Miracle-dz/UniFAR-FTUs huggingface dataset:
Decrease of VEGF-A in myeloid cells attenuates glioma progression and prolongs survival in an experimental glioma model.

BACKGROUND Glioblastomas are highly vascularized tumors with a prominent infiltration of macrophages/microglia whose role in promoting glioma growth, invasion, and angiogenesis has not been fully elucidated. METHODS The contribution of myeloid-derived vascular endothelial growth factor (VEGF) to glioma growth was analyzed in vivo in a syngeneic intracranial GL261 glioma model using a Cre/loxP system to knock out the expression of VEGF-A in CD11b + myeloid cells. Changes in angiogenesis-related gene expression profile were analyzed in mutant bone marrow-derived (BMD) macrophages in vitro. Furthermore, we studied the influence of macrophages on GL261 growth, invasiveness, and protein expression profile of angiogenic molecules as well as the paracrine effect of mutant macrophages on angiogenesis in vitro. RESULTS Myeloid cell-restricted VEGF-A deficiency leads to a growth delay of intracranial tumors and prolonged survival. The tumor vasculature in mutant mice was more regular, with increased pericyte coverage. Expression analysis revealed significant downregulation of VEGF-A and slight upregulation of TGFβ-1 in BMD macrophages from mutant mice. Endothelial tube formation was significantly decreased by conditioned media from mutant macrophages. The expression of angiogenesis-related proteins in GL261 glioma cells in co-culture experiments either with wild-type or mutant macrophages remained unchanged, indicating that effects observed in vivo are due to myeloid-derived VEGF-A deficiency. CONCLUSIONS Our results highlight the importance of VEGF derived from tumor-infiltrating myeloid cells for initiating vascularization in gliomas. The combination of antiangiogenic agents with myeloid cell-targeting strategies might provide a new therapeutic approach for glioblastoma patients.
Blood Pressure Management for Stroke Prevention and in Acute Stroke

Elevated blood pressure (BP) is the leading modifiable risk factor for stroke and the benefit of BP lowering therapy on the stroke risk reduction is well established. The optimal BP target for preventing stroke and other vascular events have been controversial, but the evidences from epidemiological studies and randomized controlled trials (RCTs) support intensive BP lowering for greater vascular protection, particularly for stroke prevention. For secondary stroke prevention, the evidence of intensive BP lowering benefit is limited since only a single RCT for patients with lacunar infarctions was conducted and most data were driven by exploratory analyses. In acute intracerebral hemorrhage, immediate BP lowering targeting systolic BP<140 mm Hg is recommended by guidelines based on the results from RCTs. In contrast, in acute ischemic stroke, early BP lowering is not usually recommended because of no benefit on functional outcome and future vascular events and potential harm of stroke progression. This review aims to summarize the updated evidence for optimal BP management for primary and secondary stroke prevention and in patients with acute stroke.
Polymerase Chain Reaction-based Cloning of Alkyl-dihydroxyacetonephosphate Synthase Complementary DNA from Guinea Pig Liver*

Peroxisomes are indispensable organelles for ether lipid biosynthesis in mammalian tissues, and the deficiency of these organelles in a number of peroxisomal disorders leads to deficiencies in ether phospholipids. We have previously purified the committed enzyme for ether lipid biosynthesis, i.e. alkyl-dihydroxyacetonephosphate synthase, to homogeneity. We have now determined the N-terminal amino acid sequence, as well as additional internal sequences obtained after cyanogen bromide cleavage of the enzyme. With primers directed against the N-terminal sequence and against a cyanogen bromide fragment sequence, a 1100-bp cDNA fragment was obtained by conventional polymerase chain reaction using first-strand cDNA from guinea pig liver as a template. The 5′ and 3′ ends of the cDNA were obtained by rapid amplification of cDNA ends. The open reading frame encodes a protein of 658 amino acids, containing the N-terminal amino acid sequence as well as the cyanogen bromide cleavage fragment sequences. The derived amino acid sequence includes a mature protein 600 amino acids long and a presequence 58 amino acids long. The latter contains a stretch of amino acids known as peroxisomal targeting signal 2. The size of the mRNA was estimated to be around 4200 nucleotides. Recombinant His-tagged alkyl-dihydroxyacetonephosphate synthase expressed in Escherichia coli was enzymatically active.
Duloxetine Augmentation in Resistant Obsessive-Compulsive Disorder: A Double-Blind Controlled Clinical Trial

