Ticagrelor alone versus ticagrelor plus aspirin from month 1 to month 12 after percutaneous coronary intervention in patients with acute coronary syndromes (ULTIMATE-DAPT): a randomised, placebo-controlled, double-blind clinical trial.

BACKGROUND: Following percutaneous coronary intervention with stent placement to treat acute coronary syndromes, international clinical guidelines generally recommend dual antiplatelet therapy with aspirin plus a P2Y12 receptor inhibitor for 12 months to prevent myocardial infarction and stent thrombosis. However, data on single antiplatelet therapy with a potent P2Y12 inhibitor earlier than 12 months after percutaneous coronary intervention for patients with an acute coronary syndrome are scarce. The aim of this trial was to assess whether the use of ticagrelor alone, compared with ticagrelor plus aspirin, could reduce the incidence of clinically relevant bleeding events without an accompanying increase in major adverse cardiovascular or cerebrovascular events (MACCE). METHODS: In this randomised, placebo-controlled, double-blind clinical trial, patients aged 18 years or older with an acute coronary syndrome who completed the IVUS-ACS study and who had no major ischaemic or bleeding events after 1-month treatment with dual antiplatelet therapy were randomly assigned to receive oral ticagrelor (90 mg twice daily) plus oral aspirin (100 mg once daily) or oral ticagrelor (90 mg twice daily) plus a matching oral placebo, beginning 1 month and ending at 12 months after percutaneous coronary intervention (11 months in total). Recruitment took place at 58 centres in China, Italy, Pakistan, and the UK. Patients were required to remain event-free for 1 month on dual antiplatelet therapy following percutaneous coronary intervention with contemporary drug-eluting stents. Randomisation was done using a web-based system, stratified by acute coronary syndrome type, diabetes, IVUS-ACS randomisation, and site, using dynamic minimisation. The primary superiority endpoint was clinically relevant bleeding (Bleeding Academic Research Consortium [known as BARC] types 2, 3, or 5). The primary non-inferiority endpoint was MACCE (defined as the composite of cardiac death, myocardial infarction, ischaemic stroke, definite stent thrombosis, or clinically driven target vessel revascularisation), with an expected event rate of 6·2% in the ticagrelor plus aspirin group and an absolute non-inferiority margin of 2·5 percentage points between 1 month and 12 months after percutaneous coronary intervention. The two co-primary endpoints were tested sequentially; the primary superiority endpoint had to be met for hypothesis testing of the MACCE outcome to proceed. All principal analyses were assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03971500, and is completed. FINDINGS: Between Sept 21, 2019, and Oct 27, 2022, 3400 (97·0%) of the 3505 participants in the IVUS-ACS study were randomly assigned (1700 patients to ticagrelor plus aspirin and 1700 patients to ticagrelor plus placebo). 12-month follow-up was completed by 3399 (>99·9%) patients. Between month 1 and month 12 after percutaneous coronary intervention, clinically relevant bleeding occurred in 35 patients (2·1%) in the ticagrelor plus placebo group and in 78 patients (4·6%) in the ticagrelor plus aspirin group (hazard ratio [HR] 0·45 [95% CI 0·30 to 0·66]; p<0·0001). MACCE occurred in 61 patients (3·6%) in the ticagrelor plus placebo group and in 63 patients (3·7%) in the ticagrelor plus aspirin group (absolute difference -0·1% [95% CI -1·4% to 1·2%]; HR 0·98 [95% CI 0·69 to 1·39]; pnon-inferiority<0·0001, psuperiority=0·89). INTERPRETATION: In patients with an acute coronary syndrome who had percutaneous coronary intervention with contemporary drug-eluting stents and remained event-free for 1 month on dual antiplatelet therapy, treatment with ticagrelor alone between month 1 and month 12 after the intervention resulted in a lower rate of clinically relevant bleeding and a similar rate of MACCE compared with ticagrelor plus aspirin. Along with the results from previous studies, these findings show that most patients in this population can benefit from superior clinical outcomes with aspirin discontinuation and maintenance on ticagrelor monotherapy after 1 month of dual antiplatelet therapy. FUNDING: The Chinese Society of Cardiology, the National Natural Scientific Foundation of China, and the Jiangsu Provincial & Nanjing Municipal Clinical Trial Project. TRANSLATION: For the Mandarin translation of the abstract see Supplementary Materials section.

