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Abstract Physical activity (PA) has been shown to reduce diabetes mortality, but largely based on imprecise self-reported data, which may hinder the development of related recommendations. Here, we perform a prospective cohort study of 4003 individuals with type 2 diabetes (T2D) from the UK Biobank with a median follow-up of 6.9 years. Duration and intensity of PA are measured by wrist-worn accelerometers over a 7-day period. We observe L-shaped associations of longer duration of PA, regardless of PA intensity, with risks of all-cause and cancer mortality, as well as a negatively linear association with cardiovascular disease mortality. 18.8%, 28.0%, and 31.1% of deaths are attributable to the lowest level of light-intensity PA, moderate-intensity PA, and vigorous-intensity PA, respectively. Collectively, our findings provide insights for clinical guidelines that should highlight the potential value of adherence to greater intensity and duration of PA for patients with T2D.

Sustainable travel behavior intervention is an essential strategy to promote the development of urban transportation. The interventions offer personalized strategies based on certain scenario and participants to promote its effectiveness over hard travel restrictions. However, personalized strategies may also bring about difficulties to identify the actual effect of the measures. Furthermore, based on current practice, to make full use of travel behavior interventions, it is necessary to construct a unified methodological evidence-based framework to assess the reliability and effectiveness of travel behavior intervention studies. In response to these issues, we applied evidence-based knowledge graph to the field of sustainable travel behavior interventions to help decision supporters design sustainable travel behavior interventions wisely and in turn avoid excessive use of hard travel restrictions. We introduced concept of evidence-based practice to conduct a systematic analysis concerning reliability and validity of current full volume empirical studies by dimensions of scenarios, types of interventions and targets. In addition, we took advantage of high extensivity and integrability of knowledge graph to organize evidence-based related elements. Result of the systematic analysis shows that in terms of reliability of evidence, school intervention is the best scenario, knowledge incentive is the best intervention type and promoting public transit and walking proportion are the best targets. Oppositely, the reliability of interventions in workplace, belonging to reward and threat along with aiming at changing travel patterns generally and lowering travel carbon emission need to be enhanced. From the study, various research prospects are raised to promote evidence quality in the field of travel behavior intervention implementation. As a pioneer study, our research contributes to the field of urban transportation in introducing concepts of evidence-based practice and enabling optimization and extension of our achievement via the usage of knowledge graph, enhancing reliability and objectivity in urban transportation decision-making.

Abstract Cryomicroneedles (cryoMNs) offer a convenient and minimally invasive way to precisely deliver therapeutic cells intradermally for treating local and systemic diseases. cryoMNs are manufactured by shaping and freezing the cell-containing cryogenic media in a microneedle template, which allows cells to be packaged in advance for direct usage in the clinic. However, the current cryoMNs require cold-chain transportation and storage and do not permit the loading of autologous cells in situ. This article introduces the second generation of cryoMNs (S-cryoMNs) that address these limitations. Specifically, S-cryoMNs are made by dipping a porous MN scaffold in the cell suspension before cryopreservation. The porous scaffold can be transported at room temperature, and researchers can load any cells with the optimized cryogenic medium. As a proof-of-concept, we examined the loading and intradermal delivery of three cell types in clinically relevant in vitro and in vivo models, including mesenchymal stem cells for wound healing, melanocytes for vitiligo treatment, and antigen-pulsed dendritic cells for cancer vaccination.

Abstract 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.

Background Depressive symptoms are established risk factors for various health outcomes. However, previous studies assessed depressive symptoms at a single time point, neglecting individual variations over time.Aims To identify depressive symptoms trajectories through repeated measures and examine their associations with cardiovascular disease (CVD), cancer and mortality.Methods This study included 20 634 UK Biobank participants free of CVD and cancer at baseline with two or more assessments of depressive symptoms during 2006–2016. Group-based trajectory modelling identified depressive symptoms trajectories. Incident CVD, cancer and mortality were followed up until 2021 through linked registries.Results Six depressive symptoms trajectories were identified: no symptoms (n=6407), mild-stable (n=11 539), moderate-stable (n=2183), severe-decreasing (n=206), moderate-increasing (n=177) and severe-stable (n=122). During a median follow-up of 5.5 years, 1471 CVD cases, 1275 cancer cases and 503 deaths were documented. Compared with the no symptoms trajectory, the mild-stable, moderate-stable and severe-stable trajectories exhibited higher CVD risk, with hazard ratios (HRs) (95% CIs) of 1.19 (1.06 to 1.34), 1.32 (1.08 to 1.34) and 2.99 (1.85 to 4.84), respectively. Moderate-increasing and severe-stable trajectories were associated with higher mortality risks, with HRs (95% CIs) of 2.27 (1.04 to 4.93) and 3.26 (1.55 to 6.88), respectively. However, the severe-decreasing trajectory was not associated with higher risks of adverse outcomes. We did not find significant associations between any trajectory and cancer.Conclusions Trajectories related to stable and increasing depressive symptoms, but not the trajectory associated with severe depressive symptoms at the initial assessment but decreasing at the follow-up, were associated with higher risks of CVD and mortality. Alleviating severe depressive symptoms at the initial onset may mitigate CVD and mortality risks.

