Miracle-dz/UniFAR-FTUs huggingface dataset:
RESPIRATORY MODULATION OF PERIPHERAL VASOCONSTRICTION:A MODELING PERSPECTIVE.

While respiratory sinus arrhythmia and blood pressure variability have been investigated extensively, there have been far fewer studies of the respiratory modulation of peripheral blood flow in humans. Existing studies have been based primarily on noninvasive measurements using digit photoplethysmography and laser-doppler flowmetry. The cumulative knowledge derived from these studies suggest that respiration can contribute to fluctuations in peripheral blood flow and volume through a combination of mechanical, hemodynamic and neural mechanisms. However, the most convincing evidence suggests that the sympathetic nervous system plays the predominant role under normal, resting conditions. This mini-review provides a consolidation and interpretation of the key findings reported in this topical area. Given the need to extract dynamic information from noninvasive measurements under largely "closed-loop" conditions, we propose that the application of analytical tools based on systems theory and mathematical modeling can be of great utility in future studies. In particular, we present an example of how the transfer relation linking respiration to peripheral vascular conductance can be derived using measurements recorded during spontaneous breathing, spontaneous sighs, and ventilator-induced sighs.
Uses and potential for cardiac magnetic resonance imaging in patients with cardiac resynchronisation pacemakers

ABSTRACT Introduction: Cardiac magnetic resonance (CMR) imaging has been shown to be safe as an imaging modality for patients with cardiac resynchronization (CRT) devices. As a widely accepted method of measuring cardiac volumes, mass, and ejection fraction, CMR has become a core part of the diagnostic panel. A number of studies have already highlighted a role in optimizing left ventricular lead placemen with evidence that scanning is useful prior to implantation to predict outcomes and optimizing device effect. By balancing the considerations of CMR with the benefits, there may be further applications. Areas covered: The aim of the review is to discuss the applications of CMR pre and post CRT implantation with an exploration into the future utility of this imaging modality. Expert opinion: CMR has underutilized potential in improving diagnostics and care for patients implanted with CRT devices. Scanning patients post CRT implantation is not conducted routinely despite multiple potential applications. By employing modern technology and techniques, there is scope to improve CMR utility postimplantation by scanning at higher field strengths whilst CRT is active. We believe CMR has utility with advances expected to translate to improved treatment response and clinical outcomes.
Tissue plasminogen activator protects hippocampal neurons from oxygen‐glucose deprivation injury

We have previously shown that tissue plasminogen activator (tPA) participates in the neurotoxicity of microglial conditioned medium (MgCM). Killing of hippocampal neurons by MgCM was prevented by both plasminogen activator inhibitor‐1 (PAI‐1) and anti‐tPA antibody. An N‐methyl‐D‐aspartate (NMDA) receptor blocker protected neurons from MgCM, suggesting that this subtype of glutamate receptor is involved. Whereas glutamate receptor‐mediated events are important in cerebral ischemia and tPA has previously been shown to enhance excitotoxicity in hippocampus, we hypothesized that tPA would exaggerate oxygen glucose deprivation (OGD) injury in cultures of hippocampal neurons. Dissociated rat hippocampal cells were grown under conditions designed to optimize neuronal growth while minimizing glial replication. At 7–10 days, cultures were subjected to OGD for 2.5 hr. Recombinant human tPA (1,000 IU) was added immediately after OGD. Viability was assessed 24 hr later. Viable, apoptotic, and necrotic cells were classified and quantified based on staining patterns of acridine orange and ethidium bromide under fluorescence microscopy. tPA alone did not alter neuronal integrity. OGD produced significant neuronal death (viability reduced by 45%, P < 0.001). tPA completely protected OGD‐exposed cultures. Potential mechanisms of tPA protection were explored. Whereas tPA antibody abolished the protective effect of tPA, its proteolytic inhibitor PAI‐1 did not alter the effect. The effect of tPA was tested in separate free radical and excitatory amino acid insults. It did not protect neurons from hydrogen peroxide (1 μM), S‐nitro‐acetylpenicillamine (10 μM), glutamate (50 μM), or NMDA (10 μM) damage but significantly attenuated injury caused by 250 μM kainate. We conclude that tPA is capable of protecting hippocampal neurons from OGD by a nonproteolytic action. The mechanism of protection was not defined, although attenuation of AMPA/kainate glutamate receptors may play a role. J. Neurosci. Res. 63:388–394, 2001. © 2001 Wiley‐Liss, Inc.
Image Subtraction Facilitates Assessment of Volume and Density Change in Ground-Glass Opacities in Chest CT

