Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo-inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo-osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by (1)H-magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline-containing compounds, creatine/phosphocreatine, and N-acetyl-aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients.     

Most of ADP x glucose linked to starch biosynthesis occurs outside the chloroplast in source leaves

Sucrose and starch are end products of two segregated gluconeogenic pathways, and their production takes place in the cytosol and chloroplast of green leaves, respectively. According to this view, the plastidial ADP.glucose (ADPG) pyrophosphorylase (AGP) is the sole enzyme catalyzing the synthesis of the starch precursor molecule ADPG. However, a growing body of evidences indicates that starch formation involves the import of cytosolic ADPG to the chloroplast. This evidence is consistent with the idea that synthesis of the ADPG linked to starch biosynthesis takes place in the cytosol by means of sucrose synthase, whereas AGP channels the glucose units derived from the starch breakdown. To test this hypothesis, we first investigated the subcellular localization of ADPG. Toward this end, we constructed transgenic potato plants that expressed the ADPG-cleaving adenosine diphosphate sugar pyrophosphatase (ASPP) from Escherichia coli either in the chloroplast or in the cytosol. Source leaves from plants expressing ASPP in the chloroplast exhibited reduced starch and normal ADPG content as compared with control plants. Most importantly however, leaves from plants expressing ASPP in the cytosol showed a large reduction of the levels of both ADPG and starch, whereas hexose phosphates increased as compared with control plants. No pleiotropic changes in photosynthetic parameters and maximum catalytic activities of enzymes closely linked to starch and sucrose metabolism could be detected in the leaves expressing ASPP in the cytosol. The overall results show that, essentially similar to cereal endosperms, most of the ADPG linked to starch biosynthesis in source leaves occurs in the cytosol.     

Regulation of antiapoptotic MCL-1 function by gossypol: mechanistic insights from in vitro reconstituted systems

Small-molecule drugs that induce apoptosis in tumor cells by activation of the BCL-2-regulated mitochondrial outer membrane permeabilization (MOMP) pathway hold promise for rational anticancer therapies. Accumulating evidence indicates that the natural product gossypol and its derivatives can kill tumor cells by targeting antiapoptotic BCL-2 family members in such a manner as to trigger MOMP. However, due to the inherent complexity of the cellular apoptotic network, the precise mechanisms by which interactions between gossypol and individual BCL-2 family members lead to MOMP remain poorly understood. Here, we used simplified systems bearing physiological relevance to examine the impact of gossypol on the function of MCL-1, a key determinant for survival of various human malignancies that has become a highly attractive target for anticancer drug design. First, using a reconstituted liposomal system that recapitulates basic aspects of the BCL-2-regulated MOMP pathway, we demonstrate that MCL-1 inhibits BAX permeabilizing function via a “dual-interaction” mechanism, while submicromolar concentrations of gossypol reverse MCL-1-mediated inhibition of functional BAX activation. Solution-based studies showed that gossypol competes with BAX/BID BH3 ligands for binding to MCL-1 hydrophobic groove, thereby providing with a mechanistic explanation for how gossypol restores BAX permeabilizing function in the presence of MCL-1. By contrast, no evidence was found indicating that gossypol transforms MCL-1 into a BAX-like pore-forming molecule. Altogether, our findings validate MCL-1 as a direct target of gossypol, and highlight that making this antiapoptotic protein unable to inhibit BAX-driven MOMP may represent one important mechanism by which gossypol exerts its cytotoxic effect in selected cancer cells.     

Functionalised collagen spheres reduce H2O2 mediated apoptosis by scavenging overexpressed ROS

Excess reactive oxygen species (ROS) has been implicated in numerous diseases including cancer, cardiovascular and neurodegenerative diseases. Overexpression of ROS can lead to oxidative stress and subsequently to H₂O₂-mediated cell apoptosis. In this study, it was demonstrated that biodegradable PLGA microspheres coated with collagen type I and decorated with MnO₂ nanoparticles acted as ROS scavengers controlling the H₂O₂-mediated apoptosis of cells undergoing oxidative stress. The results showed that the functionalized collagen spheres can protect cells even under very harsh conditions of oxidative stress.     

