Erythrocyte membrane-camouflaged polymeric nanoparticles as a biomimetic delivery platform

Efforts to extend nanoparticle residence time in vivo have inspired many strategies in particle surface modifications to bypass macrophage uptake and systemic clearance. Here we report a top-down biomimetic approach in particle functionalization by coating biodegradable polymeric nanoparticles with natural erythrocyte membranes, including both membrane lipids and associated membrane proteins for long-circulating cargo delivery. The structure, size and surface zeta potential, and protein contents of the erythrocyte membrane-coated nanoparticles were verified using transmission electron microscopy, dynamic light scattering, and gel electrophoresis, respectively. Mice injections with fluorophore-loaded nanoparticles revealed superior circulation half-life by the erythrocyte-mimicking nanoparticles as compared to control particles coated with the state-of-the-art synthetic stealth materials. Biodistribution study revealed significant particle retention in the blood 72 h following the particle injection. The translocation of natural cellular membranes, their associated proteins, and the corresponding functionalities to the surface of synthetic particles represents a unique approach in nanoparticle functionalization.     

Iron(iii) chelated paramagnetic polymeric nanoparticle formulation as a next-generation T1-weighted MRI contrast agent

Magnetic resonance imaging (MRI) is a routinely used imaging technique in medical diagnostics. To enhance the quality of MR images, contrast agents (CAs) are used, which account for nearly 40% of MRI exams in the clinic globally. The most used CAs are gadolinium-based CAs (GBCAs) but the use of GBCAs has been linked with metal-deposition in vital organs. Gadolinium deposition has been shown to be correlated with nephrogenic systemic fibrosis, a fibrosis of the skin and internal organs. Therefore, there is an unmet need for a new CA alternative to GBCAs for T₁-weighted Ce-MRI. Herein, we designed paramagnetic ferric iron(iii) ion-chelated poly(lactic-co-glycolic)acid nanoparticle formulation and routinely examined their application in Ce-MRI using clinical and ultra-high-field MRI scanners. Nanoparticles were monodispersed and highly stable at physiological pH over time with the hydrodynamic size of 130 ± 12 nm and polydispersity index of 0.231 ± 0.026. The T₁-contrast efficacy of the nanoparticles was compared with commercial agent gadopentetate dimeglumine, called Magnevist®, in aqueous phantoms in vitro and then validated in vivo by visualizing an angiographic map in a clinical MRI scanner. Relaxivities of the nanoparticles in an aqueous environment were r₁ = 10.59 ± 0.32 mmol⁻¹ s⁻¹ and r₁ = 3.02 ± 0.14 mmol⁻¹ s⁻¹ at 3.0 T and 14.1 T measured at room temperature and pH 7.4, respectively. The clinically relevant magnetic field relaxivity is three times higher compared to the Magnevist®, a clinical GBCA, signifying its potential applicability in clinical settings. Moreover, iron is an endogenous metal with known metabolic safety, and the polymer and phospholipids used in the nanoconstruct are biodegradable and biocompatible components. These properties further put the proposed T₁ agent in a promising position in contrast-enhanced MRI of patients with any disease conditions.

In pursuit of safer alternatives to Gd-based MRI contrast agents due to its toxicity and organ deposition, herein, we developed a safer and efficient clinically relevant iron(iii) chelated polymeric nanoparticle as a T₁-weighted MRI contrast agent.     

Role of diagnostic imaging in Rasmussen's encephalitis – A case report from Nepal

Rasmussen''s encephalitis (RE) is a relatively rare chronic inflammatory neurological disease that usually only affects one hemisphere of the brain. It primarily affects children under the age of 10, although it can also affect teens and adults, causing drug-resistant seizures, progressive hemiparesis, and dementia. RE presents as a challenging diagnosis with MRI as the cornerstone of the evaluation and nuclear imaging as a complementary tool. We''d like to present a case of a 12-year-old girl who was diagnosed with RE after an MRI. In this study, we examine the diagnostic criteria, differential diagnoses, and issues that underpin the diagnostic challenge in great detail.     

First jejunal artery,an alternative graft for right hepatic artery reconstruction

Common bile duct cancer invading right hepatic artery is sometimes diagnosed intraoperatively. Excision andsafe reconstruction of the artery with suitable graft is essential. Arterial reconstruction with autologous saphenous vein graft is the preferred method practiced routinely. However the right hepatic artery reconstruction has also been carried out with several other vessels like gastroduodenal artery, right gastroepiploic artery or the splenic artery. We report a case of 63-year-old man presenting with history of progressive jaundice, pruritus and impaired appetite. Following various imaging modalities including computed tomography, endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, intraductal ultrasound extrahepatic bile duct cancer was diagnosed; however, none of those detected vessel invasion. Intraoperatively, right hepatic artery invasion was revealed. Right hepatic artery was resected and reconstructed with a graft harvested from the first jejunal artery(JA). Postoperative outcome was satisfactory with a long-term graft patency. First JA can be a reliable graft option for right hepatic artery reconstruction.     

