Gaussian curvature-driven direction of cell fate toward osteogenesis with triply periodic minimal surface scaffolds.

Leaf photosynthesis, coral mineralization, and trabecular bone growth depend on triply periodic minimal surfaces (TPMSs) with hyperboloidal structure on every surface point with varying Gaussian curvatures. However, translation of this structure into tissue-engineered bone grafts is challenging. This article reports the design and fabrication of high-resolution three-dimensional TPMS scaffolds embodying biomimicking hyperboloidal topography with different Gaussian curvatures, composed of body inherent ß-tricalcium phosphate, by stereolithography-based three-dimensional printing and sintering. The TPMS bone scaffolds show high porosity and interconnectivity. Notably, compared with conventional scaffolds, they can reduce stress concentration, leading to increased mechanical strength. They are also found to support the attachment, proliferation, osteogenic differentiation, and angiogenic paracrine function of human mesenchymal stem cells (hMSCs). Through transcriptomic analysis, we theorize that the hyperboloid structure induces cytoskeleton reorganization of hMSCs, expressing elongated morphology on the convex direction and strengthening the cytoskeletal contraction. The clinical therapeutic efficacy of the TPMS scaffolds assessed by rabbit femur defect and mouse subcutaneous implantation models demonstrate that the TPMS scaffolds augment new bone formation and neovascularization. In comparison with conventional scaffolds, our TPMS scaffolds successfully guide the cell fate toward osteogenesis through cell-level directional curvatures and demonstrate drastic yet quantifiable improvements in bone regeneration.

Physical Activity, Mental Activity, and Risk of Incident Stroke: A Prospective Cohort Study.

BACKGROUND: Cumulative evidence suggests a correlation between physical or mental activity and the risk of stroke. However, the combined impact of these activities on stroke onset remains unexplored. This study identified physical and mental activity patterns using principal component analysis and investigated their associations with risk of incident stroke in the general population. METHODS: Our study was sourced from the UK Biobank cohort between 2006 and 2010. Information on physical and mental-related activities were obtained through a touch-screen questionnaire. The incident stroke was diagnosed by physicians and subsequently verified through linkage to Hospital Episode Statistics. Principal component analysis was used to identify potential physical and mental activity patterns. Cox proportional hazard regression models were performed to calculate hazard ratios (HRs) and 95% CIs of incident stroke, adjusting for potential confounders. RESULTS: The initial UK Biobank cohort originally consisted of 502 411 individuals, of whom a total of 386 902 participants (aged 38-79 years) without any history of stroke at baseline were included in our study. During a median follow-up of 7.7 years, 6983 (1.8%) cases of stroke were documented. The mean age of the included participants was 55.9 years, and the proportion of women was 55.1%. We found that multiple individual items related to physical and mental activity showed significant associations with risk of stroke. We identified 4 patterns of physical activity and 3 patterns of mental activity using principal component analysis. The adherence to activity patterns of vigorous exercise, housework, and walking predominant patterns were associated with a lower risk of stroke by 17% (HR, 0.83 [95% CI, 0.78-0.89]; 20% (HR, 0.80 [95% CI, 0.75-0.85]; and 20% (HR, 0.80 [95% CI, 0.75-0.86), respectively. Additionally, the transportation predominant pattern (HR, 1.36 [95% CI, 1.28-1.45) and watching TV pattern (HR, 1.43 [95% CI, 1.33-1.53) were found to be significantly associated with a higher risk of stroke. These associations remained consistent across all subtypes of stroke. CONCLUSIONS: Activity patterns mainly related to frequent vigorous exercise, housework, and walking were associated with lower risks of stroke and all its subtypes. Our findings provide new insights for promoting suitable patterns of physical and mental activity for primary prevention of stroke.

Neutrophils Are Associated with Higher Risk of Incident Amyotrophic Lateral Sclerosis in a BMI- and Age-Dependent Manner.

