Miracle-dz/UniFAR-FTUs huggingface dataset:
Deletion of the WNK3-SPAK kinase complex in mice improves radiographic and clinical outcomes in malignant cerebral edema after ischemic stroke

The WNK-SPAK kinase signaling pathway controls renal NaCl reabsorption and systemic blood pressure by regulating ion transporters and channels. A WNK3-SPAK complex is highly expressed in brain, but its function in this organ remains unclear. Here, we investigated the role of this kinase complex in brain edema and white matter injury after ischemic stroke. Wild-type, WNK3 knockout, and SPAK heterozygous or knockout mice underwent transient middle cerebral artery occlusion. One cohort of mice underwent magnetic resonance imaging. Ex-vivo brains three days post-ischemia were imaged by slice-selective spin-echo diffusion tensor imaging magnetic resonance imaging, after which the same brain tissues were subjected to immunofluorescence staining. A second cohort of mice underwent neurological deficit analysis up to 14 days post-transient middle cerebral artery occlusion. Relative to wild-type mice, WNK3 knockout, SPAK heterozygous, and SPAK knockout mice each exhibited a >50% reduction in infarct size and associated cerebral edema, significantly less demyelination, and improved neurological outcomes. We conclude that WNK3-SPAK signaling regulates brain swelling, gray matter injury, and demyelination after ischemic stroke, and that WNK3-SPAK inhibition has therapeutic potential for treating malignant cerebral edema in the setting of middle cerebral artery stroke.
Physical Activity, Sedentary Behavior and the Risk of Overweight and Obesity in School-Aged Children.

PURPOSE Globally, public health policies are targeting modifiable lifestyle behaviors. We explore the independent association of moderate-to-vigorous physical activity (MVPA) and sedentary behavior on the risk of childhood overweight/obesity. METHOD A cross-sectional survey of children aged 8-11 years (N = 826). Objective body mass index was used to classify children as normal weight or overweight/obese. Children wore wrist-worn Geneactiv accelerometers for 7-days and thresholds were applied to categorize MVPA and sedentary time. Screen time (ST) was parent reported. Poisson regression examined the independent association of (1) MVPA (2), objective sedentary time and (3) ST on the risk of overweight/obesity. RESULTS Overall, 23.7% (95% CI, 20.8-26.6%) of children were overweight/obese. On average, children spent 10.8% of waking time at MVPA and 61.3% sedentary. One-fifth (22.1%, 95% CI, 19.3-25.0%) of children achieved MVPA recommendations (≥ 60 min each day) and 17.5% (95% CI, 14.9-20.1%) met ST recommendations (<2 hr per day). Time spent at MVPA was inversely associated with the risk of overweight/obese independent of total sedentary time. Total time spent sedentary was not associated with overweight/obese independent of MVPA. ST was associated with an increased risk of overweight/obese independent of physical activity. CONCLUSION Few schoolchildren met physical activity and screen time recommendations suggesting population based measures are needed.
Metabolic connectomics targeting brain pathology in dementia with Lewy bodies

Dementia with Lewy bodies is characterized by α-synuclein accumulation and degeneration of dopaminergic and cholinergic pathways. To gain an overview of brain systems affected by neurodegeneration, we characterized the [18F]FDG-PET metabolic connectivity in 42 dementia with Lewy bodies patients, as compared to 42 healthy controls, using sparse inverse covariance estimation method and graph theory. We performed whole-brain and anatomically driven analyses, targeting cholinergic and dopaminergic pathways, and the α-synuclein spreading. The first revealed substantial alterations in connectivity indexes, brain modularity, and hubs configuration. Namely, decreases in local metabolic connectivity within occipital cortex, thalamus, and cerebellum, and increases within frontal, temporal, parietal, and basal ganglia regions. There were also long-range disconnections among these brain regions, all supporting a disruption of the functional hierarchy characterizing the normal brain. The anatomically driven analysis revealed alterations within brain structures early affected by α-synuclein pathology, supporting Braak’s early pathological staging in dementia with Lewy bodies. The dopaminergic striato-cortical pathway was severely affected, as well as the cholinergic networks, with an extensive decrease in connectivity in Ch1-Ch2, Ch5-Ch6 networks, and the lateral Ch4 capsular network significantly towards the occipital cortex. These altered patterns of metabolic connectivity unveil a new in vivo scenario for dementia with Lewy bodies underlying pathology in terms of changes in whole-brain metabolic connectivity, spreading of α-synuclein, and neurotransmission impairment.
Use of Sildenafil in the Treatment of Erectile Dysfunction in Patients With Spinal Cord Injury

