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1.
Nat Struct Mol Biol ; 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36604500

RESUMO

The nucleotide-binding domain (NBD), leucine rich repeat (LRR) domain containing protein family (NLR family) apoptosis inhibitory proteins (NAIPs) are cytosolic receptors that play critical roles in the host defense against bacterial infection. NAIPs interact with conserved bacterial ligands and activate the NLR family caspase recruitment domain containing protein 4 (NLRC4) to initiate the NAIP-NLRC4 inflammasome pathway. Here we found the process of NAIP activation is completely different from NLRC4. Our cryo-EM structure of unliganded mouse NAIP5 adopts an unprecedented wide-open conformation, with the nucleating surface fully exposed and accessible to recruit inactive NLRC4. Upon ligand binding, the winged helix domain (WHD) of NAIP5 undergoes roughly 20° rotation to form a steric clash with the inactive NLRC4, which triggers the conformational change of NLRC4 from inactive to active state. We also show the rotation of WHD places the 17-18 loop at a position that directly bind the active NLRC4 and stabilize the NAIP5-NLRC4 complex. Overall, these data provide structural mechanisms of inactive NAIP5, the process of NAIP5 activation and NAIP-dependent NLRC4 activation.

2.
Epigenetics Chromatin ; 16(1): 4, 2023 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-36698218

RESUMO

BACKGROUND: Cellular differentiation is marked by temporally and spatially coordinated gene expression regulated at multiple levels. DNA methylation represents a universal mechanism to control chromatin organization and its accessibility. Cytosine methylation of CpG dinucleotides regulates binding of methylation-sensitive DNA-binding transcription factors within regulatory regions of transcription, including promoters and distal enhancers. Ocular lens differentiation represents an advantageous model system to examine these processes as lens comprises only two cell types, the proliferating lens epithelium and postmitotic lens fiber cells all originating from the epithelium. RESULTS: Using whole genome bisulfite sequencing (WGBS) and microdissected lenses, we investigated dynamics of DNA methylation and chromatin changes during mouse lens fiber and epithelium differentiation between embryos (E14.5) and newborns (P0.5). Histone H3.3 variant chromatin landscapes were also generated for both P0.5 lens epithelium and fibers by chromatin immunoprecipitation followed by next generation sequencing (ChIP-seq). Tissue-specific features of DNA methylation patterns are demonstrated via comparative studies with embryonic stem (ES) cells and neural progenitor cells (NPCs) at Nanog, Pou5f1, Sox2, Pax6 and Six3 loci. Comparisons with ATAC-seq and RNA-seq data demonstrate that reduced methylation is associated with increased expression of fiber cell abundant genes, including crystallins, intermediate filament (Bfsp1 and Bfsp2) and gap junction proteins (Gja3 and Gja8), marked by high levels of histone H3.3 within their transcribed regions. Interestingly, Pax6-binding sites exhibited predominantly DNA hypomethylation in lens chromatin. In vitro binding of Pax6 proteins showed Pax6's ability to interact with sites containing one or two methylated CpG dinucleotides. CONCLUSIONS: Our study has generated the first data on methylation changes between two different stages of mammalian lens development and linked these data with chromatin accessibility maps, presence of histone H3.3 and gene expression. Reduced DNA methylation correlates with expression of important genes involved in lens morphogenesis and lens fiber cell differentiation.


Assuntos
Cromatina , Histonas , Animais , Camundongos , Histonas/metabolismo , Metilação de DNA , DNA/metabolismo , Diferenciação Celular/genética , Expressão Gênica , Mamíferos/genética
4.
Hum Vaccin Immunother ; : 2161254, 2023 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-36683193

