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As a famous prescription in China, AnGong NiuHuang (AGNH) pill exerts good neuroprotection for ischaemic stroke (IS), but its mechanism is still unclear. In this study, the neuroprotection of AGNH was evaluated in the rat IS model which were established with the surgery of middle cerebral artery occlusion (MCAO), and the potential mechanism was elucidated by transcriptomic analysis and metabolomic analysis. AGNH treatment obviously decreased the infarct volume and Zea-Longa 5-point neurological deficit scores, improved the survival percentage of rats, regional cerebral blood flow (rCBF), and rat activity distance and activity time. Transcriptomics showed that AGNH exerted its anti-inflammatory effects by affecting the regulatory network including Tyrobp, Syk, Tlr2, Myd88 and Ccl2 as the core. Integrating transcriptomics and metabolomics identified 8 key metabolites regulated by AGNH, including L-histidine, L-serine, L-alanine, fumaric acid, malic acid, and N-(L-arginino) succinate, 1-pyrroline-4-hydroxy-2-carboxylate and 1-methylhistamine in the rats with IS. Additionally, AGNH obviously reduced Tyrobp, Syk, Tlr2, Myd88 and Ccl2 at both the mRNA and protein levels, decreased IL-1β, KC-GRO, IL-13, TNF-α, cleaved caspase 3 and p65 nucleus translocation, but increased IκBα expression. Network pharmacology analysis showed that quercetin, beta-sitosterol, baicalein, naringenin, acacetin, berberine and palmatine may play an important role in protecting against IS. Taken together, this study reveals that AGNH reduced neuroinflammation and protected against IS by inhibiting Tyrobp/Syk and Tlr2/Myd88, as well as NF-κB signalling pathway and regulating multiple metabolites. [ABSTRACT FROM AUTHOR]

This study aimed to establish a population pharmacokinetic (PopPK) model using data from 2 clinical trials of zimberelimab, evaluate the pharmacokinetics (PKs) of zimberelimab, explore the feasibility of 360 mg once every 3 weeks (Q3W) and 480 mg once every 4 weeks (Q4W) as alternative dosage regimens, and analyze the exposure‐response relationship of the efficacy and safety of zimberelimab for advanced tumors. The PKs of zimberelimab were described using the 2‐compartment model with time‐dependent nonlinear elimination. The prediction‐corrected visual predictive check was used to evaluate the model's predictive value on blood drug concentrations. In total, 2165 PK observations from 321 participants were included. The PopPK model demonstrated a high level of concordance between the observed data and the predicted values, indicative of a robust fit to the PK data of zimberelimab. The PK variables were similar for the 240 mg once every 2 weeks, 360 mg Q3W, and 480 mg Q4W regimens. No covariates significantly affecting the PK variables in the final model were found. The exposure variables of zimberelimab have no obvious correlations with efficacy and safety, and 360 mg Q3W and 480 mg Q4W are worthy of further study. This study establishes a PopPK model and analyzes the exposure‐response relationship of zimberelimab, which helps to explore the potential for alternative dosing regimens and offers a foundation for optimizing therapeutic strategies for advanced cancer patients through simulation‐based methods. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a common lung disease that can lead to restricted airflow and respiratory problems, causing a significant health, economic, and social burden. Detecting the COPD stage can provide a timely warning for prompt intervention in COPD patients. However, existing methods based on inspiratory (IN) and expiratory (EX) chest CT images are not sufficiently accurate and efficient in COPD stage detection. The lung region images are autonomously segmented from IN and EX chest CT images to extract the 1 , 781 × 2 lung radiomics and 13 , 824 × 2 3D CNN features. Furthermore, a strategy for concatenating and selecting features was employed in COPD stage detection based on radiomics and 3D CNN features. Finally, we combine all the radiomics, 3D CNN features, and factor risks (age, gender, and smoking history) to detect the COPD stage based on the Auto-Metric Graph Neural Network (AMGNN). The AMGNN with radiomics and 3D CNN features achieves the best performance at 89.7 % of accuracy, 90.9 % of precision, 89.5 % of F1-score, and 95.8 % of AUC compared to six classic machine learning (ML) classifiers. Our proposed approach demonstrates high accuracy in detecting the stage of COPD using both IN and EX chest CT images. This method can potentially establish an efficient diagnostic tool for patients with COPD. Additionally, we have identified radiomics and 3D CNN as more appropriate biomarkers than Parametric Response Mapping (PRM). Moreover, our findings indicate that expiration yields better results than inspiration in detecting the stage of COPD. The workflow of this study. (a) The IN and EX lung region is segmented using a well trained U Net (R231). (b) Radiomics features are obtained through the PyRadiomics tool, and 3D CNN features are extracted using the frozen encoder in the pre trained Med3D model. (c) The IN+EX radiomics and IN+EX 3D CNN features are concatenated, and the Lasso algorithm is subsequently applied to screen for useful data. (d) The selected features and ri sk factors are sent to the AMGNN, resulting in COPD multi classification outcomes. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) use with cardiovascular (CV) clinical outcomes in type 2 diabetes (T2D) patients with acute coronary syndrome (ACS). Methods: Data of T2D patients hospitalized for ACS at Civil Aviation General Hospital from January 2019 to December 2022 were collected. Based on SGLT2i use or not, patients were stratified as SGLT2i group and SGLT2i-free group. A 1:1 nearest-neighbor propensity score-matched (PSM) was performed to adjust for the confounding factors and facilitate the robust comparisons between groups. The first occurrence of major adverse cardiovascular events (MACE) with 1 year follow-up, which consisted of CV death, all cause death, non-fatal myocardial infarction or stroke, coronary revascularization or heart failure readmission, was assessed. Kaplan–Meier analysis and Cox regressions were conducted to evaluate the prognostic significance of SGLT2i use. Subgroup analyses were performed to assess the interaction between subgroups and SGLT2i use. Results: A total of 925 patients were included, and the SGLT2i use increased from 9.9% in 2019 to 43.8% in 2022. 226 pairs were finally matched using the PSM model. During 1 year follow-up period, a total of 110 patients experienced MACE in the matched cohort, with a rate of 24.3%. Survival analyses showed cumulative incidence of MACE, CV death, and heart failure readmission in the SGLT2i group were significantly lower than the SGLT2i-free group. Additionally, the adjusted Cox analyses demonstrated that SGLT2i was associated with a 34.1% lower risk of MACE (HR 0.659, 95% CI 0.487–0.892, P = 0.007), which was primarily driven by a decrease in the risk of CV death by 12.0% (HR 0.880, 95% CI 0.7830.990, P = 0.033), and heart failure readmission by 45.5% (HR 0.545, 95% CI 0.332–0.893, P = 0.016). This MACE preventive benefit was consistent across different subgroups (P interaction > 0.05 for all comparisons). Conclusions: In T2D patients with ACS, there was a clear increasing trend in SGLT2i use. SGLT2i was associated with a significantly lower risk of MACE, driven by the decrease in the risk of CV death, and heart failure readmission. Our study confirmed real-world use and efficacy of SGLT2i in a general T2D population with ACS. [ABSTRACT FROM AUTHOR]