Introduction The aim of this study is to evaluate the efficacy of duloxetine augmentation in treatment of resistant obsessive-compulsive disorder (OCD). Methods This augmentation trial was designed as an 8-week randomized controlled, double-blind study. Forty-six patients experiencing OCD who had failed to respond to at least 12 weeks of treatment with a selective serotonin reuptake inhibitor (fluoxetine, citalopram, or fluvoxamine) were randomly allocated to receive duloxetine or sertraline plus their current anti-OCD treatment. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) was the primary outcome measure. Treatment response was defined as 25% or more decrease in scores of Y-BOCS. The mean dosage of duloxetine was 44.4 mg/d (range, 20–60 mg/d), and the mean dosage of sertraline was 123.8 mg/d (range, 50–200 mg/d). Results Forty-six patients (24 of 30 in duloxetine group and 22 of 27 in sertraline group) completed the trial. Both groups showed improvement during the 8-week study period (mean Y-BOCS total score at week 8 as compared with baseline: P < 0.001 & P < 0.001) without significant difference (P = 0.861). Those receiving duloxetine plus their initial medications experienced a mean decrease of 33.0% in Y-BOCS score, and the patients with sertraline added to their initial medication experienced a mean decrease of 34.5% in Y-BOCS. Discussion Our double-blind controlled clinical trial showed duloxetine to be as effective as sertraline in reducing obsessive and compulsive symptoms in patients with resistant OCD. However, it needs to be noted that our study is preliminary, and larger double-blind placebo-controlled studies are necessary to confirm the results.
In vivo inhibition of focal adhesion kinase causes insulin resistance

Focal adhesion kinase (FAK), a non‐receptor tyrosine kinase, has recently been implicated in the regulation of insulin resistance in vitro. However, its in vivo validation has not been attempted due to lethality of FAK knockout. Hence, to ascertain the role of FAK in the development of insulin resistance in vivo, we have down‐regulated FAK expression by delivering FAK‐specific small interfering RNA (siRNA) in mice using hydrodynamic tail vein injection. Here, we show for the first time that FAK silencing (57 ± 0.05% in muscle and 80 ± 0.08% in liver) exacerbates insulin signalling and causes hyperglycaemia (251.68 ± 8.1 mg dl−1) and hyperinsulinaemia (3.48 ± 0.06 ng ml−1) in vivo. FAK‐silenced animals are less glucose tolerant and have physiological and biochemical parameters similar to that of high fat diet (HFD)‐fed insulin‐resistant animals. Phosphorylation and expression of insulin receptor substrate 1 (IRS‐1) was attenuated by 40.2 ± 0.03% and 35.2 ± 0.6% in muscle and 52.3 ± 0.04% and 40.2 ± 0.03% in liver in FAK‐silenced mice. Akt‐Ser473‐phosphorylation decreased in muscle and liver (50.3 ± 0.03% and 70.2 ± 0.02%, respectively) in FAK‐silenced mice. This, in part, explains the mechanism of development of insulin resistance in FAK‐silenced mice. The present study provides direct evidence that FAK is a crucial mediator of insulin resistance in vivo. Considering the lethality of FAK gene knockout the approach of this study will provide a new strategy for in vivo inhibition of FAK. Furthermore, the study should certainly motivate chemists to synthesize new chemical entities for FAK activation. This may shed light on new drug development against insulin resistance.
Study of the influence of storage conditions on the quality and migration levels of antimony in polyethylene terephthalate-bottled water