OBJECTIVE: Peripheral immune markers have been associated with the progression and prognosis of amyotrophic lateral sclerosis (ALS). However, whether dysregulation of peripheral immunity is a risk factor for ALS or a consequence of motor neuron degeneration has not yet been clarified. We aimed to identify longitudinal associations between prediagnostic peripheral immunity and the risk of incident ALS. METHODS: A total of 345,000 individuals from the UK Biobank between 2006 and 2010 were included at the baseline. The counts of peripheral immune markers (neutrophils, lymphocytes, monocytes, platelets, and CRP) and its derived metrics (neutrophil-to-lymphocyte ratio [NLR], platelet-to-lymphocyte ratio [PLR], lymphocyte-to-monocyte ratio [LMR], and systemic immune-inflammation index [SII]) were analyzed in relation to the following incident ALS by Cox proportional hazard models. Subgroup and interaction analyses were performed to explore the covariates of these relationships further. RESULTS: After adjusting for all covariates, the multivariate analysis showed that high neutrophil counts and their derived metrics (NLR and SII) were associated with an increased risk of ALS incidence (per SD increment hazard ratio [HR] = 1.15, 95% confidence interval [CI] = 1.02-1.29 for neutrophils; HR = 1.15, 95% CI = 1.03-1.28 for NLR; and HR = 1.17, 95% CI = 1.05-1.30 for SII). Subgroup and interaction analyses revealed that body mass index (BMI) and age had specific effects on this association. In participants with BMI ≥ 25 or age < 65 years, higher neutrophil counts, and their metrics increased the risk of incident ALS; however, in participants with BMI < 25 or age ≥ 65 years, neutrophils had no effect on incident ALS. INTERPRETATION: Our study provides evidence that increased neutrophil levels and neutrophil-derived metrics (NLR and SII) are associated with an increased risk of developing ALS. ANN NEUROL 2023;94:942-954.

Accelerometer-measured physical activity, sedentary behavior, and risk of incident pelvic organ prolapse: a prospective cohort study in the UK Biobank.

BACKGROUND: Previous studies on physical activity (PA) and pelvic organ prolapse (POP) were largely limited to self-reported PA in athletes, soldiers, and women in postpartum. We aimed to investigate the association of accelerometer-measured PA and sedentary behavior with the risk of POP in middle-aged and elderly women. METHODS: In this prospective cohort derived from the UK Biobank, the intensity and duration of PA and sedentary behavior were measured with wrist-worn accelerometers over a 7-day period in 2013-2015 for 47,674 participants (aged 42.8-77.9 years) without pre-existing POP. Participants were followed up until the end of 2022, during which incident POP was ascertained mainly by the electronic health records. Multivariable-adjusted Cox proportional hazards models and restricted cubic splines were used to assess the associations of interest. Isotemporal substitution models were applied to test the effects of substituting a type of activity with equivalent duration of others. RESULTS: During a median follow-up of 8.0 years, 779 cases of POP were recorded. The duration of light-intensity PA (LPA) was positively whereas sedentary time was negatively associated with the risk of POP. Every additional 1 h/day of LPA elevated the risk of POP by 18% (95% confidence interval [CI], 10%-26%). In contrast, the risk decreased by 5% (95% CI, 0-8%) per 1 h/day increment in sedentary behavior. No associations were found between moderate-intensity PA (MPA) or vigorous-intensity PA (VPA) and POP, except that women who had a history of hysterectomy were more likely to develop POP when performing more VPA (53% higher risk for every additional 15 min/day). Substituting 1 h/day of LPA with equivalent sedentary time was associated with a 18% (95% CI, 11%-24%) lower risk of POP. The risk can also be reduced by 17% (95% CI, 7%-25%) through substituting 30 min/day of LPA with MPA. CONCLUSIONS: More time spent in LPA or less sedentary time was linked to an elevated risk of POP in middle-aged and elderly women, while MPA or VPA was not. Substituting LPA with equivalent duration of sedentary behavior or MPA may lower the risk of POP.

Translation and Validation of the Chinese Language Version of the Control of Allergic Rhinitis and Asthma Test in Patients with Allergic Rhinitis.

