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Objective: Based on the expression changes in the TGF-β/ALK5/Smad2/3 signal transduction pathway, the repair of cartilage injury in the rabbit knee joint was investigated and evaluated by oral administration of naringin in combination with acellular dermal matrix implantation. Methods: First, twenty New Zealand white rabbits were randomly divided into five groups: a sham operation group (Sham group), a model group (Mod group), a naringin group (Nar group), an acellular dermal matrix group (ADM group), a naringin ​+ ​acellular dermal matrix group (Nar/ADM group). After the 12th week, the repaired tissues were assessed for histomorphology and repair content of the repaired site by observing the morphological characteristics of articular cartilage. The International Cartilage Repair Society (ICRS)'s macroscopic evaluation of the cartilage repair scale and the quantitative scoring repair effect of the modified O'Driscoll grading system were used as evaluation criteria. In addition, the structure of the rabbit knee joint was evaluated by micro-CT scan, histological staining (H & E staining, Alcian blue staining, Safranin-O staining) and immunohistochemical staining (TGF-β2 immunostaining, TGF-β3 immunostaining, Sox-9 immunostaining). Results: ① The observation of the repair morphology of joint defect tissues showed that the repair effects of the Nar and ADM groups were better than that of the Mod group, and the repair effect of Nar/ADM group was the best (P

Metabolic reprogramming is a core hallmark of cancer and is key for tumorigenesis and tumor progression. Investigation of metabolic perturbation by anti-cancer compounds would allow a thorough understanding of the underlying mechanisms of these agents and identification of new anti-cancer targets. Here, we demonstrated that the administration of oleanolic acid (OA) rapidly altered cancer metabolism, particularly suppressing the purine salvage pathway (PSP). PSP restoration significantly opposed OA-induced DNA replication and cell proliferation arrest, underscoring the importance of this pathway for the anti-cancer activity of OA. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and 5′-nucleotidase (5′-NT), two metabolic enzymes essential for PSP activity, were promptly degraded by OA via the lysosome pathway. Mechanistically, OA selectively targeted superoxide dismutase 1 (SOD1) and yielded reactive oxygen species (ROS) to activate the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin complex 1 (mTORC1)/macroautophagy pathway, thus eliciting lysosomal degradation of HGPRT and 5′-NT. Furthermore, we found that the PSP was overactivated in human lung and breast cancers, with a negative correlation with patient survival. The results of this study elucidated a new anti-cancer mechanism of OA by restraining the PSP via the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway. We also identified the PSP as a new target for cancer treatment and highlighted OA as a potential therapeutic agent for cancers with high PSP activity., Graphical abstract, Mechanistic study of natural compounds with anti-cancer activity would identify new targets for cancer treatment. Here we found that the purine salvage pathway (PSP) was a crucial target of oleanolic acid (OA) for cancer therapy. Moreover, OA suppressed PSP of cancer cells via activating the SOD1/ROS/AMPK/mTORC1/macroautophagy/lysosomal pathway.

The development of blood-based biomarkers of Alzheimer's disease (AD) pathology as tools for screening the general population is essential, but persists controversies. We aimed to evaluate the effects of AD core pathological biomarkers on blood, and systematical searched Embase, PubMed and Cochrane for eligible studies. Biomarker performance was rated by random-effects meta-analysis based on the ratio of means method and multivariable-adjusted effect estimates. Finally, 150 articles were included, which demonstrated T-tau (average ratio: 1.25-1.62), P-tau 181 (1.36-2.16) and NfL (1.24-1.86) were increased, and AβPPr (0.65-0.88) were decreased from controls to amnestic mild cognitive impairment (aMCI) to AD. Furthermore, Aβ42, Aβ42/Aβ40 ratio and P-tau 217 using ultrasensitive platforms also had great diagnostic accuracy from controls to aMCI to AD. Consequently, significantly changes of blood AD core biomarkers were verified in comparison between AD, aMCI and control, supporting biomarkers were strongly valid in identifying AD and aMCI, which provides a new prospect of AD early diagnosis and progressive monitoring. This study is registered with PROSPERO, number CRD42020191927.