Summary: Understanding the molecular regulation of plant cold response is the basis for cold resistance germplasm improvement. Here, we revealed that the apple histone deacetylase MdHDA6 can perform histone deacetylation on cold‐negative regulator genes and repress their expression, leading to the positive regulation of cold tolerance in apples. Moreover, MdHDA6 directly interacts with the transcription factor MdTCP15. Phenotypic analysis of MdTCP15 transgenic apple lines and wild types reveals that MdTCP15 negatively regulates cold tolerance in apples. Furthermore, we found that MdHDA6 can facilitate histone deacetylation of MdTCP15 and repress the expression of MdTCP15, which positively contributes to cold tolerance in apples. Additionally, the transcription factor MdTCP15 can directly bind to the promoter of the cold‐negative regulator gene MdABI1 and activate its expression, and it can also directly bind to the promoter of the cold‐positive regulator gene MdCOR47 and repress its expression. However, the co‐expression of MdHDA6 and MdTCP15 can inhibit MdTCP15‐induced activation of MdABI1 and repression of MdCOR47, suggesting that MdHDA6 suppresses the transcriptional regulation of MdTCP15 on its downstream genes. Our results demonstrate that histone deacetylase MdHDA6 plays an antagonistic role in the regulation of MdTCP15‐induced transcriptional activation or repression to positively regulate cold tolerance in apples, revealing a new regulatory mechanism of plant cold response. [ABSTRACT FROM AUTHOR]