Objective: Due to the escalating global prevalence of allergic rhinitis (AR) and its status as an independent risk factor for asthma, timely and effective control of AR is crucial. Achieving this often involves the accurate assessment of AR. Currently, the Control of Allergic Rhinitis and Asthma Test (CARAT) is widely used as an assessment tool, but its measurement effectiveness in Chinese AR patients remains unclear. Therefore, this study aims to evaluate the reliability and validity of the Chinese version of the CARAT10 scale (CARAT10-C) and analyze its application value in the assessment of allergic rhinitis and asthma control trials. Methods: The study enrolled 130 patients with AR from the Ear, Nose, and Throat (ENT) outpatient department of a comprehensive teaching hospital from March to May 2022 as participants. The reliability and validity of the CARAT10-C scale were assessed using Cronbach's alpha coefficient (CAC), Kaiser-Meyer-Olkin (KMO), and Bartlett's sphericity test. Additionally, the study analyzed the effectiveness of the CARAT10-C scale in its application within the Control of Allergic Rhinitis and Asthma Test (CARAT). Results: The Cronbach's alpha coefficient ranges between 0 and 1, with higher values indicating better reliability. Significant differences in exploratory factor analysis suggest good validity. The Cronbach's alpha coefficient of the CARAT10-C scale was 0.806. Exploratory factor analysis revealed that the eigenvalues of Component 1 (3.851) and Component 2 (2.193) were both greater than 1, with a cumulative variance contribution rate (CVCR) of 60.436%. Items 6-10 were primarily loaded on Component 1 (Asthma), while items 1-4 were mainly influenced by Component 2 (AR), with loading ranges of 0.508-0.874, all significant at P < .001. The composite reliability (CAC) of the CARAT10-C scale was 0.806, exceeding 0.8, indicating high reliability. Component 1 had a CAC of 0.834, and Component 2 had a CACs of 0.807, both exceeding 0.8, indicating high reliability for both components. Conclusion: The CARAT10-C scale demonstrates good reliability and validity in the preliminary assessment of AR. It holds potential value in the evaluation and management of AR in China, although the specific application effects still require further investigation.

The associations of dietary patterns with depressive and anxiety symptoms: a prospective study.

BACKGROUND: Diet is increasingly recognized as an important risk factor for mental health. However, evidence regarding the association between diet pattern and depressive and anxiety symptoms is limited. We aimed to investigate the associations of dietary patterns characterized by a set of nutrients of interest with depressive and anxiety symptoms. METHODS: The analyses included a total of 126,819 participants in the UK Biobank who had completed at least two dietary questionnaires. Dietary data were obtained through 24-h dietary assessment at baseline between 2006 and 2010 and four rounds of online follow-ups between 2011 and 2012. Reduced rank regression was applied to derive dietary patterns (DPs) explaining variability in energy density, free sugars, saturated fat, and fiber intakes. Depressive and anxiety symptoms were measured by the Patient Health Questionnaire-9 and General Anxiety Disorder-7 between 2016 and 2017, respectively. Logistic regression models were performed to investigate the associations between dietary patterns and depressive and anxiety symptoms. RESULTS: During a mean follow-up of 7.6 years, 2746 cases of depressive symptoms and 2202 cases of anxiety symptoms were recorded. Three major DPs were derived, explaining 74% of the variation in nutrients hypothesized to be related to depressive and anxiety symptoms. DP1 was characterized by high intakes of chocolate, confectionery, butter, and low vegetable/fruit intakes. Compared to the lowest quintile of DP1, the odds ratio (95% confidence interval) of depressive symptoms for Q2-Q5 was 0.82 (0.72-0.93), 0.86 (0.76-0.98), 1.02 (0.90-1.15), and 1.17 (1.03-1.32), respectively. Compared to the lowest quintile of DP1, the odds ratio (95% CI) of anxiety symptoms for Q2-Q5 was 0.84 (0.73-0.97), 0.91 (0.79-1.05), 1.01 (0.88-1.15), and 1.18 (1.03-1.35), respectively. DP2 featured high intakes of sugar-sweetened beverages, added sugars, and low intakes of butter/cheese but showed no significant links to depressive or anxiety symptoms. DP3 was characterized by high butter and milk desserts and low alcohol/bread intakes. Compared to the lowest quintile of DP3, the odds ratio (95% CI) of depressive symptoms for Q2-Q5 was 0.90 (0.79-1.01), 1.00 (0.88-1.13), 1.06 (0.94-1.20), and 1.17 (1.03-1.32), respectively. Compared to the lowest quintile of DP3, the odds ratio (95% CI) of anxiety symptoms for Q2-Q5 was 0.90 (0.78-1.04), 1.05 (0.91-1.20), 1.02 (0.89-1.17), and 1.21 (1.05-1.38), respectively. CONCLUSIONS: A DP characterized by high intakes of chocolate and confectionery, butter, high-fat cheese, added sugars, along with low intakes of fresh fruit and vegetables, is associated with a higher risk of depressive and anxiety symptoms.

