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Microcirculation (New York, N.Y. : 1994) Jun 2024This study focuses on evaluating the disruptions in key physiological parameters during microstroke events to assess their severity.
OBJECTIVE
This study focuses on evaluating the disruptions in key physiological parameters during microstroke events to assess their severity.
METHODS
A mathematical model was developed to simulate the changes in cerebral tissue pO, glucose concentration, and temperature due to blood flow interruptions. The model considers variations in baseline cerebral blood flow (CBF), capillary density, and blood oxygen/glucose levels, as well as ambient temperature changes.
RESULTS
Simulations indicate that complete blood flow obstruction still allows for limited glucose availability, supporting nonoxidative metabolism and potentially exacerbating lactate buildup and acidosis. Partial obstructions decrease tissue pO, with minimal impact on glucose level, which can remain almost unchanged or even slightly increase. Reduced CBF, capillary density, or blood oxygen due to aging or disease enhances hypoxia risk at lower obstruction levels, with capillary density having a significant effect on stroke severity by influencing both pO and glucose levels. Conditions could lead to co-occurrence of hypoxia/hypoglycemia or hypoxia/hyperglycemia, each worsening outcomes. Temperature effects were minimal in deep brain regions but varied near the skull by 0.2-0.8°C depending on ambient temperature.
CONCLUSIONS
The model provides insights into the conditions driving severe stroke outcomes based on estimated levels of hypoxia, hypoglycemia, hyperglycemia, and temperature changes.
PubMed: 38944839
DOI: 10.1111/micc.12872 -
Acta Tropica Jun 2024Gram-positive catalase-negative cocci (GPCNCs) are significant components of the genital microbiota in sheep and goats. However, characterizing them can be difficult due...
Gram-positive catalase-negative cocci (GPCNCs) are significant components of the genital microbiota in sheep and goats. However, characterizing them can be difficult due to overlapping culture features and the limited information on their susceptibility to antibiotics. In this study, 97 foreskin and 13 vaginal swabs were investigated using a culturomic approach. Of 110 animals, 76 (69.09%) hosted GPCNCs, including strains from Streptococcaceae (37, 33.64%), Aerococcaceae (30, 27.27%), Enterococcaceae (6, 5.45%) and other minor species. With increasing antimicrobial resistance rates in livestock, surveillance programs are globally required, so we conducted a pilot study on GPCNCs isolated from the genital mucosa surfaces of sheep and goats using the minimal inhibitory concentration assay (MIC). Due to gaps in interpretative standard breakpoints, normalized resistance interpretation was used for setting epidemiological susceptibility cut-off values (CO). Of 57 suitable strains, the majority (80.71%) showed high CO with decrease susceptibility to at least one antimicrobial class, with 22.81% displaying multiresistant profiles. Of interest, combined resistances to beta-lactams, macrolides, lincosamides, and tetracyclines were detected in strains of Streptococcus plurianimalium. Further combinations, including resistance to beta-lactams, pleuromutilins, aminoglycosides, and lincosamides, were also recorded in both Streptococcus uberis and Enterococcus spp. strains. Being beta-lactams, macrolides, and tetracyclines the most used antibiotics in livestock worldwide, our results highlight the need for their prudent use. Collectively, our findings highlight that small ruminant genital microbiota can serve as reservoirs for opportunistic severe pathogens, often zoonotic, carrying multidrug resistances, thus standing for high risks for both animals and humans.
PubMed: 38944406
DOI: 10.1016/j.actatropica.2024.107305 -
Fish & Shellfish Immunology Jun 2024Infectious pancreatic necrosis virus (IPNV) is an important pathogen that is threatening the worldwide salmon and trout industry. But there is no therapeutic drug...
Infectious pancreatic necrosis virus (IPNV) is an important pathogen that is threatening the worldwide salmon and trout industry. But there is no therapeutic drug available for now. In this study, we demonstrate that MK-0608 is highly efficient against IPNV and low cytotoxic, with a 50% effective concentration (EC) of 0.20 μM and selectivity index (SI) of about 268. Time of addition assay illustrated that MK-0608 targeted the early stage of IPNV life cycle. Furthermore, we found that MK-0608 blocked IPNV attachment on the premise of sufficient pre-incubation time but MK-0608 did not influence viral internalization and release. MK-0608 could inhibit IPNV genome synthesis, and combination with ribavirin enhanced the inhibition effect, which might be functional via binding to IPNV RNA dependent RNA polymerase (RdRp), which was predicted by using molecular docking methods. In vivo test showed that IPNV was extremely suppressed in the rainbow trout (Oncorhynchus mykiss) with one single dose of MK-0608, and the higher dosage of 50 mg/kg could cause 3 log decrease of IPNV loads in fish tissues.