Highlights • As a counter-regulatory arm of the renin-angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury. • The affinity of the spike protein receptor binding domain (RBD) of the SARS-CoV-2 with human ACE2 (hACE2) largely determines the degree of clinical symptoms infected by SARS-CoV-2. • Vitamin D was found to affect ACE2, the same target of SARS-CoV-2, we therefore propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 through modulating ACE2., A novel coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has been confirmed to have the capacity to transmit from humans to humans, causing acute respiratory distress syndrome (ARDS) and acute lung injury. Angiotensin converting enzyme-2 (ACE2) has been found to be expressed on type II pneumocytes. As a counterregulatory arm of the renin-angiotensin system (RAS), ACE2 plays critical roles in the pathogenesis of ARDS and acute lung injury. The affinity of the spike protein receptor binding domain (RBD) of SARS-CoV-2 with human ACE2 (hACE2) largely determines the degree of clinical symptoms after infection by SARS-CoV-2. Previous studies have revealed that regulating the ACE2/RAS system was effective in the treatment of severe acute respiratory syndrome coronavirus (SARS-CoV)-induced ARDS and acute lung injury. Since ACE2 is the host cell receptor of both SARS-CoV-2 and SARS-CoV, regulating the ACE2/RAS system may alleviate ARDS and acute lung injury caused by SARS-CoV-2 as well as SARS-CoV. Vitamin D was found to affect ACE2, the target of SARS-CoV-2; therefore, we propose that vitamin D might alleviate ARDS and acute lung injury induced by SARS-CoV-2 by modulating ACE2.

Background White matter hyperintensities of presumed vascular origin (WMH) are one of the imaging features of cerebral small vessel disease. Controversies persist about the effects of WMH on cognitive dysfunction. This meta-analysis aimed to identify the associations of WMH with risks of cognitive impairment and dementia. Methods We searched PubMed, EMBASE and Cochrane Library for prospective studies. Primary analyses of cognitive dysfunction and sub-analyses of specific outcomes and study characteristics were conducted using random-effect models. Results Thirty-six prospective studies with 19,040 participants were included. WMH at baseline conferred a 14 % elevated risk of cognitive impairment and all-cause dementia (ACD). WMH also conferred 25 % elevated risk of Alzheimer’s disease and 73 % elevated risk of vascular dementia. Risk effects of high-grade WMH and continually increasing WMH (in volume or severity) on ACD were revealed. Periventricular WMH conferred a 1.51-fold excess risk for dementia. Conclusions WMH were associated with increased risk of cognitive dysfunction and could become a neuroimaging indicator of dementia.

In this paper the coverage problem of a mobile sensor network subject to time-varying communication delays is investigated. Each sensor is required to move along a fixed closed curve. The goal is to minimize a coverage cost function which is defined as the largest response time from the sensor network to any point on the curve. The maximum velocities of the sensors are assumed to be different from each other. This results in different input saturation constraints on the sensors with first-order dynamics. It is shown that even if time-varying communication delays exist, low gain feedback can be also used to design distributed coverage control laws for the mobile sensors. When the sensors’ delays and their derivative are both upper bounded, the sensor network is guaranteed to arrive at the optimal configuration which minimizes the coverage cost function. Moreover, in this work the maximal allowable upper bound on the sensors’ delays can be increased by choosing a lower upper bound on the sensors’ low control gains. Finally, the effectiveness of the proposed coverage control laws is verified by a numerical example.

This article deals with the set-membership state estimation problem for a class of artificial neural networks subject to time-delays and mixed malicious attacks. Both Denial-of-Service (DoS) and deception attacks are taken into consideration. The objective of the addressed problem is to design the state estimation algorithm for the artificial neural networks under investigation in spite of the existence of the malicious mixed attacks. By means of the set-membership approach in combination with certain convex optimization algorithm, the sufficient condition is established for the existence of the desired state estimator in terms of the solvability of a recursive matrix inequality. The resulting state estimation error is confined within certain pre-specified ellipsoidal region. An optimization problem is then formulated with the purpose of seeking the filtering parameters guaranteeing the locally optimal performance. Finally, the developed theoretical results are verified via an illustrative numerical example.

