Extracellular Vesicles from Mesenchymal Stem Cells Reverse Neuroinflammation and Restore Motor Coordination in Hyperammonemic Rats.

Cirrhotic patients may show minimal hepatic encephalopathy (MHE), with mild cognitive impairment and motor deficits. Hyperammonemia and inflammation are the main contributors to the cognitive and motor alterations of MHE. Hyperammonemic rats reproduce these alterations. There are no specific treatments for the neurological alterations of MHE. Extracellular vesicles from mesenchymal stem cells (MSC-EVs) are promising to treat inflammatory and immune diseases. We aimed to assess whether treatment of hyperammonemic rats with MSC-EVs reduced neuroinflammation in cerebellum and restored motor coordination and to study the mechanisms involved. The effects of MSC-EVs were studied in vivo by intravenous injection to hyperammonemic rats and ex vivo in cerebellar slices. Motor coordination was analyzed using the beam walking test. Effects on neuroinflammation were assessed by immunohistochemistry, immunofluorescence and Western blot. Injection of MSC-EVs reduced microglia and astrocytes activation in cerebellum and restored motor coordination in hyperammonemic rats. Ex vivo experiments show that MSC-EVs normalize pro-inflammatory factors, including TNFα, NF-kB activation and the activation of two key pathways leading to motor incoordination (TNFR1-NF-kB-glutaminase-GAT3 and TNFR1-CCL2-BDNF-TrkB-KCC2). TGFß in the EVs was necessary for these beneficial effects. MSC-EVs treatment reverse neuroinflammation in the cerebellum of hyperammonemic rats and the underlying mechanisms leading to motor incoordination. Therapy with MSC-EVs may be useful to improve motor function in patients with MHE.

Genetic origins, regulators, and biomarkers of cellular senescence.

This review comprehensively examines the molecular biology and genetic origins of cellular senescence. We focus on various cellular stressors and pathways leading to senescence, including recent advances in the understanding of the genetic influences driving senescence, such as telomere attrition, chemotherapy-induced DNA damage, pathogens, oncogene activation, and cellular and metabolic stress. This review also highlights the complex interplay of various signaling and metabolic pathways involved in cellular senescence and provides insights into potential therapeutic targets for aging-related diseases. Furthermore, this review outlines future research directions to deepen our understanding of senescence biology and develop effective interventions targeting senescent cells (SnCs).

Effect of infestation with Psoroptes cuniculi on reproduction and behavior of obese rabbit does (Oryctolagus cuniculi).

Parasites and obesity are health problems worldwide. Rabbits are production animals yielding one of the healthiest meats, also taking advantage of skin, hair, limbs and excreta. It is among the most frequent pets in some countries and widely used as animal model in research. Psoroptes cuniculi is a mite of high transmission rate, affecting welfare and production and obesity causes multiple metabolic, endocrine and immunological disorders, being an emerging problem in domestic animals. Obesity and acarosis are prolonged stressors, modifying the activity of the hypothalamic-pituitary-adrenal axis that can induce metabolic and behavioral disorders. Alterations caused by comorbidities could be similar to or different from those induced by each morbidity separately. We analyzed the influence of obesity on the infection degree with P. cuniculi and on behavior and production. Rabbit does induced to obesity were infected and mated; behaviors in the open field test, obesity estimation indices and productive parameters at delivery and weaning were analyzed. The acarosis induced a decrease in feed intake and a decrease in body weight, a decrease in locomotor, exploratory and chinning behaviors in normal weight and obese does. The infection induced 23% mortality at birth, obesity 45% and comorbidity 74%, while in normal weight rabbits a 6.5% was observed. Weight gain from birth to weaning was lower in the comorbid group, reaching a litter weight of 4.5±0.13 kg in healthy normal weight does and 2.6±0.67 kg in comorbid does. The disturbances induced by the comorbidity were magnified in both behavioral and productive parameters.

Comprehensive assessment for hygrothermal comfort with heat and mass fluxes through a clothing layer during cooling seasons.

