Intracellular Transport Processes Research Articles

Research Progress on the Physiological Mechanism by Which Selenium Alleviates Heavy Metal Stress in Plants: A Review

Human activities, such as mining, industrialization, industrial waste emissions, and agricultural practices, have caused heavy metals to become widespread and excessively accumulated in soil. The high concentrations of heavy metals in soil can be toxic to plants, severely affecting crop yield and quality. Moreover, these heavy metals can also enter the food chain, affecting animals and humans and leading to various serious illnesses. Selenium (Se) is not only an essential element for animals and humans but is also beneficial for plants, as it promotes their ability to respond actively to biotic and abiotic stresses. The global issue of Se deficiency in diets has made plants the primary source for human Se supplementation. This paper comprehensively reviews the effects of heavy metal stress on plant growth and development, physiological responses of plants to such stress, and the intracellular transport processes of heavy metals within plants. It particularly focuses on the mechanisms by which Se alleviates heavy metal stress in plants. Additionally, the study delves into how Se significantly enhances plant tolerance mechanisms against typical heavy metals, such as cadmium (Cd), lead (Pb), and mercury (Hg). This integrative research not only expands the boundaries of research in the field of plant heavy metal stress and Se application but also provides new perspectives and solutions for understanding and addressing complex environmental heavy metal pollution issues. By integrating these aspects, this paper not only fills existing gaps in the literature but also offers comprehensive scientific basis and strategic recommendations for environmental protection and sustainable agriculture development.

Endosymbiosis in trypanosomatids: The bacterium division depends on microtubule dynamism

Microtubules are components of the cytoskeleton that perform essential functions in eukaryotes, such as those related to shape change, motility and cell division. In this context some characteristics of these filaments are essential, such as polarity and dynamic instability. In trypanosomatids, microtubules are integral to ultrastructure organization, intracellular transport and mitotic processes. Some species of trypanosomatids co-evolve with a symbiotic bacterium in a mutualistic association that is marked by extensive metabolic exchanges and a coordinated division of the symbiont with other cellular structures, such as the nucleus and the kinetoplast. It is already established that the bacterium division is microtubule-dependent, so in this work, it was investigated whether the dynamism and remodeling of these filaments is capable of affecting the prokaryote division. To this purpose, Angomonas deanei was treated with Trichostatin A (TSA), a deacetylase inhibitor, and mutant cells for histone deacetylase 6 (HDAC6) were obtained by CRISPR-Cas9. A decrease in proliferation, an enhancement in tubulin acetylation, as well as morphological and ultrastructural changes, were observed in TSA-treated protozoa and mutant cells. In both cases, symbiont filamentation occurred, indicating that prokaryote cell division is dependent on microtubule dynamism.

The effect of resolvin D1n-3 DPA on primary oral epithelial cell migration in vitro.

Specialized pro-resolving lipid mediators (SPMs) are known for their anti-inflammatory and pro-resolving actions. The aim of the present study was to find new functions of the SPM resolvin D1n-3 DPA (RvD1n-3 DPA) on oral epithelial cells. As a starting point, we used a dataset obtained by RNA high-throughput sequencing of oral epithelial cells exposed to TNF-α and RvD1n-3 DPA versus TNF-α alone. GOrilla enrichment analysis showed that the actin cytoskeleton was significantly overrepresented after adjustment for multiple hypothesis testing. As actin, amongst others, is closely related to cell migration, we then explored whether RvD1n-3 DPA can modulate oral epithelial cell migration. To this end, we used an in vitro cell migration model, including TNF-α treatment, to mimic an inflammatory cell state. The analysis revealed that RvD1n-3 DPA increased oral epithelial cell migration in the presence but not in the absence of TNF-α. Addition of RvD1n-3 DPA also induced F actin accumulation around the cell nucleus, indicating that RvD1n-3 DPA potentially can mediate processes of intracellular transport. This indicates that this lipid mediator may be a promising therapeutic candidate in oral mucosal wound healing.

Emergent Spatiotemporal Organization in Stochastic Intracellular Transport Dynamics.

