Effect of Functional Inhibition of BACE1 on Sensitization to γ-Irradiation in Cancer Cells.

Developing strategies for the radiosensitization of cancer cells by the inhibition of genes, which harbor low toxicity to normal cells, will be useful for improving cancer radiotherapy. Here, we focused on a ß-site of amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1; ß-secretase, memapsin-2). By functional inhibition of this peptidase by siRNA, it has also recently been shown that the DNA strand break marker, γH2AX foci, increased, suggesting its involvement in DNA damage response. To investigate this possibility, we knocked down BACE1 with siRNA in cancer cell lines, and sensitization to γ-irradiation was examined by a colony formation assay, γH2AX foci and level analysis, and flow cytometry. BACE1 knockdown resulted in the sensitization of HeLa, MDA-MB-231, U2OS, and SAOS cells to γ-irradiation in a diverse range. BACE1 knockdown showed a weak radiosensitization effect in osteosarcoma U2OS cells, which has a normal p53 function. HeLa and SAOS cells, which harbor p53 dysfunction, exhibited a greater level of radiosensitization. These results suggest that BACE1 may be a potential target for the radiosensitization in particular cancer cells.

Association Between Serum Neurofilament Light Chain and Neurochemistry Deficits in Patients with Spinocerebellar Ataxia Type 3.

Extensive evidence supports the claim that the serum neurofilament light chain (sNfL) can be used as a biomarker to monitor disease severity in patients with spinocerebellar ataxia type 3 (SCA3). However, little is known about the associations between sNfL levels and neurochemical alterations in SCA3 patients. In this study, we performed a cross-sectional study to analyze the association between sNfL and brain metabolic changes in SCA3 patients. The severity of ataxia was assessed by using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). The sNfL levels and brain metabolic changes, represented by N-acetyl aspartate (NAA)/creatine (Cr) and choline complex (Cho)/Cr ratios, were measured by a single-molecule array and proton magnetic resonance spectroscopy, respectively. In this cohort, we observed consistently elevated sNfL levels and reduced brain metabolites in the cerebellar hemispheres, dentate nucleus, and cerebellar vermis. However, this correlation was further validated in the cerebellar cortex after analysis using pairwise comparisons and a Bonferroni correction. Taken together, our results further confirmed that sNfL levels were increased in SCA3 patients and were negatively correlated with metabolic changes in the cerebellar cortex. Our data also support the idea that sNfL levels are a promising potential complementary biomarker for patients with SCA3.

Evaluation of Relationships between Corticospinal Excitability and Somatosensory Deficits in the Acute and Subacute Phases of Stroke.

BACKGROUND: Somatosensory deficits are common symptoms post stroke. Repetitive transcranial magnetic stimulation (rTMS) over the motor cortex is able to promote motor rehabilitation, whereby its impact on somatosensory functioning remains unknown. This study was designed to evaluate the association between somatosensory deficits and corticospinal excitability following stroke, with the purpose to provide insights on rTMS interventions for the management of somatosensory deficits. METHODS: Somatosensory functioning and corticospinal excitability (motor-evoked potential, MEP; cortical silence period, CSP) were evaluated from a group of sixteen patients with unilateral ischemic stroke in the acute or subacute phase. RESULTS: Results indicated that the uncommon presentation of larger MEPs in ipsilesional vs. contralesional motor cortex was associated with worse somatosensory function compared to those with a smaller MEP in ipsilesional motor cortex. Moreover, increased MEP ratio (ipsilesional vs. contralesional motor cortex) was associated with better somatosensory function in patients with well-preserved somatosensory function. CONCLUSIONS: In well-recovered patients, an increased MEP ratio between the ipsilesional and contralesional motor cortex could be an indicator of improved somatosensory functioning following stroke.

Long-term sequelae of hippocampal lesions in patients with transient global amnesia: A multiparametric MRI study.