Ozone alleviates MSU-induced acute gout pain via upregulating AMPK/GAS6/MerTK/SOCS3 signaling pathway.

BACKGROUND: Gout pain seriously affects the quality of patients' life. There is still no effective treatment. The inflammatory response is the main mechanism of gout. Here, we found that ozone can reduce the inflammatory reaction in the joints of gouty mice and relieve gout pain, and we further explore its protective mechanism. METHODS: MSU was used to establish the gouty mice model. Nociception was assessed by Von Frey hairs. Cell signaling assays were performed by western blotting and immunohistochemistry. The mouse leukemia cells of monocyte macrophage line RAW264.7 were cultured to investigate the effects of ozone administration on macrophage. RESULTS: Ozone reduced inflammation, relieved gout pain and improved the paw mean intensity and duty cycle of the gouty mice. Ozone increased the phosphorylation of AMP-activated protein kinase (AMPK), induced suppressor of cytokine signaling 3 (SOCS3) expression and inhibited metallopeptidase 9 (MMP9) expression. In vivo, ozone activated AMPK to induce Gas6 release, and upregulated MerTK/SOCS3 signaling pathway to reduce inflammation in mouse macrophage line RAW264.7. Inhibitors of AMPK and MerTK, respectively abolished the analgesic and anti-inflammatory effects of ozone in vivo and in vitro. Gas6 knockout cancelled the protectively effects of ozone on gout pain and the paw mean intensity and duty cycle of gouty mice. Additionally, the level of Gas6 and protein S in plasma of patients with hyperuricemia was significantly higher than that of healthy contrast group. CONCLUSION: Ozone reduces inflammation and alleviates gout pain by activating AMPK to up-regulate Gas6/MerTK/SOCS3 signaling pathway.

Origin and adaptive evolution of UV RESISTANCE LOCUS 8-mediated signaling during plant terrestrialization.

UV RESISTANCE LOCUS 8 (UVR8) mediates photomorphogenic responses and acclimation to UV-B radiation by regulating the transcription of a series of transcription factors (TFs). However, the origin and evolution of UVR8-mediated signaling pathways remain largely unknown. In this study, we investigated the origin and evolution of the major components of the UVR8-mediated signaling pathway (UVR8, REPRESSOR OF UV-B PHOTOMORPHOGENESIS [RUP], BRI1-EMS-SUPPRESSOR1 [BES1], BES1-INTERACTING MYC-LIKE 1 (BIM1), WRKY DNA-BINDING PROTEIN 36 (WRKY36), MYB DOMAIN PROTEIN 73/77/13 [MYB73/MYB77/MYB13], and PHYTOCHROME INTERACTING FACTOR 4/5 [PIF4 and PIF5]) using comparative genomics and phylogenetic approaches. We showed that the central regulator UVR8 presented a conservative evolutionary route during plant evolution, and the evolutionary history of downstream negative regulators and TFs was different from that of green plant phylogeny. The canonical UVR8-CONSTITUTIVELY PHOTOMORPHOGENIC 1(COP1)/SUPPRESSOR OF PHYA-105 (SPA)-ELONGATED HYPOCOTYL 5 (HY5)-RUP signaling pathway originated in chlorophytes and conferred green algae the additional ability to cope with UV-B radiation. Moreover, the emergence of multiple UVR8-mediated signaling pathways in charophytes laid the foundations for the cross-talk between UV-B signals and endogenous hormone responses. Importantly, we observed signatures that reflect plant adaptations to high UV-B irradiance in subaerial/terrestrial environments, including positive selection in UVR8 and RUPs and increased copy number of some vital TFs. These results revealed that green plants not only experienced adaptive modifications in the canonical UVR8-COP1/SPA-HY5-RUP signaling pathway, but also diversified their UV-B signal transduction mechanisms through increasing cross-talk with other pathways, such as those associated with brassinosteroids and auxin. This study greatly expands our understanding of molecular evolution and adaptive mechanisms underlying plant UV-B acclimation.

