Association between electroencephalogram alpha-band oscillations and executive and processing functions in patients with cerebral small vessel diseases.

Electroencephalogram (EEG) alpha-band oscillations may reflect executive and processing function in patients with cerebral small vessel disease (CSVD). We aimed to assess such association and its relationship with CSVD severity, and to identify specific alpha-band parameters and the cut-off values for cognitive screening. We analysed the dispersion of amplitude-frequency characteristics of EEG alpha-band and different alpha-band parameters (PFα , ΔPFα , PPα , NCL) in different brain locations. We also assessed patients' executive and processing functions using verbal fluency test (VFT) and color trails test (CTT), and CSVD severity using total burden and Fazekas scores. 129 patients were recruited in the study. After adjusting for age, gender and education, PFα(F3), PFα(F4) and NCL were significantly associated with VFT-composite performance (p < 0.05). CTT-1 time and error were associated with PFα(F3), PFα(F4), ΔPFα(O1;F3) and CSVD severity (p < 0.05), whereas CTT-2 time was only associated with CSVD severity. Moreover, the correlations between alpha-band oscillations and cognitive function were higher in low than in high disease-severity group (ρ: -0.58 vs. -0.38, p < 0.05). The AUC of selected alpha-band parameters were higher than 0.8 for VFT and CTT. Specific alpha-band parameters in the frontal lobe were identified to correspond to executive and processing function. Assessing EEG alpha-band oscillations may assist in screening cognitive impairment.

A selective Fibroblast Growth Factor Receptor 1/2 PROTAC degrader with antitumor activity.

The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

Investigation into the Enhancement of Gas-Liquid Mass Transfer of Absorption of H2S by MDEA with Carbon Quantum Dots.

Although the addition of fine particles can enhance mass transfer, the stability of suspension is still a challenge. Responding to this, this study introduced carbon quantum dots (CQDs) with good hydrophilicity into a desulfurizer. N-doped carbon quantum dots (N-CQDs) were prepared by the hydrothermal method and characterized by TEM, FT-IR, and XPS. The stability and rheological properties of MDEA-based CQD solutions with different concentrations were studied. CQD solutions with low concentrations showed good stability, and the viscosity of CQD solutions was positively correlated with concentration and inversely correlated with temperature. The desulfurization experiment showed that the desulfurization effect and mass transfer enhancement of MDEA-based CQD solutions were coinfluenced by the viscosity and concentration of the solution; 0.01 vol % CQD solution had the best desulfurization effect, and the mass transfer coefficient was 0.66 mol/(m3h kPa), which increased by 26.61% compared to the base solution.

Prevalence and Risk Factors of Cerebral Small Vessel Disease from a Population-Based Cohort in China.

INTRODUCTION: Cerebral small vessel disease (CSVD) is a significant burden of morbidity and mortality among elderly people around the world. Epidemiological data with complete CSVD evaluations and a large sample size in the general population are still limited. METHODS: Community-dwelling residents in Lishui city in China from the cross-sectional survey of the Polyvascular Evaluation for Cognitive Impairment and Vascular Events (PRECISE) study were included in this study from 2017 to 2019. All participants underwent 3 Tesla brain magnetic resonance images to assess CSVD imaging markers. Demographic and risk factor data were collected. The general and age-specific prevalence of lacune, confluent white matter hyperintensity (WMH), moderate-severe enlarged perivascular spaces (EPVS), cerebral microbleed (CMB), and total CSVD score (an ordinal scale from 0 to 4, counting the presence of four imaging markers of CSVD) was evaluated. Associations between vascular risk factors and these markers were analyzed by multivariable logistic regression. RESULTS: A total of 3,063 participants were enrolled. The mean age was 61.2 years and 46.5% were men. The most prevalent CSVD marker was confluent WMH (16.7%), followed by CMB (10.2%), moderate-severe EPVS in the basal ganglia (BG-EPVS) (9.8%), and lacune (5.6%). 30.5% of the participants have at least one of the four markers (total CSVD score ≥1 points). The prevalence of CSVD markers increases as age increases. Age and hypertension were independent risk factors for four CSVD markers and the total CSVD score. CONCLUSIONS: In this Chinese cohort with community-based adults aged 50-75 years, our findings showed a prevalence of 30.5% for CSVD. The most prevalent CSVD marker was confluent WMH, followed by CMB, moderate-severe BG-EPVS, and lacune. The risk factors for CSVD must be strictly screened and controlled in adults living in the community.

