The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator.

SCH23390 is a widely used D1 dopamine receptor (D1R) antagonist that also elicits some D1R-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of 3H (+)-pentazocine to Sig1R. In this study, we investigated whether SCH23390 functions as an allosteric modulator of Sig1R. We detected increased Sig1R dissociation from binding immunoglobulin protein (BiP) and translocation of Sig1R to the plasma membrane in response to SCH23390 in transfected HEK293T and SH-SY5Y cells, respectively. Activation of Sig1R by SCH23390 was further confirmed by inhibition of GSK3ß activity in a time- and dose-dependent manner; this effect was blocked by pretreatment with the Sig1R antagonist, BD1047, and by knockdown of Sig1R. SCH23390 also inhibited GSK3ß in wild-type mice but not in Sig1R knockout mice. Finally, we showed that SCH23390 allosterically modulated the effect of the Sig1R agonist SKF10047 on inhibition of GSK3ß. This positive allosteric effect of SCH23390 was further confirmed via promotion of neuronal protection afforded by SKF10047 in primary cortical neurons challenged with MPP+. These results provide the first evidence that SCH23390 elicits functional allosteric modulation of Sig1R. Our findings not only reveal novel pharmacological effects of SCH23390 but also indicate a potential mechanism for SCH23390-mediated D1R-independent effects. Therefore, attention should be paid to these Sig1R-mediated effects when explaining pharmacological responses to SCH23390.

Combined Aerobic and Resistance Exercise Interventions for Children and Adolescents With Cancer: A Systematic Review and Meta-Analysis.

PROBLEM IDENTIFICATION: Systematic reviews in adults with cancer have shown the benefits of combined aerobic and resistance exercise (CE) interventions on physical and psychological fitness. However, data on the efficacy of CE interventions for children and adolescents are limited and discordant. LITERATURE SEARCH: The PubMed®, Embase®, Cochrane Central Register of Controlled Trials, Web of Science, and China National Knowledge Infrastructure electronic databases were searched from inception to April 19, 2022. DATA EVALUATION: Nine randomized controlled trials met the inclusion criteria. A quantitative synthesis method was used to investigate the effects of CE interventions on fatigue, cardiorespiratory fitness, physical activity levels, and health-related quality of life. SYNTHESIS: This systematic review and meta-analysis indicates that CE interventions have beneficial effects on the fatigue, cardiorespiratory fitness, and physical activity levels of this population. IMPLICATIONS FOR PRACTICE: Healthcare providers should implement CE interventions during hospital care and recommend home-based CE interventions to patients who have barriers to performing hospital-based sessions.

[CiteSpace knowledge map of research hotspots and frontiers of traditional Chinese medicine intervention in psoriasis in recent ten years].

This study aimed to investigate the development status of traditional Chinese medicine(TCM) intervention in psoriasis in recent ten years, analyze the research hotspots, and summarize the development trends to provide reference materials for scholars in this field. Taking the available literature related to the field of TCM intervention in psoriasis as the research object, the trends, contents, and source publications were statistically analyzed based on bibliometrics. The research cooperation and co-occurrence of keywords in this field were studied by the knowledge map analysis method based on CiteSpace. The total number of Chinese papers was 2 993 and English papers 285. In terms of publication trend, the annual publication of English papers was low but showed an obvious upward trend, while the increase in Chinese papers fluctuated and tended to be flat. In terms of the content of Chinese papers published, TCM ranked first according to the discipline(2 415). In English papers, the number of publications in pharmacology and pharmaceutical science was the highest(87). Literature source analysis showed that the Chinese and English journals with the most publications were China Journal of Traditional Chinese Medicine and Pharmacy and Evidence Based Complementary and Alternative Medicine, respectively. Beijing University of Chinese Medicine published the most dissertations in China(99). The authors with the most publications in Chinese and English were LI Bin(Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine) and LU Chuan-jian(Guangdong Hospital of Traditional Chinese Medicine). As revealed by the CiteSpace analysis of the research cooperation network, there were four mature and stable core teams in this field, but the cooperation intensity between different teams was weak. According to the keywords co-occurrence knowledge graph constructed by CiteSpace, the current hot keywords in this field are as follows: psoriasis, blood-heat syndrome, blood-stasis syndrome, fire needle, blood-dryness type, imiquimod, TCM bath, etiology and pathogenesis, cytokines, cupping therapy, etc. In summary, Chinese scholars have conducted active exploration and research in the field of TCM intervention in psoriasis in recent ten years. The overall development trend is good, and the breadth and depth of the research are constantly extending. It is suggested that relevant research should be free from discipline restrictions and strive for interdisciplinary integration.