RESUMO

Off-treatment HBsAg reversion occurs in a considerable number of chronic hepatitis B(CHB) patients after IFN(interferon)-induced HBsAg clearance. HBV vaccination protects the general population against HBV infection. However, it remains unclear whether HBV vaccination could prevent off-treatment HBsAg reversion in CHB patients with HBsAg clearance. CHB patients (n = 199) with HBsAg clearance were included in the current study, comprising spontaneous HBsAg clearance group (n = 51), NA (nucleoside/nucleotide analogues)-induced group (n = 36) and IFN-induced group (n = 112). Log-rank test was performed to compare the cumulative incidences of HBsAg reversion between groups. Cox regression model was used to identify the factors associated with off-treatment HBsAg reversion. The 5-year cumulative incidence of HBsAg reversion in IFN-induced group was significantly higher than that in NA-induced group or spontaneous group (27.6% vs. 3.3% vs. 8.1%, both p < .05). In IFN-induced group, 66.7% of CHB patients received HBV vaccination. The cumulative incidence of HBsAg reversion in individuals with strong responses to HBV vaccination (HBsAb level >100mIU/ml) was significantly lower than that in those with weak responses to HBV vaccination (HBsAb level ≤100mIU/ml) or without HBV vaccination in IFN-induced group (7.7% vs. 58.5% vs. 31.9%, both p < .05). Multivariate Cox regression analysis confirmed strong responses to HBV vaccination were independently associated with a lower cumulative incidence of HBsAg reversion after IFN-induced HBsAg clearance (HR = 0.246, 95%CI: 0.066-0.907, p = .035). HBV vaccination has potential to prevent off-treatment HBsAg reversion in CHB patients after IFN-induced HBsAg clearance via a sufficiently high level of HBsAb, helping clinicians optimize the clinical management of such patients.

5.
Cell Rep ; 42(1): 111972, 2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36641751

RESUMO

KRAS is widely mutated in human cancers, resulting in unchecked tumor proliferation and metastasis, which makes identifying KRAS-targeting therapies a priority. Herein, we observe that mutant KRAS specifically promotes the formation of the ERK2-p53 complex in stomach/colorectal tumor cells. Disruption of this complex by applying MEK1/2 and ERK2 inhibitors elicits strong apoptotic responses in a p53-dependent manner, validated by genome-wide knockout screening. Mechanistically, p53 physically associates with phosphorylated ERK2 through a hydrophobic interaction in the presence of mutant KRAS, which suppresses p53 activation by preventing the recruitment of p300/CBP; trametinib disrupts the ERK2-p53 complex by reducing ERK2 phosphorylation, allowing the acetylation of p53 protein by recruiting p300/CBP; acetylated p53 activates PUMA transcription and thereby kills KRAS-mutant tumors. Our study shows an important role for the ERK2-p53 complex and provides a potential therapeutic strategy for treating KRAS-mutant cancer.

6.
J Med Virol ; 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36655747

RESUMO

BACKGROUND & AIMS: Data on the dynamic changes in chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD) during antiviral therapy are scarce. We aimed to investigate the evolution of NAFLD status change in CHB patients treated with nucleos(t)ide analogues (NAs) and its influence on therapeutic outcomes. METHODS: This retrospective study included 164 HBeAg-positive CHB patients from a randomized controlled trial who were treated with NAs for 104 weeks and underwent paired liver biopsies. Histological evaluation was performed at baseline and week 104. The patients were divided into four groups according to NAFLD status changes. RESULTS: From baseline to week 104, the overall percentage of CHB patients with concurrent NAFLD increased from 17.1% to 26.2% (P = 0.044). Among them, seven of 28 patients (25.0%) with NAFLD at baseline showed NAFLD remission at week 104, while 22 of 136 patients (16.2%) without NAFLD at baseline developed new-onset NAFLD. In subgroup analyses, the new-onset and sustained NAFLD groups showed significantly lower rates of biochemical response at week 104 as compared to the sustained non-NAFLD group (77.3% and 55% vs. 93.9%, respectively; all P < 0.05), as well as fibrosis improvement (31.8% and 45.0% vs. 69.3%, respectively; all P < 0.05). NAFLD status changes did not influence the virological response, HBeAg seroconversion, and necroinflammation improvement (all P > 0.05). CONCLUSIONS: In HBeAg-positive CHB patients receiving NAs therapy, new-onset and sustained NAFLD may counteract the benefits of antiviral therapy, reducing the rate of biochemical response and fibrosis improvement. This article is protected by copyright. All rights reserved.

