The role of Aspergillus nidulans polo-like kinase PlkA in microtubule-organizing center control.

Centrosomes are important microtubule-organizing centers (MTOC) in animal cells. In addition, non-centrosomal MTOCs (ncMTOCs) have been described in many cell types. The functional analogs of centrosomes in fungi are the spindle pole bodies (SPBs). In Aspergillus nidulans, additional MTOCs have been discovered at septa (sMTOC). Although the core components are conserved in both MTOCs, their composition and organization are different and dynamic. Here, we show that the polo-like kinase PlkA binds the γ-tubulin ring complex (γ-TuRC) receptor protein ApsB and contributes to targeting ApsB to both MTOCs. PlkA coordinates the activities of the SPB outer plaque and the sMTOC. PlkA kinase activity was required for astral MT formation involving ApsB recruitment. PlkA also interacted with the γ-TuRC inner plaque receptor protein PcpA. Mitosis was delayed without PlkA, and the PlkA protein was required for proper mitotic spindle morphology, although this function was independent of its catalytic activity. Our results suggest that the polo-like kinase is a regulator of MTOC activities and acts as a scaffolding unit through interaction with γ-TuRC receptors.

Triglyceride-glucose index, symptomatic intracranial artery stenosis and recurrence risk in minor stroke patients with hypertension.

BACKGROUND: The triglyceride-glucose (TyG) index, a simple measure of insulin resistance, is associated with intracranial atherosclerosis (ICAS) and stroke. In hypertensive populations, this association may be pronounced. The aim was to investigate the relationship between TyG and symptomatic intracranial atherosclerosis (sICAS) and recurrence risk in ischemic stroke patients with hypertension. METHODS: This prospective, multicenter cohort study included patients with acute minor ischemic stroke with a preadmission diagnosis of hypertension from September 2019 to November 2021 with a 3-month follow-up. The presence of sICAS was determined by a combination of clinical manifestations, the location of the infarction, and the corresponding artery with moderate-to-severe stenosis. ICAS burden was determined by the degree and number of ICAS occurrences. Fasting blood glucose (FBG) and triglyceride (TG) were measured to calculate TyG. The main outcome was ischemic stroke recurrence during the 90-day follow-up. Multivariate regression models were used to explore the association of TyG, sICAS, and ICAS burden with stroke recurrence. RESULTS: There were 1281 patients with a mean age of 61.6 ± 11.6 years; 70.1% were male, and 26.4% were diagnosed with sICAS. There were 117 patients who experienced stroke recurrence during follow-up. Patients were categorized according to quartiles of TyG. After adjusting for confounders, the risk of sICAS was greater (OR 1.59, 95% CI 1.04-2.43, p = 0.033) and the risk of stroke recurrence was significantly higher (HR 2.02, 95% CI 1.07-3.84, p = 0.025) in the fourth TyG quartile than in the first quartile. The restricted cubic spline (RCS) plot revealed a linear relationship between TyG and sICAS, and the threshold value for TyG was 8.4. Patients were then dichotomized into low and high TyG groups by the threshold. Patients with high TyG combined with sICAS had a higher risk of recurrence (HR 2.54, 95% CI 1.39-4.65) than patients with low TyG without sICAS. An interaction effect on stroke recurrence between TyG and sICAS was found (p = 0.043). CONCLUSION: TyG is a significant risk factor for sICAS in hypertensive patients, and there is a synergistic effect of sICAS and higher TyG on ischemic stroke recurrence. TRIAL REGISTRATION NUMBER: The study was registered on 16 August 2019 at https://www.chictr.org.cn/showprojen.aspx?proj=41160 (No. ChiCTR1900025214).