BACKGROUND: MRI signal diffusion-weighted imaging (DWI) hyperintensity in the hippocampus in patients with transient global amnesia (TGA) are resolved within several days after the onset of TGA. PURPOSE: To use multiparametric MRI to unravel the sequelae of TGA. STUDY TYPE: A prospective longitudinal study. POPULATION: Eight TGA patients. FIELD STRENGTH/SEQUENCE: A 3.0T Siemens Tim Trio MRI scanner with T1 -weighted MPRAGE, diffusion-weighted echo planar imaging, and multiecho gradient-recalled echo sequences. ASSESSMENT: Brain MRI scanned within 72 hours, 2 weeks, and 3 months after onset of TGA, respectively. T1 image hippocampus was first segmented into 12 subregions using FreeSurfer and registered to DWI to locate DWI lesion. Then a T1 image with segmented hippocampus was registered to its corresponding apparent diffusion coefficient (ADC) map, fractional anisotropy (FA) map, and quantitative susceptibility map, respectively. Finally, the volume, water diffusion and anisotropy, and magnetic susceptibility of DWI lesion were analyzed. STATISTICAL TESTS: A paired samples t-test was performed to detect measurement differences between three tests. Pearson correlation was used to assess the correlations between all measurements. RESULTS: Hyperintensity was detected in the head, body, and caudate of CA1 and hippocampal tail. No significant changes existed in CA1/unit volume across the three timepoint measurements (all, P > 0.480). In Test 1, ratio ADC (DWI lesion / adjacent healthy, rADC) and ratio FA (rFA) decreased below, while ratio susceptibility increased above 1.0. In Test 2, all the episodes normalized around 1.0. In Test 3, rADC remained normalization, but rFA decreased and ratio susceptibility increased again. In Test 1 and Test 3 (vs. Test 2), decreased FA values were accompanied with lower axial diffusivity and/or higher radial diffusivity (all, P < 0.001). Moreover, rFA significantly correlated with ratio susceptibility in Test 3 (r = -0.665, P = 0.039). DATA CONCLUSION: Microstructural sequelae in hippocampus were demonstrated, which indicates that ischemic lesions may be associated with TGA. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1350-1358.

t-PA acts as a cytokine to regulate lymphocyte-endothelium adhesion in experimental autoimmune encephalomyelitis.

In this study, the capacity for t-PA to affect T cell-brain microvascular endothelial cell adhesion by acting as a cytokine was investigated. Following the treatment of a brain-derived endothelial cell line, bEnd.3, with various concentrations of t-PA, adhesion and transwell migration assays were performed. In the presence of t-PA, enhanced adhesion of T cells to bEnd.3 cells was observed. Using western blot analysis, an increase in ICAM-1 expression was detected for both t-PA-treated bEnd.3 cells and bEnd.3 cells treated with a non-enzymatic form of t-PA. In contrast, when LRP1 was blocked using a specific antibody, upregulation of ICAM-1 was inhibited and cAMP-PKA signaling was affected. Furthermore, using an EAE mouse model, administration of t-PA was associated with an increase in ICAM-1 expression by brain endothelial cells. Taken together, these findings suggest that t-PA can induce ICAM-1 expression in brain microvascular endothelial cells, and this may promote the development of EAE.

Accumulation of natural killer cells in ischemic brain tissues and the chemotactic effect of IP-10.