A comprehensive analysis is carried out for achieving hygrothermal comfort by using bidirectional heat and mass fluxes between the human skin and its surroundings during cooling seasons, considering the main characteristics of climate, metabolic rate, and clothing fabrics. As hygrothermal comfort is mainly seen as one-direction heat and mass flux from the close surroundings to the human body, without the emitted heat and mass by the human skin, the purpose of the analysis is to find out proper features of the respective clothing fabric according to the inlet boundary conditions, i.e. heat and mass flux from the human body, and the outlet boundary features, i.e. heat and mass flux due to the climate conditions. Thereby, a novel mathematical modelling is developed for heat and mass transfer, respectively. Then, the software Wolfram Mathematica is applied for the numerical solutions of the model. After the model is validated, a sensitivity analysis is carried out. Thereby, it is found that the sensible heat removal by convection, dependent on both airflow and humidity rates, has a great influence on the hygrothermal comfort. Furthermore, solar reflectivity for shortwave radiation, along with longwave radiation from the skin, have influence on the hygrothermal comfort when both ventilation and sweating are set as minimum. Therefore, if the conditions of temperature and relative humidity are proper, both high conductivity and air permeability clothes are recommended. Nevertheless, regarding the reflectivity, it depends on the presence of shortwave radiation, sweating, ventilation, and longwave radiation to consider light-toned or dark colors.

Integrated analysis of transcriptomic and proteomic alterations in mouse models of ALS/FTD identify early metabolic adaptions with similarities to mitochondrial dysfunction disorders.

OBJECTIVE: Sporadic and familial amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease that results in loss of motor neurons and, in some patients, associates with frontotemporal dementia (FTD). Apart from the accumulation of proteinaceous deposits, emerging literature indicates that aberrant mitochondrial bioenergetics may contribute to the onset and progression of ALS/FTD. Here we sought to investigate the pathophysiological signatures of mitochondrial dysfunction associated with ALS/FTD. METHODS: By means of label-free mass spectrometry (MS) and mRNA sequencing (mRNA-seq), we report pre-symptomatic changes in the cortices of TDP-43 and FUS mutant mouse models. Using tissues from transgenic mouse models of mitochondrial diseases as a reference, we performed comparative analyses and extracted unique and common mitochondrial signatures that revealed neuroprotective compensatory mechanisms in response to early damage. RESULTS: In this regard, upregulation of both Acyl-CoA Synthetase Long-Chain Family Member 3 (ACSL3) and mitochondrial tyrosyl-tRNA synthetase 2 (YARS2) were the most representative change in pre-symptomatic ALS/FTD tissues, suggesting that fatty acid beta-oxidation and mitochondrial protein translation are mechanisms of adaptation in response to ALS/FTD pathology. CONCLUSIONS: Together, our unbiased integrative analyses unveil novel molecular components that may influence mitochondrial homeostasis in the earliest phase of ALS.

Factors affecting the relative abundance in an overfished stock: red grouper (Epinephelus morio) in the Southeastern Gulf of Mexico.

The most important fisheries are recording catches below their historical averages despite increased effort. This level of overfishing is worrying and requires the establishment of feasible and precise measures to prevent a continuing decrease in biomass. Determining the factors that lead to changes in the abundance and distribution of overfished resources would allow us to identify the strengths and weaknesses of management schemes; this approach would also make it possible to estimate more accurate parameters for their evaluation. We hypothesize that environmental, temporal, spatial, and operational components contribute to the variation in the relative abundance. Thus, we analyzed the red grouper fishery, the most important demersal fishery in the southeastern Gulf of Mexico (SGM); it is locally known as escama. We employed the catch per unit effort (CPUE) as an index of relative abundance recorded by the semi-industrial fleet (kilogram per effective fishing day) and the small-scale fleet (kilogram per effective fishing hour) during the overexploitation phase (from 1996 to 2019). We fitted several variables of the components using generalized additive models (GAM) and used multi-model inference to determine the best GAM for each fleet. For both fleets, the operational and temporal components (fishing gear and year) have had a greater impact on the distribution and abundance of red grouper in the SGM than the spatial and environmental components (the place of origin and sea surface temperature). These findings encourage the exploration of métier schemes for more efficient fishery management. In addition, we have identified several strategies that would support the recovery of the resource, such as restricting fishing in the quadrants located to the northeast or regulating scuba diving. We recommend that in the future, researchers use the indices we have generated in the present study to evaluate the red grouper fishery.