Erectile dysfunction (ED) is one of the major complications after spinal cord injury (SCI) that decreases the quality of life of the patients. Although many efforts have been made to decrease ED, they are frequently cumbersome, with a high failure rate. The aim of this study was to assess the effects of sildenafil citrate at several doses, an oral agent that has been shown to improve a broad spectrum of ED. Sixty male patients with SCI were divided into 2 groups and received 25 mg or 50 mg sildenafil citrate, respectively, during a 4-week treatment period 1 hour before sexual intercourse. Our results demonstrated that sildenafil citrate significantly improved reflexogenic erectile response in both groups (P=0.02 and P=0.01, respectively). Subjects receiving sildenafil citrate reported that treatment had significantly improved their erections, frequency of sexual intercourse, satisfaction, enjoyment, sexual desire, overall sex life, sexual relationship, and self-confidence in erections (P<0.05). There was no statistically significant difference between 2 groups regarding the dosage regimen (P>0.05). The authors concluded that sildenafil citrate might be used effectively for the treatment of ED in patients with SCI, even in a low-dose (25 mg) regimen.
Tunneling effect on enhanced OLED performance using Al2O3 buffer layer

It has been found that introduction of buffer layers between organic holes transport layer and anode layer plays an important role in improving device stability and hole injection efficiency of organic light-emitting diodes (OLED). As for the mechanism of the improvement due to the buffer layer, it is still controversial. To understand the mechanism behind the enhanced performance of OLED by the buffer layer, a new model is therefore proposed which combines classical model and quantum tunneling model to explain the OLED performance improvement. A thin Al2O3 insulating buffer layer deposited on indium tin oxide (ITO) anode by atomic layer deposition has been investigated for OLED. The observed power efficiency and current efficiency improvement at the optimal thickness of 1.4 nm are well explained by the model. A series of Al2O3 films of different thicknesses were deposited on ITO anode and characterized. Their roughness, sheet resistance, surface potential, and resulted OLED current density were investigated. It is believed that the blocking of hole inject by the Al2O3 buffer layer makes more balanced carrier density in emission layer, thus enhances the current efficiency. Though less number of holes are injected in OLED due to the insertion of Al2O3 layer, quantum tunneling through the ultra-thin buffer layer play an important role to contribute to the hole injection, which avoids crossing the interface barrier, resulting in less energy consumed and power efficiency enhanced.
A method to estimate the energy consumption of deep neural networks

Deep Neural Networks (DNNs) have enabled state-of-the-art accuracy on many challenging artificial intelligence tasks. While most of the computation currently resides in the cloud, it is desirable to embed DNN processing locally near the sensor due to privacy, security, and latency concerns or limitations in communication bandwidth. Accordingly, there has been increasing interest in the research community to design energy-efficient DNNs. However, estimating energy consumption from the DNN model is much more difficult than other metrics such as storage cost (model size) and throughput (number of operations). This is due to the fact that a significant portion of the energy is consumed by data movement, which is difficult to extract directly from the DNN model. This work proposes an energy estimation methodology that can estimate the energy consumption of a DNN based on its architecture, sparsity, and bitwidth. This methodology can be used to evaluate the various DNN architectures and energy-efficient techniques that are currently being proposed in the field and guide the design of energy-efficient DNNs. We have released an online version of the energy estimation tool at energyestimation.mit. edu. We believe that this method will play a critical role in bridging the gap between algorithm and hardware design and provide useful insights for the development of energy-efficient DNNs.
Cerebellar heterogeneity and its impact on PET data quantification of 5-HT receptor radioligands