The main objectives of this study are to determine the presence of antimony in water stored in polyethylene terephthalate bottles and the influence of temperature and time over the migration levels. For this purpose, Sb determination was carried out in water at different experimental conditions: storage for one to three weeks at 25 to 80 ℃; long-term (six months) storage at room temperature between 16 and 24 ℃ and storage in car during summer which is a common consumer’s habit. In addition, water quality analysis was developed after different time–temperature storage conditions. All the samples at the end of their storage conditions were analyzed by inductively coupled plasma mass spectrometry. The limit of detection and quantification were 0.50 and 0.80 µg/L, respectively. The results for the bottled water stored during six months indicated that the average Sb concentration was 0.332 ± 0.015 µg/L. This value is below the European maximum permissible migration level of 5 µg/L. With regard to the newly bottled water, no Sb was detected at the initial time for all temperatures studied. However, the Sb concentration in water increased with both time and temperature. The levels of Sb started exceeding the European limits when the samples were stored at 60 ℃ for two weeks.
Expression of Polo-Like Kinase 1 (PLK1) Protein Predicts the Survival of Patients with Gastric Carcinoma

Objective: To assess the prognostic value of polo-like kinase 1 (PLK1), an important regulator of cell cycle progression, in patients with gastric carcinoma. Methods: PLK1 expression was determined in 160 gastric carcinoma patients by immunohistochemistry and compared with p53 expression and the proliferating cell nuclear antigen-labeling index (PCNA-LI) to evaluate the effect of PLK1 on tumor progression. Furthermore, PLK mRNA expression was determined in 26 advanced gastric cancer patients by reverse transcription-polymerase chain reaction (RT-PCR). Results: PLK mRNA expression was detected in 25 (96.2%) patients by RT-PCR. Immunohistochemical staining revealed PLK1 expression in 84 (52.5%) patients. There were no significant relationships between PLK1 expression and various clinicopathological factors. PLK1 expression was significantly correlated with the PCNA-LI, but not p53 expression. The prognosis of patients with PLK1-positive tumors was significantly worse than that of patients with PLK1-negative tumors (p < 0.05). Moreover, multivariate analysis revealed that PLK1 expression was an independent prognostic factor. Patients with PLK1-positive and high PCNA-LI tumors showed a significantly poorer prognosis than patients with PLK1-negative and/or low PCNA-LI tumors. Furthermore, the prognosis of patients with PLK1- and p53-positive tumors was significantly worse than that of patients with PLK1- and p53-negative or PLK1-negative and p53-positive tumors. Conclusion: PLK1 expression may be a critical indicator of a poor prognosis in patients with gastric carcinoma.
Foot-Tapping Rate as an Objective Outcome Measure for Parkinson Disease Clinical Trials

Objectives:To explore foot-tapping rate as a reliable and a valid measure of motor function in Parkinson disease (PD). Methods:We present data from a randomized, single-blind, outpatient study and a randomized, double-blind, placebo-controlled, crossover, inpatient study. Fifty PD subjects completed the outpatient study. A Unified Parkinson Disease Rating Scale motor score was determined for each subject. Subsequently, finger tapping, alternate (between 2 pedals) and repetitive (on 1 pedal) foot-tapping rates, and gait were measured. Thirteen PD subjects completed the inpatient study. Each subject received a daily infusion of high-dose apomorphine (APO), low-dose APO, and placebo in random order over 3 days. In this subanalysis, we compared variance and reliability of the finger- and the foot-tapping techniques during the placebo day and compared the validity of these outcome measures to detect improvement in parkinsonism during high-dose APO infusion. Results:Alternate foot tapping was reliable (interclass correlation on the placebo inpatient day, 84%). Only foot tapping detected improvement in parkinsonism with high-dose APO treatment (a measure of validity). In the outpatient study, there was a significant correlation between alternate and repetitive tapping with finger tapping (R2 = 0.28 and 0.23, respectively) and Unified Parkinson Disease Rating Scale motor score (R2 = 0.09 and 0.08), but only alternate tapping correlated with gait (R2 = 0.16). Conclusions:Alternate foot tapping was equally reliable but more valid than finger tapping. Alternate foot tapping correlated better did existing PD outcome measures than did repetitive foot tapping. Foot tapping may be a useful outcome measure for determination of dopaminergic medication effect in PD clinical trials.
Validation of spot urine in predicting 24-h sodium excretion at the individual level.