Fast Charge-Transport Interface on Primary Particles Boosts High-Rate Performance of Li-Rich Mn-Based Cathode Materials.

A Li-rich Mn-based layered oxide cathode (LLO) is one of the most promising cathode materials for achieving high-energy lithium-ion batteries. Nevertheless, the intrinsic problems including sluggish kinetics, oxygen evolution, and structural degradation lead to unsatisfactory performance in rate capability, initial Coulombic efficiency, and stability of LLO. Herein, different from the current typical surface modification, an interfacial optimization of primary particles is proposed to improve the simultaneous transport of ions and electrons. The modified interfaces containing AlPO4 and carbon can effectively increase the Li+ diffusion coefficient and decrease the interfacial charge-transfer resistance, thereby achieving fast charge-transport kinetics. Moreover, the in situ high-temperature X-ray diffraction confirms that the modified interface can improve the thermal stability of LLO by inhibiting the lattice oxygen release on the surface of the delithiated cathode material. In addition, the chemical and visual analysis of the cathode-electrolyte interface (CEI) composition clarifies that a highly stable and conductive CEI film generated on the modified electrode can facilitate interfacial kinetic transmission during cycling. As a result, the optimized LLO cathode exhibits a high initial Coulombic efficiency of 87.3% at a 0.2C rate and maintains superior high-rate stability with a capacity retention of 88.2% after 300 cycles at a 5C high rate.

Dynamic regulation of excitatory and inhibitory synaptic transmission by growth hormone in the developing mouse brain.

Normal sensory and cognitive function of the brain relies on its intricate and complex neural network. Synaptogenesis and synaptic plasticity are critical to neural circuit formation and maintenance, which are regulated by coordinated intracellular and extracellular signaling. Growth hormone (GH) is the most abundant anterior pituitary hormone. Its deficiencies could alter brain development and impair learning and memory, while GH replacement therapy in human patients and animal models has been shown to ameliorate cognitive deficits caused by GH deficiency. However, the underlying mechanism remains largely unknown. In this study, we investigated the neuromodulatory function of GH in young (pre-weaning) mice at two developmental time points and in two different brain regions. Neonatal mice were subcutaneously injected with recombinant human growth hormone (rhGH) on postnatal day (P) 14 or 21. Excitatory and inhibitory synaptic transmission was measured using whole-cell recordings in acute cortical slices 2 h after the injection. We showed that injection of rhGH (2 mg/kg) in P14 mice significantly increased the frequency of mEPSCs, but not that of mIPSCs, in both hippocampal CA1 pyramidal neurons and L2/3 pyramidal neurons of the barrel field of the primary somatosensory cortex (S1BF). Injection of rhGH (2 mg/kg) in P21 mice significantly increased the frequency of mEPSCs and mIPSCs in both brain regions. Perfusion of rhGH (1 µM) onto acute brain slices in P14 mice had similar effects. Consistent with the electrophysiological results, the dendritic spine density of CA1 pyramidal neurons and S1BF L2/3 pyramidal neurons increased following in vivo injection of rhGH. Furthermore, NMDA receptors and postsynaptic calcium-dependent signaling contributed to rhGH-dependent regulation of both excitatory and inhibitory synaptic transmission. Together, these results demonstrate that regulation of excitatory and inhibitory synaptic transmission by rhGH occurs in a developmentally dynamic manner, and have important implication for identifying GH treatment strategies without disturbing excitation/inhibition balance.