The interior of a living cell is an active, fluctuating, and crowded environment, yet it maintains a high level of coherent organization. This dichotomy is readily apparent in the intracellular transport system of the cell. Membrane-bound compartments called endosomes play a key role in carrying cargo, in conjunction with myriad components including cargo adaptor proteins, membrane sculptors, motor proteins, and the cytoskeleton. These components coordinate to effectively navigate the crowded cell interior and transport cargo to specific intracellular locations, even though the underlying protein interactions and enzymatic reactions exhibit stochastic behavior. A major challenge is to measure, analyze, and understand how, despite the inherent stochasticity of the constituent processes, the collective outcomes show an emergent spatiotemporal order that is precise and robust. This review focuses on this intriguing dichotomy, providing insights into the known mechanisms of noise suppression and noise utilization in intracellular transport processes, and also identifies opportunities for future inquiry.

An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review.

RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS's structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein's role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS-effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field's future.

Reservoir crowding in a dynamically disordered bidirectional system with narrow entrances

Motivated by the presence of imperfections in the complex processes of vehicular traffic and intracellular transport, we investigate a two-lane dynamically disordered system with narrow entrances. The movement of the particles is obstructed by the presence of defects that bind/unbind stochastically from each site. A global constraint on both the number of particles and defects is considered which is characterized by individual reservoirs. Specifically, the particle reservoir features reservoir crowding, which affects the entry-exit rates of particles. We analyzed the model within the mean-field framework and examined complex phenomena such as stationary phase diagrams, particle densities and spontaneous symmetry breaking. The role of the various parameters: binding/unbinding rate of defects, entry-exit rates of the particles, hopping rate of particles in the presence of defect and the number of particles/defects, is thoroughly examined. Our results display a rich behaviour, emphasizing the influence of reservoir crowding, resulting in both symmetric and asymmetric phases. Another important consequence is the back-and-forth transition and the persistence of a localized domain wall in the system, even for abundant particle resources. All theoretical findings are validated by extensive Monte Carlo simulations.

Evaluation of BDE-47-induced neurodevelopmental toxicity in zebrafish embryos.

There are growing concerns about the neurodevelopmental toxicity of polybrominated diphenyl ethers (PBDEs), but the toxicological phenotypes and mechanisms are not well elucidated. Here, zebrafish (Danio rerio) were exposed to 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) from 4 to 72 h post-fertilization (hpf). The results showed that BDE-47 stimulated the production of dopamine and 5-hydroxytryptamine, but inhibited expression of Nestin, GFAP, Gap43, and PSD95 in 24 hpf embryos. Importantly, we unraveled the inhibitory effects of BDE-47 on neural crest-derived melanocyte differentiation and melanin syntheses process, evidenced by disrupted expression of wnt1, wnt3, sox10, mitfa, tyrp1a, tyrp1b, tryp2, and oca2 gene in 72 hpf embryos and decreased tyrosinase activities in embryos at 48 and 72 hpf. The transcriptional activities of myosin VAa, kif5ba, rab27a, mlpha, and cdc42 genes, which are associated with intracellular transport process, were also disturbed during zebrafish development. Ultimately, these alterations led to fast spontaneous movement and melanin accumulation deficit in zebrafish embryos upon BDE-47 exposure. Our results provide an important extension for understanding the neurodevelopmental effects of PBDEs and facilitate the comprehensive evaluation of neurotoxicity in embryos.

Target search by an imported conjugative DNA element for a unique integration site along a bacterial chromosome during horizontal gene transfer.

Integrative and conjugative elements (ICEs) are mobile genetic elements that can transfer by conjugation to recipient cells. Some ICEs integrate into a unique site in the genome of their hosts. We studied quantitatively the process by which an ICE searches for its unique integration site in the Bacillus subtilis chromosome. We followed the motion of both ICEBs1 and the chromosomal integration site in real time within individual cells. ICEBs1 exhibited a wide spectrum of dynamical behaviors, ranging from rapid sub-diffusive displacements crisscrossing the cell, to kinetically trapped states. The chromosomal integration site moved sub-diffusively and exhibited pronounced dynamical asymmetry between longitudinal and transversal motions, highlighting the role of chromosomal structure and the heterogeneity of the bacterial interior in the search. The successful search for and subsequent recombination into the integration site is a key step in the acquisition of integrating mobile genetic elements. Our findings provide new insights into intracellular transport processes involving large DNA molecules.