Promoting AMPK/SR-A1-mediated clearance of HMGB1 attenuates chemotherapy-induced peripheral neuropathy.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of chemotherapy with poorly understood mechanisms and few treatments. High-mobility group box 1 (HMGB1)-induced neuroinflammation is the main cause of CIPN. Here, we aimed to illustrate the role of the macrophage scavenger receptor A1 (SR-A1) in HMGB1 clearance and CIPN resolution. METHODS: Oxaliplatin (L-OHP) was used to establish a CIPN model. Recombinant HMGB1 (rHMGB1) (his tag) was used to evaluate the phagocytosis of HMGB1 by macrophages. RESULTS: In the clinic, HMGB1 expression and MMP-9 activity were increased in the plasma of patients with CIPN. Plasma HMGB1 expression was positively correlated with the cumulative dose of L-OHP and the visual analog scale. In vitro, engulfment and degradation of rHMGB1 increased and inflammatory factor expression decreased after AMP-activated protein kinase (AMPK) activation. Neutralizing antibodies, inhibitors, or knockout of SR-A1 abolished the effects of AMPK activation on rHMGB1 engulfment. In vivo, AMPK activation increased SR-A1 expression in the dorsal root ganglion, decreased plasma HMGB1 expression and MMP-9 activity, and attenuated CIPN, which was abolished by AMPK inhibition or SR-A1 knockout in the CIPN mice model. CONCLUSION: Activation of the AMPK/SR-A1 axis alleviated CIPN by increasing macrophage-mediated HMGB1 engulfment and degradation. Therefore, promoting HMGB1 clearance may be a potential treatment strategy for CIPN. Video abstract.

The association of obesity-related dietary patterns and main food groups derived by reduced-rank regression with cardiovascular diseases incidence and all-cause mortality: findings from 116,711 adults.

PURPOSE: Research about using reduced-rank regression (RRR) to simultaneously study the effects of both individual and combined consumption of foods on cardiovascular diseases (CVD) is scarce. METHODS: This study included 116,711 CVD-free participants (a median of 11.8 year follow-up) with 2 or more 24-h online dietary assessments. A total of 210 food items were classified into 45 food groups, and the mean amount of each food group was used in RRR to derive dietary patterns (DPs) explaining the maximum shared variation in obesity-related indicators. The associations of DPs and its main food groups (|factor loading| [Formula: see text] 0.2) with the incident CVD and all-cause mortality were examined by Cox model. In cross-sectional analyses, the associations of DP scores with cardiometabolic risk factors (biomarkers) were examined by linear regression. RESULTS: The derived DP was characterized by higher intakes of beer and cider, high-sugar beverages, processed meat, red meat, artificial sweetener, and crisps, chips and savory snacks, and lower intakes of olive oil, high fiber breakfast cereals, tea, and vegetable. Compared to the lowest dietary score quintile, those in the highest were associated with higher risks of total CVD (adjusted-HR: 1.45, 95% CI 1.33-1.57) and all-cause mortality (adjusted-HR 1.31, 95% CI 1.18-1.45). We observed consumption alone of these food groups had a consistent but limited health effect on total CVD and all-cause death incidence. These associations were modified by age and sex. Higher DP scores were related to adverse biomarkers profiles. CONCLUSIONS: We developed obesity-related DPs prospectively associated with increased risks of CVD and all-cause mortality.

Study of 2,881 Nasal Bone Fractures using Multivariate Analysis.

Objective: This retrospective cohort study is aimed to provide a certain reference for the clinical prevention and treatment of nasal bone fracture, and further formulated a more perfect diagnosis and treatment plan. Methods: In detailed cases, 2881 patients with nasal bone fracture were recorded. Its general clinical data, cause of injury, fracture site, and fracture typing were collected through the database. All hospitalized patients admitted to the Ninth People's Hospital Affiliated to the School of Medicine of Shanghai Jiao Tong University with integrated medical records could be retrospectively included from June 2013 to July 2018 and comprehensively analyzed for their gender, age, fracture type and cause of injury. Results: The sex ratio of nasal bone fracture was 2.44:1. The most patients with nasal bone fracture were 19-29 years old (35.6%). The injury rate of traffic accidents was the highest, 33.8%, followed by violent strikes, 24.1%. Statistical analysis showed that the number of patients with nasal bone combined with maxillary frontal bone fracture and type II nasal bone fracture was significantly higher than other fracture types. Logistic multiple regression analysis showed that the relative risk of nasal bone fracture in men was lower (odds ratio, OR = 0.807, P < .05), and the risk of nasal bone fracture decreased with age (OR = 0.978, P < .001). Compared with car accident injury, the relative risk of simple nasal bone fracture comes from violence, exercise or collision [OR = 1.244, P < .05; OR = 1.410, P < .05; OR = 1.453, P < .05]). Conclusion: Given these findings, it's evident that nasal bone fractures exhibit distinct patterns based on individual characteristics, causes of trauma, and injury site, and relevant strategy research should be conducted.

