Understanding and controlling the interaction of graphene-based materials with cell membranes is key to the development of graphene-enabled biomedical technologies and to the management of graphene health and safety issues. Very little is known about the fundamental behavior of cell membranes exposed to ultrathin 2D synthetic materials. Here we investigate the interactions of graphene and few-layer graphene (FLG) microsheets with three cell types and with model lipid bilayers by combining coarse-grained molecular dynamics (MD), all-atom MD, analytical modeling, confocal fluorescence imaging, and electron microscopic imaging. The imaging experiments show edge-first uptake and complete internalization for a range of FLG samples of 0.5-to 10-μm lateral dimension. In contrast, the simulations show large energy barriers relative to k B T for membrane penetration by model graphene or FLG microsheets of similar size. More detailed simulations resolve this paradox by showing that entry is initiated at corners or asperities that are abundant along the irregular edges of fabricated graphene materials. Local piercing by these sharp protrusions initiates membrane propagation along the extended graphene edge and thus avoids the high energy barrier calculated in simple idealized MD simulations. We propose that this mechanism allows cellular uptake of even large multilayer sheets of micrometer-scale lateral dimension, which is consistent with our multimodal bioimaging results for primary human keratinocytes, human lung epithelial cells, and murine macrophages. molecular dynamics simulation | graphene-cell interaction | lipid membrane | edge cutting | corner penetration

The cell uptake rate of nanoparticles (NPs) coated with mixed hydrophilic/hydrophobic ligands is known to be strongly influenced by the ligand pattern on the nanoparticle surface. To help reveal the physical mechanism behind this intriguing phenomenon, here we perform dissipative particle dynamics simulations to analyze the evolution of free energy as the ligand-coated NPs pierce through a lipid bilayer. Four characteristic ligand patterns are considered: striated NPs with alternating hydrophilic and hydrophobic groups compared to NPs with randomly mixed ligands at the same hydrophilic to hydrophobic ratio, as well as NPs coated with homogeneous hydrophilic or hydrophobic ligands. The free energy analysis indicates that among the four ligand patterns under study, the striated NP encounters the lowest energy barrier during translocation across the membrane. Further analysis reveals that the translocation of the striated NP is facilitated by the constraint of its rotational degree of freedom by the anisotropic ligand pattern, which prevented the free energy of the system from sinking to a deeper valley as the NP passes through the hydrophobic core of the bilayer. Finally, the critical forces required for almost instant penetration of these patterned NPs across the bilayer are calculated and shown to be consistent with the free energy analysis. These findings provide useful guidelines for the molecular design of patterned NPs for controllable cell penetrability.

Subtelomeric imbalances are a significant cause of congenital disorders. Screening for these abnormalities has traditionally utilized GTG‐banding analysis, fluorescence in situ hybridization (FISH) assays, and multiplex ligation‐dependent probe amplification. Microarray‐based comparative genomic hybridization (array‐CGH) is a relatively new technology that can identify microscopic and submicroscopic chromosomal imbalances. It has been proposed that an array with extended coverage at subtelomeric regions could characterize subtelomeric aberrations more efficiently in a single experiment. The targeted arrays for chromosome microarray analysis (CMA), developed by Baylor College of Medicine, have on average 12 BAC/PAC clones covering 10 Mb of each of the 41 subtelomeric regions. We screened 5,380 consecutive clinical patients using CMA. The most common reasons for referral included developmental delay (DD), and/or mental retardation (MR), dysmorphic features (DF), multiple congenital anomalies (MCA), seizure disorders (SD), and autistic, or other behavioral abnormalities. We found pathogenic rearrangements at subtelomeric regions in 236 patients (4.4%). Among these patients, 103 had a deletion, 58 had a duplication, 44 had an unbalanced translocation, and 31 had a complex rearrangement. The detection rates varied among patients with a normal karyotype analysis (2.98%), with an abnormal karyotype analysis (43.4%), and with an unavailable or no karyotype analysis (3.16%). Six patients out of 278 with a prior normal subtelomere‐FISH analysis showed an abnormality including an interstitial deletion, two terminal deletions, two interstitial duplications, and a terminal duplication. In conclusion, genomic imbalances at subtelomeric regions contribute significantly to congenital disorders. Targeted array‐CGH with extended coverage (up to 10 Mb) of subtelomeric regions will enhance the detection of subtelomeric imbalances, especially for submicroscopic imbalances. © 2008 Wiley‐Liss, Inc.