Background Although lifestyle-based treatment approaches are recommended as important aspects of depression care, the quantitative influence of aggregated healthy lifestyles on depression recurrence and mortality remains unknown.Objective To investigate the association between healthy lifestyle and the risks of first-time hospitalisation for recurrent depression and mortality.Methods 26 164 adults with depression (mean (SD) age, 56.0 (7.9) years) were included from UK Biobank between 2006 and 2010 and followed up until 2022. Depression was defined as a physician’s diagnosis in hospital admissions or the use of prescribed antidepressant medication. A weighted healthy lifestyle score (HLS) was calculated based on smoking, alcohol consumption, diet, sleep pattern, physical activity, social health, employment status and greenspace interaction.Findings Over a 13.3-year follow-up, 9740 cases of first-time hospitalisation due to depression recurrence and 1527 deaths were documented. Compared with the lowest HLS tertile, the highest tertile was associated with a 27% lower risk (HR=0.73, 95% CI 0.69 to 0.77) of first-time hospitalisation for depression recurrence and a 22% (HR=0.78, 95% CI 0.68 to 0.91) lower risk of mortality among adults with depression. Lower risks of first-time hospitalisation for depression recurrence were observed among those who smoked less, drank more alcohol, followed healthier diets and sleep patterns, spent more time employed in current job or had greater exposure to greenspace.Conclusion and implications Greater adherence to healthy lifestyle was associated with a lower risk of hospitalisation and mortality among adults with pre-existing depression. Incorporating behaviour modification as an essential part of clinical practice for depressed patients could complement medication-based therapies.

Abstract Malignant melanoma (MM) is the most aggressive form of skin cancer. The delay in treatment will induce metastasis, resulting in a poor prognosis and even death. Here, a two‐step strategy for on‐site diagnosis of MM is developed based on the extraction and direct visual quantification of S100A1, a biomarker for melanoma. First, a swellable microneedle is utilized to extract S100A1 in skin interstitial fluid (ISF) with minimal invasion. After elution, antibody‐conjugated magnetic microparticles (MMPs) and polystyrene microparticles (PMPs) are introduced. A high expression level of S100A1 gives rise to a robust binding between MMPs and PMPs and reduces the number of free PMPs. By loading the reacted solution into the device with a microfluidic particle dam, the quantity of free PMPs after magnetic separation is displayed with their accumulation length inversely proportional to S100A1 levels. A limit of detection of 18.7 ng mL−1 for S100A1 is achieved. The animal experiment indicates that ISF‐based S100A1 quantification using the proposed strategy exhibits a significantly higher sensitivity compared with conventional serum‐based detection. In addition, the result is highly comparable with the gold standard enzyme‐linked immunosorbent assay based on Lin's concordance correlation coefficient, suggesting the high practicality for routine monitoring of melanoma.

Abstract 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.

Abstract The rapid diagnosis of respiratory virus infection through breath and blow remains challenging. Here we develop a wireless, battery-free, multifunctional pathogenic infection diagnosis system (PIDS) for diagnosing SARS-CoV-2 infection and symptom severity by blow and breath within 110 s and 350 s, respectively. The accuracies reach to 100% and 92% for evaluating the infection and symptom severity of 42 participants, respectively. PIDS realizes simultaneous gaseous sample collection, biomarker identification, abnormal physical signs recording and machine learning analysis. We transform PIDS into other miniaturized wearable or portable electronic platforms that may widen the diagnostic modes at home, outdoors and public places. Collectively, we demonstrate a general-purpose technology for rapidly diagnosing respiratory pathogenic infection by breath and blow, alleviating the technical bottleneck of saliva and nasopharyngeal secretions. PIDS may serve as a complementary diagnostic tool for other point-of-care techniques and guide the symptomatic treatment of viral infections.

Abstract Background The effects of insulin-like growth factor-1 (IGF-1) deficiency on cognitive decline have been consistently reported in animal studies, but the relationship between IGF-1 and human brain health remains controversial. Our study aimed to investigate the associations of serum IGF-1 concentrations with some brain-related disorders and neuroimaging features. Methods This prospective study included 369,711 participants (55.8 ± 8.1 years) from the UK biobank who had serum IGF-1 measured and were free from brain-related disorders of interest — dementia, stroke, and Parkinson’s disease (PD) — at enrollment (2006–2010). Restricted cubic splines and Cox proportional hazards models were used to detect the associations between IGF-1 concentrations and brain-related diseases. In addition, general linear regressions were applied to explore the relationship between IGF-1 concentrations and neuroimaging features (volumes of white matter, grey matter, and hippocampus and white matter hyperintensity) among a sub-sample of 36,458 participants with magnetic resonance imaging data collected since 2014. Results During a median follow-up of 12.6 years, a total of 4,857 dementia, 6,240 stroke, and 2,116 PD cases were documented. The dose–response analyses yielded U-shaped relationships between IGF-1 concentrations and risks of dementia and stroke (P

Abstract 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.

ObjectiveThe occurrence of immune-mediated diseases (IMDs) in amyotrophic lateral sclerosis (ALS) patients is widely reported. However, whether IMDs and ALS is a simple coexistence or if there exists causal relationships between the two has been a subject of great interest to researchers.MethodsA total of 454,444 participants from the prospective cohort of UK Biobank were recruited to investigate the longitudinal association between IMDs and ALS. Previously any IMDs and organ specific IMDs were analyzed in relation to the following incident ALS by Cox-proportional hazard models. Subgroup analyses were performed to explore the covariates of these relationships.ResultsAfter adjusting for potential covariates, the multivariate analysis showed that any IMDs were associated with an increased risk of ALS incidence (HR:1.42, 95%CI:1.03-1.94). IMDs of the endocrine-system and the intestinal-system were associated with increased risk of ALS incidence (endocrine-system IMDs: HR:3.01, 95%CI:1.49-6.06; intestinal system IMDs: HR:2.07, 95%CI: 1.14-3.77). Subgroup analyses revealed that immune burden, including IMD duration and the severity of inflammation had specific effects on the IMD-ALS association. In participants with IMD duration≥10 years or CRP≥1.3mg/L or females, previous IMDs increased the risk of incident ALS; however, in participants with IMD duration