Implantable Electronic Medicine Enabled by Bioresorbable Microneedles for Wireless Electrotherapy and Drug Delivery.

A combined treatment using medication and electrostimulation increases its effectiveness in comparison with one treatment alone. However, the organic integration of two strategies in one miniaturized system for practical usage has seldom been reported. This article reports an implantable electronic medicine based on bioresorbable microneedle devices that is activated wirelessly for electrostimulation and sustainable delivery of anti-inflammatory drugs. The electronic medicine is composed of a radio frequency wireless power transmission system and a drug-loaded microneedle structure, all fabricated with bioresorbable materials. In a rat skeletal muscle injury model, periodic electrostimulation regulates cell behaviors and tissue regeneration while the anti-inflammatory drugs prevent inflammation, which ultimately enhance the skeletal muscle regeneration. Finally, the electronic medicine is fully bioresorbable, excluding the second surgery for device removal.

Alkaline Phosphatase-Controllable and Red Light-Activated RNA Modification Approach for Precise Tumor Suppression.

RNA interference (RNAi) has proved to be a promising modality for disease treatment. However, the promise of conventional RNA therapeutics for clinical application is severely impeded by low delivery efficiency and susceptibility of RNAs to serum RNases. Therefore, developing advanced RNAi technology is an increasing demand for achieving precise medicine. Herein, for the first time, we propose an alkaline phosphatase (ALP)-controllable and red light-activated RNA modification (ALARM) approach for anti-tumor therapeutic application. An ALP-responsive NIR fluorogenic probe f-RCP consisting of a tumor-targeting cyclic RGD peptide, an ALP-activated photosensitizer CyOP, and an 1O2-susceptible furan module for RNA modification was rationally designed and synthesized. Studies have demonstrated that f-RCP can specifically target to liver carcinoma HepG2 cells and spontaneously emit activated NIR/photoacoustic signals upon cleavage by the ALP enzyme, allowing for sensitive detection of ALP-positive tumors. More notably, we surprisingly found that the capability of f-RCP producing singlet oxygen (1O2) under red light irradiation could be simultaneously unlocked, which can ignite the covalent cyclization reaction between furan and nucleobases of intracellular RNA molecules, leading to significant mitochondrial damage and severe apoptosis of tumor cells, in consequence realizing efficient tumor suppression. Most importantly, the potential therapeutic mechanism was first explored on the transcriptomic level. This delicate ALARM strategy may open up new insights into cancer gene therapy.

In Vivo Quantitative Assessment of a Radiation Dose Based on Ratiometric Photoacoustic Imaging of Tumor Apoptosis.

Accurately assessing the radiation level of tumors and surrounding tissues is of great significance for the optimization of clinical therapeutic interventions as well as minimizing the radiation-induced side effects. Therefore, the development of noninvasive and sensitive biological dosimeters is vital to achieve quantitative detection of a radiation dose in a living system. Herein, as a proof of concept, we report a tumor-targeted and caspase-3-activatable NIR fluorogenic probe AcDEVD-Cy-RGD consisting of a hemicyanine fluorophore as a signal reporter, a caspase-3 specific Asp-Glu-Val-Asp (DEVD) peptide, and a cyclic Arg-Gly-Asp peptide (cRGD) for tumor targeting. Upon cleavage with activated caspase-3, this probe not only displays the lighted-up NIR fluorescence, but also ratiometric photoacoustic (PA710/PA680) signals concurrently in a caspase-3 concentration-dependent manner, allowing for sensitive and quantitative detection of caspase-3 activity through both fluorescence and PA imaging, which provides the possibility for real-time monitoring of tumor cell apoptosis in a living system. More notably, we utilized this probe to successfully realize the direct visualization of tumor response to chemo- or radiotherapy and, for the first time, achieve the accurate estimation of radiation doses imparted to the tumors. We thus believe that our current strategy would offer an attractive and valuable means for the precise assessment of locally delivered radiation doses in various clinical settings.

Cardiometabolic diseases, total mortality, and benefits of adherence to a healthy lifestyle: a 13-year prospective UK Biobank study.