Evolution of orientation angles during the penetration processes of nanoparticles with different surface hydrophobicities.

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Peripherally inserted central venous catheter (PICC) is the main venous access for cancer patients when they receive chemotherapy and nutritional support, but PICC-related venous thrombosis has become one of the most common and serious complications. It is very important to further explore the relationship among these features, so that prevent and treat the PICC-related thrombosis. To investigate the clinical features and the related factors of PICC-related upper extremity asymptomatic venous thrombosis in cancer patients, and to provide theoretical basis for the prevention of venous thrombosis. A total of 127 tumor patients with PICC catheterization were selected. Thrombus was detected by color Doppler ultrasound at different times: before catheterization and 24 hours after catheterization, and every week. The study was terminated at the time of thrombosis, and patients who did not develop thrombus were terminated after 6 weeks of follow-up. The clinical characteristics and influencing factors of asymptomatic thrombosis such as vessel diameter, blood flow velocity, thrombosis time, location, and the thrombosis stages were recorded. The incidence of PICC-related upper limbs asymptomatic thrombosis was 48.82% (62/127), and the median time was 3 days. The incidence within 24-hour was 37.1% and within 1 week was 85.49%. A total of 81 venous thrombosis were found in 62 patients with asymptomatic thrombosis, there were 19 (23.5%) venous thrombosis in the deep veins while 62 (76.5%) in the superficial veins. Furthermore, thrombosis stages can be divided into 3 levels: stage I accounted for 51.85% (42/81), stage II accounted for 37.04% (30/81), and stage III accounted for 11.11% (9/81). The group trajectory analysis indicated the 3 changes of blood flow velocity during the follow-up period: downward trend, upward trend, and steady fluctuations. Survival analysis indicated that the cohort with downward trend have the high risk of thrombosis (67.90% vs 19.00% vs 45.10%). Cox proportional hazards model suggested that the patient's Eastern Cooperative Oncology Group score (hazard ratio [HR] 2.791, 95% confidence interval [CI] 0.08–0.76) and blood flow velocity (HR 0.250, 95% CI 2.01–3.87) was the risk of PICC-related asymptomatic thrombosis. PICC catheterization can affect blood flow and asymptomatic thrombosis can occur at an early stage. Patient's upper limb activities should be guided to promoting blood circulation, thus effectively preventing thrombosis. Asymptomatic thrombosis can also be detected by color Doppler ultrasound system, within a recommended time of 1 week after catheterization.

Aims: Previous studies have revealed that the increased shedding of syncytiotrophoblast extracellular vesicles (STBM) may lead to preeclampsia (PE). We aimed to identify the proteins carried by STBM and their potential pathological roles in early-onset severe PE. Methods: In this study, we performed a differential proteomic analysis of STBM from early-onset severe PE patients, using iTRAQ isobaric tags and 2D nano LC-MS/MS. STBM were generated by the in vitro explant culture method, and then verified by electron microscopy and western blot analysis. Results: A total of 18 533 unique peptides and 3 317 proteins were identified, 3 292 proteins were quantified. We identified 194 differentially expressed proteins in STBM from early-onset severe PE patients, 122 proteins were up-regulated and 72 proteins were down-regulated. Further bioinformatics analysis revealed that mitochondrion, transmembrane transport and transmembrane transporter activity were the most abundant categories in gene ontology (GO) annotation. Glycolysis/ gluconeogenesis, citrate cycle, fatty acid elongation, steroid hormone biosynthesis and oxidative phosphorylation were the five significantly represented pathways. Four differentially expressed proteins (siglec-6, calnexin, CD63 and S100-A8) related to inflammation, coagulation or immunoregulation were independently verified using western blot. Conclusions: The identification of key proteins carried by STBM may serve not only as a basis for better understanding and further exploring the etiology and pathogenesis of PE, but also as potential biomarkers and in providing targets for future therapy in PE, especially in early-onset severe PE(sPE).