Blepharospasm patients often have dry eye manifestations. Botulinum neurotoxin type A (BoNT-A) injection has been the main management for blepharospasm and absorbable punctal plug (APP) insertion is ...shown to be effective in the treatment of dry eye. However, there have been no studies investigating the combined treatment of BoNT-A and APP in blepharospasm patients with dry eye. In this retrospective study, 17 blepharospasm patients with dry eye treated by BoNT-A injection and 12 receiving BoNT-A plus APP treatment were enrolled. The efficacy was evaluated according to the Jankovic rating scale, Ocular Surface Disease Index (OSDI), fluorescein staining (FL), fluorescein tear break-up time (FBUT) and Schirmer I test (SIT). Both BoNT-A and BoNT-A+APP treatment effectively reduced the functional impairment of blepharospasm. At baseline, all the patients had high OSDI scores (BoNT-A group: 82.48 ± 7.37, BoNT-A+APP group: 78.82 ± 4.60,
= 0.112), but relatively low degrees of FL (BoNT-A group: 3.18 ± 1.01, BoNT-A+APP group: 3.50 ± 1.24,
= 0.466), FBUT (BoNT-A group: 1.71 ± 0.77, BoNT-A+APP group: 2.17 ± 0.58,
= 0.077) and SIT (BoNT-A group: 2.53 ± 0.99, BoNT-A+APP group: 3.17 ± 1.23,
= 0.153). After treatment, OSDI, FL, FBUT and SIT were all obviously restored in the two groups. When comparing the changing rates, only OSDI (BoNT-A group: -52.23% ± 15.57%, BoNT-A+APP group: -61.84% ± 9.10%,
= 0.047) and FL (BoNT-A group: -22.55% ± 25.98%, BoNT-A+APP group: -41.94% ± 14.46%,
= 0.016) showed significant differences between the two groups. This study suggests that OSDI is not applicable in the diagnosis of dry eye among blepharospasm patients. For blepharospasm patients with severe dry eye symptoms, especially those with fluorescein staining in the cornea, the combined treatment of BoNT-A and APP is more effective than using BoNT-A alone.
Since initial identification in China, the widespread geographical occurrence of plasmid-mediated colistin resistance gene mcr-1 in Enterobacteriaceae has been of great concern. In this study, a ...total of 22 Salmonella enterica were resistant to colistin, while only five isolates which belonged to ST34 Salmonella enterica serovar Typhimurium (S. Typhimurium) were mcr-1 positive. Four of them shared nearly identical PFGE type, although they were from different host species and diverse geographical locations. All the mcr-1-positive S. Typhimurium exhibited multi-resistant phenotypes including ampicillin, streptomycin, gentamicin, florfenicol, nalidixic acid, tetracycline, trimethoprim-sulfamethox, in addition to colistin. The oqxAB and aac(6')-Ib-cr genes were present alone or in combination in four (80.0%) and five (100%) isolates, respectively. The mcr-1 gene was located on a transferable IncI2 plasmid in the four genetically related strains. In the other one strain, mcr-1 was located on an approximately 190 kb IncHI2 plasmid. In conclusion, we report five mcr-1-positive S. Typhimurium/ST34 isolates. Both clonal expansion and horizontal transmission of IncI2-type plasmids were involved in the spread of the mcr-1 gene in Salmonella enterica from food-producing animals in China. There is a great need to monitor the potential dissemination of the mcr-1 gene.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and the most common subtype of non-Hodgkin lymphoma in China. However, many cases still remain biologically and clinically ...heterogeneous, indicating that the DLBCL mechanism remains unclear. MicroRNAs (miRNAs) are critically responsible for lymphomagenesis. We found that plasma miR-21 level was significantly higher in B-cell lymphoma. However, the exact contribution of miR-21 in DLBCL remains unknown.To determine the function and mechanism of miR-21 in DLBCL, miR-21 and phosphatase and tensin homolog (PTEN) expressions were examined through real-time PCR and immunohistochemical methods. Moreover, the effects of antisense oligonucleotide (ASO) targeting miR-21 (ASO-21) were observed in DLCBL cell line.MiR-21 expressions in cell line and tissues of patients were significantly higher than those in normal controls, which were inversely correlated with PTEN expression. MiR-21 expression was significantly higher in stage III/IV patients than in stage I/II patients. PTEN protein was expressed positively in only 6 patients with DLBCL (6/26). MiR-21 expression level in the PTEN-negative group was 11.73 (2.13-64.29), which was significantly higher than that in the PTEN-positive group (1.04, 0.67-15.15; P = .038). After down-regulating the miR-21 expression, apoptosis of DLBCL cells increased and PTEN protein was up-regulated in ASO-21-treated cells compared with SCO-21-treated cells by western blot.These results suggested that miR-21 affects apoptosis of lymphoma cells by regulating the expression of PTEN in DLBCL, which may be associated with increased poor prognosis for DLBCL patients and represents a useful approach for DLBCL treatment.
Pharynx and larynx cancers (PLCs) are the top killer cancers in head and neck and significantly affect the quality of life of patients. A detailed study examining the disease burden and risk factors ...of PLCs is lacking.