BACKGROUND: Cardiometabolic disease (CMD) increases the risk of mortality, but the extent to which this can be offset by adherence to a healthy lifestyle is unknown. We aimed to investigate whether and to what extent a combination of healthy lifestyle is associated with lower risk of total mortality that related to CMD. METHODS: Data for this prospective analysis was sourced from the UK Biobank with 356,967 participants aged 37 to 73 years between 2006 and 2010. Adherence to a healthy lifestyle was determined on the basis of four factors: no smoking, healthy diet, body mass index < 30 kg/m2, and regular physical activity. CMD was defined as any of incidence of diabetes, coronary heart disease and stroke at baseline. Cox proportional hazards models were used to calculate hazard ratios (HRs) and confidence intervals (CIs) of the associations of CMDs and lifestyle factors with total mortality. RESULTS: During a median follow-up of 13 years, a total of 21,473 death events occurred. The multivariable-adjusted HRs of mortality were 1.49 (95% CI 1.53-1.56) for one, 2.17 (95% CI 2.01-2.34) for two, and 3.75 (95% CI 3.04-4.61) for three CMDs. In joint exposure analysis, compared with CMDs-free and a favorable lifestyle, the HRs of mortality were 2.57 (95% CI 2.38-2.78) for patients with CMDs plus an unfavorable lifestyle and 1.58 (95% CI 1.50-1.66) for those with CMDs plus a favorable lifestyle. A favorable lifestyle attenuates the CMDs-related risk of mortality by approximately 63%. The mortality risk of CMDs-free people but have unfavorable lifestyle was higher than those who have over one CMDs but have favorable lifestyle. CONCLUSION: The potential effect of an increasing number of CMDs on total mortality appears additive, adherence to a healthy lifestyle may attenuate the CMDs-related mortality risk by more than 60%. These findings highlight the potential importance of lifestyle interventions to reduce risk of mortality across entire populations, even in patients with CMDs.

Risk of Accidents or Chronic Disorders From Improper Use of Mobile Phones: A Systematic Review and Meta-analysis.

BACKGROUND: Mobile phone use has brought convenience, but the long or improper use of mobile phones can cause harm to the human body. OBJECTIVE: We aimed to assess the impact of improper mobile phone use on the risks of accidents and chronic disorders. METHODS: We systematically searched in PubMed, EMBASE, Cochrane, and Web of Science databases for studies published prior to April 5, 2019; relevant reviews were also searched to identify additional studies. A random-effects model was used to calculate the overall pooled estimates. RESULTS: Mobile phone users had a higher risk of accidents (relative risk [RR] 1.37, 95% CI 1.22 to 1.55). Long-term use of mobile phones increased accident risk relative to nonuse or short-term use (RR 2.10, 95% CI 1.63 to 2.70). Compared with nonuse, mobile phone use resulted in a higher risk for neoplasms (RR 1.07, 95% CI 1.01 to 1.14), eye diseases (RR 2.03, 95% CI 1.27 to 3.23), mental health disorders (RR 1.16, 95% CI 1.02 to 1.32), and headaches (RR 1.25, 95% CI 1.18 to 1.32); the pooled risk of other chronic disorders was 1.20 (95% CI 0.90 to 1.59). Subgroup analyses also confirmed the increased risk of accidents and chronic disorders. CONCLUSIONS: Improper use of mobile phones can harm the human body. While enjoying the convenience brought by mobile phones, people have to use mobile phones properly and reasonably.

Origami-Inspired Structure with Pneumatic-Induced Variable Stiffness for Multi-DOF Force-Sensing.

With the emerging need for human-machine interactions, multi-modal sensory interaction is gradually pursued rather than satisfying common perception forms (visual or auditory), so developing flexible, adaptive, and stiffness-variable force-sensing devices is the key to further promoting human-machine fusion. However, current sensor sensitivity is fixed and nonadjustable after fabrication, limiting further development. To solve this problem, we propose an origami-inspired structure to achieve multiple degrees of freedom (DoFs) motions with variable stiffness for force-sensing, which combines the ductility and flexibility of origami structures. In combination with the pneumatic actuation, the structure can achieve and adapt the compression, pitch, roll, diagonal, and array motions (five motion modes), which significantly increase the force adaptability and sensing diversity. To achieve closed-loop control and avoid excessive gas injection, the ultra-flexible microfiber sensor is designed and seamlessly embedded with an approximately linear sensitivity of ∼0.35 Ω/kPa at a relative pressure of 0-100 kPa, and an exponential sensitivity at a relative pressure of 100-350 kPa, which can render this device capable of working under various conditions. The final calibration experiment demonstrates that the pre-pressure value can affect the sensor's sensitivity. With the increasing pre-pressure of 65-95 kPa, the average sensitivity curve shifts rightwards around 9 N intervals, which highly increases the force-sensing capability towards the range of 0-2 N. When the pre-pressure is at the relatively extreme air pressure of 100 kPa, the force sensitivity value is around 11.6 Ω/N. Therefore, our proposed design (which has a low fabrication cost, high integration level, and a suitable sensing range) shows great potential for applications in flexible force-sensing development.