Achieving ultrahigh fatigue resistance in AlSi10Mg alloy by additive manufacturing.

Since the first discovery of the fatigue phenomenon in the late 1830s, efforts to fight against fatigue failure have continued. Here we report a fatigue resistance phenomenon in nano-TiB2-decorated AlSi10Mg enabled by additive manufacturing. This fatigue resistance mechanism benefits from the three-dimensional dual-phase cellular nanostructure, which acts as a strong volumetric nanocage to prevent localized damage accumulation, thus inhibiting fatigue crack initiation. The intrinsic fatigue strength limit of nano-TiB2-decorated AlSi10Mg was proven to be close to its tensile strength through the in situ fatigue tests of a defect-free microsample. To demonstrate the practical applicability of this mechanism, printed bulk nano-TiB2-decorated AlSi10Mg achieved fatigue resistance more than double those of other additive manufacturing Al alloys and surpassed those of high-strength wrought Al alloys. This strategy of additive-manufacturing-assisted nanostructure engineering can be extended to the development of other dual-phase fatigue-resistant metals.

Transmembrane protein 176B regulates amino acid metabolism through the PI3K-Akt-mTOR signaling pathway and promotes gastric cancer progression.

BACKGROUND: The present study aimed to investigate the expression level, biological function, and underlying mechanism of transmembrane protein 176B (TMEM176B) in gastric cancer (GC). METHODS: TMEM176B expression was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB). The function of TMEM176B was determined by various in vitro assays including colony formation, 5-ethynyl-2'-deoxyuridine (EdU), Transwell, and flow cytometry. Bioinformatics techniques were then used to elucidate the signaling pathways associated with TMEM176B activity. Tumor formation experiments were conducted on nude mice for in vivo validation of the preceding findings. TMEM176B expression was cross-referenced to clinicopathological parameters and survival outcomes. RESULTS: It was observed that TMEM176B was overexpressed in GC cells and tissues. Targeted TMEM176B abrogation inhibited colony formation, proliferation, migration, and invasion but promoted apoptosis in GC cell lines while TMEM176B overexpression had the opposite effects. Subsequent experimental validation disclosed an association between TMEM176B and the phosphatidylinositol 3-carboxykinase (PI3K)-protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signaling axis. Moreover, TMEM176B affects GC cancer progression by regulating asparagine synthetase (ASNS). The in vivo assays confirmed that TMEM176B is oncogenic and the clinical data revealed a connection between TMEM176B expression and the clinicopathological determinants of GC. CONCLUSION: The foregoing results suggest that TMEM176B significantly promotes the development of gastric cancer and is an independent prognostic factor of it.

Associations of MRI-Derived Glymphatic System Impairment With Global White Matter Damage and Cognitive Impairment in Mild Traumatic Brain Injury: A DTI-ALPS Study.

BACKGROUND: Assessing the glymphatic function using diffusion tensor image analysis along the perivascular space (DTI-ALPS) may be helpful for mild traumatic brain injury (mTBI) management. PURPOSE: To assess glymphatic function using DTI-ALPS and its associations with global white matter damage and cognitive impairment in mTBI. STUDY TYPE: Prospective. POPULATION: Thirty-four controls (44.1% female, mean age 49.2 years) and 58 mTBI subjects (43.1% female, mean age 48.7 years), including uncomplicated mTBI (N = 32) and complicated mTBI (N = 26). FIELD STRENGTH/SEQUENCE: 3-T, single-shot echo-planar imaging sequence. ASSESSMENT: Magnetic resonance imaging (MRI) was done within 1 month since injury. DTI-ALPS was performed to assess glymphatic function, and peak width of skeletonized mean diffusivity (PSMD) was used to assess global white matter damage. Cognitive tests included Auditory Verbal Learning Test and Digit Span Test (forward and backward). STATISTICAL TESTS: Neuroimaging findings comparisons were done between mTBI and control groups. Partial correlation and multivariable linear regression assessed the associations between DTI-ALPS, PSMD, and cognitive impairment. Mediation effects of PSMD on the relationship between DTI-ALPS and cognitive impairment were explored. P-value <0.05 was considered statistically significant, except for cognitive correlational analyses with a Bonferroni-corrected P-value set at 0.05/3 ≈ 0.017. RESULTS: mTBI showed lower DTI-ALPS and higher PSMD, especially in complicated mTBI. DTI-ALPS was significantly correlated with verbal memory (r = 0.566), attention abilities (r = 0.792), executive function (r = 0.618), and PSMD (r = -0.533). DTI-ALPS was associated with verbal memory (ß = 8.77, 95% confidence interval [CI] 5.00, 12.54), attention abilities (ß = 5.67, 95% CI 4.56, 6.97), executive function (ß = 2.34, 95% CI 1.49, 3.20), and PSMD (ß = -0.79, 95% CI -1.15, -0.43). PSMD mediated 46.29%, 20.46%, and 24.36% of the effects for the relationship between DTI-ALPS and verbal memory, attention abilities, and executive function. DATA CONCLUSION: Glymphatic function may be impaired in mTBI reflected by DTI-ALPS. Glymphatic dysfunction may cause cognitive impairment related to global white matter damage after mTBI. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Delta-radiomics features for predicting the major pathological response to neoadjuvant chemoimmunotherapy in non-small cell lung cancer.

