Miracle-dz/UniFAR-FTUs huggingface dataset:
RAS residues that are distant from the GDP binding site play a critical role in dissociation factor‐stimulated release of GDP.

We have previously shown that a conserved glycine at position 82 of the yeast RAS2 protein is involved in the conversion of RAS proteins from the GDP‐ to the GTP‐bound form. We have now investigated the role of glycine 82 and neighbouring amino acids of the distal switch II region in the physiological mechanism of activation of RAS. We have introduced single and double amino acid substitutions at positions 80–83 of the RAS2 gene, and we have investigated the interaction of the corresponding proteins with a yeast GDP dissociation stimulator (SDC25 C‐domain). Using purified RAS proteins, we have found that the SDC25‐stimulated conversion of RAS from the GDP‐bound inactive state to the GTP‐bound active state was severely impaired by amino acid substitutions at positions 80–81. However, the rate and the extent of conversion from the GDP‐ to the GTP‐bound form in the absence of dissociation factor was unaffected. The insensitivity of the mutated proteins to the dissociation factor in vitro was paralleled by an inhibitory effect on growth in vivo. The mutations did not significantly affect the interaction of RAS with adenylyl cyclase. These findings point to residues 80–82 as important determinants of the response of RAS to GDP dissociation factors. This suggests a molecular model for the enhancement of nucleotide release from RAS by such factors.
The effects of frozen tissue storage conditions on the integrity of RNA and protein

Abstract Unfixed tissue specimens most frequently are stored for long term research uses at either −80° C or in vapor phase liquid nitrogen (VPLN). There is little information concerning the effects such long term storage on tissue RNA or protein available for extraction. Aliquots of 49 specimens were stored for 5–12 years at −80° C or in VPLN. Twelve additional paired specimens were stored for 1 year under identical conditions. RNA was isolated from all tissues and assessed for RNA yield, total RNA integrity and mRNA integrity. Protein stability was analyzed by surface-enhanced or matrix-assisted laser desorption ionization time of flight mass spectrometry (SELDI-TOF-MS, MALDI-TOF-MS) and nano-liquid chromatography electrospray ionization tandem mass spectrometry (nLC-ESI-MS/MS). RNA yield and total RNA integrity showed significantly better results for −80° C storage compared to VPLN storage; the transcripts that were preferentially degraded during VPLN storage were these involved in antigen presentation and processing. No consistent differences were found in the SELDI-TOF-MS, MALDI-TOF-MS or nLC-ESI-MS/MS analyses of specimens stored for more than 8 years at −80° C compared to those stored in VPLN. Long term storage of human research tissues at −80° C provides at least the same quality of RNA and protein as storage in VPLN.
Chronic alcohol overconsumption may alter gut microbial metabolism: a retrospective study of 719 13C-D-xylose breath test results

ABSTRACT Objective: Alterations of gut microbiota composition or function may participate in the pathophysiology of several diseases. We aimed to explore the effect of chronic alcohol overconsumption on gut microbial metabolism, as assessed by evaluating 13C-D-xylose breath test results. Materials and methods: We investigated all 13C-D-xylose breath tests performed at Lovisenberg Diaconal Hospital during the years 2005 to 2011, using patient files for diagnosing the patients into one of three patient categories: alcohol overconsumption, coeliac disease and functional bowel disorder. In addition, a group of healthy controls was included. The time curves of 13CO2 excretion in breath samples were divided into two phases, evaluating small intestinal absorption (0–60 min) and colonic microbial metabolism (90–240 min), respectively. Results: A total of 719 patients underwent 13C-D-xylose breath testing during the inclusion period. Thirty-five had a history of alcohol overconsumption, 66 had coeliac disease, and 216 had a functional bowel disorder, while 44 healthy controls were included for comparison. The alcohol overconsumption group had similar small intestinal phase results as the group of patients with untreated coeliac disease. During the colonic phase, the group of patients with alcohol overconsumption differed from all the other groups in terms of 13C-xylose recovery, with significantly less 13CO2 excretion compared to the other groups. Conclusion: The results suggest that patients with a history of alcohol overconsumption suffer from both small intestinal malabsorption and impaired colonic microbial metabolism. The role of gut microbiota in chronic alcohol overconsumption should be investigated further.
Anatomic Study of Femoral Patellar Groove in Fetus