Discovery and Structure-Based Design of Inhibitors of the WD Repeat-Containing Protein 5 (WDR5)-MYC Interaction.

WDR5 is a critical chromatin cofactor of MYC. WDR5 interacts with MYC through the WBM pocket and is hypothesized to anchor MYC to chromatin through its WIN site. Blocking the interaction of WDR5 and MYC impairs the recruitment of MYC to its target genes and disrupts the oncogenic function of MYC in cancer development, thus providing a promising strategy for the treatment of MYC-dysregulated cancers. Here, we describe the discovery of novel WDR5 WBM pocket antagonists containing a 1-phenyl dihydropyridazinone 3-carboxamide core that was identified from high-throughput screening and subsequent structure-based design. The leading compounds showed sub-micromolar inhibition in the biochemical assay. Among them, compound 12 can disrupt WDR5-MYC interaction in cells and reduce MYC target gene expression. Our work provides useful probes to study WDR5-MYC interaction and its function in cancers, which can also be used as the starting point for further optimization toward drug-like small molecules.

Correction: Tian et al. The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease. Biomolecules 2022, 12, 748.

In the published publication [...].

Associations between Autonomic Function and Cognitive Performance among Patients with Cerebral Small Vessel Disease.

Data linking heart rate variability (HRV) and cognitive status remains controversial and scarce, particularly in cerebral small vessel disease (CSVD) patients. Whether the association between HRV and cognitive performance exists in CSVD patients is unclear. Hence, we aimed to investigate the association between HRV and cognitive performance in patients with CSVD. This cross-sectional study was conducted among 117 CSVD patients. All patients underwent HRV assessment and global cognitive evaluation by the Mini-Mental-State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Multivariable analyses were performed to evaluate the association between HRV and cognitive status. The mean age of study population was 59.5 ± 11.8 years and 39.3% were female. After adjusting for confounding factors, a higher high frequency (HF) norm was independently associated with better MMSE scores (ß = 0.051; 95% confidence interval (CI): 0.012~0.090; p = 0.011) and MoCA scores (ß = 0.061; 95% CI: 0.017~0.105; p = 0.007), while a higher low frequency (LF)/HF ratio was independently associated with worse MMSE scores (ß = -0.492; 95% CI: -0.893~-0.092; p = 0.017) and MoCA scores (ß = -0.691; 95% CI: -1.134~-0.248; p = 0.003). The HF norm was positively associated with global cognitive performance, whereas the LF/HF ratio was negatively associated with global cognitive performance among CSVD patients. Further study of the relationship between autonomic function and cognitive performance is warranted.

Discovery of Potent Small-Molecule Inhibitors of WDR5-MYC Interaction.

WD repeat domain 5 (WDR5) is a member of the WD40-repeat protein family that plays a critical role in multiple processes. It is also a prominent target for pharmacological inhibition in diseases such as cancer, aging, and neurodegenerative disorders. Interactions between WDR5 and various partners are essential for sustaining its function. Most drug discovery efforts center on the WIN (WDR5 interaction motif) site of WDR5 that is responsible for the recruitment of WDR5 to chromatin. Here, we describe the discovery of novel WDR5 inhibitors for the other WBM (WDR5 binding motif) pocket on this scaffold protein, to disrupt WDR5 interaction with its binding partner MYC by high-throughput biochemical screening, subsequent molecule optimization, and biological assessment. These new WDR5 inhibitors provide useful probes for future investigations of WDR5 and an avenue for targeting WDR5 as a therapeutic strategy.

Comparative analysis of left atrial appendage closure efficacy and outcomes by CHA2DS2-VASc score group in patients with non-valvular atrial fibrillation.

Background: Higher CHA2DS2-VASc score is associated with an increased risk of adverse cardio-cerebrovascular events in patients with non-valvular atrial fibrillation (NVAF), regardless of oral anticoagulation (OAC) status. However, whether this association still exists in patients undergoing left atrial appendage closure (LAAC) is unknown. We evaluated the impact of CHA2DS2-VASc score on LAAC efficacy and outcomes. Methods: A total of 401 consecutive patients undergoing LAAC were included and divided into 3 groups based on CHA2DS2-VASc score (0-2, 3-4, and ≥5). Baseline characteristics, periprocedural complications, and long-term outcomes were collected and compared across all groups. Results: There were no significant differences in implantation success, periprocedural complications, and long-term outcomes across all score groups. Kaplan-Meier estimation showed that the cumulative ratio of freedom from all-cause mortality (P = 0.146), cardiovascular mortality (P = 0.519), and non-cardiovascular mortality (P = 0.168) did not differ significantly by CHA2DS2-VASc score group. LAAC decreased the risks of thromboembolism and major bleeding, resulting in a relative risk reduction (RRR) of 82.4% (P < 0.001) and 66.7% (P < 0.001) compared with expected risks in the overall cohort, respectively. Subgroup analysis indicated that observed risks of thromboembolism and major bleeding were significantly lower than the expected risks in score 3-4 and score ≥5 groups, respectively. The level of RRR increased with CHA2DS2-VASc score (P < 0.001 for trend) for thromboembolism but not for major bleeding (P = 0.2729 for trend). Conclusion: Patients with higher CHA2DS2-VASc score did not experience worse outcomes, which may be partly attributed to more benefits provided by LAAC intervention in such patients compared to those with a low score.