OBJECTIVES: To investigate if delta-radiomics features have the potential to predict the major pathological response (MPR) to neoadjuvant chemoimmunotherapy in non-small cell lung cancer (NSCLC) patients. METHODS: Two hundred six stage IIA-IIIB NSCLC patients from three institutions (Database1 = 164; Database2 = 21; Database3 = 21) who received neoadjuvant chemoimmunotherapy and surgery were included. Patients in Database1 were randomly assigned to the training dataset and test dataset, with a ratio of 0.7:0.3. Patients in Database2 and Database3 were used as two independent external validation datasets. Contrast-enhanced CT scans were obtained at baseline and before surgery. The delta-radiomics features were defined as the relative net change of radiomics features between baseline and preoperative. The delta-radiomics model and pre-treatment radiomics model were established. The performance of Immune-Related Response Evaluation Criteria in Solid Tumors (iRECIST) for predicting MPR was also evaluated. RESULTS: Half of the patients (106/206, 51.5%) showed MPR after neoadjuvant chemoimmunotherapy. For predicting MPR, the delta-radiomics model achieved a satisfying area under the curves (AUCs) values of 0.768, 0.732, 0.833, and 0.716 in the training, test, and two external validation databases, respectively, which showed a superior predictive performance than the pre-treatment radiomics model (0.644, 0.616, 0.475, and 0.608). Compared with iRECIST criteria (0.624, 0.572, 0.650, and 0.466), a mixed model that combines delta-radiomics features and iRECIST had higher AUC values for MPR prediction of 0.777, 0.761, 0.850, and 0.670 in four sets. CONCLUSION: The delta-radiomics model demonstrated superior diagnostic performance compared to pre-treatment radiomics model and iRECIST criteria in predicting MPR preoperatively in neoadjuvant chemoimmunotherapy for stage II-III NSCLC. CLINICAL RELEVANCE STATEMENT: Delta-radiomics features based on the relative net change of radiomics features between baseline and preoperative CT scans serve a vital support tool in accurately identifying responses to neoadjuvant chemoimmunotherapy, which can help physicians make more appropriate treatment decisions. KEY POINTS: • The performances of pre-treatment radiomics model and iRECIST model in predicting major pathological response of neoadjuvant chemoimmunotherapy were unsatisfactory. • The delta-radiomics features based on relative net change of radiomics features between baseline and preoperative CT scans may be used as a noninvasive biomarker for predicting major pathological response of neoadjuvant chemoimmunotherapy. • Combining delta-radiomics features and iRECIST can further improve the predictive performance of responses to neoadjuvant chemoimmunotherapy.

Is 1-methylcytosine a faithful model compound for ultrafast deactivation dynamics of cytosine nucleosides in solution?

