Isomaltodextrin,a highly branched α-glucan,increases rat colonic H2 production as well as indigestible dextrin

Colonic hydrogen (H₂) protects against inflammation-induced oxidative stress. We examined the effect of a new highly branched α-glucan, isomaltodextrin (IMD), on colonic H₂ production in rats. Rats were fed a 16.7% IMD, 8.8% indigestible dextrin (ID), or 10.4% high amylose cornstarch diet (Expt. 1), were fed diets containing 3.3–16.7% IMD (Expt. 2), or were fed diets containing 16.7% IMD or 5.2% fructooligosaccharide (FOS) (Expt. 3), for 14 days. Compared with the control group, feeding IMD or other α-glucans dose dependently and significantly increased H₂ excretion and portal H₂ concentration. The ability of IMD to increase H₂ production was not inferior to that of FOS. The cecal Firmicutes/Bacteroidetes ratio in the IMD group was 5–14% of that in the control group. The cecal abundance of bifidobacteria was significantly greater in the IMD group than in the control group. Taken together, IMD, as well as other α-glucans, significantly increased colonic H₂ production in a dose-dependent manner.     

Intrauterine growth retardation, mild frontonasal dysplasia, phocomelic upper limbs with absent thumbs and a variety of internal malformations including choanal atresia, congenital heart defects, polysplenia, absent gall bladder as well as genitourinary anomalies. A possibly "new" MCA syndrome?

Report on a female infant who showed intrauterine growth retardation; dysmorphic face with relative macrocephaly, mild frontonasal dysplasia, and small dysmorphic ears; phocomelic upper limbs with absent thumbs and radiologically poor differentiation of the long tubular bones but normal lower limbs. Autopsy revealed multiple internal abnormalities including choanal atresia, complex heart malformation, bilobed lung on the right, polysplenia, absent gall bladder as well as genitourinary anomalies. This condition represents a possibly "new" MCA syndrome with poor prognosis and yet unknown etiology.     

“Make Everything as Simple as Possible,But Not Simpler”: A Simple Approach is as Good as a Complex Algorithm for Insulin Dose Self-Adjustment

Abbreviations:A1c = glycated hemoglobin A1cDM2 = type 2 diabetes mellitusRCT = randomized controlled trialSMBG = self-monitoring blood glucose     

Fluorinated N,N′-diarylureas as AMPK activators

Adenosine monophosphate-activated kinase (AMPK) plays a central role in regulating energy homeostasis in eukaryotic cells. AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and regulates mTOR signaling by activating TSC2. Due to its important roles in cell metabolism, AMPK is an attractive target for metabolic diseases, such as type II diabetes and obesity. AMPK activators, such as metformin, that are used for diabetes treatment are also effective anticancer agents. However, the efficacies of many known AMPK activators are relatively low. For example, metformin activates AMPK at millimolar levels. In this study, we identified a novel family of AMPK activators, namely fluorinated N,N′-diarylureas, that activate AMPK at 1–3 μM concentrations. These novel agents strongly inhibit the proliferation of colon cancer cells. We studied the potential mechanisms of these agents, performed a structure–activity relationship (SAR) study and identified several fluorinated N,N′-diarylureas as potent AMPK activators.     

The Cell and Protoplasm as Container,Object, and Substance, 1835–1861

This article revisits the development of the protoplasm concept as it originally arose from critiques of the cell theory, and examines how the term “protoplasm” transformed from a botanical term of art in the 1840s to the so-called “living substance” and “the physical basis of life” two decades later. I show that there were two major shifts in biological materialism that needed to occur before protoplasm theory could be elevated to have equal status with cell theory in the nineteenth century. First, I argue that biologists had to accept that life could inhere in matter alone, regardless of form. Second, I argue that in the 1840s, ideas of what formless, biological matter was capable of dramatically changed: going from a “coagulation paradigm” (Pickstone, 1973) that had existed since Theophrastus, to a more robust conception of matter that was itself capable of movement and self-maintenance. In addition to revisiting Schleiden and Schwann’s original writings on cell theory, this article looks especially closely at Hugo von Mohl’s definition of the protoplasm concept in 1846, how it differed from his primordial utricle theory of cell structure two years earlier. This article draws on Lakoff and Johnson’s theory of “ontological metaphors” to show that the cell, primordial utricle, and protoplasm can be understood as material container, object, and substance, and that these overlapping distinctions help explain the chaotic and confusing early history of cell theory.     

