Background:
The long-term effects of dose reduction of atypical antipsychotics on cognitive function and symptomatology in stable patients with schizophrenia remain unclear. We sought to determine ...the change in cognitive function and symptomatology after reducing risperidone or olanzapine dosage in stable schizophrenic patients.
Methods:
Seventy-five stabilized schizophrenic patients prescribed risperidone (≥4 mg/day) or olanzapine (≥10 mg/day) were randomly divided into a dose-reduction group (n=37) and a maintenance group (n=38). For the dose-reduction group, the dose of antipsychotics was reduced by 50%; for the maintenance group, the dose remained unchanged throughout the whole study. The Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, and Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery were measured at baseline, 12, 28, and 52 weeks. Linear mixed models were performed to compare the Positive and Negative Syndrome Scale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects and MATRICS Consensus Cognitive Battery scores between groups.
Results:
The linear mixed model showed significant time by group interactions on the Positive and Negative Syndrome Scale negative symptoms, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, attention/vigilance, working memory and total score of MATRICS Consensus Cognitive Battery (all p<0.05). Post hoc analyses showed significant improvement in Positive and Negative Syndrome Scale negative subscale, Negative Symptom Assessment-16, Rating Scale for Extrapyramidal Side Effects, speed of processing, working memory and total score of MATRICS Consensus Cognitive Battery for the dose reduction group compared with those for the maintenance group (all p<0.05).
Conclusions:
This study indicated that a risperidone or olanzapine dose reduction of 50% may not lead to more severe symptomatology but can improve speed of processing, working memory and negative symptoms in patients with stabilized schizophrenia.
Long noncoding RNAs (lncRNAs) play important roles in various biological processes such as proliferation, cell death and differentiation. Here, we show that a liver-enriched lncRNA, named liver ...fibrosis-associated lncRNA1 (lnc-LFAR1), promotes liver fibrosis. We demonstrate that lnc-LFAR1 silencing impairs hepatic stellate cells (HSCs) activation, reduces TGFβ-induced hepatocytes apoptosis in vitro and attenuates both CCl
- and bile duct ligation-induced liver fibrosis in mice. Lnc-LFAR1 promotes the binding of Smad2/3 to TGFβR1 and its phosphorylation in the cytoplasm. Lnc-LFAR1 binds directly to Smad2/3 and promotes transcription of TGFβ, Smad2, Smad3, Notch2 and Notch3 which, in turn, results in TGFβ and Notch pathway activation. We show that the TGFβ1/Smad2/3/lnc-LFAR1 pathway provides a positive feedback loop to increase Smad2/3 response and a novel link connecting TGFβ with Notch pathway. Our work identifies a liver-enriched lncRNA that regulates liver fibrogenesis and suggests it as a potential target for fibrosis treatment.Activated hepatic stellate cells are the principal contributors to liver fibrosis by secreting a variety of pro-fibrogenic cytokines . Here Zhang et al. demonstrate that a liver-enriched lncRNA, lnc-LFAR1, promotes liver fibrosis and HSC activation by activating TGFβ and Notch signaling.
Paclitaxel (PTX) is a first-line drug for late-stage non-small cell lung cancer (NSCLC) patients who do not benefit from targeted therapy or immunotherapy. However, patients invariably develop ...resistance to PTX upon prolonged treatments. Although diverse mechanisms leading to PTX resistance have been well-documented in the literature, strategies to overcome PTX resistance in NSCLC based on these mechanisms are still challenging. In this article, we reviewed recent advancements elucidating major mechanisms of PTX resistance in NSCLC, including the overexpression of ABC transporters, alternations to tubulin structures, and the involvement of cytokines, miRNAs, kinase signaling pathways, and epithelial-mesenchymal transition. Potential markers of PTX resistance or PTX response that could help to direct treatment decisions and restore cellular sensitivity to PTX were also discussed. Finally, we summarized the corresponding strategies to overcome PTX resistance in NSCLC cells, which might provide new insights into clinical trials and benefit lung cancer patients in the future.