In the quantification of positron emission tomography (PET) radiotracer binding, a commonly used method is reference tissue modeling (RTM). RTM necessitates a proper reference and a ubiquitous choice for G-protein coupled receptors is the cerebellum. We investigated regional differences in uptake within the grey matter of the cerebellar hemispheres (CH), the cerebellar white matter (CW), and the cerebellar vermis (CV) for five PET radioligands targeting the serotonin system. Furthermore, we evaluated the impact of choosing different reference regions when quantifying neocortical binding. The PET and MR images are part of the Cimbi database: 5-HT1AR ([11C]CUMI-101, n = 8), 5-HT1BR ([11C]AZ10419369, n = 36), 5-HT2AR ([11C]Cimbi-36, n = 29), 5-HT4R ([11C]SB207145, n = 59), and 5-HTT ([11C]DASB, n = 100). We employed SUIT and FreeSurfer to delineate CV, CW, and CH and quantified mean standardized uptake values (SUV) and nondisplaceable neocortical binding potential (BPND). Statistical difference was assessed with paired nonparametric two-sided Wilcoxon signed-rank tests and multiple comparison corrected via false discovery rate. We demonstrate significant radioligand specific regional differences in cerebellar uptake. These differences persist when using different cerebellar regions for RTM, but the influence on the neocortical BPND is small. Nevertheless, our data highlight the importance of validating each radioligand carefully for defining the optimal reference region.
CYP3A4-Mediated Ester Cleavage as the Major Metabolic Pathway of the Oral Taxane 3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183)

3′-tert-Butyl-3′-N-tert-butyloxycarbonyl-4-deacetyl-3′-dephenyl-3′-N-debenzoyl-4-O-methoxycarbonyl-paclitaxel (BMS-275183) is an orally available taxane analog that has the potential to be used as an oral agent to treat cancers. The compound is similar to the two clinically intravenously administered taxanes, paclitaxel and docetaxel, in that it contains a baccatin ring linked to a side chain through an ester bond. Unlike the other taxanes, the hydrolysis of this ester bond leads to formation of a free baccatin core (M13) that was the major metabolism pathway in incubations of [14C]BMS-275183 in human liver microsomes (HLMs) in the presence of NADPH, but it was not formed in incubations with human liver cytosol or HLM in the absence of NADPH. The other prominent metabolites formed in HLM incubations resulted from oxidation of t-butyl groups on the side chain (M20, M20B, M21, M22, and M23). All these metabolites were formed by cDNA-expressed CYP3A and not by other cytochrome P450 (P450) enzymes tested. Formation of these metabolites was selectively inhibited by ketoconazole and troleandomycin. The formation of M13 followed Michaelis-Menten kinetics with the Km values of 1.3 to 2.4 μM in HLM or CYP3A4; the Vmax value for the formation of M13 and M23 in the cDNA-expressed CYP3A4 matched well (within 2-fold difference) with that determined in HLM when expressed in units of per picomole of P450. These results showed that BMS-275183 is metabolized by CYP3A4 to yield baccatin through oxidation of side-chain t-butyl groups. An intramolecular cyclization of a side-chain hydroxylation metabolite is proposed to be responsible for the formation of M13, the side-chain hydrolysis metabolite.
Type-2 diabetes mellitus reduces cortical thickness and decreases oxidative metabolism in sensorimotor regions after stroke

