Schizophrenia (SZ) is a complex neuropsychiatric disorder, affecting 1% of the world population. Long-standing clinical observations and molecular data have pointed to a possible vascular deficiency ...that could be acting synergistically with neuronal dysfunction in SZ. As SZ is a neurodevelopmental disease, the use of human-induced pluripotent stem cells (hiPSC) allows disease biology modeling while retaining the patient's unique genetic signature. Previously, we reported a VEGFA signaling impairment in SZ-hiPSC-derived neural lineages leading to decreased angiogenesis. Here, we present a functional characterization of SZ-derived brain microvascular endothelial-like cells (BEC), the counterpart of the neurovascular crosstalk, revealing an intrinsically defective blood-brain barrier (BBB) phenotype. Transcriptomic assessment of genes related to endothelial function among three control (Ctrl BEC) and five schizophrenia patients derived BEC (SZP BEC), revealed that SZP BEC have a distinctive expression pattern of angiogenic and BBB-associated genes. Functionally, SZP BEC showed a decreased angiogenic response in vitro and higher transpermeability than Ctrl BEC. Immunofluorescence staining revealed less expression and altered distribution of tight junction proteins in SZP BEC. Moreover, SZP BEC's conditioned media reduced barrier capacities in the brain microvascular endothelial cell line HCMEC/D3 and in an in vivo permeability assay in mice. Overall, our results describe an intrinsic failure of SZP BEC for proper barrier function. These findings are consistent with the hypothesis tracing schizophrenia origins to brain development and BBB dysfunction.
Nanofiltration (NF), as a selective Mg(II) and Ca(II) separation and concentration treatment, and electrodialysis with bipolar membranes (EDBM) were evaluated for the valorization of seawater ...desalination reverse osmosis brines (60NaCl/L) to produce both rich Mg(II) and Ca(II) brines for phosphate recovery and HCl and NaOH as chemicals for desalination treatments.
A NF pilot plant, using NF270 membranes at 20bar, provided a rich Mg(II) (8.3gMg(II)/L) and Ca(II) (2.1gCa(II)/L) brine on the concentrated stream with enrichment factors of 3.2 for Mg(II) and 2.5 for Ca(II). The NF permeate stream containing 50±2gNaCl/L was treated to remove residual Mg(II) (760mg/L) and Ca(II) (415mg/L) by chemical precipitation with Na2CO3 and NaOH before the EDBM unit. Divalent cations free brine containing NaCl (50gNaCl/L) were fed into the EDBM stack in order to produce NaOH and HCl under recirculation configuration. Constant voltage and acid and base concentrations at different initial conditions were evaluated to obtain the maximum acid and base concentration (approximately 1M NaOH/HCl) at 9V. No substantial effect of initial acid and base concentrations on the overall performance was observed. An energy consumption of 2.6kWh/kg NaOH and current efficiency of 77±3% were calculated.
•NF was used to concentrate and separate Ca–Mg from RO brine for phosphate recovery.•NF permeate stream precipitation treatment was done to remove residual Ca and Mg.•EDBM was applied to produce HCl and NaOH as chemicals for desalination treatments.•Rich Mg and Ca concentrate stream and rich NaCl permeate stream were obtained by NF.•NaOH and HCl up to 1M were obtained at 9V by EDBM using RO divalent free brines.
Magdalena River basin potamodromous fishes have two annual reproductive seasons: the subienda in the first half of the year and the mitaca in the second. Both upstream migrations are c. 30–45 days ...long; after that, with the onset of the rainy season, fishes spawn and remain in the river (resident individuals) or start a downstream movement (the bajanza) to return to the Magdalena floodplain lakes (nursery, shelter and feeding grounds). Due to their particular gonad development the bocachico Prochilodus magdalenae and probably the comelón Leporinus muyscorum are physiologically able to undertake two annual basin migrations. In the presence of dams or hydropower structures, fishes are able to find alternative migration routes. Some species should be re‐classified in their migratory behaviour.