Background: Evidence for the effect of dietary sodium intake on the risk of cardiovascular disease has been controversial. One of the main explanations for the conflicting results lies in the great variability associated with measurement methods for sodium intake. Spot urine collection is a convenient method commonly used for sodium estimation, but its validity for predicting 24-h urinary sodium excretion at the individual level has not been well evaluated among the general population.Objective: The aim of this study was to evaluate the validity of the Kawasaki, the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT), and the Tanaka formulas in predicting 24-h urinary sodium excretion by using spot urine samples in Chinese adults.Design: We analyzed the relative and absolute differences and misclassification at the individual level from 3 commonly used methods for estimating sodium intake among 141 Chinese community residents.Results: The mean measured 24-h sodium excretion was 220.8 mmol/d. The median (95% CIs) differences between measured sodium and those estimated from the Kawasaki, INTERSALT, and Tanaka methods were 6.4 mmol/d (-17.5, 36.8 mmol/d), -67.3 mmol/d (-96.5, -46.9 mmol/d), and -42.9 mmol/d (-59.1, -24.8 mmol/d), respectively. The proportions of relative differences >40% with the Kawasaki, INTERSALT, and Tanaka methods were 31.2%, 41.1%, and 22.0%, respectively; and the absolute difference for the 3 methods was >51.3 mmol/d (3 g salt) in approximately half of the participants. The misclassification rate was 63.1% for the Kawasaki method, 78.7% for the INTERSALT method, and 66.0% for the Tanaka method at the individual level.Conclusion: The results from our study do not support the use of spot urine to estimate 24-h urinary sodium excretion at the individual level because of its poor performance with respect to misclassification. This trial was registered at www.chictr. org.cn as ChiCTR-IOR-16010278.
Huperzine A attenuates amyloid β‐peptide fragment 25‐35‐induced apoptosis in rat cortical neurons via inhibiting reactive oxygen species formation and caspase‐3 activation

Huperzine A, a novel Lycopodium alkaloid originally discovered in the Chinese herb Qian Ceng Ta (Huperzia serrata), is a reversible, potent, and selective acetylcholinesterase (AChE) inhibitor and has been extensively used for the treatment of Alzheimer's disease (AD) in China. The present studies were designed to investigate effects of huperzine A on amyloid β‐peptide fragment 25‐35 (Aβ25‐35)‐induced neuronal apoptosis and potential mechanisms in primary cultured rat cortical neurons. After exposure of the cells to Aβ25‐35 (20 μM), apoptotic cell death was observed as evidenced by a significant decrease in cell viability, alteration of neuronal morphology, and DNA fragmentation. Pretreatment of the cells with huperzine A (0.01–10 μM) prior to Aβ25‐35 exposure significantly elevated the cell survival and reduced Aβ25‐35‐induced nuclei fragmentation. Reactive oxygen species (ROS)‐based fluorescence, caspase‐3‐like fluorogenic cleavage, and Western blot analysis demonstrated that huperzine A reduced Aβ25‐35‐induced ROS formation in a dose‐dependent manner, and 1 μM of huperzine A attenuated Aβ25‐35‐induced caspase‐3 activity at 6, 12, 24, and 48 hr posttreatment. Our results provide the first direct evidence that huperzine A protects neurons against Aβ25‐35‐induced apoptosis via the inhibition of ROS formation and caspase‐3 activity. © 2002 Wiley‐Liss, Inc.
Laser Interstitial Thermal Therapy Technology, Physics of Magnetic Resonance Imaging Thermometry, and Technical Considerations for Proper Catheter Placement During Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy.

Laser-induced thermal therapy has become a powerful tool in the neurosurgical armamentarium. The physics of laser therapy are complex, but a sound understanding of this topic is clinically relevant, as many centers have incorporated it into their treatment algorithm, and educated patients are demanding consideration of its use for their disease. Laser ablation has been used for a wide array of intracranial lesions. Laser catheter placement is guided by stereotactic planning; however, as the procedure has popularized, the number of ways in which the catheter can be inserted has also increased. There are many technical nuances for laser placement, and, to date, there is not a clear understanding of whether any one technique is better than the other. In this review, we describe the basic physics of magnetic resonance-guided laser-induced thermal therapy and describe the several common techniques for accurate Visualase laser catheter placement in a stepwise fashion. ABBREVIATIONS MRg-LITT, magnetic resonance-guided laser-induced thermal therapyPAD, precision aiming device.
MRI correlates of neurofibrillary tangle pathology at autopsy