Objectives:To study the impact of image subtraction of registered images on the detection of change in pulmonary ground-glass nodules identified on chest CT. Materials and Methods:A cohort of 33 individuals (25 men, 8 women; age range 51–75 years) with 37 focal ground-glass opacities (GGO) were recruited from a lung cancer screening trial. For every participant, 1 to 3 follow-up scans were available (total number of pairs, 84). Pairs of scans of the same nodule were registered nonrigidly and then subtracted to enhance differences in size and density. Four observers rated size and density change of the GGO between pairs of scans by visual comparison alone and with additional availability of a subtraction image and indicated their confidence. An independent experienced chest radiologist served as an arbiter having all reader data, clinical data, and follow-up examinations available. Nodule pairs for which the arbiter could not establish definite progression, regression, or stability were excluded from further evaluation. This left 59 and 58 pairs for evaluation of size and density change, respectively. Weighted kappa statistics (&kgr;w) were used to assess interobserver agreement and agreement with the arbiter. Statistical significance was tested with a &kgr; z-test. Results:When the subtraction image was available, the average interobserver &kgr;w improved from 0.52 to 0.66 for size change and from 0.47 to 0.57 for density change. Average agreement with the arbiter improved from 0.61 to 0.76 for size change and from 0.53 to 0.64 for density change. The effect was more pronounced when observer confidence without the subtraction image was low: agreement improved from 0.26 to 0.57 and from 0.19 to 0.47 in those cases. Conclusions:Image subtraction improves the evaluation of subtle changes in pulmonary ground-glass opacities and decreases interobserver variability.
Caloric tests in clinical practice in benign paroxysmal positional vertigo

Abstract Background: The value of caloric tests in benign paroxysmal positional vertigo (BPPV) patients is unclear. Objectives: To analyze the features and clinical significance of caloric tests in BPPV patients. Materials and methods: About 2192 patients (256 BPPV and 1936 non-BPPV) who complained of dizziness triggered by movement, accompanied by the symptom of hearing loss or a history of vertigo, participated in this prospective clinical study. All subjects received a caloric test, 213 BPPV patients underwent follow-up for at least 6 months after canalith repositioning procedures (CRPs). Results: (1) The abnormal canal paresis (CP) prevalence of BPPV was 57%. (2) The curative rate of single CRP decreased during follow-up from 90.1% after 7 days to 61% after 6 months and was significantly lower in patients with (54.1%) than in those without (70.1%) an abnormal CP at 6 months post-treatment (p = .01). (3) The recurrent rate was significantly higher in BPPV patients with abnormal CP (25.2%) than with normal CP (12.5%; p = .017). Conclusions and significance: Patients with abnormal CP needed more CRPs and were more prone to relapse. The value of the caloric test in treatment planning and predicting recurrence in BPPV patients should be emphasized.
Newly Generated and Non-Newly Generated “Immature” Neurons in the Mammalian Brain: A Possible Reservoir of Young Cells to Prevent Brain Aging and Disease?

Brain plasticity is important for translational purposes since most neurological disorders and brain aging problems remain substantially incurable. In the mammalian nervous system, neurons are mostly not renewed throughout life and cannot be replaced. In humans, the increasing life expectancy explains the increase in brain health problems, also producing heavy social and economic burden. An exception to the “static” brain is represented by stem cell niches leading to the production of new neurons. Such adult neurogenesis is dramatically reduced from fish to mammals, and in large-brained mammals with respect to rodents. Some examples of neurogenesis occurring outside the neurogenic niches have been reported, yet these new neurons actually do not integrate in the mature nervous tissue. Non-newly generated, “immature” neurons (nng-INs) are also present: Prenatally generated cells continuing to express molecules of immaturity (mostly shared with the newly born neurons). Of interest, nng-INs seem to show an inverse phylogenetic trend across mammals, being abundant in higher-order brain regions not served by neurogenesis and providing structural plasticity in rather stable areas. Both newly generated and nng-INs represent a potential reservoir of young cells (a “brain reserve”) that might be exploited for preventing the damage of aging and/or delay the onset/reduce the impact of neurological disorders.
Foxp3+ regulatory T cells, immune stimulation and host defence against infection