Geothermal and structural features of La Palma island (Canary Islands) imaged by ambient noise tomography.

La Palma island is located in the NW of the Canary Islands and is one of the most volcanically active of the archipelago, therefore the existence of geothermal resources on the island is highly probable. The main objective of this work is to detect velocity anomalies potentially related to active geothermal reservoirs on La Palma island, by achieving a high-resolution seismic velocity model of the first few kilometres of the crust using Ambient Noise Tomography (ANT). The obtained ANT model is merged with a recent local earthquake tomography model. Our findings reveal two high-velocity zones in the island's northern and southern parts, that could be related to a plutonic intrusion and old oceanic crust materials. Conversely, four low-velocity zones are imaged in the southern part of the island. Two of them can be related to hydrothermal alteration zones located beneath the Cumbre Vieja volcanic complex. This hypothesis is reinforced by comparing the S-wave velocity model with the seismicity recorded during the pre-eruptive phase of the 2021 Tajogaite eruption, which revealed an aseismic volume coinciding with these low-velocity zones. Another low-velocity zone is observed in the southern part of the island, which we interpret as highly fractured rocks which could favour the ascent of hot fluids. A last low-velocity zone is observed in the central part of the island and associated with loose deposits generated by the Aridane valley mega landslide.

Spatio-temporal velocity variations observed during the pre-eruptive episode of La Palma 2021 eruption inferred from ambient noise interferometry.

On Sept. 19th, 2021, a volcanic eruption began on the island of La Palma (Canary Islands, Spain). The pre-eruptive episode was characterized by seismicity and ground deformation that started only 9.5 days before the eruption. In this study, we applied seismic interferometry to the data recorded by six broadband seismic stations, allowing us to estimate velocity variations during the weeks preceding the eruption. About 9.5 days before the eruption, we observed a reduction in the seismic velocities is registered next to the eruptive centers that opened later. Furthermore, this zone overlaps with the epicenters of a cluster of volcano-tectonic earthquakes located at shallow depth (< 4 km) and detached from the main cluster of deeper seismicity. We interpret the decrease in seismic velocities and the occurrence of such a shallow earthquake cluster as the effect of hydrothermal fluid released by the ascending magma batch and reaching the surface faster than the magma itself.

Cu2+-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate by reptile sera.

This study shows the EDTA-resistant, Ca2+ and Cu2+-dependent hydrolysis of O-hexyl 2,5-dichlorophenyl phosphoramidate (HDCP) compound in reptiles sera determined by spectrophotometry UV/Vis and chiral chromatography. Samples of ten reptile species were incubated with aliquot of 100 or 400 µM HDCP in presence of 100 or 300 µM Cu2+, or 2.5 mM Ca2+ or 5 mM EDTA at 37 °C for 30-60 min. The results shown an activator effect of Cu2+ on HDCP hydrolysis in freshwater turtles sera (Trachemys scripta, Chelydra serpentina and Macrochelys temminckii) because the levels of 2,5-dichlorophenol (DCP; product hydrolysis) were similar (∼37 µM DCP) to chicken serum (positive control group). The marine turtles (Chelonia mydas and Eretmochelys imbricata) and crocodiles (Crocodylusacutus and Crocodylus moreletii) showed ∼50% less HDCPase activity (13-17 µM DCP) compared to the HDCPase activity of the freshwater turtle species. Terrestrial reptile species (snakes and lizards) showed around 25% of activity (7-13 µM DCP) with both copper concentrations. These Cu2+-dependent hydrolysis were stereospecific to R(+)-HDCP (p˂0.05) in the three freshwater turtle species that showed similar hydrolysis to the chicken serum. However, the Ca2+ did not show a significant activating effect on the HDCPase activity (1-8 µM DCP) in any reptile serum. Their hydrolysis levels were very similar to those of EDTA-resistant activity. The present study demonstrates a Cu2+-dependent A-esterase (HDCPase) activity in turtles and points serum albumin as the cuproprotein responsible for this activity, reinforcing its N-terminal sequence (DAEH) as a catalytic center.