Objective: We have developed a baroreceptor-inspired microneedle skin patch for pressure-controlled drug release. Impact Statement: This design is inspired by the skin baroreceptors, which are mechanosensitive elements of the peripheral nervous system. We adopt the finger touching to trigger the electric stimulation, ensuring a fast-response and user-friendly administration with potentially minimal off-target effects. Introduction: Chronic skin diseases bring about large, recurrent skin damage and often require convenient and timely transdermal treatment. Traditional methods lack spatiotemporal controllable dosage, leaving a risk of skin irritation or drug resistance issues. Methods: The patch consists of drug-containing microneedles and stretchable electrode array. The electrode array, integrated with the piezoconductive switch and flexible battery, provides a mild electric current only at the spot that is pressed. Drugs in microneedles will then flow along the current into the skin tissues. The stretchable feature also provides the mechanical robustness and electric stability of the device on large skin area. Results: This device delivers Cy3 dye in pig skin with spatiotemporally controlled dosage, showing ~8 times higher fluorescence intensity than the passive delivery. We also deliver insulin and observe the reduction of the blood glucose level in the mouse model upon pressing. Compared with passive delivery without pressing, the dosage of drugs released by the simulation is 2.83 times higher. Conclusion: This baroreceptor-inspired microneedle skin patch acts as a good example of the biomimicking microneedle device in the precise control of the drug release profile at the spatiotemporal resolution.

Transdermal drug delivery systems (TDDs) avoid gastrointestinal degradation and hepatic first-pass metabolism, providing good drug bioavailability and patient compliance. One emerging type of TDDs is the wearable patch worn on the skin surface to deliver medication through the skin. They can generally be grouped into passive and active types, depending on the properties of materials, design principles and integrated devices. This review describes the latest advancement in the development of wearable patches, focusing on the integration of stimulus-responsive materials and electronics. This development is deemed to provide a dosage, temporal, and spatial control of therapeutics delivery.

Abstract 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 core of agricultural product supply chain management is to emphasise the use of integrated thoughts and concepts to guide the management practices of enterprises. That is, the operation of the entire supply chain is guided by consumer demand rather than the individual management of links, and the entire supply chain is strictly controlled as a system. Based on big data technology, this paper constructs a high-performance agricultural product recommendation algorithm. Aiming at the lagging construction of my country’s agricultural product supply chain network facilities, low integration of various operating links, high logistics costs, imbalances in supply and demand, and serious agricultural product quality and safety issues, this paper combines the big data technology to study the agricultural product intelligent supply chain system, and uses the network equilibrium method to construct the agricultural product supply chain network model that considers the effort level of multiple producers and retailers. Finally, this paper proves the reliability of the system model in this paper through experimental research.

Abstract Background Growing evidence has showed an association between habitual glucosamine use and type 2 diabetes (T2D). However, the effect of habitual glucosamine use on risk of dementia remains poorly understood. Our study aimed to examine the association between glucosamine use and risk of dementia and further to identify the mediating role of T2D in the association. Methods A total of 495,942 participants from UK Biobank who completed a questionnaire on habitual glucosamine use were included at baseline (2006–2010) and then followed up for incidence of dementia until 2020. Cox proportional hazard regressions were performed to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident dementia. Markov multi-state models were used to explore the role of incidence of T2D during the follow-up in the association. Results Overall, 18.80% of the participants reported habitual use of glucosamine at baseline. A total of 6831 dementia events were recorded during a median follow-up of 11 years. In fully adjusted models, habitual glucosamine use was associated with a significantly lower risk of dementia (HR = 0.87, 95% CI: 0.82–0.93). Multi-state models showed that the association between glucosamine use and dementia was mediated by the incidence of T2D during the follow-up (HR of dementia without T2D: 0.92, 95% CI: 0.86–0.99; HR of post-T2D dementia: 0.79, 95% CI: 0.67–0.93). Conclusions Our findings reveal that habitual use of glucosamine supplement is associated with a lower risk of dementia, which might be explained by incidence of T2D.

Background The evidence regarding the association between leucocyte telomere length (LTL) and brain health is sparse and inconclusive.Aims To investigate the associations of LTL with brain structure and the risk of dementia based on a large-scale prospective study.Methods LTL in the peripheral blood was measured by the quantitative polymerase chain reaction (qPCR) assay from 439 961 individuals in the UK Biobank recruited between 2006 and 2010 and followed up until 2020. Electronic health records were used to record the incidence of dementia, including Alzheimer’s disease (AD) and vascular dementia (VD). The brain structure, including total and regional brain volume, of 38 740 participants was then assessed by magnetic resonance imaging (MRI).Results During a median follow-up of 11.6 years, a total of 5 820 (1.3%) dementia cases were documented. The restricted cubic spline model showed significant overall associations between LTL and the risk of dementia and AD (p for overall

Abstract Combinational immunotherapy of dendritic cell (DC) vaccines and anti‐programmed cell death protein 1 antibodies (aPD1) has been regarded as a promising strategy for cancer treatment because it not only induces tumor‐specific T cell immune responses, but also prevents failure of T cell functions by the immune suppressive milieu of tumors. Microneedles have emerged as an innovative platform for efficient transdermal immunotherapies. However, co‐delivery of DC vaccines and aPD1 via microneedles has not been studied since conventional microneedle platforms are unsuitable for fragile therapeutics like living cells and antibodies. This study employs our newly invented cryomicroneedles (cryoMNs) to co‐deliver DC vaccines and aPD1 for the combinational immunotherapy. CryoMNs are fabricated by stepwise cryogenic micromoulding of cryogenic medium with pre‐suspended DCs and aPD1, which are further integrated with a homemade handle for convenient application. The viability of DCs in cryoMNs remains above 85%. CryoMNs are mechanically strong enough to insert into porcine and mouse skin, successfully releasing DCs and aPD1 inside skin tissue after melting. Co‐delivery of ovalbumin (OVA)‐pulsed DCs (OVA‐DCs) and aPD1 via cryoMNs induced higher antigen‐specific cellular immune responses compared with the mono‐delivery of OVA‐DCs or aPD1. Finally, administration with cryoMNs co‐encapsulated with OVA‐DCs and aPD1 increases the infiltration of effector T cells in the tumor, resulting in stronger anti‐tumor therapeutic efficacy in both prophylactic and therapeutic melanoma models compared with administration with cryoMNs loaded with OVA‐DCs or aPD1. This study demonstrates the great potential of cryoMNs as a co‐delivery system of therapeutic cells and biomacromolecules for combinational therapies.