Integration of metabolomics and proteomics reveals the underlying hepatotoxic mechanism of perfluorooctane sulfonate (PFOS) and 6:2 chlorinated polyfluoroalkyl ether sulfonic acid (6:2 Cl-PFESA) in primary human hepatocytes

Perfluorooctane sulfonate (PFOS) and its alternative 6:2 chlorinated polyfluorinated ether sulfonate (6:2 Cl-PFESA) are ubiquitous in various environmental and human samples. They have been reported to have hepatotoxicity effects, but the potential mechanisms remain unclear. Herein, we integrated metabolomics and proteomics analysis to investigate the altered profiles in metabolite and protein levels in primary human hepatocytes (PHH) exposed to 6:2 Cl-PFESA and PFOS at human exposure relevant concentrations. Our results showed that 6:2 Cl-PFESA exhibited higher perturbation effects on cell viability, metabolome and proteome than PFOS. Integration of metabolomics and proteomics revealed that the alteration of glycerophospholipid metabolism was the critical pathway of 6:2 Cl-PFESA and PFOS-induced lipid metabolism disorder in primary human hepatocytes. Interestingly, 6:2 Cl-PFESA-induced cellular metabolic process disorder was associated with the cellular membrane-bounded signaling pathway, while PFOS was associated with the intracellular transport process. Moreover, the disruption effects of 6:2 Cl-PFESA were also involved in inositol phosphate metabolism and phosphatidylinositol signaling system. Overall, this study provided comprehensive insights into the hepatic lipid toxicity mechanisms of 6:2 Cl-PFESA and PFOS in human primary hepatocytes.

Isogeometric analysis-based physics-informed graph neural network for studying traffic jam in neurons

The motor-driven intracellular transport plays a crucial role in supporting a neuron cell’s survival and function, with motor proteins and microtubule (MT) structures collaborating to promptly deliver the essential materials to the right location in neuron. The disruption of transport may lead to the onset of various neurodegenerative diseases. Therefore, it is essential to study how neurons regulate the material transport process and have a better understanding of the traffic jam formation. In our earlier work, we developed a PDE-constrained optimization model and an isogeometric analysis (IGA) solver to simulate traffic jams induced by MT reduction and MT swirl. Here, we develop a novel IGA-based physics-informed graph neural network (PGNN) to quickly predict normal and abnormal transport phenomena such as traffic jam in different neuron geometries. In particular, the proposed method learns from the IGA simulation of the intracellular transport process and provides accurate material concentration prediction of normal transport and MT-induced traffic jam. The IGA-based PGNN model contains simulators to handle local prediction of both normal and two MT-induced traffic jams in pipes, as well as another simulator to predict normal transport in bifurcations. Bézier extraction is adopted to incorporate the geometry information into the simulators to accurately compute the physics informed loss function with PDE residuals. Moreover, a GNN assembly model is adopted to tackle different neuron morphologies by assembling local prediction into the entire geometry. In summary, the well-trained model effectively predicts the distribution of transport velocity and material concentration during traffic jam and normal transport with an average error less than 10% compared to IGA simulations. The effectiveness of the proposed model is demonstrated within several complex neuron geometries.

Exploring differentially expressed genes in hypothalamic, pars tuberalis and pineal gland transcriptomes in different sexual behavior phenotypes in rams using RNA-Seq.