Sequences that form DNA secondary structures, such as G-quadruplexes (G4s) and intercalated-Motifs (iMs), are abundant in the human genome and play various physiological roles. However, they can also ...interfere with replication and threaten genome stability. Multiple lines of evidence suggest G4s inhibit replication, but the underlying mechanism remains unclear. Moreover, evidence of how iMs affect the replisome is lacking. Here, we reconstitute replication of physiologically derived structure-forming sequences to find that a single G4 or iM arrest DNA replication. Direct single-molecule structure detection within solid-state nanopores reveals structures form as a consequence of replication. Combined genetic and biophysical characterisation establishes that structure stability and probability of structure formation are key determinants of replisome arrest. Mechanistically, replication arrest is caused by impaired synthesis, resulting in helicase-polymerase uncoupling. Significantly, iMs also induce breakage of nascent DNA. Finally, stalled forks are only rescued by a specialised helicase, Pif1, but not Rrm3, Sgs1, Chl1 or Hrq1. Altogether, we provide a mechanism for quadruplex structure formation and resolution during replication and highlight G4s and iMs as endogenous sources of replication stress.
Investigation of new materials for biomedical applications has represented a relevant subject in the latest decade, enhancing versatile properties of lipids. It has been documented that the ...capabilities of lipid-based systems improve when they combine with polymers, proteins, and sugars. In this field, understanding the driving forces behind such hybrid systems is mandatory for biomedical applications. From this perspective, it is crucial to investigate the biophysical properties of this kind of material. Here, we investigate the biophysical properties of hybrid membranes composed of 1,2-dipalmitoyl-
sn
-glycero-3-phosphocholine (DPPC), cholesterol, and octyl-
β
-D-glucopyranoside (OGP). Lipid/sugar materials could have potential properties to use as nanovesicles for drug delivery. We encapsulate ibuprofen in lipid/sugar vesicles and evaluate their thermodynamics, hydrodynamics, and morphological properties by differential scanning calorimetry, dynamic light scattering, and scanning electron microscopy. We found that OGP combined with cholesterol modifies thermodynamic parameters of membranes such as phase transition temperature, enthalpy change, and cooperativity. Lipid vesicles containing OGP at 6.0 mM loaded with ibuprofen demonstrated good stability after 3 months of storage. Furthermore, electronic microscopy revealed the presence of well-defined liposomes. We conclude that cholesterol and OGP can act synergistically in polar–nonpolar spaces of the DPPC bilayer, where the hydrophobic nature of ibuprofen leads to incorporation into this hybrid core, which implies changes in the fluidity and compactness of the membrane occurring at temperatures of biological relevance. This investigation provides crucial knowledge regarding the biophysical properties of thermo-responsive biohybrid vesicles potentially to use in nanomedicine, which could be of practical reference for designing innovative drug delivery systems.
Graphical Abstract
There are few data on
Crassostrea virginica
physiological rates across the range of salinities and temperatures to which they are regularly exposed, and this limits the applicability of growth and ...production models using these data. The objectives of this study were to quantify, in winter (17 °C) and summer (27 °C), the clearance and oxygen consumption rates of
C. virginica
from Louisiana across a range of salinities typical of the region (3, 6, 9, 15 and 25). Salinity and season (temperature and reproduction) affected
C. virginica
physiology differently; salinity impacted clearance rates with reduced feeding rates at low salinities, while season had a strong effect on respiration rates. Highest clearance rates were found at salinities of 9–25, with reductions ranging from 50 to 80 and 90 to 95% at salinities of 6 and 3, respectively. Oxygen consumption rates in summer were four times higher than in winter. Oxygen consumption rates were within a narrow range and similar among salinities in winter, but varied greatly among individuals and salinities in summer. This likely reflected varying stages of gonad development. Valve movements measured at the five salinities indicated oysters were open 50–60% of the time in the 6–25 salinity range and ~ 30% at a salinity of 3. Reduced opening periods, concomitant with narrower valve gap amplitudes, are in accord with the limited feeding at the lowest salinity (3). These data indicate the need for increased focus on experimental determination of optimal ranges and thresholds to better quantify oyster population responses to environmental changes.