Starch-binding domains as CBM families–history,occurrence, structure,function and evolution

The term “starch-binding domain” (SBD) has been applied to a domain within an amylolytic enzyme that gave the enzyme the ability to bind onto raw, i.e. thermally untreated, granular starch. An SBD is a special case of a carbohydrate-binding domain, which in general, is a structurally and functionally independent protein module exhibiting no enzymatic activity but possessing potential to target the catalytic domain to the carbohydrate substrate to accommodate it and process it at the active site. As so-called families, SBDs together with other carbohydrate-binding modules (CBMs) have become an integral part of the CAZy database (http://www.cazy.org/). The first two well-described SBDs, i.e. the C-terminal Aspergillus-type and the N-terminal Rhizopus-type have been assigned the families CBM20 and CBM21, respectively. Currently, among the 85 established CBM families in CAZy, fifteen can be considered as families having SBD functional characteristics: CBM20, 21, 25, 26, 34, 41, 45, 48, 53, 58, 68, 69, 74, 82 and 83. All known SBDs, with the exception of the extra long CBM74, were recognized as a module consisting of approximately 100 residues, adopting a β-sandwich fold and possessing at least one carbohydrate-binding site. The present review aims to deliver and describe: (i) the SBD identification in different amylolytic and related enzymes (e.g., CAZy GH families) as well as in other relevant enzymes and proteins (e.g., laforin, the β-subunit of AMPK, and others); (ii) information on the position in the polypeptide chain and the number of SBD copies and their CBM family affiliation (if appropriate); (iii) structure/function studies of SBDs with a special focus on solved tertiary structures, in particular, as complexes with α-glucan ligands; and (iv) the evolutionary relationships of SBDs in a tree common to all SBD CBM families (except for the extra long CBM74). Finally, some special cases and novel potential SBDs are also introduced.     

How specific are "target-specific" drugs? Celecoxib as a case in point

With the push to develop the next blockbuster drugs, continued surveillance of current bestsellers may not be given the full attention due. Upon wide-spread use, unexpected adverse effects begin to emerge. Although touted as highly specific, many of the newly developed drugs are likely to have secondary molecular targets-a potential cause of adverse effects. A molecular pharmacology approach that screens for multiple drug targets may shed light on the mechanisms that underlie both desired and adverse side-effects.     

Design,synthesis, and evaluation of novel l-phenylglycine derivatives as potential PPARγ lead compounds

In accordance with the structural characteristics of thiazolidinedione drugs and highly bioactive tyrosine derivatives, we tentatively designed the l-phenylglycine derivatives TM1 and TM2 based on basic principles of drug design and then synthesized them. The in vitro screening of peroxisome proliferator-activated receptor gamma (PPARγ) activated activity, α-glucosidase inhibitory and dipeptidyl peptidase-4 inhibitory activities showed that the novel molecule M5 had efficient PPAR response element (PPRE) activated activity (PPRE relative activity 105.04% at 10?μg·mL^?1 compared with the positive control pioglitazone, with 100% activity). Therefore, M5 was selected as the hit compound from which the TM3 and TM4 series of compounds were further designed and synthesized. Based on the PPRE relative activities of TM3 and TM4, we discovered another new molecule, TM4h, which had the strongest PPRE relative activity (120.42% at 10?μg·mL^?1). In addition, the concentration-dependent activity of the highly active compounds was determined by assaying their half-maximal effective concentration (EC₅₀) values. The molecular physical parameter calculation and the molecular toxicity prediction were used to theoretically evaluate the lead-likeness and safety of the active compounds. In conclusion, we identified a potential PPARγ lead molecule and developed a tangible strategy for antidiabetic drug development.     

Women tolerate drug therapy for coronary artery disease as well as men do,but are treated less frequently with aspirin, β-blockers,or statins

Background: Women have worse morbidity, mortality, and health-related quality-of-life outcomes associated with coronary artery disease (CAD) compared with men. This may be related to underutilization of drug therapies, such as aspirin, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, or statins. No studies have sought to describe the relationship of gender with adverse reactions to drug therapy (ADRs) for CAD in clinical practice.Objective: The aim of this study was to determine the prevalence of ADRs associated with common CAD drug therapies in women and men in clinical practice.Methods: In a cohort of consecutive outpatients with CAD, detailed chart abstraction was performed to determine the use of aspirin, β-blocker, ACE inhibitor, and statin therapy, as well as the ADRs reported for these treatments. Baseline clinical characteristics were also determined to identify the independent association of gender with use of standard drug treatments for CAD.Results: Consecutive patients with CAD (153 men, 151 women) were included in the study. Women and men were observed to have a similar prevalence of cardiac risk factors and comorbidities, except that men had significantly higher prevalence of atrial fibrillation (30 [19.6%] men vs 15 [9.9%] women; P = 0.03) and significantly lower mean (SD) high-density lipoprotein cholesterol concentrations (45 [16] mg/dL for men vs 55 [19] mg/dL for women; P < 0.001). No significant differences were observed between the sexes in the prevalence of ADRs; however, significantly fewer women than men were treated with statins (118 [78.1%] vs 139 [90.8%], respectively; P = 0.003). After adjusting for clinical characteristics, women were also found to be less likely than men to receive aspirin (odds ratio [OR] = 0.164; 95% CI, 0.083–0.322; P = 0.001) and β-blockers (OR = 0.184; 95% CI, 0.096-0.351; P = 0.001).Conclusions: Women and men experienced a similar prevalence of ADRs in the treatment of CAD; however, women were significantly less likely to be treated with aspirin, β-blockers, and statins than were their male counterparts. To optimize care for women with CAD, further study is needed to identify the cause of this gender disparity in therapeutic drug use.     

