Spontaneous Switching among Conformational Ensembles in Intrinsically Disordered Proteins.

The common conception of intrinsically disordered proteins (IDPs) is that they stochastically sample all possible configurations driven by thermal fluctuations. This is certainly true for many IDPs, which behave as swollen random coils that can be described using polymer models developed for homopolymers. However, the variability in interaction energy between different amino acid sequences provides the possibility that some configurations may be strongly preferred while others are forbidden.

Qualitative, exploratory pilot study to investigate how people living with posterior cortical atrophy, their carers and clinicians experience tests used to assess vision.

Objectives: To investigate the experiences and views of people living with posterior cortical atrophy (PCA), their family carers and healthcare professionals of vision assessment tests.

Design: A qualitative investigation using video recordings of vision assessments, semistructured interviews and audio recordings of a focus group. Interviews and focus group used broad, open questions around the topic to prompt and guide discussion.

Oxytocin and vasopressin inhibit hyper-aggressive behaviour in socially isolated mice.

Despite the high prevalence of aggression across a wide range of disorders, there is a severe lack of pharmacological treatments. Recent rodent studies have shown both centrally and peripherally administered oxytocin is effective in reducing territorial aggression, an adaptive form of aggression not reflective of pathological hyper-aggression. The current study tested i.

Cardiac Therapeutics in Horses.

Many cardiac therapeutics lack significant evidence of benefit in the horse, and in many cases their use is based on extrapolation of evidence from other species. In recent years there has been a push to develop a better understanding of both the pharmacodynamics and pharmacokinetics of these drugs. Recent data have described the use of antiarrhythmic agents including sotalol, flecainide, and amiodarone.

Using a Real-Time Locating System to Measure Walking Activity Associated with Wandering Behaviors Among Institutionalized Older Adults.

A real-time locating system (RTLS) can be used to track the walking activity of institutionalized older adults in long-term care who are at risk for wandering behaviors. The benefits of a RTLS are objective and continuous measurements of activity. Self-report methods of activity, especially wandering, by health care staff are vulnerable to floor effects and recall bias, and continuous clinical or research observation over the long-term can be time-consuming and expensive.

The application of Lempel-Ziv and Titchener complexity analysis for equine telemetric electrocardiographic recordings.

The analysis of equine electrocardiographic (ECG) recordings is complicated by the absence of agreed abnormality classification criteria. We explore the applicability of several complexity analysis methods for characterization of non-linear aspects of electrocardiographic recordings. We here show that complexity estimates provided by Lempel-Ziv '76, Titchener's T-complexity and Lempel-Ziv '78 analysis of ECG recordings of healthy Thoroughbred horses are highly dependent on the duration of analysed ECG fragments and the heart rate.

Tag-on-Demand: exploiting amber codon suppression technology for the enrichment of high-expressing membrane protein cell lines.

Membrane proteins play key roles in the evolution of numerous diseases and as a result have become the most dominant class of targets for therapeutic intervention. However, their poor expression and detection oftentimes prohibit drug discovery and screening efforts. Herein, we have developed an approach, named 'Tag-on-Demand' that exploits amber suppression to control the expression of 'tagged' membrane proteins for detection and selections, yet can be turned off for expression of the protein in its native form.

Evidence for Household Transmission of Rotavirus in the United States, 2011-2016.

Background: Rotavirus is a leading cause of acute gastroenteritis (AGE) in children and is highly transmissible. In this study, we assessed the presence of AGE in household contacts (HHCs) of pediatric patients with laboratory-confirmed rotavirus.

Methods: Between December 2011 and June 2016, children aged 14 days to 11 years with AGE were enrolled at 1 of 7 hospitals or emergency departments as part of the New Vaccine Surveillance Network.

Functional genomics of epilepsy-associated mutations in the GABA receptor subunits reveal that one mutation impairs function and two are catastrophic.