7.
Microbiol Spectr ; : e0454222, 2023 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-36655994

RESUMO

Rapid and reliable diagnosis is important for the management of individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The rapid antigen detection test (RADT) is a rapid, inexpensive, and easy method. Several studies have reported that RADTs performed well in many countries; however, very few studies have been reported in China. In this study, we assessed the performance of the RADT (Ediagnosis COVID-19 antigen test kit). This study was conducted in a centralized isolation site in Shanghai and enrolled 716 patients with COVID-19 and 203 noninfected participants. Nasopharyngeal swabs from all participants were collected on the same day and tested using the RADT and real-time reverse transcription-PCR (RT-PCR). The performance of the RADT was evaluated in different scenarios, such as threshold cycle (CT) values, symptomatic phase, and symptoms on the day of testing. The results demonstrated that the sensitivity for patients with CT values lower than 20 was 96.55% (95% confidence interval [CI], 87.05 to 99.4). The sensitivities were 78.4% (95% CI, 69.96 to 85.05) for participants within 5 days after the first RT-PCR-positive result and 90.77% (95% CI, 80.34 to 96.19) within 5 days after symptom onset. Moreover, the sensitivity of the RADT was more than 80% for patients with symptoms on the day of testing, including fever (89.29%), cough (86.84%), stuffy nose (92.59%), runny nose (92%), sore throat (81.25%), and muscle pain (80.77%), especially for those with upper respiratory tract symptoms. The specificity of the RADT was good in all scenarios. During the SARS-CoV-2 epidemic, Ediagnosis performed excellently in individuals with a higher viral load (evidenced by lower CT values), individuals in the early symptomatic phase, and especially those with upper respiratory tract symptoms. IMPORTANCE RADTs have demonstrated excellent performance in many counties for screening SARS-CoV-2 infection, but very few studies have been conducted in China. The performance of RADTs is largely related to different real-life scenarios. In our study, the performance of the RADT was evaluated in different scenarios, such as CT values, symptomatic phase, and symptoms on the day of testing. The results demonstrated that Ediagnosis (an RADT made in China) performed excellently for individuals with a higher viral load (evidenced by lower CT values), individuals in the early symptomatic phase, and especially those with upper respiratory tract symptoms.

8.
J Clin Transl Hepatol ; 11(2): 304-313, 2023 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-36643032

RESUMO

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

9.
Neural Regen Res ; 18(5): 1062-1066, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-36254994

RESUMO

Multi-target neural circuit-magnetic stimulation has been clinically shown to improve rehabilitation of lower limb motor function after spinal cord injury. However, the precise underlying mechanism remains unclear. In this study, we performed double-target neural circuit-magnetic stimulation on the left motor cortex and bilateral L5 nerve root for 3 successive weeks in a rat model of incomplete spinal cord injury caused by compression at T10. Results showed that in the injured spinal cord, the expression of the astrocyte marker glial fibrillary acidic protein and inflammatory factors interleukin 1ß, interleukin-6, and tumor necrosis factor-α had decreased, whereas that of neuronal survival marker microtubule-associated protein 2 and synaptic plasticity markers postsynaptic densification protein 95 and synaptophysin protein had increased. Additionally, neural signaling of the descending corticospinal tract was markedly improved and rat locomotor function recovered significantly. These findings suggest that double-target neural circuit-magnetic stimulation improves rat motor function by attenuating astrocyte activation, thus providing a theoretical basis for application of double-target neural circuit-magnetic stimulation in the clinical treatment of spinal cord injury.