Abstract Microneedle (MN)‐based diagnostic devices can efficiently access skin interstitial fluid (ISF) for accurate and minimally invasive detection of health‐related biomarkers. This work reports a biomarker (i.e., glucose or alcohol) monitoring MN device that is composed of swellable MNs and electrochemical test strip. This device is constructed by adhering MN patch on the electrochemical strips using the chitosan as the connecting layer. The MNs penetrate the skin for extraction of ISF that flows to the backing layer of MNs and is analyzed by the test strip. In the in vitro skin models, this device accurately detects the glucose from 0 mM to 12 mM and alcohol from 0 mM to 20 mM. In vivo experiment shows this MN device is capable of minimally invasive sampling of ISF and analysis of glucose levels to determine the glycemic status of mice.

Engineering peptide assembly that controls integrin ligand presentation on the molecular level possesses by far the highest ligand density, expanding the perspective of ligand-density-dependent modulation.

To improve the specificity of immunotherapy, here the authors report the design of a semiconducting polymer immunomodulatory nanoparticle with sonodynamic process to remotely release immune-modulators for deep-tissue precision cancer sono-immunotherapy.

Abstract 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

PurposeTo investigate information-seeking behavior related to urticaria before and during the COVID-19 pandemic in China.MethodsSearch query data for terms related to urticaria were retrieved using Baidu Index database from October 23, 2017 to April 23, 2022, and daily COVID-19 vaccination doses data were obtained from the website of the Chinese Center for Disease Control and Prevention. Among the 23 eligible urticaria search terms, four urticaria themes were generated as classification, symptom, etiology, and treatment of urticarial, respectively. Baidu Search Index (BSI) value for each term were extracted to analyze and compare the spatial and temporal distribution of online search behavior for urticaria before and after the COVID-19 pandemic, and to also explore the correlation between search query and daily COVID-19 vaccination doses.ResultsThe classification of urticaria accounted for nearly half of the urticaria queries on the internet. Regular seasonal patterns of BSI were observed in urticaria-related online search, by attaining its highest level in spring and summer and lowest level in winter. The BSIs of all urticaria themes significantly increased after the COVID-19 pandemic than that before the pandemic (all P

Co-delivery of chemotherapeutics and immunostimulant or chemoimmunotherapy is an emerging strategy in cancer therapy. The precise control of the targeting and release of agents is critical in this methodology. This article proposes the asynchronous release of the chemotherapeutic agents and immunostimulants to realize the synergistic effect between chemotherapy and immunotherapy. To obtain a proof-of-concept, a co-delivery system was prepared via a drug-delivering-drug (DDD) strategy for cytosolic co-delivery of Poly I:C, a synthetic dsRNA analog to activate RIG-I signaling, and PTX, a commonly used chemotherapeutics, in which pure PTX nanorods were sequentially coated with Poly I:C and mannuronic acid via stimulating the RIG-I signaling axis. The co-delivery system with a diameter of 200 nm enables profound immunogenicity of cancer cells, exhibiting increased secretion of cytokines and chemokines, pronounced immune response in vivo, and significant inhibition of tumor growth. Also, we found that intracellularly sustained release of cytotoxic agents could elicit the immunogenicity of cancer cells. Overall, the intracellular asynchronous release of chemotherapeutics and immunomodulators is a promising strategy to promote the immunogenicity of cancer cells and augment the antitumor immune response.

Hypertrophic scars are unfavorable skin diseases characterized by excessive collagen deposition. Although systemic treatments exist in clinic to manage hypertrophic scars, they pose significant side effects and tend to lose efficacy over prolonged applications. Traditional Chinese medicine (TCM) offers as a promising candidate to treat pathological scars. A large number of TCMs have been studied to show anti-scarring effect, however, the natural barrier of the skin impedes their penetration, lowering its therapeutic efficacy. Herein, we reported the use of dissolvable hyaluronic acid (HA) microneedles (MNs) as a vehicle to aid the transdermal delivery of therapeutic agent, a model TCM called shikonin for the treatment of hypertrophic scars. Here, shikonin was mixed with HA to make MNs with adequate mechanical strength for skin penetration, making its dosage controllable during the fabrication process. The therapeutic effect of the shikonin HA MNs was studied in vitro using HSFs and then further verified with quantitative reverse transcriptase polymerase chain reaction. Our data suggest that the shikonin HA MNs significantly reduce the viability and proliferation of the HSFs and downregulate the fibrotic-related genes (i.e., TGFβ1, FAP-α and COL1A1). Furthermore, we observed a localized therapeutic effect of the shikonin HA MNs that is beneficial for site-specific treatment.

Abstract Background Migraine constitutes a global health burden, and its pathophysiology is not well-understood; research evaluating cerebral perfusion and altered blood flow between brain areas using non-invasive imaging techniques, such as arterial spin labeling, have been scarce. This study aimed to assess cerebral blood flow (CBF) and its connectivity of migraine. Methods This study enrolled 40 patients with episodic migraine without aura (MwoA), as well as 42 healthy patients as control (HC). Two groups of normalized CBF and CBF connectivity were compared, and the relationship between CBF variation and clinical scale assessment was further evaluated. Results In comparison to HC subjects, MwoA patients exhibited higher CBF in the right middle frontal orbital gyrus (ORBmid.R) and the right middle frontal gyrus, while that in Vermis_6 declined. The increased CBF of ORBmid.R was positively correlated with both the Visual Light Sensitivity Questionnaire-8 (VLSQ-8) and the monthly attack frequency score. In MwoA, significantly decreased CBF connectivity was detected between ORBmid.R and the left superior frontal gyrus, the right putamen, the right caudate, as well as the right angular gyrus. In addition, increased CBF connectivity was observed between the left calcarine cortex and ORBmid.R. Conclusions Our results indicate that migraine patients exhibit abnormalities in regional CBF and feature CBF connection defects at the resting state. The affected areas involve information perception, information integration, and emotional, pain and visual processing. Our findings might provide important clues for the pathophysiology of migraine.

