Protein-Protein Conjugates: Tyrosine Delivers.

The residues cysteine and lysine are the undisputed champions of bioconjugation chemistry. Targeting other amino acids has been touted as a potential way to improve the synthesis of protein–peptide and protein–protein conjugates that are widely studied for their potential therapeutic ability and used as tools for understanding biological function. Now, a team of researchers at the University of California, Berkeley, have targeted solvent-exposed tyrosine residues to develop a method of preparing such conjugates

Grade IV frostbite requiring bilateral below knee amputations: a case report

A rare case of grade IV frostbite is presented resulting in bilateral below knee amputations. This case highlights the importance of early versus late amputation as well as the importance of close collaboration between the rehabilitation, surgical, psychosocial, and public health disciplines in this rare and challenging problem that still may be encountered in the United Kingdom

Deuteronomy and Numbers

Four light isotopes - D, ^3He, ^4He and ^7Li - were produced by nuclear reactions a few seconds after the big bang. New measurements of ^3He in the ISM by Gloeckler and Geiss and of deuterium in high redshift hydrogen clouds by Tytler and his collaborators provide further confirmation of big-bang nucleosynthesis and new insight about the density of ordinary matter (baryons).Comment: 6 pages LaTeX with 1 eps Figur

Developments in Dilatometry for Characterisation of Electrochemical Devices

Since the 1970s, electrochemical dilatometry (ECD) has been used to investigate the dilation of layered host materials due to the intercalation of guest ions, atoms or molecules, and has recently gained traction in application to various electrochemical devices, such as lithium-ion batteries (LiBs), which have electrodes that undergo volume changes during cycling, resulting in particle cracking and electrode degradation. With resolution capabilities spanning tens of microns down to a few nanometres, dilatometry is a valuable tool in understanding how commonly used electrodes dilate and degrade and can therefore be of critical value in improving their performance. In recent years, there has been a plethora of studies using dilatometry as a monitoring tool for understanding operating performance in various electrochemical devices; however, to our knowledge, there has been no in-depth review of this body of research to date. This paper seeks to address this by reviewing how dilatometry works and how it has been used for the characterisation of electrochemical energy storage devices

Bench-to-bedside review: The gut as an endocrine organ in the critically ill

In health, hormones secreted from the gastrointestinal tract have an important role in regulating gastrointestinal motility, glucose metabolism and immune function. Recent studies in the critically ill have established that the secretion of a number of these hormones is abnormal, which probably contributes to disordered gastrointestinal and metabolic function. Furthermore, manipulation of endogenous secretion, physiological replacement and supra-physiological treatment (pharmacological dosing) of these hormones are likely to be novel therapeutic targets in this group. Fasting ghrelin concentrations are reduced in the early phase of critical illness, and exogenous ghrelin is a potential therapy that could be used to accelerate gastric emptying and/or stimulate appetite. Motilin agonists, such as erythromycin, are effective gastrokinetic drugs in the critically ill. Cholecystokinin and peptide YY concentrations are elevated in both the fasting and postprandial states, and are likely to contribute to slow gastric emptying. Accordingly, there is a rationale for the therapeutic use of their antagonists. So-called incretin therapies (glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide) warrant evaluation in the management of hyperglycaemia in the critically ill. Exogenous glucagon-like peptide-2 (or its analogues) may be a potential therapy because of its intestinotropic properties

Antitumor activity of the ERK inhibitor SCH772984 [corrected] against BRAF mutant, NRAS mutant and wild-type melanoma.

BackgroundIn melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma.MethodsThe 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.ResultsSensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.ConclusionsCombining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors

Comparative study of energy management systems for a hybrid fuel cell electric vehicle - A novel mutative fuzzy logic controller to prolong fuel cell lifetime

Hybrid fuel cell battery electric vehicles require complex energy management systems (EMS) in order to operate effectively. Poor EMS can result in a hybrid system that has low efficiency and a high rate of degradation of the fuel cell and battery pack. Many different types of EMS have been reported in the literature, such as equivalent consumption minimisation strategy and fuzzy logic controllers, which typically focus on a single objective optimisations, such as minimisation of H2 usage. Different vehicle and system specifications make the comparison of EMSs difficult and can often lead to misleading claims about system performance. This paper aims to compare different EMSs, against a range of performance metrics such as charge sustaining ability and fuel cell degradation, using a common modelling framework developed in MATLAB/Simulink - the Electric Vehicle Simulation tool-Kit (EV-SimKit). A novel fuzzy logic controller is also presented which mutates the output membership function depending on fuel cell degradation to prolong fuel cell lifetime – the Mutative Fuzzy Logic Controller (MFLC). It was found that while certain EMSs may perform well at reducing H2 consumption, this may have a significant impact on fuel cell degradation, dramatically reducing the fuel cell lifetime. How the behaviour of common EMS results in fuel cell degradation is also explored. Finally, by mutating the fuzzy logic membership functions, the MFLC was predicted to extend fuel cell lifetime by up to 32.8%

A Comparison of the Accuracy and Reliability of the Wahoo KICKR and SRM Power Meter

The Wahoo KICKR cycling trainer is a new direct-drive electromagnetically braked bike-trainer that allows cyclists to use their own bicycles as ergometer. It is purported to provide ±3% accuracy in power, despite costing considerably less than other cycling ergometers. The purpose of this study was to assess the accuracy and reliability of several KICKR units against the more established SRM power meter using a first-principles based dynamic calibration rig (CALRIG).Five KICKRs and one SRM unit were assessed by a CALRIG-driven incremental test. Following a 15 min warm-up and ‘calibration’ as per manufacturer instructions, power was increased (starting at 50 W) by 50 W every 2 min up to 400 W. Each unit was tested twice non-consecutively, in random order. Data was recorded at 1 Hz, with the last 10 s of each stage being averaged for analysis. The mean error (%) and coefficient of determination (R2) versus CALRIG; as well as the change in mean error and Typical Error of Measurement (TEM) (expressed as a % coefficient of variation) between trials was calculated for each device.The mean error across all KICKR units was -1.5% (range: -3.1% to 0.0%) compared to -1.6% reported by the SRM. R2 >0.999 was found for all KICKR units and SRM compared to the CALRIG. The mean TEM for the KICKRs was 1.5% (range: 1.1% to 1.9%), whereas the SRM reported 0.7%. For test-retest reproducibility, two KICKRs had statistically significant changes in mean error, with an average 1.3% change across all KICKRs. Comparatively, the SRM reported a 0.4% change between trials. The Wahoo KICKR trainer measures power to a similar level of accuracy to the more reputable SRM power meter during an incremental exercise test. Although not as reproducible, the KICKR still demonstrates an acceptable level of reliability for assessing cycling performance