BACKGROUND: Stroke is accompanied by a distinguished inflammatory reaction that is initiated by the infiltration of immunocytes, expression of cytokines, and other inflammatory mediators. As natural killer cells (NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system, we investigated the mechanism of NK cells-induced brain injuries after cerebral ischemia and the chemotactic effect of IP-10 simultaneously. METHODS: NK cells infiltration, interferon-gamma (IFN-γ) and IP-10 expression were detected by immunohistochemistry, immunofluorescence, PCR and flow cytometry in human and C57/BL6 wild type mouse ischemic brain tissues. The ischemia area was detected via 2,3,5-triphenyltetrazolium chloride staining. CXCR3 mean fluorescence intensity of isolated NK cells was measured by flow cytometry. The neuronal injury made by NK cells was examined via apoptosis experiment. The chemotactic of IP-10 was detected by migration and permeability assays. RESULTS: In human ischemic brain tissue, infiltrations of NK cells were observed and reached a peak at 2 to 5 days. In a permanent middle cerebral artery occlusion (pMCAO) model, infiltration of NK cells into the ischemic infarct region reached their highest levels 12 hours after ischemia. IFN-γ-positive NK cells and levels of the chemokine IP-10 were also detected within the ischemic region, from 6 hours up to 4 days after pMCAO was performed, and IFN-γ levels decreased after NK cells depletion in vivo. Co-culture experiments of neural cells with NK cells also showed that neural necrosis was induced via IFN-γ. In parallel experiments with IP-10, the presence of CXCR3 indicates that NK cells were affected by IP-10 via CXCR3, and the effect was dose-dependent. After IP-10 depletion in vivo, NK cells decreased. In migration assays and permeability experiments, disintegration of the blood-brain barrier (BBB) was observed following the addition of NK cells. Moreover, in the presence of IP-10 this injury was aggravated. CONCLUSIONS: All findings support the hypothesis that NK cells participate in cerebral ischemia and promote neural cells necrosis via IFN-γ. Moreover, IP-10 intensifies injury to the BBB by NK cells via CXCR3.

Comprehensive analysis of the role of cuproptosis-related genes in the prognosis and immune infiltration of adrenocortical Carcinoma.

Background: Cuproptosis is a recently discovered form of nonapoptotic programmed cell death. However, no research on cuproptosis in the context of adrenocortical carcinoma has been conducted, and the prognostic value of assessing cuproptosis remains unclear. Methods: In this study, we established comprehensive models to assess gene expression changes, mutation status, and prognosis prediction and developed a prognostic nomogram for cuproptosis-related genes. Using data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Genotype-Tissue Expression (GTEx) databases, an analysis of 11 cuproptosis-related genes was performed. Additionally, a risk scoring method and nomogram were used to assess the relationships among cuproptosis-associated genes, transcript expression, clinical characteristics, and prognosis. The connections among tumors, immune checkpoints, and immune infiltration were also analyzed. Results: The patterns observed in patients with adrenocortical carcinoma who were assessed using cuproptosis-associated risk scores provide useful information for understanding gene mutations, clinical outcomes, immune cell infiltration, and immune checkpoint analysis results. FDX1, LIPT1, MTF1, COX11, CYP2D6, DLAT, ATP7Band CDKN2A were differentially expressed in patients with adrenocortical carcinoma and normal controls. In addition, higher risk scores were significantly associated with poor overall survival and progression-free interval. The nomogram model subsequently developed to facilitate the clinical application of the analysis showed good predictive and calibration capabilities. GSE10927 and GSE33371 were used for independent cohort validation. Moreover, CDKN2A, FDX1, and other cuproptosis-related genes were significantly associated with immune infiltration and checkpoints. Conclusion: We confirmed that our model had excellent predictive ability in patients with adrenocortical carcinoma. Therefore, an in-depth evaluation of patients using cuproptosis-related risk scores is clinically essential and can assist in therapy in the future.

Upscaling net ecosystem CO2 exchanges in croplands: The application of integrating object-based image analysis and machine learning approaches.

Accurately estimating the net ecosystem exchange of CO2 (NEE) in cropland ecosystems is essential for understanding the impacts of agricultural practices and climate conditions. However, significant uncertainties persist in the estimation of regional cropland NEE due to landscape heterogeneity and variations in the efficacy of upscaling models. Here, we applied an integrated approach that combined object-based image analysis (OBIA) techniques with advanced machine learning (ML) approaches to upscale regional cropland NEE. We conducted a thorough evaluation of the upscaling approach across four distinct cropland areas characterized by diverse climate conditions. Our study confirmed that OBIA techniques can efficiently segment cropland objects, thereby enhancing the representation and accuracy of characteristics relevant to cropland features. The sequential least squares programming algorithm, among the three methods used for ML model integration, demonstrated exceptional performance in predicting NEE, with an R2 value exceeding 0.80 across all study areas and peaking at 0.90 in the most successful area. On average, there was an 18 % improvement compared to the poorest-performing ML model and a 6 % enhancement compared to the best-performing ML model. The upscaled regional products exhibited superior performance in characterizing cropland NEE patterns compared to pixel-based products. Additionally, we utilized the SHapley Additive exPlanations (SHAP) to assess driver importance, revealing that phenology and radiation had the greatest influence on prediction accuracy, followed by temperature and soil moisture. This study highlights the potential of integrating OBIA techniques with machine learning approaches for upscaling regional cropland NEE, while concurrently reducing estimation uncertainties.