Impacts and challenges of United States medical students during the COVID-19 pandemic

The delivery of medical student education has changed rapidly during the coronavirus disease 2019 (COVID-19) pandemic. Students in their pre-clinical years have transitioned to online courses and examinations. Students in their clinical years are not permitted on clinical rotations, and face uncertainties in career exploration and the residency application process. Medical students in all stages of training are volunteering and helping their communities. The future presence of COVID-19 throughout the United States is unknown, and medical students are eager to return to their training. This paper outlines current challenges in medical student education and the various responses that have been adopted. We also discuss possible future directions for students through involvement in telemedicine, outpatient clinic visits, and non-respiratory inpatient care tasks as adequate personal protective equipment, COVID-19 testing, and resources become more widely available.     

Genetic removal of p70 S6K1 corrects coding sequence length-dependent alterations in mRNA translation in fragile X syndrome mice

Loss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene specificity of altered messenger RNA (mRNA) translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA sequencing on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint (RF) abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in RF abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.

Loss of expression or function of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS), the most prevalent inherited form of intellectual disability and the leading monogenic cause of autism. FMRP is an RNA-binding protein whose primary function is widely believed to be to repress messenger RNA (mRNA) translation in neurons. Accordingly, elevated net de novo protein synthesis is observed in the brains of FXS model mice (1). Precise control of translation is especially critical in the brain because rapid protein synthesis underlies long-lasting synaptic plasticity, multiple forms of which are impaired in FXS mice (2). There is consensus that dysregulated translation underlies a majority of phenotypes exhibited by FXS mice, including autism-like behaviors (3). Restoring translational homeostasis in the brain therefore presents an attractive therapeutic concept in FXS. Accordingly, genetic deletion of the translation stimulator p70 S6 kinase 1 (S6K1) in FXS mice rescues multiple phenotypes, including exaggerated translation, aberrant synaptic plasticity and dendritic morphology, and autism-like behaviors (4). Given that aberrant mRNA translation is a core pathophysiology of FXS, and that restoring translational homeostasis corrects pathological phenotypes, it is evident that one way to understand the molecular basis of FXS is to 1) identify mistranslated mRNAs, 2) ascertain the mechanism(s) by which the translation of these mRNAs is altered in FXS, and 3) establish how these translation mechanisms are corrected in models of FXS rescue.Several studies have attempted to identify aberrantly translated mRNAs in FXS mice (5–7). Intriguingly, all three analyses noted that a large fraction of differentially translated genes showed reduced ribosome association in FXS. Although several explanations have been offered for this puzzling finding, a recent study observing similar reductions in ribosome association with depletion of FMRP in Drosophila oocytes led its authors to challenge the dogma that FMRP loss causes increased de novo protein synthesis (8). There is also limited overlap among the genes identified as aberrantly translated in the studies, necessitating further investigations to clarify the translational targets of FMRP. Moreover, very little is known about the molecular mechanisms by which translational homeostasis is restored through genetic reduction of S6K1 in FXS mice.In this study, we sought to identify the mRNAs that are mistranslated in FXS mouse brains, ascertain the molecular basis of the alteration in translation, and investigate the mechanism by which genetic deletion of S6K1 normalizes the aberrant translation to levels observed in wild-type (WT) littermates. We carried out ribosome profiling and RNA sequencing (RNA-Seq) on cortical lysates from ∼P30 WT, FXS, S6K1 knockout, and double knockout (DKO) mice. Consistent with previous studies, we observed that the majority of genes with differential ribosome association in FXS displayed reduced ribosome footprint (RF) abundance. Using molecular assays, we discovered evidence that this reduction reflects a global increase in the rate of ribosome translocation in FXS neurons, is captured by a decreased number of translating ribosomes at steady state, and is normalized by pharmacological inhibition of S6K1. We also observed that alterations in RF abundance and mRNA expression show opposing associations with coding sequence (CDS) length in FXS mice and summate as a positive-to-negative linear gradation in log-fold changes (LFCs) in translation efficiency (TE, RF/mRNA) with CDS length. Remarkably, this gradation is prevented by the genetic removal of S6K1 in FXS mice. Therefore, we have uncovered the identities of mistranslated mRNAs in FXS, the mechanistic basis of aberrant translation and a molecular mechanism for correction of de novo protein synthesis with genetic reduction of S6K1 in FXS mice.