Apples (Malus × domestica Borkh.) can be categorized into early-, medium-, and late-ripening cultivars based on the length of the fruit developmental phases. The lengthening of the apple ripening period has a direct impact on its economic worth and market competitiveness, although the underlying mechanism is mostly unclear. In the current study, the development and maturation of the early-ripening 'Geneva Early' (GE) and late-ripening 'Hanfu' (HF) cultivars of apple fruit were studied using transcriptomics to detect and identify the changes of differential genes. Results showed that the two varieties had different ripening periods, but in both, the development process of fruit ripening required cell division, cell expansion, starch accumulation, and secondary metabolite accumulation. In the early stages of fruit development (G1 to G2), the GE's fruit size was larger than HF's, and the GO analysis revealed an enrichment in genes involved in the metabolism of fatty acids and carbon molecules. In G2 phase, the GE involved numerous regulatory factors of hormonal pathways, while in HF this phase was mainly enriched in the metabolism of sugars and carbohydrates. The results indicated that during GE development, the relevant genes regulating fruit development were expressed earlier than HF, which made fruit development enter the next development phase earlier, thereby shortening the fruit development phase. These findings contributed to an improved understanding of the molecular basis of apple ripening and provide a reliable reference for apple breeding using genomics. [ABSTRACT FROM AUTHOR]

The Chinese medicine formula Pien Tze Huang (PZH) has been applied to the treatment of various diseases, the reported anti-tumor mechanisms included regulation of inflammation-associated cytokine secretion and cancer growth pathways. However, the potential influence of PZH on tumor metabolism remains unclear. This study aimed to investigate the global effect of PZH on hepatocellular carcinoma (HCC) compared with the anti-tumor agent sorafenib based on tandem mass tag (TMT) label proteomic and phosphoproteomic analysis in addition to parallel reaction monitoring (PRM) verification. It was observed that PZH could inhibit tumor weight by 59–69% in different concentrations. TMT proteomic studies indicated that fructose/mannose metabolism and glucagon signaling pathway in PZH group, and arachidonic acid metabolism and PPAR signaling pathway in sorafenib group, were significantly enriched, while glycolysis/gluconeogenesis pathway was found to be enriched remarkably both in PZH and sorafenib groups in TMT phosphoproteomic study. PRM verification further indicated that both PZH and sorafenib could down-regulate phosphorylations of the glycolytic enzymes phosphofructokinases 1, fructose-bisphosphate Aldolase A, phosphoglycerate mutase 2 and lactate dehydrogenase A chain, while phosphorylations of long chain fatty acid CoA ligase in fatty acid activation and acetyl-coenzyme A synthetase in glycolysis were significantly inhibited by PZH and sorafenib, respectively. This study proposed that PZH shared a similar anti-tumor mechanism of metabolic regulation to sorafenib, but differed in the regulation of some metabolic nodes. This is the first time to uncover the relationship between the anti-tumor effect of PZH and metabolic related enzymes, which distinguished from the known mechanisms of PZH. These data provided the potential molecular basis for PZH acting as a therapeutic drug for HCC, and offered cues of manipulation on Warburg effect under the treatment of PZH. [ABSTRACT FROM AUTHOR]

The phenomenon of brain recovery after long-term abstinence has been reported in substance use disorders. However, few longitudinal studies have been conducted to observe the potential recovery in heroin users, and little is known about the neural mechanism underlying the decreased craving after prolonged abstinence. The 8-month longitudinal study was carried out in 29 heroin users and 30 healthy controls. By choosing the L_DLPFC, which was activated by the heroin cue as the seeding region, different brain connection patterns were compared between healthy controls and heroin users by using Granger causality analysis (GCA) at baseline. Then, a paired t test was employed to detect the potential recovery of L_DLPFC circuits after prolonged abstinence. The visual analog scale (VAS) and trail-making test-A (TMT-A) were adopted to investigate craving and cognitive control impairment, respectively. The neuroimaging changes were then correlated with behavioral improvements. Similar analyses were applied for the mirrored right DLPFC to verify the lateralization hypothesis of the DLPFC in addiction. In the longitudinal study, enhanced GCA coefficients were observed in the L_DLPFC-R_insula circuit of heroin users after long-term abstinence and were associated with craving score changes. At baseline, decreased GCA coefficients from the left DLPFC to the bilateral SMA and right putamen, together with the reduced GCA strength from the bilateral OFC to the left DLPFC, were found between HUs and HCs. Our findings extended the brain recovery phenomenon into the field of heroin and suggested that the increased regulation of the L_DLPFC over the insula after prolonged abstinence was important for craving inhibition. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a preventable, treatable, progressive chronic disease characterized by persistent airflow limitation. Patients with COPD deserve special consideration regarding treatment in this fragile population for preclinical health management. Therefore, this paper proposes a novel lung radiomics combination vector generated by a generalized linear model (GLM) and Lasso algorithm for COPD stage classification based on an auto-metric graph neural network (AMGNN) with a meta-learning strategy. Firstly, the parenchyma images were segmented from chest high-resolution computed tomography (HRCT) images by ResU-Net. Second, lung radiomics features are extracted from the parenchyma images by PyRadiomics. Third, a novel lung radiomics combination vector (3 + 106) is constructed by the GLM and Lasso algorithm for determining the radiomics risk factors (K = 3) and radiomics node features (d = 106). Last, the COPD stage is classified based on the AMGNN. The results show that compared with the convolutional neural networks and machine learning models, the AMGNN based on constructed novel lung radiomics combination vector performs best, achieving an accuracy of 0.943, precision of 0.946, recall of 0.943, F1-score of 0.943, and ACU of 0.984. Furthermore, it is found that our method is effective for COPD stage classification. [ABSTRACT FROM AUTHOR]