The immune system is intricately regulated allowing potent effectors to expand and become rapidly mobilized after infection, while simultaneously silencing potentially detrimental responses that averts immune‐mediated damage to host tissues. This relies in large part on the delicate interplay between immune suppressive regulatory CD4+ T (Treg) cells and immune effectors that without active suppression by Treg cells cause systemic and organ‐specific autoimmunity. Although these beneficial roles have been classically described as counterbalanced by impaired host defence against infection, newfound protective roles for Treg cells against specific viral pathogens (e.g. herpes simplex virus 2, lymphocytic choriomeningitis virus, West Nile virus) have been uncovered using transgenic mice that allow in vivo Treg‐cell ablation based on Foxp3 expression. In turn, Foxp3+ Treg cells also provide protection against some parasitic (Plasmodium sp., Toxoplasma gondii) and fungal (Candida albicans) pathogens. By contrast, for bacterial and mycobacterial infections (e.g. Listeria monocytogenes, Salmonella enterica, Mycobacterium tuberculosis), experimental manipulation of Foxp3+ cells continues to indicate detrimental roles for Treg cells in host defence. This variance is probably related to functional plasticity in Treg cell suppression that shifts discordantly following infection with different types of pathogens. Furthermore, the efficiency whereby Treg cells silence immune activation coupled with the plasticity in Foxp3+ cell activity suggest that overriding Treg‐mediated suppression represents a prerequisite ‘signal zero’ that together with other stimulation signals [T‐cell receptor (signal 1), co‐stimulation (signal 2), inflammatory cytokines (signal 3)] are essential for T‐cell activation in vivo. Herein, the importance of Foxp3+ Treg cells in host defence against infection, and the significance of infection‐induced shifts in Treg‐cell suppression are summarized.
Diamonds and the African Lithosphere

Data and inferences drawn from studies of diamond inclusions, xenocrysts, and xenoliths in the kimberlites of southern Africa are combined to characterize the structure of that portion of the Kaapvaal craton that lies within the mantle. The craton has a root composed in large part of peridotites that are strongly depleted in basaltic components. The asthenosphere boundary shelves from depths of 170 to 190 kilometers beneath the craton to approximately 140 kilometers beneath the mobile belts bordering the craton on the south and west. The root formed earlier than 3 billion years ago, and at that time ambient temperatures in it were 900� to 1200�C; these temperatures are near those estimated from data for xenoliths erupted in the Late Cretaceous or from present-day heat-flow measurements. Many of the diamonds in southern Africa are believed to have crystallized in this root in Archean time and were xenocrysts in the kimberlites that brought them to the surface.
A simple derivation of BV bounds for inhomogeneous relaxation systems

We consider relaxation systems of transport equations with heterogeneous source terms and with boundary conditions, which limits are scalar conservation laws. Classical bounds fail in this context and in particular BV estimates. They are the most standard and simplest way to prove compactness and convergence. We provide a novel and simple method to obtain partial BV regularity and strong compactness in this framework. The standard notion of entropy is not convenient either and we also indicate another, but closely related, notion. We give two examples motivated by renal flows which consist of 2 by 2 and 3 by 3 relaxation systems with 2-velocities but the method is more general.
Increasing incidence of colorectal cancer in young adults in Europe over the last 25 years

