A Novel Cell-Penetrating Peptide Derived from Human Eosinophil Cationic Protein

Cell-penetrating peptides (CPPs) are short peptides which can carry various types of molecules into cells; however, although most CPPs rapidly penetrate cells in vitro, their in vivo tissue-targeting specificities are low. Herein, we describe cell-binding, internalization, and targeting characteristics of a newly identified 10-residue CPP, denoted ECP^32–41, derived from the core heparin-binding motif of human eosinophil cationic protein (ECP). Besides traditional emphasis on positively charged residues, the presence of cysteine and tryptophan residues was demonstrated to be essential for internalization. ECP^32–41 entered Beas-2B and wild-type CHO-K1 cells, but not CHO cells lacking of cell-surface glycosaminoglycans (GAGs), indicating that binding of ECP^32–41 to cell-surface GAGs was required for internalization. When cells were cultured with GAGs or pre-treated with GAG-digesting enzymes, significant decreases in ECP^32–41 internalization were observed, suggesting that cell-surface GAGs, especially heparan sulfate proteoglycans were necessary for ECP^32–41 attachment and penetration. Furthermore, treatment with pharmacological agents identified two forms of energy-dependent endocytosis, lipid-raft endocytosis and macropinocytosis, as the major ECP^32–41 internalization routes. ECP^32–41 was demonstrated to transport various cargoes including fluorescent chemical, fluorescent protein, and peptidomimetic drug into cultured Beas-2B cells in vitro, and targeted broncho-epithelial and intestinal villi tissues in vivo. Hence this CPP has the potential to serve as a novel vehicle for intracellular delivery of biomolecules or medicines, especially for the treatment of pulmonary or gastrointestinal diseases.     

Sarcopenia Is Independently Associated with Cardiovascular Disease in Older Korean Adults: The Korea National Health and Nutrition Examination Survey (KNHANES) from 2009

Background

The association between sarcopenia and cardiovascular disease (CVD) in elderly people has not been adequately assessed. The aim of this study was to investigate whether CVD is more prevalent in subjects with sarcopenia independent of other well-established cardiovascular risk factors in older Korean adults.

Method

This study utilized the representative Korean population data from the Korea National Health and Nutrition Examination Survey (KNHANES) which was conducted in 2009. Subjects older than 65 years of age with appendicular skeletal muscle mass (ASM) determined by dual energy X-ray absorptiometry were selected. The prevalence of sarcopenia in the older Korean adults was investigated, and it was determined whether sarcopenia is associated with CVD independent of other well-known risk factors.

Results

1,578 subjects aged 65 years and older with the data for ASM were selected, and the overall prevalence of sarcopenia was 30.3% in men and 29.3% in women. Most of the risk factors for CVD such as age, waist circumference, body mass index, fasting plasma glucose and total cholesterol showed significant negative correlations with the ratio between appendicular skeletal muscle mass and body weight. Multiple logistic regression analysis demonstrated that sarcopenia was associated with CVD independent of other well-documented risk factors, renal function and medications (OR, 1.768; 95% CI, 1.075–2.909, P = 0.025).

Conclusions

Sarcopenia was associated with the presence of CVD independent of other cardiovascular risk factors after adjusting renal function and medications.     

Divergent Selection and Local Adaptation in Disjunct Populations of an Endangered Conifer,Keteleeria davidiana var. formosana (Pinaceae)

The present study investigated the genetic diversity, population structure, F _ST outliers, and extent and pattern of linkage disequilibrium in five populations of Keteleeria davidiana var. formosana, which is listed as a critically endangered species by the Council of Agriculture, Taiwan. Twelve amplified fragment length polymorphism primer pairs generated a total of 465 markers, of which 83.74% on average were polymorphic across populations, with a mean Nei’s genetic diversity of 0.233 and a low level of genetic differentiation (approximately 6%) based on the total dataset. Linkage disequilibrium and HICKORY analyses suggested recent population bottlenecks and inbreeding in K. davidiana var. formosana. Both STRUCTURE and BAPS observed extensive admixture of individual genotypes among populations based on the total dataset in various clustering scenarios, which probably resulted from incomplete lineage sorting of ancestral variation rather than a high rate of recent gene flow. Our results based on outlier analysis revealed generally high levels of genetic differentiation and suggest that divergent selection arising from environmental variation has been driven by differences in temperature, precipitation, and humidity. Identification of ecologically associated outliers among environmentally disparate populations further support divergent selection and potential local adaptation.     