The authors performed a biometric analysis of the femoral patellar groove in fetus and compared their findings with those observed in adults. Forty-four formalin-preserved fetuses were studied (13-38 weeks). Digitalized images were used to obtain measurements (α angle of the groove, trochlear slopes &thetas;L and &thetas;M). A comparison of means of independent samples between our series and adults was performed. For each angle of the distal epiphysis (α, &thetas;L, &thetas;M) there was no significant difference between this fetal series and adults. This is the first biometry of the fetal patellar groove. The morphology of the lower femur appears to be the same in fetus and adults. The results of this study suggest that the anatomic characteristics of the patellar groove could have been integrated into the genome during the course of evolution. This would be in favor of a genetic origin of patellar groove dysplasia.
Hypoactive Sexual Desire Disorder and Current Pharmacotherapeutic Options in Women

Hypoactive Sexual Desire Disorder (HSDD) is the most common female sexual dysfunction. The diagnosis of HSDD requires the existence of personal distress or interpersonal difficulties associated with low sexual desire, that cannot be explained by any other psychiatric affection and that is not exclusively due to a disease or substance. HSDD can have a serious effect on emotional wellbeing and interpersonal relationships, and it occurs in premenopausal and postmenopausal women. The Decreased Sexual Desire Screener is a shortened diagnostic method designed to help doctors who are not specialized in female sexual dysfunction to diagnose acquired HSDD in women. There is evidence that treatment with androgens or with estrogens is effective in HSDD; however, important unanswered questions still exist. Presently, new therapeutic strategies to combat HSDD are being researched, including novel methods of testosterone provision and drugs that act upon the CNS.
Limits to Speciation Inferred from Times to Secondary Sympatry and Ages of Hybridizing Species along a Latitudinal Gradient

Range expansions are critical to renewed bouts of allopatric or parapatric speciation. Limits on range expansions—and, by implication, speciation—include dispersal ability and permeability of geographical barriers. In addition, recently diverged taxa may interfere with each other, preventing mutual expansion of each other’s range into sympatry, because reproductive isolation is incomplete and/or ecological competition particularly strong. On the basis of geographical distributions and mitochondrial DNA phylogenetic information for 418 recently diverged species of New World birds, we estimate that secondary sympatry takes on the order of millions of years following population splitting and hence could impose an important limit on the rate of range expansion, thereby limiting further rounds of species formation. Average rates of achievement of sympatry have been faster in the temperate region (we estimate 1.7 million years to sympatry at 60°) than in the tropics (3.2 million years to sympatry at the equator). Evidence from the ages of species with hybrid zones implies that one factor associated with the slowed sympatry in the tropics is the rate of accumulation of reproductive isolation.
Regulation of Ribosome Detachment from the Mammalian Endoplasmic Reticulum Membrane*

In current models, protein translocation in the endoplasmic reticulum (ER) occurs in the context of two cycles, the signal recognition particle (SRP) cycle and the ribosome cycle. Both SRP and ribosomes bind to the ER membrane as a consequence of the targeting process of translocation. Whereas SRP release from the ER membrane is regulated by the GTPase activities of SRP and the SRP receptor, ribosome release from the ER membrane is thought to occur in response to the termination of protein synthesis. We report that ER-bound ribosomes remain membrane-bound following the termination of protein synthesis and in the bound state can initiate the translation of secretory and cytoplasmic proteins. Two principal observations are reported. 1) Membrane-bound ribosomes engaged in the synthesis of proteins lacking a signal sequence are released from the ER membrane as ribosome-nascent polypeptide complexes. 2) Membrane-bound ribosomes translating secretory proteins can access the translocon in an SRP receptor-independent manner. We propose that ribosome release from the ER membrane occurs in the context of protein translation, with release occurring by default in the absence of productive nascent polypeptide-membrane interactions.
Effects of Tetracyclines on Neutrophil, Gingival, and Salivary Collagenases