Reproductive seasonality is a limiting factor in sheep production. Sexual behavior is a key element in reproductive efficiency, and this function is regulated by the hypothalamus-pituitary-gonadal (HPG) axis. To understand the mechanisms of sexual behavior, transcriptomic sequencing technology was used to identify differentially expressed genes (DEGs) in the hypothalamus (HT), pars tuberalis (PT) and pineal gland (PG) in Rasa Aragonesa rams with different sexual behavior. Bioinformatics analysis of the 16,401 identified genes by RNA-Seq revealed 103 and 12 DEGs in the HT and the PG, respectively, at a false discovery rate (FDR) of 5% with an absolute value of expression ≥ 1 (log2FC). However, no DEGs were found in the PT. Functional annotation and pathway enrichment analysis showed that DEGs of HT were enriched mainly in neuroactive ligand-receptor interactions and signaling pathways, including notable candidate genes such as MTNR1A, CHRNA2, FSHB, LHB, GNRHR, AVP, PRL, PDYN, CGA, GABRD, and TSHB, which play a crucial role in sexual behavior. The GnRH and cAMP signaling pathways were also highlighted. In addition, gene set enrichment analysis (GSEA) identified potential pathways, dominated mainly by biological process category, that could be responsible for the differences in sexual behavior observed in rams. The intracellular protein transport and pattern specification process were enriched within the PT and the transcription factor binding and protein ubiquitination pathways for the PG. Thus, these pathways together may play an important role in the regulation of the sexual behavior in Rasa Aragonesa rams through the hypothalamic-pituitary-gonadal axis. The validation of 5 DEGs using reverse transcription quantitative polymerase chain reaction (RT-qPCR) showed expression patterns like the found with RNA-Seq. Overall, these results contribute to understanding the genomic basis of sexual behavior in rams. Our study demonstrates that multiple networks and pathways orchestrate sexual behavior in sheep.

Regulatory role of phosphoproteins in the development of bovine small intestine during early life.

The small intestine is the primary site of nutrient digestion and absorption, which plays a key role in the survival of neonatal calves. A comprehensive assessment of the phosphoproteomic changes in the small intestine of neonatal calves is unavailable; therefore, we used phosphopeptide enrichment coupled with liquid chromatography-tandem mass spectrometry to investigate the changes in the phosphoproteome profile in the bovine small intestine during the first 36 h of life. Twelve neonatal male calves were assigned to one of the following groups: (1) calves not fed colostrum and slaughtered approximately 2 h postpartum (n = 3), (2) calves fed colostrum at 1 to 2 h and slaughtered 8 h postpartum (n = 3), (3) calves fed 2 colostrum meals (at 1-2 and 10-12 h) and slaughtered 24 h postpartum (n = 3), (4) calves fed 3 colostrum meals (at 1-2, 10-12, and 22-24 h) and slaughtered 36 h postpartum (n = 3). Mid-duodenal, jejunal, and ileal samples of the calves were collected after slaughter. We identified 1,678 phosphoproteins with approximately 3,080 phosphosites, which were mainly Ser (89.9%), Thr (9.8%), and Tyr (0.3%) residues; they belonged to the prodirected (52.9%), basic (20.4%), acidic (16.6%), and Tyr-directed (1.7%) motif categories. The regional differentially expressed phosphoproteins included zonula occludens 2, sorting nexin 12, and protein kinase C, which are mainly associated with developmental processes, intracellular transport, vesicle-mediated transport, and immune system process. They are enriched in the endocytosis, tight junction, insulin signaling, and focal adhesion pathways. The temporal differentially expressed phosphoproteins included occludin, epsin 1, and bridging integrator 1, which were mainly associated with macromolecule metabolic process, cell adhesion, and growth. They were enriched in the spliceosomes, adherens junctions, and tight junctions. The observed changes in the phosphoproteins in the tissues of small intestine suggest the protein phosphorylation plays an important role in nutrient transport and immune response of calves during early life, which needs to be confirmed in a larger study.

Membrane Association Allosterically Regulates Phospholipase A2 Enzymes and Their Specificity.

