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COPI vesicles can impact the regulation of the cisterna shape [[13]] or the generation of COPI-coated buds in order to facilitate the subsequent uncoating of Golgi membranes [[8]]. Today, the future paradigm of intracellular transport could be based on four competing models, namely the vesicular model, the cisterna maturation-progression model, the diffusion model, and the kiss-and-run model. Transformation of COPI-coated buds into vesicles could accelerate the uncoating of Golgi membranes from COPI. [Extracted from the article]

Peroxiporins are a specialized subset of aquaporins, which are integral membrane proteins primarily known for facilitating water transport across cell membranes. In addition to the classical water transport function, peroxiporins have the unique capability to transport hydrogen peroxide (H2O2), a reactive oxygen species involved in various cellular signaling pathways and regulation of oxidative stress responses. The regulation of H2O2 levels is crucial for maintaining cellular homeostasis, and peroxiporins play a significant role in this process by modulating its intracellular and extracellular concentrations. This ability to facilitate the passage of H2O2 positions peroxiporins as key players in redox biology and cellular signaling, with implications for understanding and treating various diseases linked to oxidative stress and inflammation. This review provides updated information on the physiological roles of peroxiporins and their implications in disease, emphasizing their potential as novel biomarkers and drug targets in conditions where they are dysregulated, such as inflammation and cancer. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) diseases are the leading causes of death and disabilities in the world. It is quite challenging to treat CNS diseases efficiently because of the blood–brain barrier (BBB). It is a physical barrier with tight junction proteins and high selectivity to limit the substance transportation between the blood and neural tissues. Thus, it is important to understand BBB transport mechanisms for developing novel drug carriers to overcome the BBB. This paper introduces the structure of the BBB and its physiological transport mechanisms. Meanwhile, different strategies for crossing the BBB by using nanomaterial-based drug carriers are reviewed, including carrier-mediated, adsorptive-mediated, and receptor-mediated transcytosis. Since the viral-induced CNS diseases are associated with BBB breakdown, various neurotropic viruses and their mechanisms on BBB disruption are reviewed and discussed, which are considered as an alternative solution to overcome the BBB. Therefore, most recent studies on virus-mimicking nanocarriers for drug delivery to cross the BBB are also reviewed and discussed. On the other hand, the routes of administration of drug-loaded nanocarriers to the CNS have been reviewed. In sum, this paper reviews and discusses various strategies and routes of nano-formulated drug delivery systems across the BBB to the brain, which will contribute to the advanced diagnosis and treatment of CNS diseases. [ABSTRACT FROM AUTHOR]

The emergence of multi-drug-resistant tuberculosis strains poses a significant challenge to modern medicine. The development of new antituberculosis drugs is hindered by the low permeability of many active compounds through the extremely strong bacterial cell wall of mycobacteria. In order to estimate the ability of potential antimycobacterial agents to diffuse through the outer mycolate membrane, the free energy profiles, the corresponding activation barriers, and possible permeability modes of passive transport for a series of known antibiotics, modern antituberculosis drugs, and prospective active drug-like molecules were determined using molecular dynamics simulations with the all-atom force field and potential of mean-force calculations. The membranes of different chemical and conformational compositions, density, thickness, and ionization states were examined. The typical activation barriers for the low-mass molecules penetrating through the most realistic membrane model were 6–13 kcal/mol for isoniazid, pyrazinamide, and etambutol, and 19 and 25 kcal/mol for bedaquilin and rifampicin. The barriers for the ionized molecules are usually in the range of 37–63 kcal/mol. The linear regression models were derived from the obtained data, allowing one to estimate the permeability barriers from simple physicochemical parameters of the diffusing molecules, notably lipophilicity and molecular polarizability. [ABSTRACT FROM AUTHOR]