Distinct Emotional and Cardiac Responses to Audio Erotica between Genders.

Emotional and cardiac responses to audio erotica and their gender differences are relatively unclear in the study of the human sexual response. The current study was designed to investigate gender differences regarding positive and negative emotional responses to erotica, as well as its association with cardiac response. A total of 40 healthy participants (20 women) were exposed to erotic, neutral, and happy audio segments during which emotions and heart rate changes were evaluated. Our data showed distinct emotional responses to erotica between genders, in which women reported a higher level of shame than men and rated erotic audios as less pleasant than happy audios. Meanwhile, men reported erotic and happy audios as equally pleasant. These results were independent of cardiac changes, as both sexes demonstrated comparable heart rate deceleration when exposed to erotica relative to neutral and happy stimuli. Our results highlight the role of sociocultural modulation in the emotional response to erotica.

How do aerosols above the residual layer affect the planetary boundary layer height?

We revealed that the absorption aerosol lying below or above the morning residual layer (MRL) promotes (stove effect, heating the MRL layer) or strongly inhibits (dome effect, heating the temperature inversion layer) the development of planetary boundary layer (PBL) after sunrise, while scattering aerosol exhibits similar suppression (surface or aloft umbrella effect) on the PBL regardless of its vertical location. However, the role of different type of aerosols (i.e., strong absorption aerosol and purely scattering aerosol) present from MRL to upper atmosphere remains lacking and therefore, needs to be further explored. Utilizing a large-eddy simulation model constrained by the in-situ observations in urban Beijing, we observed that the dome inhibition of absorption aerosols on PBL development becomes weaker as elevating the aerosol layer, and the effect (virtual dome effect) remains no change beyond a certain height, which is defined as the dome effective height z. This height z is highly related to the surface sensible heat flux. By comparison, the altitude of light-scattering aerosols relative to the MRL was less important. The scattering aerosols exhibit similar inhibition from MRL to upper atmosphere (aloft umbrella effect), but to a weaker extent than the virtual dome effect. The virtual dome effect and aloft umbrella effect play a leading role during some extremely polluted scenarios with deep aerosol layer, such as sandstorms and volcanic eruptions. Aerosol dome, virtual dome, and aloft umbrella effects, together with aerosol stove and surface umbrella effects, further advance the understanding on aerosol-PBL interactions, which is, more broadly, applied to interpret the impact of aerosol on PBL over other ecosystems as well as exoplanet atmospheres.

Treatment of the acute thromboembolic event during endovascular embolization of intracranial aneurysm.

OBJECTIVE: The study aimed to discuss the treatment of acute thromboembolic event (TE) during endovascular embolization of intracranial aneurysms. METHODS: Between April 2013 and April 2019, 158 patients with 167 intracranial aneurysms were treated with endovascular embolization in our hospital, in which 9 cases of acute TEs occurred during the embolization procedures. The clinical data, radiological findings and treatments of the 9 patients were reviewed and analyzed. RESULTS: The TEs occurred at the aneurysmal neck in 3 patients, at distal part of the parent artery in 3, in the stent in 2, and at the proximal part of the parent artery in 1. Intra-arterial (IA) infusion of tirofiban were performed in 6 patients, mechanical thromboectomy (MT) with a stent in 2 patients, and combined use of the two methods in 1 patients. According to the modified Thrombolysis In Cerebral Infarction (mTICI) score, 7 patients had recanalization of 2b/3a, 1 patients had recanalization of 1, and 1 patients had recanalization of 0. At discharge, the mRS score was 0 in 3 patients, 1 in 3 patients, and 2, 3, 4 in 1 patient each. 6 months after the endovascular treatment, the mRS score was 0 in 5 patients, 1 in 2 patients, and 3 in 1 patient. CONCLUSIONS: IA tirofiban and MT are effective remedies for the acute TE during endovascular embolization of intracranial aneurysm, reasonable selection of which may improve the prognosis of patients.