Water-soluble proteins as well as membrane-bound proteins associate with membrane surfaces and bind specific lipid molecules in specific sites on the protein. Membrane surfaces include the traditional bilayer membranes of cells and subcellular organelles formed by phospholipids. Monolayer membranes include the outer monolayer phospholipid surface of intracellular lipid droplets of triglycerides and various lipoproteins including HDL, LDL, VLDL, and chylomicrons. These lipoproteins circulate in our blood and lymph systems and contain triglycerides, cholesterol, cholesterol esters, and proteins in their interior, and these are sometimes interspersed on their surfaces. Similar lipid-water interfaces also occur in mixed micelles of phospholipids and bile acids in our digestive system, which may also include internalized triglycerides and cholesterol esters. Diacyl phospholipids constitute the defining molecules of biological membranes. Phospholipase A1 (PLA1) hydrolyzes phospholipid acyl chains at the sn-1 position of membrane phospholipids, phospholipase A2 (PLA2) hydrolyzes acyl chains at the sn-2 position, phospholipase C (PLC) hydrolyzes the glycerol-phosphodiester bond, and phospholipase D (PLD) hydrolyzes the polar group-phosphodiester bond. Of the phospholipases, the PLA2s have been the most well studied at the mechanistic level. The PLA2 superfamily consists of 16 groups and numerous subgroups, and each is generally described as one of 6 types. The most well studied of the PLA2s include extensive genetic and mutational studies, complete lipidomics specificity characterization, and crystallographic structures. This Account will focus principally on results from deuterium exchange mass spectrometric (DXMS) studies of PLA2 interactions with membranes and extensive molecular dynamics (MD) simulations of their interactions with membranes and specific phospholipids bound in their catalytic and allosteric sites. These enzymes either are membrane-bound or are water-soluble and associate with membranes before extracting their phospholipid substrate molecule into their active site to carry out their enzymatic hydrolytic reaction. We present evidence that when a PLA2 associates with a membrane, the membrane association can result in a conformational change in the enzyme whereby the membrane association with an allosteric site on the enzyme stabilizes the enzyme in an active conformation on the membrane. We sometimes refer to this transition from a "closed" conformation in aqueous solution to an "open" conformation when associated with a membrane. The enzyme can then extract a single phospholipid substrate into its active site, and catalysis occurs. We have also employed DXMS and MD simulations to characterize how PLA2s interact with specific inhibitors that could lead to potential therapeutics. The PLA2s constitute a paradigm for how membranes interact allosterically with proteins, causing conformational changes and activation of the proteins to enable them to extract and bind a specific phospholipid from a membrane for catalysis, which is probably generalizable to intracellular and extracellular transport and phospholipid exchange processes as well as other specific biological functions. We will focus on the four main types of PLA2, namely, the secreted (sPLA2), cytosolic (cPLA2), calcium-independent (iPLA2), and lipoprotein-associated PLA2 (Lp-PLA2) also known as platelet-activating factor acetyl hydrolase (PAF-AH). Studies on a well-studied specific example of each of the four major types of the PLA2 superfamily demonstrate clearly that protein subsites can show precise specificity for one of the phospholipid hydrophobic acyl chains, often the one at the sn-2 position, including exquisite sensitivity to the number and position of double bonds.

Barley Ror1 encodes a class XI myosin required for mlo-based broad-spectrum resistance to the fungal powdery mildew pathogen.

Loss-of-function alleles of plant MLO genes confer broad-spectrum resistance to powdery mildews in many eudicot and monocot species. Although barley (Hordeum vulgare) mlo mutants have been used in agriculture for more than 40 years, understanding of the molecular principles underlying this type of disease resistance remains fragmentary. Forward genetic screens in barley have revealed mutations in two Required for mlo resistance (Ror) genes that partially impair immunity conferred by mlo mutants. While Ror2 encodes a soluble N-ethylmaleimide-sensitive factor-attached protein receptor (SNARE), the identity of Ror1, located at the pericentromeric region of barley chromosome 1H, remained elusive. We report the identification of Ror1 based on combined barley genomic sequence information and transcriptomic data from ror1 mutant plants. Ror1 encodes the barley class XI myosin Myo11A (HORVU.MOREX.r3.1HG0046420). Single amino acid substitutions of this myosin, deduced from non-functional ror1 mutant alleles, map to the nucleotide-binding region and the interface between the relay-helix and the converter domain of the motor protein. Ror1 myosin accumulates transiently in the course of powdery mildew infection. Functional fluorophore-labeled Ror1 variants associate with mobile intracellular compartments that partially colocalize with peroxisomes. Single-cell expression of the Ror1 tail region causes a dominant-negative effect that phenocopies ror1 loss-of-function mutants. We define a myosin motor for the establishment of mlo-mediated resistance, suggesting that motor protein-driven intracellular transport processes are critical for extracellular immunity, possibly through the targeted transfer of antifungal and/or cell wall cargoes to pathogen contact sites.