In this paper, we simulate the changes in the structure and transport properties of an anion-exchange membrane (CJMA-7, Hefei Chemjoy Polymer Materials Co. Ltd., China) caused by its modification with a perfluorosulfonated ionomer (PFSI). The modification was made in several stages and included keeping the membrane at a low temperature, applying a PFSI solution on its surface, and, subsequently, drying it at an elevated temperature. We applied the known microheterogeneous model with some new amendments to simulate each stage of the membrane modification. It has been shown that the PFSI film formed on the membrane-substrate does not affect significantly its properties due to the small thickness of the film (≈4 µm) and similar properties of the film and substrate. The main effect is caused by the fact that PFSI material "clogs" the macropores of the CJMA-7 membrane, thereby, blocking the transport of coions through the membrane. In this case, the membrane microporous gel phase, which exhibits a high selectivity to counterions, remains the primary pathway for both counterions and coions. Due to the above modification of the CJMA-7 membrane, the coion (Na+) transport number in the membrane equilibrated with 1 M NaCl solution decreased from 0.11 to 0.03. Thus, the modified membrane became comparable in its transport characteristics with more expensive IEMs available on the market. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is a global health concern affecting millions worldwide. One of the critical challenges in CKD is the accumulation of uremic toxins such as p-cresol sulfate (pCS) and indoxyl sulfate (IS), which contribute to systemic damage and CKD progression. Understanding the transport mechanisms of these prominent toxins is essential for developing effective treatments. Here, we investigated whether pCS and IS are routed to the plasma membrane or to the cytosol by two key transporters, SLC22A11 and OAT1. To distinguish between cytosolic transport and plasma membrane insertion, we used a hyperosmolarity assay in which the accumulation of substrates into HEK-293 cells in isotonic and hypertonic buffers was measured in parallel using LC-MS/MS. Judging from the efficiency of transport (TE), pCS is a relevant substrate of SLC22A11 at 7.8 ± 1.4 µL min−1 mg protein−1 but not as good as estrone-3-sulfate; OAT1 translocates pCS less efficiently. The TE of SLC22A11 for IS was similar to pCS. For OAT1, however, IS is an excellent substrate. With OAT1 and p-aminohippuric acid, our study revealed an influence of transporter abundance on the outcomes of the hyperosmolarity assay; very high transport activity confounded results. SLC22A11 was found to insert both pCS and IS into the plasma membrane, whereas OAT1 conveys these toxins to the cytosol. These disparate transport mechanisms bear profound ramifications for toxicity. Membrane insertion might promote membrane damage and microvesicle release. Our results underscore the imperative for detailed structural inquiries into the translocation of small molecules. [ABSTRACT FROM AUTHOR]

Cellular respiration is associated with at least six distinct but intertwined biological functions. (1) biosynthesis of ATP from ADP and inorganic phosphate, (2) consumption of respiratory substrates, (3) support of membrane transport, (4) conversion of respiratory energy to heat, (5) removal of oxygen to prevent oxidative damage, and (6) generation of reactive oxygen species (ROS) as signaling molecules. Here we focus on function #6, which helps the organism control its mitochondria. The ROS bursts typically occur when the mitochondrial membrane potential (MMP) becomes too high, e.g., due to mitochondrial malfunction, leading to cardiolipin (CL) oxidation. Depending on the intensity of CL damage, specific programs for the elimination of damaged mitochondria (mitophagy), whole cells (apoptosis), or organisms (phenoptosis) can be activated. In particular, we consider those mechanisms that suppress ROS generation by enabling ATP synthesis at low MMP levels. We discuss evidence that the mild depolarization mechanism of direct ATP/ADP exchange across mammalian inner and outer mitochondrial membranes weakens with age. We review recent data showing that by protecting CL from oxidation, mitochondria-targeted antioxidants decrease lethality in response to many potentially deadly shock insults. Thus, targeting ROS- and CL-dependent pathways may prevent acute mortality and, hopefully, slow aging. [ABSTRACT FROM AUTHOR]