Band Edge Engineering of Oxide Photoanodes for Photoelectrochemical Water Splitting: Integration of Subsurface Dipoles with Atomic‐Scale Control

One of the crucial parameters dictating the efficiency of photoelectrochemical water‐splitting is the semiconductor band edge alignment with respect to hydrogen and oxygen redox potentials. Despite the importance of metal oxides in their use as photoelectrodes, studies to control the band edge alignment in aqueous solution have been limited predominantly to compound semiconductors with modulation ranges limited to a few hundred mV. The ability to modulate the flat band potential of oxide photoanodes by as much as 1.3 V, using the insertion of subsurface electrostatic dipoles near a Nb‐doped SrTiO₃/aqueous electrolyte interface is reported. The tunable range achieved far exceeds previous reports in any semiconductor/aqueous electrolyte system and suggests a general design strategy for highly efficient oxide photoelectrodes.     

Model of cellular mechanotransduction via actin stress fibers

Mechanical stresses due to blood flow regulate vascular endothelial cell structure and function and play a key role in arterial physiology and pathology. In particular, the development of atherosclerosis has been shown to correlate with regions of disturbed blood flow where endothelial cells are round and have a randomly organized cytoskeleton. Thus, deciphering the relation between the mechanical environment, cell structure, and cell function is a key step toward understanding the early development of atherosclerosis. Recent experiments have demonstrated very rapid (\(\sim \)100 ms) and long-distance (\(\sim \)10 \(\upmu \)m) cellular mechanotransduction in which prestressed actin stress fibers play a critical role. Here, we develop a model of mechanical signal transmission within a cell by describing strains in a network of prestressed viscoelastic stress fibers following the application of a force to the cell surface. We find force transmission dynamics that are consistent with experimental results. We also show that the extent of stress fiber alignment and the direction of the applied force relative to this alignment are key determinants of the efficiency of mechanical signal transmission. These results are consistent with the link observed experimentally between cytoskeletal organization, mechanical stress, and cellular responsiveness to stress. Based on these results, we suggest that mechanical strain of actin stress fibers under force constitutes a key link in the mechanotransduction chain.     

Core-satellite populations and seasonality of water meter biofilms in a metropolitan drinking water distribution system

Drinking water distribution systems (DWDSs) harbor the microorganisms in biofilms and suspended communities, yet the diversity and spatiotemporal distribution have been studied mainly in the suspended communities. This study examined the diversity of biofilms in an urban DWDS, its relationship with suspended communities and its dynamics. The studied DWDS in Urbana, Illinois received conventionally treated and disinfected water sourced from the groundwater. Over a 2-year span, biomass were sampled from household water meters (n=213) and tap water (n=20) to represent biofilm and suspended communities, respectively. A positive correlation between operational taxonomic unit (OTU) abundance and occupancy was observed. Examined under a ‘core-satellite'' model, the biofilm community comprised 31 core populations that encompassed 76.7% of total 16 S rRNA gene pyrosequences. The biofilm communities shared with the suspended community highly abundant and prevalent OTUs, which related to methano-/methylotrophs (i.e., Methylophilaceae and Methylococcaceae) and aerobic heterotrophs (Sphingomonadaceae and Comamonadaceae), yet differed by specific core populations and lower diversity and evenness. Multivariate tests indicated seasonality as the main contributor to community structure variation. This pattern was resilient to annual change and correlated to the cyclic fluctuations of core populations. The findings of a distinctive biofilm community assemblage and methano-/methyltrophic primary production provide critical insights for developing more targeted water quality monitoring programs and treatment strategies for groundwater-sourced drinking water systems.     

Gender Difference in the Epidemiological Association between Metabolic Syndrome and Olfactory Dysfunction: The Korea National Health and Nutrition Examination Survey

Metabolic syndrome (MetS) is associated with a higher risk of morbidity and/or mortality for various chronic diseases. The aim of this study was to investigate the relationships of MetS and its components with olfactory dysfunction in a representative Korean population. We analyzed the data from the Korean National Health and Nutrition Examination Survey (2008–2010). A total of 11,609 adults who underwent otolaryngological examination were evaluated. The olfactory function was classified as normosmia or hyposmia by a self-report questionnaire according to the sense problems of smell during the past 3 months. MetS was diagnosed if a participant had at least three of the following: (1) WC ≥90 cm in men and ≥80 cm in women; (2) fasting blood sugar ≥ 100 mg/dL or medication use for elevated glucose; (3) fasting triglyceride ≥ 150 mg/dL or cholesterol-lowering medication use; (4) HDL-cholesterol <40 mg/dL in men and <50 mg/dL in women or cholesterol-lowering medication use; and (5) SBP ≥ 130 mmHg and/or DBP ≥ 85 mmHg or antihypertensive drug use for patients with a history of hypertension. The prevalence of olfactory dysfunction in the study population was 6.3%. The prevalence of olfactory dysfunction was significantly higher in older people with MetS than in those without MetS in both sexes (male, 42.0 ± 3.4% vs. 34.7 ± 0.9%, p = 0.0354; female, 46.2 ± 2.8% vs. 37.8 ± 0.8%, p = 0.0026). However, elevated waist circumference, elevated fasting glucose, elevated triglycerides, reduced HDL cholesterol, elevated blood pressure, severe stress, depressed mood, and suicidal ideation were significantly associated with olfactory dysfunction only in women. After controlling for confounders, olfactory dysfunction was significantly associated with MetS (odds ratio, 1.352; 95% confidence interval, 1.005–1.820) only in women. MetS are associated with olfactory dysfunction only in Korean women.     