A number of epilepsy-causing mutations have recently been identified in the genes of the α1, β3, and γ2 subunits comprising the γ-aminobutyric acid type A (GABA) receptor. These mutations are typically dominant, and in certain cases, such as the α1 and β3 subunits, they may lead to a mix of receptors at the cell surface that contain no mutant subunits, a single mutated subunit, or two mutated subunits. To determine the effects of mutations in a single subunit or in two subunits on receptor activation, we created a concatenated protein assembly that links all five subunits of the α1β3γ2 receptor and expresses them in the correct orientation.

The role of p53 in developmental syndromes.

While it is well appreciated that loss of the p53 tumor suppressor protein promotes cancer, growing evidence indicates that increased p53 activity underlies the developmental defects in a wide range of genetic syndromes. The inherited or de novo mutations that cause these syndromes affect diverse cellular processes, such as ribosome biogenesis, DNA repair, and centriole duplication, and analysis of human patient samples and mouse models demonstrates that disrupting these cellular processes can activate the p53 pathway. Importantly, many of the developmental defects in mouse models of these syndromes can be rescued by loss of p53, indicating that inappropriate p53 activation directly contributes to their pathogenesis.

Successful Use of Quality Improvement Methodology to Reduce Inpatient Length of Stay in Bronchiolitis Through Judicious Use of Intermittent Pulse Oximetry.

Background And Objectives: The American Academy of Pediatrics 2014 bronchiolitis guidelines recommend against the routine use of continuous pulse oximetry (CPO) because it has been implicated in prolonging the length of stay (LOS). At our institution, infants admitted with bronchiolitis were monitored by using CPO during the entire hospital stay and intermittent desaturations <90% appeared to delay discharge. This quality improvement initiative was designed to reduce the LOS by decreasing the use of CPO in stable infants with nonsevere bronchiolitis.

A viral-fusion-peptide-like molecular switch drives membrane insertion of botulinum neurotoxin A1.

Botulinum neurotoxin (BoNT) delivers its protease domain across the vesicle membrane to enter the neuronal cytosol upon vesicle acidification. This process is mediated by its translocation domain (H), but the molecular mechanism underlying membrane insertion of H remains poorly understood. Here, we report two crystal structures of BoNT/A1 H that reveal a novel molecular switch (termed BoNT-switch) in H, where buried α-helices transform into surface-exposed hydrophobic β-hairpins triggered by acidic pH.

Amber suppression coupled with inducible surface display identifies cells with high recombinant protein productivity.

Cell line development (CLD) for biotherapeutics is a time- and resource-intensive process requiring the isolation and screening of large numbers of clones to identify high producers. Novel methods aimed at enhancing cell line screening efficiency using markers predictive of productivity early in the CLD process are needed to reliably generate high-yielding cell lines. To enable efficient and selective isolation of antibody expressing Chinese hamster ovary cells by fluorescence-activated cell sorting, we developed a strategy for the expression of antibodies containing a switchable membrane-associated domain to anchor an antibody to the membrane of the expressing cell.

Erratum: Short-Term Outcomes for Veterans Receiving Basal Insulin, Metformin, and a Sulfonylurea Who Are Started on a Third Noninsulin Agent Versus Prandial Insulin. 2018;31:261-266 (doi.org/10.2337/ds17-0068).

[This corrects the article on p. 261 in vol. 31, PMID: 30140142.

Double trouble in the South Pacific subtropical gyre: Increased plastic ingestion by fish in the oceanic accumulation zone.

Fish are an important food source for South Pacific (SP) island countries, yet there is little information on contamination of commercial marine fish species by plastic. The aim of our study was to perform a broad-scale assessment of plastic ingestion by fish common in the diet of SP inhabitants. We examined 932 specimens from 34 commercial fish species across four SP locations, and some of the prey they ingested, for the presence of marine plastics.

Management factors and clinical implications of glandular and squamous gastric disease in horses.

Background: To date, risk factors for equine glandular gastric disease (EGGD) have not been described in Thoroughbred racehorses.

Objectives: To determine management factors associated with EGGD, identify clinical signs in affected horses, and compare these to equine squamous gastric disease (ESGD).

Animals: The study was carried out on 109 Thoroughbred racehorses from 8 training yards (3 in the United Kingdom and 5 in Australia).

Single Cell Transcriptomics Reveal Abnormalities in Neurosensory Patterning of the Mutant Mouse Ear.

