The Okavango giant mafic dyke swarm (NE Botswana): its structural significance within the Karoo Large Igneous Province

The structural organization of a giant mafic dyke swarm, the Okavango complex, in the northern Karoo Large Igneous Province (LIP) of NE Botswana is detailed. This N110E-oriented dyke swarm extends for 1500 km with a maximum width of 100 km through Archaean basement terranes and Permo-Jurassic sedimentary sequences. The cornerstone of the study is the quantitative analysis of N>170 (exposed) and N>420 (detected by ground magnetics) dykes evidenced on a ca. 80-km-long section lying in crystalline host-rocks, at high-angle to the densest zone of the swarm (Shashe area). Individual dykes are generally sub-vertical and parallel to the entire swarm. Statistical analysis of width data indicates anomalous dyke frequency (few data <5.0 m) and mean dyke thickness (high value of 17 m) with respect to values classically obtained from other giant swarms. Variations of mean dyke thicknesses from 17 (N110E swarm) to 27 m (adjoining and coeval N70E giant swarm) are assigned to the conditions hosting fracture networks dilated as either shear or pure extensional structures, respectively, in response to an inferred NNW?SSE extension. Both fracture patterns are regarded as inherited brittle basement fabrics associated with a previous (Proterozoic) dyking event. The Okavango N110E dyke swarm is thus a polyphase intrusive system in which total dilation caused by Karoo dykes (estimated frequency of 87%) is 12.2% (6315 m of cumulative dyke width) throughout the 52-km-long projected Shashe section. Assuming that Karoo mafic dyke swarms in NE Botswana follow inherited Proterozoic fractures, as similarly applied for most of the nearly synchronous giant dyke complexes converging towards the Nuanetsi area, leads us to consider that the resulting triple junction-like dyke/fracture pattern is not a definitive proof for a deep mantle plume in the Karoo LIP

МІКРОБІОМ У ФІЗІОЛОГІЇ ЛЮДИНИ

Basic facts concerning human microbiome. Long-term coevolution of the human organism and microbe community has led to the formation of an additional anatomical structure in the human body that was named microbiome. This unique microbe structure has a complex organ organization that functions in mutual consent with all other human organs and systems. Localization of microbiome in the human body. All biotopes of the human body (oral cavity, hair, nose, ears, urogenital system, skin, eyes, gastrointestinal tract, and bronchopulmonary system) have their own unique and specific microbe complex that consists of specialized microbes with various functions. Besides, all these local microbiomes are in continuous interactions with each other and with macroorganism making the united superorganism system. Microbiome functional activity. Microbiome takes active part in realization of a wide spectrum of vitally important physiological processes, including energetic homeostasis and metabolism, synthesis of vitamins and other significant nutrients, endocrine signaling, preventing pathogen colonization, regulation of immune function, metabolism of xenobiotics, toxins, carcinogens and other harmful substances. Most these functions are closely connected and tightly implicated with human physiology. Changes of microbiome during ontogenesis. Microbiome formation begins long before childbirth and continues 2–3 years after it. In the course of the organism maturation and aging, microbiome changes appreciably. Microbiome improvement at all stages of human life is of the utmost importance for improving health of all age group population. Microbiome damages in etiology of human diseases. Numerous investigations showed that microbiome changes are associated with a large spectrum of gastrointestinal and systemic diseases, including inflammatory intestinal diseases, asthma, obesity, metabolic syndrome, cardiovascular pathology, autoimmune, neurobehavioral and many other diseases. Modern approaches to microbiome improvement. To date, many different methods of therapeutic influence on microbiome have been proposed: changing diet, applying probiotics, prebiotics or their complexes (synbiotics), using functional foodstuffs, carrying out fecal transplantation etc. The authors propose universal approaches to prophylaxes of microbiome disturbances and its reversal in people of different age categories; its efficiency has been convincingly demonstrated in clinics.Загальні відомості про мікробіом людини. В результаті тривалої коеволюції людини з мікробним співтовариством сконструйовано і вдосконалено додаткову анатомічну структуру тіла людини, яка отримала назву мікробіом. Цей унікальний мікробний орган має складну органну структуру, функціонуючу у взаємній згоді з усіма іншими органами та системами людини. Локалізація мікробіому в тілі людини. Всі біотопи тіла людини (ротова порожнина, волосся, ніс, вуха, сечостатеві шляхи, шкіра, очі, шлунково-кишковий тракт, бронхо-легенева системи) містять свій власний унікальний специфічний складний мікробний комплекс, що складається зі спеціалізованих мікробів з різними функціями. При цьому всі локальні мікробіоми перебувають у постійній взаємодії між собою і з макроорганізмом, утворюючи єдину надорганізмову систему. Функціональна активність мікробіому. Мікробіом бере активну участь в реалізації широкого спектра життєво важливих фізіологічних процесів, включаючи енергетичний гомеостаз і метаболізм, синтез вітамінів та інших важливих нутрієнтів, ендокринну сигналізацію, регуляцію імунної функції, метаболізм ксенобіотиків, токсинів, канцерогенів та інших шкідливих сполук, запобігає колонізації патогенами. Більшість цих функцій взаємопов’язана та тісно переплетена з фізіологією людини. Зміни мікробіому в онтогенезі. Процес формування мікробіому починається задовго до народження дитини і продовжується 2-3 роки після народження. У міру дорослішання та старіння організму спостерігаються помітні зміни мікробіому. Підтримка мікробіому на всіх етапах життя людини має величезне значення для поліпшення здоров’я населення всіх вікових категорій. Місце мікробіомних порушень в етіології захворювань людини. Багатьма дослідженнями показано, що зміни в мікробіомі асоціюються з широким спектром шлунково-кишкових і системних захворювань, включаючи запальні хвороби кишечнику, астму, ожиріння, метаболічний синдром, серцево-судинну патологію, автоімунні, нейроповедінкові, та з багатьма іншими хворобами. Сучасні підходи до оздоровлення мікробіому. Сьогодні пропонуються різні методи терапевтичного впливу на мікробіом: зміна дієти, застосування пробіотиків, пребіотиків або їх комплексів (синбіотиків), продуктів функціонального харчування, ентеросорбентів, проведення фекальної трансплантації та ін. Авторами запропоновані універсальні підходи до профілактики мікробіомних порушень та їх усунення в осіб різних вікових категорій, ефективність яких переконливо доведена клінікою

