Correction: Delivery mechanism of doxorubicin by PEG-DPPE micelles on membrane invasion by dynamic simulations.

Correction for 'Delivery mechanism of doxorubicin by PEG-DPPE micelles on membrane invasion by dynamic simulations' by Lina Zhao et al., Phys. Chem. Chem. Phys., 2023, 25, 16114-16125, https://doi.org/10.1039/D2CP05946K.

Self-Association of ACE-2 with Different RBD Amounts: A Dynamic Simulation Perspective on SARS-CoV-2 Infection.

Transmissibility of SARS-CoV-2 initially relies on its trimeric Spike-RBDs to tether the ACE-2 on host cells, and enhanced self-association of ACE-2 engaged with Spike facilitates the viral infection. Two primary packing modes of Spike-ACE2 heteroproteins exist potentially due to discrepant amounts of RBDs loading on ACE-2, but the resultant self-association difference is inherently unclear. We used extensive coarse-grained dynamic simulations to characterize the self-association efficiency, the conformation relevance, and the molecular mechanism of ACE-2 with different RBD amounts. It was revealed that the ACE-2 hanging two/full RBDs (Mode-A) rapidly dimerized into the heteroprotein complex in a compact "linear" conformation, while the bare ACE-2 showed weakened self-association and a protein complex. The RBD-tethered ectodomains of ACE-2 presented a more upright conformation relative to the membrane, and the intermolecular ectodomains were predominantly packed by the neck domains, which was obligated to the rapid protein self-association in a compact pattern. Noted is the fact that the ACE-2 tethered by a single RBD (Mode-B) retained considerable self-association efficiency and clustering capability, which unravels the interrelation of ACE-2 colocalization and protein cross-linkage. The molecular perspectives in this study expound the self-association potency of ACE-2 with different RBD amounts and the viral activity implications, which can greatly enhance our comprehension of SARS-CoV-2 infection details.

Delivery mechanism of doxorubicin by PEG-DPPE micelles on membrane invasion by dynamic simulations.

Exploiting micelles of polyethylene glycol-dipalmitoylglycerophosphoethanolamine (PEG-DPPE) as a drug delivery approach is of great promise for improving therapeutic targeting and the half-lives of drugs. To optimize the micelle carriers, pending issues concerning the kinetics underlying the carrier-membrane interplay and the specific contributions of the micelle hydrophobic/hydrophilic components remain to be addressed. Relying on MARTINI coarse-grain (CG) molecular dynamics simulations, we explored the carrier-membrane fusion dynamics of PEG-DPPE micelles with different PEG repetitions in delivering doxorubicin (DOX). A bilayer model composed of 20% phosphatidylglycerol (POPG) and 80% phosphatidylcholine (POPC) was constructed to mimic anionic cancer cell membranes. The CG model of DOX was pioneeringly constructed herein, and it was found to distribute at the hydrophilic/hydrophobic interface of the PEGylated micelles, in agreement with experimental results. The free DOXs cause insignificant disorder of the membrane organization, whereas the PEG-DPPE micelles encapsulating DOX lead to a remarkable membrane invasion supported by the order parameter of the lipid acyl carbon tails and the membrane permeation free energy of DOX. The carrier-bilayer interaction shows a stepwise form attributed to the rearrangement of the zwitterionic/anionic lipids upon the absorption of the DOX-micelle complex on a membrane locality, which initiates the rapid release of DOX to the bilayer interior. Benefiting from the enhanced micelle-membrane interplay, the PEG1250-DPPE micelles result in severe bilayer breakage and deeper membrane insertion of DOX compared to the PEG2000-DPPE micelles. This study provides new theoretical insights into the mechanism of PEG-DPPE micelles in delivering drugs through membranes, which is of benefit for further optimization of PEGylated delivery systems.

Molecular basis of PIP2-dependent conformational switching of phosphorylated CD44 in binding FERM.