Chemical components of Magnoliae Officinalis Cortex of different origins and with different tree ages before and after being processed with ginger juice:a qualitative and quantitative analysis / 中国中药杂志

This study aimed to investigate the impact of ginger juice on chemical profile of Magnoliae Officinalis Cortex(MOC) when they were processed together. Ultra-high-performance liquid chromatography coupled to quadrupole-orbitrap high-resolution mass spectrometry(UHPLC-Q-Orbitrap HRMS) was used for qualitative analysis of the chemical component of MOC samples before and after being processed with ginger juice. UPLC was performed to observe the content variation of eight main components in processed MOC. A total of 174 compounds were identified or tentatively deduced from processed and unprocessed MOC samples according to MS data obtained in positive and negative ion mode. After MOC was processed with ginger juice, the peak areas of most phenolics increased, while the peak areas of most phenylethanoid glycosides decreased; as for neolignans, oxyneolignans, other lignans and alkaloids, changes in the peak area were variable, and the peak areas of terpenoid-lignans varied little. Additionally, gingerols and diarylheptanoids were only detected in the processed MOC sample. The contents of syringin, magnoloside A, and magnoloside B decreased significantly in the processed MOC sample while no significant difference was observed in the contents of magnoflorine, magnocurarine, honokiol, obovatol, and magnolol. This study comprehensively explored the content variation of chemical components in processed and unprocessed MOC samples derived from different regions and with different tree ages using UPLC and UHPLC-Q-Orbitrap HRMS, and summarized the variation characteristics of various compounds. The results provide a data foundation for further research on pharmacodynamic substances of MOC processed with ginger juice.

Machine Learning-Based Rapid Detection of Volatile Organic Compounds in a Graphene Electronic Nose.

Rapid detection of volatile organic compounds (VOCs) is growing in importance in many sectors. Noninvasive medical diagnoses may be based upon particular combinations of VOCs in human breath; detecting VOCs emitted from environmental hazards such as fungal growth could prevent illness; and waste could be reduced through monitoring of gases produced during food storage. Electronic noses have been applied to such problems, however, a common limitation is in improving selectivity. Graphene is an adaptable material that can be functionalized with many chemical receptors. Here, we use this versatility to demonstrate selective and rapid detection of multiple VOCs at varying concentrations with graphene-based variable capacitor (varactor) arrays. Each array contains 108 sensors functionalized with 36 chemical receptors for cross-selectivity. Multiplexer data acquisition from 108 sensors is accomplished in tens of seconds. While this rapid measurement reduces the signal magnitude, classification using supervised machine learning (Bootstrap Aggregated Random Forest) shows excellent results of 98% accuracy between 5 analytes (ethanol, hexanal, methyl ethyl ketone, toluene, and octane) at 4 concentrations each. With the addition of 1-octene, an analyte highly similar in structure to octane, an accuracy of 89% is achieved. These results demonstrate the important role of the choice of analysis method, particularly in the presence of noisy data. This is an important step toward fully utilizing graphene-based sensor arrays for rapid gas sensing applications from environmental monitoring to disease detection in human breath.

Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists.

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both Gq-mediated calcium flux and ß-arrestin recruitment assays, which revealed that these compounds exhibited no ß-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward Gq signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT2C signaling pathways and the development of alternative antipsychotic medications.

Discovery of novel MIF inhibitors that attenuate microglial inflammatory activation by structures-based virtual screening and in vitro bioassays.

Macrophage migration inhibitory factor (MIF) is a pluripotent pro-inflammatory cytokine and is related to acute and chronic inflammatory responses, immune disorders, tumors, and other diseases. In this study, an integrated virtual screening strategy and bioassays were used to search for potent MIF inhibitors. Twelve compounds with better bioactivity than the prototypical MIF-inhibitor ISO-1 (IC50 = 14.41 µM) were identified by an in vitro enzymatic activity assay. Structural analysis revealed that these inhibitors have novel structural scaffolds. Compound 11 was then chosen for further characterization in vitro, and it exhibited marked anti-inflammatory efficacy in LPS-activated BV-2 microglial cells by suppressing the activation of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). Our findings suggest that MIF may be involved in the regulation of microglial inflammatory activation and that small-molecule MIF inhibitors may serve as promising therapeutic agents for neuroinflammatory diseases.

Dysregulation of iron homeostasis and methamphetamine reward behaviors in Clk1-deficient mice.

