Four-dimensional metal-organic frameworks Evans, Jack D; Bon, Volodymyr; Senkovska, Irena ...
Nature communications,
06/2020, Letnik:
11, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Recognising timescale as an adjustable dimension in porous solids provides a new perspective to develop novel four-dimensional framework materials. The deliberate design of three-dimensional porous ...framework architectures is a developed field; however, the understanding of dynamics in open frameworks leaves a number of key questions unanswered: What factors determine the spatiotemporal evolution of deformable networks? Can we deliberately engineer the response of dynamic materials along a time-axis? How can we engineer energy barriers for the selective recognition of molecules? Answering these questions will require significant methodological development to understand structural dynamics across a range of time and length scales.
Shear stress stimuli differentially regulate cellular functions based on the pattern, magnitude as well as duration of the flow. Shear stress can modify intracellular kinase activities and ...cytoskeleton reorganization to result in changes of cell behavior. Mesenchymal stem cells (MSCs) are mechano‐sensitive cells, but little is known about the effects of oscillatory shear stress (OS). In this study, we demonstrate that OS of 0.5 ± 4 dyn/cm2 induces directional reorganization of F‐actin to mediate the fate choice of MSCs through the regulation of β‐catenin. We also found that intercellular junction molecules are the predominant mechanosensors of OS in MSCs to deliver the signals that result in directional rearrangement of F‐actin, as well as the increase of phosphorylated β‐catenin (pβ‐catenin) after 30 minutes of OS stimulation. Depolymerization of F‐actin and increase in pβ‐catenin also lead to the upregulation of Wnt inhibitory factors sclerostin and dickkopf‐1. Inhibition of β‐catenin/Wnt signaling pathway is accompanied by the upregulation of sex determining region Y‐box2 and NANOG to control self‐renewal. In conclusion, the reorganization of actin cytoskeleton and increase in β‐catenin phosphorylation triggered by OS regulate the expression of pluripotency genes via the β‐catenin/Wnt signaling pathway to differentially direct fate choices of MSCs at different time points. Results from this study have provided new information regarding how MSCs respond to mechanical cues from their microenvironment in a time‐dependent fashion, and such biophysical stimuli could be administered to guide the fate and differentiation of stem cells in addition to conventional biochemical approaches. Stem Cells 2015;33:429–442
Background
Diabetic retinopathy (DR), whose standard diagnosis is performed by human experts, has high prevalence and requires a more efficient screening method. Although machine learning (ML)–based ...automated DR diagnosis has gained attention due to recent approval of IDx-DR, performance of this tool has not been examined systematically, and the best ML technique for use in a real-world setting has not been discussed.
Objective
The aim of this study was to systematically examine the overall diagnostic accuracy of ML in diagnosing DR of different categories based on color fundus photographs and to determine the state-of-the-art ML approach.
Methods
Published studies in PubMed and EMBASE were searched from inception to June 2020. Studies were screened for relevant outcomes, publication types, and data sufficiency, and a total of 60 out of 2128 (2.82%) studies were retrieved after study selection. Extraction of data was performed by 2 authors according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses), and the quality assessment was performed according to the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2). Meta-analysis of diagnostic accuracy was pooled using a bivariate random effects model. The main outcomes included diagnostic accuracy, sensitivity, and specificity of ML in diagnosing DR based on color fundus photographs, as well as the performances of different major types of ML algorithms.
Results
The primary meta-analysis included 60 color fundus photograph studies (445,175 interpretations). Overall, ML demonstrated high accuracy in diagnosing DR of various categories, with a pooled area under the receiver operating characteristic (AUROC) ranging from 0.97 (95% CI 0.96-0.99) to 0.99 (95% CI 0.98-1.00). The performance of ML in detecting more-than-mild DR was robust (sensitivity 0.95; AUROC 0.97), and by subgroup analyses, we observed that robust performance of ML was not limited to benchmark data sets (sensitivity 0.92; AUROC 0.96) but could be generalized to images collected in clinical practice (sensitivity 0.97; AUROC 0.97). Neural network was the most widely used method, and the subgroup analysis revealed a pooled AUROC of 0.98 (95% CI 0.96-0.99) for studies that used neural networks to diagnose more-than-mild DR.