Transdermal biosensing focuses on the qualitative and quantitative collection and detection of biomarkers on and in the skin layers. In comparison to the blood‐based diagnosis, transdermal sensing technologies provide pain‐free, convenient, patient‐friendly, and infection‐avoiding methods to collect biosignals from transdermal samples such as interstitial fluid (ISF) and sweat. This article summarizes the latest trends in transdermal biosensing including the technologies and their application blueprints. Specifically, the current transdermal biosensing technologies including microneedles, microfluidics, and reverse iontophoresis are introduced first. Subsequently, their roles in daily health status monitoring, disease diagnosis and therapy monitoring are discussed in detail. Finally, an overview of the future blueprints and application prospects of transdermal biosensing is provided.

Abstract Background Granger causality analysis (GCA) has been used to investigate the pathophysiology of migraine. Amygdala plays a key role in pain modulation of migraine attack. However, the detailed neuromechanism remained to be elucidated. We applied GCA to explore the amygdala-based directional effective connectivity in migraine without aura (MwoA) and to determine the relation with clinical characteristics. Methods Forty-five MwoA patients and forty age-, sex-, and years of education-matched healthy controls(HCs) underwent resting-state functional magnetic resonance imaging (fMRI). Bilateral amygdala were used as seed regions in GCA to investigate directional effective connectivity and relation with migraine duration or attack frequency. Results MwoA patients showed significantly decreased effective connectivity from right amygdala to right superior temporal gyrus, left superior temporal gyrus and right precentral gyrus compared with HCs. Furthermore, MwoA patients demonstrated significantly decreased effective connectivity from the left amygdala to the ipsilateral superior temporal gyrus. Also, MwoA patients showed enhanced effective connectivity from left inferior frontal gyrus to left amygdala. Effective connectivity outflow from right amygdala to right precentral gyrus was negatively correlated to disease duration. Conclusions Altered directional effective connectivity of amygdala demonstrated that neurolimbic pain networks contribute to multisensory integration abnormalities and deficits in pain modulation of MwoA patients.

The initiation and development of major inflammatory diseases, i.e., cancer, vascular inflammation, and some autoimmune diseases are closely linked to the immune system. Biologics-based immunotherapy is exerting a critical role against these diseases, whereas the usage of the immunomodulators is always limited by various factors such as susceptibility to digestion by enzymes in vivo, poor penetration across biological barriers, and rapid clearance by the reticuloendothelial system. Drug delivery strategies are potent to promote their delivery. Herein, we reviewed the potential targets for immunotherapy against the major inflammatory diseases, discussed the biologics and drug delivery systems involved in the immunotherapy, particularly highlighted the approved therapy tactics, and finally offer perspectives in this field.

Abstract An effective wound management strategy needs accurate assessment of wound status throughout the whole healing process. This can be achieved by examining molecular biomarkers including proteins, DNAs, and RNAs. However, existing methods for quantifying these biomarkers such as immunohistochemistry and quantitative polymerase chain reaction are usually laborious, resource‐intensive, and disruptive. This article reports the development and utilization of mRNA nanosensors (i.e., NanoFlare) that are topically applied on cutaneous wounds to reveal the healing status through targeted and semi‐quantitative examination of the mRNA biomarkers in skin cells. In 2D and 3D in vitro models, the efficacy and efficiency of these nanosensors are demonstrated in revealing the dynamic changes of mRNA biomarkers for different stages of wound development. In mouse models, this platform permits the tracking and identification of wound healing stages and a normal and diabetic wound healing process by wound healing index in real time.

Summary: Background: As one of the most common lifestyles today, sedentary behaviour is a risk factor for many health conditions. To inform potential behavioural guideline development, we aimed to estimate the theoretical effects of replacing sedentary behaviour with different intensity of physical activity on risks of 45 common non-communicable diseases (NCDs). Methods: A total of 360,047 participants (aged 37-73 years) in the UK Biobank free of the 45 common non-communicable diseases (NCDs) were included. Information on sedentary time (sum of television watching, computer using and driving behaviour) and physical activity (measured by International Physical Activity Questionnaire questionnaire) were collected by self-reported at baseline. Participants were followed up for 45 NCDs diagnosis according to the ICD-10 code using linkage to national health records until 2020. Isotemporal substitution models were used to investigate substituting sedentary time with light physical activity (LPA), moderate physical activity (MPA) and vigorous physical activity (VPA) after adjusting for potential confounders. Finding: Participants who reported > 6 h/day compared with ≤ 2 h/day sedentary time had higher risks of 12 (26.7%) of 45 NCDs, including ischemic heart disease, diabetes, chronic obstructive pulmonary disease, asthma, chronic kidney disease, chronic liver disease, thyroid disorder, depression, migraine, gout, rheumatoid arthritis and diverticular disease. Theoretically, replacing sedentary time with equivalent LPA, MPA and VPA was associated with risk reductions in 4, 6 and 10 types of NCDs, respectively. Among long sedentary time (> 6 h/day), replacing 1 h/day sedentary time with equivalent VPA showed stronger associations with 5 NCDs (diabetes, depression, chronic liver disease, diverticular disease and sleep disorder), with a larger risk reduction of 11%-31%. Interpretation: Sedentary time is associated with multiple adverse health conditions, replacing sedentary time with any equivalent amounts of VPA than LPA and MPA could be associated with risk reductions of more types of NCDs. Funding: National Natural Science Foundation of China.