Chronic administration of methamphetamine (METH) leads to physical and psychological dependence. It is generally accepted that METH exerts rewarding effects via competitive inhibition of the dopamine transporter (DAT), but the molecular mechanism of METH addiction remains largely unknown. Accumulating evidence shows that mitochondrial function is important in regulation of drug addiction. In this study,  we investigated the role of Clk1, an essential mitochondrial hydroxylase for ubiquinone (UQ), in METH reward effects. We showed that Clk1+/- mutation significantly suppressed METH-induced conditioned place preference (CPP), accompanied by increased expression of DAT in plasma membrane of striatum and hippocampus due to Clk1 deficiency-induced inhibition of DAT degradation without influencing de novo synthesis of DAT. Notably, significantly decreased iron content in striatum and hippocampus was evident in both Clk1+/- mutant mice and PC12 cells with Clk1 knockdown. The decreased iron content was attributed to increased expression of iron exporter ferroportin 1 (FPN1) that was associated with elevated expression of hypoxia-inducible factor-1α (HIF-1α) in response to Clk1 deficiency both in vivo and in vitro. Furthermore, we showed that iron played a critical role in mediating Clk1 deficiency-induced alteration in DAT expression, presumably via upstream HIF-1α. Taken together, these data demonstrated that HIF-1α-mediated changes in iron homostasis are involved in the Clk1 deficiency-altered METH reward behaviors.

A method to calculate the number of dynamic HDFS copies based on file access popularity.

HDFS heterogeneous clusters usually have multiple storage media at the same time. How to efficiently read and write file copies and reasonably use various storage media is a problem to be solved. Dynamically adjusting the number of copies is important in HDFS, which can solve the problem of accessing a large number of hot files at the same time and improve the efficiency of cluster services. A method is introduced to calculate the number of dynamic HDFS copies based on file access popularity in this paper. Firstly, an algorithm was proposed to predict file popularity based on the cuckoo search optimization Markov model. The unbiased grey model is used to predict the accessing file's popularity at the next moment according to the recent access of the file. The cuckoo search is used to optimize the Markov model, and the prediction error is corrected. Then, the calculation method of the number of copies is designed based on the prediction of the popularity of the file to be accessed and the availability of the node. The experiment shows that the proposed method has a high fitting degree with the actual value, and the MAPE is 3.08%, and it is the smallest, compared with several commonly used prediction models. In CloudSim4.0 simulation platform, multiple users write 10 files to the cluster at the same time, and the change number of copies is calculated according to the predicted value at the next moment, so as to improve the user access efficiency.

Establishment of artificial neural network model for predicting lymph node metastasis in patients with stage Ⅱ-Ⅲ gastric cancer / 中华胃肠外科杂志

Objective: To establish a neural network model for predicting lymph node metastasis in patients with stage II-III gastric cancer. Methods: Case inclusion criteria: (1) gastric adenocarcinoma diagnosed by pathology as stage II-III (the 8th edition of AJCC staging); (2) no distant metastasis of liver, lung and abdominal cavity in preoperative chest film, abdominal ultrasound and upper abdominal CT; (3) undergoing R0 resection. Case exclusion criteria: (1) receiving preoperative neoadjuvant chemotherapy or radiotherapy; (2) incomplete clinical data; (3) gastric stump cancer.Clinicopathological data of 1231 patients with stage II-III gastric cancer who underwent radical surgery at the Fujian Medical University Union Hospital from January 2010 to August 2014 were retrospectively analyzed. A total of 1035 patients with lymph node metastasis were confirmed after operation, and 196 patients had no lymph node metastasis. According to the postoperative pathologic staging. 416 patients (33.8%) were stage Ⅱ and 815 patients (66.2%) were stage III. Patients were randomly divided into training group (861/1231, 69.9%) and validation group (370/1231, 30.1%) to establish an artificial neural network model (N+-ANN) for the prediction of lymph node metastasis. Firstly, the Logistic univariate analysis method was used to retrospectively analyze the case samples of the training group, screen the variables affecting lymph node metastasis, determine the variable items of the input point of the artificial neural network, and then the multi-layer perceptron (MLP) to train N+-ANN. The input layer of N+-ANN was composed of the variables screened by Logistic univariate analysis. Artificial intelligence analyzed the status of lymph node metastasis according to the input data and compared it with the real value. The accuracy of the model was evaluated by drawing the receiver operating characteristic (ROC) curve and obtaining the area under the curve (AUC). The ability of N+-ANN was evaluated by sensitivity, specificity, positive predictive values, negative predictive values, and AUC values. Results: There were no significant differences in baseline data between the training group and validation group (all P>0.05). Univariate analysis of the training group showed that preoperative platelet to lymphocyte ratio (PLR), preoperative systemic immune inflammation index (SII), tumor size, clinical N (cN) stage were closely related to postoperative lymph node metastasis. The N+-ANN was constructed based on the above variables as the input layer variables. In the training group, the accuracy of N+-ANN for predicting postoperative lymph node metastasis was 88.4% (761/861), the sensitivity was 98.9% (717/725), the specificity was 32.4% (44/136), the positive predictive value was 88.6% (717/809), the negative predictive value was 84.6% (44/52), and the AUC value was 0.748 (95%CI: 0.717-0.776). In the validation group, N+-ANN had a prediction accuracy of 88.4% (327/370) with a sensitivity of 99.7% (309/310), specificity of 30.0% (18/60), positive predictive value of 88.0% (309/351), negative predictive value of 94.7% (18/19), and an AUC of 0.717 (95%CI:0.668-0.763). According to the individualized lymph node metastasis probability output by N+-ANN, the cut-off values of 0-50%, >50%-75%, >75%-90% and >90%-100% were applied and patients were divided into N0 group, N1 group, N2 group and N3 group. The overall prediction accuracy of N+-ANN for pN staging in the training group and the validation group was 53.7% and 54.1% respectively, while the overall prediction accuracy of cN staging for pN staging in the training group and the validation group was 30.1% and 33.2% respectively, indicating that N+-ANN had a better prediction than cN stage. Conclusions: The N+-ANN constructed in this study can accurately predict postoperative lymph node metastasis in patients with stage Ⅱ-Ⅲ gastric cancer. The N+-ANN based on individualized lymph node metastasis probability has better accurate prediction for pN staging as compared to cN staging.