1-Methylcytosine (1mCyt) is the base for nucleoside N1-methylpseudodeoxycytidine of Hachimoji nucleic acids and a frequently used model compound for theoretical studies on excited states of cytosine nucleosides. However, there is little experimental characterization of spectra and photo-dynamic properties of 1mCyt. Herein, we report a comprehensive investigation into excited state dynamics and effects of solvents on fluorescence dynamics of 1mCyt in both water and acetonitrile. The study employed femtosecond broadband time-resolved fluorescence, transient absorption, and steady-state spectroscopy, along with density functional theory and time-dependent density functional theory calculations. The results obtained provide the first experimental evidence for identifying a dark-natured ∼5.7 ps lifetime nπ* state in the ultrafast non-radiative deactivation with 1mCyt in aqueous solution. This study also demonstrates a significant effect of the solvent on 1mCyt's fluorescence emission, which highlights the crucial role of solute-solvent hydrogen bonding in altering structures and reshaping the radiative as well as nonradiative dynamics of the 1mCyt's ππ* state in the aprotic solvent compared to the protic solvent. The solvent effect exhibited by 1mCyt is distinctive from that known for deoxycytidine, indicating the need for caution in using 1mCyt for modelling the ultrafast dynamics of Cyt nucleosides in solvents with varying properties. Overall, our study unveils a deactivation mechanism that confers a high degree of photo-stability for 1mCyt in solution, shedding light on the molecular basis for solvent-induced effects on the excited state dynamics of nucleobases and derivatives.

Analytic and heuristic process for prudent antimicrobial use in animals: What are triggers and how do they work?

The over and misuse of antimicrobials in animal agriculture causes a prevailing crisis for humans, animals, and the environment. From the One Health approach perspective, the formation process of adopting prudent antimicrobial use (AMU), once established, can be used to mitigate this crisis. The study aimed to determine the analytic-based and heuristic-based process that evoked prudent AMU among animal farmers by synthesis of stimulus-organism-response framework and dual-system theory and to explore gender differences on risk-benefit trade-offs. A structural equation model was employed to test the proposed hypotheses with field survey data from 1100 small-scale farmers. The results reveal that for the analytic-based process, social influence, antimicrobial-related threats, and self-efficacy are all salient stimuli having indirect effects on intention via the two organisms of perceived risks and perceived benefits. For heuristic-based process, farmers' altruistic value orientations are positively associated with intention. An interesting fact is that threat awareness has two opposite effects on intention, namely, the suppression effect and the enhancement effect. Moreover, the negative effect of perceived risks on intention is greater among female farmers, compared to male counterparts. These findings provide valuable insights for the forming of theory-based intervention strategies to perfect China's national action plan.

A RhoA structure with switch II flipped outward revealed the conformational dynamics of switch II region.

Small GTPase RhoA switches from GTP-bound state to GDP-bound state by hydrolyzing GTP, which is accelerated by GTPases activating proteins (GAPs). However, less study of RhoA structural dynamic changes was conducted during this process, which is essential for understanding the molecular mechanism of GAP dissociation. Here, we solved a RhoA structure in GDP-bound state with switch II flipped outward. Because lacking the intermolecular interactions with guanine nucleotide, we proposed this conformation of RhoA could be an intermediate after GAP dissociation. Further molecular dynamics simulations found the conformational changes of switch regions are indeed existing in RhoA and involved in the regulation of GAP dissociation and GEF recognition. Besides, the guanine nucleotide binding pocket extended to switch II region, indicating a potential "druggable" cavity for RhoA. Taken together, our study provides a deeper understanding of the dynamic properties of RhoA switch regions and highlights the direction for future drug development.

A high-efficient and naked-eye visible CRISPR/Cas9 system in Arabidopsis.

MAIN CONCLUSION: Introducing 35S-dsRED2 into the Cas9 vector which expresses naked-eye visible dsRED2 greatly facilitates the genetic screening, and the WUS promoter driving the Cas9 expression can improve editing efficiency in Arabidopsis. CRISPR/Cas9-dependent genome editing has been applied to generate random insertions and deletions, targeted insertions or replacements, and precise base changes for both fundamental studies in many plant species and crop improvement. To simplify the screening procedure for target gene-edited transformants, we introduced a CaMV 35S-driven dsRED2 cassette (35S-dsRED2) into the Cas9 vector to express the naked-eye visible protein dsRED2, which can be observed under white light, greatly facilitated the genetic screening and reduced labor intensity without using any instrument. In addition, the WUS promoter was used to drive the expression of Cas9, which successfully improved the target genes editing efficiency and enabled the homozygous mutagenesis of two genes in T1 generation in Arabidopsis. Considering the conserved function and expression pattern of WUS across the plant species, this dsRED2-WUS/Cas9 system could also be used in many crops.

Role of Nuclear Receptor Subfamily 1 Group D Member 1 in the Proliferation, Migration of Vascular Smooth Muscle Cell, and Vascular Intimal Hyperplasia.

