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Due to the COVID-19 pandemic, a number of States of Emergency were announced in Japan, that drastically and suddenly shifted teaching practices in tertiary education. This study explores how teachers working within this field navigated this pedagogical shift. Furthermore, examples will be given for both the potential restrictions and benefits of utilizing distance learning in EFL tertiary education. The research is based upon both a review of existing literature concerned with EFL education, as well as two qualitative interviews with university teachers based in Japan. The collected data underwent thematic analysis, and the results indicated that complications were brought about by this new teaching approach, such as a lack of social interaction. However, some benefits were also apparent, such as stakeholders becoming more familiar with instructional technology, or the discovery of more effective teaching methods. This study aims to look at how this technology may be used in the future to not only alleviate pressure brought about by extreme circumstances, but also to enrich the learning environment in contemporary tertiary education settings in Japan.

The purpose of this study was to identify the patient, injury, and treatment factors associated with infection of bicondylar plateau fractures and to evaluate whether center variation exists.Retrospective review.Eighteen academic trauma centers.A total of 1,287 patients with 1,297 OTA type 41-C bicondylar tibia plateau fractures who underwent open reduction and internal fixation were included. Exclusion criteria were follow-up less than 120 days, insufficient documentation, and definitive treatment only with external fixation.Open reduction and internal fixation.Superficial and deep infection.One hundred one patients (7.8%) developed an infection. In multivariate regression analysis, diabetes (DM) (OR [odds ratio] 3.24; P ≤ 0.001), alcohol abuse (EtOH) (OR 1.8; P = 0.040), dual plating (OR 1.8; P ≤ 0.001), and temporary external fixation (OR 2.07; P = 0.013) were associated with infection. In a risk-adjusted model, we found center variation in infection rates (P = 0.030).In a large series of patients undergoing open reduction and internal fixation of bicondylar plateau fractures, the infection rate was 7.8%. Infection was associated with DM, EtOH, combined dual plating, and temporary external fixation. Center expertise may also play a role because one center had a statistically lower rate and two trended toward higher rates after adjusting for confounders.Level IV-Therapeutic retrospective cohort study.

Probody therapeutics (Pb-Txs) are conditionally activated antibody–drug conjugates (ADCs) designed to remain inactive until proteolytically activated in the tumor microenvironment, enabling safer targeting of antigens expressed in both tumor and normal tissue. Previous attempts to target CD71, a highly expressed tumor antigen, have failed to establish an acceptable therapeutic window due to widespread normal tissue expression. This study evaluated whether a probody–drug conjugate targeting CD71 can demonstrate a favorable efficacy and tolerability profile in preclinical studies for the treatment of cancer. CX-2029, a Pb-Tx conjugated to maleimido-caproyl-valine-citrulline-p-aminobenzyloxycarbonyl-monomethyl auristatin E, was developed as a novel cancer therapeutic targeting CD71. Preclinical studies were performed to evaluate the efficacy and safety of this anti-CD71 PDC in patient-derived xenograft (PDX) mouse models and cynomolgus monkeys, respectively. CD71 expression was detected at high levels by IHC across a broad range of tumor and normal tissues. In vitro, the masked Pb-Tx form of the anti-CD71 PDC displayed a >50-fold reduced affinity for binding to CD71 on cells compared with protease-activated, unmasked anti-CD71 PDC. Potent in vivo tumor growth inhibition (stasis or regression) was observed in >80% of PDX models (28/34) at 3 or 6 mg/kg. Anti-CD71 PDC remained mostly masked (>80%) in circulation throughout dosing in cynomolgus monkeys at 2, 6, and 12 mg/kg and displayed a 10-fold improvement in tolerability compared with an anti-CD71 ADC, which was lethal. Preclinically, anti-CD71 PDC exhibits a highly efficacious and acceptable safety profile that demonstrates the utility of the Pb-Tx platform to target CD71, an otherwise undruggable target. These data support further clinical development of the anti-CD71 PDC CX-2029 as a novel cancer therapeutic.

