response of primary structure equipped with typical single-degree-of-freedom vibration absorbers is formulated, and background modes are incorporated with the purpose of achieving an accurate tuning of vibration absorber. Specifically, the three-element type is investigated as the damping element of the vibration absorber embedded in the cutting tool contributes to the stiffness, although it demonstrates medium performance of vibration suppression according to non-dimensional analysis. The experimentally tuned frequency response function of the turning cutting tool with three-element vibration absorber achieves 87.1% reduction on the amplitude of the target mode. Finally, several configurations of internal turning operations are carried out to validate the design of the vibration absorber.

The cutter with large length-diameter ratio has wide applications in machining structural parts with deep cavity and deep hole features. However, chatter occurs as its declined dynamic stiffness. The impact damper has been utilised to suppress machining vibration due to its simplicity and effectivity. A turning cutter with large length-diameter ratio is designed based on embedded impact damper. The dynamic model is built based on mode superposition method. The influence of cutting force and damping parameters on velocity response status (linear and nonlinear) is analysed. Design parameters of the impact damper are optimised numerically for achieving linear response. Finally, modal tests and machining tests are conducted. The experimental results show that the surface roughness of workpiece (aluminium alloy 7075) is decreased from Ra 1.95 μm to Ra 1.28 μm when the spindle speed n = 500 r/min, feed rate f = 0.05 mm/r, and cutting depth ap= 0.40 mm.

The neural substrates for predatory hunting, an evolutionarily conserved appetitive behavior, remain largely undefined. Photoactivation of zona incerta (ZI) GABAergic neurons strongly promotes hunting of both live and artificial prey. Conversely, photoinhibition of these neurons or deletion of their GABA function severely impairs hunting. Here electrophysiological recordings reveal that ZI neurons integrate prey-related multisensory signals and discriminate prey from non-prey targets. Visual or whisker sensory deprivation reduces calcium responses induced by prey introduction and attack and impair hunting. ZI photoactivation largely corrects the hunting impairment caused by sensory deprivations. Motivational and reinforcing assays reveal that ZI photoactivation is associated with a strong appetitive drive, causing repetitive self-stimulatory behaviors. These ZI neurons project to the periaqueductal gray matter to induce hunting and motivation. Thus, we have delineated the function of ZI GABAergic neurons in hunting, which integrates prey-related sensory signals into prey detection and attack and induces a strong appetitive motivational drive. Sensory detection of prey triggers hunting actions in predators. Zhao et al. show that the zona incerta integrates prey-related multisensory signals and induces a motivational drive to guide prey detection and promote predatory attack.

Viral infections are increasing and probably long-lasting global risks. In this study, a chemical library was exploited by phenotypic screening to discover new antiviral inhibitors. After optimizations from hit to lead, a novel potent small molecule (RYL-634) was identified, showing excellent broad-spectrum inhibition activity against various pathogenic viruses, including hepatitis C virus, dengue virus, Zika virus, chikungunya virus, enterovirus 71, human immunodeficiency virus, respiratory syncytial virus, and others. The mechanism of action and potential targets of RYL-634 were further explored by the combination of activity-based protein profiling and other techniques. Finally, human dihydroorotate dehydrogenase was validated as the major target of RYL-634. We did not observe any mutant resistance under our pressure selections with RYL-634, and it had a strong synergistic effect with some Food and Drug Administration-approved drugs. Hence, there is great potential for developing new broad-spectrum antivirals based on RYL-634.

STAT6 is an attractive therapeutic target for human cancers and other human diseases. Starting from a STAT6 ligand with Ki= 3.5 μM binding affinity, we obtained AK-068 with Ki= 6 nM to STAT6 and at least >85-fold binding selectivity over STAT5. Using AK-068 and cereblon ligands, we discovered AK-1690 as the first, potent and selective PROTAC STAT6 degrader. AK-1690 effectively induces degradation of STAT6 protein in cells with DC50values of as low as 1 nM while showing minimal effect on other STAT members up to 10 μM. A single dose of AK-1690 effectively depletes STAT6 in mouse tissues. Determination of the first cocrystal structure of STAT6 in complex with AK-1690 provides a structural basis for their interactions. AK-1690 is a powerful tool with which to investigate the roles of STAT6 in human diseases and biological processes and a promising lead compound for further optimization.