Design,synthesis, and evaluation of simple phenol amides as ERRγ agonists

Herein we report the design and synthesis of a series of simple phenol amide ERRγ agonists based on a hydrazone lead molecule. Our structure activity relationship studies in this series revealed the phenol portion of the molecule to be required for activity. Attempts to replace the hydrazone with more suitable chemotypes led to a simple amide as a viable alternative. Differential hydrogen-deuterium exchange experiments were used to help understand the structural basis for binding to ERRγ and aid in the development of more potent ligands.     

IL-1β, IL-6, and RANTES as Biomarkers of Chikungunya Severity

Background

Little is known about the immunopathogenesis of Chikungunya virus. Circulating levels of immune mediators and growth factors were analyzed from patients infected during the first Singaporean Chikungunya fever outbreak in early 2008 to establish biomarkers associated with infection and/or disease severity.

Methods and Findings

Adult patients with laboratory-confirmed Chikungunya fever infection, who were referred to the Communicable Disease Centre/Tan Tock Seng Hospital during the period from January to February 2008, were included in this retrospective study. Plasma fractions were analyzed using a multiplex-microbead immunoassay. Among the patients, the most common clinical features were fever (100%), arthralgia (90%), rash (50%) and conjunctivitis (40%). Profiles of 30 cytokines, chemokines, and growth factors were able to discriminate the clinical forms of Chikungunya from healthy controls, with patients classified as non-severe and severe disease. Levels of 8 plasma cytokines and 4 growth factors were significantly elevated. Statistical analysis showed that an increase in IL-1β, IL-6 and a decrease in RANTES were associated with disease severity.

Conclusions

This is the first comprehensive report on the production of cytokines, chemokines, and growth factors during acute Chikungunya virus infection. Using these biomarkers, we were able to distinguish between mild disease and more severe forms of Chikungunya fever, thus enabling the identification of patients with poor prognosis and monitoring of the disease.     

Endemic Mimosa species can serve as mycorrhizal "resource islands" within semiarid communities of the Tehuacán-Cuicatlán Valley,Mexico

This paper explores if Mimosa species (Fabaceae-Mimosoideae) can serve as arbuscular mycorrhizal (AM) and nutrient "resource islands" in six plant communities in the semiarid valley of Tehuacán-Cuicatlán, Mexico. Spatial heterogeneity related to the occurrence of Mimosa species results in temporal differences in AM-fungal spore numbers and soil nutrients. A higher number of AM-fungal spores were found in the soil below the canopies of six endemic Mimosa species than in the soil from non-vegetated areas. For four species, Mimosa adenantheroides, Mimosa calcicola, Mimosa luisana and Mimosa polyantha, the soil below their canopies had more AM-fungal spores than the soil in non-vegetated areas during the wet season than during the dry season. Two species, Mimosa lacerata and Mimosa texana var. filipes, however, had more spores under their canopies during the dry season than during the wet season. Although physical differences are present within and between sites, in general the soil below the canopies of Mimosa species had significantly higher nutrient levels than the soil from non-vegetated areas. Mimosa species thus form "resource islands" that are not only rich in nutrients but also in mycorrhizal propagules. Mimosa species can serve as mycorrhizal "resource islands" by directly affecting AM-fungal spore dynamics and/or by serving as spore-traps. A range of plants associated with Mimosa species may benefit from the higher number of AM propagules. We believe that the use of Mimosa resource islands as an option for biodiversity conservation and for land restoration ought to be considered in the Valley.     

Roles of the volatile terpene, 1,8-cineole,in plant–herbivore interactions: a foraging odor cue as well as a toxin?

Olfaction is an important sense for many animals, yet its role in foraging by herbivores is poorly known. Many plants contain volatile compounds, such as terpenes, that are not only volatile but can be toxic if ingested. Volatile terpenes can be used by herbivores to assess leaf quality, but there is little evidence for whether they are also used as a searching cue. We applied the giving-up density (GUD) framework to examine fine-scale foraging by two free-ranging mammalian herbivores, the brush-tail possum (Trichosurus vulpecula) and the swamp wallaby (Wallabia bicolor), using patches with food and an inedible matrix that varied in content of a volatile terpene, 1,8-cineole. We tested the effect of (1) increasing dietary cineole concentration, and (2) masking the food odor by adding cineole to the inedible matrix, thus overriding the smell released by the diet. In both species GUD was affected by dietary cineole; a high cineole concentration raised GUD, consistent with its role as a toxin. There was a significant effect of masking on GUD for wallabies but not for possums, suggesting that odor was an important foraging cue at the feeding patch only for the former. Differences in ecological niche and diet may explain this pattern. We suggest that herbivores, such as the swamp wallaby, opportunistically eavesdrop on plant volatiles, i.e., take advantage of the signal proffered for a different function. The cost of this eavesdropping for plants, however, is presumably counteracted by other ecological benefits of these volatiles, including a reduction in leaf consumption as a function of toxicity.