Drought resistance in plants is influenced by multiple signaling pathways that involve various transcription factors, many target genes, and multiple types of epigenetic modifications. Studies on epigenetic modifications of drought focus on DNA methylation and histone modifications, with fewer on chromatin remodeling. Changes in chromatin accessibility can play an important role in abiotic stress in plants by affecting RNA polymerase binding and various regulatory factors. However, the changes in chromatin accessibility during drought in apples are not well understood. In this study, the landscape of chromatin accessibility associated with the gene expression of apple (GL3) under drought conditions was analyzed by Assay for Transposase Accessible Chromatin with high-throughput sequencing (ATAC-seq) and RNA-seq. Differential analysis between drought treatment and control identified 23,466 peaks of upregulated chromatin accessibility and 2447 peaks of downregulated accessibility. The drought-induced chromatin accessibility changed genes were mainly enriched in metabolism, stimulus, and binding pathways. By combining results from differential analysis of RNA-seq and ATAC-seq, we identified 240 genes with higher chromatin accessibility and increased gene expression under drought conditions that may play important functions in the drought response process. Among them, a total of nine transcription factor genes were identified, including ATHB7, HAT5, and WRKY26. These transcription factor genes are differentially expressed with different chromatin accessibility motif binding loci that may participate in apple response to drought by regulating downstream genes. Our study provides a reference for chromatin accessibility under drought stress in apples and the results will facilitate subsequent studies on chromatin remodelers and transcription factors. [ABSTRACT FROM AUTHOR]

Hybrid complex anions of ginsenosides resulted from direct infusion-tandem mass spectrometry Energy-resolved MS (ER-MS)7 was utilized to discriminate noncovalent binding from covalent linkage I via i building breakdown graphs for ions of interest. In our previous study,5 we discussed the I pros i and I cons i of DI-MS/MS toward in-depth chemical characterization of complex matrices, in comparison to liquid chromatography-MS/MS (LC-MS/MS). [Extracted from the article]

Compared with healthy controls, heroin users (HUs) show evidence of structural and functional brain alterations. However, little is known about the possibility of brain recovery after protracted heroin abstinence. The purpose of this study was to investigate whether brain recovery is possible after protracted abstinence in HUs. A total of 108 subjects with heroin addiction completed structural and functional scans, and 61 of those subjects completed 8‐month follow‐up scans. Resting‐state data and 3D‐T1 MR images were collected for all participants, first at baseline and again after 8 months. Cognitive function and craving were measured by the Trail Making Test‐A (TMT‐A) and Visual Analog Scale for Craving, respectively. The cortical thickness and resting‐state functional connectivity (RSFC) differences were then analyzed and compared between baseline and follow‐up, and correlations were obtained between neuroimaging and behavioral changes. HUs demonstrated improved cognition (shorter TMT‐A time) and reduced craving at the follow‐up (HU2) relative to baseline (HU1), and the cortical thickness in the bilateral superior frontal gyrus (SFG) was significantly greater at HU2 than at HU1. Additionally, the RSFC of the left SFG with the inferior frontal gyrus (IFG), insula, and nucleus accumbens and that of the right SFG with the IFG, insula and orbitofrontal cortex (OFC) were increased at HU2. The changes in TMT‐A time were negatively correlated with the RSFC changes between the left SFG and the bilateral IFG, the bilateral caudate, and the right insula. The changes in craving were negatively correlated with the RSFC changes between the left OFC and the bilateral SFG. Our results demonstrated that impaired frontal‐limbic neurocircuitry can be partially restored, which might enable improved cognition as well as reduced craving in substance‐abusing individuals. We provided novel scientific evidence for the partial recovery of brain circuits implicated in cognition and craving after protracted abstinence. Highlights: Improved cognition and reduced craving were observed in heroin users (HUs) after 8 months of abstinence.HUs demonstrated increased superior frontal gyrus (SFG) cortical thickness after 8 months of abstinence.Increased resting‐state functional connectivity within SFG circuits was correlated with improved cognition and reduced craving; Brain circuit recovery was detected as a result of protracted abstinence in HUs. [ABSTRACT FROM AUTHOR]

