IgG light chain-independent secretion of heavy chain dimers: consequence for therapeutic antibody production and design

Rodent monoclonal antibodies with specificity towards important biological targets are developed for therapeutic use by a process of humanisation. This process involves the creation of molecules, which retain the specificity of the rodent antibody but contain predominantly human coding sequence. Here we show that some humanised heavy chains can fold, form dimers and be secreted even in the absence of light chain. Quality control of recombinant antibody assembly in vivo is thought to rely upon folding of the heavy chain CH1 domain. This domain acts as a switch for secretion, only folding upon interaction with the light chain CL domain. We show that the secreted heavy-chain dimers contain folded CH1 domains and contribute to the heterogeneity of antibody species secreted during the expression of therapeutic antibodies. This subversion of the normal quality control process is dependent upon the heavy chain variable domain, is prevalent with engineered antibodies and can occur when only the Fab fragments are expressed. This discovery will impact on the efficient production of both humanised antibodies as well as the design of novel antibody formats

Airway management in neonates and infants: European Society of Anaesthesiology and Intensive Care and British Journal of Anaesthesia joint guidelines.

Airway management is required during general anaesthesia and is essential for life-threatening conditions such as cardiopulmonary resuscitation. Evidence from recent trials indicates a high incidence of critical events during airway management, especially in neonates or infants. It is important to define the optimal techniques and strategies for airway management in these groups. In this joint European Society of Anaesthesiology and Intensive Care (ESAIC) and British Journal of Anaesthesia (BJA) guideline on airway management in neonates and infants, we present aggregated and evidence-based recommendations to assist clinicians in providing safe and effective medical care. We identified seven main areas of interest for airway management: i) preoperative assessment and preparation; ii) medications; iii) techniques and algorithms; iv) identification and treatment of difficult airways; v) confirmation of tracheal intubation; vi) tracheal extubation, and vii) human factors. Based on these areas, Population, Intervention, Comparison, Outcomes (PICO) questions were derived that guided a structured literature search. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was used to formulate the recommendations based on those studies included with consideration of their methodological quality (strong '1' or weak '2' recommendation with high 'A', medium 'B' or low 'C' quality of evidence). In summary, we recommend: 1. Use medical history and physical examination to predict difficult airway management (1С). 2. Ensure adequate level of sedation or general anaesthesia during airway management (1B). 3. Administer neuromuscular blocker before tracheal intubation when spontaneous breathing is not necessary (1С). 4. Use a videolaryngoscope with an age-adapted standard blade as first choice for tracheal intubation (1B). 5. Apply apnoeic oxygenation during tracheal intubation in neonates (1B). 6. Consider a supraglottic airway for rescue oxygenation and ventilation when tracheal intubation fails (1B). 7. Limit the number of tracheal intubation attempts (1C). 8. Use a stylet to reinforce and preshape tracheal tubes when hyperangulated videolaryngoscope blades are used and when the larynx is anatomically anterior (1C). 9. Verify intubation is successful with clinical assessment and end-tidal CO2 waveform (1C). 10. Apply high-flow nasal oxygenation, continuous positive airway pressure or nasal intermittent positive pressure ventilation for postextubation respiratory support, when appropriate (1B)

Conformational changes associated with the binding of zinc acetate at the putative active site of XcTcmJ, a cupin from Xanthomonas campestris pv. campestris

The crystal structure of an RmlC-type cupin with zinc acetate bound at the putative active site reveals significant differences from a previous structure without any bound ligand. The functional implications of the ligand-induced conformational changes are discussed

Measurement of the inclusive isolated-photon cross section in pp collisions at √s = 13 TeV using 36 fb−1 of ATLAS data

The differential cross section for isolated-photon production in pp collisions is measured at a centre-of-mass energy of 13 TeV with the ATLAS detector at the LHC using an integrated luminosity of 36.1 fb. The differential cross section is presented as a function of the photon transverse energy in different regions of photon pseudorapidity. The differential cross section as a function of the absolute value of the photon pseudorapidity is also presented in different regions of photon transverse energy. Next-to-leading-order QCD calculations from Jetphox and Sherpa as well as next-to-next-to-leading-order QCD calculations from Nnlojet are compared with the measurement, using several parameterisations of the proton parton distribution functions. The predictions provide a good description of the data within the experimental and theoretical uncertainties. [Figure not available: see fulltext.