Supplementary Data from Nonclinical Efficacy and Safety of CX-2029, an Anti-CD71 Probody–Drug Conjugate

Supernova (SN) siblings -- two or more SNe in the same parent galaxy -- are useful tools for exploring progenitor stellar populations as well as properties of the host galaxies such as distance, star formation rate, dust extinction, and metallicity. Since the average SN rate for a Milky Way-type galaxy is just one per century, a large imaging survey is required to discover an appreciable sample of SN siblings. From the wide-field Zwicky Transient Facility (ZTF) Bright Transient Survey (BTS; which aims for spectroscopic completeness for all transients which peak brighter than $r{, Comment: 14 pages, 4 tables, 7 figures, accepted to MNRAS

Background An essential determinant of a neuron’s functionality is its neurotransmitter phenotype. We previously identified a defined subpopulation of cholinergic neurons required for social orienting behavior in zebrafish. Results We transcriptionally profiled these neurons and discovered that they are capable of synthesizing both acetylcholine and GABA. We also established a constellation of transcription factors and neurotransmitter markers that can be used as a “transcriptomic fingerprint” to recognize a homologous neuronal population in another vertebrate. Conclusion Our results suggest that this transcriptomic fingerprint and the cholinergic-GABAergic neuronal subtype that it defines are evolutionarily conserved.

Disturbances are important determinants of diversity, and the combination of their aspects (e.g., disturbance intensity, frequency) can result in complex diversity patterns. Here, we leverage an important approach to classifying disturbances in terms of temporal span to understand the implications for species coexistence: pulse disturbances are acute and discrete events, while press disturbances occur continuously through time. We incorporate the resultant mortality rates into a common framework involving disturbance frequency and intensity. Press disturbances can be encoded into models in two distinct ways, and we show that the appropriateness of each depends on the type of data available. Using this framework, we compare the effects of pulse versus press disturbance on both asymptotic and transient dynamics of a two-species Lotka-Volterra competition model to understand how they engage with equalizing mechanisms of coexistence. We show that press and pulse disturbances differ in transient behavior, though their asymptotic diversity patterns are similar. Our work shows that these differences depend on how the underlying disturbance aspects interact and that the two ways of characterizing press disturbances can lead to contrasting interpretations of disturbance-diversity relationships. Our work demonstrates how theoretical modeling can strategically guide and help the interpretation of empirical work.

Animal development requires coordinated communication between cells. The Connexin family of proteins is a major contributor to intercellular communication in vertebrates by forming gap junction channels that facilitate the movement of ions, small molecules, and metabolites between cells. Additionally, individual hemichannels can provide a conduit to the extracellular space for paracrine and autocrine signaling. Connexin-mediated communication is widely used in epithelial, neural, and vascular development and homeostasis, and most tissues likely use this form of communication. In fact, Connexin disruptions are of major clinical significance contributing to disorders developing from all major germ layers. Despite the fact that Connexins serve as an essential mode of cellular communication, the temporal and cell-type-specific expression patterns of connexin genes remain unknown in vertebrates. A major challenge is the large and complex connexin gene family. To overcome this barrier, we determined the expression of all connexins in zebrafish using single-cell RNA-sequencing of entire animals across several stages of organogenesis. Our analysis of expression patterns has revealed that few connexins are broadly expressed, but rather, most are expressed in tissue- or cell-type-specific patterns. Additionally, most tissues possess a unique combinatorial signature of connexin expression with dynamic temporal changes across the organism, tissue, and cell. Our analysis has identified new patterns for well-known connexins and assigned spatial and temporal expression to genes with no-existing information. We provide a field guide relating zebrafish and human connexin genes as a critical step toward understanding how Connexins contribute to cellular communication and development throughout vertebrate organogenesis.