To date, our understanding of the role of abnormal hippocampal volume in imaging studies of insomnia disorders (ID) has remained in apparent contradiction. Given that hippocampal function can be mapped to anatomically defined substructures, the hippocampal substructure volume can be examined in detail at present. In this study, we examined the volumes of hippocampal substructures between IDs and healthy controls (HC) to accurately find hippocampal markers of ID. First, we used the automated hippocampal substructure module in FreeSurfer6.0 to inspect T1-weighted magnetic resonance images between 22 IDs and 30 HC. Then, 12 hippocampal substructures were computed. Volumetric assessment was performed at the hippocampal substructure level between groups. Our study revealed significant reduced volume of the bilateral fimbria in IDs compared with HC (p < 0.05/12, Bonferroni corrected), although there was no difference in the total volume of hippocampus. In addition, the correlation analysis showed that the total hippocampal volume of the left hemisphere was negatively correlated with Pittsburgh Sleep Quality Index (PSQI) scores. With regard to hippocampal substructure results, negative correlations were detected between bilateral fimbria volume and clinical variables (i.e., PSQI, SDS, and SAS) in all subjects. Taken together, we revealed marked differences in the volume of the hippocampal substructure between IDs and HC, which provided a more accurate structural imaging marker for the pathological of ID. [ABSTRACT FROM AUTHOR]

Pien Tze Huang (PZH) is a valuable traditional Chinese medicine, which has a variety of biological activities such as clearing heat-toxin, resolving blood stasis, detoxifying, relieving pain, and anti-inflammation. PZH has a partial role in suppressing the progression of CRC, while the underlying mechanism is a pending mystery; especially whether PZH mediates the immune escape of CRC remains unclear. Our study reported that PZH suppressed the proliferative activity of CRC by inhibiting Wnt/β-catenin signaling to down-regulate the expression of PCNA and Cyclin D1. In addition, PZH suppressed the immune escape of CRC and elevated the infiltration of CD8+ T cells in tumor tissues, which depends on the suppression of PD-L1 levels via inhibiting IFNGR1-JAK1-STAT3-IRF1 signaling. More importantly, PZH pharmacologically elevated the antitumor efficacy of anti-PD-1/PD-L1 immunotherapy as demonstrated by slower tumor growth, higher infiltration and function of CD8+ T cells in the combination of PZH and PD-1/PD-L1 antibody compared with monotherapy with either agent. These results demonstrate that PZH has the potential role in inhibiting CRC proliferation and immune evasion, especially the synergistic enhancement effect of PZH on immunotherapy. [ABSTRACT FROM AUTHOR]

Background. Alcoholism is known to cause liver toxicity and is extensively researched. On the other hand, stress, depression, and obesity are interrelated conditions with alcoholism, and their medications would affect the liver itself. In this study, we investigated the effects of the drugs fluoxetine and atorvastatin on the liver and compared with those of alcohol in a mouse model. Methods. Comparisons of animals treated with the three drugs were carried out: serum aspartate transaminase (AST), alanine transaminase (ALT), and albumin were measured; liver tumor necrosis factor alpha (TNF alpha) and transforming growth factor beta (TGF beta-1) levels were evaluated; proliferative cells were detected via immunohistochemistry (IHC) targeting on proliferating cell nuclear antigen (PCNA) and minichromosome maintenance complex component 2 (MCM2); for apoptosis, IHC targeting on activated caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) were employed; and histopathology was also documented in all groups. Results. For ALT, AST, albumin, and liver TNF alpha, only the ethanol group surged to significantly higher levels. For TGF beta-1, both ethanol and atorvastatin groups reached a significantly higher level. PCNA and MCM2 showed increased proliferation in the livers of all three groups, with the ethanol group having the highest number of positive cells followed by atorvastatin and then the fluoxetine group. As for cell death, both ethanol and fluoxetine groups showed significantly more apoptosis than control in TUNEL and activated caspase-3, while in the atorvastatin group, activated caspase-3 positive cells increased significantly, but the increase in TUNEL-positive cells did not reach statistical significance. [ABSTRACT FROM AUTHOR]