The connexin gene family is the most prevalent gene that contributes to hearing loss. Connexins 26 and 30, encoded by GJB2 and GJB6, respectively, are the most abundantly expressed connexins in the inner ear. Connexin 43, which is encoded by GJA1, appears to be widely expressed in various organs, including the heart, skin, the brain, and the inner ear. The mutations that arise in GJB2, GJB6, and GJA1 can all result in comprehensive or non-comprehensive genetic deafness in newborns. As it is predicted that connexins include at least 20 isoforms in humans, the biosynthesis, structural composition, and degradation of connexins must be precisely regulated so that the gap junctions can properly operate. Certain mutations result in connexins possessing a faulty subcellular localization, failing to transport to the cell membrane and preventing gap junction formation, ultimately leading to connexin dysfunction and hearing loss. In this review, we provide a discussion of the transport models for connexin 43, connexins 30 and 26, mutations affecting trafficking pathways of these connexins, the existing controversies in the trafficking pathways of connexins, and the molecules involved in connexin trafficking and their functions. This review can contribute to a new way of understanding the etiological principles of connexin mutations and finding therapeutic strategies for hereditary deafness. [ABSTRACT FROM AUTHOR]

Putrescine is a bioactive polyamine. Its retinal concentration is strictly controlled to maintain a healthy sense of vision. The present study investigated putrescine transport at the blood–retinal barrier (BRB) to gain a better understanding of the mechanisms of putrescine regulation in the retina. Our microdialysis study showed that the elimination rate constant during the terminal phase was significantly greater (1.90-fold) than that of [14C]D-mannitol, which is a bulk flow marker. The difference in the apparent elimination rate constants of [3H]putrescine and [14C]D-mannitol was significantly decreased by unlabeled putrescine and spermine, suggesting active putrescine transport from the retina to the blood across the BRB. Our study using model cell lines of the inner and outer BRB showed that [3H]putrescine transport was time-, temperature-, and concentration-dependent, suggesting the involvement of carrier-mediated processes in putrescine transport at the inner and outer BRB. [3H]Putrescine transport was significantly reduced under Na+-free, Cl−-free, and K+-replacement conditions, and attenuated by polyamines or organic cations such as choline, a choline transporter-like protein (CTL) substrate. Rat CTL1 cRNA-injected oocytes exhibited marked alterations in [3H]putrescine uptake, and CTL1 knockdown significantly reduced [3H]putrescine uptake in model cell lines, suggesting the possible participation of CTL1 in putrescine transport at the BRB. [ABSTRACT FROM AUTHOR]

In the present paper, new pyrimidine derivatives were designed, synthesized and analyzed in terms of their anticancer properties. The tested compounds were evaluated in vitro for their antitumor activity. The cytotoxic effect on normal human dermal fibroblasts (NHDF) was also determined. According to the results, all the tested compounds exhibited inhibitory activity on the proliferation of all lines of cancer cells (colon adenocarcinoma (LoVo), resistant colon adenocarcinoma (LoVo/DX), breast cancer (MCF-7), lung cancer (A549), cervical cancer (HeLa), human leukemic lymphoblasts (CCRF-CEM) and human monocytic (THP-1)). In particular, their feature stronger influence on the activity of P-glycoprotein of cell cultures resistant to doxorubicin than doxorubicin. Tested compounds have more lipophilic character than doxorubicin, which determines their affinity for the molecular target and passive transport through biological membranes. Moreover, the inhibitory potential against topoisomerase II and DNA intercalating properties of synthesized compounds were analyzed via molecular docking. [ABSTRACT FROM AUTHOR]

The main component of blood and lymphatic vessels is the endothelium covering their luminal surface. It plays a significant role in many cardiovascular diseases. Tremendous progress has been made in deciphering of molecular mechanisms involved into intracellular transport. However, molecular machines are mostly characterized in vitro. It is important to adapt this knowledge to the situation existing in tissues and organs. Moreover, contradictions have accumulated within the field related to the function of endothelial cells (ECs) and their trans-endothelial pathways. This has induced necessity for the re-evaluation of several mechanisms related to the function of vascular ECs and intracellular transport and transcytosis there. Here, we analyze available data related to intracellular transport within ECs and re-examine several hypotheses about the role of different mechanisms in transcytosis across ECs. We propose a new classification of vascular endothelium and hypotheses related to the functional role of caveolae and mechanisms of lipid transport through ECs. [ABSTRACT FROM AUTHOR]