The main objective of this study was to develop an enzyme‐linked immunosorbent assay (ELISA) for Seriola lalandi vitellogenin (Vtg). Nucleotide sequences corresponding to VtgAa, VtgAb and VtgC were obtained from S. lalandi liver transcriptomic data. Two peptides (12 amino acids each) were synthesized according to the predicted conserved regions of VtgAa and VtgAb, and used to generate two polyclonal antibodies in rabbits: anti‐S. lalandi VtgA and anti‐S. lalandi VtgB. Plasma from male S. lalandi treated with 17β‐estradiol (E₂) was fractionated to produce the Vtg standard and analysed through SDS‐PAGE and Western blot. LC‐MS/MS analysis showed that the fraction corresponding to the highest peak consisted mainly of VtgAa and VtgAb. Two homologous antibodies (anti‐S. lalandi VtgA and anti‐S. lalandi VtgB) and one heterologous antibody (anti‐Mugil cephalus Vtg) were tested to develop the S. lalandi ELISA. While the antibodies against the Vtg peptides were not effectively recognizing the Vtg standard, parallelism was confirmed between the M. cephalus Vtg standard and the S. lalandi Vtg standard. The ELISA developed is highly specific (no cross‐reaction with other proteins present in plasma when samples were diluted over 1:20), precise (the inter‐assay coefficient of variation at 50% binding was 13%) and sensitive (19 ng/ml). The assay was validated by quantifying the plasma Vtg levels in females at the start of the reproductive season and in E₂‐treated males.

We present a comprehensive optical and near-infrared census of the fields of 90 short gamma-ray bursts (GRBs) discovered in 2005-2021, constituting all short GRBs for which host galaxy associations are feasible ($\approx$ 60% of the total Swift short GRB population). We contribute 245 new multi-band imaging observations across 49 distinct GRBs and 25 spectra of their host galaxies. Supplemented by literature and archival survey data, the catalog contains 335 photometric and 40 spectroscopic data sets. The photometric catalog reaches $3\sigma$ depths of $\gtrsim 24-27$ mag and $\gtrsim 23-26$ mag for the optical and near-infrared bands, respectively. We identify host galaxies for 84 bursts, in which the most robust associations make up 54% (49/90) of events, while only a small fraction, 6.7%, have inconclusive host associations. Based on new spectroscopy, we determine 17 host spectroscopic redshifts with a range of $z\approx 0.15-1.6$ and find that $\approx$ 25-44% of Swift short GRBs originate from $z>1$. We also present the galactocentric offset catalog for 83 short GRBs. Taking into account the large range of individual measurement uncertainties, we find a median of projected offset of $\approx 7.9$ kpc, for which the bursts with the most robust associations have a smaller median of $\approx 4.9$ kpc. Our catalog captures more high-redshift and low-luminosity hosts, and more highly-offset bursts than previously found, thereby diversifying the population of known short GRB hosts and properties. In terms of locations and host luminosities, the populations of short GRBs with and without detectable extended emission are statistically indistinguishable. This suggests that they arise from the same progenitors, or from multiple progenitors which form and evolve in similar environments. All of the data products are available on the BRIGHT website., Comment: 53 pages, 9 figures, 6 tables, submitted

The use of a brake power meter at each wheel of a bicycle is a valid means to calculate energy losses due to braking. However, methodology utilizing the torque and angular velocity at each wheel independently are not able to reflect energy lost to braking when the rear wheel is skidding. This study tested the possibility of using the angular velocity of the front wheel, but the torque of the rear brake, to calculate rear brake power. Two cyclists completed 100 braking trials across three days on a mixture of paved and gravel surfaces with a mixture of skidding and non-skidding. The estimated total energy removed from the bicycle-rider system was calculated as the sum of brake work and estimates of drag and rolling resistance. This energy removed from the bicycle-rider system displayed a strong positive relationship with the change in kinetic energy of the bicycle-rider system during braking on paved (r2=0.955; p