Dysfunction of the sleep-wake transition is considered to be associated with the pathology of patients with primary insomnia (PI). Previous animal study had reported that brain circuits between the striatum and cortex can regulate sleep-wake transitions. So far, few studies have systematically explored the structural connectivity of the striatum-centered circuits and their potential roles in patients with PI. In this study, we chosen the striatum as the seed and 10 priori target regions as masks to assess the structural connectivity by using seed-based classification with a diffusion tensor imaging (DTI) probabilistic tractography method. Track strengths of the striatum-centered circuits were compared between 22 patients with PI (41.27 ± 9.21 years) and 30 healthy controls (HC) (35.2 ± 8.14 years). Pittsburgh Sleep Quality Index (PSQI) was used to measure the sleep quality in all participants. Lower track strengths (left striatum- anterior cingulate cortex (ACC), left striatum- dorsal anterior cingulate cortex (dACC), left striatum-Hippocampus, and right striatum-Hippocampus) were observed in patients with PI compared to HC. Additionally, the lower track strengths of brain circuits mentioned above were negatively correlated with PSQI. Taken together, our findings revealed the lower tract strength of frontostriatal circuits in patients with PI and HC, which provided the implications of the system-level structural connections of frontostriatal circuits in the pathology of PI. We suggested that the track strengths of the frontostriatal circuits calculated from DTI can be the potential neuroimaging biomarkers of the sleep quality in patients with PI. [ABSTRACT FROM AUTHOR]

High levels of impulsivity are a risk factor for the initiation of heroin use and a core behavioral characteristic of heroin dependence. Impulsivity also contributes to the maintenance of drug use and hinders effective therapy. Here we sought to identify neuroimaging markers of impulsivity in heroin-dependent individuals (HDI), with a focus on the nucleus accumbens (NAc), a key region implicated in impulsivity and drug addiction generally. Volume and resting-state functional connectivity (RSFC) differences of the bilateral NAc were investigated between 21 HDI and 21 age-, gender-, nicotine-, alcohol-matched healthy controls (HC). The neuroimaging results were then correlated with the Barratt Impulsivity Scales (BIS-11). Higher motor impulsivity (t = 2.347, p = 0.0253) and larger right NAc volume (F (1,38) = 4.719, p = 0.036) was observed in HDI. The right NAc volume was positively correlated with BIS total (r = 0.6196, p = 0.0239) /motor (r = 0.5921, p = 0.0330) scores in HC and BIS motor (r = 0.5145, p = 0.0170) score in HDI. A negative correlation was found between RSFC of the right NAc-bilateral superior frontal gyrus (SFG) and motor impulsivity in HDI (left: r=-0.6537, p = 0.0013; right: r=-0.6167, p = 0.0029) and HC (left: r=-0.6490,p = 0.0164; right: r=-0.6993, p = 0.0078). We aimed to reveal novel multimodality neuroimaging biomarkers of the higher impulsivity in HDI by focusing on the NAc and corresponding functional circuits. Higher motor impulsivity was observed in HDI. Furthermore, the volume of the right NAc and the RSFC strength of right NAc-SFG could be neuroimaging biomarkers for the severity of impulsivity in HDI. These potential biomarkers could be a target for novel treatments in HDI. [ABSTRACT FROM AUTHOR]

Background: Zimberelimab (GLS-010) is a novel fully human monoclonal immunoglobulin G4 (IgG4) against the programmed cell death-1 (PD-1) receptor. Aim: To evaluate the affinity, competitive blocking capability, T cell activation effect, cytotoxic effector functions by Fc, preliminary anti-tumor activity, and pharmacokinetics of GLS-010. Methods: The affinity of GLS-010 to PD-1 and the ability of GLS-010 to block the PD-L1/2 to PD-1 interaction on the cell surface were measured. An allogeneic mixed lymphocyte reaction was conducted to evaluate the inhibitory effect of GLS-010 on Tregs and stimulatory effect on T cell proliferation and activation. Pharmacodynamics and pharmacokinetics were evaluated in tumor-bearing mice and cynomolgus monkeys, respectively. Results: The equilibrium dissociation constant (KD) for the association between GLS-010 and PD-1 was 1.75×10-10 M. GLS-010 could effectively block the binding of PD-L1/2 to PD-1. GLS-010 showed statistically significant anti-tumor effects in the MC38 model in human PD-1 knock-in mice. The RO rate on in the low-, moderate-, and high-dose groups were 64.50%-48.53% in CD3+T, 58.87%-40.12% in CD8+T, and 66.26%-49.07% in CD4+T, respectively. With the increasing dose from 2 mg/kg to 18 mg/kg, the systemic exposure level of GLS-010 (AUC0-last) and C0 increased proportionally, while the proportion of AUC0-last was higher than the proportion of the increase in the dose. Conclusions: As a fully human anti-PD-1 monoclonal antibody, GLS-010 has a high affinity to PD-1 and shows potent anti-tumor effects in vivo and in vitro. The results support that GLS-010 could be investigated in clinical trials in tumor patients. [ABSTRACT FROM AUTHOR]