Individuals with type-2 diabetes mellitus experience poor motor outcomes after ischemic stroke. Recent research suggests that type-2 diabetes adversely impacts neuronal integrity and function, yet little work has considered how these neuronal changes affect sensorimotor outcomes after stroke. Here, we considered how type-2 diabetes impacted the structural and metabolic function of the sensorimotor cortex after stroke using volumetric magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS). We hypothesized that the combination of chronic stroke and type-2 diabetes would negatively impact the integrity of sensorimotor cortex as compared to individuals with chronic stroke alone. Compared to stroke alone, individuals with stroke and diabetes had lower cortical thickness bilaterally in the primary somatosensory cortex, and primary and secondary motor cortices. Individuals with stroke and diabetes also showed reduced creatine levels bilaterally in the sensorimotor cortex. Contralesional primary and secondary motor cortex thicknesses were negatively related to sensorimotor outcomes in the paretic upper-limb in the stroke and diabetes group such that those with thinner primary and secondary motor cortices had better motor function. These data suggest that type-2 diabetes alters cerebral energy metabolism, and is associated with thinning of sensorimotor cortex after stroke. These factors may influence motor outcomes after stroke.
Effect of Hepatic Cytochrome P450 (P450) Oxidoreductase Deficiency on 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine-DNA Adduct Formation in P450 Reductase Conditional Null Mice

2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), formed during the cooking of foods, induces colon cancer in rodents. PhIP is metabolically activated by cytochromes P450 (P450s). To evaluate the role of hepatic P450s in the bioactivation of PhIP, we used Reductase Conditional Null (RCN) mice, in which cytochrome P450 oxidoreductase (POR), the unique electron donor to P450s, can be specifically deleted in hepatocytes by pretreatment with 3-methylcholanthrene (3-MC), resulting in the loss of essentially all hepatic P450 function. RCN mice were treated orally with 50 mg/kg b.wt. PhIP daily for 5 days, with and without 3-MC pretreatment. PhIP-DNA adducts (i.e., N-(deoxyguanosin-8-yl)-2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine [dG-C8-PhIP]), measured by liquid chromatography-tandem mass spectrometry, were highest in colon (1362 adducts/108 deoxynucleosides), whereas adduct levels in liver were ∼3.5-fold lower. Whereas no differences in PhIP-DNA adduct levels were found in livers with active POR versus inactivated POR, adduct levels were on average ∼2-fold lower in extrahepatic tissues of mice lacking hepatic POR. Hepatic microsomes from RCN mice with or without 3-MC pretreatment were also incubated with PhIP and DNA in vitro. PhIP-DNA adduct formation was ∼8-fold lower with hepatic microsomes from POR-inactivated mice than with those with active POR. Most of the hepatic microsomal activation of PhIP in vitro was attributable to CYP1A. Our results show that PhIP-DNA adduct formation in colon involves hepatic N-oxidation, circulation of activated metabolites via the bloodstream to extrahepatic tissues, and further activation, resulting in the formation of dG-C8-PhIP. Besides hepatic P450s, PhIP may be metabolically activated mainly by a non-P450 pathway in liver.
Phenacetin Pharmacokinetics in CYP1A2-Deficient Beagle Dogs

Phenacetin is widely used as an in vitro probe to measure CYP1A2 activity across species. To investigate whether phenacetin can be used as an in vivo probe substrate to phenotype CYP1A2 activity in dogs, beagle dogs previously genotyped for a single nucleotide polymorphism that yields an inactive CYP1A2 protein were selected and placed into one of three groups: CC (wild-type), CT (heterozygous), or TT (homozygous mutants). The dogs were dosed with phenacetin orally at 5 and 15 mg/kg and intravenously at 15 mg/kg. Plasma samples were analyzed by liquid chromatography-tandem mass spectrometry, and phenacetin and its primary metabolite, acetaminophen, were monitored. After intravenous dosing, all groups showed similar exposure of phenacetin irrespective of genotype. After oral dosing at 15 mg/kg, the exposure of phenacetin in CC and CT dogs was similar, but phenacetin exposure was 2-fold greater in TT dogs. Exposure of the metabolite, acetaminophen, was similar in all groups; however, the mean acetaminophen/phenacetin ratio in TT dogs was 1.7 times less than that observed in CC dogs. Similar trends between the groups of dogs with respect to phenacetin exposure were also observed after a lower 5 mg/kg p.o. dose of phenacetin; however, a proportionally greater amount of acetaminophen was generated. Although oral exposure of phenacetin was 2-fold higher and acetaminophen exposure was 2-fold lower in CYP1A2-deficient (TT) dogs, these results were considered modest and suggest that phenacetin is not a selective or robust in vivo probe to measure CYP1A2 enzyme activity in the dog.
White matter hyperintensities associated with small vessel disease impair social cognition beside attention and memory