Objective The incidence of colorectal cancer (CRC) declines among subjects aged 50 years and above. An opposite trend appears among younger adults. In Europe, data on CRC incidence among younger adults are lacking. We therefore aimed to analyse European trends in CRC incidence and mortality in subjects younger than 50 years. Design Data on age-related CRC incidence and mortality between 1990 and 2016 were retrieved from national and regional cancer registries. Trends were analysed by Joinpoint regression and expressed as annual percent change. Results We retrieved data on 143.7 million people aged 20–49 years from 20 European countries. Of them, 187 918 (0.13%) were diagnosed with CRC. On average, CRC incidence increased with 7.9% per year among subjects aged 20–29 years from 2004 to 2016. The increase in the age group of 30–39 years was 4.9% per year from 2005 to 2016, the increase in the age group of 40–49 years was 1.6% per year from 2004 to 2016. This increase started earliest in subjects aged 20–29 years, and 10–20 years later in those aged 30–39 and 40–49 years. This is consistent with an age-cohort phenomenon. Although in most European countries the CRC incidence had risen, some heterogeneity was found between countries. CRC mortality did not significantly change among the youngest adults, but decreased with 1.1%per year between 1990 and 2016 and 2.4% per year between 1990 and 2009 among those aged 30–39 years and 40–49 years, respectively. Conclusion CRC incidence rises among young adults in Europe. The cause for this trend needs to be elucidated. Clinicians should be aware of this trend. If the trend continues, screening guidelines may need to be reconsidered.
Changes in Carotid Artery Flow Velocities after Stent Implantation: A Fluid Dynamics Study with Laser Doppler Anemometry

Purpose: To study the influence of stent size and location on flow patterns in a physiological carotid model. Methods: Wallstents were positioned in silicon models of the carotid artery at various locations: 2 stents appropriately sized to the anatomy were placed in (1) the internal carotid artery (ICA) and (2) the ICA extending completely into the common carotid artery so as to cover the external carotid artery (ECA) orifice. Another 2 stents were placed in the ICA extending (1) partially and (2) completely into the bulb to simulate stent displacement and disproportion between stent size and the original vessel geometry. Measurements were performed with laser Doppler anemometry (LDA) using pulsatile flow conditions (Reynolds number=250; flow 0.431 L/min; ICA:ECA flow rate ratio 70:30) in hemodynamically relevant cross sections. The hemodynamic changes were analyzed with 1-dimensional flow profiles. Results: With the stent in the ICA, no changes of the normal flow profile were seen. For stents positioned in the ICA and extending partially or completely into the carotid bulb, the flow behavior was affected by the resistance of the stent to flow in the ECA. Hemodynamically relevant disturbances were seen in the ICA and ECA, especially in the separation zones (regions along the walls just after a bifurcation, bend, or curve). The ICA:ECA flow rate ratios shifted from 70:30 to 71.3:28.7 and from 70:30 to 75.1:24.9, respectively, in the 2 malpositioned stent models. With the stent placed in the ICA extending completely into the CCA, the ICA:ECA flow rate ratio shifted from 70:30 to 72.4:27.6. In this configuration, there were no notable flow changes in the ICA, but a clear diminishing of the separation zones in the ECA separation zones. Conclusions: Anatomically correct positioning of appropriately sized stents does not lead to relevant flow disturbances in the ICA. In the ECA, depending on the position, size, and interstices of the stent, the physiological flow was considerably disturbed when any part of the stent covered the inflow of the vessel. Disturbances were seen when the stent was positioned into the bulb. For clinical application, stent location and size must be carefully determined so that the stent covers the bifurcation completely or is in the ICA only.
Pyridine derivatives as anticancer lead compounds with Fatty Acid Synthase as the target: An in silico‐guided in vitro study

For the past few decades, structure‐based drug discovery (SBDD) has become an inevitable technique in the drug development process for screening hit compounds against therapeutic targets. Here, we have successfully used the SBDD approach viz. virtual high‐throughput screening to identify potential inhibitors against the Ketoacyl synthase (KS) domain of Fatty acid synthase (FASN). Overexpression of FASN, and subsequent enhancement of de novo lipogenesis is a key survival strategy of cancer cells. Hence, targeting lipid metabolism using FASN inhibitors has been considered as a promising method to induce metabolic stress, thereby posing a survival disadvantage to cancer cells. In the present study, we have successfully identified eight FASN inhibitors from Asinex Elite database by implementing in silico tools. Five of the hit compounds share a common ring structure, which enables characteristic binding interactions with FASN‐KS. Among them, in vitro validation showed that SFA 22637550 possesses significant FASN inhibitory activity and antiproliferative effect in human cancer cells of various origins. The maximum sensitivity was exhibited towards HepG2 hepatocellular carcinoma cells (IC50 = 28 µM). The mode of cell death was found to be apoptosis with a significant increase in SubG0 population without affecting any other phases of the cell cycle. The current study puts forward an excellent core structure for the development of potent FASN inhibitors for successfully targeting cancer cell metabolism, thereby causing selective cell death.
Ensemble confidence intervals for binomial proportions

We propose two measures of performance for a confidence interval for a binomial proportion p: the root mean squared error and the mean absolute deviation. We also devise a confidence interval for p based on the actual coverage function that combines several existing approximate confidence intervals. This “Ensemble” confidence interval has improved statistical properties over the constituent confidence intervals. Software in an R package, which can be used in devising and assessing these confidence intervals, is available on CRAN.
[Effect of metformin on the expression of SIRT1 and UCP2 in rat liver of type 2 diabetes mellitus and nonalcoholic fatty liver].

