Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice

In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H⁺-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients.     

Respiratory Function in Healthy Taiwanese Infants: Tidal Breathing Analysis,Passive Mechanics,and Tidal Forced Expiration

Background

Although infant lung function (ILF) testing is widely practiced in developed Western countries it is not typically performed in Eastern countries, and lung measurements are scarce for Asian infants. Therefore, this study aimed to establish normal reference values for Taiwanese infants.

Materials and Methods

Full-term infants without any chronic diseases and major anomalies were enrolled in the Prediction of Allergies in Taiwanese Children (PATCH) cohort study. Detailed medical data, such as body weight and length, birth history, and histories of previous illness and hospitalization were recorded. Lung function measurements such as analysis of tidal breathing, passive respiratory mechanics, and forced tidal expiratory flow-volume curves were obtained through Jaeger Masterscreen BabyBody Paediatrics System. Multiple linear analyses were performed to determine various parameters of the lung function tests.

Results

ILF test parameters were collected from 126 infants, and 189 tests were performed. The results revealed that the ratio of time to peak expiratory flow to total expiratory time, the ratio of volume to peak expiratory flow to total expiratory volume, and the ratio of inspiratory time to total respiratory time remained relatively constant despite differences in age. However, body length is the strongest independent variable influencing tidal volume, respiratory rate, resistance, compliance, and maximal expiratory flow at functional residual capacity.

Conclusion

According to our review of relevant literature, this is the first study to establish a reference data of ILF tests in the Asian population. This study provided reference values and regression equations for several variables of lung function measurements in healthy infants aged less than 2 years. With these race-specific reference data, ILF can more precisely and efficiently diagnose respiratory diseases in infants of Chinese ethnicity.     

Dusp5 negatively regulates IL‐33‐mediated eosinophil survival and function

Mitogen-activated protein kinase (MAPK) activation controls diverse cellular functions including cellular survival, proliferation, and apoptosis. Tuning of MAPK activation is counter-regulated by a family of dual-specificity phosphatases (DUSPs). IL-33 is a recently described cytokine that initiates Th2 immune responses through binding to a heterodimeric IL-33Rα (ST2L)/IL-1α accessory protein (IL-1RAcP) receptor that coordinates activation of ERK and NF-κB pathways. We demonstrate here that DUSP5 is expressed in eosinophils, is upregulated following IL-33 stimulation and regulates IL-33 signaling. Dusp5^−/− mice have prolonged eosinophil survival and enhanced eosinophil effector functions following infection with the helminth Nippostrongylus brasiliensis. IL-33-activated Dusp5^−/− eosinophils exhibit increased cellular ERK1/2 activation and BCL-X_L expression that results in enhanced eosinophil survival. In addition, Dusp5^−/− eosinophils demonstrate enhanced IL-33-mediated activation and effector functions. Together, these data support a role for DUSP5 as a novel negative regulator of IL-33-dependent eosinophil function and survival.     

Production of an Attenuated Phenol-Soluble Modulin Variant Unique to the MRSA Clonal Complex 30 Increases Severity of Bloodstream Infection

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of morbidity and death. Phenol-soluble modulins (PSMs) are recently-discovered toxins with a key impact on the development of Staphylococcus aureus infections. Allelic variants of PSMs and their potential impact on pathogen success during infection have not yet been described. Here we show that the clonal complex (CC) 30 lineage, a major cause of hospital-associated sepsis and hematogenous complications, expresses an allelic variant of the PSMα3 peptide. We found that this variant, PSMα3N22Y, is characteristic of CC30 strains and has significantly reduced cytolytic and pro-inflammatory potential. Notably, CC30 strains showed reduced cytolytic and chemotactic potential toward human neutrophils, and increased hematogenous seeding in a bacteremia model, compared to strains in which the genome was altered to express non-CC30 PSMα3. Our findings describe a molecular mechanism contributing to attenuated pro-inflammatory potential in a main MRSA lineage. They suggest that reduced pathogen recognition via PSMs allows the bacteria to evade elimination by innate host defenses during bloodstream infections. Furthermore, they underscore the role of point mutations in key S. aureus toxin genes in that adaptation and the pivotal importance PSMs have in defining key S. aureus immune evasion and virulence mechanisms.     

Mutations in Global Regulators Lead to Metabolic Selection during Adaptation to Complex Environments