Comparison of efficacy of femoral tunnel creation with figure-of-four position and traditional knee hyperflexed position for arthroscopic anterior cruciate ligament reconstruction using tendon autograft / 中华创伤杂志

Objective:To compare the efficacy of arthroscopic anterior cruciate ligament reconstruction using tendon autograft with figure-of-four position and traditional knee hyperflexed position for femoral tunnel creation.Methods:A retrospective case series study was conducted to analyze the clinical data of 46 patients with ACL injury admitted to Second Affiliated Hospital of Harbin Medical University from August 2019 to October 2019, including 26 males and 20 females; aged 24-40 years [(31.1±7.5)years]. All patients underwent arthroscopic ACL reconstruction using tendon autograft. The femoral tunnel was created with figure-of-four position in 21 patients (figure-of-four position group) and with traditional knee hyperflexed position in 25 patients (knee hyperflexed position group). The operation time was compared between the two groups. The center position, length and angle of femoral tunnel were evaluated and measured by three dimensional CT reconstruction and Bernard quadrant method at 8 weeks postoperatively. The knee function was assessed by knee Lysholm score preoperatively, at 8 weeks and at 1 year postoperatively. Complications were observed as well.Results:All patients were followed up for 2-20 months [(15.3±2.1)months]. The operation time was (28.5±2.6)minutes in figure-of-four position group, significantly less than (39.5±2.4)minutes in knee hyperflexed position group ( P<0.05). The tunnel center position was located at (27.1±1.4)% and (25.1±2.6)% within the Bernard quadrant in figure-of-four position group, similar with (28.1±2.8)% and (26.1±3.1)% in knee hyperflexed position group (all P>0.05). Total tunnel length and thick tunnel length were (42.1±2.4)mm and (34.1±2.4)mm in figure-of-four position group, significantly longer than (38.2±2.5)mm and (31.1±2.7)mm in knee hyperflexed position group (all P<0.05). The coronal plane angle of the tunnel was (41.1±2.4)° in figure-of-four position group, significantly smaller than (47.5±2.6)° in knee hyperflexed position group ( P<0.05). The sagittal plane angle of the tunnel was (42.1±1.4)° in figure-of-four position group, significantly greater than (37.1±1.8)° in knee hyperflexed position group ( P<0.05). Figure-of-four position group showed the knee Lysholm score of (53.4±5.2)points preoperatively, (97.1±1.4)points at 8 weeks postoperatively and (98.3±2.3)points at 1 year postoperatively. Knee hyperflexed position group showed the knee Lysholm score of (54.3±7.4)points preoperatively, (97.1±1.6)points at 8 weeks postoperatively and (98.1±1.3)points at 1 year postoperatively. The knee Lysholm score did not differ significantly between the two groups (all P>0.05), but the knee function was significantly improved in both groups when compared with that before the operation (all P<0.05). There were 1 patient with femoral tunnel fracture, one with injury to the medial condylar cartilage and one with injury to the posterior root of lateral meniscus in knee hyperflexed position group, while no above-mentioned complications occurred in figure-of-four position group ( P<0.05). Conclusion:Arthroscopic ACL reconstruction using tendon autograft with femoral tunnel creation through figure-of-four position and traditional knee hyperflexed position can both contribute knee functional recovery, but the figure-of-four position has the advantages of short operation time, accurate tunnel positioning, favorable length and angle of the tunnel and less complications.

