Unveiling cytokine charge disparity as a potential mechanism for immune regulation.

Cytokines are small signaling proteins that regulate the immune responses to infection and tissue damage. Surface charges of cytokines determine their in vivo fate in immune regulation, e.g.

Adaptable, turn-on maturation (ATOM) fluorescent biosensors for multiplexed detection in cells.

A grand challenge in biosensor design is to develop a single-molecule, fluorescent protein-based platform that can be easily adapted to recognize targets of choice. Here, we created a family of adaptable, turn-on maturation (ATOM) biosensors consisting of a monobody (circularly permuted at one of two positions) or a nanobody (circularly permuted at one of three positions) inserted into a fluorescent protein at one of three surface loops. Multiplexed imaging of live human cells coexpressing cyan, yellow and red ATOM sensors detected biosensor targets that were specifically localized to various subcellular compartments.

Adaptable, Turn-On Monobody (ATOM) Fluorescent Biosensors for Multiplexed Detection in Cells.

A grand challenge in biosensor design is to develop a single molecule, fluorescent protein-based platform that can be easily adapted to recognize targets of choice. Conceptually, this can be achieved by fusing a small, antibody-like binding domain to a fluorescent protein in such a way that target binding activates fluorescence. Although this design is simple to envision, its execution is not obvious.

Screening asymptomatic men for prostate cancer: A comparison of international guidelines on prostate-specific antigen testing.

Objective: To summarise and compare the key recommendations on prostate-specific antigen (PSA)-based screening for prostate cancer, and so highlight where more evidence is required to facilitate consistent recommendations.

Methods: The Medline database and websites of 18 national screening organisations and professional associations were searched between January 2010 and November 2020 to identify screening guidelines published in English, considering recent clinical trials.

Results: Population-based PSA testing of asymptomatic men is not widely recommended.

Engineering a Fluorescent Protein Color Switch Using Entropy-Driven β-Strand Exchange.

Protein conformational switches are widely used in biosensing. They are often composed of an input domain (which binds a target ligand) fused to an output domain (which generates an optical readout). A central challenge in designing such switches is to develop mechanisms for coupling the input and output signals conformational changes.

Development and performance testing of the low-cost, 3D-printed, smartphone-compatible 'Tansen Videolaryngoscope' vs. Pentax-AWS videolaryngoscope vs. direct Macintosh laryngoscope: A manikin study.

Background: While videolaryngoscopes help in the management of difficult airways, they remain too expensive for those with limited resources. We have developed a robust, re-usable, low-cost videolaryngoscope at United Mission Hospital Tansen, Nepal, by combining a smartphone-compatible endoscope capable of capturing still and video images with a three dimensional-printed, channelled, hyperangulated blade. The computer-aided design file for the videolaryngoscope blade was emailed and printed in London before evaluation of its performance on a difficult airway manikin.

Bench Testing of a Bubble Noninvasive Ventilation Device in an Infant Lung Simulator.

Background: Infant respiratory distress remains a significant problem worldwide, leading to more than one million neonatal deaths each year. The cost, maintenance, energy, and personnel required to implement ventilators have proven to be a barrier in many resource-limited settings. To address these barriers, a nonelectric bubble noninvasive positive pressure ventilation (NIV) device was developed.

Reproducing Patient-Specific Hemodynamics in the Blalock-Taussig Circulation Using a Flexible Multi-Domain Simulation Framework: Applications for Optimal Shunt Design.

For babies born with hypoplastic left heart syndrome, several open-heart surgeries are required. During Stage I, a Norwood procedure is performed to construct an appropriate circulation to both the systemic and the pulmonary arteries. The pulmonary arteries receive flow from the systemic circulation, often using a Blalock-Taussig (BT) shunt between the innominate artery and the right pulmonary artery.

Myocardial late gadolinium enhancement in specific cardiomyopathies by cardiovascular magnetic resonance: a preliminary experience.

Late gadolinium enhancement cardiovascular magnetic resonance (CMR) can visualize myocardial interstitial abnormalities. The aim of this study was to assess whether regions of abnormal myocardium can also be visualized by late enhancement gadolinium CMR in the specific cardiomyopathies. A retrospective review of all referrals for gadolinium CMR with specific cardiomyopathy over 20 months.

Pre- and post-synaptic sympathetic function in human hibernating myocardium.

Purpose: Impaired pre-synaptic noradrenaline uptake-1 mechanism has been reported in a swine model of hibernating myocardium (HM). To ascertain whether adrenergic neuroeffector abnormalities are present in human HM, we combined functional measurements in vivo using cardiovascular magnetic resonance (CMR) and positron emission tomography (PET) to assess pre- and post-synaptic sympathetic function.

Methods: Twelve patients with coronary artery disease and chronic left ventricular (LV) dysfunction underwent CMR at baseline and 6 months after bypass for assessment of regional and global LV function and identification of segments with reversible dysfunction.

Myocardial pre-synaptic sympathetic function correlates with glucose uptake in the failing human heart.

Purpose: We have previously shown that the myocardium of patients with heart failure (HF) is insulin resistant. Chronic beta-adrenergic stimulation has been implicated in insulin resistance in cultured cardiomyocytes in vitro, where sustained noradrenaline stimulation inhibited insulin-modulated glucose uptake. As the failing heart is characterized by increased sympathetic drive, we hypothesized that there is a correlation between pre-synaptic sympathetic function and insulin sensitivity in the myocardium of patients with HF.

Intractable Bacillus cereus bacteremia in a preterm neonate.

Although often regarded as a contaminant, Bacillus spp. have been implicated in serious systemic infections. The incidence of such infections is low with only a few cases reported in the literature.

The pathologic basis of Q-wave and non-Q-wave myocardial infarction: a cardiovascular magnetic resonance study.