Association of the cellular adhesive protein CD44 and the N-terminal (FERM) domain of cytoskeleton adaptors is critical for cell proliferation, migration, and signaling. Phosphorylation of the cytoplasmic domain (CTD) of CD44 acts as an important regulator of the protein association, but the structural transformation and dynamics mechanism remain enigmatic. In this study, extensive coarse-grained simulations were employed to explore the molecular details in the formation of CD44-FERM complex under S291 and S325 phosphorylation, a modification path known to exert reciprocal effects on the protein association. We find that phosphorylation of S291 inhibits complexation by causing the CTD of CD44 to adopt a more closed structure. In contrast, S325 phosphorylation liberates the CD44-CTD from the membrane surface and promotes the linkage with FERM. The phosphorylation-driven transformation is found to occur in a PIP2-dependent manner, with PIP2 effecting the relative stability of the closed and open conformation, and a replacement of PIP2 by POPS greatly abrogates this effect. The revealed interdependent regulation mechanism by phosphorylation and PIP2 in the association of CD44 and FERM further strengthens our understanding of the molecular basis of cellular signaling and migration.

Who would rescue the dilemma of Chinese elderly care? An evolutionary game analysis and simulation research on the formalization of the domestic service industry with subsidy policy.

Since China entered the aging society, the surging demand for elderly care and the industrial upgrading of "silver economy" has forced the domestic service industry to face endogenous challenges. Among them, the formalization of the domestic service industry can effectively reduce the transaction costs and risks of actors, innovate the endogenous vitality of the industry, and promote the improvement of elderly care quality through a triangular employment relationship. By constructing a tripartite asymmetric evolutionary game model of clients, domestic enterprises and governmental departments, this study uses the stability theorem of differential equations to explore the influencing factors and action paths of the system's evolutionary stable strategies (ESS), and uses the research data collected from China to assign values to models for simulation analysis. This study finds that the ratio of the initial ideal strategy, the difference between profits and costs, subsidies to clients, and subsidies or punishments for breach of contract to domestic enterprises are the key factors affecting the formalization of the domestic service industry. Subsidy policy programs can be divided into long-term and periodic programs, and there are differences in the influence paths and effects of the key factors in different situations. Increasing domestic enterprises' market share with employee management systems, formulating subsidy programs for clients, and setting up evaluation and supervision mechanisms are efficient ways through which to promote the formalization of the domestic service industry in China. Subsidy policy of governmental departments should focus on improving the professional skills and quality of elderly care domestic workers, and also encourage domestic enterprises with employee management systems at the same time, to expand the scope of service beneficiaries by running nutrition restaurants in communities, cooperating with elderly care institutions, etc.

Molecular mechanism of CD44 homodimerization modulated by palmitoylation and membrane environments.

The homodimerization of CD44 plays a key role in an intercellular-to-extracellular signal transduction and tumor progression. Acylated modification and specific membrane environments have been reported to mediate translocation and oligomerization of CD44; however, the underlying molecular mechanism remains elusive. In this study, extensive molecular dynamics simulations are performed to characterize the dimerization of palmitoylated CD44 variants in different bilayer environments. CD44 forms homodimer depending on the cysteines on the juxta-membrane domains, and the dimerization efficiency and packing configurations are defected by their palmitoylated modifications. In the phase-segregated (raft included) membrane, homodimerization of the palmitoylated CD44 is hardly observed, whereas PIP2 addition compensates to realize dimerization. However, the structure of CD44 homodimer formed in the phase-segregated bilayer turns susceptive and PIP2 addition allows for an extensive conformation of the cytoplasmic domain, a proposal prerequisite to access the cytoskeleton linker proteins. The results unravel a delicate competitive relationship between PIP2, lipid raft, and palmitoylation in mediating protein homodimerization, which helps to clarify the dynamic dimer conformations and involved cellular signaling of the CD44 likewise proteins.

Prediction of Epidemic Spread of the 2019 Novel Coronavirus Driven by Spring Festival Transportation in China: A Population-Based Study.