PubMed: 38944252
DOI: 10.1016/j.fsi.2024.109732 -
Archives of Biochemistry and Biophysics Jun 2024About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but...
About 140 million people worldwide live at an altitude above 2500 m. Studies have showed an increase of the incidence of hyperuricemia among plateau populations, but little is known about the possible mechanisms. This study aims to assess the effects of high altitude on hyperuricemia and explore the corresponding mechanisms at the histological, inflammatory and molecular levels. This study finds that intermittent hypobaric hypoxia (IHH) exposure results in an increase of serum uric acid level and a decrease of uric acid clearance rate. Compared with the control group, the IHH group shows significant increases in hemoglobin concentration (HGB) and red blood cell counts (RBC), indicating that high altitude hyperuricemia is associated with polycythemia. This study also shows that IHH exposure induces oxidative stress, which causes the injury of liver and renal structures and functions. Additionally, altered expressions of organic anion transporter 1 (OAT1) and organic cation transporter 1 (OCT1) of kidney have been detected in the IHH exposed rats. The adenosine deaminase (ADA) expression levels and the xanthione oxidase (XOD) and ADA activity of liver of the IHH exposure group have significantly increased compared with those of the control group. Furthermore, the spleen coefficients, IL-2, IL-1β and IL-8, have seen significant increases among the IHH exposure group. TLR/MyD88/NF-κB pathway is activated in the process of IHH induced inflammatory response in joints. Importantly, these results jointly show that IHH exposure causes hyperuricemia. IHH induced oxidative stress along with liver and kidney injury, unusual expression of the uric acid synthesis/excretion regulator and inflammatory response, thus suggesting a potential mechanism underlying IHH-induced hyperuricemia.
PubMed: 38944139
DOI: 10.1016/j.abb.2024.110078 -
The Journal of Biological Chemistry Jun 2024One of seven natural CO fixation pathways, the anaerobic Wood-Ljungdahl Pathway (WLP) is unique in generating CO as a metabolic intermediate, operating through...
One of seven natural CO fixation pathways, the anaerobic Wood-Ljungdahl Pathway (WLP) is unique in generating CO as a metabolic intermediate, operating through organometallic intermediates, and in conserving (versus utilizing) net ATP. The key enzyme in the WLP is acetyl-CoA synthase (ACS), which uses an active site [2Ni-4Fe-4S] cluster (A-cluster), a CO tunnel, and an organometallic (Ni-CO, Ni-methyl, and Ni-acetyl) reaction sequence to generate acetyl-CoA. Here we reveal that an alcove, which interfaces the tunnel and the A-cluster, is essential for CO fixation and autotrophic growth by the WLP. In vitro spectroscopy, kinetics, binding, and in vivo growth experiments reveal that a Phe229A substitution at one wall of the alcove decreases CO affinity thirty-fold and abolishes autotrophic growth; however, a F229W substitution enhances CO binding 80-fold. Our results indicate the structure of the alcove is exquisitely tuned to concentrate CO near the A-cluster; protect ACS from CO loss during catalysis, provide a haven for inhibitory CO, and stabilize the tetrahedral coordination at the Ni site where CO binds. The directing, concentrating, and protective effects of the alcove explain the inability of F209A to grow autotrophically. The alcove also could help explain current controversies over whether ACS binds CO and methyl through a random or ordered mechanism. Our work redefines what we historically refer to as the metallocenter "active site". The alcove is so crucial for enzymatic function that we propose it is part of the active site. The community should now look for such alcoves in all "gas handling" metalloenzymes.
PubMed: 38944127
DOI: 10.1016/j.jbc.2024.107503 -
The Journal of Biological Chemistry Jun 2024The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic...
The beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the predominant β-secretase, cleaving the amyloid precursor protein (APP) via the amyloidogenic pathway. In addition, BACE1 as an amyloid degrading enzyme (ADE), cleaves Aβ to produce the C-terminally truncated non-toxic Aβ fragment Aβ34 which is an indicator of amyloid clearance. Here, we analyzed effects of BACE1 inhibitors on its opposing enzymatic functions, i.e., amyloidogenic (Aβ producing) and amyloidolytic (Aβ degrading) activities, using cell culture models with varying BACE1/APP ratios. Under high level BACE1 expression, low-dose inhibition unexpectedly yielded a two-fold increase in Aβ42 and Aβ40 levels. The concomitant decrease in Aβ34 and secreted APPβ levels suggested that the elevated Aβ42 and Aβ40 levels were due to the attenuated Aβ degrading activity of BACE1. Notably, the amyloidolytic activity of BACE1 was impeded at lower BACE1 inhibitor concentrations compared to its amyloidogenic activity, thereby suggesting that the Aβ degrading activity of BACE1 was more sensitive to inhibition than its Aβ producing activity. Under endogenous BACE1 and APP levels, "low-dose" BACE1 inhibition affected both the Aβ producing and degrading activities of BACE1, i.e., significantly increased Aβ42/Aβ40 ratio and decreased Aβ34 levels, respectively. Further, we incubated recombinant BACE1 with synthetic Aβ peptides and found that BACE1 has higher affinity for Aβ substrates over APP. In summary, our results suggest that stimulating BACE1's ADE activity and halting Aβ production without decreasing Aβ clearance could still be a promising therapeutic approach with new, yet to be developed, BACE1 modulators.
PubMed: 38944120
DOI: 10.1016/j.jbc.2024.107510 -
International Journal of Biological... Jun 2024Nanocellulose@chitosan (nc@ch) composite beads were prepared via coagulation technique for the elimination of malachite green dye from aqueous solution. As malachite...
Nanocellulose@chitosan (nc@ch) composite beads were prepared via coagulation technique for the elimination of malachite green dye from aqueous solution. As malachite green dye is highly used in textile industries for dyeing purpose which after usage shows fatal effects to the ecosystems and human beings also. In this study the formulated nanocellulose@chitosan composite beads were characterized by Particle size analysis (PSA), Field emission scanning electron microscopy (FESEM), Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) analysis were done to evaluate nanoparticles size distribution, morphological behaviour, functional group entities and degree of crystallinity of prepared beads. The nanocomposite beads adsorption performance was investigated for malachite green (MG) dye and BET analysis were also recorded to know about porous behaviour of the nanocomposite beads. Maximum removal of malachite green (MG) dye was found to be 72.0 mg/g for 100 ppm initial dye concentration. For accurate observations linear and non-linear modelling was done to know about the best-fitted adsorption model during the removal mechanism of dye molecules, on evaluating it has been observed that Langmuir isotherm and Freundlich isotherm show best-fitted observation in the case of linear and non-linear isotherm respectively (R = 0.96 & R = 0.957). In the case of kinetic linear models, the data was well fitted with pseudo-second-order showing chemosorption mechanism (R = 0.999), and in the case of non-linear kinetic model pseudo first order showed good fit showing physisorption mechanism during adsorption (R = 0.999). The thermodynamic study showed positive values for ΔH° and ΔS° throughout the adsorption process respectively, implying an endothermic behaviour. In view of cost effectiveness, desorption or regeneration study was done and it was showed that after the 5th cycle, the removal tendency had decreased from 48 to 38 % for 20-100 ppm dye solution accordingly. Thus, nanocomposite beads prepared by the coagulation method seem to be a suitable candidate for dye removal from synthetic wastewater and may have potential to be used in small scale textile industries for real wastewater treatment.
PubMed: 38944080
DOI: 10.1016/j.ijbiomac.2024.133512 -
International Journal of Biological... Jun 2024Composite bio-based hydrogels have been obtaining a significant attention in recent years as one of the most promising drug delivery systems. In the present study, the...
Composite bio-based hydrogels have been obtaining a significant attention in recent years as one of the most promising drug delivery systems. In the present study, the preparation of composite chitosan-starch hydrogel using maleic acid as a cross-linker was optimized with the help of response surface methodology. The synthesized hydrogel was fluorescent owing to clustering of large number of functional groups. Different analytical techniques, including XRD, FTIR, SEM, XPS, fluorescence and BET were utilized to characterize the prepared hydrogel. XRD analysis confirmed the formation of non-crystalline hydrogel with random arrangement of macromolecular chains. The composite hydrogel exhibited good swelling percentage with pH sensitivity, hemocompatibility and degradability. BET analysis confirmed that the variation in concentration of crosslinker significantly influences the pore volume of the hydrogel. The synthesized composite chitosan-starch hydrogel was utilized as a prospective candidate for controlling drug release. Cefixime as a model drug was loaded onto the synthesized hydrogel utilizing the swelling diffusion method. SEM micrographs showed uniform distribution of drug molecules in the drug loaded hydrogel. In vitro drug release experiments indicated the swelling dependent drug release behaviour of chitosan-starch hydrogel with higher drug release at pH 7.4 (93.08 %) compared to pH 1.2 (67.85 %). The composite chitosan-starch hydrogel was able to prolong and control the drug release up to 12 h. The drug release from the hydrogel followed Korsmeyer-Peppas and Makoid-Banakar model with Fickian diffusion mechanism. Further, the composite hydrogel displayed excitation dependent fluorescence emission with most intense blue emission band at 425 nm with an excitation wavelength of 350 nm. The inclusion of cefixime drug in the hydrogel matrix significantly reduced the fluorescence intensity; the decrease was linearly correlated to the concentration of the drug. Moreover, the fluorescence emission the chitosan-starch hydrogel was found to be dependent upon pH. The synthesized hydrogel is expected to be a potential candidate for controlled drug release as well as for fluorescent sensing applications.
