BackgroundGenetic studies have shown that C9orf72, SOD1, TARDBP and FUS are the most common mutated genes in amyotrophic lateral sclerosis (ALS). Here, we performed a meta-analysis to determine the ...mutation frequencies of these major ALS-related genes in patients with ALS.MethodsWe performed an extensive literature research to identify all original articles reporting frequencies of C9orf72, SOD1, TARDBP and FUS mutations in ALS. The mutation frequency and effect size of each study were combined. Possible sources of heterogeneity across studies were determined by meta-regression, sensitivity analysis and subgroup analysis.Results111 studies were included in the meta-analysis. The overall pooled mutation frequencies of these major ALS-related genes were 47.7% in familial amyotrophic lateral sclerosis (FALS) and 5.2% in sporadic ALS (SALS). A significant difference was identified regarding the frequencies of mutations in major ALS genes between European and Asian patients. In European populations, the most common mutations were the C9orf72 repeat expansions (FALS 33.7%, SALS 5.1%), followed by SOD1 (FALS 14.8%, SALS 1.2%), TARDBP (FALS 4.2%, SALS 0.8%) and FUS mutations (FALS 2.8%, SALS 0.3%), while in Asian populations the most common mutations were SOD1 mutations (FALS 30.0%, SALS 1.5%), followed by FUS (FALS 6.4%, SALS 0.9%), C9orf72 (FALS 2.3%, SALS 0.3%) and TARDBP (FALS 1.5%, SALS 0.2%) mutations.ConclusionsThese findings demonstrated that the genetic architecture of ALS in Asian populations is distinct from that in European populations, which need to be given appropriate consideration when performing genetic testing of patients with ALS.
Abstract
Pro-inflammatory M1 macrophages, via activating hepatic stellate cells, contribute to liver fibrosis. In this study, we examined the mechanism and the significance of a signaling axis, ...METTL3/MALAT1/PTBP1/USP8/TAK1, in regulating pyroptosis and M1 polarization of hepatic macrophages. Liver fibrosis model was established in vivo by CCl
4
treatment; M1 polarization was induced in vitro by treating macrophages with lipopolysaccharide or interferon γ. Expressions of METTL3, MALAT1, PTBP1, USP8, and TAK1 were measured by RT-PCR and/or Western blot in Kupffer cells (KCs) isolated from in vivo model or in vitro activated macrophages. Macrophage phenotypes including inflammation (RT-qPCR analysis of a panel of proinflammatory cytokines and ELISA on productions of interleukin (IL)−1β and IL-18) and pyroptosis (Western blot of NLRP3, Caspase-1, and GSDMD) were investigated. The impact of METTL3 on m
6
A methylation of MALAT1 was examined by methylated RNA immunoprecipitation (RIP), the interaction between PTBP1 and MALAT1 or USP8 mRNA by combining RNA pull-down, RIP, and RNA stability assays, and the crosstalk between USP8 and TAK1 by co-immunoprecipitation and protein degradation assays. Functional significance of individual component of METTL3/MALAT1/PTBP1/USP8/TAK1 axis was assessed by combining gain-of-function and loss-of-function approaches. In KCs isolated from in vivo liver fibrosis model or in vitro M1-polarized macrophages, METTL3 was up-regulated, and sequentially, it increased MALAT1 level via m
6
A methylation, which promoted USP8 mRNA degradation through the interaction with PTBP1. Reduced USP8 expression regulated the ubiquitination and protein stability of TAK1, which promoted pyroptosis and inflammation of macrophages. The signaling cascade METTL3/MALAT1/PTBP1/USP8/TAK1, by essentially stimulating pyroptosis and inflammation of macrophages, aggravates liver fibrosis. Therefore, targeting individual components of this axis may benefit the treatment of liver fibrosis.