Background: Neurofibrillary tangles (NFTs), composed of hyperphosphorylated tau proteins, are one of the pathologic hallmarks of Alzheimer disease (AD). We aimed to determine whether patterns of gray matter atrophy from antemortem MRI correlate with Braak staging of NFT pathology. Methods: Eighty-three subjects with Braak stage III through VI, a pathologic diagnosis of low- to high-probability AD, and MRI within 4 years of death were identified. Voxel-based morphometry assessed gray matter atrophy in each Braak stage compared with 20 pathologic control subjects (Braak stages 0 through II). Results: In pairwise comparisons with Braak stages 0 through II, a graded response was observed across Braak stages V and VI, with more severe and widespread loss identified at Braak stage VI. No regions of loss were identified in Braak stage III or IV compared with Braak stages 0 through II. The lack of findings in Braak stages III and IV could be because Braak stage is based on the presence of any NFT pathology regardless of severity. Actual NFT burden may vary by Braak stage. Therefore, tau burden was assessed in subjects with Braak stages 0 through IV. Those with high tau burden showed greater gray matter loss in medial and lateral temporal lobes than those with low tau burden. Conclusions: Patterns of gray matter loss are associated with neurofibrillary tangle (NFT) pathology, specifically with NFT burden at Braak stages III and IV and with Braak stage itself at higher stages. This validates three-dimensional patterns of atrophy on MRI as an approximate in vivo surrogate indicator of the full brain topographic representation of the neurodegenerative aspect of Alzheimer disease pathology.
Accurate Treatment of Comptonization in X-Ray Illuminated Accretion Disks

A large fraction of accreting black hole and neutron star systems present clear evidence of the reprocessing of X-rays in the atmosphere of an optically thick accretion disk. The main hallmarks of X-ray reflection include fluorescent K-shell emission lines from iron (∼6.4–6.9 keV), the absorption iron K-edge (∼7–9 keV), and a broad featureless component known as the Compton hump (∼20–40 keV). This Compton hump is produced as the result of the scattering of high-energy photons (E ≳ 10 keV) of the relatively colder electrons (Te ∼ 105–107 K) in the accretion disk, in combination with photoelectric absorption from iron. The treatment of this process in most current models of ionized X-ray reflection has been done using an approximated Gaussian redistribution kernel. This approach works sufficiently well up to ∼100 keV, but it becomes largely inaccurate at higher energies and at relativistic temperatures (Te ∼ 109 K). We present new calculations of X-ray reflection using a modified version of our code xillver, including an accurate solution for Compton scattering of the reflected unpolarized photons in the disk atmosphere. This solution takes into account quantum electrodynamic and relativistic effects allowing the correct treatment of high photon energies and electron temperatures. We show new reflection spectra computed with this model, and discuss the improvements achieved in reproducing the correct shape of the Compton hump, the discrepancies with previous calculations, and the expected impact of these new models in the interpretation of observational data.
Incipient post‐zygotic barrier in a model system of ecological speciation with gene flow

The role of post‐zygotic isolation in nonallopatric ecological speciation is still mostly unknown and information on the nature and strength of these barriers in well‐known speciation models is essential for a deeper understanding of such processes. The Galician ecotypes of the marine snail Littorina saxatilis represent one of the best studied cases of nonallopatric ecological speciation. Here, we test the existence of incipient post‐zygotic isolation by comparing the fertility of male hybrids with that of both pure forms [ridged and banded (RB) and smooth and unbanded (SU) ecotypes]. We analysed the degree of sperm DNA fragmentation (SDF) of individuals morphologically classified as RB, SU and hybrids, sampled from two locations. SDF analyses were chosen to study sperm quality because, in other animal species, SDF rates correlate with important parameters for speciation research, such as fertilization and abortion rates and viability of adult progeny. In the present work, hybrids showed significantly higher SDF rates than RB and SU males in one location and significantly higher variances in both locations. These results suggest the existence of an incipient post‐zygotic barrier, the strength of which may vary across the Galician shore, and highlight the potential of SDF analyses for speciation research.