Repairing high‐load connective tissues, such as ligaments, by surgically implanting artificial grafts after injury is challenging because they lack biointegration with host bones for stable interfaces. Herein, a high‐performance helical composite fiber (HCF) ligament by wrapping aligned carbon nanotube (CNT) sheets around polyester fibers is proposed. Anterior cruciate ligament (ACL) reconstruction surgery shows that HCF grafts could induce effective bone regeneration, thus allowing the narrowing of bone tunnel defects. Such repair of the bone tunnel is in strong contrast to the tunnel enlargement of more than 50% for commercial artificial ligaments made from bare polyester fibers. Rats reconstructed with this HCF ligament show normal jumping, walking, and running without limping. This work allows bone regeneration in vivo through a one‐step surgery without seeding cells or transforming growth factors, thereby opening an avenue for high‐performance artificial tissues. A biomimetic high‐performance fiber ligament is fabricated from helical polyester fibers wrapped in aligned carbon nanotube (CNT) sheets. This fiber ligament induces effective bone regeneration in vivo and thus enables the rats to jump, walk, and run normally without limping.

Brain-derived neurotrophic factor (BDNF) plays a crucial role in human obesity. Yet, the neural circuitry supporting the BDNF-mediated control of energy homeostasis remains largely undefined. To map key regions that might provide inputs to or receive inputs from the paraventricular nucleus (PVN) BDNF neurons, a key type of cells in regulating feeding and thermogenesis, we used rabies virus-based transsynaptic labeling and adeno-associated virus based anterograde tracing techniques to reveal their whole-brain distributions. We found that dozens of brain regions provide dense inputs to or receive dense inputs from PVN BDNF neurons, including several known weight control regions and several novel regions that might be functionally important for the BDNF-mediated regulation of energy homeostasis. Interestingly, several regions show very dense reciprocal connections with PVN BDNF neurons, including the lateral septum, the preoptic area, the ventromedial hypothalamic nucleus, the paraventricular thalamic nucleus, the zona incerta, the lateral parabrachial nucleus, the subiculum, the raphe magnus nucleus, and the raphe pallidus nucleus. These strong anatomical connections might be indicative of important functional connections. Therefore, we provide an outline of potential neural circuitry mediated by PVN BDNF neurons, which might be helpful to resolve the complex obesity network.

GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54−/−mice. These phenotypes were confirmed in chimeric mice with GPR54deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54−/−mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis (EAE) developed in the Gpr54−/−mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54−/−mice compared to the respective wild-type control, suggesting a defect in self-tolerance resulting from GPR54deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.

Porous SnO2@C@VO2composite hollow nanospheres were ingeniously constructed through the combination of layer-by-layer deposition and redox reaction. Moreover, to optimize the electrochemical properties, SnO2@C@VO2composite hollow nanospheres with different contents of the external VO2were also studied. On the one hand, the elastic and conductive carbon as interlayer in the SnO2@C@VO2composite can not only buffer the huge volume variation during repetitive cycling but also effectively improve electronic conductivity and enhance the utilizing rate of SnO2and VO2with high theoretical capacity. On the other hand, hollow nanostructures of the composite can be consolidated by the multilayered nanocomponents, resulting in outstanding cyclic stability. In virtue of the above synergetic contribution from individual components, SnO2@C@VO2composite hollow nanospheres exhibit a large initial discharge capacity (1305.6 mAhg–1) and outstanding cyclic stability (765.1 mAhg–1after 100 cycles). This design of composite hollow nanospheres may be extended to the synthesis of other nanomaterials for electrochemical energy storage.