Understanding the vesicular trafficking of receptors and receptor ligands in the brain capillary endothelium is essential for the development of the next generations of biologics targeting neurodegenerative diseases. Such complex biological questions are often approached by in vitro models in combination with various techniques. Here, we present the development of a stem cell-based human in vitro blood-brain barrier model composed of induced brain microvascular endothelial cells (iBMECs) on the modular µSiM (a microdevice featuring a silicon nitride membrane) platform. The µSiM was equipped with a 100 nm thick nanoporous silicon nitride membrane with glass-like imaging quality that allowed the use of high-resolution in situ imaging to study the intracellular trafficking. As a proof-of-concept experiment, we investigated the trafficking of two monoclonal antibodies (mAb): an anti-human transferrin receptor mAb (15G11) and an anti-basigin mAb (#52) using the µSiM-iBMEC-human astrocyte model. Our results demonstrated effective endothelial uptake of the selected antibodies; however, no significant transcytosis was observed when the barrier was tight. In contrast, when the iBMECs did not form a confluent barrier on the µSiM, the antibodies accumulated inside both the iBMECs and astrocytes, demonstrating that the cells have an active endocytic and subcellular sorting machinery and that the µSiM itself does not hinder antibody transport. In conclusion, our µSiM-iBMEC-human astrocyte model provides a tight barrier with endothelial-like cells, which can be used for high-resolution in situ imaging and for studying receptor-mediated transport and transcytosis in a physiological barrier. [ABSTRACT FROM AUTHOR]

The salt permeability through three commercial cation-exchange membranes with different morphologies is investigated in aqueous NaCl solutions. Ion-exchange membranes (IEMs) find application in different processes such as electrodialysis, reverse osmosis, diffusion dialysis, membrane electrolysis, membrane fuel cells and ion exchange bioreactors. The aim of this paper is the experimental determination of the electrolyte permeability in the following membranes: MK-40 membrane, Nafion N324 membrane and Nafion 117 membrane. The latter is selected as being a reference membrane. The effect of an increase in the NaCl concentration in the solutions on membranes transport properties is analyzed. With regard to membranes sorption, a decrease in the water content was observed when the external electrolyte concentration is increased. Concerning permeation through the membranes, the salt permeability increased with concentration for the Nafion 117 membrane and remained nearly constant for the other two membranes. A close relation between the degree of liquid sorption by the membranes and the electrolyte permeability was observed. [ABSTRACT FROM AUTHOR]

Tight junctions form a barrier to control passive transport of ions and small molecules across epithelia and endothelia. In addition to forming a barrier, some of claudins control transport properties of tight junctions by forming charge- and size-selective ion channels. It has been suggested claudin monomers can form or incorporate into tight junction strands to form channels. Resolving the crystallographic structure of several claudins in recent years has provided an opportunity to examine structural basis of claudins in tight junctions. Computational and theoretical modeling relying on atomic description of the pore have contributed significantly to our understanding of claudin pores and paracellular transport. In this paper, we review recent computational and mathematical modeling of claudin barrier function. We focus on dynamic modeling of global epithelial barrier function as a function of claudin pores and molecular dynamics studies of claudins leading to a functional model of claudin channels. [ABSTRACT FROM AUTHOR]

Glucose is a basic nutrient in most of the creatures; its transport through biological membranes is an absolute requirement of life. This role is fulfilled by glucose transporters, mediating the transport of glucose by facilitated diffusion or by secondary active transport. GLUT (glucose transporter) or SLC2A (Solute carrier 2A) families represent the main glucose transporters in mammalian cells, originally described as plasma membrane transporters. Glucose transport through intracellular membranes has not been elucidated yet; however, glucose is formed in the lumen of various organelles. The glucose-6-phosphatase system catalyzing the last common step of gluconeogenesis and glycogenolysis generates glucose within the lumen of the endoplasmic reticulum. Posttranslational processing of the oligosaccharide moiety of glycoproteins also results in intraluminal glucose formation in the endoplasmic reticulum (ER) and Golgi. Autophagic degradation of polysaccharides, glycoproteins, and glycolipids leads to glucose accumulation in lysosomes. Despite the obvious necessity, the mechanism of glucose transport and the molecular nature of mediating proteins in the endomembranes have been hardly elucidated for the last few years. However, recent studies revealed the intracellular localization and functional features of some glucose transporters; the aim of the present paper was to summarize the collected knowledge. [ABSTRACT FROM AUTHOR]

