Plasma microRNA levels following resection of metastatic melanoma

Melanoma remains the leading cause of skin cancer–related deaths. Surgical resection and adjuvant therapies can result in disease-free intervals for stage III and stage IV disease; however, recurrence is common. Understanding microRNA (miR) dynamics following surgical resection of melanomas is critical to accurately interpret miR changes suggestive of melanoma recurrence. Plasma of 6 patients with stage III (n = 2) and stage IV (n = 4) melanoma was evaluated using the NanoString platform to determine pre- and postsurgical miR expression profiles, enabling analysis of more than 800 miRs simultaneously in 12 samples. Principal component analysis detected underlying patterns of miR expression between pre- vs postsurgical patients. Group A contained 3 of 4 patients with stage IV disease (pre- and postsurgical samples) and 2 patients with stage III disease (postsurgical samples only). The corresponding preoperative samples to both individuals with stage III disease were contained in group B along with 1 individual with stage IV disease (pre- and postsurgical samples). Group A was distinguished from group B by statistically significant analysis of variance changes in miR expression ( P < .0001). This analysis revealed that group A vs group B had downregulation of let-7b-5p, miR-520f, miR-720, miR-4454, miR-21-5p, miR-22-3p, miR-151a-3p, miR-378e, and miR-1283 and upregulation of miR-126-3p, miR-223-3p, miR-451a, let-7a-5p, let-7g-5p, miR-15b-5p, miR-16-5p, miR-20a-5p, miR-20b-5p, miR-23a-3p, miR-26a-5p, miR-106a-5p, miR-17-5p, miR-130a-3p, miR-142-3p, miR-150-5p, miR-191-5p, miR-199a-3p, miR-199b-3p, and miR-1976. Changes in miR expression were not readily evident in individuals with distant metastatic disease (stage IV) as these individuals may have prolonged inflammatory responses. Thus, inflammatory-driven miRs coinciding with tumor-derived miRs can blunt anticipated changes in expression profiles following surgical resection

A novel FRET-based screen in high-throughput format to identify inhibitors of malarial and human glucose transporters

The glucose transporter PfHT is essential to the survival of the malaria parasite Plasmodium falciparum and has been shown to be a druggable target with high potential for pharmacological intervention. Identification of compounds against novel drug targets is crucial to combating resistance against current therapeutics. Here, we describe the development of a cell-based assay system readily adaptable to high-throughput screening that directly measures compound effects on PfHT-mediated glucose transport. Intracellular glucose concentrations are detected using a genetically encoded fluorescence resonance energy transfer (FRET)-based glucose sensor. This allows assessment of the ability of small molecules to inhibit glucose uptake with high accuracy (Z′ factor of >0.8), thereby eliminating the need for radiolabeled substrates. Furthermore, we have adapted this assay to counterscreen PfHT hits against the human orthologues GLUT1, -2, -3, and -4. We report the identification of several hits after screening the Medicines for Malaria Venture (MMV) Malaria Box, a library of 400 compounds known to inhibit erythrocytic development of P. falciparum. Hit compounds were characterized by determining the half-maximal inhibitory concentration (IC(50)) for the uptake of radiolabeled glucose into isolated P. falciparum parasites. One of our hits, compound MMV009085, shows high potency and orthologue selectivity, thereby successfully validating our assay for antimalarial screening

The SERTS-97 Rocket Experiment on Study Activity on the Sun: Flight 36.167-GS on 1997 November 18

This paper describes mainly the 1997 version of the Solar EUV Rocket Telescope and Spectrograph (SERTS-97), a scientific experiment that operated on NASA's suborbital rocket flight 36.167-GS. Its function was to study activity on the Sun and to provide a cross calibration for the CDS instrument on the SOHO satellite. The experiment was designed, built, and tested by the Solar Physics Branch of the Laboratory for Astronomy and Solar Physics at the Goddard Space Flight Center (GSFC). Other essential sections of the rocket were built under the management of the Sounding Rockets Program Office. These sections include the electronics, timers, IGN despin, the SPARCS pointing controls, the S-19 flight course correction section, the rocket motors, the telemetry, ORSA, and OGIVE

Moving biochemistry and molecular biology courses online in times of disruption: Recommended practices and resources ‐ a collaboration with the faculty community and ASBMB

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163423/2/bmb21354_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163423/1/bmb21354.pd

Unimodality Problems in Ehrhart Theory

Ehrhart theory is the study of sequences recording the number of integer points in non-negative integral dilates of rational polytopes. For a given lattice polytope, this sequence is encoded in a finite vector called the Ehrhart $h^*$-vector. Ehrhart $h^*$-vectors have connections to many areas of mathematics, including commutative algebra and enumerative combinatorics. In this survey we discuss what is known about unimodality for Ehrhart $h^*$-vectors and highlight open questions and problems.Comment: Published in Recent Trends in Combinatorics, Beveridge, A., et al. (eds), Springer, 2016, pp 687-711, doi 10.1007/978-3-319-24298-9_27. This version updated October 2017 to correct an error in the original versio

Training needs for staff providing remote services in general practice: a mixed-methods study