Accelerated dryland expansion regulates future variability in dryland gross primary production.

Drylands cover 41% of Earth's surface and are the largest source of interannual variability in the global carbon sink. Drylands are projected to experience accelerated expansion over the next century, but the implications of this expansion on variability in gross primary production (GPP) remain elusive. Here we show that by 2100 total dryland GPP will increase by 12 ± 3% relative to the 2000-2014 baseline. Because drylands will largely expand into formerly productive ecosystems, this increase in dryland GPP may not increase global GPP. Further, GPP per unit dryland area will decrease as degradation of historical drylands outpaces the higher GPP of expanded drylands. Dryland expansion and climate-induced conversions among sub-humid, semi-arid, arid, and hyper-arid subtypes will lead to substantial changes in regional and subtype contributions to global dryland GPP variability. Our results highlight the vulnerability of dryland subtypes to more frequent and severe climate extremes and suggest that regional variations will require different mitigation strategies.

Vasogenic cerebral edema associated with the disability in activities of daily living in patients with chronic obstructive pulmonary disease.

INTRODUCTION: The aim of this study was to explore whether patients with chronic obstructive pulmonary disease (COPD) develop vasogenic cerebral edema, and whether this edema contributes to the COPD-related disability. METHODS: Eighteen stable patients with COPD and 17 matched healthy volunteers were enrolled. Apparent diffusion coefficient (ADC) values were calculated by voxel-based analysis using DTI-Studio software based on diffusion tensor imaging. COPD-related disability was calculated using activities of daily living (ADL) scale. RESULTS: In patients with COPD, ADC increased in the white matter fiber tracts including the bilateral anterior cingulum and posterior corpus callosum and in the white matter fibers connecting the bilateral insular cortices, sub-lobar cortices, and pars triangularis cortices and the left rectus and olfactory gyrus. However, after further controlling for cigarette smoking, the difference in ADC values in the posterior corpus callosum between groups disappeared. Patients with COPD had significantly higher scores in ADL than that in controls. Moreover, ADL scores were positively correlated with the increased regional ADC values. CONCLUSION: Vasogenic cerebral edema occurs in patients with COPD. Cigarette smoking may be a risk factor for COPD-related vasogenic edema. Vasogenic cerebral edema may be related to the COPD-related ADL impairment.

[Alpha,beta-poly[(N-hydroxypropyl/aminoethyl)-DL-aspartamide -co-L-lysine]: potential non-viral vehicle for gene delivery].

A series of Poly[aspartic acid-co-L-lysine](PAL) are copolycondensed by DL-aspartice acid and L-lysine with different ratios. Their constructions are identified by the spectra of 1H-NMR, FT-IR, X-Ray). These spectra are proved to have good regularity of these copolymers. alpha,beta-Poly[(N-hydroxypropyl/aminoethyl)-DL-Aspartamide-co-L-lysine] (PHAAL) is synthesized by ring-opening poly [aspartic acid-co-lysine] (PAL). PHAAL has good degradability in the phosphoric acid buffer solution (0.01 M, pH = 7.4) in the enzyme solution (Papain, Trypsine). PHAAL appeared tobe low cytotoxicity in Hela, ECV-304, Bcap37 cell lines, which was quantified by MTT assay. The combination ability of PHAAL with plasmid DNA was evaluated by agarose gel electrophoresis with agarose gel (1.0% w/v) containing ethidium bromide (0.25 microg/ml). The PHAAL with higher ratios of lysine in the copolymers have higher ability of condensing DNA. In summary, PHAAL, the polyaminoacid materials, could be one kind of macromolecule materials tobeused as the non-viral gene vehicle.