Internal and External Load Control in Team Sports through a Multivariable Model

Data related to 141 sessions of 10 semi-professional basketball players were analyzed during the competitive period of the 2018-2019 season using a multivariable model to determine possible associations between internal and external load variables and fatigue. Age, height, weight, sessional rate of perceived exertion (sRPE), summated-heart-rate-zones, heart rate variability, total accelerations and decelerations were the covariates, and post-session countermovement jump loss (10% or higher) the response variable. Based on the results observed, a rise in sRPE and accelerations and decelerations could be associated with increased lower-body neuromuscular fatigue. Observing neuromuscular fatigue was 1,008 times higher with each additional sRPE arbitrary unit (AU). Each additional high-intensity effort also increased the probability of significant levels of neuromuscular fatigue by 1,005 times. Fatigue arising from demanding sporting activities is acknowledged as a relevant inciting event leading to injuries. Thus, the methodology used in this study can be used then to monitor neuromuscular fatigue onset, also enhancing proper individual adaptations to training. Key points

• Several internal and external load variables show associations with an increase in local neuromuscular fatigue detected through the countermovement jump test.
• Our main findings show promising results detecting the lower-body neuromuscular fatigue originated by specific training through and ecological, practical, and low time-consuming methodology. The proposed method can outline the players’ physiological state and inform decisions regarding the application of different training loads within a complex setting and multi-factorial process.

Key words: Monitoring, muscle fatigue, countermovement jump, performance, basketball     

Efficacy and safety of chemotherapy in older versus non-older patients with advanced gastric cancer: A real-world data,non-inferiority analysis

Objective

Advanced gastric cancer (AGC) is a common neoplasm in older adults. Nevertheless, there are few specific management data in the literature. The aim of this study was to assess non-inferiority of survival and efficacy-related outcomes of chemotherapy used in older vs non-older patients with AGC.

Neuropilin-1: A feasible link between liver pathologies and COVID-19

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has a tremendous impact on the health of millions of people worldwide. Unfortunately, those suffering from previous pathological conditions are more vulnerable and tend to develop more severe disease upon infection with the new SARS-CoV-2. This coronavirus interacts with the angiotensin-converting enzyme 2 receptor to invade the cells. Recently, another receptor, neuropilin-1 (NRP-1), has been reported to amplify the viral infection. Interestingly, NRP-1 is expressed in nonparenchymal liver cells and is related to and upregulated in a wide variety of liver-related pathologies. It has been observed that SARS-CoV-2 infection promotes liver injury through several pathways that may be influenced by the previous pathological status of the patient and liver expression of NRP-1. Moreover, coronavirus disease 2019 causes an inflammatory cascade called cytokine storm in patients with severe disease. This cytokine storm may influence liver sinusoidal-cell phenotype, facilitating viral invasion. In this review, the shreds of evidence linking NRP-1 with liver pathologies such as hepatocellular carcinoma, liver fibrosis, nonalcoholic fatty liver disease and inflammatory disorders are discussed in the context of SARS-CoV-2 infection. In addition, the involvement of the infection-related cytokine storm in NRP-1 overexpression and the subsequent increased risk of SARS-CoV-2 infection are also analyzed. This review aims to shed some light on the involvement of liver NRP-1 during SARS-CoV-2 infection and emphasizes the possible involvement this receptor with the observed liver damage.     

African burned area and fire carbon emissions are strongly impacted by small fires undetected by coarse resolution satellite data

Fires are a major contributor to atmospheric budgets of greenhouse gases and aerosols, affect soils and vegetation properties, and are a key driver of land use change. Since the 1990s, global burned area (BA) estimates based on satellite observations have provided critical insights into patterns and trends of fire occurrence. However, these global BA products are based on coarse spatial-resolution sensors, which are unsuitable for detecting small fires that burn only a fraction of a satellite pixel. We estimated the relevance of those small fires by comparing a BA product generated from Sentinel-2 MSI (Multispectral Instrument) images (20-m spatial resolution) with a widely used global BA product based on Moderate Resolution Imaging Spectroradiometer (MODIS) images (500 m) focusing on sub-Saharan Africa. For the year 2016, we detected 80% more BA with Sentinel-2 images than with the MODIS product. This difference was predominately related to small fires: we observed that 2.02 Mkm² (out of a total of 4.89 Mkm²) was burned by fires smaller than 100 ha, whereas the MODIS product only detected 0.13 million km² BA in that fire-size class. This increase in BA subsequently resulted in increased estimates of fire emissions; we computed 31 to 101% more fire carbon emissions than current estimates based on MODIS products. We conclude that small fires are a critical driver of BA in sub-Saharan Africa and that including those small fires in emission estimates raises the contribution of biomass burning to global burdens of (greenhouse) gases and aerosols.