Age-related white matter hyperintensities (WMH) are a manifestation of white matter damage seen on magnetic resonance imaging (MRI). They are related to vascular risk factors and cognitive impairment. This study investigated the cognitive profile at different stages of WMH in a large community-dwelling sample; 849 subjects aged 21 to 79 years were classified on the 4-stage Fazekas scale according to hyperintense lesions seen on individual T2-weighted fluid-attenuated inversion recovery MRI scans. The evaluation of cognitive functioning included seven domains of cognitive performance and five domains of subjective impairment, as proposed by the DSM-5. For the first time, the impact of age-related WMH on Theory of Mind was investigated. Differences between Fazekas groups were analyzed non-parametrically and effect sizes were computed. Effect sizes revealed a slight overall cognitive decline in Fazekas groups 1 and 2 relative to healthy subjects. Fazekas group 3 presented substantial decline in social cognition, attention and memory, although characterized by a high inter-individual variability. WMH groups reported subjective cognitive decline. We demonstrate that extensive WMH are associated with specific impairment in attention, memory, social cognition, and subjective cognitive performance. The detailed neuropsychological characterization of WMH offers new therapeutic possibilities for those affected by vascular cognitive decline.
An immunohistochemical study of arterial lesions due to pulmonary hypertension in patients with congenital heart defects

Abstract In order to understand some of the cellular mechanisms of interaction in secondary pulmonary vaso-occlusive disease, we studied 21 lung biopsies from patients with different types of congenital cardiac defects. Their ages ranged from four to 248 months (mean 71.5 months; median 41 months). Changes in the cytoskeleton and extracellular matrix were assessed in the arterial wall. Immunostaining was applied to formalin-fixed, paraffin- embedded tissue, using antibodies to muscle-specific actin, vimentin and fibronectin in supra-optimal dilution. The staining for muscle-specific actin in the medial layer revealed a heterogenous pattern, with areas exhibiting low or absent labelling, reflecting a process of dedifferentiation of the smooth muscle cells in those segments. Within intimal proliferative lesions, the expression of muscle-specific actin was variable, being weak in some lesions and strong in those showing concentrically arranged intimal smooth muscle cells, suggesting a reversion of the migrated cells to the contractile phenotype. The endothelial cells of arteries from cases presenting severe qualitative lesions exhibited strong expression of vimentin, reflecting their heightened regenerative activity and/or their necessity to maintain their shape. The expression of fibronectin was greater in the predominantly cellular lesions of the intima when compared to the fibrotic lesions, indicating the role of that matrix glycoprotein in cellular migration and in replicative processes.
EPI-CKD is a poor predictor of GFR in pregnancy

Background Estimated glomerular filtration rate (eGFR) is a widespread tool used to screen high risk populations for renal disease. We have previously reported that the Modified Diet in Renal Disease (MDRD) equation is not a clinically useful in pregnancy.1 Recently, Levey et al2 have published a modification of the previous formula (epi-CKD) to improve prediction at higher filtration rates. Using our previously published data we have evaluated the new equation in pregnancy. Methods 24 women were serially studied in early and late pregnancy and postpartum. On each occasion GFR was measured using the ‘gold standard’ method of inulin clearance (Cin) and this value compared to predicted GFR using the epi-CKD formula. Results There was no significant difference between Cin and epi-CKD values (p>0.05) in the postnatal period in keeping with the formula being a useful tool in healthy adults outside of pregnancy. Throughout pregnancy, however, the formula significantly underestimated GFR. This was most pronounced in late pregnancy when precision testing as measured by linear regression, yielded an R2 value of 0.01 and concordance, measured by the Bland-Altman method, was poor with a bias of 40 ml/min/1.73 m2. Conclusion The epi-CKD formula significantly underestimates GFR in pregnancy, similarly to the previously reported MDRD formula. Correlation is poor and the magnitude of discrepancy with actual GFR is such that it would be expected to mislead clinical decisions.