Lithium–carbon dioxide (Li–CO2) battery technology presents a promising opportunity for carbon capture and energy storage. Despite tremendous efforts in Li–CO2 batteries, the complex ...electrode/electrolyte/CO2 triple‐phase interfacial processes remain poorly understood, in particular at the nanoscale. Here, using in situ atomic force microscopy and laser confocal microscopy‐differential interference contrast microscopy, we directly observed the CO2 conversion processes in Li–CO2 batteries at the nanoscale, and further revealed a laser‐tuned reaction pathway based on the real‐time observations. During discharge, a bi‐component composite, Li2CO3/C, deposits as micron‐sized clusters through a 3D progressive growth model, followed by a 3D decomposition pathway during the subsequent recharge. When the cell operates under laser (λ=405 nm) irradiation, densely packed Li2CO3/C flakes deposit rapidly during discharge. Upon the recharge, they predominantly decompose at the interfaces of the flake and electrode, detaching themselves from the electrode and causing irreversible capacity degradation. In situ Raman shows that the laser promotes the formation of poorly soluble intermediates, Li2C2O4, which in turn affects growth/decomposition pathways of Li2CO3/C and the cell performance. Our findings provide mechanistic insights into interfacial evolution in Li–CO2 batteries and the laser‐tuned CO2 conversion reactions, which can inspire strategies of monitoring and controlling the multistep and multiphase interfacial reactions in advanced electrochemical devices.
Using in situ atomic force microscopy, laser confocal microscopy‐differential interference contrast microscopy and Raman spectroscopy, we explored the electrode/electrolyte interfacial evolution in Li–CO2 batteries. The results indicate that the laser alters the reaction pathways of the CO2 reduction processes, which changes the morphological evolution of the discharge products at the interfaces, and in turn, affects the cell performance.
Objectives
Preoperative differentiation between benign parotid gland tumors (BPGT) and malignant parotid gland tumors (MPGT) is important for treatment decisions. The purpose of this study was to ...develop and validate an MRI-based radiomics nomogram for the preoperative differentiation of BPGT from MPGT.
Methods
A total of 115 patients (80 in training set and 35 in external validation set) with BPGT (
n
= 60) or MPGT (
n
= 55) were enrolled. Radiomics features were extracted from T1-weighted and fat-saturated T2-weighted images. A radiomics signature model and a radiomics score (Rad-score) were constructed and calculated. A clinical-factors model was built based on demographics and MRI findings. A radiomics nomogram model combining the Rad-score and independent clinical factors was constructed using multivariate logistic regression analysis. The diagnostic performance of the three models was evaluated and validated using ROC curves on the training and validation datasets.
Results
Seventeen features from MR images were used to build the radiomics signature. The radiomics nomogram incorporating the clinical factors and radiomics signature had an AUC value of 0.952 in the training set and 0.938 in the validation set. Decision curve analysis showed that the nomogram outperformed the clinical-factors model in terms of clinical usefulness.
Conclusions
The above-described radiomics nomogram performed well for differentiating BPGT from MPGT, and may help in the clinical decision-making process.
Key Points
•
Differential diagnosis between BPGT and MPGT is rather difficult by conventional imaging modalities.
•
A radiomics nomogram integrated with the radiomics signature, clinical data, and MRI features facilitates differentiation of BPGT from MPGT with improved diagnostic efficacy.
A supramolecular organic framework (SOF) was fabricated based on the tetraphenylethylene derivative MV-TPE with four methylated viologen units, tetraphenylethylene derivative NA-TPE with four ...methoxynaphthyl units, and cucurbit8uril (CB8) through encapsulation-enhanced donor-acceptor interaction. When the hydrophobic dye 4,7-bis(thien-2-yl)-2,1,3-benzothiadiazole (DBT) is introduced into the aqueous solution of a SOF, an efficient energy transfer process can take place from the SOF to DBT. In addition, after the addition of amphoteric sulforhodamine 101 (SR101), a two-step sequential energy transfer process can occur from the SOF to DBT and then to SR101. Furthermore, a white emission with the CIE coordinate of (0.31, 0.32) can be realized by the direct addition of SR101 to the SOF. Moreover, to utilize the harvested energy from the SOF + DBT + SR101 system, we tried to apply the SOF-based light-harvesting systems (LHSs) as a catalyst to advance the aerobic cross-dehydrogenative coupling (CDC) reaction in water. To our delight, under the promotion of 0.45 mol% catalyst, the yield of the reaction reached 87%, which exhibited the promising potential of SOF-based LHSs in the promotion of the CDC reaction.