We conducted a systematic review and meta-analysis to evaluate the association between parental diabetes mellitus and the risk of ADHD in offspring. The PubMed, EMBASE, Cochrane, and Web of Science databases were searched from inception to May 31, 2019. Thirteen observational studies containing 5,052,736 participants were included. Two reviewers independently extracted data and assessed the quality of the studies using predefined standard procedures. Random-effects model were used. We found that maternal pregestational diabetes mellitus (PGDM) was associated with an increased risk of ADHD in offspring (odds ratio [OR]: 1.40; 95% confidence interval [CI]:1.31-1.50) in adjusted analyses. Increased risks of ADHD in offspring were also observed among those with maternal preexisting type 1 diabetes (T1D) (OR: 1.39; 95% CI: 1.27-1.52) and paternal T1D (OR: 1.20; 95% CI: 1.13-1.28) in adjusted analyses. Sensitivity analyses supported the robustness of our findings. Future studies should use robust designs to address whether the association with parental diabetes mellitus is causal.

Controversies persist about the associations of body mass index (BMI) with risk of cognitive impairment and dementia. This study aimed to evaluate these associations from various aspects, in which Embase, PubMed and Cochrane databases were searched to identify prospective studies up to May 2019. Random-effects meta-analyses and dose-response meta-analysis were conducted, involving twenty-nine of 20,083 identified literatures. Meta-analysis showed that midlife underweight, obesity and late-life underweight conferred 1.39-, 1.31- and 1.64-fold excess risk for cognitive impairment and dementia, while late-life overweight and obesity conferred 21% and 25% reduced risk. In dose-response meta-analysis, all cause dementia (ACD), Alzheimer's disease (AD) and vascular dementia (VaD) risk in midlife was significantly elevated when BMI surpassed 29, 30 and 32 kg/m2. AD risk in late-life was decreased when BMI was under 27 kg/m2, while this protection for VaD was absent when BMI surpassed 39 kg/m2. Higher BMI produced opposite exerted opposite effects on dementia in mid- and late-age population. Firstly reported, a dose-response relationship further supports the guideline from the standpoint of dementia prevention.

The consequences of vitamin D deficiency regarding sepsis in children remain controversial. We conducted a meta-analysis of studies evaluating the association between vitamin D status and sepsis in children.We used EMBASE, Ovid Medline and Cochrane Library to conduct a meta-analysis of studies published in English before November 21, 2017.Among 1146 initially identified studies, we included 13 studies according to predefined inclusion criteria comprising 975 patients and 770 control participants. According to a random effects model, the mean difference in 25(OH)D levels (nmol/L) between participants with sepsis (444) and controls (528) was (mean difference, -18.55; 95% confidence interval (CI), -19.45 to -17.66, p 0.05). The association between vitamin D deficiency and sepsis was significant, with an odds ratio (OR) = 1.13 (95% CI, 1.18 to 1.50, p 0.05). Factors that could explain differences in the results include the study location/medical conditions, study design, 25(OH)D assay methods, diagnostic sepsis at different ages, diagnostic criteria for sepsis, and sepsis with comorbidities.The association between vitamin D deficiency/lower 25(OH)D levels and sepsis was significant in children and neonates. Further studies are required to confirm the results by considering more confounders.

Although the Mobi-C artificial disc and the ROI-C cervical cage have been widely used in the treatment of cervical degenerative disc diseases (CDDD), few reports addressed the features of combined application of both devices. This study is aimed at comparing the clinical and radiological outcomes of treating contiguous two-level CDDD using Mobi-C and ROI-C combined in a hybrid surgery (HS) with anterior cervical discectomy and fusion (ACDF) using ROI-C. We reviewed ninety-one patients who underwent HS (n = 48) or ACDF (n = 43) surgery for symptomatic contiguous two-level CDDD.2 years' clinical and radiological outcomes were reviewed and evaluated retrospectively. At the last follow-up, significant improvement in the mean VAS, JOA, and NDI scores was found both in the HS and ACDF groups (p 0.05), while the differences between groups were not significant (p 0.05). The global range of motion (ROM) in the HS group was significantly larger than that in the ACDF group (p 0.05). The local lordosis improved significantly after surgery in all patients (p 0.05). Bone resorption and heterotopic ossification (HO) were found after surgery. The result showed that, for the selected patients, HS may provide an alternative approach for the treatment of contiguous two-level CDDD. HS also offers the benefit of both greater global ROM and greater ROM at the Mobi-C index level. Some degree of bone resorption may be an integral component in the early stage of bony fusion in the cage index level. Further studies and long-term follow-up are still needed.