10.
J Trace Elem Med Biol ; 76: 127112, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36481603

RESUMO

BACKGROUND: Cinnabar, a mercury-containing mineral medicine, has long been widely used in pediatric prescriptions. The safety of cinnabar-containing prescriptions, particularly for children, is drawing increasing attention worldwide. However, whether cinnabar and these pediatric prescriptions have adverse effects on neurobehavior is unknown. Yi-Nian-Jin (YNJ), a classic pediatric prescription, contains 5.66% (w/w) cinnabar, along with other four herbs. YNJ is widely prescribed to promote digestion, eliminate phlegm, and prevent constipation in children (aged 0-6 years). In this study, we used YNJ as an example of cinnabar-containing pediatric prescriptions to determine mercury absorption, distribution, and accumulation and further investigate its potential neurotoxicity in juvenile rats. MATERIAL AND METHODS: Low (67.9 mg/kg), middle (169.8 mg/kg), and high dose (339.6 mg/kg) of cinnabar, and low (1.2 g/kg), middle (3.0 g/kg), and high dose (6.0 g/kg) of YNJ were used in this study, corresponding to 3, 7.5, and 15 times the clinically equivalent dose, respectively. Juvenile rats were orally administered different doses of cinnabar or YNJ for 14 consecutive days. The mercury content in rat blood and tissues (brain, liver, and kidney) and serum biochemical changes on day 14 of consecutive administration and on day 14 after cessation were measured. Moreover, a series of behavioral assays (open field, elevated plus-maze, and Morris water maze assays) were performed after 14 consecutive days of administration. RESULTS: The mercury absorption, distribution, and accumulation of cinnabar and YNJ in juvenile rats were substantially different. Mercury in cinnabar was absorbed to a greater extent than that in YNJ, and the mercury content in cinnabar high-dose group (cinnabar-H) was approximately seven times higher than that in YNJ high-dose group (YNJ-H) on day 14 of administration. In contrast, compared with that of cinnabar, the mercury content in YNJ accumulated more in the tissues, especially in the brain and kidney. Repeated administration of cinnabar or YNJ did not affect liver function, renal function, learning, and memory in juvenile rats. However, repeated administration of YNJ at a high dose (6.0 g/kg) affected locomotor activity in juvenile rats. Repeated administration of cinnabar (339.6 mg/kg) or YNJ (>1.2 g/kg) induced anxiety-related behavior in juvenile rats. CONCLUSIONS: Mercury in YNJ exhibited lower absorption but higher accumulation in tissues than those of the mercury in cinnabar. Consecutive oral administration of cinnabar or YNJ had no impact on liver function, renal function, learning, and memory, but could cause motor dysfunction and anxiety in juvenile rats.


Assuntos
Compostos de Mercúrio , Mercúrio , Ratos , Animais , Rim , Fígado
11.
Analyst ; 148(2): 227-232, 2023 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-36537473

RESUMO

Nanoscale infrared (nano-IR) microscopy enables label-free chemical imaging with a spatial resolution below Abbe's diffraction limit through the integration of atomic force microscopy and infrared radiation. Peak force infrared (PFIR) microscopy is one of the emerging nano-IR methods that provides non-destructive multimodal chemical and mechanical characterization capabilities using a straightforward photothermal signal generation mechanism. PFIR microscopy has been demonstrated to work for a wide range of heterogeneous samples, and it even allows operation in the fluid phase. However, the current PFIR microscope requires customized hardware configuration and software programming for real-time signal acquisition and processing, which creates a high barrier to PFIR implementation. In this communication, we describe a type of lock-in amplifier-based PFIR microscopy that can be assembled with generic, commercially available equipment without special hardware or software programming. We demonstrate this method on soft matters of structured polymer blends and blocks, as well as biological cells of E. coli. The lock-in amplifier-based PFIR reduces the entry barrier for PFIR microscopy and makes it a competitive nano-IR method for new users.


Assuntos
Escherichia coli , Polímeros , Microscopia de Força Atômica/métodos , Raios Infravermelhos , Espectrofotometria Infravermelho/métodos
12.
N Engl J Med ; 2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36577095

RESUMO

BACKGROUND: Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir). RESULTS: A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%). CONCLUSIONS: Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