Dual Versus Mono Antiplatelet Therapy in Patients with Acute Mild-to-Moderate Stroke: A Multicentre Perspective Cohort Study.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the association between different antiplatelet therapy regimens and the functional outcomes and bleeding complications among mild-to-moderate ischaemic stroke patients based on real-world data. METHODS: We used data from the SEACOAST trial (Safety and efficacy of aspirin-clopidogrel in acute noncardiogenic minor ischaemic stroke) to analyse the data of patients with mild-to-moderate stroke within 72 h after onset who were treated with aspirin or clopidogrel alone or a combination of clopidogrel and aspirin from September 2019 to November 2021. Propensity score matching (PSM) was used to balance the differences between groups. We performed an analysis to evaluate the association of different antiplatelet regimens and 90-day disability, which was defined as a modified Rankin Scale score ≥2, as well as disability ascribed to index or recurrent stroke by the local investigator. In terms of safety, we then compared the bleeding events between the two groups. RESULTS: A total of 2822 mild-to-moderate ischaemic stroke patients were treated with either clopidogrel plus aspirin (n = 1726, 61.2%) or aspirin/clopidogrel (n = 1096, 38.8%). Of 1726 patients in the dual antiplatelet group, 1350 (78.5%) received less than or equal to 30 days of combined therapy. At 90 days, 433 (15.3%) patients were disabled. Patients who received combined therapy had a lower overall disability rate (13.7% versus 17.9%; OR 0.78 (0.6-1.01); P = 0.064). However, investigators found that index stroke was the reason for significantly fewer patients in the dual antiplatelet group having disability (8.4% versus 12%; OR, 0.72 (0.52-0.98); P = 0.038). There was no statistically significant difference in the incidence of moderate to severe bleeding complications between the dual and mono antiplatelet drug regimens (0.4% versus 0.2%; HR 1.5 (0.25, 8.98); P = 0.657). CONCLUSION: Aspirin plus clopidogrel was associated with a reduction in the incidence of disability attributed to index stroke. There was no statistically significant difference in the incidence of moderate to severe bleeding complications between the two antiplatelet drug regimens. TRIAL REGISTRATION NUMBER: ChiCTR1900025214.

LncRNA Opa interacting protein 5-antisense RNA 1 (OIP5-AS1) promotes the migration, invasion and epithelial-mesenchymal transition (EMT) through targeting miR-147a/insulin-like growth factor 1 receptor (IGF1R) pathway in cervical cancer tissues and cell model.

BACKGROUND: Two factors involved in regulation, long noncoding RNA Opa interacting protein 5-antisense RNA 1 (lncRNA OIP5-AS1) and microRNA-147a, were found in cervical cancer. Therefore, the investigation of the specific regulation of miR-147a by OIP5-AS1 was performed in cervical cancer. METHOD: The cervical cancer tissues were collected from patients with cervical cancer (n = 50). The expression of OIP5-AS1, miR-147a, proteins in epithelial-mesenchymal transition (EMT) process and insulin-like growth factor 1 receptor (IGF1R) were measured by quantitative real-time polymerase chain reaction (qRT-PCT) or western blotting. Cell motility and the relationship between OIP5-AS1 and miR-147a were detected or analyzed by wound healing test, Transwell assay, dual-luciferase reporter assay, RNA binding protein immunoprecipitation assay or Pearson correlation in OIP5-AS1, or miR-147a over-expressed and/or suppressed cervical cancer cells. RESULTS: OIP5-AS1 showed the high-expression and miR-147a showed the low-expression in tumor tissues collected from patients with cervical cancer and cell lines Hela, CaSki, Siha, and ME-180. The low-expression of OIP5-AS1 suppressed the motility of Caski cells, as well as up-regulated the level of E-cadherin, which a key protein in EMT. There were targeting sites between miR-147a and OIP5-AS1. OIP5-AS1 induced the down-regulation of miR-147a, so miR-147a was inversely correlated with OIP5-AS1. The down-regulation of miR-147a increased IGF1R and E-cadherin, and these increases were alleviated by OIP5-AS1 knockdown. CONCLUSION: LncRNA OIP5-AS1 promotes the migration, invasion and EMT of cervical cancer cells via targeting miR-147a/IGF1R pathway.

Quantitative analysis of facial symmetry by using three-dimensional technology.

BACKGROUND: Facial symmetry is becoming increasingly important in today's orthodontic treatment. But the asymmetrical boundary is not clearly demarcated. Stereophotogrammetry has a clear advantage in measuring facial asymmetry. The aim of this study was to quantify the facial asymmetry by three-dimensional (3D) technology as well as to study whether the evaluation by non-experts about facial asymmetry was consistent with the analysis by 3D technology. METHODS: The facial symmetry of 330 patients was evaluated by 10 non-experts. 3D facial images were taken using 3dMD stereophotogrammetry equipment. The original face and its mirror shell were divided into 7 regions and the surface matching was measured in the whole face and all regional areas. The degree of symmetry was calculated by the software 3-matic STL 9.0. The difference between the two groups was analyzed by Independent-Samples T Test and the diagnostic efficiency of symmetry degree was analyzed by ROC curve analysis. The consistency between the symmetric degree and the result of evaluation was analyzed by Pearson correlation analysis. RESULTS: The ROC analysis revealed significant diagnostic values in the determination of the facial asymmetry of lip, chin, cheek and lateral mandible areas. The cut-off values of symmetry degree were between 60 and 80%. The evaluation was middle correlation with the symmetric degree of the whole face. CONCLUSIONS: The chin and lateral mandible contribute most significantly to the facial symmetry. The objective measurement of facial symmetry, 3D technology, is reliable.