Background Contemporary general practice includes many kinds of remote encounter. The rise in telephone, video and online modalities for triage and clinical care requires clinicians and support staff to be trained, both individually and as teams, but evidence-based competencies have not previously been produced for general practice. Aim To identify training needs, core competencies, and learning methods for staff providing remote encounters. Design and setting Mixed-methods study in UK general practice. Method Data were collated from longitudinal ethnographic case studies of 12 general practices; a multi-stakeholder workshop; interviews with policymakers, training providers, and trainees; published research; and grey literature (such as training materials and surveys). Data were coded thematically and analysed using theories of individual and team learning. Results Learning to provide remote services occurred in the context of high workload, understaffing, and complex workflows. Low confidence and perceived unmet training needs were common. Training priorities for novice clinicians included basic technological skills, triage, ethics (for privacy and consent), and communication and clinical skills. Established clinicians’ training priorities include advanced communication skills (for example, maintaining rapport and attentiveness), working within the limits of technologies, making complex judgements, coordinating multi-professional care in a distributed environment, and training others. Much existing training is didactic and technology focused. While basic knowledge was often gained using such methods, the ability and confidence to make complex judgements were usually acquired through experience, informal discussions, and on-the-job methods such as shadowing. Whole-team training was valued but rarely available. A draft set of competencies is offered based on the findings. Conclusion The knowledge needed to deliver high-quality remote encounters to diverse patient groups is complex, collective, and organisationally embedded. The vital role of non-didactic training, for example, joint clinical sessions, case-based discussions, and in-person, whole-team, on-the-job training, needs to be recognised

Flukicidal effects of abietane diterpenoid derived analogues against the food borne pathogen Fasciola hepatica.

Control of liver fluke infections remains a significant challenge in the livestock sector due to widespread distribution of drug resistant parasite populations. In particular, increasing prevalence and economic losses due to infection with Fasciola hepatica is a direct result of drug resistance to the gold standard flukicide, triclabendazole. Sustainable control of this significant zoonotic pathogen, therefore, urgently requires the identification of new anthelmintics. Plants represent a source of molecules with potential flukicidal effects and, amongst their secondary metabolites, the diterpenoid abietic acids can be isolated in large quantities. In this study, nineteen (19) chemically modified abietic acid analogues (MC_X) were first evaluated for their anthelmintic activities against F. hepatica newly excysted juveniles (NEJs, from the laboratory-derived Italian strain); from this, 6 analogues were secondly evaluated for their anthelmintic activities against adult wild strain flukes. One analogue, MC010, was progressed further against 8-week immature- and 12-week mature Italian strain flukes. Here, MC010 demonstrated moderate activity against both of these intra-mammalian fluke stages (with an adult fluke EC50 = 12.97 µM at 72 h post culture). Overt mammalian cell toxicity of MC010 was inferred from the Madin-Darby bovine kidney (MDBK) cell line (CC50 = 17.52 µM at 24 h post culture) and demonstrated that medicinal chemistry improvements are necessary before abietic acid analogues could be considered as potential anthelmintics against liver fluke pathogen

Riparian buffers can help mitigate biodiversity declines in oil palm agriculture

Agricultural expansion drives biodiversity decline in forested tropical regions. Consequently, it is important to understand the conservation value of remnant forest in production landscapes. In a tropical landscape dominated by oil palm we characterized faunal communities across eight taxa occurring within riparian forest buffers, which are legally protected alongside rivers, and compared them to nearby recovering logged forest. Buffer width was the main predictor of species richness and abundance, with widths of 40-100 m on each side of the river supporting broadly equivalent levels of biodiversity to logged forest. However, width responses varied markedly among taxa, and buffers often lacked forest-dependent species. Much wider buffers than are currently mandated are needed to safeguard most species. The largest biodiversity gains are achieved by increasing relatively narrow buffers. To provide optimal conservation outcomes in tropical production landscapes we encourage policymakers to prescribe width requirements for key taxa and different landscape contexts.Newton-Ungku Omar Fund (grants 216433953, 537134717) – delivered by the British Council and funded by the UK Department for Business, Energy and Industrial Strategy and the Malaysian Industry-Government Group for High Technology – as well as the UK Natural Environment Research Council (NE/K016407/1, NE/K016261/1; https://lombok.nerc-hmtf.info/). MJS was supported by a Research Leadership Award from the Leverhulme Trust

Characterization of systematic error in Advanced LIGO calibration

The raw outputs of the detectors within the Advanced Laser Interferometer Gravitational-Wave Observatory need to be calibrated in order to produce the estimate of the dimensionless strain used for astrophysical analyses. The two detectors have been upgraded since the second observing run and finished the year-long third observing run. Understanding, accounting, and/or compensating for the complex-valued response of each part of the upgraded detectors improves the overall accuracy of the estimated detector response to gravitational waves. We describe improved understanding and methods used to quantify the response of each detector, with a dedicated effort to define all places where systematic error plays a role. We use the detectors as they stand in the first half (six months) of the third observing run to demonstrate how each identified systematic error impacts the estimated strain and constrain the statistical uncertainty therein. For this time period, we estimate the upper limit on systematic error and associated uncertainty to be $< 7\%$ in magnitude and $< 4$ deg in phase ($68\%$ confidence interval) in the most sensitive frequency band 20-2000 Hz. The systematic error alone is estimated at levels of $< 2\%$ in magnitude and $< 2$ deg in phase