Conclusions
This meta-analysis demonstrated high diagnostic accuracy of ML algorithms in detecting DR on color fundus photographs, suggesting that state-of-the-art, ML-based DR screening algorithms are likely ready for clinical applications. However, a significant portion of the earlier published studies had methodology flaws, such as the lack of external validation and presence of spectrum bias. The results of these studies should be interpreted with caution.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The centrosome, a non‐membranous organelle, constrains various soluble molecules locally to execute its functions. As the centrosome is surrounded by various dense components, we hypothesized that it ...may be bordered by a putative diffusion barrier. After quantitatively measuring the trapping kinetics of soluble proteins of varying size at centrosomes by a chemically inducible diffusion trapping assay, we find that centrosomes are highly accessible to soluble molecules with a Stokes radius of less than 5.8 nm, whereas larger molecules rarely reach centrosomes, indicating the existence of a size‐dependent diffusion barrier at centrosomes. The permeability of this barrier is tightly regulated by branched actin filaments outside of centrosomes and it decreases during anaphase when branched actin temporally increases. The actin‐based diffusion barrier gates microtubule nucleation by interfering with γ‐tubulin ring complex recruitment. We propose that actin filaments spatiotemporally constrain protein complexes at centrosomes in a size‐dependent manner.
Synopsis
Centrosomes maintain a discrete protein composition without a membrane boundary. This study shows that a size‐dependent diffusion barrier composed of branched actin filaments restricts access to centrosomes and gates microtubule nucleation by interfering with γ‐TuRC recruitment.
Large molecules (≥ 6.0 nm in stokes radius) rarely or cannot access centrosome core regions including the centriolar lumen and pericentriolar matrix.
The permeability of the centrosome diffusion barrier is tightly regulated by branched actin filaments.
The permeability of centrosomal diffusion barriers decreases in anaphase correlating with a temporal increase in branched actin filaments.
The centrosomal diffusion barrier gates γ‐TuRC recruitment and interferes with microtubule nucleation.
Centrosomes maintain a discrete protein composition without a membrane boundary. This study shows that a size‐dependent diffusion barrier composed of branched actin filaments restricts access to centrosomes and gates microtubule nucleation by interfering with γ‐TuRC recruitment.
This study was conducted to investigate the mechanism of action and extent of selective dopaminergic neurodegeneration caused by exposure to trichloroethylene (TCE) leading to the endogenous ...formation of the neurotoxin 1-trichloromethyl-1,2,3,4-tetrahydro-β-carboline (TaClo) in rodents. Beginning at 3 months of age, male C57BL/6 mice received oral TCE dissolved in vehicle for 8 months. Dopaminergic neuronal loss was assessed by nigral tyrosine hydroxylase (TH) immunoreactivity. Selective dopaminergic neurodegeneration was determined based on histological analysis of non-dopaminergic neurons in the brain. Behavioral assays were evaluated using open field activity and rotarod tests. Mitochondrial complex I activity, oxidative stress markers, and microglial activation were also examined in the substantia nigra. The level of TaClo was detected using HPLC-electrospray ionization tandem mass spectrometry. Dopaminergic neurotoxicity of TaClo was determined in midbrain organotypic cultures from rat pups. Following 8 months of TCE treatment, there was a progressive and selective loss of 50% of the dopaminergic neurons in mouse substantia nigra (SN) and about 50% loss of dopamine and 72% loss of 3,4-dihydroxyphenylacetic acid in the striatum, respectively. In addition, motor deficits, mitochondrial impairment, oxidative stress, and inflammation were measured. TaClo content was quantified in the brain after TCE treatment. In organotypic cultures, TaClo rather than TCE induced dopaminergic neuronal loss, similar to MPP
+
. TCE exposure may stimulate the endogenous formation of TaClo, which is responsible for dopaminergic neurodegeneration. However, even prolonged administration of TCE was insufficient for producing a greater than 50% loss of nigral dopamine neurons, indicating that additional co-morbid factors would be needed for mimicking the profound loss of dopamine neurons seen in Parkinson’s disease.