Data on mortality and disability-adjusted life-years (DALYs) were extracted from the Global Burden of Disease Study 2019. The estimated annual percentage change (EAPC) of the age-standardized mortality rate was calculated using a generalized linear model with a Gaussian distribution. Mortality and DALYs were stratified according to the sociodemographic index (SDI), age, gender, and risk factors. The association between the SDI and mortality rate was measured using Spearman's correlation.
Between 1990 and 2019, the total number of deaths due to PLCs increased by 60.7% (95% confidence intervals: 39.32 to 66.8), from 192.38 thousand in 1990 to 309.16 thousand in 2019, and the total DALYs due to PLCs increased by 49.41% (95% confidence intervals: 30.15 to 53.27), from 5.91 million in 1990 to 8.83 million in 2019. The age-standardized mortality rate declined for larynx cancer (from 2.19 in 1990 to 1.49 in 2019) and nasopharynx cancer (1.26 to 0.86) but increased slightly for other pharynx cancer (1.25 to 1.37). The death number of PLCs was significantly higher in men aged 50 to 70 years, which accounts for 46.05% and 43.83% of the total deaths in 1990 and 2019, respectively. Low and low-middle countries had the greatest age-standardized mortality rate for larynx and other pharynx cancer, while low-middle and middle countries dominated for nasopharynx cancer. The leading risk factors for PLCs were smoking and alcohol use, which account for 37.92% and 58.84% in total DALYs rate of PLCs, and the influence of risk factors was significant in men.
The total number of deaths and DALYs due to PLCs increased from 1990 to 2019. Countries with relatively low SDI and middle-aged and older men had the greatest burden of PLCs. Building better health care systems in relatively low SDI countries and improving strategies of smoking and alcohol control should be a priority in health policy.
Arthritis is a group of highly prevalent joint disorders, and osteoarthritis (OA) and rheumatoid arthritis are the two most common types. The high prevalence of arthritis causes severe burdens on ...individuals, society and the economy. Currently, the primary treatment of arthritis is to relieve symptoms, but the development of arthritis cannot be effectively prevented. Studies have revealed that the disrupted balance of enzymes determines the pathological changes in arthritis. In particular, the increased levels of matrix metalloproteinases and the decreased expression of endogenous antioxidant enzymes promote the progression of arthritis. New therapeutic strategies have been developed based on the expression characteristics of these enzymes. Biomaterials have been designed that are responsive when the destructive enzymes MMPs are increased or have the activities of the antioxidant enzymes that play a protective role in arthritis. Here, we summarize recent studies on biomaterials associated with MMPs and antioxidant enzymes involved in the pathological process of arthritis. These enzyme-related biomaterials have been shown to be beneficial for arthritis treatment, but there are still some problems that need to be solved to improve efficacy, especially penetrating the deeper layer of articular cartilage and targeting osteoclasts in subchondral bone. In conclusion, enzyme-related nano-therapy is challenging and promising for arthritis treatment.
Sensory information is transferred to the cerebellar cortex
via
the mossy fiber–granule cell (MF–GC) pathway, which participates in motor coordination and motor learning. We previously reported that ...chronic ethanol exposure from adolescence facilitated the sensory-evoked molecular layer interneuron–Purkinje cell synaptic transmission in adult mice
in vivo
. Herein, we investigated the effect of chronic ethanol exposure from adolescence on facial stimulation-evoked MF–GC synaptic transmission in the adult mouse cerebellar cortex using electrophysiological recording techniques and pharmacological methods. Chronic ethanol exposure from adolescence induced an enhancement of facial stimulation-evoked MF–GC synaptic transmission in the cerebellar cortex of adult mice. The application of an N-methyl-
D
-aspartate receptor (NMDAR) antagonist, D-APV (250 μM), induced stronger depression of facial stimulation-evoked MF–GC synaptic transmission in chronic ethanol-exposed mice compared with that in control mice. Chronic ethanol exposure-induced facilitation of facial stimulation evoked by MF–GC synaptic transmission was abolished by a selective GluN2A antagonist, PEAQX (10 μM), but was unaffected by the application of a selective GluN2B antagonist, TCN-237 (10 μM), or a type 1 metabotropic glutamate receptor blocker, JNJ16259685 (10 μM). These results indicate that chronic ethanol exposure from adolescence enhances facial stimulation-evoked MF–GC synaptic transmission
via
GluN2A, which suggests that chronic ethanol exposure from adolescence impairs the high-fidelity transmission capability of sensory information in the cerebellar cortex by enhancing the NMDAR-mediated components of MF–GC synaptic transmission in adult mice
in vivo
.