The Underlying Role of the Glymphatic System and Meningeal Lymphatic Vessels in Cerebral Small Vessel Disease.

There is a growing prevalence of vascular cognitive impairment (VCI) worldwide, and most research has suggested that cerebral small vessel disease (CSVD) is the main contributor to VCI. Several potential physiopathologic mechanisms have been proven to be involved in the process of CSVD, such as blood-brain barrier damage, small vessels stiffening, venous collagenosis, cerebral blood flow reduction, white matter rarefaction, chronic ischaemia, neuroinflammation, myelin damage, and subsequent neurodegeneration. However, there still is a limited overall understanding of the sequence and the relative importance of these mechanisms. The glymphatic system (GS) and meningeal lymphatic vessels (mLVs) are the analogs of the lymphatic system in the central nervous system (CNS). As such, these systems play critical roles in regulating cerebrospinal fluid (CSF) and interstitial fluid (ISF) transport, waste clearance, and, potentially, neuroinflammation. Accumulating evidence has suggested that the glymphatic and meningeal lymphatic vessels played vital roles in animal models of CSVD and patients with CSVD. Given the complexity of CSVD, it was significant to understand the underlying interaction between glymphatic and meningeal lymphatic transport with CSVD. Here, we provide a novel framework based on new advances in main four aspects, including vascular risk factors, potential mechanisms, clinical subtypes, and cognition, which aims to explain how the glymphatic system and meningeal lymphatic vessels contribute to the progression of CSVD and proposes a comprehensive insight into the novel therapeutic strategy of CSVD.

Epidemiological investigation of swine Japanese encephalitis virus based on RT-RAA detection method.

JEV is one of the zoonotic pathogens that cause serious diseases in humans. JEV infection can cause abortion, mummified foetus and stillbirth in sows, orchitis and semen quality decline in boars, causing huge economic losses to pig industry. In order to investigate the epidemiology of JEV in pigs in Sichuan province, a rapid and efficient fluorescent Reverse transcription recombinase-aided amplification (RT-RAA) detection method was established. Aborted fetuses and testicular swollen boar samples were detected by RT-RAA in pigs in the mountain areas around Sichuan Basin, and the detection rate of JEV was 6.49%. The positive samples were identified as JEV GI strain and GIIIstrain by sequencing analysis. We analyzed the whole gene sequence of a positive sample for the GI virus. The Envelope Protein (E protein) phylogenetic tree analysis was far related to the Chinese vaccine strain SA14-14-2, and was most closely related to the JEV GI strains SH17M-07 and SD0810 isolated from China. The results showed that we established an efficient, accurate and sensitive method for clinical detection of JEV, and JEV GI strains were prevalent in Sichuan area. It provides reference for the prevention and control of JEV in Sichuan.

Discovery of the Clinical Candidate MAK683: An EED-Directed, Allosteric, and Selective PRC2 Inhibitor for the Treatment of Advanced Malignancies.

Polycomb Repressive Complex 2 (PRC2) plays an important role in transcriptional regulation during animal development and in cell differentiation, and alteration of PRC2 activity has been associated with cancer. On a molecular level, PRC2 catalyzes methylation of histone H3 lysine 27 (H3K27), resulting in mono-, di-, or trimethylated forms of H3K27, of which the trimethylated form H3K27me3 leads to transcriptional repression of polycomb target genes. Previously, we have shown that binding of the low-molecular-weight compound EED226 to the H3K27me3 binding pocket of the regulatory subunit EED can effectively inhibit PRC2 activity in cells and reduce tumor growth in mouse xenograft models. Here, we report the stepwise optimization of the tool compound EED226 toward the potent and selective EED inhibitor MAK683 (compound 22) and its subsequent preclinical characterization. Based on a balanced PK/PD profile, efficacy, and mitigated risk of forming reactive metabolites, MAK683 has been selected for clinical development.

