A recycling amplifier architecture based on the folded cascode transconductance amplifier is described. The proposed amplifier delivers an appreciably enhanced performance over that of the ...conventional folded. This is achieved by using previously idle devices in the signal path, which results in an enhanced transconductance, gain, and slew rate. Moreover, the input referred noise and offset analyses are included to demonstrate that the proposed modifications have no adverse effects on these design metrics. Transistor-level simulations and experimental results in TSMC 0.18 mum CMOS process confirm the theoretical results. When compared to the conventional folded cascode, and for the same area and power budgets, the proposed amplifier has almost twice the bandwidth (134.2 MHz versus 70.7 MHz) and better than twice the slew rate (94.1 V/mus versus 42.1 V/mus) while driving the same 5.6 pF load. Also a gain enhancement of 7.6 dB is observed.
Damage to the CNS can cause a differential spatio-temporal release of multiple factors, such as nucleotides, ATP and UTP. The latter interact with neuronal and glial nucleotide receptors. The P2Y2 ...nucleotide receptor (P2Y2R) has gained prominence as a modulator of gliotic responses after CNS injury. Still, the molecular mechanisms underlying these responses in glia are not fully understood. Membrane-raft microdomains, such as caveolae, and their constituent caveolins, modulate receptor signaling in astrocytes; yet, their role in P2Y2R signaling has not been adequately explored. Hence, this study evaluated the role of caveolin-1 (Cav-1) in modulating P2Y2R subcellular distribution and signaling in human 1321N1 astrocytoma cells. Recombinant hP2Y2R expressed in 1321N1 cells and Cav-1 were found to co-fractionate in light-density membrane-raft fractions, co-localize via confocal microscopy, and co-immunoprecipitate. Raft localization was dependent on ATP stimulation and Cav-1 expression. This hP2Y2R/Cav-1 distribution and interaction was confirmed with various cell model systems differing in the expression of both P2Y2R and Cav-1, and shRNA knockdown of Cav-1 expression. Furthermore, shRNA knockdown of Cav-1 expression decreased nucleotide-induced increases in the intracellular Ca2+ concentration in 1321N1 and C6 glioma cells without altering TRAP-6 and carbachol Ca2+ responses. In addition, Cav-1 shRNA knockdown also decreased AKT phosphorylation and altered the kinetics of ERK1/2 activation in 1321N1 cells. Our findings strongly suggest that P2Y2R interaction with Cav-1 in membrane-raft caveolae of 1321N1 cells modulates receptor coupling to its downstream signaling machinery. Thus, P2Y2R/Cav-1 interactions represent a novel target for controlling P2Y2R function after CNS injury.
Obesity is usually associated with low-grade inflammation, which determines the appearance of comorbidities like atherosclerosis and insulin resistance. Infiltrated macrophages in adipose tissue are ...partly responsible of this inflammatory condition. Numerous studies point to the existence of close intercommunication between macrophages and adipocytes and pay particular attention to the proinflammatory cytokines released by both cell types. However, it has been recently described that in both, circulation and tissue level, there are extracellular vesicles (including microvesicles and exosomes) containing miRNAs, mRNAs, and proteins that can influence the inflammatory response. The objective of the present research is to investigate the effect of exosomes released by lipopolysaccharide (LPS)-activated macrophages on gene expression and cell metabolism of adipocytes, focusing on the differential exosomal miRNA pattern between LPS- and non-activated macrophages. The results show that the exosomes secreted by the macrophages do not influence the preadipocyte-to-adipocyte differentiation process, fat storage, and insulin-mediated glucose uptake in adipocytes. However, exosomes induce changes in adipocyte gene expression depending on their origin (LPS- or non-activated macrophages), including genes such as
CXCL5
,
SOD
,
TNFAIP3
,
C3
, and
CD34
. Some of the pathways or metabolic processes upregulated by exosomes from LPS-activated macrophages are related to inflammation (complement activation, regulation of reactive oxygen species, migration and activation of leukocyte, and monocyte chemotaxis), carbohydrate catabolism, and cell activation. miR-530, chr9_22532, and chr16_34840 are more abundant in exosomes from LPS-activated macrophages, whereas miR-127, miR-143, and miR-486 are more abundant in those secreted by non-activated macrophages.