Ocean acidification (OA) and antibiotic pollution pose severe threats to the fitness of keystone species in marine ecosystems. However, the combined effects of OA and antibiotic pollution on the intestinal microbiota of marine organisms are still not well known. In this study, we exposed the herbivorous gastropod Trochus niloticus, a keystone species to maintains the stability of coral reef ecosystems, to acidic seawater (pH 7.6) and/or sulfamethoxazole (SMX, 100 ng/L, 1000 ng/L) for 28 days and determined their impacts on (1) the accumulation of SMX in the intestine of T. niloticus; (2) the characteristics of the intestinal microbiota in T. niloticus; (3) the relative abundances of sulfonamide resistance genes (i.e., sul1 and sul2) and intI1 in the intestinal microbiota of T. niloticus. Our results show that OA exposure leads to dramatic microbiota dysbiosis in the intestine of T. niloticus, including changes in bacterial community diversity and structure, decreased abundances of dominant species, existences of characteristic taxa, and altered functional predictions. In addition, SMX exposure at environmentally relevant concentrations had little effect on the intestinal microbiota of T. niloticus, whether in isolation or in combination with OA. However, after exposure to the higher SMX concentration (1000 ng/L), the accumulation of SMX in the intestine of T. niloticus could induce an increase in the copies of sul2 in the intestinal microbiota. These results suggest that the intestinal health of T. niloticus might be affected by OA and SMX, which might lead to fitness loss of the keystone species in coral reef ecosystems.

Two new 1, 8-naphthalimide-based fluorophore compounds, 4-piperazinyl-N-(4-Pyr-idinyl)-1, 8-naphthalimide (RB1) and 4-phenyl-N-(3-hydroxyphenyl)-1, 8-naphth- alimide (RB2) were synthesized via two-steps nucleophilic substitution reactions and Suzuki coupling reaction. The chemical structures of the title compounds were characterized by 1H NMR, 13C NMR, HRMS and FT-IR spectral analysis. Thermogravimetric analysis results show that the degradation temperatures of two compounds were about 300 °C. The single-crystal XRD analysis revealed that both RB1 and RB2 crystallize in the monoclinic P21/c (No. 14) space group, with lattice parameters of RB1 a = 15.3016(10), b = 15.4468(9), c = 7.1919(4) A, β = 95.384(2)°, V = 1692.38(18) A3, Z = 4 and RB2 a = 16.1990(3), b = 15.9460(3), c = 7.5870(15) A, β = 98.718(5)°, V = 1937.2(7) A3, Z = 4 respectively. Both crystals of two compounds have parallel offset stacking with extensive intermolecular interactions (hydrogen bond, C–H⋅⋅⋅π interaction), which are correspondence with the molecular packing of J-aggregation. The UV–vis and fluorescence properties of two compounds in different solvents were investigated, indicated that ICT characteristics of RB1 in organic solvents. Moreover, RB1 crystal can excite the strong green fluorescence with good thermal and optical stability qualifying it as a potential application in the fields of crystal luminescent functional materials.

Oil sludge (OS) is composed of water, oil and inert solids (silica, clay minerals, etc.). Although solids were ubiquitous in oil sludge, its potential effects on altering pyrolysis characteristics had rarely been studied. Therefore, the role that solids played during the pyrolysis process of oil sludge was investigated by thermogravimetric analysis (TGA) in this study. The kinetic triplets of both OS (contained solids) and extracted oil (EO, solid-free) from OS during the pyrolysis processes were determined by a combined method, including the integral master-plots method and iso-conversional method. The activation energy values for OS pyrolysis varied between 28 and 107 kJ mol−1, and pre-exponential factor ranged from 10 to 104 s−1. Whereas, the activation energy values for EO pyrolysis ranged from 67 to 193 kJ mol−1, and its pre-exponential factor varied from 106 to 1010 s−1. These results suggested that inert solids had positive influences on the pyrolysis of OS because the activation energy for OS pyrolysis was obviously lower than that for EO pyrolysis. The comparison of kinetic models between OS and EO illustrated that solids not only provided sufficient surface for the devolatilization of hydrocarbon but also acted as nucleating agent in char formation.