Infectious diseases are recognised as one of the greatest global threats to biodiversity and ecosystem functioning. Consequently, there is a growing urgency to understand the speed at which adaptive phenotypes can evolve and spread in natural populations to inform future management. Here we provide evidence of rapid genomic changes in wild Australian blacklip abalone (Haliotis rubra) following a major population crash associated with an infectious disease. A genome wide association study on H. rubra was conducted using pooled whole genome re-sequencing data from commercial fishing stocks varying in historical exposure to haliotid herpesvirus-1 (HaHV-1). Approximately 25,000 SNP loci associated with virus exposure were identified, many of which mapped to genes known to contribute to HaHV-1 immunity in the New Zealand pāua (H. iris) and herpesvirus response pathways in haliotids and other animal systems. These findings indicate genetic changes across a single generation in H. rubra fishing stocks decimated by HaHV-1, with stock recovery determined by rapid evolutionary changes leading to virus resistance. This is a novel example of rapid adaptation in natural populations of a non-model marine organism, highlighting the pace at which selection can potentially act to counter disease in wildlife communities.

Larval zebrafish have been established as an excellent model for examining vertebrate biology, with many researchers using the system for neuroscience. Controlling a fast escape response of the fish, the Mauthner cells and their associated network are an attractive model, given their experimental accessibility and fast development, driving ethologically relevant behavior in the first five days of development. Here, we describe methods for immunostaining electrical and chemical synapse proteins at 3-7 days post fertilization (dpf) in zebrafish using tricholoracetic acid fixation. The methods presented are ideally suited to easily visualize neural circuits and synapses within the fish.

Cosmic and ultraviolet rays are pervasive and often difficult to avoid, for atmospheric pollution has caused an increase in harmful radiation reaching the Earth's surface due to the rapid depletion of the ozone layer. Because the deterioration of the ozone layer is a recent phenomenon, it is important to understand the rays’ effects on the DNA of organisms. It is also an area of interest in the field of astrobiology as humans begin to consider the possibility of long-term exposure of crops to these types of radiation in prolonged space travel. The Bioballoon project, described in this paper, was a payload for a weather balloon built to expose samples of yeast and seeds to cosmic and ultraviolet rays in the middle to upper stratosphere. After plating the yeast and planting the seeds, it was found that although cosmic and UV radiation appeared to induce mutations in yeast genes, they do not produce significant phenotypic differences in plants.

Barnes, MJ, Miller, A, Reeve, D, and Stewart, RJ. Acute neuromuscular and endocrine responses to two different compound exercises: squat vs. deadlift. J Strength Cond Res 33(9): 2381-2387, 2019-Anecdotally, it is believed that the deadlift exercise brings about greater levels of central fatigue than other exercises; however, no empirical evidence exists to support this view. In addition, little is known about the acute endocrine response to heavy deadlift exercise and how this may differ from other similar compound exercises. Therefore, the aim of this study was to identify and compare the acute, neuromuscular and endocrine responses to squat and deadlift exercises. Ten resistance-trained males completed 8 sets of 2 repetitions at 95% of 1 repetition maximum. Maximum voluntary isometric contraction (MVIC) force of the quadriceps, along with measures of central (voluntary activation [VA] and surface electromyography) and peripheral (electrically evoked control stimulus) fatigue were made before and 5 and 30 minutes after exercise. In addition, salivary testosterone and cortisol were measured at these same time points. MVIC was reduced after the completion of both exercises (p = 0.007); however, no difference between exercises was evident. Similarly, although VA changed over time (p = 0.0001), no difference was observed between exercises. As a measure of peripheral fatigue, force from the control stimulus changed over time (p = 0.003) with a greater decrease evident after the squat (p = 0.034). Electromyography was reduced over time (p = 0.048) but no difference was seen between exercises. No change was seen in testosterone and cortisol. Although a greater absolute load and larger volume load were completed for the deadlift, no difference in central fatigue was evident between the 2 compound exercises. The greater peripheral fatigue observed after squat exercise may be due to the greater work completed by the quadriceps with this exercise. These results suggest that separate periodization, tapering, and programming considerations may be unnecessary when using the squat and deadlift to develop muscular strength.