ABSTRACT: Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) cause neointimal hyperplasia after percutaneous vascular interventions. Nuclear receptor subfamily 1 group D member 1 (NR1D1), a crucial member of circadian clock, is involved in the regulation of atherosclerosis and cellular proliferation. However, whether NR1D1 affects vascular neointimal hyperplasia remains unclear. In this study, we found that activating NR1D1 reduced injury-induced vascular neointimal hyperplasia. Overexpression of NR1D1 reduced the number of Ki-67-positive VSMCs and migrated VSMCs after platelet-derived growth factor (PDGF)-BB treatment. Mechanistically, NR1D1 suppressed the phosphorylation of AKT and 2 main effectors of the mammalian target of rapamycin complex 1 (mTORC1), S6, and 4EBP1 in PDGF-BB-challenged VSMCs. Re-activation of mTORC1 by Tuberous sclerosis 1 siRNA (si Tsc1 ) and re-activation of AKT by SC-79 abolished NR1D1-mediated inhibitory effects on proliferation and migration of VSMCs. Moreover, decreased mTORC1 activity induced by NR1D1 was also reversed by SC-79. Simultaneously, Tsc1 knockdown abolished the vascular protective effects of NR1D1 in vivo. In conclusion, NR1D1 reduces vascular neointimal hyperplasia by suppressing proliferation and migration of VSMCs in an AKT/mTORC1-dependent manner.

Stable perovskite solar cells with 22% efficiency enabled by inhibiting migration/loss of iodide ions.

Iodide ions (I- and I3-) in perovskites tend to migrate resulting in phase segregation and degradation of perovskite films and devices under illumination or operation conditions. In order to overcome this intrinsic difficulty, passivation and additive strategies have been developed in many studies. In this work, we introduced polyetheramine (PEA) into perovskite films to inhibit the migration and loss of iodides and suppress defects related to these migrated ions. The perovskite films with PEA barely suffered iodide loss even under long-term ultraviolet (UV) illumination and possessed a lower trap density than that of the pristine films before and after aging under UV illumination. Density functional theory (DFT) calculations revealed that PEA can form strong interactions with iodides and Pb2+ in perovskites via PbO and H-I bonds, and the iodide ions (I- and I3-) could be locked firmly by PEA, preventing them from migration or loss. Using this method, the efficiency of perovskite solar cells (PSCs) can be improved from 19.71% (without PEA) to 22.02% (with PEA). After 200 h of maximum power point (MPP) tracking, the efficiency of PSCs with PEA remained 89% of its initial value and that of PSCs without PEA fully degraded.

Sclerosing angiomatoid nodular transformation of the spleen: multimodality imaging features and literature review.

OBJECTIVE: The purpose of this study was to evaluate the CT and MRI findings, clinicopathologic features, and differential diagnosis of Sclerosing angiomatoid nodular transformation (SANT). METHODS AND MATERIALS: Seven men and seven women with pathological diagnoses of SANT were included in this retrospect study. Patients underwent at least one radiological examination before surgery. The number, shape, margin, size, attenuation, signal intensity, homogeneity, and enhancing pattern of the lesion were evaluated by two abdominal radiologists independently. Immunohistochemistry reports were available for 11 patients. The immunoreactivity to the vascular markers CD8, CD31, and CD34 was assessed. RESULTS: The 14 SANT patients (7 men, 7 women; mean age, 43.5 years; age range, 24-56 years) presented with a single lesion and showed no specific clinical symptoms. Among 14 patients, 12 patients underwent MR scan, 5 patients underwent CT scan and 3 patients underwent PET-CT. On CT, all 5 lesions showed hypodensity on non-contrast images and spoke-wheel enhancing pattern after contrast administration, and calcification was observed. On T2WI, 10 cases(83.3%)showed hypointensity and 2 cases (16.7%) showed hyperintensity with central hypointensity. On T1WI, 10 cases (83.3%) were isointense and 2 cases (16.7%) were slightly hypointense. 10 cases (83.3%) showed hypointensity on DWI and 2 cases (16.7%) showed slightly hyperintensity on DWI. After contrast administration, all 12 lesions showed progressive enhancement. 18 F-fluorodeoxyglucose (FDG) uptake in the tumor was seen in all three cases that underwent PET-CT. The maximum standardized uptake value (SUVmax) was 4.5, 5.1, and 3.8 respectively. RESULTS: Apart from the progressive spoke-wheel enhancing pattern, DWI and ADC findings will add value to the diagnosis of SANT.