The aim of this study was to elucidate whether the membrane nanodomain protein AtFlot1 is involved in vesicular transport pathways and regulation of the P-type H+-ATPase content in plasma membrane of A. thaliana under salt stress. Transmission electron microscopy revealed changes in the endosomal system of A. thaliana root cells due to knockout mutation SALK_205125C (Atflot1ko). Immunoblotting of the plasma membrane-enriched fractions isolated from plant organs with an antibody to the H+-ATPase demonstrated changes in the H+-ATPase content in plasma membrane in response to the Atflot1ko mutation and salt shock. Expression levels of the main H+-ATPase isoforms, PMA1 and PMA2, as well as endocytosis activity of root cells determined by endocytic probe FM4-64 uptake assay, were unchanged in the Atflot1ko mutant. We have shown that AtFlot1 participates in regulation of the H+-ATPase content in the plasma membrane. We hypothesized that AtFlot1 is involved in both exocytosis and endocytosis, and, thus, contributes to the maintenance of cell ion homeostasis under salt stress. The lack of a pronounced Atflot1ko phenotype under salt stress conditions may be due to the assumed ability of Atflot1ko to switch vesicular transport to alternative pathways. Functional redundancy of AtFlot proteins may play a role in the functioning of these alternative pathways. [ABSTRACT FROM AUTHOR]

Artificial ion-exchange and other charged membranes, such as biomembranes, are self-organizing nanomaterials built from macromolecules. The interactions of fragments of macromolecules results in phase separation and the formation of ion-conducting channels. The properties conditioned by the structure of charged membranes determine their application in separation processes (water treatment, electrolyte concentration, food industry and others), energy (reverse electrodialysis, fuel cells and others), and chlore-alkali production and others. The purpose of this review is to provide guidelines for modeling the transport of ions and water in charged membranes, as well as to describe the latest advances in this field with a focus on power generation systems. We briefly describe the main structural elements of charged membranes which determine their ion and water transport characteristics. The main governing equations and the most commonly used theories and assumptions are presented and analyzed. The known models are classified and then described based on the information about the equations and the assumptions they are based on. Most attention is paid to the models which have the greatest impact and are most frequently used in the literature. Among them, we focus on recent models developed for proton-exchange membranes used in fuel cells and for membranes applied in reverse electrodialysis. [ABSTRACT FROM AUTHOR]

The transcytosis of lipids through enterocytes occurs through the delivery of lipid micelles to the microvilli of enterocytes, consumption of lipid derivates by the apical plasma membrane (PM) and then their delivery to the membrane of the smooth ER attached to the basolateral PM. The SER forms immature chylomicrons (iChMs) in the ER lumen. iChMs are delivered at the Golgi complex (GC) where they are subjected to additional glycosylation resulting in maturation of iChMs. ChMs are secreted into the intercellular space and delivered into the lumen of lymphatic capillaries (LCs). The overloading of enterocytes with lipids induces the formation of lipid droplets inside the lipid bilayer of the ER membranes and transcytosis becomes slower. Here, we examined components of the enterocyte-to-lymphatic barriers in newly born rats before the first feeding and after it. In contrast to adult animals, enterocytes of newborns rats exhibited apical endocytosis and a well-developed subapical endosomal tubular network. These enterocytes uptake membranes from amniotic fluid. Then these membranes are transported across the polarized GC and secreted into the intercellular space. The enterocytes did not contain COPII-coated buds on the granular ER. The endothelium of blood capillaries situated near the enterocytes contained only a few fenestrae. The LCs were similar to those in adult animals. The first feeding induced specific alterations of enterocytes, which were similar to those observed after the lipid overloading of enterocytes in adult rats. Enlarged chylomicrons were stopped at the level of the LAMP2 and Neu1 positive post-Golgi structures, secreted, fused, delivered to the interstitial space, captured by the LCs and transported to the lymph node, inducing the movement of macrophages from lymphatic follicles into its sinuses. The macrophages captured the ChMs, preventing their delivery into the blood. [ABSTRACT FROM AUTHOR]