Processed and ultra-processed foods (UPF) consumption has been associated with development of noncommunicable chronic diseases (NCD). This systematic review aims to summarise and discuss evidence of ...the relationship between food consumption according to degree of food processing and cardiometabolic risk. Data search was conducted in databases as PubMed, Bireme and Science Direct until July 2018. Studies have shown a positive association of UPF consumption with excess body weight, hypertension, dyslipidemia and metabolic syndrome features. However, disparities found in the studies analysed regarding dietary assessment, confounding factors and differences in food classifications makes comparisons between studies difficult. In conclusion, current evidences indicate the need to monitor UPF intake in global population. However, more studies are necessary to interpret better these associations with similar methodologies used in the studies. As well as longitudinal analyses can help to improve comparisons between outcomes and establish cause-effect relationship between UPF intake and cardiometabolic risk.
Abstract
Eighty-four Angus crossbred heifers (13 ± 1 mo of age, 329.5 ± 61.92 kg of body weight BW) were used in a generalized randomized block design with a 2 × 2 factorial arrangement of ...treatments. The factors evaluated were: 1) diet type (whole plant sorghum silage SS vs. byproducts-based BP), and 2) feed additive: Aspergillus oryzae prebiotic (AOP; 2 g/d) vs. Negative control (CTL; 0 g/d), resulting in four treatments: sorghum silage-control (SC), sorghum silage-AOP (SA), byproducts-control (BC), and byproducts-AOP (BA). Heifers were stratified by body weight (BW), randomly assigned to treatments (21 heifers per treatment) and housed in 12 pens equipped with two GrowSafe feed bunks each to measure individual dry matter intake (DMI). After a 14-d adaptation, BW was measured every 14 d for 56 d. Chewing activity was monitored through collar-mounted HR-Tags (heat-related tags). Following the performance period, apparent total tract digestibility was measured in 40 heifers, using indigestible neutral detergent fiber as a marker. Heifers fed with the BP diets had greater DMI (2.92% vs. 2.59% of BW, P < 0.01) and average daily gain (ADG; 1.16 vs. 0.68 kg, P ≤ 0.01) than heifers fed with SS diets. Compared with BP-fed animals, heifers consuming the SS diets had 23 more visits/d to the feed bunks (P ≤ 0.01), consumed 53% less dry matter on each visit (P ≤ 0.01), and spent 39% more min chewing/d and 63% more min chewing/kg of DMI (P ≤ 0.01). However, chewing measured in min/kg of neutral detergent fiber intake was not affected by treatment (average 111.3 min/kg of NDF intake). Feeding AOP improved gain:feed (GF) by 15% in BP-fed heifers (0.120 vs. 0.104 kg/kg; P < 0.05). Inclusion of AOP increased organic matter digestibility (OMD) in SS diets (55.88% vs. 49.83%; P < 0.01), whereas it decreased OMD in BP diets (61.67% vs. 65.77%; P < 0.05). In conclusion, ADG and GF of BP-fed heifers was greater than SS-fed heifers, and GF was greater with AOP supplementation in BP-fed heifers. Improvement in GF in BP-fed heifers was likely not related to differences in nutrient digestibility as AOP inclusion did not enhance digestibility in the BP diet. Additionally, the effects of the AOP inclusion appear to be diet-dependent, where the 15% improvement in GF by AOP occurred in heifers fed with the more fermentable diet. Therefore, further research should explore the mechanisms responsible for the observed improvements in growth performance when feeding AOP to BP-fed heifers.
Dietary inclusion of an Aspergillus oryzae prebiotic affects animal responses of growing heifers differently depending on the basal diet.
Lay Summary
This experiment evaluated the effects of the dietary inclusion or not of Aspergillus oryzae prebiotic (AOP; 2 g/d) in two contrasting diets: sorghum silage-based (SS) vs. byproducts-based (BP), on growth performance, nutrient digestibility, and feeding behavior of growing heifers. A total of 84 Angus crossbred heifers were used in the study. Heifers fed with the BP diets had greater feed intake, average daily gain, and final body weight. In addition, heifers fed with the BP diets had reduced number of visits to the feed bunk but consumed more in each visit than heifers fed with the SS diets. Additionally, heifers fed with the BP diets had lesser chewing activity measured in total min/d and in min/kg of dry matter intake; however, chewing activity measured in min/kg of neutral detergent fiber was not influenced by treatments. The inclusion of AOP increased the gain:feed ratio by 15% in heifers fed with the BP diet but did not influence this variable in the SS diet. The inclusion of AOP increased nutrient digestibility in heifers fed with the SS diet and decreased nutrient digestibility in heifers fed with the BP diet. These results show that feeding AOP can enhance growth performance in beef heifers in a diet-dependent manner.