The characterization and regulation of matrix metalloproteinases (MMPs) have been studied to determine their role(s) in periodontal tissue destruction. Progress in elucidating the roles of MMPs in periodontal tissue destruction has led to a new concept involving the chemotherapeutic inhibition on MMPs, a therapeutic strategy which less than a decade ago was considered "a difficult and perhaps impossible task. " Tetracyclines/doxycycline (DOXY) and their chemically modified nonantimicrobial derivatives (CMTs) are known to inhibit the matrix metalloproteinases, especially preferring human neutrophil collagenase (MMP-8), and prevent the oxidative activation of procollagenases. We characterized by Western blotting the molecular forms and cellular sources of gingival tissue, dental plaque, gingival crevicular fluid (GCF), and salivary MMPs associated with periodontitis. Also the molecular forms of tissue inhibitors of matrix metalloproteinases (TIMP-1 and TIMP-2) in periodontitis were studied by Western blot. Neutrophil (PMN)-derived MMPs were found to predominate in periodontitis, and phospholipase C present in increased amounts in periodontitis sites was found to be a potential inducer of PMN degranulation. We further studied the effects of DOXY on molecular forms of different latent and active MMPs purified from different cellular sources (PMNs, fibroblasts, keratinocytes) and present in vivo in oral exudates (gingival extracts, GCF, and saliva). DOXY inhibition of activated (oxidatively or proteolytically) MMPs were not associated with MMP fragmentation. Michaelis-Menten plots of initial rates of degradation of soluble type I collagen revealed an apparent Km value of 0.3-0.6 microM for MMP-8, and 75 microM DOXY inhibited MMP-8 in a manner which did not result in changes in apparent Km value but did prevent the initial degradation reaching Vmax providing evidence for noncompetitive inhibition. Treatment of patients with long-term DOXY medication results in decreased MMP-8 activities/levels in gingival tissue, crevicular fluid, and saliva, but not fragmentation of MMP-8 in vivo. These data further support and extend the key role of PMN-MMPs in periodontitis, and the activities of these PMN MMPs can be inhibited directly by therapeutic levels of DOXY.
Improving the Prevention of Cardiovascular Disease in Primary Health Care: The Model for Prevention Study Protocol

Background Cardiovascular disease (CVD) is the leading cause of death globally, and accounted for nearly 31% of all deaths in Australia in 2011. The primary health care sector is at the frontline for addressing CVD, however, an evidence-to-practice gap exists in CVD risk assessment and management. General practice plays a key role in CVD risk assessment and management, but this sector cannot provide ongoing lifestyle change support in isolation. Community-based lifestyle modification services and programs provided outside the general practice setting have a key role in supporting and sustaining health behavior change. Fostering linkages between the health sector and community-based lifestyle services, and creating sustainable systems that support these sectors is important. Objective The objective of the study Model for Prevention (MoFoP) is to take a case study approach to examine a CVD risk reduction intervention in primary health care, with the aim of identifying the key elements required for an effective and sustainable approach to coordinate CVD risk reduction across the health and community sectors. These elements will be used to consider a new systems-based model for the prevention of CVD that informs future practice. Methods The MoFoP study will use a mixed methods approach, comprising two complementary research elements: (1) a case study, and (2) a pre/post quasi-experimental design. The case study will consider the organizations and systems involved in a CVD risk reduction intervention as a single case. The pre/post experimental design will be used for HeartLink, the intervention being tested, where a single cohort of patients between 45 and 74 years of age (or between 35 and 74 years of age if Aboriginal or Torres Strait Islander) considered to be at high risk for a CVD event will be recruited through general practice, provided with enhanced usual care and additional health behavior change support. A range of quantitative and qualitative data will be collected. This will include individual health and well being data collected at baseline and again at 12 months for HeartLink participants, and systems related data collected over the period of the intervention to inform the case study. Results The intervention is currently underway, with results expected in late 2015. Conclusions Gaining a better understanding of CVD prevention in primary health care requires a research approach that can capture and express its complexity. The MoFoP study aims to identify the key elements for effective CVD prevention across the health and community sectors, and to develop a model to better inform policy and practice in this key health priority area for Australia.
Comparison of problem-gambling and non-problem-gambling youths seeking treatment for marijuana abuse.

