Nanodiamond Vectors Functionalized with Polyethylenimine for siRNA Delivery

The enormous therapeutic potential of RNA interference (RNAi) has long been recognized. While efficient small interfering RNA (siRNA) delivery vectors exist, many sacrifice biocompatibility, which can challenge their applicability as a therapeutic agent. Nanodiamonds (NDs) represent promising strategies for efficient siRNA delivery given the multitude of beneficial properties integrated into one platform that include uniform particle sizes, material scalability, the ability to carry nearly any type of therapeutic, and preserved biocompatibility, among others. Here we present a broadly applicable ND delivery platform that demonstrates biocompatible siRNA delivery with enhanced efficacy in media, signifying the translational potential of this approach

Additional file 1 of Mental health and resilience after the covid-19 pandemic: a multi-ethnic longitudinal survey

Additional file 1: Table 1. Demographics of analysis cohort, full cohort, and non-responders at each survey timing (Kessler-10 and Short Warwick Edinburgh Mental Well-being Scale questions). Table 2. Demographics of analysis cohort, full cohort, and non-responders at each survey timing (Connor-Davidson Resilience Scale-10 questions). Table 3. Demographics of unique dropouts at each study wave

EGFR Inhibitor Erlotinib Delays Disease Progression but Does Not Extend Survival in the SOD1 Mouse Model of ALS

<div><p></p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that causes progressive paralysis due to motor neuron death. Several lines of published evidence suggested that inhibition of epidermal growth factor receptor (EGFR) signaling might protect neurons from degeneration. To test this hypothesis in vivo, we treated the SOD1 transgenic mouse model of ALS with erlotinib, an EGFR inhibitor clinically approved for oncology indications. Although erlotinib failed to extend ALS mouse survival it did provide a modest but significant delay in the onset of multiple behavioral measures of disease progression. However, given the lack of protection of motor neuron synapses and the lack of survival extension, the small benefits observed after erlotinib treatment appear purely symptomatic, with no modification of disease course.</p></div

Animal n per treatment group in each study.

<p>Animal n per treatment group in each study.</p

Time-to-event analysis of behavior and survival.

<p>V: Vehicle; E: Erlotinib.</p

Study design and timelines.

<p>(A) Study 1: timeline for survival study. n = 106 mice (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062342#pone-0062342-t001" target="_blank">Table 1</a> for breakdown of n per genotype and treatment) received daily IP doses of erlotinib from 5 weeks of age onwards, and their lifespan was measured. Mice were assessed in neurological exams 2 times/week between 6–9 weeks, 3 times/week from 9 weeks of age onwards, and tested on the balance beam at 17 weeks of age. (B) Study 2: timeline for histological endpoints study. Mice (n = 34; see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0062342#pone-0062342-t001" target="_blank">Table 1</a> for breakdown by genotype and treatment) were dosed from 5–9 weeks of age, and euthanized for tissue collection at 9 weeks.</p

Erlotinib does not preserve motor neuron synapses in SOD1 Tg mice.

<p>(A) Erlotinib did not improve loss of motor neuron innervation to the gastrocnemius muscle, examined at 9 weeks of age. As a control for the innervation score, the soleus muscle, which is a slow-twitch muscle that is resistant to disease at this age, showed no loss of innervation. The n/group is listed below each bar. (B) Example image of innervated and denervated synapses. Alpha-bungarotoxin labels the postsynaptic site of each NMJ (green, top); VChAT labels the apposing presynaptic site of the NMJ (red, middle). Bottom: merge. Arrow points to the one denervated synapse among the synapses in this field (alpha-bungarotoxin-positive synapse lacking the presynaptic marker). Scalebar 20 µm. V – vehicle; E – erlotinib.</p

Erlotinib alleviates disease symptoms of SOD1 Tg mice.

<p>(A) Erlotinib trends toward delay in the age of onset of weight loss. This effect approaches significance, p = 0.0527 (Wilcoxon test). (B) Erlotinib delays the age of early symptom onset (p = 0.0061, Wilcoxon test). (C) Erlotinib improves the ability of mice to perform in the wire hang test, as shown by the age at which mice were last able to hang from the wire for 60s (p = 0.0479, log-rank test). The greatest difference between treatment groups is early on (∼40–110 days), suggesting a loss of efficacy of the drug as the disease becomes more severe.</p

Erlotinib improves performance of SOD1 Tg mice on the balance beam.

<p>At ∼17 weeks of age, erlotinib-treated mice performed better on balance beams of 3 different sizes than vehicle-treated littermates, both for number of foot slips (A) and for latency to traverse the beam (B). Each point is the average of 3 trials per mouse. Bars represent group mean values. V – vehicle; E – erlotinib.</p

Additional file 2: Figure S1. of Using peer review to distribute group work marks equitably between medical students

Each page represents one student, whose names have been replaced by Roman or Greek capitals. The index student referred in each page is indicated by the down arrow (↓) on the top row of letters. The upper chart indicates the marks the index student gave to each peer (black or colored circles), together with the average points awarded to that peer (grey bars). The lower chart indicates the marks each peer gives the index student (circles) and the average mark the index student received. Note: these marks are the raw marks prior to scaling. If any mark is more than 1.5 marks away from average, this is indicated by coloring the circle (orange for less, red for much [2.5] less, light blue for more, dark blue for much [2.5] more), increasing the shading on the bar, and adding an arrow. By maximizing the graph on screen and running through each page as a slide show, faculty can quickly assess for the presence of collusion between students. (PDF 140 kb