A supramolecular organic framework was fabricated through encapsulation-enhanced donor-acceptor interaction for the construction of artificial light-harvesting systems for photocatalysis.
MK-8776 is a recently described inhibitor that is highly selective for checkpoint kinase 1 (Chk1), which can weaken the DNA repair capacity in cancer cells to achieve chemo-sensitization. A number of ...studies show that MK-8776 enhances the cytotoxicity of hydroxyurea and gemcitabine without increasing normal tissue toxicities. Thus far, there is no evidence that MK-8776 can be used as a radiotherapy sensitization agent. In this study, we investigated the effects of MK-8776 on the radiosensitivity of 3 human triple-negative breast cancer (TNBC) cell lines MDA-MB-231, BT-549 and CAL-51. MK-8776 dose-dependently inhibited the proliferation of MDA-MB-231, BT-549 and CAL-51 cells with IC
values of 9.4, 17.6 and 2.1 μmol/L, respectively. Compared with irradiation-alone treatment, pretreatment with a low dose of MK-8776 (100-400 nmol/L) significantly increased irradiation-induced γH2A.X foci in the 3 TNBC cell lines, suggesting enhanced DNA damage by MK-8776, inhibited the cell proliferation and increased the radiosensitivity of the 3 TNBC cell lines. Similar results were obtained in MDA-MB-231 xenograft tumors in nude mice that received MK-8776 (15 or 40 mg/kg, ip) 26 d after irradiation. To explore the mechanisms underlying the radio-sensitization by MK-8776, we used TEM and found that irradiation significantly increased the numbers of autophagosomes in the 3 TNBC cell lines. Moreover, irradiation markedly elevated the levels of Atg5, and promoted the transformation of LC3-I to LC3-II in the cells. Pretreatment with the low dose of MK-8776 suppressed these effects. The above results suggest that MK-8776 increases human TNBC radiosensitivity by inhibiting irradiation-induced autophagy and that MK-8776 may be a potential agent in the radiosensitization of human TNBC.
Prototype lanthanide metal-organic frameworks (LnMOFs), Ln(BTC) (Ln = Eu and Tb; BTC = benzene-1,3,5-tricarboxylate), have been considered as luminescent sensors for detecting toxic anions, while ...their neutral pore structures have limited the entrance and encapsulation of anions to produce highly anion-responsive photoluminescence (PL). To facilitate anions to enter the pore space of Ln(BTC), a one-pot synthesis method was proposed in which BTC was partially replaced with its structural analogue L·BF
(H
L·BF
= 2,4,6-tricarboxy-1-methylpyridinium tetrafluoroborate) which consists of an anion affinity site of cationic methylpyridinium. Compared to the original Ln(BTC), the co-doped cationic framework Eu
Tb
-BTC
L
is highly sensitive for detecting different toxic anions by tuning the energy absorption of organic chromophores, the energy transfer efficiency to Ln
ions and the energy allocation between different Ln
ions in the PL spectra. We demonstrated that the Eu
Tb
-BTC
L
PL sensor has the capability of decoding various toxic anions with a clearly differentiable and unique emission intensity ratio of
D
→
F
(Tb
, 545 nm) to
D
→
F
(Eu
, 618 nm) transitions (I
/I
). Compared to Ln(BTC), the co-doped Eu
Tb
-BTC
L
presents self-calibrating, high distinguishable and stable PL signals for detecting toxic anions.
The composition of protection monolayer exerts great influence on the molecular and electronic structures of atomically precise monolayer protected metal nanoclusters. Four isostructural ...Ag/cyanurate/phosphine metallamacrocyclic monolayer protected Ag22 nanoclusters are synthesized by kinetically controlled in‐situ ligand formation‐driven strategy. These eight‐electron superatomic silver nanoclusters feature an unprecedented interfacial bonding structure with diverse E‐Ag (E=O/N/P/Ag) interactions between the Ag13 core and metallamacrocyclic monolayer, and displays thermally activated delayed fluorescence (TADF), benefiting from their distinct donor‐acceptor type electronic structures. This work not only unmasks a new core‐shell interface involving cyanurate ligand but also underlines the significance of high‐electron‐affinity N‐heterocyclic ligand in synthesizing TADF metal nanoclusters. This is the first mixed valence Ag0/I nanocluster with TADF characteristic.