Doxorubicin induces severe cardiotoxicity, accompanied by the high level of bilirubin in the blood. The conventional wisdom is that bilirubin is considered as a marker of liver damage. By contrast, here we aim to explore the potential protective effect of bilirubin on doxorubicin-induced cardiotoxicity, and investigate the mechanism for drug development. Doxorubicin was used to establish cardiotoxicity model in vitro and in vivo. The electrocardiogram (ECG), echocardiography and molecular biological methods were used to detect the effects of bilirubin on doxorubicin-induced cardiotoxicity. Consecutive intraperitoneal injection of bilirubin for 7 days significantly attenuated doxorubicin-induced arrhythmia, prolonged survival time and reduced the levels of aspartate aminotransferase (AST), lactate dehydrogenase (LDH), creatine kinase MB (CK-MB) and α-hydroxybutyrate dehydrogenase (α-HBDH) in mice. Bilirubin also markedly inhibited doxorubicin-induced phosphorylation of c-Jun N-terminal kinase (JNK) and connexin 43 (Cx43), and improved gap junction function in vitro and in vivo. In addition, bilirubin activated adenosine 5′-monophosphate (AMP)-activated protein kinase (AMPK) and induced suppressor of cytokine signaling 3 (SOCS3) expression, which was abolished by Axl inhibition. Moreover, pretreatment with AMPK agonist or AMPK inhibitor could mimic or abolish the cardioprotective effect of bilirubin on H9C2 cells in vitro, respectively. Altogether, bilirubin upregulates gap junctions’ function to protect against doxorubicin-induced cardiotoxicity by activating AMPK-Axl-SOCS3 signaling axis. We enrich the physiological function of bilirubin, and provide theoretical support for drug development.

Injuries within the peripheral nervous system (PNS) lead to sensory and motor deficits, as well as neuropathic pain, which strongly impair the life quality of patients. Although most current PNS injury treatment approaches focus on using growth factors/small molecules to stimulate the regrowth of the injured nerves, these methods neglect another important factor that strongly hinders axon regeneration—the presence of axonal inhibitory molecules. Therefore, this work sought to explore the potential of pathway inhibition in promoting sciatic nerve regeneration. Additionally, the therapeutic window for using pathway inhibitors was uncovered so as to achieve the desired regeneration outcomes. Specifically, we explored the role of Wnt signaling inhibition on PNS regeneration by delivering Wnt inhibitors, sFRP2 and WIF1, after sciatic nerve transection and sciatic nerve crush injuries. Our results demonstrate that WIF1 promoted nerve regeneration ( p

Atherosclerosis (AS) is a lipid-driven chronic inflammatory disease occurring at the arterial subendothelial space. Macrophages play a critical role in the initiation and development of AS. Herein, targeted codelivery of anti-miR 155 and anti-inflammatory baicalein is exploited to polarize macrophages toward M2 phenotype, inhibit inflammation and treat AS. The codelivery system consists of a carrier-free strategy (drug-delivering-drug, DDD), fabricated by loading anti-miR155 on baicalein nanocrystals, named as baicalein nanorods (BNRs), followed by sialic acid coating to target macrophages. The codelivery system, with a diameter of 150 nm, enables efficient intracellular delivery of anti-miR155 and polarizes M1 to M2, while markedly lowers the level of inflammatory factors in vitro and in vivo. In particular, intracellular fate assay reveals that the codelivery system allows for sustained drug release over time after internalization. Moreover, due to prolonged blood circulation and improved accumulation at the AS plaque, the codelivery system significantly alleviates AS in animal model by increasing the artery lumen diameter, reducing blood pressure, promoting M2 polarization, inhibiting secretion of inflammatory factors and decreasing blood lipids. Taken together, the codelivery could potentially be used to treat vascular inflammation.

Thin section analysis, X-ray diffraction, conventional scanning electron microscopy (SEM), high-resolution Ar+ ion polishing SEM, mercury intrusion, nitrogen adsorption, total organic carbon (TOC) content and porosity analyses were used to determine the mineral composition, microstructure and micro-pore volume of shale reservoirs from different depths in the Upper Ordovician Wufeng Formation and Lower Silurian Longmaxi Formation in southeastern Sichuan Basin. There are slight differences in the content of siliceous, clay, carbonate and other minerals in shale reservoirs of well D1 in the deep layer and well J1 in the shallow layer, and the longitudinal changes are similar. Only high-quality shale layers with a silica content greater than 40% have different thicknesses. The shale reservoirs of the Wufeng-Longmaxi formations in the deep and shallow layers are dominated by micro-pores in organic matter disseminated in the shale matrix, and the microfractures around the boundaries of silt particles or organic grains and micro-foliation seams parallel to bedding plane are also common, while and intergranular pores are not developed. The high quality shale reservoir at the bottom is structurally isotropic, and the vertical and horizontal structural anisotropy becomes stronger upwards, with thinner micro-lamina and more foliation seams. The TOC content is high at the bottom, and diminishes upwards. The porosity at the bottom shows the same changing trend, indicating a large contribution of organic pores; however, the decrease in porosity is significantly smaller than that of TOC, which is inferred to be related to the existence of more inorganic pores in the shale. The mineral composition, microstructure, TOC and porosity of the Wufeng-Longmaxi shales in the deep and shallow layers have similar changes with depth. Compared with well J1 in the shallow layer, the high-quality reservoir in well D1 in the deep layer has a larger number of micro-pores, meso-pores, macro-pores and total pore volume, which might be explained by more inorganic pores such as grain boundary pores.The shale reservoirs of the Wufeng-Longmaxi formations in the southeastern Sichuan Basin maintain a good porosity under deep burial conditions and have good storage space.