Epidemiology of overweight and obesity among high school seniors in Beijing / 中国学校卫生

Objective@#To analyze the prevalence and changing trend of overweight and obesity among high school seniors in Beijing from 2009 to 2018, and to provide scientific basis for health and education departments to work out effective measures to prevent and control overweight and obesity among adolescents.@*Methods@#The physical examination data of 700 588 high school seniors in Beijing from 2009 to 2018 were selected to describe the distribution characteristics of the detection rate of overweight and obesity, and to analyze whether there are differences in the prevalence of overweight and obesity among different genders and regions.@*Results@#From 2009 to 2018, the prevalence rate of total overweight and obesity of high school seniors in Beijing showed an increasing trend by year ( χ 2=3.58, P <0.01). After 2016, the rising trend was more stable, and it declined for the first time in 2018. The prevalence of overweight ( χ 2=6 681.34, P <0.01) and obesity ( χ 2=15 663.08, P <0.01) were higher in male than in female. The prevalence of overweight and obesity in urban students was higher than that in suburban students (29.55%,27.95%; χ 2=211.43, P < 0.01 ), the prevalence of obesity in urban students was higher than that in suburban students from 2009 to 2013, and the prevalence of obesity in suburban students was higher than that in urban students from 2014 to 2018. The districts and counties with the highest detection rates of overweight and obesity are Shijingshan District (overweight: 19.06%, obesity: 13.99%), and the districts and counties with the lowest detection rates of overweight and obesity are Yanqing District (overweight: 13.48%, obesity: 7.18%).@*Conclusion@#From 2009 to 2018, the prevalence of overweight and obesity among high school seniors in Beijing has been increasing by year, and tends to be stable after 2016. Significant upward trend in obesity prevalence in suburban areas of Beijing has been observed.

Barriers to medication adherence in a rural-urban dual economy: a multi-stakeholder qualitative study.

BACKGROUND: One of the most cost-effective treatments for secondary prevention of stroke and other non-communicable diseases is a long-term medication regimen. However, the complexities of medication adherence extend far beyond individual behavior change, particularly in low- and middle-income countries. The purpose of this study was to examine stakeholder perspectives on barriers to medication adherence for stroke patients in Beijing, China, identifying opportunities to improve care and policy in resource-constrained settings. METHODS: We conducted a qualitative, phenomenological analysis of data obtained from 36 individuals. Participants were patients; caregivers; healthcare providers; and representatives from industry and government, purposively selected to synthesize multiple perspectives on medication management and adherence for stroke secondary prevention in Beijing, China. Data was analyzed by thematic analysis across iterative coding cycles. RESULTS: Four major themes characterized barriers on medication adherence, across stakeholders and geographies: limitations driven by individual patient knowledge / attitudes; lack of patient-provider interaction time; lack of coordination across the stratified health system; and lack of affordability driven by high overall costs and limited insurance policies. CONCLUSIONS: These barriers to medication management and adherence suggest opportunities for policy reform and local practice changes, particularly for multi-tiered health systems. Findings from this study in Beijing, China could be explored for applicability in other low- and middle-income countries with urban centers serving large geographic regions.

Left Atrial Appendage Closure Yields Favorable Cardio- and Cerebrovascular Outcomes in Patients With Non-valvular Atrial Fibrillation and Prior Stroke.

