Towards a formal description of the collapse approach to the inflationary origin of the seeds of cosmic structure

Inflation plays a central role in our current understanding of the universe. According to the standard viewpoint, the homogeneous and isotropic mode of the inflaton field drove an early phase of nearly exponential expansion of the universe, while the quantum fluctuations (uncertainties) of the other modes gave rise to the seeds of cosmic structure. However, if we accept that the accelerated expansion led the universe into an essentially homogeneous and isotropic space-time, with the state of all the matter fields in their vacuum (except for the zero mode of the inflaton field), we can not escape the conclusion that the state of the universe as a whole would remain always homogeneous and isotropic. It was recently proposed in [A. Perez, H. Sahlmann and D. Sudarsky, "On the quantum origin of the seeds of cosmic structure," Class. Quant. Grav. 23, 2317-2354 (2006)] that a collapse (representing physics beyond the established paradigm, and presumably associated with a quantum-gravity effect a la Penrose) of the state function of the inflaton field might be the missing element, and thus would be responsible for the emergence of the primordial inhomogeneities. Here we will discuss a formalism that relies strongly on quantum field theory on curved space-times, and within which we can implement a detailed description of such a process. The picture that emerges clarifies many aspects of the problem, and is conceptually quite transparent. Nonetheless, we will find that the results lead us to argue that the resulting picture is not fully compatible with a purely geometric description of space-time.Comment: 53 pages, no figures. Revision to match the published versio

CentrosomeDB: a human centrosomal proteins database

Active research on the biology of the centrosome during the past decades has allowed the identification and characterization of many centrosomal proteins. Unfortunately, the accumulated data is still dispersed among heterogeneous sources of information. Here we present centrosome:db, which intends to compile and integrate relevant information related to the human centrosome. We have compiled a set of 383 likely human centrosomal genes and recorded the associated supporting evidences. Centrosome:db offers several perspectives to study the human centrosome including evolution, function and structure. The database contains information on the orthology relationships with other species, including fungi, nematodes, arthropods, urochordates and vertebrates. Predictions of the domain organization of centrosome:db proteins are graphically represented at different sections of the database, including sets of alternative protein isoforms, interacting proteins, groups of orthologs and the homologs identified with blast. Centrosome:db also contains information related to function, gene–disease associations, SNPs and the 3D structure of proteins. Apart from important differences in the coverage of the set of centrosomal genes, our database differentiates from other similar initiatives in the way information is treated and analyzed. Centrosome:db is publicly available at http://centrosome.dacya.ucm.es

Management of Glucocorticoid-Induced Osteoporosis

This review summarizes the available evidence-based data that form the basis for therapeutic intervention and covers the current status of glucocorticoid-induced osteoporosis (GIOP) management, regulatory requirements, and risk-assessment options. Glucocorticoids are known to cause bone loss and fractures, yet many patients receiving or initiating glucocorticoid therapy are not appropriately evaluated and treated. An European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis workshop was convened to discuss GIOP management and to provide a report by a panel of experts. An expert panel reviewed the available studies that discussed approved therapeutic agents, focusing on randomized and controlled clinical trials reporting on bone mineral density and/or fracture risk of at least 48weeks' duration. There is no evidence that GIOP and postmenopausal osteoporosis respond differently to treatments. The FRAX algorithm can be adjusted according to glucocorticoid dose. Available antiosteoporotic therapies such as bisphosphonates and teriparatide are efficacious in GIOP management. Several other agents approved for the treatment of postmenopausal osteoporosis may become available for GIOP. It is advised to stop antiosteoporotic treatment after glucocorticoid cessation, unless the patient remains at increased risk of fracture. Calcium and vitamin D supplementation as an osteoporosis-prevention measure is less effective than specific antiosteoporotic treatment. Fracture end-point studies and additional studies investigating specific subpopulations (pediatric, premenopausal, or elderly patients) would strengthen the evidence base and facilitate the development of intervention thresholds and treatment guideline

Socio-economic status and the risk of developing hand, hip or knee osteoarthritis: a region-wide ecological study

SummaryObjectiveTo determine the association between socio-economic status (SES) and risk of hand, hip or knee osteoarthritis (OA) at a population level.DesignRetrospective ecological study using the System for the Development of Research in Primary Care (SIDIAP) database (primary care anonymized records for >5 million people in Catalonia (Spain)). Urban residents >15 years old (2009–2012) were eligible. Outcomes: Validated area-based SES deprivation index MEDEA (proportion of unemployed, temporary workers, manual workers, low educational attainment and low educational attainment among youngsters) was estimated for each area based on census data as well as incident diagnoses (ICD-10 codes) of hand, hip or knee OA (2009–2012). Zero-inflated Poisson models were fitted to study the association between MEDEA quintiles and the outcomes.ResultsCompared to the least deprived, the most deprived areas were younger (43.29 (17.59) vs 46.83 (18.49), years (Mean SD), had fewer women (49.1% vs 54.8%), a higher percentage of obese (16.2% vs 8.4%), smokers (16.9% vs 11.9%) and high-risk alcohol consumption subjects (1.5% vs 1.3%). Compared to the least deprived, the most deprived areas had an excess risk of OA: age-sex-adjusted Incidence Rate Ratio (IRR) 1.26 (1.11–1.42) for hand, 1.23 (1.17–1.29) hip, and 1.51 (1.45–1.57) knee. Adjustment for obesity attenuated this association: 1.06 (0.93–1.20), 1.04 (0.99–1.09), and 1.23 (1.19–1.28) respectively.ConclusionsDeprived areas have higher rates OA (hand, hip, knee). Their increased prevalence of obesity accounts for a 50% of the excess risk of knee OA observed. Public health interventions to reduce the prevalence of obesity in this population could reduce health inequalities