The spindle pole body of Aspergillus nidulans is asymmetrical and contains changing numbers of γ-tubulin complexes.

Centrosomes are important microtubule-organizing centers (MTOCs) in animal cells. In addition, non-centrosomal MTOCs (ncMTOCs) are found in many cell types. Their composition and structure are only poorly understood. Here, we analyzed nuclear MTOCs (spindle-pole bodies, SPBs) and septal MTOCs in Aspergillus nidulans They both contain γ-tubulin along with members of the family of γ-tubulin complex proteins (GCPs). Our data suggest that SPBs consist of γ-tubulin small complexes (γ-TuSCs) at the outer plaque, and larger γ-tubulin ring complexes (γ-TuRC) at the inner plaque. We show that the MztA protein, an ortholog of the human MOZART protein (also known as MZT1), interacted with the inner plaque receptor PcpA (the homolog of fission yeast Pcp1) at SPBs, while no interaction nor colocalization was detected between MztA and the outer plaque receptor ApsB (fission yeast Mto1). Septal MTOCs consist of γ-TuRCs including MztA but are anchored through AspB and Spa18 (fission yeast Mto2). MztA is not essential for viability, although abnormal spindles were observed frequently in cells lacking MztA. Quantitative PALM imaging revealed unexpected dynamics of the protein composition of SPBs, with changing numbers of γ-tubulin complexes over time during interphase and constant numbers during mitosis.This article has an associated First Person interview with the first author of the paper.

Potent, non-covalent reversible BTK inhibitors with 8-amino-imidazo[1,5-a]pyrazine core featuring 3-position bicyclic ring substitutes.

Bruton's tyrosine kinase (BTK) is a Tec family kinase with a well-defined role in the B cell receptor (BCR) pathway. It has become an attractive kinase target for selective B cell inhibition, and for the treatment of B cell related diseases. Many BTK inhibitors have been discovered for the treatment of cancer and rheumatoid arthritis, including a series of BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine we recently reported. The X-ray crystal structures of BTK with inhibitors were also published, which provided great help for the SAR design. Here we report our SAR work introducing ring constraints for the 3-position piperidine amides on the BTK inhibitors based on 8-amino-imidazo[1,5-a]pyrazine. This modification improved the potency in BTK inhibitions, as well as the PK profile and the off-target selectivity. The dose-dependent efficacy of two BTK inhibitors was observed in the rat collagen induced arthritis (CIA) model.

Macrophage migration inhibitory factor promotes the invasion and metastasis of oral squamous cell carcinoma through matrix metalloprotein-2/9.

Macrophage migration inhibitory factor (MIF) has been shown to closely associate with the malignant progression of a variety of human carcinomas. However, the role and its underlying molecular mechanisms of MIF in the invasion and metastasis of oral squamous cell carcinoma (OSCC) still remains unclear. Here, we found that MIF silencing reduced the cell proliferation, migration, and invasion, as well as matrix metalloprotein-2 (MMP-2) and MMP-9 in OSCC cells. Overexpression of MMP-2 or MMP-9 restored the migration and invasion of MIF-knockdown cells, indicating that MMP-2 and MMP-9 are downstream targets of MIF. In the xenograft model, MIF silencing inhibited tumor growth and in lymph metastasis model, MIF silencing reduced tumor metastasis. More importantly, immunohistochemistry staining in a tissue microarray (TMA) demonstrated that MIF expression was positively correlated with clinic stage, recurrence, metastasis, and poor prognosis of patients with OSCC as well as with the levels of MMP-2 or MMP-9 in TMA. Therefore, our findings suggest that MIF may promote the invasion and metastasis of OSCC through the activation of MMP-2 and MMP-9 and prompt further investigation into the therapeutic value of MIF for OSCC treatment.

NR2F1 contributes to cancer cell dormancy, invasion and metastasis of salivary adenoid cystic carcinoma by activating CXCL12/CXCR4 pathway.