13.
Neurosurgery ; 2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36512828

RESUMO

BACKGROUND: WHO grade 2 meningiomas, including atypical, chordoid, and clear cell subtypes, form a heterogenous group of meningiomas with varying aggressiveness and clinical behavior. OBJECTIVE: To demonstrate the differences of clinical-histopathological characteristics and long-term outcomes among these 3 subtypes. METHODS: A total of 609 consecutive patients diagnosed with WHO grade 2 meningiomas (543 atypical meningiomas [AMs], 36 chordoid meningiomas [CMs], and 30 clear cell meningiomas [CCMs]) from 2010 to 2018 were enrolled in this study. We compared the clinical-histopathological characteristics and long-term outcomes in these 3 subtypes and assessed survival differences among the subtypes. Targeted panel sequencing of meningioma-relevant genes was performed in the cases of CM. RESULTS: The patients with CCM were significantly younger than those with AM (P < .001) and CM (P = .016). CMs were more likely to receive gross total resection than AMs and CCMs (P = .033). The Ki-67 index was lower (P < .001) while the progesterone receptors-positive rate was higher (P = .034) in CM than in AM and CCM. Importantly, survival analysis demonstrated that CM had better progression-free survival (P = .022) and overall survival (P = .0056) than non-CM tumors. However, the PFS of CM was still worse than WHO grade 1 meningiomas (P < .001). Alterations in NF2 (20.6%) and KMT2C (26.5%) were associated with poorer PFS in CM (P = .013 for NF2; P = .021 for KMT2C). CONCLUSION: Patients with CM had better long-term postoperative outcomes than the other WHO grade 2 subtypes. A lower Ki-67 index, higher PR status, higher extent of resection, and lower frequency of NF2 alteration might contribute to favorable clinical outcomes of CM.

14.
Ann Nucl Med ; 2022 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-36586034

RESUMO

OBJECTIVE: To evaluate the efficiency of a novel lymph node radiotracer 99mTc-rituximab in sentinel lymph node (SLN) lymphoscintigraphy and SLN biopsy (SLNB), and the influence of SLNB results on the prognosis of cutaneous malignant melanoma (CMM) patients. METHODS: A retrospective study was performed on 533 patients with CMM who underwent lymphoscintigraphy and SLNB. All patients received a preoperative peritumoral injection of 11.1-18.5 MBq of 99mTc-rituximab 0.5 to 1 h before lymphoscintigraphy and SLNB. RESULTS: The detection rate of lymphoscintigraphy and SLNB was both 99.81% (532/533), and the average number of detected SLNs was 2.1 (range 1 to 8) and 2.7 (range 1 to 11) per patient, respectively. 12.1% SLNs and 22.2% patients were found metastatic, with an average of 1.5 (range 1 to 5) metastatic SLNs per patient. The SLN metastatic rates were different in patients with different Breslow thickness, Clark levels, ulceration, mitotic counts, and HMB45 expression (p < 0.05). Ninety patients were proceeded with the regional lymph node dissection (RLND) after SLNB, and the sensitivity, specificity and accuracy of SLNB in metastatic diagnosis is 97.4, 100 and 96.7%, respectively. And SLNs with metastases was an independent prognostic factor for OS and PFS by multivariate prognostic analyses (HR was 5.9 and 4.3, p < 0.001). For patients with metastatic SLNs, the non-SLNs with metastasis and non-SLNs without metastasis in RLND, and observation groups showed different mean PFS as 14.9, 24.8 and 25.5 months (p = 0.018), but no statistically significant difference existed in the OS. CONCLUSION: The novel radiotracer 99mTc-rituximab could identify SLNs specifically in SLN lymphoscintigraphy and SLNB in CMM patients, and the pathology obtained from SLNB rather than from RLND better indicated the staging and long-term prognosis.