Aims
To explore the risk factors of falls and the gender differences based on demographic and disease characteristics, physical capability, and fear of falling in older adults with diabetes visiting ...outpatient clinics in Taiwan.
Design
Cross‐sectional design.
Methods
A total of 485 patients with type 2 diabetes aged between 65 and 80 years were recruited from three endocrine outpatient clinics in Taiwan. Demographic and disease characteristics, fall history in the previous one year and fear of falling were collected by a self‐reported questionnaire. Calf circumference, handgrip strength, one‐leg standing and time up‐and‐go tests were all performed to assess the physical capability of participants. Data were collected from May 2019 to May 2020.
Results
Female gender (OR = 1.75), handgrip strength (OR = 2.43) and fear of falling (OR = 3.38) were important risk factors of falls overall, although fear of falling (OR = 4.69) was the only important risk factor of falls in males, while handgrip strength (OR = 3.48) and fear of falling (OR = 2.86) were important risk factors of falls in females. The sensitivity of simultaneous screening handgrip strength and fear of falling were 85.7, 86.4 and 86.2 in males, females and older adults overall with diabetes, respectively.
Conclusion
Fear of falling was an important risk factor of falls in both genders, especially in males. Handgrip strength was an important risk factor of falls specifically for females. By simultaneously screening fear of falling and handgrip strength, risk of falls in older adults with diabetes at outpatient clinics could be identified in a more timely manner.
Impact
Nurses could periodically and simultaneously assess fear of falling and handgrip strength of older adults with diabetes at outpatient clinics. For those are identified at risk of falls on either fear of falling or handgrip strength, nurses could provide corresponding interventions to reduce the fear of falling or improve muscle strength to prevent such falls.
Exploration of metal clusters (MCs) adaptive to both aqueous and oil phases without disturbing their size is promising for a broad scope of applications. The state-of-the-art approach
ligand-binding ...may perturb MCs' size due to varied metal-ligand binding strength when shuttling between solvents of different polarity. Herein, we applied physical confinement of a series of small noble MCs (<1 nm) inside ionic organic cages (I-Cages), which by means of anion exchange enables reversible transfer of MCs between aqueous and hydrophobic solutions without varying their ultrasmall size. Moreover, the MCs@I-Cage hybrid serves as a recyclable, reaction-switchable catalyst featuring high activity in liquid-phase NH
BH
(AB) hydrolysis reaction with a turnover frequency (TOF) of 115 min
.
A Cu(II) metal–organic framework (MOF), Cu2(bdc)2(dabco), was found to be an efficient heterogeneous catalyst for controlled photopolymerization under visible light. The MOF, composed of ...photostimulable metal sites, was used to catalyze both photoinitiation as well as radical chain control and required no external photoinitiator, dye sensitizer, or ligand. A simple light trigger allowed the photoreduction of Cu(II) to the active Cu(I) state, enabling controlled atom transfer radical polymerization (ATRP). Compared to conventional ATRP with homogeneous catalysts, the ionic-bonded framework imparts high stability and robustness to the catalytic Cu(II) species. Therefore, the polymerization of vinylpyridines (2-vinylpyridine, 2VP; and 4-vinylpyridine, 4VP), usually challenging by traditional polymerization strategies, was controlled up to high conversion (>85%) in 90 min, forming polymers with Đ < 1.3. Methacrylates such as 2-(dimethylamino)ethyl methacrylate (DMAEMA) and methyl methacrylate were polymerized by the Cu(II) MOF with good control as well. Moreover, as a heterogeneous catalyst, the MOF was easily separated, recovered, and repeatedly used for several photopolymerizations of 2VP and DMAEMA.