OBJECTIVE To observe the effect of metformin on the expression of SIRT1 and UCP2 in rat liver of type 2 diabetes mellitus (T2DM) with nonalcoholic fatty liver disease (NAFLD), and discuss the pathogenesis of T2DM with NAFLD, and the treatment with and possible mechanism of metformin. METHODS Thirty-six male SD rats were randomly divided into a normal control group (group NC, n=12), a T2DM with NAFLD group (group MC, n=12), and a metformin group (group A, n=12). We established the model of T2DM with NAFLD rats by feeding high-fat and high-sugar diet and injecting STZ. After the success establishment of the model, the metformin group was given metformin 300 mg/(kg.d) for 8 weeks. At the end of the experiment, we measured FBG, ALT, AST, TC, TG, HDL-C, LDL-C, VLDL, FFAs, FINs and HOMA-IR respectively in group NC, MC and A. We observed the change of liver tissue pathology by HE, determined the expression of SIRT1 and UCP2 in rat liver by immunohistochemical method and real-time quantitative method. RESULTS FBG, ALT, AST, TC, TG, LDL-C, VLDL, FFAs, FINs and HOMA-IR were higher in group MC than in group NC (P<0.05), while HDL-C was obviously lower in group MC than in group NC (P<0.05). After the metformin treatment, the serum parameters in the rats had improved in group NC compared with in group MC (P<0.05). On immunohistochemical staining and mRNA level, the expression of SIRT1 was obviously lower in group MC than in group NC (P<0.05), and the expression of UCP2 was obviously higher in group MC than in group NC (P<0.05). After the metformin treatment, the expression of SIRT1 was higher than in group MC (P<0.05), and the expression of UCP2 was lower than in group MC (P<0.05). There was negative correlation between the expression of SIRT1 and UCP2 (r=-0.61, P<0.01). CONCLUSION The expression of SIRT1 is low and the expression of UCP2 is high in rat liver of T2DM with NAFLD. Metformin can increase the expression of SIRT1 and reduce the expression of UCP2, with negative correlation between the expression of SIRT1 and UCP2.
Gibberellins Act Downstream of Arabis PERPETUAL FLOWERING 1 to Accelerate Floral Induction during Vernalization 1 [ OPEN ]

Regulation of flowering by endogenous and environmental signals ensures that reproduction occurs under optimal conditions tomaximize reproductive success. Involvement of the growth regulator gibberellin (GA) in the control of flowering by environmental cues varies among species. Arabis alpina Pajares, a model perennial member of the Brassicaceae, only undergoes floral induction during vernalization, allowing definition of the role of GA specifically in this process. The transcription factor PERPETUAL FLOWERING1 (PEP1) represses flowering until its mRNA levels are reduced during vernalization. Genome-wide analyses of PEP1 targets identified genes involved in GA metabolism and signaling, and many of the binding sites in these genes were specific to the A. alpina lineage. Here, we show that the pep1 mutant exhibits an elongated-stem phenotype, similar to that caused by treatment with exogenous GA, consistent with PEP1 repressing GA responses. Moreover, in comparison with the wild type, the pep1mutant contains higher GA4 levels and is more sensitive to GA prior to vernalization. Upon exposure to cold temperatures, GA levels fall to low levels in the pep1mutant and in wild-type plants, but GA still promotes floral induction and the transcription of floral meristem identity genes during vernalization. Reducing GA levels strongly impairs flowering and inflorescence development in response to short vernalization treatments, but longer treatments overcome the requirement for GA. Thus, GA accelerates the floral transition during vernalization in A. alpina, the down-regulation of PEP1 likely increases GA sensitivity, and GA responses contribute to determining the length of vernalization required for flowering and reproduction.