Spleen is a large immune organ in the body. Splenic operations such as splenectomy and intrasplenic injection are of paramount importance for immunological research and splenic diseases. Fluorescence imaging can vastly simplify these operations, but a specific spleen‐targeting probe is still unavailable. Herein, the first specific spleen‐accumulated fluorescent probe, VIX‐S is reported, which fluoresces at 1064 nm and is highly stable. Systematic studies reveal the superior targeting and imaging performance of VIX‐S for the spleen in both nude and haired mice. In vivo imaging indicates that the probe can image the morphology of spleen with a signal‐background ratio of at least two‐fold higher than that of the liver. Moreover, the application of VIX‐S in imaging‐guided splenic operation, including splenic injury and intrasplenic injection, is demonstrated, which may provide a practice tool for spleen research in the animal model. A spleen‐accumulated fluorescent probe, VIX‐S, is reported which displays NIR‐II fluorescence and superior targeting ability toward spleen in mice. The probe is used to image the spleen in vivo clearly and demonstrates its application in imaging‐guided splenic operation, including splenic injury and intrasplenic injection.

The industrial robot has been employed in the field of machining processes due to its high flexibility, while its applications are restricted by the structural disadvantages (i.e., poor stiffness and low positional accuracy). The robotic high flexibility is evidenced by the ability of reaching a specified position through various postures. Therefore it is important to identify the dynamic behaviours of a specific point at different postures. The frequency responses of the cutter tip of a robot are measured by separating the working area into several layers. The result shows that dynamic characteristics are dependent on posture. The critical depth of cut is ranged from 0.35 mm to 0.93 mm by taking an example of spindle speed 2,000 rpm. And the critical depth of cut when feeding in Y direction is much larger than the X direction.

Cerebral cavernous malformations (CCMs) are a cause of stroke and seizure for which no effective medical therapies yet exist. CCMs arise from the loss of an adaptor complex that negatively regulates MEKK3–KLF2/4 signalling in brain endothelial cells, but upstream activators of this disease pathway have yet to be identified. Here we identify endothelial Toll-like receptor 4 (TLR4) and the gut microbiome as critical stimulants of CCM formation. Activation of TLR4 by Gram-negative bacteria or lipopolysaccharide accelerates CCM formation, and genetic or pharmacologic blockade of TLR4 signalling prevents CCM formation in mice. Polymorphisms that increase expression of the TLR4 gene or the gene encoding its co-receptor CD14 are associated with higher CCM lesion burden in humans. Germ-free mice are protected from CCM formation, and a single course of antibiotics permanently alters CCM susceptibility in mice. These studies identify unexpected roles for the microbiome and innate immune signalling in the pathogenesis of a cerebrovascular disease, as well as strategies for its treatment.

Rapid response and strong mechanical properties are desired for smart materials used in soft actuators. A bioinspired hybrid hydrogel actuator was designed and prepared by series combination of three trunks of tough polymer–clay hydrogels to accomplish the comprehensive actuation of “extension–grasp–retraction” like a fishing rod. The hydrogels with thermo-creep and thermo-shrinking features were successively irradiated by near-infrared (NIR) to execute extension and retraction, respectively. The GO in the hydrogels absorbed the NIR energy and transformed it into thermo-energy rapidly and effectively. The hydrogel with adhesion or magnetic force was adopted as the “hook” of the hybrid hydrogel actuator for grasping object. The hook of the hybrid hydrogel actuator was replaceable according to applications, even with functional materials other than hydrogels. This study provides an innovative concept to explore new soft actuators through combining response hydrogels and programming the same stimulus.

Based on the modeling of circular corner milling process, the implicit three-step four-order ADAMS numerical analysis method is presented in this article to solve the differential equation of milling dynamics, which considers non-uniform variation of the radial depth of cut and nonlinear feature of tool–workpiece system. The dynamic cutting forces are predicted in time domain and experimentally verified. On this basis, with comprehensive application of time-domain stability criteria for predicted data, the chatter stability of the milling process is simulated. The predicted stability lobe diagrams are compared against experimental results to confirm the validity of the simulation algorithm, which provides an effective way to optimize cutting parameters for circular corner milling.