Protein conformation is critically linked to function and often controlled by interactions with regulatory factors. Here we report the selection of camelid-derived single-domain antibodies ...(nanobodies) that modulate the conformation and spectral properties of the green fluorescent protein (GFP). One nanobody could reversibly reduce GFP fluorescence by a factor of 5, whereas its displacement by a second nanobody caused an increase by a factor of 10. Structural analysis of GFP-nanobody complexes revealed that the two nanobodies induce subtle opposing changes in the chromophore environment, leading to altered absorption properties. Unlike conventional antibodies, the small, stable nanobodies are functional in living cells. Nanobody-induced changes were detected by ratio imaging and used to monitor protein expression and subcellular localization as well as translocation events such as the tamoxifen-induced nuclear localization of estrogen receptor. This work demonstrates that protein conformations can be manipulated and studied with nanobodies in living cells.
The feasibility of substituting a conventional pre-treatment, consisting of dioxi-chlorination, coagulation/flocculation, settling and sand filtration, of a drinking water treatment plant (DWTP) by ...direct ultrafiltration (UF) has been assessed from a microbiological standpoint. Bacterial indicators, viral indicators and human viruses have been monitored in raw river, ultrafiltered and conventionally pre-treated water samples during two years. Direct UF has proven to remove bacterial indicators quite efficiently and to a greater extent than the conventional process does. Nevertheless, the removal of small viruses such as some small bacteriophages and human viruses (e.g. enteroviruses and noroviruses) is lower than the current conventional pre-treatment.
Membrane integrity has been assessed during two years by means of tailored tests based on bacteriophages with different properties (MS-2, GA and PDR-1) and bacterial spores (Bacillus spores). Membrane integrity has not been compromised despite the challenging conditions faced by directly treating raw river water. Bacteriophage PDR-1 appears as a suitable microbe to test membrane integrity, as its size is slightly larger than the considered membrane pore size. However, its implementation at full scale plant is still challenging due to difficulties in obtaining enough phages for its seeding.
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•Direct UF appeared as a suitable alternative to a DWTP conventional pre-treatment.•Direct UF ensured the removal of >5 log10 units of bacteria and viruses >60 nm.•Direct UF guaranteed 3 log10 units removal of viral indicators and viruses <40 nm.•Naturally occurring somatic coliphages are suitable to monitor UF virus performance.•Bacillus spores and PDR-1 appeared as suitable microbes to monitor membrane integrity.
Water scarcity in the Mediterranean basin has been solved by using seawater desalination reverse osmosis technology (SWD-RO). This technology produces brine which is discharged back into the sea ...resulting in an environmental impact on marine ecosystems. Under the circular economy approach, the aim of this work is to recover resources from NaCl-rich brine (~60–70g/L), e.g. in the form of NaOH and HCl, by integration of two ion exchange-based membrane technologies and quantify the electrical energy consumption. Electrodialysis (ED) incorporating monovalent selective cation exchange membranes as divalent ions purification and concentration of the NaCl present in the SWD-RO brine, was integrated with bipolar membrane ED (EDBM) to produce NaOH and HCl. Current densities of 0.30–0.40kA/m2 at two temperature ranges simulating different seawater temperature regimes (15–18°C and 22–28°C) were tested and a pure NaCl solution was used as starting concentrate stream. NaCl-rich brines with 100 or 200g NaCl/L were obtained by ED and then introduced in the EDBM stack producing HCl and NaOH up to 2M, depending on the initial concentrations. A minimum energy consumption of 1.7kWh/kg NaOH was calculated when working by EDBM with initial concentrations of 104g NaCl/L and 0.24M HCl and NaOH.
•Seawater desalination reverses osmosis (SWD-RO) brine was valorized as NaOH and HCl.•ED was used to purify and concentrate SWD-RO brine into divalent-free NaCl solutions.•100 to 200g NaCl/L brines were achieved by ED depending on current and temperature.•EDBM was applied to produce HCl and NaOH as chemicals for pH adjustment treatments.•NaOH and HCl up to 2M were obtained at 9V by EDBM using an ED pretreated brine.
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