PubMed: 38944079
DOI: 10.1016/j.ijbiomac.2024.133486 -
Water Research Jun 2024Pesticide metabolites are frequently detected in groundwater, often exceeding the concentrations of their parent pesticides. Ceasing the application of certain...
Pesticide metabolites are frequently detected in groundwater, often exceeding the concentrations of their parent pesticides. Ceasing the application of certain pesticides has often not led to the expected decrease in metabolite concentrations in groundwater, which is potentially caused by residues in soil. Whereas pesticide residues in soils are well-documented, there are only few studies about metabolite residues. We investigated if the soil/unsaturated zone can act as a long-term source for metabolites in groundwater by combining soil analysis, groundwater analysis and numerical modelling. The field study focused on the herbicide chloridazon (CLZ) and its frequently detected metabolites desphenyl-chloridazon (DPC) and methyl-desphenyl-chloridazon (MDPC) while in the model additional pesticides and metabolites were considered. In soil samples from an agricultural area, where the last CLZ application was 5 to 10 years ago, we observed 10 times (DPC: 0.22 - 7.4 µg kg) and 6 times (MDPC: 0.12 - 3.1 µg kg) higher metabolite concentrations compared to CLZ (< 0.050 - 1.0 µg kg). Calculations suggested that the majority of the metabolites (DPC: 63 - 96%, MDPC: 74 - 97%) were sorbed despite their lower sorption tendency. The metabolite retention was in particular related to the organic carbon content. The calculated pore water concentrations were highest in the deepest part of the soil profile (75 - 100 cm) with median concentrations of 3.6 and 1.7 µg L for DPC and MDPC, respectively. The groundwater concentrations of DPC and MDPC were 3 to 3.5 times higher in monitoring wells downgradient from the agricultural zone than upgradient of it. This increase highlights the potential of soil and unsaturated zone as a long-term metabolite source after the application stop of pesticides, consistent with the calculated elevated pore water concentrations. Numerical flow and transport model simulations suggested that this input from soil and unsaturated zone can cause elevated metabolite concentrations (> 0.1 µg L) in groundwater over more than one decade. The study highlights that soil and unsaturated zone can act as a long-term source of pesticide metabolites even if they have much higher mobility than the parent compound.
PubMed: 38944001
DOI: 10.1016/j.watres.2024.121901 -
Marine Pollution Bulletin Jun 2024The Timavo River estuary (northern Adriatic Sea) is characterised by strong thermohaline stratification that keeps the deep waters hypoxic. The consequence is an harmful...
Effect of forced aeration on the biogeochemical cycle of nutrients and metal(loid)s as a remedy for hypoxia in a permanently stratified estuary (Gulf of Trieste, northern Adriatic Sea).
The Timavo River estuary (northern Adriatic Sea) is characterised by strong thermohaline stratification that keeps the deep waters hypoxic. The consequence is an harmful algal bloom at the surface in summer that can be mitigated with a forced aeration system installed at the bottom to improve water oxygenation. The nutrient and metal(loid) cycle was investigated, before and during reoxygenation, using an in situ benthic chamber coupled with sampling and analyses of the water column, sediments and porewater. Dissolved oxygen (DO) decreased along the water column and quickly within the benthic chamber when aeration was not in operation, resulting in hypoxia (2.29 mg L) at the bottom and consequent increase in nutrient and metal(loid) concentrations. In contrast, DO levels increased during the activation of the forced aeration system, which proved effective in mitigating oxygen depletion and the efflux of metal(loid)s and nutrients into the overlying water.
PubMed: 38943896
DOI: 10.1016/j.marpolbul.2024.116632