Supplemental Digital Content is available in the text.

Low-frequency vibration suppression is challenging in practical engineering problems due to the harsh requirement for vibration reduction devices, which requires constant low stiffness over a wide amplitude range. A passive tuned mass damper (TMD) composed of a positive stiffness module (PSM) in parallel with a negative stiffness module (NSM) is proposed, which are implemented by serial double-parallelograms (DP) and parallel-DP, respectively. The PSM has a large deflection range of constant stiffness for a given beam length, while the NSM offers negative stiffness within a certain deflection range when applied with axial load above the critical threshold. Based on the closed-form modeling of the stiffness modules using the beam constraint model (BCM), the design and analysis of the PSM and NSM are carried out considering the nonlinearity under large deflections. Afterward, with the structure of TMD implemented, its stiffness characteristics and low-frequency tunability are experimentally validated. Finally, the application on a suspension bridge model shows that a maximum of 29.8-dB vibration reduction of low-frequency mode is attained within the frequency range of interest. The proposed TMD well attenuates the vibrations excited by sweep sinusoidal and harmonic excitations under prespecified threshold levels of acceleration.

Mammals must inflate their lungs and breathe within minutes of birth to survive. A key regulator of neonatal lung inflation is pulmonary surfactant, a lipoprotein complex which increases lung compliance by reducing alveolar surface tension (Morgan, 1971). Whether other developmental processes also alter lung mechanics in preparation for birth is unknown. We identify prenatal lymphatic function as an unexpected requirement for neonatal lung inflation and respiration. Mice lacking lymphatic vessels, due either to loss of the lymphangiogenic factor CCBE1 or VEGFR3 function, appear cyanotic and die shortly after birth due to failure of lung inflation. Failure of lung inflation is not due to reduced surfactant levels or altered development of the lung but is associated with an elevated wet/dry ratio consistent with edema. Embryonic studies reveal active lymphatic function in the late gestation lung, and significantly reduced total lung compliance in late gestation embryos that lack lymphatics. These findings reveal that lymphatic vascular function plays a previously unrecognized mechanical role in the developing lung that prepares it for inflation at birth. They explain respiratory failure in infants with congenital pulmonary lymphangiectasia, and suggest that inadequate late gestation lymphatic function may also contribute to respiratory failure in premature infants.

The secreted protein CCBE1 is required for lymphatic vessel growth in fish and mice, and mutations in the CCBE1gene cause Hennekam syndrome, a primary human lymphedema. Here we show that loss of CCBE1 also confers severe anemia in midgestation mouse embryos due to defective definitive erythropoiesis. Fetal liver erythroid precursors of Ccbe1null mice exhibit reduced proliferation and increased apoptosis. Colony-forming assays and hematopoietic reconstitution studies suggest that CCBE1 promotes fetal liver erythropoiesis cell nonautonomously. Consistent with these findings, Ccbe1lacZreporter expression is not detected in hematopoietic cells and conditional deletion of Ccbe1in hematopoietic cells does not confer anemia. The expression of the erythropoietic factors erythropoietin and stem cell factor is preserved in CCBE1 null embryos, but erythroblastic island (EBI) formation is reduced due to abnormal macrophage function. In contrast to the profound effects on fetal liver erythropoiesis, postnatal deletion of Ccbe1does not confer anemia, even under conditions of erythropoietic stress, and EBI formation is normal in the bone marrow of adult CCBE1 knockout mice. Our findings reveal that CCBE1 plays an essential role in regulating the fetal liver erythropoietic environment and suggest that EBI formation is regulated differently in the fetal liver and bone marrow.