Nuclear receptor subfamily 1 group D member 1 suppresses the proliferation, migration of adventitial fibroblasts, and vascular intimal hyperplasia via mammalian target of rapamycin complex 1/ß-catenin pathway.

BACKGROUND: In-stent restenosis hardly limits the therapeutic effect of the percutaneous vascular intervention. Although the restenosis is significantly ameliorated after the application of new drug-eluting stents, the incidence of restenosis remains at a high level. OBJECTIVE: Vascular adventitial fibroblasts (AFs) play an important role in intimal hyperplasia and subsequent restenosis. The current study was aimed to investigate the role of nuclear receptor subfamily 1, group D, member 1 (NR1D1) in the vascular intimal hyperplasia. METHODS AND RESULTS: We observed increased expression of NR1D1 after the transduction of adenovirus carrying Nr1d1 gene (Ad-Nr1d1) in AFs. Ad-Nr1d1 transduction significantly reduced the numbers of total AFs, Ki-67-positive AFs, and the migration rate of AFs. NR1D1 overexpression decreased the expression level of ß-catenin and attenuated the phosphorylation of the effectors of mammalian target of rapamycin complex 1 (mTORC1), including mammalian target of rapamycin (mTOR) and 4E binding protein 1 (4EBP1). Restoration of ß-catenin by SKL2001 abolished the inhibitory effects of NR1D1 overexpression on the proliferation and migration of AFs. Surprisingly, the restoration of mTORC1 activity by insulin could also reverse the decreased expression of ß-catenin, attenuated proliferation, and migration in AFs induced by NR1D1 overexpression. In vivo, we found that SR9009 (an agonist of NR1D1) ameliorated the intimal hyperplasia at days 28 after injury of carotid artery. We further observed that SR9009 attenuated the increased Ki-67-positive AFs, an essential part of vascular restenosis at days 7 after injury to the carotid artery. CONCLUSION: These data suggest that NR1D1 inhibits intimal hyperplasia by suppressing the proliferation and migration of AFs in a mTORC1/ß-catenin-dependent manner.

The relationship between self-esteem and mental disability in patients with schizophrenia: the mediating role of resilience and the moderating role of gender.

This study aims to verify the mediating role of resilience between self-esteem and mental disability and to analyze the moderating role of gender in the relationship between resilience and mental disability in patients with schizophrenia. Patients with schizophrenia have been selected from Harbin Psychiatric (Baiyupao) Hospital and Daqing Third Hospital in Heilongjiang Province from January to December 2021. The study recruited a total of 220 patients with schizophrenia, including 120 males and 100 females to measure their self-esteem, resilience and mental disability. The results were as follows: Self-esteem and resilience are important protective factors that have a buffering effect on mental disability. The mediating effect of resilience on self-esteem and mental disability is stronger in males than in females. The results provide new ideas for delaying mental disability and for formulating intervention programs and applying them to clinical practice. The study indicates that psychiatric medical staff should not only treat the patients with schizophrenia psychotic symptoms but also improve their self-esteem and resilience through effective intervention to reduce the occurrence of mental disability.

Toll-like receptor 4 signaling pathway mediates both liver and kidney injuries in mice with hepatorenal syndrome.

Hepatorenal syndrome (HRS) is a complication of cirrhosis with high morbidity and mortality. Nevertheless, the underlying mechanism involving how kidney injury aggravates the progression of cirrhosis remains unclear. This study aims to explore the role of the Toll-like receptor 4 (TLR4) signaling pathway in mediating liver and kidney injuries in HRS mice induced by unilateral ureteral obstruction (UUO) and/or bile duct ligation (BDL). Two weeks after UUO, there were no obvious pathological changes in mouse liver and the unligated side of kidney. Nevertheless, impaired liver and kidney functions, inflammatory response, and fibrosis were examined in mice after 2 wk of BDL. Compared with those of other groups, mice in the BDL + UUO group presented severer liver and kidney injuries, higher levels of inflammatory factors, and faster deposition of collagens, suggesting that kidney injuries accelerated the aggravation of HRS. Correlation analysis identified a positive correlation between expression levels of inflammatory factors and fibrotic levels. Meanwhile, TLR4 and its ligand MyD88 were upregulated during the process of liver and kidney injuries in HRS mice. Further animal experiments in transgenic TLR4-/- mice or in those treated with TAK242, a small molecule inhibitor of TLR4, showed that blocking the TLR4 signaling pathway significantly improved survival quality and survival rate in HRS mice by alleviating liver fibrosis and kidney injury. It is concluded that kidney dysfunction plays an important role in the aggravation of cirrhosis, which may be attributed to the TLR4 signaling pathway. Targeting TLR4 could be a promising therapeutic strategy for protecting both liver and kidneys in patients with HRS.NEW & NOTEWORTHY Our study established BDL, UUO, and BDL + UUO models, providing a novel idea for analyzing liver and kidney diseases. It is highlighted that the kidney injury accelerated the aggravation of HRS via inflammatory response, which could be protected by inhibiting the TLR4 signaling pathway. We believed that targeting TLR4 was a promising therapeutic strategy for protecting both liver and kidney functions in patients with HRS.