BACKGROUND: Salivary adenoid cystic carcinoma (SACC) can recur after removal of the primary tumor and treatment, where they can keep no clinical symptoms and dormant state for 10-15 years. NR2F1 has been demonstrated to regulate the tumor cell dormancy in various malignant tumors and has a potential impact on recurrence and metastasis of carcinoma. However, the role and significance of NR2F1 in SACC dormancy still remain unknown. METHODS: A total number of 59 patients with a diagnosis of SACC were included to detected expression of NR2F1, Ki-67 by immunohistochemical (IHC) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick and labeling (TUNEL). Fisher's exact test was used to examine the NR2F1 expression and clinicopathologic parameters of SACC. In vitro, SACC cell lines were transfected NR2F1 and knockdown NR2F1 respectively. CCK-8, flow cytometry, wound healing assay and transwell invasion determined SACC cell proliferation, apoptosis, cell cycle, migration and invasion respectively. Chromatin immunoprecipitation (ChIP) assays were utilized to demonstrate the potential role of NR2F1 in SACC invasion via CXCL12/CXCR4 axis. In vivo, xenografts of nude mice via subcutaneous injection or tail vein injection were used to testify the results in vitro. RESULTS: Among the 59 patients with SACC, 23.73% (14/59) were positive to NR2F1 expression, a lower rate of expression compared with 60% (6/10) in normal salivary gland samples. NR2F1 was correlated with metastasis, relapse and dormancy of SACC. SACC cells with transfected NR2F1 remained dormant, as well as enhanced invasion and metastasis. Knockdown of NR2F1 via siRNA after NR2F1 overexpression restored the proliferation and the cell number in G2/M phases, and reduced the abilities of migration and invasion. In addition, NR2F1 promoted the expression of CXCL12 and CXCR4, and overexpression of CXCL12 at least partly rescued the proliferation, migration, and invasion activities induced by NR2F1 silencing. CONCLUSIONS: NR2F1 may be an underlying mechanism of SACC recurrence and metastasis via regulating tumor cell dormancy through CXCL12/CXCR4 pathway.

HSP27 associates with epithelial-mesenchymal transition, stemness and radioresistance of salivary adenoid cystic carcinoma.

Epithelial-mesenchymal transition (EMT) has been shown to associate with cancer stem cells and radioresistance. However, it is obscure whether EMT itself or specific EMT regulators play causal roles in these properties of salivary adenoid cystic carcinoma (SACC). Here, we exhibited that overexpression of HSP27 drove the migration and invasion, induced EMT, as well as mediated TGF-ß1-induced EMT in SACC cells, accompanying the up-regulation of Snail1 and Prrx1. Conversely, HSP27 silencing reduced the migration and invasion and contributed to MET of SACC cells. HSP27 indirectly down-regulates the expression of E-cadherin through activating Snail1 and Prrx1 expressions. Overexpression of Snail1 or Prrx1 restored the migration and invasion in HSP27 knockdown cells. Enforced expression of HSP27 enhanced colony formation, CD133+ /CD44+ population and radioresistance of SACC cell lines. In addition, HSP27 expression was positively associated with radioresistance and poor prognosis of SACC patients as well as with the expression of Prrx1 or Snail1 in SACC tissues. The data confirm an important function for HSP27 in SACC progression through regulating EMT and stemness, and they imply the possible association between EMT and radioresistance of SACC.

Microtubule-organizing centers of Aspergillus nidulans are anchored at septa by a disordered protein.

Microtubule-organizing centers (MTOCs) are large, multi-subunit protein complexes. Schizosaccharomyces pombe harbors MTOCs at spindle pole bodies, transient MTOCs in the division plane (eMTOCs) and nuclear-envelope associated MTOCs in interphase cells (iMTOCs). In the filamentous fungus Aspergillus nidulans SPBs and septum-associated MTOCs were described. Although comparable to S. pombe eMTOCs, A. nidulans sMTOCS are permanent septum-associated structures. The composition of sMTOCs is poorly understood and how they are targeted to septa was unknown. Here, we show that in A. nidulans several SPB outer plaque proteins also locate to sMTOCs while other SPB proteins do not, including SfiA, a protein required for SPB duplication in Saccharomyces cerevisiae and S. pombe and PcpA, the anchor for γ-TuSCs at the SPB inner plaque. The A. nidulans disordered protein Spa18Mto2 and the centrosomin-domain containing protein ApsBMto1 were required for recruiting the γ-TuRC component GcpC to sMTOCs and for seeding MT formation from septa. Testing different septum-associated proteins for a role in sMTOC function, Spa10 was identified. It forms a septal pore disc structure, recruits Spa18 and ApsB to septa and is required for sMTOC activity. This is the first evidence for a septum-specific protein, Spa10, as anchor for a specific class of MTOCs.

Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology.

Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 µM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 µM h; F% = 70).

Discovery of novel BTK inhibitors with carboxylic acids.

We report the design and synthesis of a series of novel Bruton's Tyrosine Kinase (BTK) inhibitors with a carboxylic acid moiety in the ribose pocket. This series of compounds has demonstrated much improved off-target selectivities including adenosine uptake (AdU) inhibition compared to the piperidine amide series. Optimization of the initial lead compound 4 based on BTK enzyme inhibition, and human peripheral blood mononuclear cell (hPBMC) and human whole blood (hWB) activity led to the discovery of compound 40, with potent BTK inhibition, reduced off target activities, as well as favorable pharmacokinetic profile in both rat and dog.

Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis.

8-Amino-imidazo[1,5-a]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as 6, exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6. This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13, 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.

Social defeat stress induces liver injury by modulating endoplasmic reticulum stress in C57BL/6J mice.

Social defeat stress is associated with endoplasmic reticulum (ER) stress, inflammation and apoptosis. ER stress is thought to contribute to many lifestyle diseases such as liver injury, cardiovascular dysfunction and depression. We investigated the expression of the ER stress markers RNA-dependent protein kinase-like ER kinase (PERK), eukaryotic translation initiation factor 2α (eIF2α) and C/EBP homologous protein (CHOP), as well as inflammatory and apoptotic factors, to assess how social defeat stress induces liver injury. Furthermore, we evaluated the effects of the ER stress inhibitor phenylbutyric acid (PBA) and ER stress inducer thapsigargin (TG) on liver injury. Adult mice were divided into the control, social defeat, social defeat + PBA, TG, PBA and TG + PBA groups. The social defeat and social defeat + PBA groups were simultaneously exposed to social defeat stress for 10 days. The social defeat + PBA, TG, PBA and TG + PBA groups were treated with PBA or TG via intraperitoneal injections. PBA was injected 1 h before the TG injection into the TG + PBA group. Liver samples from six groups of mice were analyzed by histological analysis and western blotting. Social defeat stress promoted ER stress, increased the expression of inflammatory factors and induced apoptosis in the liver of socially defeated mice, which was reversed by PBA. Moreover, ER stress induces TG-induced liver injury by initiating ER stress. Social defeat stress initiates ER stress, promotes the expression of inflammatory and apoptotic factors, and induces liver injury. PBA suppresses liver injury caused by social defeat stress and TG treatment.

Minor stroke patients with mild-moderate diastolic blood pressure derive greater benefit from dual antiplatelet therapy.

Not only systolic blood pressure (SBP) but also diastolic blood pressure (DBP) increases the risk of recurrence in the short- or long-term outcomes of stroke. The interaction between DBP and antiplatelet treatment for China stroke patients is unclear. This multicenter, observational cohort study included 2976 minor ischemic stroke patients. Patients accepted single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) after arrival, and baseline DBP levels were trichotomized into <90 mmHg, 90-110 mmHg and ≥110 mmHg. We explore the interaction effect between antiplatelet therapy and DBP on 90-days composite vascular events. A total of 257 (8.6%) patients reached a composite vascular event during follow-up. The interaction term between DBP levels and treatment group (SAPT vs. DAPT) was significant (P for interaction = 0.013). DAPT's adjusted HR for composite events in patients with DBP between 90 and 110 mmHg was 0.56 (95% confidence interval, 0.36 0.88; P = 0.011) and DBP ≥ 110 mmHg was 4.35 (95% confidence interval, 1.11-19.94; P = 0.046). The association between treatment and DBP was still consistent after propensity score matching of the baseline characteristics. The interaction term of DBP × treatment was not significant for the safety outcomes of severe bleeding (P for interaction = 0.301) or hemorrhage stroke (P for interaction = 0.831). In this cohort study based on the real world, patients with a DBP between 90 and 110 mmHg received a greater benefit from 90 days of DAPT than those with lower and higher baseline DBP. REGISTRATION: ( https://www.chictr.org.cn ; Unique identifier: ChiCTR1900025214).

The Neural Response Process of Cognitive Decision Making: An ERP Study.