MARCKS Is an Essential Regulator of Reactive Oxygen Species Production in the Monocytic Cell Type.

Myristoylated alanine-rich C-kinase substrate (MARCKS) is a ubiquitous protein mediating versatile effects in a variety of cell types, including actin crosslinking, signal transduction, and intracellular transport processes. MARCKS’s functional role in monocyte/macrophages, however, has not yet been adequately addressed. Thus, the aim of this study was to further elucidate the impact of MARCKS on central cellular functions of monocytic cells. To address this topic, we generated monocytic THP-1 (Tohoku Hospital Pediatrics-1)-derived MARCKS wildtype and knockout (KO) cells using the CRISPR/Cas9 technique. Remarkably, in the absence of MARCKS, both total and intracellular reactive oxygen species (ROS) production were strongly suppressed but restored following transient MARCKS re-transfection. In contrast, proliferation, differentiation, cytokine expression, and phagocytosis remained unaltered. A complete inhibition of ROS production could also be achieved in THP-1-derived PKCβ KO cells or in PKC inhibitor Staurosporine-treated primary human monocytes. MARCKS deficiency also involved reduced basal Akt phosphorylation and delayed re-phosphorylation. Further analyses indicated that long-term TNF pre-incubation strongly enhances monocytic ROS production, which was completely blocked in MARCKS and PKCβ KO cells. Collectively, our study demonstrates that MARCKS is an essential molecule enabling ROS production by monocytic cells and suggests that MARCKS is part of a signal cascade involved in ROS formation.

Whole Transcriptome-Based Study to Speculate upon the Silkworm Yellow Blood Inhibitor (I) Gene and Analyze the miRNA-Mediated Gene Regulatory Network

White cocoon is developed and used as a natural fiber, and different silkworm strains have different cocoon colors. Natural-colored cocoons are preferred by people, however, the cocoon color mainly settles on sericin and it basically falls off after reeling. Currently, there are no varieties applied to production due to the formation mechanism of cocoon color is not clear. The formation of cocoon color involves multiple gene regulations. Previous studies have shown that the main genes regulating cocoon traits are the yellow blood (Y) gene, yellow blood inhibitor (I) gene, and yellow cocoon (C) gene. Among them, the products of the Y gene and C gene have been studied, but the I gene is still unclear. In this study, the midgut tissues of the yellow (NB) and the white (306) cocoon silkworm were analyzed by whole transcriptome sequencing. The results showed that there are 1639 DE-circRNAs, 70 DE-miRNAs, and 3225 DE-mRNAs, including 1785 up-regulated genes and 1440 down-regulated genes. GO and KEGG annotation results indicated that DE-mRNAs are mainly involved in intracellular transport, signal transduction, lipid transport, and metabolic processes. Two key genes, KWMTBOMO10339 and KWMTBOMO16553, were screened out according to the annotation results, which were involved in amino acid transport and ion exchange function, respectively. The interaction analysis between ncRNA and target genes showed that there were five miRNAs regulating these two genes. The qPCR analysis showed that the I gene was down-regulated, and the miRNA expression profiles were most up-regulated. Therefore, during the yellow and white cocoon formation, KWMTBOMO10339 and KWMTBOMO16553 may be regulated by miRNA, resulting in the non-expression of KWMTBOMO10339 and KWMTBOMO16553 in yellow cocoon silkworm, and the pigment molecules can enter hemolymph from the midgut to form yellow blood, then transport to the middle silk gland to finally form yellow cocoons.