Four isostructural Ag22 nanoclusters protected by a metallamacrocyclic monolayer were synthesized in high yields by in‐situ ligand formation strategy. The high‐electron‐affinity triazine‐based cyanurate ligands endow the clusters with unique core‐shell interfacial bonding structure and donor‐acceptor type electronic structure, resulting in the first mixed valence Ag0/I nanocluster with thermally activated delayed fluorescence (TADF) characteristic.
To determine whether virtual reality-assisted therapy (VRAT) significantly improves the treatment of peripheral or central vestibular disorders when compared with conventional vestibular physical ...therapy (CVPT) alone. Indicators of vestibular symptoms are used to determine this.
Two reviewers independently searched PubMed, EMBASE, ClinicalTrials.gov, Web of Science, and the Cochrane Collaboration database from January 2010 to January 2022 for studies reporting on VRAT in vestibular disorders.
Randomized controlled trials (RCTs) were included that mainly focused on the following measures: the Dizziness Handicap Inventory (DHI), Simulator Sickness Questionnaire, visual analog scale, and balance measures such as the Activities-specific Balance Confidence Scale (ABC), timed Up and Go test, sensory organization test, and center of pressure. The primary outcome was assessment of symptomatic changes before and after VRAT.
Two authors independently conducted the literature search and selection. After screening, meta-analysis was performed on the RCTs using RevMan 5.3 software.
The results showed that VRAT produced significantly greater improvement than CVPT alone in scores of DHI-Total (standardized mean difference SMD: -7.09, 95% confidence interval CI: -12.17, -2.00, P=.006), DHI-Functional (SMD=-3.66, 95% CI: -6.34, -0.98, P=.007), DHI-Physical (SMD=-3.14, 95% CI: -5.46, -0.83, P=.008), and DHI-Emotional (SMD=-3.10, 95% CI: -5.13, -1.08, P=.003). ABC scores did not show improvement (SMD: 0.58, 95% CI: -3.69, 4.85, P=.79). Subgroup analysis showed that DHI-Total between-group differences were insignificant for central vestibular disorders (SMD=-1.47, 95% CI: -8.71, -5.78, P=.69), although peripheral disorders showed significant improvements (SMD=-9.58, 95% CI: -13.92, -5.25, P<.0001). However, the included studies showed high heterogeneity (I
>75%).
VRAT may offer additional benefits for rehabilitation from vestibular diseases, especially peripheral disorders, when compared with CVPT alone. However, because of high heterogeneity and limited data, additional studies with a larger sample size and more sensitive and specific measurements are required to conclusively determine the evidence-based utility of virtual reality.
A hydroclassified combinatorial saturation mutagenesis (HCSM) strategy was proposed for reshaping the substrate binding pocket by dividing 20 amino acids into four groups based on their ...hydrophobicity and size. These smart HCSM libraries could significantly reduce screening effort especially for the simultaneous mutagenesis of three or more residues and lacking high throughput screening methods. Employing HCSM strategy, the stereoselectivity of KpADH, an alcohol dehydrogenase from Kluyveromyces polysporus, was efficiently improved to 99.4% ee. (4-Chlorophenyl)(pyridin-2-yl)methanone (CPMK), generally regarded as a “hard-to-reduce” ketone, was used as a model substrate, and its corresponding chiral alcohol products could be utilized as antihistamine precursors. The best variant 50C10 displayed higher binding affinity and catalytic efficiency toward CPMK with K M/k cat of 59.3 s–1·mM–1, 3.51-fold that of KpADH. Based on MD simulations, increased difference between two binding pockets, enhanced hydrophobicity, and π–π and halogen–alkyl interactions were proposed to favor the enantioselective recognition and substrate binding in 50C10. Substrate spectrum analysis revealed that 50C10 exhibited improved enantioselectivity toward diaryl ketones especially with halo- or other electron-withdrawing groups. As much as 500 mM CPMK could be asymmetrically reduced into chiral diaryl alcohols with ee of 99.4% and a space–time yield of 194 g·L–1·d–1 without addition of external NADP+. This study provides an effective mutagenesis strategy for the protein engineering of substrate specificity and enantioselectivity.
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