Experimental studies showed that the use of MSCs-EVs as treatment for liver fibrosis may be more effective than MSCs therapy, as they can go through biological barriers and transport their anti-fibrotic cargo to target cells. The review by Krawczenko and Klimczak is focused on the role of mesenchymal stem/stromal cells of adipose tissue origin (AT-MSCs) and their secretome in the regulation of damaged tissue regeneration [[15]]. Currently, the effectiveness of MSCs therapies has been verified in 1430 clinical trials, registered at the www.clinicaltrials.gov (as of 24 May 2022), concerning the supportive therapy of cells and organs transplantations; osteoarticular, autoimmune, cardiovascular and neurodegenerative diseases; and recently, on COVID-19 treatment. Mesenchymal stem/stromal cells (MSC) have been extensively studied over the last 30 years in the context of their regenerative and immunomodulatory activities for potential application in regenerative medicine. [Extracted from the article]

The year 2016 marked the 20th anniversary of the death of Marcelle Grenson and the 50th anniversary of her first publication on yeast amino acid transport, the topic to which, as Professor at the Free University of Brussels (ULB), she devoted the major part of her scientific career. M. Grenson was the first scientist in Belgium to introduce and apply genetic analysis in yeast to dissect the molecular mechanisms that were underlying complex problems in biology. Today, M. Grenson is recognized for the pioneering character of her work on the diversity and regulation of amino acid transporters in yeast. The aim of this tribute is to review the major milestones of her forty years of scientific research that were conducted between 1950 and 1990. [ABSTRACT FROM AUTHOR]

Parabens are effective preservatives widely used in cosmetic products and processed food, with high human exposure. Recent evidence suggests that parabens exert estrogenic effects. This work investigated the potential interference of parabens with the estrogen-activating enzyme 17β-hydroxysteroid dehydrogenase (17β-HSD) 1 and the estrogen-inactivating 17β-HSD2. A ligand-based 17β-HSD2 pharmacophore model was applied to screen a cosmetic chemicals database, followed by in vitro testing of selected paraben compounds for inhibition of 17β-HSD1 and 17β-HSD2 activities. All tested parabens and paraben-like compounds, except their common metabolite p-hydroxybenzoic acid, inhibited 17β-HSD2. Ethylparaben and ethyl vanillate inhibited 17β-HSD2 with IC50 values of 4.6 ± 0.8 and 1.3 ± 0.3 μM, respectively. Additionally, parabens size-dependently inhibited 17β-HSD1, whereby hexyl- and heptylparaben were most active with IC50 values of 2.6 ± 0.6 and 1.8 ± 0.3 μM. Low micromolar concentrations of hexyl- and heptylparaben decreased 17β-HSD1 activity, and ethylparaben and ethyl vanillate decreased 17β-HSD2 activity. However, regarding the very rapid metabolism of these compounds to the inactive p-hydroxybenzoic acid by esterases, it needs to be determined under which conditions low micromolar concentrations of these parabens or their mixtures can occur in target cells to effectively disturb estrogen effects in vivo. [ABSTRACT FROM AUTHOR]

Based on our previous proteomic study on Cavitating Ultrasound Aspirator (CUSA) fluid pools of Newly Diagnosed (ND) and Recurrent (R) glioblastomas (GBMs) of tumor core and periphery, as defined by 5-aminolevulinc acid (5-ALA) metabolite fluorescence, this work aims to apply a bioinformatic approach to investigate specifically into three sub-proteomes, i.e., Not Detected in Brain (NB), Cancer Related (CR) and Extracellular Vesicles (EVs) proteins following selected database classification. The study of these yet unexplored specific datasets aims to understand the high infiltration capability and relapse rate that characterizes this aggressive brain cancer. Out of the 587 proteins highly confidently identified in GBM CUSA pools, 53 proteins were classified as NB. Their gene ontology (GO) analysis showed the over-representation of blood coagulation and plasminogen activating cascade pathways, possibly compatible with Blood Brain Barrier damage in tumor disease and surgery bleeding. However, the NB group also included non-blood proteins and, specifically, histones correlated with oncogenesis. Concerning CR proteins, 159 proteins were found in the characterized GBM proteome. Their GO analysis highlighted the over-representation of many pathways, primarily glycolysis. Interestingly, while CR proteins were identified in ND-GBM exclusively in the tumor zones (fluorescence positive core and periphery zones) as predictable, conversely, in R-GBM they were unexpectedly characterized prevalently in the healthy zone (fluorescence negative tumor periphery). Relative to EVs protein classification, 60 proteins were found. EVs are over-released in tumor disease and are important in the transport of biological macromolecules. Furthermore, the presence of EVs in numerous body fluids makes them a possible low-invasive source of brain tumor biomarkers to be investigated. These results give new hints on the molecular features of GBM in trying to understand its aggressive behavior and open to more in-depth investigations to disclose potential disease biomarkers. [ABSTRACT FROM AUTHOR]

