CNS targets of adipokines

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this record.Our understanding of adipose tissue as an endocrine organ has been transformed over the last twenty years. During this time a number of adipocyte-derived factors or adipokines have been identified. This paper will review evidence for how adipokines acting via the central nervous system (CNS) regulate normal physiology and disease pathology. The reported CNS-mediated effects of adipokines are varied and include the regulation of energy homeostasis, autonomic nervous system activity, the reproductive axis, neurodevelopment, cardiovascular function, and cognition. Due to the wealth of information available and the diversity of their known functions, the archetypal adipokines leptin and adiponectin will be the focused on extensively. Other adipokines with established CNS actions will also be discussed. Due to the difficulties associated with studying CNS function on a molecular level in humans, the majority of our knowledge, and as such the studies described in this paper, comes from work in experimental animal models; however, where possible the relevant data from human studies are also highlighted

An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples.

MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed.  Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination

Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network.  It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented.  For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations.  We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent.  We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines.  Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase

Global and local patterns of population structure and their role in the evolution and demography of Plasmodium falciparum

In this thesis, I study the role of genetic population structure in the evolution and demography of Plasmodium falciparum by focusing on the recent onset of artemisinin resistance in Southeast Asia, an alarming event for global public health. I describe the population structure of Plasmodium falciparum in the Thai-Cambodian border region, characterizing sympatric but differentiated subpopulations associated with artemisinin resistance. I show evidence that they are the product of recent founder events and seem the primary force spreading resistance. Next, I study a superset of the kelch13 mutations associated with artemisinin resistance, assessing their relationship with population structure and recent founder effects. Each resistant subpopulation possesses a distinct kelch13 allele that, in conjunction with a particular genetic background, seem to have driven recent founder effects. I examine the demography of these resistance alleles using patterns of haplotype sharing and show that the primary mode of spread consists of independent mutational events, with limited gene flow within countries in East Southeast Asia. Subsequently, I assess the origin of kelch13 mutations observed in African isolates, concluding that they are indigenous and have originated independently. These observations undermine localized resistance containment as a strategy for malaria control and suggest that population structure and founder effects may predate and facilitate the emergence of resistance. Therefore, monitoring these phenomena could warn about the development of resistance before phenotypic evidence materializes. Next, given the importance of demographic inference to inform malaria control programs and the advent of large genomic datasets, I develop a fast and scalable method to build the ancestral haplotype graph. I show that this data structure, composed of a collection of local haplotype trees, is informative about the recent genealogical history of the sequences and can be used to summarize and study shared haplotype patterns along the genome. I describe a set of algorithms with quasilinear time complexity as a first step in the development of scalable demographic inferential methods that can be applied to several thousands of sequences. I also evaluate how mixed infections affect the analysis of deep sequencing data and review the FWS statistic, a relative measure of inbreeding and complexity of infection. In doing so, I show that the original FWS estimator discards the diversity encoded by rare variants and provide an alternative estimator without such bias that is simpler, more intuitive and has a better resolution.</p

Global and local patterns of population structure and their role in the evolution and demography of Plasmodium falciparum

In this thesis, I study the role of genetic population structure in the evolution and demography of Plasmodium falciparum by focusing on the recent onset of artemisinin resistance in Southeast Asia, an alarming event for global public health. I describe the population structure of Plasmodium falciparum in the Thai-Cambodian border region, characterizing sympatric but differentiated subpopulations associated with artemisinin resistance. I show evidence that they are the product of recent founder events and seem the primary force spreading resistance. Next, I study a superset of the kelch13 mutations associated with artemisinin resistance, assessing their relationship with population structure and recent founder effects. Each resistant subpopulation possesses a distinct kelch13 allele that, in conjunction with a particular genetic background, seem to have driven recent founder effects. I examine the demography of these resistance alleles using patterns of haplotype sharing and show that the primary mode of spread consists of independent mutational events, with limited gene flow within countries in East Southeast Asia. Subsequently, I assess the origin of kelch13 mutations observed in African isolates, concluding that they are indigenous and have originated independently. These observations undermine localized resistance containment as a strategy for malaria control and suggest that population structure and founder effects may predate and facilitate the emergence of resistance. Therefore, monitoring these phenomena could warn about the development of resistance before phenotypic evidence materializes. Next, given the importance of demographic inference to inform malaria control programs and the advent of large genomic datasets, I develop a fast and scalable method to build the ancestral haplotype graph. I show that this data structure, composed of a collection of local haplotype trees, is informative about the recent genealogical history of the sequences and can be used to summarize and study shared haplotype patterns along the genome. I describe a set of algorithms with quasilinear time complexity as a first step in the development of scalable demographic inferential methods that can be applied to several thousands of sequences. I also evaluate how mixed infections affect the analysis of deep sequencing data and review the FWS statistic, a relative measure of inbreeding and complexity of infection. In doing so, I show that the original FWS estimator discards the diversity encoded by rare variants and provide an alternative estimator without such bias that is simpler, more intuitive and has a better resolution.</p

SnoopCGH

SnoopCGH is a java desktop application for visualising and exploring comparative genomic hybridization (CGH) data. The software allows the user to interactively analyse several sets of data simultaneously. The input is based on a tab-, space- or comma-delimited format, containing series of log intensity values corresponding to one or more comparisons or samples

Analysis of Plasmodium falciparum diversity in natural infections by deep sequencing.

Malaria elimination strategies require surveillance of the parasite population for genetic changes that demand a public health response, such as new forms of drug resistance. Here we describe methods for the large-scale analysis of genetic variation in Plasmodium falciparum by deep sequencing of parasite DNA obtained from the blood of patients with malaria, either directly or after short-term culture. Analysis of 86,158 exonic single nucleotide polymorphisms that passed genotyping quality control in 227 samples from Africa, Asia and Oceania provides genome-wide estimates of allele frequency distribution, population structure and linkage disequilibrium. By comparing the genetic diversity of individual infections with that of the local parasite population, we derive a metric of within-host diversity that is related to the level of inbreeding in the population. An open-access web application has been established for the exploration of regional differences in allele frequency and of highly differentiated loci in the P. falciparum genome