Adaptation to ecologically complex environments can provide insights into the evolutionary dynamics and functional constraints encountered by organisms during natural selection. Adaptation to a new environment with abundant and varied resources can be difficult to achieve by small incremental changes if many mutations are required to achieve even modest gains in fitness. Since changing complex environments are quite common in nature, we investigated how such an epistatic bottleneck can be avoided to allow rapid adaptation. We show that adaptive mutations arise repeatedly in independently evolved populations in the context of greatly increased genetic and phenotypic diversity. We go on to show that weak selection requiring substantial metabolic reprogramming can be readily achieved by mutations in the global response regulator arcA and the stress response regulator rpoS. We identified 46 unique single-nucleotide variants of arcA and 18 mutations in rpoS, nine of which resulted in stop codons or large deletions, suggesting that subtle modulations of ArcA function and knockouts of rpoS are largely responsible for the metabolic shifts leading to adaptation. These mutations allow a higher order metabolic selection that eliminates epistatic bottlenecks, which could occur when many changes would be required. Proteomic and carbohydrate analysis of adapting E. coli populations revealed an up-regulation of enzymes associated with the TCA cycle and amino acid metabolism, and an increase in the secretion of putrescine. The overall effect of adaptation across populations is to redirect and efficiently utilize uptake and catabolism of abundant amino acids. Concomitantly, there is a pronounced spread of more ecologically limited strains that results from specialization through metabolic erosion. Remarkably, the global regulators arcA and rpoS can provide a “one-step” mechanism of adaptation to a novel environment, which highlights the importance of global resource management as a powerful strategy to adaptation.     

Garcimultiflorone G,a Novel Benzoylphloroglucinol Derivative from Garcinia multiflora with Inhibitory Activity on Neutrophil Pro‐Inflammatory Responses

A novel benzoylphloroglucinol derivative, garcimultiflorone G ( 1 ), was isolated from the fruits of Garcinia multiflora. The structure of 1 was determined through extensive 1D‐ and 2D‐NMR, and MS analyses. Garcimultiflorone G ( 1 ) showed inhibitory effects against superoxide anion (O$\rm{{_{2}^{{^\cdot} -}}}$ ) generation and elastase release by human neutrophils in response to formyl‐L ‐methionyl‐L ‐leucyl‐L ‐phenylalanine/cytochalasin B (fMLP/CB), with IC₅₀ values of 6.97±1.56 and 11.70±1.58 μM , respectively.     

The Association between Atrium Electromechanical Interval and Pericardial Fat

Objectives

Pericardial fat (PCF) may induce local inflammation and subsequent structural remodeling of the left atrium (LA). However, the adverse effects of PCF on LA are difficult to be evaluated and quantified. The atrial electromechanical interval determined by transthoracic echocardiogram was shown to be a convenient parameter which can reflect the process of LA remodeling. The goal of the present study was to investigate the association between the electromechanical interval and PCF.

Methods and Results

A total of 337 patients with mean age of 51.9±9.0 years were enrolled. The electromechanical interval (PA-PDI) defined as the time interval from the initiation of the P wave deflection to the peak of the mitral inflow A wave on the pulse wave Doppler imaging was measured for every patient. The amount of PCF was determined by multi-detector computed tomography. The PA-PDI interval was significantly correlated with the amount of PCF (r = 0.641, p value <0.001). Graded prolongation of PA-PDI interval was observed across 3 groups of patients divided according to the tertile values of PCF. The AUC for the PA-PDI interval in predicting an increased amount of PCF (third tertile) was 0.796. At a cutoff value of 130 ms identified by the ROC curve, the sensitivity and specificity of PA-PDI interval in identifying patients with a highest tertile of PCF were 63.4% and 85.3%, respectively.

Conclusions

The PA-PDI intervals were longer in patients with an increased amount of PCF. It may be a useful parameter to represent the degree of PCF-related atrial remodeling.     

Atrial fibrillation pacing decreases intravascular shear stress in a New Zealand white rabbit model: implications in endothelial function

Atrial fibrillation (AF) is characterized by multiple rapid and irregular atrial depolarization, leading to rapid ventricular responses exceeding 100 beats per minute (bpm). We hypothesized that rapid and irregular pacing reduced intravascular shear stress (ISS) with implication to modulating endothelial responses. To simulate AF, we paced the left atrial appendage of New Zealand White rabbits (n = 4) at rapid and irregular intervals. Surface electrical cardiograms were recorded for atrial and ventricular rhythm, and intravascular convective heat transfer was measured by microthermal sensors, from which ISS was inferred. Rapid and irregular pacing decreased arterial systolic and diastolic pressures (baseline, 99/75 mmHg; rapid regular pacing, 92/73; rapid irregular pacing, 90/68; p < 0.001, n = 4), temporal gradients ( ${\partial\tau/\partial t}$ from 1,275 ± 80 to 1,056 ± 180 dyne/cm² s), and reduced ISS (from baseline at 32.0 ± 2.4 to 22.7 ± 3.5 dyne/cm²). Computational fluid dynamics code demonstrated that experimentally inferred ISS provided a close approximation to the computed wall shear stress at a given catheter to vessel diameter ratio, shear stress range, and catheter position. In an in vitro flow system in which time-averaged shear stress was maintained at ${{\tau_{\rm avg}} = 23 \pm 4\, {\rm dyn}\, {\rm cm}^{-2} {\rm s}^{-1}}$ , we further demonstrated that rapid pulse rates at 150 bpm down-regulated endothelial nitric oxide, promoted superoxide (O ₂ ^.? ) production, and increased monocyte binding to endothelial cells. These findings suggest that rapid pacing reduces ISS and ${\partial\tau/\partial t}$ , and rapid pulse rates modulate endothelial responses.