Intra-cellular active transport by native cargos is ubiquitous. We investigate the motion of spherical nano-particles (NPs) grafted with flexible polymers that end with a nuclear localization signal peptide. This peptide allows the recruitment of several mammalian dynein motors from cytoplasmic extracts. To determine how motor–motor interactions influenced motility on the single microtubule level, we conducted bead-motility assays incorporating surface adsorbed microtubules and combined them with model simulations that were based on the properties of a single dynein. The experimental and simulation results revealed long time trajectories: when the number of NP-ligated motors Nm increased, run-times and run-lengths were enhanced and mean velocities were somewhat decreased. Moreover, the dependence of the velocity on run-time followed a universal curve, regardless of the system composition. Model simulations also demonstrated left- and right-handed helical motion and revealed self-regulation of the number of microtubule-bound, actively transporting dynein motors. This number was stochastic along trajectories and was distributed mainly between one, two, and three motors, regardless of Nm. We propose that this self-regulation allows our synthetic NPs to achieve persistent motion that is associated with major helicity. Such a helical motion might affect obstacle bypassing, which can influence active transport efficiency when facing the crowded environment of the cell. [ABSTRACT FROM AUTHOR]

Mitochondria are well-known to function as the primary sites of ATP synthesis in most mammalian cells, including the renal proximal tubule. Other functions have also been associated with different mitochondrial activities, including the regulation of redox status and the initiation of mitophagy and apoptosis. Mechanisms for the membrane transport of glutathione (GSH) and various GSH-derived metabolites across the mitochondrial inner membrane of renal proximal tubular cells are critical determinants of these functions and may serve as pharmacological targets for potential therapeutic approaches. Specific interactions of reactive intermediates, derived from drug metabolism, with molecular components in mitochondria have been identified as early steps in diverse forms of chemically-induced nephrotoxicity. Applying this key observation, we developed a novel hypothesis regarding the identification of early, sensitive, and specific biomarkers of exposure to nephrotoxicants. The underlying concept is that upon exposure to a diverse array of environmental contaminants, as well as therapeutic drugs whose efficacy is limited by nephrotoxicity, renal mitochondria will release both high- and low-molecular-weight components into the urine or the extracellular medium in an in vitro model. The detection of these components may then serve as indicators of exposure before irreversible renal injury has occurred. [ABSTRACT FROM AUTHOR]

Cytokinins are a class of phytohormones, signalling molecules specific to plants. They act as regulators of diverse physiological processes in complex signalling pathways. It is necessary for plants to continuously regulate cytokinin distribution among different organs, tissues, cells, and compartments. Such regulatory mechanisms include cytokinin biosynthesis, metabolic conversions and degradation, as well as cytokinin membrane transport. In our review, we aim to provide a thorough picture of the latter. We begin by summarizing cytokinin structures and physicochemical properties. Then, we revise the elementary thermodynamic and kinetic aspects of cytokinin membrane transport. Next, we review which membrane-bound carrier proteins and protein families recognize cytokinins as their substrates. Namely, we discuss the families of "equilibrative nucleoside transporters" and "purine permeases", which translocate diverse purine-related compounds, and proteins AtPUP14, AtABCG14, AtAZG1, and AtAZG2, which are specific to cytokinins. We also address long-distance cytokinin transport. Putting all these pieces together, we finally discuss cytokinin distribution as a net result of these processes, diverse in their physicochemical nature but acting together to promote plant fitness. [ABSTRACT FROM AUTHOR]