Competitive interference among rhizobia reduces benefits to hosts.

The capacity of beneficial microbes to compete for host infection-and the ability of hosts to discriminate among them-introduces evolutionary conflict that is predicted to destabilize mutualism. We investigated fitness outcomes in associations between legumes and their symbiotic rhizobia to characterize fitness impacts of microbial competition. Diverse Bradyrhizobium strains varying in their capacity to fix nitrogen symbiotically with a common host plant, Acmispon strigosus, were tested in full-factorial coinoculation experiments involving 28 pairwise strain combinations. We analyzed the effects of interstrain competition and host discrimination on symbiotic-interaction outcomes by relativizing fitness proxies to clonally infected and uninfected controls. More than one thousand root nodules of coinoculated plants were genotyped to quantify strain occupancy, and the Bradyrhizobium strain genome sequences were analyzed to uncover the genetic bases of interstrain competition outcomes. Strikingly, interstrain competition favored a fast-growing, minimally beneficial rhizobia strain. Host benefits were significantly diminished in coinoculation treatments relative to expectations from clonally inoculated controls, consistent with competitive interference among rhizobia that reduced both nodulation and plant growth. Competition traits appear polygenic, linked with inter-strain allelopathic interactions in the rhizosphere. This study confirms that competition among strains can destabilize mutualism by favoring microbes that are superior in colonizing host tissues but provide minimal benefits to host plants. Moreover, our findings help resolve the paradox that despite efficient host control post infection, legumes nonetheless encounter rhizobia that vary in their nitrogen fixation.

Simultaneous Multi-Omics Analysis by Direct Infusion Mass Spectrometry (SMAD-MS).

Combined multi-omics analysis of proteomics, polar metabolomics, and lipidomics requires separate liquid chromatography-mass spectrometry (LC-MS) platforms for each omics layer. This requirement for different platforms limits throughput and increases costs, preventing the application of mass spectrometry-based multi-omics to large scale drug discovery or clinical cohorts. Here, we present an innovative strategy for simultaneous multi-omics analysis by direct infusion (SMAD) using one single injection without liquid chromatography. SMAD allows quantification of over 9,000 metabolite m/z features and over 1,300 proteins from the same sample in less than five minutes. We validated the efficiency and reliability of this method and then present two practical applications: mouse macrophage M1/M2 polarization and high throughput drug screening in human 293T cells. Finally, we demonstrate relationships between proteomic and metabolomic data are discovered by machine learning.

Mechanism of ADP-Inhibited ATP Hydrolysis in Single Proton-Pumping FoF1-ATP Synthase Trapped in Solution.

FoF1-ATP synthases in mitochondria, in chloroplasts, and in most bacteria are proton-driven membrane enzymes that supply the cells with ATP made from ADP and phosphate. Different control mechanisms exist to monitor and prevent the enzymes' reverse chemical reaction of fast wasteful ATP hydrolysis, including mechanical or redox-based blockade of catalysis and ADP inhibition. In general, product inhibition is expected to slow down the mean catalytic turnover. Biochemical assays are ensemble measurements and cannot discriminate between a mechanism affecting all enzymes equally or individually. For example, all enzymes could work more slowly at a decreasing substrate/product ratio, or an increasing number of individual enzymes could be completely blocked. Here, we examined the effect of increasing amounts of ADP on ATP hydrolysis of single Escherichia coli FoF1-ATP synthases in liposomes. We observed the individual catalytic turnover of the enzymes one after another by monitoring the internal subunit rotation using single-molecule Förster resonance energy transfer (smFRET). Observation times of single FRET-labeled FoF1-ATP synthases in solution were extended up to several seconds using a confocal anti-Brownian electrokinetic trap (ABEL trap). By counting active versus inhibited enzymes, we revealed that ADP inhibition did not decrease the catalytic turnover of all FoF1-ATP synthases equally. Instead, increasing ADP in the ADP/ATP mixture reduced the number of remaining active enzymes that operated at similar catalytic rates for varying substrate/product ratios.