16.
J Plant Physiol ; 280: 153861, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36399835

RESUMO

AKT1 is an inward-rectifying K+ channel that was originally thought to function only within a low-affinity K+ concentration range. However, the growth of an akt1 mutant of Arabidopsis was shown to be severely inhibited within a high-affinity range. This suggested that AKT1 may also be a high-affinity K+ transporter, but it remains unclear how the two modes of AKT1 coordinate to uptake K+. One gene (MeAKT2) encodes for a putatively inward-rectifying K+ channel and was isolated from cassava. Relative to other tissues, the MeAKT2 gene was expressed mainly in roots, and its transcriptional level was observed to be significantly increased under low-K+ conditions. Functional analyses were performed using a yeast expression system. When MeAKT2 was expressed alone in yeast cells, transgenic yeast could grow only in nutrient media supplied with >0.5 mM potassium. A yeast two-hybrid assay showed that both MeCIPK10 and MeCIPK12 clearly interacted with MeAKT2. Additionally, 0.05 mM K+ was sufficient for the growth of yeast cells co-expressing MeAKT2 with MeCIPK10, but also their co-expression significantly enhanced the growth capacity of yeast cells in the low range of K+ concentrations. Change in K+ uptake rate in co-transgenic yeast cells grown across a wide range of K+ concentrations showed that MeAKT2-mediated K+ uptake displayed a biphasic pattern, but also the switching from low-to high-affinity K+ uptake was regulated by CIPK10. This indicated that MeAKT2 functioned as a dual-affinity transporter to uptake K+ under both low- and high-affinity K+ conditions.

17.
Front Pharmacol ; 13: 965770, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36339553

RESUMO

Objective: The aim of this research was to investigate the therapeutic efficacy of lenvatinib combined with sequential transarterial chemoembolization (TACE) on primary hepatocellular carcinoma (HCC) and the effects on serum basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Method: A total of 104 patients with primary HCC, admitted to People's Hospital of Leshan from April 2018 to January 2021, were selected as the study subjects and were divided into the TACE-LEN group (n = 53) who were treated with lenvatinib combined with sequential TACE and the TACE group (n = 51) who were treated with TACE alone, according to the appropriate treatment modalities. The clinical efficacy 8 weeks after treatment; the serum levels of total bilirubin, conjugated bilirubin, and alanine aminotransferase (ALT); the prothrombin time (PT); the indocyanine green retention rate at 15 min (ICGR15); and the serum bFGF and VEGF levels before treatment and at 8 weeks after treatment were compared between the two groups. The incidence of adverse events and the survival rates at 18 months were also recorded for both groups. COX regression analysis was used to analyze the risk factors affecting the survival of patients. Results: Eight weeks after treatment, the objective response rate was higher in the TACE-LEN group than in the TACE group (77.36% vs. 56.36%, p < 0.05), but there were no statistically significant differences in the bilirubin and ALT levels, the PT, and the ICGR15 between the two groups (p > 0.05). The serum bFGF and VEGF levels post-therapeutic were lower in the TACE-LEN group than in the TACE group (p < 0.05). The differences in the incidence of postoperative adverse events and the survival rate within 6 months were not statistically significant between the two groups (p > 0.05). In addition, the survival rates within 12 and 18 months after treatment were higher in the TACE-LEN group than in the TACE group than in the TACE group (81.1% vs. 64.7%, 69.8% vs. 49.1%, p < 0.05). ICG-R15 and treatment regimen are risk factors for survival. Conclusion: The worse the liver reserve is, the worse the prognosis is. The combination of TACE and lenvatinib showed better efficacy and longer survival than TACE monotherapy for HCC patients and reduced the levels of bFGF and VEGF.

18.
Nano Lett ; 22(22): 9174-9180, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36368003

RESUMO

The mechanical detection of photothermal expansion from infrared (IR) absorption with an atomic force microscope (AFM) bypasses Abbe's diffraction limit, forming the chemical imaging technique of AFM-IR. Here, we develop a Fourier transform AFM-IR technique with peak force infrared microscopy and broadband femtosecond IR pulses. A Michelson interferometer creates a pair of IR pulses with controlled time delays to generate photothermal signals transduced by AFM to form an interferogram. A Fourier transform is performed to recover IR absorption spectra. We demonstrate the Fourier transform AFM-IR microscopy on a polymer blend and hexagonal boron nitride. An intriguing observation is the vertical asymmetry of the interferogram, which suggests the presence of multiphoton absorption processes under the tip-enhancement and femtosecond IR lasers. Our method demonstrates the feasibility of time-domain detection of the AFM-IR signal in the mid-IR regime and paves the way toward multiphoton vibrational spectroscopy at the nanoscale below the diffraction limit.