Crowdsourced assessment of common genetic contribution to predicting anti-TNF treatment response in rheumatoid arthritis

Correction: vol 7, 13205, 2016, doi:10.1038/ncomms13205Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in Bone-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h(2) = 0.18, P value = 0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.Peer reviewe

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

The effect of coastal storms and hurricanes on two south shore Long Island embayments

This paper aims to determine how coastal storms and hurricanes affect water quality and pollution levels in Moriches and Quantuck Bays, specifically Hurricane Hermine. After conducting research in both bays, I have concluded that the hurricane did not have a large impact on the pollution levels in the bays. Sensors were deployed at three different stations to determine temperature, dissolved oxygen (DO), salinity, and water levels. Hermine decreased temperature and DO and increased salinity and water levels for 4-6 days in the bays. Temperature decreased by a maximum of 12°F in both bays while DO levels decreased by 2-4mg/L in both bays. Salinity increased by 2-3psu in both bays and the tides increased by 0.3 in Moriches bay and 0.5 feet in Quantuck bay. The minimal changes in dissolved oxygen, salinity, temperature and water levels, and the short amount of time it took to return to normal levels suggest that the hurricane was not large enough to affect the water quality. In order to determine if coastal storms affect the water quality of these bays, I would need to deploy additional sensors to collect more data and continue to monitor the bays and see how they are affected by a storm larger than a Category One

The unidirectional prosaccade switch-cost: no evidence for the passive dissipation of an oculomotor task-set inertia

Cognitive flexibility is a core component of executive function and supports the ability to 'switch' between different tasks. Our group has examined the cost associated with switching between a prosaccade (i.e., a standard task requiring a saccade to veridical target location) and an antisaccade (i.e., a non-standard task requiring a saccade mirror-symmetrical to veridical target) in predictable (i.e., AABB) and unpredictable (e.g., AABAB…) switching paradigms. Results have shown that reaction times (RTs) for a prosaccade preceded by an antisaccade (i.e., task-switch trial) are longer than when preceded by its same task-type (i.e., task-repeat trial), whereas RTs for antisaccade task-switch and task-repeat trials do not differ. The asymmetrical switch-cost has been attributed to an antisaccade task-set inertia that proactively delays a subsequent prosaccade (i.e., the unidirectional prosaccade switch-cost). A salient question arising from previous work is whether the antisaccade task-set inertia passively dissipates or persistently influences prosaccade RTs. Accordingly, participants completed separate AABB (i.e., A = prosaccade, B = antisaccade) task-switching conditions wherein the preparation interval for each trial was 'short' (1000-2000 ms; i.e., the timeframe used in previous work), 'medium' (3000-4000 ms) and 'long' (5000-6000 ms). Results demonstrated a reliable prosaccade switch-cost for each condition (ps < 0.02) and two one-sided test statistics indicated that switch cost magnitudes were within an equivalence boundary (ps < 0.05). Hence, null and equivalence tests demonstrate that an antisaccade task-set inertia does not passively dissipate and represents a temporally persistent feature of oculomotor control

Data Resource Profile : United Kingdom Optimum Patient Care Research Database

Funding Unfunded project management, medical writing, and statistical support were provided by Momentum Data, UK, a specialist real-world evidence company. Acknowledgements This study is based wholly on data from the Optimum Patient Care Research Database (opcrd.co.uk) obtained under license from Optimum Patient Care Limited and its execution is approved by recognized experts affiliated to the Respiratory Effectiveness Group. However, the interpretation and conclusion contained in this report are those of the author/s alone.Peer reviewedPublisher PD