Peacekeeping mitigates killing, but nonlethal violence also influences both positive peace and stability. We evaluate peacekeepers’ effect on one such type of abuse, sexual violence. We posit that peacekeepers raise the cost of abuses and foster institutional and cultural changes that curb violence. We find that missions both reduce the chance of any violence and limit its prevalence; larger deployments and multidimensional missions are more effective. Governments curtail violence more quickly than rebels do in response to military contingents; rebels are especially responsive when missions include large civilian components. These findings contribute to our understanding of peacekeeping in three primary ways: we expand the evaluation of peacekeeping to consider nonlethal violence; we draw attention to mission size, capacity to use force, and civilian-led programming as determinants of effectiveness; and we demonstrate how addressing nonlethal violence requires similar tools as lethal violence but is further enhanced by specific civilian-led initiatives.

Knockdown of cardiac myosin binding protein C (cMyBP-C), which is the cause of many cases of hypertrophic cardiomyopathy in humans, results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function, but it is unclear whether these effects can be reversed. Using the Tet-Off system, Giles et al. show that these phenotypes can be induced and reversed with reexpression of cMyBP-C on the null background., The loss of cardiac myosin binding protein C (cMyBP-C) results in left ventricular dilation, cardiac hypertrophy, and impaired ventricular function in both constitutive and conditional cMyBP-C knockout (MYBPC3 null) mice. It remains unclear whether the structural and functional phenotypes expressed in the MYBPC3 null mouse are reversible, which is an important question, since reduced expression of cMyBP-C is an important cause of hypertrophic cardiomyopathy in humans. To investigate this question, we generated a cardiac-specific transgenic mouse model using a Tet-Off inducible system to permit the controlled expression of WT cMyBP-C on the MYBPC3 null background. Functional Tet-Off mice expressing WT cMyBP-C (FT-WT) were generated by crossing tetracycline transactivator mice with responder mice carrying the WT cMyBP-C transgene. Prior to dietary doxycycline administration, cMyBP-C was expressed at normal levels in FT-WT myocardium, which exhibited similar levels of steady-state force and in vivo left ventricular function as WT mice. Introduction of dietary doxycycline for four weeks resulted in a partial knockdown of cMyBP-C expression and commensurate impairment of systolic and diastolic function to levels approaching those observed in MYBPC 3 null mice. Subsequent withdrawal of doxycycline from the diet resulted in the reexpression of cMyBP-C to levels comparable to those observed in WT mice, along with near-complete recovery of in vivo ventricular function. These results show that the cardiac phenotypes associated with MYBPC3 null mice are reversible. Our work also validates the use of the Tet-Off inducible system as a means to study the mechanisms underlying hypertrophic cardiomyopathy.

Introduction: The development of immune-related adverse events (irAEs) has been associated with improved efficacy of immune checkpoint inhibitors in patients with urothelial cancer, melanoma, and NSCLC. Whether this association exists in patients with SCLC is currently unknown. Methods: We conducted a multicenter retrospective study to evaluate the relationship between irAEs and immunotherapy efficacy in SCLC. To account for the lead-time bias resulting from the time-dependent nature of irAEs, the development of irAEs was considered as a time-varying covariate in univariate and multivariate Cox proportional hazard models. Results: Of the 183 patients treated with immunotherapy, 73 (39.9%) experienced at least one irAE. A total of 42 patients (22.9%) had grade 1 to 2 irAEs, whereas 31 patients (16.9%) had grade 3 to 4 irAEs. The median time of onset to the first irAE was 24 days (interquartile range: 14–55). The baseline clinicopathologic features were well-balanced between patients with and without irAEs. At a median follow-up of 24 months (95% confidence interval [CI]: 17.0–31.6), the median progression-free survival was significantly longer in the irAE group than the non-irAE group (3.8 versus 1.3 mo, p < 0.0001). The median overall survival was also significantly longer among patients with irAEs than patients without irAEs (13.8 versus 2.9 mo, p < 0.0001). When analyzed as a time-varying covariate, the development of irAEs was associated with a significant improvement in progression-free survival (hazard ratio: 0.44 [95% CI: 0.29–0.66], p < 0.001) and overall survival (hazard ratio: 0.47 [95% CI: 0.32–0.71], p < 0.001) in multivariate models. Conclusions: The development of irAEs is associated with improved clinical outcomes for immunotherapy in patients with advanced SCLC.