Elastic interaction between Mauna Loa and Kilauea evidenced by independent component analysis.

The contrasting dynamics between Mauna Loa and Kilauea have been studied over the last 100 years from multiple viewpoints. The fact that dynamic changes of one volcano trigger a dynamic response of the other volcano indicates a connection may exist. Petrological works show a direct relationship between the magmatic systems of these two volcanoes is not possible. We analysed DInSAR data and GPS measurements of ground deformation patterns associated with the activity of Mauna Loa and Kilauea volcanoes. The DInSAR SBAS dataset spans the interval between 2003 and 2010, and was acquired along ascending and descending orbits of the ENVISAT (ESA) satellite under different look angles. Of the 10 tracks that cover the Big Island (Hawai'i), 4 cover both volcanic edifices. Using GPS measurements, we computed the areal strain on 15 triplets of stations for Kilauea volcano and 11 for Mauna Loa volcano. DInSAR data was analysed by applying Independent Component Analysis (ICA) to decompose the time-varying ground deformation pattern of both volcanoes. The results revealed anticorrelated ground deformation behaviour of the main calderas of Mauna Loa and Kilauea, meaning that the opposite response is seen in the ground deformation of one volcano with respect to the other. At the same time, Kilauea exhibits a more complex pattern, with an additional component, which appears not to be correlated with the dynamics of Mauna Loa. The GPS areal strain time series support these findings. To corroborate and help interpret the results, we performed inverse modelling of the observed ground deformation pattern using analytical source models. The results indicate that the ground deformation of Mauna Loa is associated with a dike-shaped source located at 6.2 km depth. In comparison, the anticorrelated ground deformation of Kilauea is associated with a volumetric source at 1.2 km depth. This excludes a hydraulic connection as a possible mechanism to explain the anticorrelated behaviour; instead, we postulate a stress-transfer mechanism. To support this hypothesis, we performed a 3D numerical modelling of stress and strain fields in the study area, determining the elastic interaction of each source over the others. The most relevant finding is that the Mauna Loa shallow plumbing system can affect the shallowest magmatic reservoir of Kilauea, while the opposite scenario is unlikely. Conversely, the second independent component observed at Kilauea is associated to a sill-shaped source located at a depth of 3.5 km, which is less affected by this interaction process.

Rapid magma ascent beneath La Palma revealed by seismic tomography.

For the first time, we obtained high-resolution images of Earth's interior of the La Palma volcanic eruption that occurred in 2021 derived during the eruptive process. We present evidence of a rapid magmatic rise from the base of the oceanic crust under the island to produce an eruption that was active for 85 days. This eruption is interpreted as a very accelerated and energetic process. We used data from 11,349 earthquakes to perform travel-time seismic tomography. We present high-precision earthquake relocations and 3D distributions of P and S-wave velocities highlighting the geometry of magma sources. We identified three distinct structures: (1) a shallow localised region (< 3 km) of hydrothermal alteration; (2) spatially extensive, consolidated, oceanic crust extending to 10 km depth and; (3) a large sub-crustal magma-filled rock volume intrusion extending from 7 to 25 km depth. Our results suggest that this large magma reservoir feeds the La Palma eruption continuously. Prior to eruption onset, magma ascended from 10 km depth to the surface in less than 7 days. In the upper 3 km, melt migration is along the western contact between consolidated oceanic crust and altered hydrothermal material.

Histometric and morphological damage caused by Serratia marcescens to the tick Rhipicephalus microplus (Acari: Ixodidae).