Concurrent chemoradiotherapy (CCRT) is the standard treatment for patients with unresectable, nonmetastatic locoregionally advanced squamous-cell carcinoma of the head and neck (LASCCHN). This ...randomized, open-label, phase III clinical trial compared the efficacy between standard CCRT and two different induction chemotherapy (ICT) regimens followed by CCRT.
Patients with untreated LASCCHN were randomly assigned to ICT (three cycles), with either docetaxel (Taxotere), cisplatin and 5-fluorouracil (TPF arm) or cisplatin and 5-fluorouracil (PF arm), followed by CCRT 7 weeks of radiotherapy (RT) with cisplatin 100 mg/m2 on days 1, 22 and 43; or 7 weeks of CCRT alone. The primary end points were progression-free survival (PFS) and time-to-treatment failure (TTF).
In the intention-to-treat (ITT) population (n = 439), the median PFS times were 14.6 (95% CI, 11.6–20.4), 14.3 (95% CI, 11.8–19.3) and 13.8 months (95% CI, 11.0–17.5) at TPF-CCRT, PF-CCRT and CCRT arms, respectively (log-rank P = 0.56). The median TTF were 7.9 (95% CI, 5.9–11.8), 7.9 (95% CI, 6.5–11.8) and 8.2 months (95% CI, 6.7–12.6) for TPF-CCRT, PF-CCRT and CCRT alone, respectively (log-rank P = 0.90). There were no statistically significant differences for overall survival (OS). Toxic effects from ICT-CCRT were manageable.
Overall, this trial failed to show any advantage of ICT-CCRT over CCRT alone in patients with unresectable LASCCHN (ClinicalTrials.gov number, NCT00261703).
In the southern spring–summer season of 2001–2002 six cultivars (Orfeo, Arroz Tuscola, Barbucho, Coscorrón, Pinto and Tórtola) of common beans (
Phaseolus vulgaris L.) were grown under two ...frequencies of irrigation in the central zone of Chile. Control plants were irrigated every 7 days and water stress plants were irrigated every 21 days. Leaf water potential (
Ψ
W), leaf relative water content (RWC), turgid weight to dry weight ratio (TW/DW), osmotic potential at full turgor (
ψ
S
100
), osmotic adjustment (OA), elasticity module of the cell wall (
ɛ) and cell size of the palisade and spongy tissue were evaluated at 74–76 days after sowing (DAS) in completely developed leaves. Water stressed plants showed lower
Ψ
W than in control plants in all the varieties with values that averaged −1.4 and −0.9
MPa, respectively. According to the Drought Resistance Index (DRI) calculated from field measurements, among the cultivars studied, Orfeo was the most resistant to water stress and Arroz Tuscola, the most susceptible. A close negative relationship between leaf TW/DW and DRI under water stress conditions was observed (
r
2
=
0.63). Leaf TW/DW decreased considerably with water stress in cultivar Orfeo (15%) but the decrease was higher in Tórtola (22%), and there was also a decrease (although smaller) in Pinto (11%). Arroz Tuscola under stress did not present an important change in TW/DW, but presented one of the highest values of TW/DW. There was a strong negative correlation between DRI and palisade cell size under water stress conditions (
r
2
=
0.85) and a strong positive one between palisade cell size and TW/DW (
r
2
=
0.86) thus higher DRI was associated with small palisade cell size and small TW/DW. The most resistant cultivar Orfeo did not show a decrease in
ψ
S
100
calculated from the pressure–RWC relationships and its resistance was not associated with maintenance of leaf TW/DW under water stress.
ψ
S
100
calculated from the pressure–RWC relationships decreased only in the cultivar Coscorrón. Cultivar Orfeo showed a strong decrease (35%) of
ɛ, in association to a higher cell wall elasticity (CWE) and as consequence maintained better its cell turgescence but this was also the case of Tórtola (56%) and Pinto (34%) and to a lesser extent of Barbucho (18%). This was not the case for Arroz Tuscola where
ɛ and CWE were not changed. These results suggest that CWE and to a lesser extent leaf TW/DW can be important components of the water stress adaptation mechanism in this specie that could contribute to the higher resistance to water stress of Orfeo compared to Arroz Tuscola.
•Fatigue life predictions were performed in wires with geometric discontinuities.•S-N curves were produced to calibrate and to validate the numerical methodology.•A new approach to evaluate the ...equivalent stress in the Volume Method is proposed.•The effect of the fatigue process zone size in the life predictions is evaluated.