Nephrotoxicity Assessment with Human Kidney Tubuloids using Spherical Nucleic Acid-Based mRNA Nanoflares.

Drug-induced nephrotoxicity represents an important cause of acute kidney injury with associated patient morbidity and mortality and is often responsible for termination of drug development, after extensive resource allocation. We have developed a human kidney tubuloid system that phenocopies, in 3D culture, kidney proximal tubules, a primary injury site of most nephrotoxicants. Traditional end point assays are often performed on 2D cultures of cells that have lost their differentiated phenotype. Herein, we pair a tubuloid system with Nanoflare (NF) mRNA nanosensors to achieve a facile, real-time assessment of drug nephrotoxicity. Using kidney injury molecule-1 (KIM-1) mRNA as a model injury biomarker, we verify NF specificity in engineered and adenovirus-transfected cells and confirm their efficacy to report tubular cell injury by aristolochic acid and cisplatin. The system also facilitates nephrotoxicity screening as demonstrated with 10 representative anticancer moieties. 5-Fluorouracil and paclitaxel induce acute tubular injury, as reflected by an NF signal increase.

The origin of SPA reveals the divergence and convergence of light signaling in Archaeplastida.

Plants have evolved various photoreceptors to adapt to changing light environments, and photoreceptors can inactivate the large CONSTITUTIVE PHOTOMORPHOGENIC/DE-ETIOLATED/FUSCA (COP/DET/FUS) protein complex to release their repression of photoresponsive transcription factors. Here, we tracked the origin and evolution of COP/DET/FUS in Archaeplastida and found that most components of COP/DET/FUS were highly conserved. Intriguingly, the COP1-SUPPRESSOR OF PHYA-105 (SPA) protein originated in Chlorophyta but subsequently underwent a distinct evolutionary history in Viridiplantae. SPA experienced duplication events in the ancestors of specific clades after the colonization of land by plants and was divided into two clades (clades A and B) within euphyllophytes (ferns and seed plants). Our phylogenetic and experimental evidences support a new evolutionary model to clarify the divergence and convergence of light signaling during plant evolution.

A network analysis framework of genetic and nongenetic risks for type 2 diabetes.

Both genetic and nongenetic factors have been found to be associated with type 2 diabetes, however, the correlation between them is still unclear. In the present study, we aimed to fully decipher the nongenetic and genetic factor association network for type 2 diabetes. We identified risk factors for type 2 diabetes by systematically searching for related meta-analyses and genome-wide association studies (GWAS) database. Among a total of 27,822 studies screened, 202 articles were eligible, from which 174 nongenetic factors and 210 genetic factors associated with type 2 diabetes were identified. Then, we obtained 584 associations between the nongenetic and genetic factors of type 2 diabetes, based on which a risk factor association network was conducted. The nongenetic factors could be classified into seven categories according to the Global Burden of Diseases (GBD). Of these seven categories of nongenetic factors, five were found to be correlated with genes associated with type 2 diabetes, including environmental risks, behavioral risks, metabolic risks, related disease of type 2 diabetes, and treatments. Specifically, air pollutants of environmental risks, alcohol using of behavioral risks, obesity of metabolic risks, rheumatoid arthritis of related disease risk, and simvastatin of treatment was correlated with the largest number of genes. In summary, the correlation between genetic factors and nongenetic factors identified in this study indicates that there is a common phenotype-genotype association in type 2 diabetes, with the combinations of genotypes ("genetic signature") clustering in phenotypes related to type 2 diabetes. Thus, we should take a systematic approach to explore the relationship of various factors for type 2 diabetes, as well as other noncommunicable diseases.