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease; its cause is unknown, and it leads to notable health problems. Currently, only two drugs are recommended ...for IPF treatment. Although these drugs can mitigate lung function decline, neither can improve nor stabilize IPF or the symptoms perceived by patients. Therefore, the development of novel treatment options for pulmonary fibrosis is required. The present study investigated the effects of a novel compound, caffeic acid ethanolamide (CAEA), on human pulmonary fibroblasts and evaluated its potential to mitigate bleomycin-induced pulmonary fibrosis in mice. CAEA inhibited TGF-β-induced α-SMA and collagen expression in human pulmonary fibroblasts, indicating that CAEA prevents fibroblasts from differentiating into myofibroblasts following TGF-β exposure. In animal studies, CAEA treatment efficiently suppressed immune cell infiltration and the elevation of TNF-α and IL-6 in bronchoalveolar lavage fluid in mice with bleomycin-induced pulmonary fibrosis. Additionally, CAEA exerted antioxidant effects by recovering the enzymatic activities of oxidant scavengers. CAEA directly inhibited activation of TGF-β receptors and protected against bleomycin-induced pulmonary fibrosis through inhibition of the TGF-β/SMAD/CTGF signaling pathway. The protective effect of CAEA was comparable to that of pirfenidone, a clinically available drug. Our findings support the potential of CAEA as a viable method for preventing the progression of pulmonary fibrosis.
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•CAEA inhibits the formation of myofibroblasts.•CAEA alleviates pulmonary injury and fibrosis in response to bleomycin.•CAEA recovers the enzymatic activities of oxidant scavengers.•CAEA acts as a TGFBR antagonist and inhibits TGF-β/SMAD/CTGF signaling pathway.•The protective effect of CAEA was comparable to that of pirfenidone.
Hyperlipidemia and oxidative stress with elevated oxidized low-density lipoprotein (ox-LDL) exacerbate hepatic inflammation and fibrosis. The plasma level of low-density lipoprotein (LDL) is ...controlled by proprotein convertase subtilisin/kexin 9 (PCSK9). Alirocumab is a monoclonal antibody that decreases LDL via inhibiting PCSK9 function. Apart from lipid-lowering effects, alirocumab exerts anti-inflammation, anti-angiogenesis and anti-oxidant effects. This study aims to investigate the impact of alirocumab treatment on common bile duct ligation (BDL)-induced biliary cirrhotic rats. After a 4-week treatment of alirocumab, the hemodynamic data, blood biochemistry, ox-LDL level, oxidative stress markers, severity of hepatic encephalopathy and abnormal angiogenesis of BDL rats were measured and compared to the control group. BDL rats presented cirrhotic pictures and elevated ammonia, total cholesterol, LDL and ox-LDL levels compared to the control group. Alirocumab decreased plasma levels of total cholesterol, LDL, and oxidative stress markers; however, it did not affect the hemodynamics, liver and renal biochemistry, and the plasma levels of ammonia and ox-LDL. The motor activities, portal-systemic collaterals and mesenteric vascular density were not significantly different between alirocumab-treated and control groups. In addition, it did not affect hepatic inflammation, intrahepatic angiogenesis, liver fibrosis and free cholesterol accumulation in the liver of BDL rats. In conclusion, PCSK9 inhibition by alirocumab treatment ameliorates hyperlipidemia and systemic oxidative stress in biliary cirrhotic rats. However, it does not affect the plasma level of ox-LDL, intrahepatic inflammation and fibrosis. In addition, PCSK9 inhibition has a neutral effect on abnormal angiogenesis and hepatic encephalopathy in biliary cirrhotic rats.
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