OBJECTIVE To evaluate the prevalence and correlates of problem gambling (PG) in marijuana-abusing adolescents. METHOD A retrospective analysis was conducted of data collected from participants entering treatment for marijuana abuse in Philadelphia, Pennsylvania, and Hartford, Connecticut, between 1998 and 2000. RESULTS Of 255 adolescents interviewed, 22% experienced gambling problems. Compared with non-problem gamblers (NPGs), PGs were more likely to be male, of African-American ethnicity, and to live in single-parent homes. Multivariate general linear models compared the two groups with respect to psychosocial problems. After controlling for age, gender, and race, differences between the groups emerged in drug use severity, legal difficulties, psychiatric problems, and human immunodeficiency virus risk behaviors. PGs reported a greater frequency of overall drug and alcohol use and greater intensity of marijuana use than their NPG counterparts. They had more illegal activity and greater somatization and anxiety symptoms, as well as higher levels of victimization. Compared with NPGs, PGs also reported more recent sexual partners. CONCLUSIONS These data suggest that PG is common in marijuana-abusing youths and that they have increased psychosocial problems. These data suggest the need for early identification and treatment of PG in substance-abusing adolescents.
Thio Modification of Yeast Cytosolic tRNA Is an Iron-Sulfur Protein-Dependent Pathway

ABSTRACT Defects in the yeast cysteine desulfurase Nfs1 cause a severe impairment in the 2-thio modification of uridine of mitochondrial tRNAs (mt-tRNAs) and cytosolic tRNAs (cy-tRNAs). Nfs1 can also provide the sulfur atoms of the iron-sulfur (Fe/S) clusters generated by the mitochondrial and cytosolic Fe/S cluster assembly machineries, termed ISC and CIA, respectively. Therefore, a key question remains as to whether the biosynthesis of Fe/S clusters is a prerequisite for the 2-thio modification of the tRNAs in both of the subcellular compartments of yeast cells. To elucidate this question, we asked whether mitochondrial ISC and/or cytosolic CIA components besides Nfs1 were involved in the 2-thio modification of these tRNAs. We demonstrate here that the three CIA components, Cfd1, Nbp35, and Cia1, are required for the 2-thio modification of cy-tRNAs but not of mt-tRNAs. Interestingly, the mitochondrial scaffold proteins Isu1 and Isu2 are required for the 2-thio modification of the cy-tRNAs but not of the mt-tRNAs, while mitochondrial Nfs1 is required for both 2-thio modifications. These results clearly indicate that the 2-thio modification of cy-tRNAs is Fe/S protein dependent and thus requires both CIA and ISC machineries but that of mt-tRNAs is Fe/S cluster independent and does not require key mitochondrial ISC components except for Nfs1.
The Double Democratic Deficit*

This chapter will sketch how the EU has reacted to the financial crisis and in particular to the unfolding sovereign debt crisis, revealing major flaws in EMU’s architecture. It will not only address these design flaws but attempt to evaluate the underlying causes, reasons and motives of the architects and decision takers by comparing the more “federalist” Werner Plan with the more “intergovernmental” blueprint of the EMU of the Maastricht Treaty, connect it with the paradigm change on economic governance discussed by Schulmeister in Chap. 2 and show the consequences for the crisis and its management in terms of efficiency, equity and democratic accountability.
Associations between prenatal physical activity, birth weight, and DNA methylation at genomically imprinted domains in a multiethnic newborn cohort