After the 2019 novel coronavirus (2019-nCoV) outbreak, we estimated the distribution and scale of more than 5 million migrants residing in Wuhan after they returned to their hometown communities in Hubei Province or other provinces at the end of 2019 by using the data from the 2013-2018 China Migrants Dynamic Survey (CMDS). We found that the distribution of Wuhan's migrants is centred in Hubei Province (approximately 75%) at a provincial level, gradually decreasing in the surrounding provinces in layers, with obvious spatial characteristics of circle layers and echelons. The scale of Wuhan's migrants, whose origins in Hubei Province give rise to a gradient reduction from east to west within the province, and account for 66% of Wuhan's total migrants, are from the surrounding prefectural-level cities of Wuhan. The distribution comprises 94 districts and counties in Hubei Province, and the cumulative percentage of the top 30 districts and counties exceeds 80%. Wuhan's migrants have a large proportion of middle-aged and high-risk individuals. Their social characteristics include nuclear family migration (84%), migration with families of 3-4 members (71%), a rural household registration (85%), and working or doing business (84%) as the main reason for migration. Using a quasi-experimental analysis framework, we found that the size of Wuhan's migrants was highly correlated with the daily number of confirmed cases. Furthermore, we compared the epidemic situation in different regions and found that the number of confirmed cases in some provinces and cities in Hubei Province may be underestimated, while the epidemic situation in some regions has increased rapidly. The results are conducive to monitoring the epidemic prevention and control in various regions.

Retinal gene expression and visually evoked behavior in diabetic long evans rats.

PURPOSE: Patients with diabetic retinopathy may experience severe vision loss due to macular edema and neovascularization secondary to vascular abnormalities. However, before these abnormalities become apparent, there are functional deficits in contrast sensitivity, color perception, and dark adaptation. The goals of this study are to evaluate early changes (up to 3 months) in retinal gene expression, selected visual cycle proteins, and optokinetic tracking (OKT) in streptozotocin (STZ)-induced diabetic rats. METHODS: Retinal gene expression in diabetic Long Evans rats was measured by whole genome microarray 7 days, 4 weeks, and 3 months after the onset of hyperglycemia. Select gene and protein changes were probed by polymerase chain reaction (PCR) and immunohistochemistry, respectively, and OKT thresholds were measured using a virtual optokinetics system. RESULTS: Microarray analysis showed that the most consistently affected molecular and cellular functions were cell-to-cell signaling and interaction, cell death, cellular growth and proliferation, molecular transport, and cellular movement. Further analysis revealed reduced expression of several genes encoding visual cycle proteins including lecithin/retinol acyltransferase (LRAT), retinal pigment epithelium (RPE)-specific protein 65 kDa (RPE65), and RPE retinal G protein-coupled receptor (RGR). These molecular changes occurred simultaneously with a decrease in OKT thresholds by 4 weeks of diabetes. Immunohistochemistry revealed a decrease in RPE65 in the RPE layer of diabetic rats after 3 months of hyperglycemia. CONCLUSIONS: The data presented here are further evidence that inner retinal cells are affected by hyperglycemia simultaneously with blood retinal barrier breakdown, suggesting that glial and neuronal dysfunction may underlie some of the early visual deficits in persons with diabetes.

In vivo time-lapse imaging delineates the zebrafish pituitary proopiomelanocortin lineage boundary regulated by FGF3 signal.

The anterior pituitary gland (adenohypophysis) comprises anterior and intermediate lobes (the pars distalis and pars intermedia) arising from placodal ectoderm at the anterior neural ridge. Signaling molecules including SHH, FGF, WNT, BMP and Notch are involved in regulating primordial pituitary proliferation and lineage determination. However, morphogenic events and molecular mechanisms governing anterior and intermediate lobe specification are not clear. Pituitary expression of proopiomelanocortin (POMC), the common precursor for adrenocorticotropin (ACTH) of pars distalis corticotropes and alpha-melanocyte-stimulating hormone (alpha-MSH) of pars intermedia melanotropes, provides a unique marker for anterior and intermediate lobe morphogenesis. We performed time-lapse confocal microscopy lineage tracing in live zebrafish embryos expressing GFP driven by the pomc promoter and show distinct migration pathways of POMC cells destined to the anterior and intermediate lobes. Using morpholino oligonucleotides, we show that hypomorphic FGF3 down-regulation induces specific defects of pars intermedia POMC cells while pomc, growth hormone and prolactin expression remain intact in the pars distalis. This lineage-specific process is independent of the FGF3 effect on early pituitary specifying transcription factors as indicated by normal Lim3 and Pit1 expression in hypomorphic FGF3 morphants. These findings suggest that the FGF3 signal, in addition to its previously described role of regulating progenitor proliferation and survival, delineates the melanotrope and corticotrope lineage boundary, contributing to establishment of the pituitary pars distalis and pars intermedia.