Objectives: The purpose of this study was to determine the pathologic basis of Q-wave (QW) and non-Q-wave (NQW) myocardial infarction (MI).

Background: The QW/NQW distinction remains in wide clinical use but the meaning of the difference remains controversial. We hypothesized that measurement of total MI size and transmural extent by late gadolinium enhancement cardiovascular magnetic resonance (CMR) would identify the pathologic basis of QWs.

Program of cell survival underlying human and experimental hibernating myocardium.

Hibernating myocardium refers to chronically dysfunctional myocardium in patients with coronary artery disease in which cardiac viability is maintained and whose function improves after coronary revascularization. It is our hypothesis that long-term adaptive genomic mechanisms subtend the survival capacity of this ischemic myocardium. Therefore, the goal of this study was to determine whether chronic repetitive ischemia elicits a gene program of survival protecting hibernating myocardium against cell death.

Breath-hold signal-loss sequence for the qualitative assessment of flow disturbances in cardiovascular MR.

Purpose: To develop a breath-hold segmented sequence which generates similar patterns of signal loss to a non-breath-hold, relatively long echo time, conventional gradient echo sequence for the qualitative assessment of valvular heart disease.

Materials And Methods: Both velocity-sensitized and acceleration-sensitized segmented sequences were developed. The sensitivities were empirically adjusted to give similar degrees of signal loss to a conventional sequence.

Magnetic resonance to assess the aortic valve area in aortic stenosis: how does it compare to current diagnostic standards?

Objectives: The purpose of the present study was to evaluate whether magnetic resonance (MR) planimetry of the aortic valve area (AVA) may prove to be a reliable, non-invasive diagnostic tool in the assessment of aortic valve stenosis, and how the results compare with current diagnostic standards.

Background: Current standard techniques for assessing the severity of aortic stenosis include transthoracic and transesophageal echocardiography (TEE) as well as transvalvular pressure measurements during cardiac catheterization.

Methods: Forty consecutive patients underwent cardiac catheterization, TEE, and MR.

Role of flanking sequences and phosphorylation in the recognition of the simian-virus-40 large T-antigen nuclear localization sequences by importin-alpha.

The nuclear import of simian-virus-40 large T-antigen (tumour antigen) is enhanced via phosphorylation by the protein kinase CK2 at Ser112 in the vicinity of the NLS (nuclear localization sequence). To determine the structural basis of the effect of the sequences flanking the basic cluster KKKRK, and the effect of phosphorylation on the recognition of the NLS by the nuclear import factor importin-alpha (Impalpha), we co-crystallized non-autoinhibited Impalpha with peptides corresponding to the phosphorylated and non-phosphorylated forms of the NLS, and determined the crystal structures of the complexes. The structures show that the amino acids N-terminally flanking the basic cluster make specific contacts with the receptor that are distinct from the interactions between bipartite NLSs and Impalpha.

Defective importin beta recognition and nuclear import of the sex-determining factor SRY are associated with XY sex-reversing mutations.

The architectural transcription factor SRY (sex-determining region of the Y chromosome) plays a key role in sex determination as indicated by the fact that mutations in SRY are responsible for XY gonadal dysgenesis in humans. Although many SRY mutations reduce DNA-binding/bending activity, it is not clear how SRY mutations that do not affect interaction with DNA contribute to disease. The SRY high-mobility group domain harbors two nuclear localization signals (NLSs), and here we examine SRY from four XY females with missense mutations in these signals.

Phosphorylation of insulin-like growth factor binding protein-3 by deoxyribonucleic acid-dependent protein kinase reduces ligand binding and enhances nuclear accumulation.

The IGF binding proteins (IGFBPs) regulate the mitogenic effects of IGFs in the extracellular environment. Several members of this family, including IGFBP-3, also appear to have IGF-independent effects on cell function. For IGFBP-3 and IGFBP-5, both of which are translocated to the cell nuclei, these effects may be related to their putative nuclear actions.

Recombinant modular transporters for cell-specific nuclear delivery of locally acting drugs enhance photosensitizer activity.

The search for new pharmaceuticals that are specific for diseased rather than normal cells in the case of cancer and viral disease has raised interest in locally acting drugs that act over short distances within the cell and for which different cell compartments have distinct sensitivities. Thus, photosensitizers (PSs) used in anti-cancer therapy should ideally be transported to the most sensitive subcellular compartments in order for their action to be most pronounced. Here we describe the design, production, and characterization of the effects of bacterially expressed modular recombinant transporters for PSs comprising 1) alpha-melanocyte-stimulating hormone as an internalizable, cell-specific ligand; 2) an optimized nuclear localization sequence of the SV40 large T-antigen; 3) an Escherichia coli hemoglobin-like protein as a carrier; and 4) an endosomolytic amphipathic polypeptide, the translocation domain of diphtheria toxin.

Coronary artery bypass graft patency: assessment with true ast imaging with steady-state precession versus gadolinium-enhanced MR angiography.

Purpose: To compare the accuracy of multisection true fast imaging with steady-state precession (FISP) with gadolinium-enhanced magnetic resonance (MR) angiography for the detection of coronary artery bypass graft patency.

Materials And Methods: Twenty-five patients with coronary artery bypass grafts who had recently undergone conventional coronary angiography underwent MR angiography with a 1.5-T system.

Pulmonary vein diameter reduction after radiofrequency catheter ablation for paroxysmal atrial fibrillation evaluated by contrast-enhanced three-dimensional magnetic resonance imaging.

Background: Radiofrequency catheter ablation (RFCA) is a promising intervention to treat atrial fibrillation. However, pulmonary vein (PV) stenosis after RFCA has been reported. The aim of this study was to investigate the incidence and time course of pulmonary vein stenosis after RFCA within a period of 3 months.