The aim of this work is to predict fatigue life of aluminum alloy wires 6201-T81 containing geometric discontinuities using the Theory of Critical Distances (TCD). These wires were taken from a 900 MCM All Aluminum Alloy Conductor (AAAC 900 MCM) used in overhead power transmission lines. The equivalent stress was evaluated by means of the Point Method (PM) and the Volume Method (VM), based on the maximum principal stress (σ1). Regarding the latter method, a new approach to evaluate the equivalent stress inside a material volume defined by the shape of a sphere is presented. The relation between the critical distance and the number of cycles to failure was calibrated using two distinct methodologies: the first one uses two S-N curves, one curve of a plain wire and the other of a notched wire; the second methodology also uses two S-N curves, however, in this case, both curves refer to wires containing different geometric discontinuities. Therefore, S-N curves of wires containing artificial geometric discontinuities like holes and notches were produced, both to calibrate the critical distance relation and to validate the life predictions. When the life estimations were performed based on the first calibration, the results were considered not satisfactory. However, when the second calibration was used, almost all the predictions were inserted within scatter bands regarding the experimental data used to calibrate the model. The authors believe that the difference in accuracy between predictions obtained by the two calibration methods could be related to a statistical size effect associated to the fatigue process zone size.
In light of Medical Hydrology, thermal waters (TW) are all-natural mineral waters that emerge inside a thermal resort and have therapeutic applications. Their beneficial effect has been empirically ...recognized for centuries, being indicated for symptom alleviation and/or treatment of several diseases, almost all associated with inflammation. Indeed, an anti-inflammatory effect has been attributed to many different Portuguese TW but there is no scientific validation supporting this empiric knowledge. In the present study, we aimed to investigate the anti-inflammatory properties of 14 TW pertaining to thermal centers located in the Central Region of Portugal, and grouped according to their ionic profile. Mouse macrophage cells stimulated with lipopolysaccharide (LPS), a Toll-like receptor 4 agonist, were exposed to culture medium prepared in TW. Metabolism, nitric oxide (NO) production, inducible nitric oxide synthase (iNOS) expression levels and the scavenging capacity of TW, were investigated in vitro. 11 out of 14 TW reduced NO production and/or iNOS expression, and/or scavenging activity, in macrophages exposed to LPS. The sulphated/calcic TW did not show any effect on at least one of the inflammatory parameters evaluated. Two sulphurous/bicarbonate/sodic TW and the sulphurous/chlorinated/sodic TW promoted an increase in NO production and/or iNOS expression. Our results validate, for the first time, the anti-inflammatory properties of Portuguese TW, supporting their therapeutic use in the treatment of inflammation-related diseases and promoting their putative application in cosmetic products and medical devices.
The mode of acquisition and causes for the variable clinical spectrum of coronavirus disease 2019 (COVID-19) remain unknown. We utilized a reverse genetics system to generate a GFP reporter virus to ...explore severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis and a luciferase reporter virus to demonstrate sera collected from SARS and COVID-19 patients exhibited limited cross-CoV neutralization. High-sensitivity RNA in situ mapping revealed the highest angiotensin-converting enzyme 2 (ACE2) expression in the nose with decreasing expression throughout the lower respiratory tract, paralleled by a striking gradient of SARS-CoV-2 infection in proximal (high) versus distal (low) pulmonary epithelial cultures. COVID-19 autopsied lung studies identified focal disease and, congruent with culture data, SARS-CoV-2-infected ciliated and type 2 pneumocyte cells in airway and alveolar regions, respectively. These findings highlight the nasal susceptibility to SARS-CoV-2 with likely subsequent aspiration-mediated virus seeding to the lung in SARS-CoV-2 pathogenesis. These reagents provide a foundation for investigations into virus-host interactions in protective immunity, host susceptibility, and virus pathogenesis.
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•A SARS-CoV-2 infectious cDNA clone and reporter viruses are generated•SARS-CoV-2 and SARS-CoV neutralization assays show limited cross neutralization•SARS-CoV-2 shows a gradient infectivity from the proximal to distal respiratory tract•Ciliated airway cells and AT-2 cells are primary targets for SARS-CoV-2 infection
Hou et al. present a reverse genetics system for SARS-CoV-2, which is then used to make reporter viruses to quantify the ability of patient sera and antibodies to neutralize infectious virus and to examine viral tropism along the human respiratory tract.
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