First-passage times in complex energy landscapes: a case study with nonmuscle myosin II assembly

Complex energy landscapes often arise in biological systems, e.g. for protein folding, biochemical reactions, or intracellular transport processes. Their physical effects are frequently reflected in the first-passage times (FPTs) arising from these energy landscapes. However, their calculation is notoriously challenging and it is often difficult to identify the most relevant features of a given energy landscape. Here we show how this can be achieved by coarse-graining the Fokker–Planck equation to a master equation and decomposing its FPTs in an iterative process. We apply this method to the electrostatic interaction between two rods of nonmuscle myosin II (NM2), which is the main molecular motor for force generation in nonmuscle cells. Energy landscapes are computed directly from the amino acid sequences of the three different isoforms. Our approach allows us to identify the most relevant energy barriers for their self-assembly into NM2 minifilaments and how they change under force. In particular, we find that antiparallel configurations are more stable than parallel ones, but also show more changes under mechanical loading. Our work demonstrates the rich dynamics that can be expected for NM2-assemblies under mechanical load and in general shows how one can identify the most relevant energy barriers in complex energy landscapes.

Expression Analysis of Genes Involved in Transport Processes in Mice with MPTP-Induced Model of Parkinson's Disease.

Processes of intracellular and extracellular transport play one of the most important roles in the functioning of cells. Changes to transport mechanisms in a neuron can lead to the disruption of many cellular processes and even to cell death. It was shown that disruption of the processes of vesicular, axonal, and synaptic transport can lead to a number of diseases of the central nervous system, including Parkinson’s disease (PD). Here, we studied changes in the expression of genes whose protein products are involved in the transport processes (Snca, Drd2, Rab5a, Anxa2, and Nsf) in the brain tissues and peripheral blood of mice with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced models of PD. We detected changes in the expressions of Drd2, Anxa2, and Nsf at the earliest modeling stages. Additionally, we have identified conspicuous changes in the expression level of Anxa2 in the striatum and substantia nigra of mice with MPTP-induced models of PD in its early stages. These data clearly suggest the involvement of protein products in these genes in the earliest stages of the pathogenesis of PD.

Modeling intracellular transport and traffic jam in 3D neurons using PDE-constrained optimization

Abstract The intracellular transport process plays an important role in delivering essential materials throughout branched geometries of neurons for their survival and function. Many neurodegenerative diseases have been associated with the disruption of transport. Therefore, it is essential to study how neurons control the transport process to localize materials to necessary locations. Here, we develop a novel optimization model to simulate the traffic regulation mechanism of material transport in three-dimensional complex geometries of neurons. The transport is controlled to avoid traffic jams of materials by minimizing a predefined objective function. The optimization subjects to a set of partial differential equation (PDE) constraints that describe the material transport process based on a macroscopic molecular-motor-assisted transport model of intracellular particles. The proposed PDE-constrained optimization model is solved in complex tree structures by using the isogeometric analysis. Different simulation parameters are used to introduce traffic jams and study how neurons handle the transport issue. Specifically, we successfully model and explain the traffic jam caused by the reduced number of microtubules (MTs) and MT swirls. In summary, our model effectively simulates the material transport process in healthy neurons and also explains the formation of a traffic jam in abnormal neurons. Our results demonstrate that both geometry and MT structure play important roles in achieving an optimal transport process in neurons.

Modeling material transport regulation and traffic jam in neurons using PDE-constrained optimization

The intracellular transport process plays an important role in delivering essential materials throughout branched geometries of neurons for their survival and function. Many neurodegenerative diseases have been associated with the disruption of transport. Therefore, it is essential to study how neurons control the transport process to localize materials to necessary locations. Here, we develop a novel optimization model to simulate the traffic regulation mechanism of material transport in complex geometries of neurons. The transport is controlled to avoid traffic jam of materials by minimizing a pre-defined objective function. The optimization subjects to a set of partial differential equation (PDE) constraints that describe the material transport process based on a macroscopic molecular-motor-assisted transport model of intracellular particles. The proposed PDE-constrained optimization model is solved in complex tree structures by using isogeometric analysis (IGA). Different simulation parameters are used to introduce traffic jams and study how neurons handle the transport issue. Specifically, we successfully model and explain the traffic jam caused by reduced number of microtubules (MTs) and MT swirls. In summary, our model effectively simulates the material transport process in healthy neurons and also explains the formation of a traffic jam in abnormal neurons. Our results demonstrate that both geometry and MT structure play important roles in achieving an optimal transport process in neuron.