As a critical component of cortico‐striato‐thalamo‐cortical loop in addiction, our understanding of the thalamus in impaired cognition of heroin users (HU) has been limited. Due to the complex thalamic connection with cortical and subcortical regions, thalamus was divided into prefrontal (PFC), occipital (OC), premotor, primary motor, sensory, temporal, and posterior parietal association subregions according to white matter tractography. We adopted seven subregions of bilateral thalamus as regions of interest to systematically study the implications of distinct thalamic nuclei in acute abstinent HU. The volume and resting‐state functional connectivity (RSFC) differences of the thalamus were investigated between age‐, gender‐, and alcohol‐matched 37 HU and 33 healthy controls (HCs). Trail making test‐A (TMT‐A) was adopted to assess cognitive function deficits, which were then correlated with neuroimaging findings. Although no significant different volumes were found, HU group showed decreased RSFC between left PFC_thalamus and middle temporal gyrus as well as between left OC_thalamus and inferior frontal gyrus and supplementary motor area relative to HCs. Meanwhile, the higher TMT‐A scores in HU were negatively correlated with PFC_thalamic RSFC with inferior temporal gyrus, fusiform, and precuneus. Craving scores were negatively correlated with OC_thalamic RSFC with accumbens, hippocampus, and insula. Opiate Withdrawal Scale scores were negatively correlated with left PFC/OC_thalamic RSFC with orbitofrontal cortex and medial PFC. We indicated two thalamus subregions separately involvement in cognitive control and craving to reveal the implications of thalamic subnucleus in pathology of acute abstinent HU. [ABSTRACT FROM AUTHOR]

Background: Histone lysine methylation plays an important role in plant development and stress responses by activating or repressing gene expression. Histone lysine methylation is catalyzed by a class of SET-domain group proteins (SDGs). Although an increasing number of studies have shown that SDGs play important regulatory roles in development and stress responses, the functions of SDGs in apple remain unclear. Results: A total of 67 SDG members were identified in the Malus×domestica genome. Syntenic analysis revealed that most of the MdSDG duplicated gene pairs were associated with a recent genome-wide duplication event of the apple genome. These 67 MdSDG members were grouped into six classes based on sequence similarity and the findings of previous studies. The domain organization of each MdSDG class was characterized by specific patterns, which was consistent with the classification results. The tissue-specific expression patterns of MdSDGs among the 72 apple tissues in the different apple developmental stages were characterized to provide insight into their potential functions in development. The expression profiles of MdSDGs were also investigated in fruit development, the breaking of bud dormancy, and responses to abiotic and biotic stress; the results indicated that MdSDGs might play a regulatory role in development and stress responses. The subcellular localization and putative interaction network of MdSDG proteins were also analyzed. Conclusions: This work presents a fundamental comprehensive analysis of SDG histone methyltransferases in apple and provides a basis for future studies of MdSDGs involved in apple development and stress responses. [ABSTRACT FROM AUTHOR]

To analyze the distribution pattern concerning multi-nozzle interference spray particle granularity between hydraulic supports, the present study conducts atomization interference experimental characterization for three types of nozzles used in coal mines based on a Doppler laser interference spray dust suppression simulation experimental system. The results indicate that for single-nozzle atomization, the impact of spray pressure on spray droplet size is gradually subdued, and a spray pressure of 8 MPa yields the best result; compared with single-nozzle spray, the multi-nozzle atomization interference effect can downsize the spray field overlapping zone, leading to an improved uniformity of overall spray particle distribution. As the spray field overlapping coefficient k increases, the particle size of the interference spray field decreases first and then increases. As the spray field overlapping coefficient reaches 0.4, the distribution of spray droplet size is most concentrated, corresponding to the optimal atomized dust suppression effect. Practical testing indicates that the optimal spray field overlapping coefficient measured at a fully mechanized mining face agrees well with the experimental result. Under the optimal parameters, the average total dust and respirable dust suppression rates measured at various measuring points on the downwind side during support relocation reach 78.93% and 80.53%, respectively. [ABSTRACT FROM AUTHOR]