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration. [ABSTRACT FROM AUTHOR]

The evolution of the eukaryotic cell from the primal endosymbiotic event involved a complex series of adaptations driven primarily by energy optimization. Transfer of genes from endosymbiont to host and concomitant expansion (by infolding) of the endosymbiont's chemiosmotic membrane greatly increased output of adenosine triphosphate (ATP) and placed selective pressure on the membrane at the host–endosymbiont interface to sustain the energy advantage. It is hypothesized that critical functions at this interface (metabolite exchange, polypeptide import, barrier integrity to proteins and DNA) were managed by a precursor β-barrel protein ("pβB") from which the voltage-dependent anion-selective channel (VDAC) descended. VDAC's role as hub for disparate and increasingly complex processes suggests an adaptability that likely springs from a feature inherited from pβB, retained because of important advantages conferred. It is proposed that this property is the remarkable structural flexibility evidenced in VDAC's gating mechanism, a possible origin of which is discussed. [ABSTRACT FROM AUTHOR]

Phytate and phytases in seeds are the subjects of numerous studies, dating back as far as the early 20th century. Most of these studies concern the anti-nutritional properties of phytate, and the prospect of alleviating the effects of phytate with phytase. As reasonable as this may be, it has led to a fragmentation of knowledge, which hampers the appreciation of the physiological system at hand. In this review, we integrate the existing knowledge on the chemistry and biosynthesis of phytate, the globoid cellular structure, and recent advances on plant phytases. We highlight that these components make up a system that serves to store and—in due time—release the seed's reserves of the mineral nutrients phosphorous, potassium, magnesium, and others, as well as inositol and protein. The central component of the system, the phytate anion, is inherently rich in phosphorous and inositol. The chemical properties of phytate enable it to sequester additional cationic nutrients. Compartmentalization and membrane transport processes regulate the buildup of phytate and its associated nutrients, resulting in globoid storage structures. We suggest, based on the current evidence, that the degradation of the globoid and the mobilization of the nutrients also depend on membrane transport processes, as well as the enzymatic action of phytase. [ABSTRACT FROM AUTHOR]

The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood–brain and blood–placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation. [ABSTRACT FROM AUTHOR]

In this article, we present a method for the enhanced molecular dynamics simulation of protein and DNA systems called potential of mean force (PMF)-enriched sampling. The method uses partitions derived from the potentials of mean force, which we determined from DNA and protein structures in the Protein Data Bank (PDB). We define a partition function from a set of PDB-derived PMFs, which efficiently compensates for the error introduced by the assumption of a homogeneous partition function from the PDB datasets. The bias based on the PDB-derived partitions is added in the form of a hybrid Hamiltonian using a renormalization method, which adds the PMF-enriched gradient to the system depending on a linear weighting factor and the underlying force field. We validated the method using simulations of dialanine, the folding of TrpCage, and the conformational sampling of the Dickerson–Drew DNA dodecamer. Our results show the potential for the PMF-enriched simulation technique to enrich the conformational space of biomolecules along their order parameters, while we also observe a considerable speed increase in the sampling by factors ranging from 13.1 to 82. The novel method can effectively be combined with enhanced sampling or coarse-graining methods to enrich conformational sampling with a partition derived from the PDB. [ABSTRACT FROM AUTHOR]

The SQUAMOSA promoter binding protein (SBP)-box gene family is a plant-specific transcription factor family. This family plays a crucial role in plant growth and development. In this study, 20 SBP-box genes were identified in the tea plant genome and classified into six groups. The genes in each group shared similar exon-intron structures and motif positions. Expression pattern analyses in five different tissues demonstrated that expression in the buds and leaves was higher than that in other tissues. The cis-elements and expression patterns of the CsSBP genes suggested that the CsSBP genes play active roles in abiotic stress responses; these responses may depend on the abscisic acid (ABA), gibberellic acid (GA), and methyl jasmonate (MeJA) signaling pathways. Our work provides a comprehensive understanding of the CsSBP family and will aid in genetically improving tea plants. [ABSTRACT FROM AUTHOR]