The discovery of a non-competitive GOT1 inhibitor, hydralazine hydrochloride, via a coupling reaction-based high-throughput screening assay.

Glutamate oxaloacetate transaminase 1 (GOT1) plays a key role in aberrant glutamine metabolism. GOT1 suppression can arrest tumor growth and prevent the development of cancer, indicating GOT1 as a potential anticancer target. Reported GOT1 inhibitors, on the other hand, are quite restricted. Here, we developed and optimized a coupling reaction-based high-throughput screening assay for the discovery of GOT1 inhibitors. By using this screening assay, we found that the cardiovascular drug hydralazine hydrochloride inhibited GOT1 catalytic activity, with an IC50 of 26.62 ± 7.45 µM, in a non-competitive and partial-reversible manner. In addition, we determined the binding affinity of hydralazine hydrochloride to GOT1, with a Kd of 16.54 ± 8.59 µM, using a microscale thermophoresis assay. According to structure-activity relationship analysis, the inhibitory activity of hydralazine hydrochloride is mainly derived from its hydrazine group. Furthermore, it inhibits the proliferation of cancer cells MCF-7 and MDA-MB-468 with a slight inhibitory effect compared to other tested cancer cells, highlighting GOT1 as a promising therapeutic target for the treatment of breast cancer.

Cognitive impairment in mild traumatic brain injury: a diffusion kurtosis imaging and volumetric study.

BACKGROUND: A significant number of patients with mild traumatic brain injury (mTBI) would experience cognitive deficit. PURPOSE: To investigate the brain structural changes in sub-acute mTBI by diffusion kurtosis imaging (DKI) and volumetric analysis, and to assess the relationship between brain structural changes and cognitive functions. MATERIAL AND METHODS: A total of 23 patients with sub-acute mTBI and 24 control participants were recruited. All the participants underwent examinations of neuropsychological tests, DKI, and magnetic resonance imaging (MRI)-based morphological scans. Images were investigated using whole brain-based analysis and further regions of interest-based analysis for subcortical nuclei. The neuropsychological tests were compared between the mTBI and the control group. Correlation analysis was performed to examine the relationship between gray matter (GM) volume, DKI parameters, and cognitive functions. RESULTS: Compared with control participants, mTBI patients performed worse in the domains of verbal memory, attention and executive function (P < 0.05). No regional GM volume differences were observed between the mTBI and control groups (P > 0.05). Using DKI, patients with mTBI showed lower mean kurtosis (MK) in widespread white matter (WM) regions and several subcortical nuclei (P < 0.05), and higher mean diffusivity (MD) in the right pallidum (P < 0.05). Lower MK value of multiple WM regions and several subcortical nuclei correlated with cognitive impairment (P < 0.05). CONCLUSION: DKI was sensitive in detecting brain microstructural changes in patients with sub-acute mTBI showing lower MK value in widespread WM regions and several subcortical nuclei, which were statistically associated with cognitive deficits.

Control of IgG glycosylation in CHO cell perfusion cultures by GReBA mathematical model supported by a novel targeted feed, TAFE.