The wind–sand climate prevalent in the central and western regions of Inner Mongolia results in significant damage to wind turbine blade coatings due to sand erosion. This not only leads to a decline ...in power generation but also poses safety risks. This study replicated the wind–sand environment of Alashan and numerically simulated the erosion and wear process of the blade coatings of a 1.5 MW horizontal axis wind turbine under rotational conditions using the DPM model. Additionally, erosion tests were conducted on the operating wind rotor in a wind tunnel. The simulation results demonstrate that sand particle trajectories in the rotating domain are influenced by vortex, incoming wind speed, and sand particle size. For small-sized sand particles, variations in wind speed do not substantially alter the number of particles in contact with the wind turbine blades. However, alterations in the momentum of these particles lead to changes in the impact force on the coating surface. Conversely, the change of wind speed will not only alter the number of large-size sand particles in contact with the wind rotor but also modify the impact force on the coating surface. Furthermore, after impacting the blade, small sand particles continue to move along an approximate helical trajectory with the airflow, while large-size sand particles swiftly rebound. Through statistical analysis of erosion pits on the blade surface after the erosion experiments, it was observed that, in comparison among the leading edge, windward side, trailing edge, and leeward side, the leading edge presents the greatest number of erosion pits, whereas the leeward side has the fewest. Along the spanwise direction, the 0.7R-blade tip segment exhibits the highest count, while the blade root-0.3R section displays the fewest number of pits. The wear morphology of the blade coating was observed from the blade root to tip. The leading edge coating exhibits a range from shallow pits to coating flaking and deeper gouge pits. On the windward side, the coating displays wear patterns varying from tiny cutting pits to cutting marks, and then to gouge pits and coating flaking. Erosion morphology of the trailing edge evolves from only minor scratches to spalling pits, further deepening and enlarging. These research findings provide a basis for the study of zoning-adapted coating materials for wind turbine blades in wind–sand environments.
More than half of all cancer patients receive chemotherapy, however, some of them easily acquire drug resistance. Resistance to chemotherapy has become a massive obstacle to achieve high rates of ...pathological complete response during cancer therapy. S-phase kinase-associated protein 2 (Skp2), as an E3 ligase, was found to be highly correlated with drug resistance and poor prognosis. In this review, we summarize the mechanisms that Skp2 confers to drug resistance, including the Akt-Skp2 feedback loop, Skp2-p27 pathway, cell cycle and mitosis regulation, EMT (epithelial-mesenchymal transition) property, enhanced DNA damage response and repair, etc. We also addressed novel molecules that either inhibit Skp2 expression or target Skp2-centered interactions, which might have vast potential for application in clinics and benefit cancer patients in the future.
In order to improve the conveying performance of the eccentric telescopic rod conveyor, theoretical analysis is used to find rotation center position of the telescopic rod and the relationship among ...various structural parameters of the conveyor with position alteration of the eccentric axis. A mathematical model of one periodic conveying capacity of the device and the velocity and acceleration equations of the telescopic rod end are established. The multi-objective optimization analysis are done by the virtual prototyping technology and the multi-island genetic algorithm, which takes the maximum conveying volume of one periodic and minimum acceleration of the rod end as the optimization goals. The results show that after multi-objective optimization, the conveying efficiency is improved, while the impact of telescopic rod striking on materials during the conveying process is reduced and the overall performance is better. Then, an example is taken to verify the mathematical models and multi-objective optimization analysis results, and the wireless acceleration test system is used to test the telescopic rod end acceleration before and after the structural optimization. The experimental and mathematical model calculation results show good agreement before and after the structural parameters’ optimization. The study shows that the mathematical model and the multi-objective optimization results are credible. It provides a theoretical and methodological reference for the practical design and optimization of eccentric telescopic rod conveyor.
To accurately predict fatigue life and reliability of the forage crusher rotor, the stress load spectrum of the rotor is obtained via the two-way fluid-structure coupling method, which calculates the ...coupled flow field in the forage crusher and rotor structure. The fatigue life of the rotor is predicted, and its reliability is analyzed. Finally, the rotor is optimized by a multiisland genetic algorithm. The results indicate that the fatigue life prediction based on fracture mechanics theory and the Gerber average stress correction method is more suitable for the prediction of the rotor’s fatigue life. After optimization, the fatigue life cycles of the rotor are increased from 1.229×10
8
to 7.67×10
8
and the reliability is increased from 89.4 % to 99.7 %. This meets the reliability requirement of key parts of agricultural and animal husbandry machinery. This study provides a reference for the prediction and optimization of fatigue life and reliability of forage crushers.