Rhipicephalus microplus tick is the ectoparasite causing the greatest economic losses in the livestock industry. Multi-resistance in ticks is increasing, generating the inefficiency of traditional ixodicides, for which biological control has been proposed as an alternative. In this work, we analyze the histomorphological damage caused by the bacterial strain EC-35 on Rhipicephalus microplus. The ixodicidal effect of EC-35 total protein was evaluated on larval or adult ticks comparing with the commercial ixodicide coumaphos 0.02% as a control. Female ticks were processed using the paraffin-embedding technique and stained with hematoxylin-eosin. Also, the pathogenicity of EC-35 was evaluated by capillary feeding and coelom inoculation tests. The identification of the bacterium was performed using the molecular markers 16S RNA and rpoB, by PCR and sequencing technique, and the evolutionary distance was analyzed by Bayesian phylogenetic inference. No differences were observed in the perimeter and area of larvae treated with EC-35 or Coumaphos. The thickness of the integument decreased a 65% with the EC-35 treatment (6.01 ± 0.6 µm) and of 30% in coumaphos (12.04 ± 1.2 µm) in larvae compared with the control group (18.41 ± 2 µm), while no difference was found in adult ticks. The capillary feeding test and coelom inoculation with EC-35 showed an inhibition of reproductive potential of 99.8 ± 7 and an oviposition Inhibition 97 ± 3.02%. The EC-35 strain was genetically related to Serratia marcescens, concluding that these bacteria caused high mortality, oviposition Inhibition, and integument thinning and drastic loss of histoarchitecture in R. microplus tick larvae.

Identification of NLRP3PYD Homo-Oligomerization Inhibitors with Anti-Inflammatory Activity.

Inflammasomes are multiprotein complexes that represent critical elements of the inflammatory response. The dysregulation of the best-characterized complex, the NLRP3 inflammasome, has been linked to the pathogenesis of diseases such as multiple sclerosis, type 2 diabetes mellitus, Alzheimer's disease, and cancer. While there exist molecular inhibitors specific for the various components of inflammasome complexes, no currently reported inhibitors specifically target NLRP3PYD homo-oligomerization. In the present study, we describe the identification of QM380 and QM381 as NLRP3PYD homo-oligomerization inhibitors after screening small molecules from the MyriaScreen library using a split-luciferase complementation assay. Our results demonstrate that these NLRP3PYD inhibitors interfere with ASC speck formation, inhibit pro-inflammatory cytokine IL1-ß release, and decrease pyroptotic cell death. We employed spectroscopic techniques and computational docking analyses with QM380 and QM381 and the PYD domain to confirm the experimental results and predict possible mechanisms underlying the inhibition of NLRP3PYD homo-interactions.

Lung Adenocarcinoma Transcriptomic Analysis Predicts Adenylate Kinase Signatures Contributing to Tumor Progression and Negative Patient Prognosis.

The ability to detect and respond to hypoxia within a developing tumor appears to be a common feature amongst most cancers. This hypoxic response has many molecular drivers, but none as widely studied as Hypoxia-Inducible Factor 1 (HIF-1). Recent evidence suggests that HIF-1 biology within lung adenocarcinoma (LUAD) may be associated with expression levels of adenylate kinases (AKs). Using LUAD patient transcriptome data, we sought to characterize AK gene signatures related to lung cancer hallmarks, such as hypoxia and metabolic reprogramming, to identify conserved biological themes across LUAD tumor progression. Transcriptomic analysis revealed perturbation of HIF-1 targets to correlate with altered expression of most AKs, with AK4 having the strongest correlation. Enrichment analysis of LUAD tumor AK4 gene signatures predicts signatures involved in pyrimidine, and by extension, nucleotide metabolism across all LUAD tumor stages. To further discriminate potential drivers of LUAD tumor progression within AK4 gene signatures, partial least squares discriminant analysis was used at LUAD stage-stage interfaces, identifying candidate genes that may promote LUAD tumor growth or regression. Collectively, these results characterize regulatory gene networks associated with the expression of all nine human AKs that may contribute to underlying metabolic perturbations within LUAD and reveal potential mechanistic insight into the complementary role of AK4 in LUAD tumor development.