An extract of Ulmus macrocarpa improves cellular immunity in immuno-suppressed models

An extract of Ulmus macrocarpa Hance, commonly known as the large-fruited elm, has been prescribed as a traditional medicine. In this study, we aimed to investigate the cellular immune effects of U. macrocarpa stem cortex extracts on cyclophosphamide (CY)-treated splenocytes and mice. A methanol extract showed an improved survival rate of splenocytes after 72?h. The extract was successively partitioned with dichloromethane, ethyl acetate, n-butanol, and water; and the fractions so obtained were also examined for their proliferative activity. Among them, the water fraction of U. macrocarpa showed the highest proliferation of splenocytes and was used throughout the present study. We tested the survival rate of splenocytes through dose-dependent treatment of CY and the suppression of the survival effect by CY was recovered by treatment with the water extract of U. macrocarpa. To determine the mechanism involved, we examined the expression of B-cell lymphoma-extra large (Bcl-xL) anti-apoptotic protein. CY decreased Bcl-xL protein levels in resting splenocyte cultures, whereas splenocytes were exposed to water extracts of U. macrocarpa in the presence of CY; however, elevations in Bcl-xL were observed at 96?h. Mice splenocytes treated with water extract of U. macrocarpa for cellular immunity showed an increase in the activity of the mixed lymphocyte reaction (MLR), cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. In addition, mice receiving a water extract of U. macrocarpa recovered the CTL, NK, and MLR activities suppressed by CY administration. Consequently, U. macrocarpa improves the cell-mediated immune response and provides an insight on cell-based tonic materials.     

Prognostic Value of Lactate and Central Venous Oxygen Saturation after Early Resuscitation in Sepsis Patients

The objective of this study was to evaluate the prognostic value of static and dynamic variables of central venous oxygen saturation (ScvO₂) and lactate in patients with severe sepsis or septic shock who underwent early quantitative resuscitation. We also investigated whether ScvO₂ measured after initial resuscitation could provide additive prognostic value to that of lactate. We analyzed the sepsis registry for patients presenting to the emergency department and included patients with simultaneous measurements of lactate and ScvO₂ at the time of presentation (H0) and 6 hours (H6) after resuscitation. The primary outcome was 28-day mortality and multivariable logistic analysis was used to adjust for confounders. A total of 363 patients were included, and the overall 28-day mortality was 18%. The area under the receiver operator characteristic curve for predicting 28-day mortality was as follows: lactate (H6), 0.81; lactate (H0), 0.73; relative lactate change, 0.67; ScvO₂ (H6), 0.65; relative ScvO₂ change 0.59; ScvO₂ (H0), 0.58. Patients with lactate normalization showed significantly lower 28-day mortality compared to patients without lactate normalization (3% vs. 28%, P<0.01). However, in those who achieved ScvO₂ (H6) ≥70%, there was a significant difference in 28-mortality only in patients without lactate normalization (21% vs. 39%, P<0.01) but no difference in those with lactate normalization (4% vs. 3%, P = 0.71). In multivariable analysis, lactate normalization was significantly associated with 28-day mortality (adjusted odds ratio [OR] for 28-day mortality, 0.20; 95% confidence interval [CI], 0.07–0.54; P <0.01), but ScvO₂ (H6) ≥70% showed only a marginal association (the adjusted OR for 28-day mortality, 0.51; 95% CI, 0.26–1.01; P = 0.05). ScvO₂ (H6) ≥70% was associated with 28-day mortality only in cases without lactate normalization in subgroup analysis (adjusted OR 0.37, 95% CI, 0.18–0.79; P = 0.01). Six-hour lactate was the strongest predictor of 28-day mortality in patients with severe sepsis or septic shock. Six-hour ScvO₂ provided additional prognostic value only in cases where lactate values were not normalized after resuscitation.