Conservation strategies are rarely systematically evaluated, which reduces transparency, hinders the cost-effective deployment of resources, and hides what works best in different contexts. Using data on the iconic and critically endangered orangutan (Pongo spp.), we developed a novel spatiotemporal framework for evaluating conservation investments. We show that around USD 1 billion was invested between 2000 and 2019 into orangutan conservation by governments, nongovernmental organizations, companies, and communities. Broken down by allocation to different conservation strategies, we find that habitat protection, patrolling, and public outreach had the greatest return on investment for maintaining orangutan populations. Given the variability in threats, land-use opportunity costs, and baseline remunerations in different regions, there were differential benefits per dollar invested across conservation activities and regions. We show that although challenging from a data and analysis perspective, it is possible to fully understand the relationships between conservation investments and outcomes and the external factors that influence these outcomes. Such analyses can provide improved guidance toward a more effective biodiversity conservation. Insights into the spatiotemporal interplays between the costs and benefits driving effectiveness can inform decisions about the most suitable orangutan conservation strategies for halting population declines. Although our study focuses on the three extant orangutan species of Sumatra and Borneo, our findings have broad application for evidence-based conservation science and practice worldwide.

Animal-level agility and robustness in robots cannot be accomplished by solely relying on blind locomotion controllers. A significant portion of a robot’s ability to traverse terrain comes from reacting to the external world through visual sensing. However, embedding the sensors and compute that provide sufficient accuracy at high speeds is challenging, especially if the robot has significant space limitations. In this paper, we propose a system integration of a small-scale quadruped robot, the MIT Mini-Cheetah Vision, that exteroceptively senses the terrain and dynamically explores the world around it at high velocities. Through extensive hardware and software development, we demonstrate a fully untethered robot with all hardware onboard running a locomotion controller that combines state-of-the-art Regularized Predictive Control (RPC) with Whole-Body Impulse Control (WBIC). We devise a hierarchical state estimator that integrates kinematic, IMU, and localization sensor data to provide state estimates specific to path planning and locomotion tasks. Our integrated system has demonstrated robust autonomous waypoint tracking in dynamic real-world environments at speeds of over 1 m/s with high rates of success.

Introduction Lung cancer is associated with severe coronavirus disease 2019 (COVID-19) infections. Symptom overlap between COVID-19 and lung cancer may complicate diagnostic evaluation. We aimed to investigate the incidence, symptoms, differential diagnosis, and outcomes of COVID-19 in patients with lung cancer. Methods To determine an at-risk population for COVID-19, we retrospectively identified patients with lung cancer receiving longitudinal care within a single institution in the 12 months (April 1, 2019 to March 31, 2020) immediately preceding the COVID-19 pandemic, including an “active therapy population” treated within the last 60 days of this period. Among patients subsequently referred for COVID-19 testing, we compared symptoms, laboratory values, radiographic findings, and outcomes of positive versus negative patients. Results Between April 1, 2019 and March 31, 2020, a total of 696 patients received longitudinal care, including 406 (58%) in the active therapy population. Among 55 patients referred for COVID-19 testing, 24 (44%) were positive for COVID-19, representing a cumulative incidence of 3.4% (longitudinal population) and 1.5% (active therapy population). Compared with patients who were COVID-19 negative, those who were COVID-19 positive were more likely to have a supplemental oxygen requirement (11% versus 54%, p = 0.005) and to have typical COVID-19 pneumonia imaging findings (5 versus 56%, p = 0.001). Otherwise, there were no marked differences in presenting symptoms. Among patients who were COVID-19 negative, alternative etiologies included treatment-related toxicity (26%), atypical pneumonia (22%), and disease progression (22%). A total of 16 patients positive for COVID-19 (67%) required hospitalization, and seven (29%) died from COVID-related complications. Conclusions COVID-19 was infrequent in this lung cancer population, but these patients experienced high rates of morbidity and mortality. Oncologists should maintain a low threshold for COVID-19 testing in patients with lung cancer presenting with acute symptoms.