The chromatin remodeling protein CHD7 is critical for proper formation of the mammalian inner ear. Humans with heterozygous pathogenic variants in exhibit CHARGE syndrome, characterized by hearing loss and inner ear dysplasia, including abnormalities of the semicircular canals and Mondini malformations. heterozygous null mutant mice also exhibit dysplastic semicircular canals and hearing loss.

Automated CT Perfusion Prediction of Large Vessel Acute Stroke from Intracranial Atherosclerotic Disease.

Background And Purpose: We have observed that large vessel occlusion acute strokes (LVOS) due to intracranial atherosclerotic disease (ICAD) present with more benign CT perfusion (CTP) profiles, which we presume to potentially represent enhanced collateralization compared to embolic LVOS. We aim to determine if CTP profiles can predict ICAD in LVOS.

Methods: Retrospective review of a prospectively collected interventional stroke database from September 2010 to March 2015.

A Stroke Reduction Health Plan for Older Adults in Rural Sussex County, Delaware.

Stroke is a leading cause of death and disability among adults age 65 and over in the United States. Modifiable risk factors for stroke include: obesity, poor nutrition, and lack of exercise. Sussex County, Delaware has the highest stroke rate among older adults in the state.

Development and internal validation of the multivariable CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) clinical risk prediction model.

Background: Intensive care unit (ICU) outcome prediction models, such as Acute Physiology And Chronic Health Evaluation (APACHE), were designed in general critical care populations and their use in obstetric populations is contentious. The aim of the CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) study was to develop and internally validate a multivariable prognostic model calibrated specifically for pregnant or recently delivered women admitted for critical care.

Methods: A retrospective observational cohort was created for this study from 13 tertiary facilities across five high-income and six low- or middle-income countries.

Surveillance for colorectal cancer survivors in an integrated safety-net health system in the United States.

Introduction: Guideline-recommended surveillance reduces likelihood of colorectal cancer (CRC) recurrence, yet surveillance rates are low in the United States (US). Little is known about CRC surveillance rates among patients without health insurance and their primary care clinicians/oncologists' attitudes towards surveillance care.

Methods: A retrospective study of 205 patients diagnosed with Stage I-III CRC from 2008-2010 was conducted in an integrated system with a network of providers delivering care to patients lacking health insurance coverage.

Publisher Correction: Precision and accuracy of single-molecule FRET measurements-a multi-laboratory benchmark study.

This paper was originally published under standard Springer Nature copyright. As of the date of this correction, the Analysis is available online as an open-access paper with a CC-BY license. No other part of the paper has been changed.

High-throughput screening of antibody-expressing CHO clones using an automated shaken deep-well system.

Biopharmaceutical protein manufacturing requires the highest producing cell lines to satisfy current multiple grams per liter requirements. Screening more clones increases the probability of identifying the high producers within the pool of available transfectant candidate cell lines. For the predominant industry mammalian host cell line, Chinese hamster ovary (CHO), traditional static-batch culture screening does not correlate with the suspension fed-batch culture used in manufacturing, and thus has little predictive utility.

Ultrasmall targeted nanoparticles with engineered antibody fragments for imaging detection of HER2-overexpressing breast cancer.

Controlling the biodistribution of nanoparticles upon intravenous injection is the key to achieving target specificity. One of the impediments in nanoparticle-based tumor targeting is the inability to limit the trafficking of nanoparticles to liver and other organs leading to smaller accumulated amounts in tumor tissues, particularly via passive targeting. Here we overcome both these challenges by designing nanoparticles that combine the specificity of antibodies with favorable particle biodistribution profiles, while not exceeding the threshold for renal filtration as a combined vehicle.

Perioperative antibiotics should be used for placement of implanted central venous ports: A propensity analysis evaluating risk.

Objective: To quantify risk for CRI based on PABX use in CVAP placement for cancer patients.

Summary Background Data: Central venous access ports (CVAP) are totally implanted devices used for chemotherapy. There is a temporal risk for catheter related infection (CRI) to insertion and perioperative prophylactic antibiotics (PABX) use is a contested issue among practitioners.