Abstract Objectives To investigate the structural and functional connectivity changes of lateral geniculate nucleus (LGN) and their relationships with clinical characteristics in patients without aura. Methods Conventional MRI, 3D structure images and resting state functional MRI were performed in 30 migraine patients without aura (MwoA) and 22 healthy controls (HC). The lateral geniculate nucleus volumes and the functional connectivity (FC) of bilateral lateral geniculate nucleus were computed and compared between groups. Results The lateral geniculate nucleus volumes in patient groups did not differ from the controls. The brain regions with increased FC of the left LGN mainly located in the left cerebellum and right lingual gyrus in MwoA compared with HC. The increased FC of right LGN located in left inferior frontal gyrus in MwoA compared with HC. The correlation analysis showed a positive correlation between VLSQ-8 score and the increased FC of left cerebellum and right lingual gyrus. Conclusions Photophobia in MwoA could be mediated by abnormal resting state functional connectivity in visual processing regions, the pain perception regulatory network and emotion regulation network. This result is valuable to further understanding about the clinical manifestation and pathogenesis of migraine.

Summary: Background: Existing evidence suggest an association of cardiovascular health (CVH) level with cardiometabolic disease (CMD) and mortality, but the effect of CVH on life expectancy, particularly survival years in CMD patients, has not been well-established. This study aimed to investigate the association of CVH defined using the 7-item tool from the American Heart Association (AHA) with life expectancy in people with and without CMD. Methods: Between 2006 and 2010, a total of 341,331 participants (age 37–73 years) in the UK Biobank were examined and thereafter followed up to 2020. The CVH raised by the AHA included 4 behavioral (smoking, diet, physical activity, body mass index) and 3 biological (fasting glucose, blood cholesterol, blood pressure) metrics, coded on a three-point scale (0, 1, 2). The CVH score was the sum of 7 metrics (score range 0–14) and was then categorized into poor (scores 0–6), intermediate (7–11), and ideal (12–14) CVH. The flexible parametric survival models were applied to estimate life expectancy. Findings: During a median follow-up of 11.4 years, 18,420 (5.4%) deaths occurred. The multivariable-adjusted hazard ratio (HRs) of all-cause mortality were 2.21 (95% CI: 1.77 to 2.75) for male and 2.63 (95% CI: 2.22 to 3.12) for female with prevalent CMD and a poor CVH compared with CMD-free and ideal CVH group, an ideal CVH attenuated the CMD-related risk of mortality by approximately 62% for male and 53% for female. In CMD patients, an ideal CVH compared to poor CVH was associated with additional life years gain of 5.50 (95% CI: 3.94–7.05) for male 4.20 (95% CI: 2.77–5.62) for female at the age of 45 years. Corresponding estimates in those without CMD were 4.55 (95% CI: 3.62–5.48) and 4.89 (95% CI: 3.99–5.79), respectively. Ideal smoking status, fasting glucose and physical activity for male and ideal smoking status, cholesterol level and physical activity for female contributed to the greatest survival benefit. Interpretation: An ideal CVH is associated with a lower risk of premature mortality and longer life expectancy whether in general population or CMD patients. Our study highlights the benefits of maintaining better CVH across the life course and calls attention to the need for comprehensive strategies (healthy behavioral lifestyle and biological phenotypes) to preserve and restore a higher CVH level. Funding: Scientific Research Foundation for Scholars of HZNU (Grant No. 4265C50221204119)

BackgroundMobile phone use has brought convenience, but the long or improper use of mobile phones can cause harm to the human body. ObjectiveWe aimed to assess the impact of improper mobile phone use on the risks of accidents and chronic disorders. MethodsWe 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. ResultsMobile 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. ConclusionsImproper 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.

Background:The EAT-Lancet Commission has promulgated a sustainable dietary guideline and recommended that it was designed to improve the human health and support environmental sustainability.Objective:This research was designed to explore the association between this healthy diet pattern (EAT-Lancet diet pattern, EAT-LDP) and risk of type 2 diabetes (T2D).Methods:Between 2006 and 2010, a total of 59,849 participants from the UK Biobank without diabetes, cardiovascular disease, or cancers were included at baseline. The EAT-LDP score was constructed on the sum of 14 food components and then categorized into three tertiles. Multivariable Cox proportional hazards regression models were conducted to explore the association between EAT-LDP score and the risk of incident T2D. A mediation analysis was also implemented to disentangle the role of body mass index (BMI) and waist circumference in the relationship between EAT-LDP score and T2D.Results:During a median follow-up of 10 years, 2,461 incident T2D cases were recorded. In analyses that compared tertile 3 of the EAT-LDP score (highest) with tertile 1 (lowest), the hazard ratio (HR) for T2D was 0.81 (95% CI: 0.72–0.90) after adjusting for sociodemographic status and health-related factors. Participants who reported a one-point increase in the diet score were associated with a 6% decrease in risk of T2D (HR: 0.94, 95% CI: 0.91–0.97). A significant indirect association was observed between the EAT-LDP score and T2D (β: 0.66, 95% CI: 0.65–0.67), indicating that 44% of the association of EAT-LDP score with T2D was mediated by BMI. Additionally, 40% of the association of EAT-LDP score with T2D was mediated by waist circumference was also observed.Conclusions:Our findings indicate that a higher adherence to EAT-LDP contributes to lower risk of T2D. Further independent validation is needed to be conducted before applying the EAT-LDP to inform dietary guidelines.

Abstract Microneedles (MNs) offer a simple and minimally invasive way to sample skin interstitial fluid for bioanalysis. Through the integration with portable or wearable sensing devices, it allows us to get qualitative information about some biomarkers in situ. This work is to show a MN platform with open groove channels that are manufactured using photopolymerization 3D printing. The grooves on the needle surface permit that liquid flows from the tips to the base under the influence of capillary force. The ultimate MN device can penetrate skin and tissues and sample liquid in the skin model. By taking the glucose as the model biomarker, we demonstrate that the biomarkers in the extracted liquid can be analyzed in situ by the commercial test strips attached to the back.