The Type IIn supernova (SN) 2005ip is one of the most well-studied and long-lasting examples of a SN interacting with its circumstellar environment. The optical light curve plateaued at a nearly constant level for more than five years, suggesting ongoing shock interaction with an extended and clumpy circumstellar medium (CSM). Here we present continued observations of the SN from $\sim 1000-5000$ days post-explosion at all wavelengths, including X-ray, ultraviolet, near-infrared, and mid-infrared. The UV spectra probe the pre-explosion mass loss and show evidence for CNO processing. From the bolometric light curve, we find that the total radiated energy is in excess of $10^{50}$ erg, the progenitor star's pre-explosion mass-loss rate was $\gtrsim 1 \times 10^{-2}\,{\rm M_{\odot}~ yr}^{-1}$, and the total mass lost shortly before explosion was $\gtrsim 1\,{\rm M_\odot}$, though the mass lost could have been considerably larger depending on the efficiency for the conversion of kinetic energy to radiation. The ultraviolet through near-infrared spectrum is characterised by two high density components, one with narrow high-ionisation lines, and one with broader low-ionisation H I, He I, [O I], Mg II, and Fe II lines. The rich Fe II spectrum is strongly affected by Ly$\alpha$ fluorescence, consistent with spectral modeling. Both the Balmer and He I lines indicate a decreasing CSM density during the late interaction period. We find similarities to SN 1988Z, which shows a comparable change in spectrum at around the same time during its very slow decline. These results suggest that, at long last, the shock interaction in SN 2005ip may finally be on the decline., Comment: 16 pages, 9 figures, 9 tables. Accepted to MNRAS

Courses to help medical students pass ‘Finals’ already exist but are typically expensive or can only be attended by a limited number of students. We describe the success of ‘The National Finals Revision Day' (NFRD) course, which we believe is sustainable and unique in terms of its combined scale and cost (£10 per person). The course was organised and taught by 12 junior doctors. In total, 300 students attended from 55% of UK medical schools. Attendees found the course both relevant (96.4%) and cost-effective (97%), whilst the 11 medical and surgical talks were of a high standard (90.1%). The organising committee felt confident to organise their own teaching course in the future with 100% having already run a course themselves since the NFRD course. The NFRD course was also used by 11/12 (91.7%) of the organising committee to achieve their Annual Review of Competency Progression (ARCP) and 12/12 (100%) of the organising committee to obtain jobs on training programmes in the UK. We provide guidance about how to organise similar large-scale events for those interested. Moving forward, the teaching course will be run at: (i) multiple times; (ii) multiple UK venues; (iii) run over two days to cover more medical and surgical topics; and (iv) include the option of attending via video link.

MicroRNAs (miRs) are small non-coding RNAs that can have large impacts on oncogenic pathways. Possible functions of dysregulated miRs have not been studied in neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNFs). In PNFs, Schwann cells (SCs) have biallelic NF1 mutations necessary for tumorigenesis. We analyzed a miR microarray comparing with normal and PNF SCs and identified differences in miR expression, and we validated in mouse PNFs versus normal mouse SCs by qRT-PCR. Among these, miR-155 was a top overexpressed miR, and its expression was regulated by RAS/MAPK signaling. Overexpression of miR-155 increased mature Nf1-/- mouse SC proliferation. In SC precursors, which model tumor-initiating cells, pharmacological and genetic inhibition of miR-155 decreased PNF-derived sphere numbers in vitro, and we identified Maf as a miR-155 target. In vivo, global deletion of miR-155 significantly decreased tumor number and volume, increasing mouse survival. Fluorescent nanoparticles entered PNFs, suggesting that an anti-miR might have therapeutic potential. However, treatment of established PNFs using anti-miR-155 peptide nucleic acid-loaded nanoparticles marginally decreased tumor numbers and did not reduce tumor growth. These results suggest that miR-155 plays a functional role in PNF growth and/or SC proliferation, and that targeting neurofibroma miRs is feasible, and might provide novel therapeutic opportunities.