In this work, a novel fractional-order extended state observer (FOESO)-based linear active disturbance rejection control (LADRC) method is firstly proposed for a hypersonic vehicle (HV) to address ...the measurement noise problem. The uncertainty and external disturbance of an HV was discussed and addressed by the active disturbance rejection control and many different control methods in recent decades. However, the research of an HV with measurement noise is insufficient. For the LADRC, the anti-noise ability is highly dependent on the bandwidth of the extended state observer (ESO). Meanwhile, the control performance of the LADRC is relevant to the bandwidth. The FOESO is presented, aiming to address the tradeoff of the control performance or noise suppression. The FOESO-based LADRC (FOESO-LADRC) introduces fractional calculus. It can enhance the anti-noise ability with little influence on the control performance. The simulation results show that the FOESO-LADRC has a significant improvement in the noise suppression. In addition, compared with the LADRC, it obtains a better solution to address the tradeoff between the bandwidth and noise impact.
Cancer evades host immune surveillance by virtue of poor immunogenicity. Here, we report an immune suppressor, designated as PTIR1, that acts as a promotor of tumor immune resistance. PTIR1 is ...selectively induced in human cancers via alternative splicing of DDX58 (RIG-I), and its induction is closely related to poor outcome in patients with cancer. Through blocking the recruitment of leukocytes, PTIR1 facilitates cancer immune escape and tumor-intrinsic resistance to immunotherapeutic treatments. Unlike RIG-I, PTIR1 is capable of binding to the C terminus of UCHL5 and activates its ubiquitinating function, which in turn inhibits immunoproteasome activity and limits neoantigen processing and presentation, consequently blocking T cell recognition and attack against cancer. Moreover, we find that the adenosine deaminase ADAR1 induces A-to-I RNA editing on DDX58 transcript, thus triggering PTIR1 production. Collectively, our data uncover the immunosuppressive role of PTIR1 in tumorigenesis and propose that ADAR1-PTIR1-UCHL5 signaling is a potential cancer immunotherapeutic target.
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•PTIR1 is an alternative splicing isoform of RIG-I•Inducible PTIR1 can frequently be detected in cancers•PTIR1 facilitates cancer immune escape via inhibition of neoantigen processing•ADAR1 acts as the master regulator for PTIR1 induction
Song et al. show that an alternative splicing isoform of RIG-I acts as a promoter of tumor resistance in multiple cancers, thus designated as PTIR1. In light of the inhibitory role of PTIR1 in control of immunoproteasome activity, they propose that ADAR1-PTIR1-UCHL5 signaling is a potential target for cancer immunotherapy.
Nephrotoxicity is a common adverse effect induced by various chemicals, necessitating the development of reliable toxicity screening models for nephrotoxicity assessment. In this study, we assessed a ...group of nephrotoxicity indicators derived from different toxicity pathways, including conventional endpoints and kidney tubular injury biomarkers such as clusterin (CLU), kidney injury molecule-I (KIM-1), osteopontin (OPN), and neutrophil gelatinase-associated lipocalin (NGAL), using HK-2 and induced pluripotent stem cells (iPSCs)-derived renal proximal tubular epithelial-like cells (PTLs). Among the biomarkers tested, OPN emerged as the most discerning and precise marker. The predictive potential of OPN was tested using a panel of 10 nephrotoxic and 5 non-nephrotoxic compounds. The results demonstrated that combining OPN with the half-maximal inhibitory concentration (IC50) enhanced the diagnostic accuracy in both cellular models. Additionally, PTLs cells showed superior predictive efficacy for nephrotoxicity compared to HK-2 cells in this investigation. The two cellular models were utilized to evaluate the nephrotoxicity of lanthanum. The findings indicated that lanthanum possesses nephrotoxic properties; however, the degree of nephrotoxicity was relatively low, consistent with the outcomes of in vivo experiments.
•Successfully established the iPSCs-based nephrotoxicity in vitro replacement model (PTLs).•OPN may be a sensitive potential biomarker to predict nephrotoxicity in vitro.•Combination of IC50 and OPN can significantly improve the prediction efficiency of nephrotoxicity.•PTLs has a better ability to evaluate nephrotoxicity than HK-2.•Lanthanum has a low degree of nephrotoxicity.
Leaf color mutants in higher plants are considered to be ideal materials for studying the chlorophyll biosynthesis, photosynthesis mechanism and chloroplast development. Herein, we identified a ...spontaneous mutant, yc412, in cultivated cucumber that exhibited yellow cotyledons. The yellow-lethal mutant was diagnosed with an abnormal chloroplast ultrastructure, and reduced photosynthetic capacity and pigment content. Through bulked segregant analysis-based whole-genome sequencing and fine genetic mapping, we narrowed the yellow cotyledons (yc) locus to a 96.8 kb interval on chromosome 3. By resequencing and molecular cloning, we showed that Csyc is a potential candidate gene, which encodes a yellow stripe-like (YSL) transporter. The T to C mutation in the promoter region of Csyc caused the yellow cotyledon phenotype in yc412. Compared to YZU027A (WT), the expression of Csyc was significantly downregulated in the cotyledons of yc412. Silencing of Csyc in cucumber via virus-induced gene silencing resulted in chlorotic leaves, mainly by suppressing the chlorophyll content. Furthermore, a comparative transcriptome analysis revealed that chloroplast-related genes and chlorophyll biosynthesis genes were significantly downregulated in yc412 cotyledons. Our results provide new insights into the molecular function of the YSL transporter in plant chloroplast development and chlorophyll synthesis.
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