Abstract The development of potent antibiotic alternatives with rapid bactericidal properties is of great importance in addressing the current antibiotic crisis. One representative example is the topical delivery of predatory bacteria to treat ocular bacterial infections. However, there is a lack of suitable methods for the delivery of predatory bacteria into ocular tissue. This work introduces cryomicroneedles (cryoMN) for the ocular delivery of predatory Bdellovibrio bacteriovorus (B. bacteriovorus) bacteria. The cryoMN patches are prepared by freezing B. bacteriovorus containing a cryoprotectant medium in a microneedle template. The viability of B. bacteriovorus in cryoMNs remains above 80% as found in long‐term storage studies, and they successfully impede the growth of gram‐negative bacteria in vitro or in a rodent eye infection model. The infection is significantly relieved by nearly six times through 2.5 days of treatment without substantial effects on the cornea thickness and morphology. This approach represents the safe and efficient delivery of new class of antimicrobial armamentarium to otherwise impermeable ocular surface and opens up new avenues for the treatment of ocular surface disorders.

The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is unclear so far. The purpose of this study is to explore the key role of Ufbp1 in liver fibrosis caused by ketosis in vivo and in vitro. Liver tissues were collected from ketotic cows and Ufbp1 conditional knockout (CKO) mice in vivo. However, Ufbp1–/– mouse embryonic fibroblast cells and Hela cells were used for in vitro validation. Subsequently, various assays were performed to reveal the underlying molecular mechanisms of the Ufbp1 protective effect. In this study, hepatic fibrosis, endoplasmic reticulum (ER) stress, and apoptosis were reported in the liver of ketotic cows, fibrotic markers (alpha-smooth muscle actin, Collagen1) and ER stress markers (glucose-regulated protein 78, CEBP homologous protein) were upregulated remarkably, and the apoptosis-related genes (Bcl2, Bax) were in line with expectations. Interestingly, Ufbp1 expression was almost disappeared, and Smad2/Smad3 protein was largely phosphorylated in the liver of ketotic cows, but Ufbp1 deletion caused Smad3 phosphorylation apparently, rather than Smad2, and elevated ER stress was observed in the CKO mice model. At the cellular level, Ufbp1 deficiency led to serious fibrotic and ER stress response, Smad3 was activated by phosphorylation significantly and then was translocated into the nucleus, whereas p-Smad2 was largely unaffected in embryonic fibroblast cells. Ufbp1 overexpression obviously suppressed Smad3 phosphorylation in Hela cells. Ufbp1 was found to be in full combination with Smad3 using endogenous immunoprecipitation. Taken together, our findings suggest that downregulation or ablation of Ufbp1 leads to Smad3 activation, elevated ER stress, and hepatocyte apoptosis, which in turn causes liver fibrosis. Ufbp1 plays a protective role in ketosis-induced liver injury.

Abstract Background Functional connectivity (FC) has been used to investigate the pathophysiology of migraine. Accumulating evidence is pointing toward malfunctioning of brainstem structures, i.e., the red nucleus (RN) and substantia nigra (SN), as an important factor in migraine without aura (MwoA). We aimed to identify atypical FC between the RN and SN and other brain areas in patients with MwoA and to explore the association between RN and SN connectivity changes and performance on neuropsychological tests in these patients. Methods Resting-state functional magnetic resonance imaging (fMRI) data were obtained from 30 patients with MwoA and 22 age-, sex-, and years of education-matched healthy controls (HC). The FC of the brainstem structures was analyzed using a standard seed-based whole-brain correlation method. The results of the brainstem structure FC were assessed for correlations with other clinical features. Results Patients with MwoA exhibited reduced left RN-based FC with the left middle frontal gyrus, reduced right RN-based FC with the ipsilateral superior parietal lobe, and increased FC with the ipsilateral cerebellum. Additionally, patients with MwoA demonstrated significantly decreased right SN-based FC with the right postcentral gyrus, left parietal lobule, and left superior frontal gyrus. Hypo-connectivity between the right SN and right postcentral gyrus was negatively correlated with disease duration (r = − 0.506, P = 0.004). Additionally, increased connectivity of the right RN to the ipsilateral cerebellar lobes was positively correlated with the Headache Impact Test-6 scores (r = 0.437, P = 0.016). Conclusions The present study suggested that patients with MwoA have disruption in their RN and SN resting-state networks, which are associated with specific clinical characteristics. The changes focus on the regions associated with cognitive evaluation, multisensory integration, and modulation of perception and pain, which may be associated with migraine production, feedback, and development. Taken together, these results may improve our understanding of the neuropathological mechanism of migraine.

Summary: Nano-structures of biological systems can produce diverse spectroscopic effects through interactions with broadband light. Although structured coloration at the surface has been extensively studied, natural spectroscopic contrasts in deep tissues are poorly understood, which may carry valuable information for evaluating the anatomy and function of biological systems. Here we investigated the spectroscopic characteristics of an important geometry in deep tissues at the nanometer scale: packed nano-cylinders, in the near-infrared window, numerically predicted and experimentally proved that transversely oriented and regularly arranged nano-cylinders could selectively backscatter light of the long wavelengths. Notably, we found that the spectroscopic contrast of nanoscale fibrous structures was sensitive to the pressure load, possibly owing to the changes in the orientation, the degree of alignment, and the spacing. To explore the underlying physical basis, we further developed an analytical model based on the radial distribution function in terms of their radius, refractive index, and spatial distribution. : Infrared Optics; Medical Imaging; Optical Imaging; Spectroscopy Subject Areas: Infrared Optics, Medical Imaging, Optical Imaging, Spectroscopy

DNA nanostructures hold great promise for drug delivery, but systemic administration is problematic. Here, the authors demonstrate that framework nucleic acids (FNAs) improve drug accumulation in tumours in topical application and that penetration depth is controllable through adjusting FNA size.