Cystic fibrosis (CF) is a lethal genetic disorder most commonly caused by the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. It is not readily amenable to gene therapy because of its systemic nature and challenges including in vivo gene delivery and transient gene expression. Here, we use triplex-forming PNA molecules and donor DNA in biodegradable polymer nanoparticles to correct F508del. We confirm modification with sequencing and a functional chloride efflux assay. In vitro correction of chloride efflux occurs in up to 25% of human cells. Deep sequencing reveals negligible off-target effects in partially homologous sites. Intranasal application of nanoparticles in CF mice produces changes in nasal epithelium potential differences consistent with corrected CFTR, with gene correction also detected in lung tissue. This work represents facile genome engineering in vivo with oligonucleotides using a nanoparticle system to achieve clinically relevant levels of gene editing without off-target effects.

Calcium balance is essential for a multitude of physiological processes, ranging from cell signaling to maintenance of bone health. Adequate intestinal absorption of calcium is a major factor for maintaining systemic calcium homeostasis. Recent observations indicate that a reduction of gastric acidity may impair effective calcium uptake through the intestine. This article reviews the physiology of gastric acid secretion, intestinal calcium absorption, and their respective neuroendocrine regulation and explores the physiological basis of a potential link between these individual systems.

Background: Pressure-volume (PV) loops provide a wealth of information on cardiac function but are not readily available in clinical routine or in clinical trials. This study aimed to develop and validate a noninvasive method to compute individualized left ventricular PV loops. Methods: The proposed method is based on time-varying elastance, with experimentally optimized model parameters from a training set (n=5 pigs), yielding individualized PV loops. Model inputs are left ventricular volume curves from cardiovascular magnetic resonance imaging and brachial pressure. The method was experimentally validated in a separate set (n=9 pig experiments) using invasive pressure measurements and cardiovascular magnetic resonance images and subsequently applied to human healthy controls (n=13) and patients with heart failure (n=28). Results: There was a moderate-to-excellent agreement between in vivo-measured and model-calculated stroke work (intraclass correlation coefficient, 0.93; bias, −0.02±0.03 J), mechanical potential energy (intraclass correlation coefficient, 0.57; bias, −0.04±0.03 J), and ventricular efficiency (intraclass correlation coefficient, 0.84; bias, 3.5±2.1%). The model yielded lower ventricular efficiency ( P <0.0001) and contractility ( P <0.0001) in patients with heart failure compared with controls, as well as a higher potential energy ( P <0.0001) and energy per ejected volume ( P <0.0001). Furthermore, the model produced realistic values of stroke work and physiologically representative PV loops. Conclusions: We have developed the first experimentally validated, noninvasive method to compute left ventricular PV loops and associated quantitative measures. The proposed method shows significant agreement with in vivo-derived measurements and could support clinical decision-making and provide surrogate end points in clinical heart failure trials.

Intestinal fluid secretion is pivotal in the creation of an ideal environment for effective enzymatic digestion, nutrient absorption and stool movement. Since fluid cannot be actively secreted into the gut, this process is dependent on an osmotic gradient, which is mainly created by chloride transport by the enterocyte. A pathological dysbalance between fluid secretion and absorption leads to obstruction or potentially fatal diarrhoea. This article reviews the widely accepted model of intestinal chloride secretion with an emphasis on the molecular players involved in this tightly regulated process.

An estimated 4 billion episodes of diarrhea occur each year. As a result, 2–3 million children and 0.5–1 million adults succumb to the consequences of this major healthcare concern. The majority of these deaths can be attributed to toxin mediated diarrhea by infectious agents, such as E. coli, V. cholerae or Rotavirus. Our understanding of the pathophysiological processes underlying these infectious diseases has notably improved over the last years. This review will focus on the cellular mechanism of action of the most common enterotoxins and the latest specific therapeutic approaches that have been developed to contain their lethal effects.