Cognitive decision has the basic characteristics of risk avoidance and benefit seeking. To explore the neural response process of cognitive decision making, we asked 32 undergraduates to make a decision on whether to accept a specific treatment option with a certain cure rate and a certain risk rate while recording their electrical brain responses. The results showed that more participants chose the treatment option with a high cure rate and moderate or low risk. Compared with low and high risk, medium risk produced greater N1 and smaller P300. Low risk produced larger LPP than the moderate risk in the left hemisphere. The right prefrontal region appeared to have a smaller LPP for low risk than for high risk. The results suggest that individuals prioritize risk when making cognitive decisions. In addition, in medium-risk conditions, solution integration is more difficult. The effect of benefit size appears at the late stage of cognitive decision making and adjusts the effect of risk. These results support the satisfaction principle of decision making.

The Adjustment of Complexity on Sarcasm Processing in Chinese: Evidence from Reading Time Indicators.

It is controversial whether sarcasm processing should go through literal meaning processing. There is also a lack of eye movement evidence for Chinese sarcasm processing. In this study, we used eye movement experiments to explore the processing differences between sarcastic and literal meaning in Chinese text and whether this was regulated by sentence complexity. We manipulated the variables of complexity and literality. We recorded 33 participants' eye movements when they were reading Chinese text and the results were analyzed by a linear mixed model. We found that, in the early stage of processing, there was no difference between the processing time of the sarcastic meaning and the literal meaning of simple remarks, whereas for complex remarks, the time needed to process the sarcastic meaning was longer than that needed to process the literal meaning. In the later stage of processing, regardless of complexity, the processing time of the sarcastic meaning was longer than that of the literal meaning. These results suggest that sarcastic speech processing in Chinese is influenced by literal meaning, and the effect of literal meaning on sarcastic remarks is regulated by complexity. Sarcastic meaning was expressed differently in different stages of processing. These results support the hierarchical salience hypothesis of the serial modular model.

Effects of syllable boundaries in Tibetan reading.

Interword spaces exist in the texts of many languages that use alphabetic writing systems. In most cases, interword spaces, as a kind of word boundary information, play an important role in the reading process of readers. Tibetan also uses alphabetic writing, its text has no spaces between words as word boundary markers. Instead, there are intersyllable tshegs (" "), which are superscript dots. Interword spaces play an important role in reading as word boundary information. Therefore, it is interesting to investigate the role of tshegs and what effect replacing tshegs with spaces will have on Tibetan reading. To answer these questions, Experiment 1 was conducted in which 72 Tibetan undergraduates read three-syllable-boundary conditions (normal, spaced, and untsheged). However, in Experiment 1, because we performed the experimental operations of deleting tshegs and replacing tshegs, the spatial information distribution of Tibetan sentences under different operating conditions was different, which may have a certain potential impact on the experimental results. To rule out the underlying confounding factor, in Experiment 2, 58 undergraduates read sentences for both untsheged and alternating-color conditions. Overall, the global and local analyses revealed that tshegs, spaces, and alternating-color markers as syllable boundaries can help readers segment syllables in Tibetan reading. In Tibetan reading, both spaces and tshegs are effective visual syllable segmentation cues, and spaces are more effective visual syllable segmentation cues than tshegs.

Association of serum brain-derived neurotrophic factor level and early response to antipsychotic drug in first-episode patients with schizophrenia.

OBJECTIVES: To investigate the role of Brain derived neurotrophic factor (BDNF) in the psychotic symptoms in first-episode patients with schizophrenia and whether BDNF levels were associated with the improvement of psychotic symptoms after risperidone treatment. METHODS: 89 schizophrenia patients and 90 healthy controls were recruited, the schizophrenia patients were assigned into early response or early non-response groups at 2 weeks based on improvement in the positive and negative symptoms scale (PANSS) total score. All patients were treated with risperidone for 2 weeks, their serum BDNF levels were compared at baseline and after 2 weeks treatment. RESULTS: We found that patients had lower BDNF levels, compared to controls at baseline. After 2 weeks of treatment of risperidone, BDNF levels were significantly increased and psychotic symptoms were decreased in early response group. Correlation analysis showed that the change of BDNF levels after treatment was correlated with the change of PANSS total score. Further regression analysis showed that the change in BDNF levels was an independent predictor for the improvement in psychotic symptoms. CONCLUSIONS: Our findings reveal that the level of BDNF was lower in first-episode schizophrenic patients, moreover, the changes in serum BDNF levels may have a predictive effect on the early improvement in psychotic symptoms in the first 2 weeks.