Introduction: Patients with non-valvular atrial fibrillation (NVAF) and previous stroke are at significantly higher risk of stroke recurrence. Data on the efficacy of left atrial appendage closure (LAAC) on these patients is limited. The aim of this study was to investigate the differences of LAAC efficacy on long-term cardio- and cerebrovascular outcomes in NVAF patients with vs. without prior stroke. Methods: Three hundred and seventy consecutive NVAF patients who underwent LAAC were enrolled and divided into stroke and non-stroke groups based on history of previous stroke. Endpoints, such as thromboembolism, major bleeding, and mortality post-LAAC, were followed up among groups. Results: Patients in the stroke group had higher mean CHA2DS2-VASc and HAS-BLED scores compared to the non-stroke group (5.1 vs. 3.6 and 4.1 vs. 3.4, both P < 0.001, respectively). Over a median follow-up of 2.2 years, there were no significant differences in incidence rates of thromboembolism, device-related thrombus (DRT), major bleeding, and combined efficacy endpoints between the two groups. In both stroke and non-stroke groups, LAAC decreased the risk of thromboembolism [relative risk reduction (RRR) 87.5%, P = 0.034, and 74.6%, P = 0.004, respectively] and major bleeding (RRR 68.8%, P = 0.034, and 68.6%, P = 0.007, respectively) compared with predicted risk. The RRR in thromboembolism was greater in patients with vs. without prior stroke (OR 2.45, 95% CI: 1.20-5.12, P = 0.016). The incidence rates of all-cause mortality and non-cardiovascular death were similar between the two groups, but the risks of cardiovascular death post-LAAC both before (1.4% vs. 8.1%, respectively, P = 0.038) and after adjustment for confounding factors (P = 0.048) were significantly decreased in the stroke group. Conclusions: Patients with vs. without prior stroke did not exhibit a worse clinical prognosis after LAAC. LAAC may provide an increased benefit in cardio-cerebrovascular outcomes in patients with previous stroke compared to those without previous stroke. Further research is necessary to evaluate the efficacy of LAAC in this field.

Relationship between ischemic stroke locations, etiology subtypes, neurological outcomes, and autonomic cardiac function.

BACKGROUND: Post-stroke autonomic nervous dysfunction measured with heart rate variability (HRV) is correlated with the traditional risk factors and poor outcome. This study aimed to investigate the association between HRV and infarct locations, etiology subtypes, and neurological functional outcomes in patients with acute ischemic stroke (AIS). METHODS: In this prospective observational study, 186 consecutive patients were assigned to four major stroke severity categories based on the National Institutes of Health Stroke Scale score (NIHSS) and the modified Rankin Scale score (mRS): mild (NIHSS 0-4) stroke, moderate (NIHSS 5-14) stroke, 'favorable' (mRS 0-2) group, and 'unfavorable' (mRS 3-5) group. HRV time domain parameters were applied to evaluate the autonomic function of patients within 1 week after admission. All patients were classified into different etiology subtypes based on the TOAST (modified Trial of ORG 10172 in Acute Stroke Treatment) classification. The association of HRV with stroke location, etiology subtypes, neurological outcome was explored for all participants. Univariate and multivariate analyses were applied to explore the prediction value of HRV. RESULTS: 160 participants had large artery atherosclerotic infarction (LAA), 61 had right internal carotid artery system infarction (R-ICA), and 61 had vertebrobasilar artery system infarction (VB). Root-mean-square of differences (RMSSD) of adjacent RR intervals and the proportion calculated by dividing the interbeat interval differences >50 ms (pNN50) in patients of VB group was significantly lower than those of patients in R-ICA group (P < 0.01).  HRV parameters in the LAA group was significantly lower than non-LAA group (P < 0.01). At discharge, significant lower HRV presented in the unfavorable group and moderate group (P < 0.05). After logistic univariate and multivariate analysis, lower SDNN (OR = 1.019; 95% CI = 1.003-1.035; p= 0.021) was independently associated with unfavorable mRS and higher NIHSS at discharge (OR = 1.013; 95%CI = 1.003-1.024; p= 0.015). Only SDNN showed predictive value for mRS≥3 (OR = 1.012; 95%CI = 1.002-1.022; p= 0.016) at 1 year. CONCLUSIONS: HRV measured after admission is related to the AIS infarction basin, TOAST subtypes, and neurological outcomes at discharge suggesting a possible role for HRV in evaluating AIS and identifying high-risk patients.

A new pressurization-insulation and pre-sealing system to improve pressure in cubic press from 6 GPa to 12 GPa.

In this paper, a pressurization-insulation and pre-sealing (PIPS) system is designed to increase the cell pressure of the widely used large volume cubic press without sacrificing cell volume. The sample chamber was sandwiched between a pair of tungsten carbide anvils used as the pressurization system. Ultra-high pressure in the cavity was up to about 12 GPa, and the pressure limit had increased by 100% in contrast with that of an anvil-gasket (AG) system. Furthermore, the confining pressure around the sample chamber was supported by grade 304 stainless steel and a zirconia-calcium oxide solid solution before a press load of 2.8 MN was applied as well as by four surrounding anvils. The relationship between the sample chamber pressure and the press load for this system was calibrated at room temperature using transitions in zinc telluride. With samples of similar volumes, the proposed system retained not only stability but also uniform pressure and temperature fields, in contrast with the AG system and the anvil-preformed gasket cubic press pressurization system. The results of more than 20 experiments show that the proposed PIPS system can operate stably under a press load of 4.2 MN, corresponding cell pressure of 10 GPa, and temperature in the cell exceeding 1800 °C by using graphite as a heater.