Fire plays an important role in the Earth system, impacting climate and air quality and affecting vegetation, soils, and human assets (1–3). Global annual BA is currently estimated to be between 4.2 and 4.7 million km² (4–6). Fires burn naturally in many ecosystems, but currently, the majority of fires have an anthropogenic origin and are often used as a land management tool [e.g., in the deforestation process (4, 5)]. Fires impact climate by releasing greenhouse gases and aerosols and by modifying surface albedo (6–8).Satellite sensors are the preferred way to estimate BA, as they provide frequent and comprehensive observations of surface reflectance and thermal properties (9). However, most existing products are based on coarse spatial-resolution images (≥500 m), which provide a global view of fire occurrence almost daily but may have important omission and commission errors, particularly where fires are small in size (10). In fact, several regional assessments of those global BA products have identified substantial omission errors when compared to fire perimeters (11–15). Omission of small fires may be the cause of observing higher omission than commission errors in existing validation efforts of global BA products (15–17).A first approach to estimate the contribution of these small fires was proposed by Randerson et al. (18) based on a statistical method overlaying BA and active fire detections. They estimated that small fires led to an additional 24 to 54% BA compared to previous estimates. Thanks to recent developments in satellite instruments and computing power, we can now map BA with substantially higher spatial resolution (≤30 m) and for large geographic regions (19–21), reducing the dependency on statistical methods and active fire detections.Our main goal was to compare a new BA dataset generated from medium-resolution images and its resulting fire carbon emissions with existing information based on global BA datasets derived from coarse-resolution data. We focused our analysis on Africa, as it accounts for about 70% of global BA (22) and about half of global fire carbon emissions (23). The medium-resolution BA product was developed from Sentinel-2 MultiSpectral Instrument (MSI) data under the Fire Disturbance project of the European Space Agency’s Climate Change Initiative (CCI) program. The product, named FireCCISFD11, covers the whole of sub-Saharan Africa at 20-m resolution for the year 2016 (21) (see Materials and Methods). We have compared this product with three global BA datasets derived from MODIS data: MCD64A1C6 (22), the Global Fire Emission Database version 4s (GFED4s) (23), and the Global Fire Atlas (GFA) (24). MCD64A1C6 is the most recent version of a widely used BA product for global analysis of biomass burning impacts (9, 25). GFED4s is based on an older version of the MCD64A1 dataset (C5.1) but includes BA estimates from small fires based on a statistical approach. This product is only available at 0.25° spatial resolution (23). The GFA was derived from the MCD64A1C6 product. It generates burned patches from detected burned pixels using contextual analysis (24). Our comparative analysis between FireCCISFD11 and global products included total BA (with MCD64A1 and GFED4s), fire size distribution (with MCD64A1 and GFA), BA stratified by land cover (MCD64A1), and fire emissions (derived from MCD64A1 and GFED4s).     

Clinical,physical, physiological,and dietary patterns of obese and sedentary adults with primary hypertension characterized by sex and cardiorespiratory fitness: EXERDIET-HTA study

The main purpose of this study was to determine some key physical, physiological, clinical, and nutritional markers of health status in obese and sedentary adults (54.0 ± 8.1 years, 141 men and 68 women) with primary hypertension (HTN) characterized by sex and cardiorespiratory fitness (CRF) level. The studied population showed a high cardiovascular risk (CVR) profile including metabolically abnormal obese, with poor CRF level (22.5 ± 5.6 mL·kg^?1·min^?1), exercise-induced HTN (Systolic Blood Pressure>210 mmHg in men and >190 mmHg in women at the end of the exercise test) and with non-healthy adherence to dietary pattern (Dietary Approaches to Stop Hypertension, 46.3%; Mediterranean Diet, 41.1%; and Healthy Diet Indicator, 37.1%). Women showed a better biochemical and dietary pattern profile than men (lower values, P < 0.05, in triglycerides, mean difference = 26.3; 95% CI = 0.9–51.7 mg/dL, aspartate transaminase, mean difference = 4.2; 95% CI = 0.3–8.0 U/L; alanine transaminase, mean difference = 8.2; 95% CI = 1.6–14.8 U/L; gamma-glutamyl transpeptidase, mean difference = 11.0; 95% CI = -1.1–23.2 U/L and higher values, P = 0.002, in high-density lipoprotein cholesterol, mean difference = 5.0, 95% CI = -13.3–3.3 mg/dL), but physical and peak exercise physiological characteristics were poorer. A higher CRF level might contribute to the attenuation of some CVR factors, such as high body mass index, non-dipping profile, and high hepatic fat. The results strongly suggest that targeting key behaviors such as improving nutritional quality and CRF via regular physical activity will contribute to improving the health with independent beneficial effects on CVR factors.