Glycoproteins as diagnostic and prognostic biomarkers for neurodegenerative diseases: A glycoproteomic approach.

Neurodegenerative diseases (NDs) are incurable and can develop progressively debilitating disorders, including dementia and ataxias. Alzheimer's disease and Parkinson's disease are the most common NDs that mainly affect the elderly people. There is an urgent need to develop new diagnostic tools so that patients can be accurately stratified at an early stage. As a common post-translational modification, protein glycosylation plays a key role in physiological and pathological processes. The abnormal changes in glycosylation are associated with the altered biological pathways in NDs. The pathogenesis-related proteins, like amyloid-ß and microtubule-associated protein tau, have altered glycosylation. Importantly, specific glycosylation changes in cerebrospinal fluid, blood and urine are valuable for revealing neurodegeneration in the early stages. This review describes the emerging biomarkers based on glycoproteomics in NDs, highlighting the potential applications of glycoprotein biomarkers in the early detection of diseases, monitoring of the disease progression, and measurement of the therapeutic responses. The mass spectrometry-based strategies for characterizing glycoprotein biomarkers are also introduced.

Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases.

The sigma-1 (σ1) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ1 receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ1 receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ1 receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ1 selective orthosteric ligands or allosteric modulators.

Two-dimensional CaFCl: ultra-wide bandgap, strong interlayer quantum confinement, and n-type doping.

Two-dimensional (2D) ultra-wide bandgap (UWBG) semiconductors have attracted tremendous attention because of their unique electronic properties and promising applications. Using first-principles calculations, monolayer (bilayer) CaFCl has a cleavage energy of 0.93 J m-2 (0.72 J m-2), suggesting that the exfoliation of monolayer and few-layer materials from the bulk phase could be feasible. The CaFCl monolayer is an UWBG semiconductor with a direct bandgap of 6.62 eV. In addition to the dynamic and thermodynamic stability, it can remain thermally stable at 2200 K, suitable for operation in high-temperature environments. The bandgap of monolayer CaFCl can be tuned by external strain and layer thickness. The decrease of the layer thickness leads to not only a bandgap increase but also an indirect-to-direct bandgap transition, suggesting a strong interlayer quantum confinement effect. Under biaxial strain, the direct bandgap can also be turned into an indirect one. The adsorption of a tetrathiafulvalene (TTF) molecule introduces deep donor states in the gap of CaFCl. Under an external electric field with direction from CaFCl to TTF, the TTF-derived donor states move closer to the conduction band edge of CaFCl and then the adsorption complex becomes effectively n-doped. Furthermore, monolayer CaFCl exhibits pronounced optical absorption in the ultraviolet range of the solar spectrum. These results render CaFCl an attractive 2D material for applications in flexible nanoelectronic and optoelectronic devices.

Mechanical activation to enhance the natural floatability of waste printed circuit boards.

The metal in the waste printed circuit boards (WPCBs) is an excellent secondary metal resource. WPCBs were ground to dissociate, and impurities in the dissociated product were removed by gradient flotation to recover valuable metals in this study. The effects of crushing methods on size composition and dissociation state of the crushed products were studied. Then the gradient flotation experiment was designed to verify the natural floatability of ground materials. Grinding test shows that impact crushing has greater grinding fineness (-0.074 mm) than shear crushing, which is 42.14% and 26.18% respectively with 5 min grinding. The flotation test results illustrate that the natural floatability of impurities increases with the grinding fineness, that is, the yield of floats increases without flotation reagents. For impact crushing and shear crushing, the floats yields are 38.48% and 31.75% respectively, accompanied by 70.53% and 65.46% impurity removal for ground materials with 5 min grinding. Subsequently, 21.61% and 26.35% of impurities can be further removed with the aid of collector. Finally, the recovery of Cu in concentrate reaches 67.84% and 65.75%, respectively. FT-IR proves that the excellent floatability of particles is caused by the significant hydrophobic group. Mechanical grinding has been proved to have double effects of improving dissociation and natural floatability.