Assuntos
Lasers , Polímeros , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Microscopia de Força Atômica/métodos , Polímeros/química , Análise de Fourier
19.
Front Oncol ; 12: 1017618, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36353559

RESUMO

Objective: This study aimed to evaluate the 18F-FDG PET/CT in differentiating lung metastasis(LM) from primary lung cancer(LC) in patients with colorectal cancer (CRC). Methods: A total of 120 CRC patients (80 male, 40 female) who underwent 18F-FDG PET/CT were included. The diagnosis of primary lung cancer or lung metastasis was based on histopathology The patients were divided into a training cohort and a validation cohort randomized 1:1. Independent risk factors were extracted through the clinical information and 18F-FDG PET/CT imaging characteristics of patients in the validation cohort, and then a diagnostic model was constructed and a nomograms was made. ROC curve, calibration curve, cutoff, sensitivity, specificity, and accuracy were used to evaluate the prediction performance of the diagnostic model. Results: One hundred and twenty Indeterminate lung lesions (ILLs) (77 lung metastasis, 43 primary lung cancer) were analyzed. No significant difference in clinical characteristics and imaging features between the training and the validation cohorts (P > 0. 05). Using uni-/multivariate analysis, pleural tags and contour were identified as independent predictors. These independent predictors were used to establish a diagnostic model with areas under the receiver operating characteristic curves (AUCs) of 0.92 and 0.89 in the primary and validation cohorts, respectively. The accuracy rate of the diagnostic model for differentiating LM from LC were higher than that of subjective diagnosis (P < 0.05). Conclusions: Pleural tags and contour were identified as independent predictors. The diagnostic model of ILLs in patients with CRC could help differentiate between LM and LC.

20.
J Neurosurg ; : 1-10, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36334291

RESUMO

OBJECTIVE: Benefits of adjuvant radiotherapy (ART) after gross-total resection (GTR) of de novo atypical meningiomas (AMs) are controversial, and factors predictive of radiotherapy benefits in patients with de novo AMs after GTR are unknown. The authors aimed to evaluate the benefits of ART and explore potential factors sensitizing AMs to ART. METHODS: A total of 231 consecutive patients who were pathologically diagnosed with de novo AMs and treated with GTR (Simpson class I-III resections) from 2010 to 2018 were enrolled in the study. Clinicopathological and prognostic information was collected and analyzed. Univariate and multivariate Cox analyses were used to evaluate prognostic predictors and compare the response to radiotherapy. Propensity score matching (PSM) was used to balance the confounding bias in subgroups. RESULTS: A total of 138 patients (59.74%) received ART. Progesterone receptor (PR) expression was positive in 157 patients (67.97%). During the mean follow-up period of 76.25 months, 65 patients (28.14%) experienced recurrence and 38 (16.45%) died of tumor progression. For disease-specific survival (DSS), ART was a better prognostic factor via univariate (p = 0.003) and multivariate (p = 0.025) analyses. For progression-free survival (PFS), univariate Cox analysis showed that ART improved PFS (p = 0.013), but multivariate analysis did not (p = 0.068). Positive PR expression (p = 0.019), age 53.5 years or younger (p = 0.012), and Ki-67 7.5% or lower (p = 0.025) were independent prognostic predictors for better PFS. In the subcohort analysis, the beneficial impact of ART was observed in the PR-negative cohort (p = 0.002) but not in the PR-positive cohort (p = 0.86). The heterogeneity analysis demonstrated that the PR-negative cohort was more sensitive to ART than the PR-positive cohort (p = 0.036). ART was not found to be associated with better PFS in younger patients (≤ 53.5 years, p = 0.14), older patients (> 53.5 years, p = 0.085), those with a Ki-67 index ≤ 7.5% (p = 0.068), or those with a Ki-67 > 7.5% (p = 0.13). The contrasting effects of ART in the PR-negative versus PR-positive cohorts remained true even after PSM, confirming that PR-negative, but not PR-positive, de novo AMs benefited from ART after GTR. CONCLUSIONS: ART was an independent prognostic factor for DSS of patients with de novo AMs treated with GTR (p = 0.025), but not for PFS (p = 0.068). Negative PR expression was a radiosensitive biomarker on PFS for de novo AM patients after GTR.

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