Low dose of flurbiprofen axetil decrease the rate of acute kidney injury after operation: a retrospective clinical data analysis of 9915 cases.

BACKGROUND: Flurbiprofen axetil (FA) is a commonly prescribed agent to relieve perioperative pain, but the relationship between FA and postoperative acute kidney injury (AKI) remains unclear. This study attempted to evaluate the effects of different dose of perioperative FA on postoperative AKI. METHODS: A total of 9915 patients were enrolled for this retrospective study. The clinical characteristics and the prevalence of postoperative AKI among patients non-using, using low dose (50-100 mg), middle dose (100-250 mg) and large dose (≧250 mg) of FA were analyzed respectively. The impact of different dose of FA on postoperative AKI was analyzed using univariable and multivariate logistic regression analysis. RESULTS: The prevalence of postoperative AKI was 6.7% in the overall subjects and 5.1% in 2446 cases who used FA. The incidence of AKI in low dose group was significantly less than that of non use group (4.5% vs 7.2%, P < 0.001), but the incidence of AKI in large dose group was significantly higher than that in the non-use group (18.8% vs 7.2%, P < 0.001). However, there was no significant difference between patients without using FA and subjects using middle dose of FA (7.2% vs 5.6%, p = 0.355). Multivariate logistic regression analysis showed that low dose of FA was a protective factor for postoperative AKI (OR = 0.75, p = 0.0188), and large dose of FA was a risk factor for postoperative AKI (OR = 4.8, p < 0.0001). CONCLUSIONS: The impact of FA on postoperative AKI was dose-dependent, using of low dose FA (50-100 mg) perioperatively may effectively reduce the incidence of postoperative AKI.

The Association of Autonomic Nervous System Function With Ischemic Stroke, and Treatment Strategies.

Acute ischemic stroke, especially minor stroke, and transient ischemic attack have high risks of recurrence and exacerbation into severe ischemic strokes. It remains challenging to perform risk stratification and screen high-risk groups for initiation of early treatment in these patients. Moreover, with the growing population of patients with chronic small vessel disease, the mechanisms and clinical implications require further investigation. Traditional tools such as the ABCD2 score (age, blood pressure, clinical features, duration of symptoms, diabetes) have only moderate predictive value in patients with transient ischemic attack or minor stroke. By contrast, measurement of changes in heart rate variability (HRV) is an important and novel tool for risk stratification and outcome prediction in patients with cardiovascular diseases, as it reflects the overall level of autonomic nervous system dysfunction. Thus, abnormal HRV may be useful for prognosis and improve stratification of stroke patients with diverse risks. HRV may also partially explain autonomic nervous dysfunction and other manifestations during the process of chronic cerebral small vessel disease. In summary, measurement of HRV may contribute to early initiation of interventions in acute or chronic stroke patients using novel treatments involving rebalancing of autonomic nervous system function.

Upregulation of CD11b and CD86 through LSD1 inhibition promotes myeloid differentiation and suppresses cell proliferation in human monocytic leukemia cells.

LSD1 (Lysine Specific Demethylase1)/KDM1A (Lysine Demethylase 1A), a flavin adenine dinucleotide (FAD)-dependent histone H3K4/K9 demethylase, sustains oncogenic potential of leukemia stem cells in primary human leukemia cells. However, the pro-differentiation and anti-proliferation effects of LSD1 inhibition in acute myeloid leukemia (AML) are not yet fully understood. Here, we report that small hairpin RNA (shRNA) mediated LSD1 inhibition causes a remarkable transcriptional activation of myeloid lineage marker genes (CD11b/ITGAM and CD86), reduction of cell proliferation and decrease of clonogenic ability of human AML cells. Cell surface expression of CD11b and CD86 is significantly and dynamically increased in human AML cells upon sustained LSD1 inhibition. Chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR) analyses of histone marks revealed that there is a specific increase of H3K4me2 modification and an accompanied increase of H3K4me3 modification at the respective CD11b and CD86 promoter region, whereas the global H3K4me2 level remains constant. Consistently, inhibition of LSD1 in vivo significantly blocks tumor growth and induces a prominent increase of CD11b and CD86. Taken together, our results demonstrate the anti-tumor properties of LSD1 inhibition on human AML cell line and mouse xenograft model. Our findings provide mechanistic insights into the LSD1 functions in controlling both differentiation and proliferation in AML.