The N-linked glycosylation pattern is an important quality attribute of therapeutic glycoproteins. It has been reported by our group and by others that different carbon sources, such as glucose, mannose and galactose, can differently impact the glycosylation profile of glycoproteins in mammalian cell culture. Acting on the sugar feeding is thus an attractive strategy to tune the glycan pattern. However, in case of feeding of more than one carbon source simultaneously, the cells give priority to the one with the highest uptake rate, which limits the usage of this tuning, e.g. the cells favor consuming glucose in comparison to galactose. We present here a new feeding strategy (named 'TAFE' for targeted feeding) for perfusion culture to adjust the concentrations of fed sugars influencing the glycosylation. The strategy consists in setting the sugar feeding such that the cells are forced to consume these substrates at a target cell specific consumption rate decided by the operator and taking into account the cell specific perfusion rate (CSPR). This strategy is applied in perfusion cultures of Chinese hamster ovary (CHO) cells, illustrated by ten different regimes of sugar feeding, including glucose, galactose and mannose. Applying the TAFE strategy, different glycan profiles were obtained using the different feeding regimes. Furthermore, we successfully forced the cells to consume higher proportions of non-glucose sugars, which have lower transport rates than glucose in presence of this latter, in a controlled way. In previous work, a mathematical model named Glycan Residues Balance Analysis (GReBA) was developed to model the glycosylation profile based on the fed carbon sources. The present data were applied to the GReBA to design a feeding regime targeting a given glycosylation profile. The ability of the model to achieve this objective was confirmed by a multi-round of leave-one-out cross-validation (LOOCV), leading to the conclusion that the GReBA model can be used to design the feeding regime of a perfusion cell culture to obtain a desired glycosylation profile.

A signature of seven immune-related genes predicts overall survival in male gastric cancer patients.

BACKGROUND: Gastric cancer (GC) has a high mortality rate and is one of the most fatal malignant tumours. Male sex has been proven as an independent risk factor for GC. This study aimed to identify immune-related genes (IRGs) associated with the prognosis of male GC. METHODS: RNA sequencing and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed IRGs between male GC and normal tissues were identified by integrated bioinformatics analysis. Univariate and multivariate Cox regression analyses were applied to screen survival-associated IRGs. Then, GC patients were separated into high- and low-risk groups based on the median risk score. Furthermore, a nomogram was constructed based on the TCGA dataset. The prognostic value of the risk signature model was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index and calibration curves. In addition, the gene expression dataset from the Gene Expression Omnibus (GEO) was also downloaded for external validation. The relative proportions of 22 types of infiltrating immune cells in each male GC sample were evaluated using CIBERSORT. RESULTS: A total of 276 differentially expressed IRGs were screened, including 189 up-regulated and 87 down-regulated genes. Subsequently, a seven-IRGs signature (LCN12, CCL21, RNASE2, CGB5, NRG4, AGTR1 and NPR3) was identified to be significantly associated with the overall survival (OS) of male GC patients. Survival analysis indicated that patients in the high-risk group exhibited a poor clinical outcome. The results of multivariate analysis revealed that the risk score was an independent prognostic factor. The established nomogram could be used to evaluate the prognosis of individual male GC patients. Further analysis showed that the prognostic model had excellent predictive performance in both TCGA and validated cohorts. Besides, the results of tumour-infiltrating immune cell analysis indicated that the seven-IRGs signature could reflect the status of the tumour immune microenvironment. CONCLUSIONS: Our study developed a novel seven-IRGs risk signature for individualized survival prediction of male GC patients.

Probabilistic model by Bayesian network for the prediction of antibody glycosylation in perfusion and fed-batch cell cultures.

Glycosylation is a critical quality attribute of therapeutic monoclonal antibodies (mAbs). The glycan pattern can have a large impact on the immunological functions, serum half-life and stability. The medium components and cultivation parameters are known to potentially influence the glycosylation profile. Mathematical modelling provides a strategy for rational design and control of the upstream bioprocess. However, the kinetic models usually contain a very large number of unknown parameters, which limit their practical applications. In this article, we consider the metabolic network of N-linked glycosylation as a Bayesian network (BN) and calculate the fluxes of the glycosylation process as joint probability using the culture parameters as inputs. The modelling approach is validated with data of different Chinese hamster ovary cell cultures in pseudo perfusion, perfusion, and fed batch cultures, all showing very good predictive capacities. In cases where a large number of cultivation parameters is available, it is shown here that principal components analysis can efficiently be employed for a dimension reduction of the inputs compared to Pearson correlation analysis and feature importance by decision tree. The present study demonstrates that BN model can be a powerful tool in upstream process and medium development for glycoprotein productions.