The secreted protein CCBE1 is required for lymphatic vessel growth in fish and mice, and mutations in the CCBE1 gene cause Hennekam syndrome, a primary human lymphedema. Here we show that loss of CCBE1 also confers severe anemia in midgestation mouse embryos due to defective definitive erythropoiesis. Fetal liver erythroid precursors of Ccbe1 null mice exhibit reduced proliferation and increased apoptosis. Colony-forming assays and hematopoietic reconstitution studies suggest that CCBE1 promotes fetal liver erythropoiesis cell nonautonomously. Consistent with these findings, Ccbe1lacZ reporter expression is not detected in hematopoietic cells and conditional deletion of Ccbe1 in hematopoietic cells does not confer anemia. The expression of the erythropoietic factors erythropoietin and stem cell factor is preserved in CCBE1 null embryos, but erythroblastic island (EBI) formation is reduced due to abnormal macrophage function. In contrast to the profound effects on fetal liver erythropoiesis, postnatal deletion of Ccbe1 does not confer anemia, even under conditions of erythropoietic stress, and EBI formation is normal in the bone marrow of adult CCBE1 knockout mice. Our findings reveal that CCBE1 plays an essential role in regulating the fetal liver erythropoietic environment and suggest that EBI formation is regulated differently in the fetal liver and bone marrow.

The differential pulse voltammetric (DPV) indirect determination of aluminium using l-dopa under alkaline conditions on a glassy carbon working electrode was studied. The proposed method relies on the linear decrease of the DPV anodic peak current of l-dopa with increase in the concentration of aluminium added. Under the optimum experimental conditions (pH 8.5, 0.08 M NH₄Cl–NH₃·H₂O buffer solution, and 4 × 10⁻⁴ M l-dopa), the linear range is 2–18 × 10⁻⁷ M Al ^III. The detection limit is 7.6 × 10⁻⁸ M and the relative standard deviation for 8 × 10⁻⁷ M Al ^III is 3.5% (n = 8). A number of foreign species were examined as potential interferents. The method was applied to the determination of aluminium in drinking waters, synthetic renal dialysate, sodium chloride injection, sucrafate, hydrothorax, blood, urine and hair samples. The physiological significance is discussed.

Ethyl benzoate (EB), bis(2-ethyl hexyl) sebacate (BEHS), di-n-butyl phthalate (DNBP), and bis(2-ethyl hexyl) phthalate (BEHP) were employed as internal electron donors of heterogeneous Ziegler-Natta catalysts and the obtained polypropylene (PP) samples were fractionated by temperature rising elution fractionation (TREF). The influence of different internal donors on the tacticity distributions of PPs was compared. PPs have narrower tacticity distributions with aromatic esters. Based on TREF results, different interactions of internal donor, which may depend on their structures, were proposed. The effects of internal donors on microstructure of the fractions, especially the first fractions, were examined.

The multi-degrees-of-freedom (MDOF) tuned mass damper (TMD) has proven its ability to suppress multiple modes of interest, and it possesses less mounting space than multiple single degree-of-freedom TMDs of equal damping mass. However, it is challenging to implement the exact design of MDOF TMDs having expected vibration modes. The conceptual design of MDOF TMD containing visualized DOFs is first presented by the graphical approach, and the visualization of the quantitative relationship between the freedoms and constraints of TMD is attained. Then, dynamics modeling is analytically formulated by incorporating experimental data, and optimization of MDOF TMD considering background modes is performed. Two scenarios of MDOF TMD (i.e., 2DOFs TMD and 3DOFs TMD) are simulated. Vibration suppression of single dominant mode and multiple modes are achieved, corresponding to the case when the primary structure is subjected to wide and narrow band harmonic excitations, respectively. Afterward, a TMD with one rotational and two translational (1R2 T) DOFs is designed by embodying the geometric constraint patterns by flexible beams, and changeable elastic elements are incorporated. Experiments show that the first, second, and third bending modes of the cantilever beam are suppressed by 80.0%, 67.5%, and 61.2%, respectively, by the 3DOFs TMD for multiple modes suppression.

In the present work, predominantly syndiotactic polystyrene samples were prepared with different catalysts and polymerization conditions and the obtained polymers were used for assignments of stereochemical structures of polystyrene. Assignment was carried out by comparison of 13C NMR spectra of polystyrenes with different syndiotacticity and based on polymerization mechanism. Assignments were also compared with results in the previous work.