The exonuclease Xrn1 activates transcription and translation of mRNAs encoding membrane proteins

The highly conserved 5'-3' exonuclease Xrn1 regulates gene expression in eukaryotes by coupling nuclear DNA transcription to cytosolic mRNA decay. By integrating transcriptome-wide analyses of translation with biochemical and functional studies, we demonstrate an unanticipated regulatory role of Xrn1 in protein synthesis. Xrn1 promotes translation of a specific group of transcripts encoding membrane proteins. Xrnl-dependence for translation is linked to poor structural RNA contexts for translation initiation, is mediated by interactions with components of the translation initiation machinery and correlates with an Xrnl-dependence for mRNA localization at the endoplasmic reticulum, the translation compartment of membrane proteins. Importantly, for this group of mRNAs, Xrn1 stimulates transcription, mRNA translation and decay. Our results uncover a crosstalk between the three major stages of gene expression coordinated by Xrn1 to maintain appropriate levels of membrane proteins

International Osteoporosis Foundation and European Calcified Tissue Society Working Group. Recommendations for the screening of adherence to oral bisphosphonates

Background Low adherence to oral bisphosphonates is a common problem that jeopardizes the efficacy of treatment of osteoporosis. No clear screening strategy for the assessment of compliance is widely accepted in these patients. Methods The International Osteoporosis Foundation and the European Calcified Tissue Society have convened a working group to propose a screening strategy to detect a lack of adherence to these drugs. The question to answer was whether the bone turnover markers (BTMs) PINP and CTX can be used to identify low adherence in patients with postmenopausal osteoporosis initiating oral bisphosphonates for osteoporosis. The findings of the TRIO study specifically address this question and were used as the basis for testing the hypothesis. Results Based on the findings of the TRIO study, specifically addressing this question, the working group recommends measuring PINP and CTX at baseline and three months after starting therapy to check for a decrease above the least significant change (decrease of more than 38% for PINP and 56% for CTX). Detection rate for the measurement of PINP is 84%, for CTX 87% and, if variation in at least one is considered when measuring both, the level of detection is 94.5%. Conclusions If a significant decrease is observed the treatment can continue but if no decrease occurs the clinician should reassess to identify problems with the treatment, mainly low adherence</p

Hypofractionated radiation therapy and temozolomide in patients with glioblastoma and poor prognostic factors. A prospective, single-institution experience

Background: Hypofractionated radiation therapy is a feasible and safe treatment option in elderly and frail patients with glioblastoma. The aim of this study was to evaluate the effectiveness of hypofractionated radiation therapy with concurrent temozolomide in terms of feasibility and disease control in primary glioblastoma patients with poor prognostic factors other than advanced age, such as post-surgical neurological complications, high tumor burden, unresectable or multifocal lesions, and potential low treatment compliance due to social factors or rapidly progressive disease. Material and methods: GTV included the surgical cavity plus disease visible in T1WI-MRI, FLAIR-MRI and in the MET-uptake. The CTV was defined as the GTV plus 1.5-2 cm margin; the PTV was the CTV+0.3 cm margin. Forty, fourty-five, and fifty grays in 15 fractions were prescribed to 95% of PTV, CTV, and GTV, respectively. Treatment was delivered using IMRT or the VMAT technique. Simultaneously, 75 mg/m2/day of temozolomide were administered. Results: Between January 2010 and November 2017, we treated a total of 17 patients. The median age at diagnosis was 68-years; median KPS was 50-70%. MGMT-methylation status was negative in 5 patients, and 8 patients were IDH-wildtype. Eight of 18 patients were younger than 65-years. Median tumor volume was 26.95cc; median PTV volume was 322cc. Four lesions were unresectable; 6 patients underwent complete surgical resection. Median residual volume was 1.14cc. Progression-free survival was 60% at 6 months, 33% at 1-year and 13% at 2-years (median OS = 7 months). No acute grade 3-5 toxicities were documented. Symptomatic grade 3 radiation necrosis was observed in one patient. Conclusions: Patients with poor clinical factors other than advanced age can be selected for hypofractionated radiotherapy. The OS and PFS rates obtained in our series are similar to those in patients treated with standard fractionation, assuring good treatment adherence, low rates of toxicity and probable improved cost-effectiveness

Transkingdom Networks: A Systems Biology Approach to Identify Causal Members of Host-Microbiota Interactions

Improvements in sequencing technologies and reduced experimental costs have resulted in a vast number of studies generating high-throughput data. Although the number of methods to analyze these "omics" data has also increased, computational complexity and lack of documentation hinder researchers from analyzing their high-throughput data to its true potential. In this chapter we detail our data-driven, transkingdom network (TransNet) analysis protocol to integrate and interrogate multi-omics data. This systems biology approach has allowed us to successfully identify important causal relationships between different taxonomic kingdoms (e.g. mammals and microbes) using diverse types of data