Birth weight is a commonly used indicator of the fetal environment and a predictor of future health outcomes. While the etiology of birth weight extremes is likely multifactorial, epidemiologic data suggest that prenatal physical activity (PA) may play an important role. The mechanisms underlying this association remain unresolved, although epigenetics has been proposed. This study aimed to estimate associations between prenatal PA, birth weight, and newborn DNA methylation levels at differentially methylated regions (DMRs) regulating 4 imprinted genes known to be important in fetal development. Study participants (N = 1281) were enrolled as part of the Newborn Epigenetics Study. Prenatal PA was ascertained using the Pregnancy Physical Activity Questionnaire, and birth weight data obtained from hospital records. Among 484 term mother-infant pairs, imprinted gene methylation levels were measured at DMRs using bisulfite pyrosequencing. Generalized linear and logistic regression models were used to estimate associations. After adjusting for preterm birth and race/ethnicity, we found that infants born to mothers in the highest quartile of total non-sedentary time had lower birth weight compared to infants of mothers in the lowest quartile (β = −81.16, SE = 42.02, P = 0.05). These associations appeared strongest among male infants (β = −125.40, SE = 58.10, P = 0.03). Methylation at the PLAGL1 DMR was related to total non-sedentary time (P < 0.05). Our findings confirm that prenatal PA is associated with reduced birth weight, and is the first study to support a role for imprinted gene plasticity in these associations. Larger studies are required.
Antioxidant properties of the essential oil of Eugenia caryophyllata and its antifungal activity against a large number of clinical Candida species

Many essential oils are known to possess an antioxidant activity and antifungal properties and therefore they potentially act as antimycotic agents. Essential oil of clove (Eugenia caryophyllata) was isolated by hydrodistillation. The chemical composition of the essential oil was analysed by gas chromatography and gas chromatography/mass spectroscopy. The antioxidant effect of the tested oil was evaluated by measuring its 2,2‐diphenyl‐l‐1‐picrylhydrazil radical scavenging ability and the antiradical dose required to cause a 50% inhibition (IC50) was recorded. The antifungal activity of essential oils was evaluated against 53 human pathogenic yeasts using a disc paper diffusion method. Our results show that the major components present in the clove bund oil were eugenol (88.6%), eugenyl acetate (5.6%), β‐caryophyllene (1.4%) and 2‐heptanone (0.9%). The tested essential oil exhibited a very strong radical scavenging activity (IC50 = 0.2 μg ml−1) when compared with the synthetic antioxidant (tert‐butylated hydroxytoluene, IC50 = 11.5 μg ml−1). On the other hand, this species displayed an important antifungal effect against the tested strains. It is clear that clove oil shows powerful antifungal activity; and it can be used as an easily accessible source of natural antioxidants and in pharmaceutical applications.
Metabolic age modelling: the lesson from centenarians

Evolutionary theories of ageing, and data emerging from cellular and molecular biology of ageing, suggested that animals and humans capable of reaching an age close to the extreme limit of the life span should be equipped with a very efficient network of anti‐ageing mechanisms. Indeed several evidences have demonstrated that starting from young to very old subjects, ageing is associated with a progressive remodelling. Thus, a new paradigm, the remodelling theory of age, was proposed. This theory, focusing on the human immune system, suggested that immunosenescence is the net result of the continuous adaptation of the body to the deteriorative changes occurring over time. According to this hypothesis, body resources are continuously optimized, and immunosenescence must be considered a very dynamic process including both loss and gain. Whether the metabolic pathways and the endocrine functions are also part of the age remodelling is not investigated. The aim of this review is to focus on the age‐related changes in metabolic pathways and endocrine functions and to demonstrate that healthy centenarians (HC) represent the best living example of successful age‐remodelling in whom the age remodelling has occurred without problems. In order to design the clinical picture of such successful ageing, anthropometric, endocrine and metabolic characteristics of healthy centenarians (HC), compared with aged subject, have been outlined.
Fourth-quarter Economic Growth and Time-varying Expected Returns

We show that fourth-quarter macroeconomic growth rates strongly predict the returns of the aggregate market, smalland large-cap stocks, portfolios sorted on book-to-market and dividend yields, bond returns, and international stock returns, whereas growth rates during the other quarters do not predict returns. Fourth-quarter economic growth rates contain considerably more information about expected returns than standard variables used in the literature, are robust to the choice of macro variable, and work in-sample, out-of-sample, and in subsamples. To help explain these results, we show that economic growth and growth in consumer confidence are correlated during the fourth quarter, but not during the other quarters: When economic growth is low during the fourth quarter, confidence in the economy is also low such that investors require higher future returns. We discuss rational and behavioral reasons why fourth-quarter economic growth, growth in consumer confidence, and expected returns are related.