Development and characterization of an inducible Dicer conditional knockout mouse model of Parkinson's disease: validation of the antiparkinsonian effects of a sigma-1 receptor agonist and dihydromyricetin.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by motor impairment and progressive loss of dopamine (DA) neurons. At present, the acute application of neurotoxic drugs such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are commonly used to simulate the pathology of PD; however, it is difficult to induce the progressive pathogenesis of PD with these models. In this study, we employed DAT promoter-mediated Cre transgenic mice to establish tamoxifen-inducible Dicer conditional knockout (cKO) mice in an effort to mimic the progressive loss of DA neurons and the development of PD-like behavioral phenotypes. The results showed that Dicer cKO mice exhibited progressive loss of DA neurons in the substantia nigra (SN) following tamoxifen administration. Significant DA loss was observed 6 weeks after tamoxifen administration; accordingly, progressive motor function impairment was also observed. We also found that a significant neuroinflammatory response, as evidenced by microglial proliferation, another hallmark of PD pathogenesis, accompanied the loss of DA neurons. The acute application of levo-DOPA (L-DOPA) relieved the PD-like motor impairments in Dicer cKO mice to exert its antiparkinsonian action, indicating that the model can be used to evaluate the antiparkinsonian efficacy of PD drugs. To further elucidate the potential application of this novel PD animal model for PD drug development, we employed the powerful neuroprotective agent dihydromyricetin (DHM) (10 mg/kg) and the selective sigma-1 receptor agonist PRE-084 (1 mg/kg), both of which were previously shown to produce antiparkinsonian effects. The results indicated that the chronic administration of either DHM or PRE-084 attenuated the Dicer cKO-induced loss of DA neurons and motor impairments, although the two drugs acted through different mechanisms. These data indicate that the Dicer cKO mouse model may be a useful model for investigating the pathological development of PD and intervention-mediated changes. In conclusion, this transgenic mouse model appears to simulate the progressive pathogenesis of PD and may be a potentially useful model for PD drug discovery.

Key roles of Rho GTPases, YAP, and Mutant P53 in anti-neoplastic effects of statins.

Emerging epidemiological and preclinical studies have focused on statins and mevalonate pathway to identify potential therapeutic target and clarify the underlying mechanism of the anti-neoplastic effects. Reductions of mevalonate or isoprenoids, caused by statins, would further decrease the isoprenylation of Rho GTPases which is the crucial step for Rho GTPases to anchor on inner cellular membrane. Following anchoring, activated Rho GTPases can mediate a series of cellular activities such as cytoskeleton reprogramming, front-rear polarity, and cell-ECM adhesion. These changes not only facilitate tumor cell detachment and migration but also bring great mechanical changes to directly activate YAP, the major nuclear mechanotransducer, to translocate into nucleus. Recently, statins have been identified as potent inhibitors of YAP. Once entering nucleus, YAP would combine TEADs to promote the transcription of about 100 genes, which are involved in cell proliferation, cell cycle regulation, stemness, invasion, and metastasis. Besides, statins are able to promote the degradation of misfolded mutant p53 (mutp53), which is an oncogene in a variety of human malignancies. Reduction in mevalonate-5-phosphate (MVP), also induced by statins, would impair the stability of DNAJA1-mutp53 complex; then, elevated C terminus of Hsc70-interacting protein (CHIP) mediates the nuclear export and degradation of misfolded mutp53 through ubiquitin-proteasome pathway. It is worth noted that YAP, mutp53, and mevalonate pathway form two positive feedback loops. It is reasonable to believe that Rho GTPases, YAP, and mutp53 are determinants for statins as anti-cancer agents: tumor cells harboring mutp53 and nuclear-located YAP would be more sensitive to statins.