Protein-protein interaction and signaling crosstalk contribute to the regulation of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) and broaden their cellular function.
This ...review covers key historic discoveries and recent advances in our understanding of the broad function of PXR and CAR and their regulation by protein-protein interaction and signaling crosstalk.
PXR and CAR were first discovered as xenobiotic receptors; however, it is clear that PXR and CAR perform a much broader range of cellular functions through protein-protein interaction and signaling crosstalk, which typically mutually affect the function of all the partners involved. Future research on PXR and CAR should, therefore, look beyond their xenobiotic function.
It has been reported that folic acid supplementation before and/or during pregnancy could reduce the risk of congenital heart defects (CHDs). However, the results from limited epidemiologic studies ...have been inconclusive. We investigated the associations between maternal folic acid supplementation, dietary folate intake, and the risk of CHDs.
A birth cohort study was conducted in 2010-2012 at the Gansu Provincial Maternity & Child Care Hospital in Lanzhou, China. After exclusion of stillbirths and multiple births, a total of 94 births were identified with congenital heart defects, and 9,993 births without any birth defects. Unconditional logistic regression was used to estimate the associations.
Compared to non-users, folic acid supplement users before pregnancy had a reduced risk of overall CHDs (OR: 0.42, 95% CI: 0.21-0.86, Ptrend = 0.025) after adjusted for potential confounders. A protective effect was observed for certain subtypes of CHDs (OR: 0.37, 95% CI: 0.16-0.85 for malformation of great arteries; 0.26, 0.10-0.68 for malformation of cardiac septa; 0.34, 0.13-0.93 for Atrial septal defect). A similar protective effect was also seen for multiple CHDs (OR: 0.49, 95% CI: 0.26-0.93, Ptrend = 0.004). Compared with the middle quartiles of dietary folate intake, lower dietary folate intake (<149.88 μg/day) during pregnancy were associated with increased risk of overall CHDs (OR: 1.63, 95% CI: 1.01-2.62) and patent ductus arteriosus (OR: 1.85, 95% CI: 1.03-3.32). Women who were non-user folic acid supplement and lower dietary folate intake have almost 2-fold increased CHDs risk in their offspring.
Our study suggested that folic acid supplementation before pregnancy was associated with a reduced risk of CHDs, lower dietary folate intake during pregnancy was associated with increased risk. The observed associations varied by CHD subtypes. A synergistic effect of dietary folate intake and folic acid supplementation was also observed.
Mild traumatic brain injury (mTBI) causes persisting post-concussion syndrome for many patients without abnormalities on conventional neuroimaging. Currently, there is no method for identifying ...at-risk cases at an early stage for directing concussion management and treatment. SNTF is a calpain-derived N-terminal proteolytic fragment of spectrin (α
-spectrin1-1176) generated in damaged axons following mTBI. Preliminary human studies suggest that elevated blood SNTF on the day of mTBI correlates with white matter disruption and lasting brain dysfunction. Here, we further evaluated serum SNTF as a prognostic marker for persistent brain dysfunction in uncomplicated mTBI patients treated in a Level I trauma center emergency department. Compared with healthy controls (
= 40), serum SNTF increased by 92% within 24 h of mTBI (
= 95;
< 0.0001), and as a diagnostic marker exhibited 100% specificity and 37% sensitivity (AUC = 0.87). To determine whether the subset of mTBI cases positive for SNTF preferentially developed lasting brain dysfunction, serum levels on the day of mTBI were compared with multiple measures of brain performance at 90 days post-injury. Elevated serum SNTF correlated significantly with persistent impairments in cognition and sensory-motor integration, and predicted worse performance in each test on a case by case basis (AUC = 0.68 and 0.76, respectively). SNTF also predicted poorer recovery of cognitive stress function from 30 to 90 days (AUC = 0.79-0.90). These results suggest that serum SNTF, a surrogate marker for axonal injury after mTBI, may have potential for the rapid prognosis of lasting post-concussion syndrome and impaired functional recovery following CT-negative mTBI. They provide further evidence linking axonal injury to persisting brain dysfunction after uncomplicated mTBI. A SNTF blood test, either alone or combined with other markers of axonal injury, may have important utilities for research, prognosis, management and treatment of concussion.
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