A miniaturized quarter-wavelength microstrip patch antenna is developed to monitor the mechanical deformation of building structures. In order to minimize the physical dimension as well as improve the sensitivity of resonant frequency of the patch antenna, via holes are added to the antenna and the operational resonant frequency of the antenna is designed to be 2.4 GHz. Practical measurement for the resonant frequency is implemented to figure out the relationship between mechanical deformation and resonant frequency. Additional tensile tests are employed by increasing strain increments per loading step so that a larger shift caused by a larger deformation can be reached. It is revealed that the transmission efficiency of mechanical deformation is about 70% and the proposed antenna can sensitively monitor the mechanical deformation of building structures. Furthermore, different substrates in the antenna are investigated and the measurement results show that the RT5870 substrate has much better transmission efficiency than FR4 substrate. The proposed different antennas are designed to meet the specific needs of practical applications. [ABSTRACT FROM AUTHOR]

Rab29 (also referred as Rab7L1) is a novel Rab protein, and is recently demonstrated to regulate phagocytosis and traffic from the Golgi to the lysosome. However, its roles in membrane trafficking have not been investigated extensively. Our results in this study revealed that Rab29 is associated with the trans-Golgi network (TGN), and is essential for maintaining the integrity of the TGN, because inhibition of the activity of Rab29 or depletion of Rab29 resulted in fragmentation of the TGN marked by TGN46. Expression of the dominant negative form Rab29T21N or shRNA-Rab29 also altered the distribution of mannose-6-phosphate receptor (M6PR), and interrupted the retrograde trafficking of M6PR through monitoring the endocytosis of CD8-tagged calcium dependent M6PR (cdM6PR) or calcium independent M6PR (ciM6PR), but without significant effects on the anterograde trafficking of vesicular stomatitis virus G protein (VSV-G). Our results suggest that Rab29 is essential for the integrity of the TGN and participates in the retrograde trafficking of M6PRs. [ABSTRACT FROM AUTHOR]

The subcellular location and cell biological function of small GTPase Rab40c in mammalian cells have not been investigated in detail. In this study, we demonstrated that the exogenously expressed GFP-Rab40c associates with lipid droplets marked by neutral lipid specific dye Oil red or Nile red, but not with the Golgi or endosomal markers. Further examination demonstrated that Rab40c is also associated with ERGIC-53 containing structures, especially under the serum starvation condition. Rab40c is increasingly recruited to the surface of lipid droplets during lipid droplets formation and maturation in HepG2 cells. Rab40c knockdown moderately decreases the size of lipid droplets, suggesting that Rab40c is involved in the biogenesis of lipid droplets. Stimulation for adipocyte differentiation increases the expression of Rab40c in 3T3-L1 cells. Rab40c interacts with TIP47, and is appositionally associated with TIP47-labeled lipid droplets. In addition, over-expression of Rab40c causes the clustering of lipid droplets independent of its GTPase activity, but completely dependent of the intact SOCS box domain of Rab40c. In addition, Rab40c displayed self-interaction as well as interaction with TIP47 and the SOCS box is essential for its ability to induce clustering of lipid droplets. Our results suggest that Rab40c is a novel Rab protein associated with lipid droplets, and is likely involved in modulating the biogenesis of lipid droplets. [ABSTRACT FROM AUTHOR]

A correction to the article "RILP interacts with HOPS complex via VPS41 subunit to regulate endocytic trafficking. " in the December 2, 2014 issue is presented which discusses the role of Rab-interacting lysosomal protein (RILP) on the formation of endosomal membranes.

Plasma process control applications require acquisition of diagnostic data at a rate faster than the characteristic timescale of perturbations to the plasma. Diagnostics based on optical emission spectroscopy of intense emission lines permit rapid noninvasive measurements with low-resolution (∼1 nm), fiber-coupled spectrographs, which are included on many plasma process tools for semiconductor processing. Here the authors report on rapid analysis of Ar emissions with such a system to obtain electron temperatures, electron densities, and metastable densities in argon and argon/mixed-gas (Ar/N2, Ar/O2, Ar/H2) inductively coupled plasmas. Accuracy of the results (compared to measurements made by Langmuir probe and white-light absorption spectroscopy) are typically better than ±15% with a time resolution of 0.1 s, which is more than sufficient to capture the transient behavior of many processes, limited only by the time response of the spectrograph used. [ABSTRACT FROM AUTHOR]