The genetic basis of multiple sclerosis: a model for MS susceptibility

<p>Abstact</p> <p>Background</p> <p>MS-pathogenesis is known to involve both multiple environmental events, and several independent genetic risk-factors.</p> <p>Methods</p> <p>A model of susceptibility is developed and a mathematical analysis undertaken to elucidate the nature of genetic susceptibility to MS and to understand the constraints that are placed on the genetic basis of MS, both by the known epidemiological facts of this disease and by the known frequency of the HLA DRB1*1501 allele in the general populations of northern Europe and North America.</p> <p>Results</p> <p>For the large majority of cases (possibly all), MS develops, in part, because an individual is genetically susceptible. Nevertheless, 2.2% or less of the general population is genetically susceptible. Moreover, from the model, the number of susceptibility-loci that need to be in a "susceptible allelic state" to produce MS-susceptibility is small (11-18), whereas the total number of such susceptibility-loci is large (50-200), and their "frequency of susceptibility" is low (i.e., ≤ 0.12). The optimal solution to the model equations (which occurs when 80% of the loci are recessive) predicts the epidemiological data quite closely.</p> <p>Conclusions</p> <p>The model suggests that combinations of only a small number of genetic loci in a "susceptible allelic state" produce MS-susceptibility. Nevertheless, genome-wide associations studies with hundreds of thousands of SNPs, are plagued by both false-positive and false-negative identifications and, consequently, emphasis has been rightly placed on the replicability of findings. Nevertheless, because genome-wide screens don't distinguish between true susceptibility-loci and disease-modifying-loci, and because only true susceptibility-loci are constrained by the model, unraveling the two will not be possible using this approach.</p> <p>The model also suggests that HLA DRB1 may not be as uniquely important for MS-susceptibility as currently believed. Thus, this allele is only one among a hundred or more loci involved in MS susceptibility. Even though the "frequency of susceptibility" at the HLA DRB1 locus is four-fold that of other loci, the penetrance of those susceptible genotypes that include this allele is no different from those that don't. Also, almost 50% of genetically-susceptible individuals, lack this allele. Moreover, of those who have it, only a small fraction (≤ 5.2%) are even susceptible to getting MS.</p

Active oceanic spreading in the northern north Fiji basin : results of the NOFI cruise of R/V l'Atalante (Newstarmer project)

The South Pandora and the Tripartite Ridges are active spreading centers located in the northern part of the North Fiji Basin. These spreading centers were surveyed over a distance of 750 km during the NOFI cruise of R/V L'Atalante (August-September 1994) which was conducted in the frame of the french-japanese Newstarmer cooperation project. SIMRAD EM12-dual full coverage swath bathymetric and imagery data as well as airgun 6-channel seismic, magnetics and gravity profiles were recorded along an off-axis from 170°40'E to 178°E. Dredging and piston coring were also performed along and off-axis. The axial domain of the South Pandora Ridge is divided into 5 first-order segments characterized by contrasted morphologies. The average width of the active domain is 20 km and corresponds either to bathymetric highs or to deep elongated grabens. The bathymetric highs are volcanic constructions, locally faulted and rifted, which can obstruct totally the axial valley. The grabens show the typical morphology of slow spreading axes, with two steep walls flanking a deep axial valley. Elongated lateral ridges may be present on both sides of the grabens. Numerous volcanoes, up to several kilometers in diameter, occur on both flanks of the South Pandora Ridge. The Tripartite Ridge consists of three main segments showing a sigmoid shape. Major changes in the direction of the active zones are observed at the segment discontinuities. These discontinuities show various geometrical patterns which suggest complex transform relay zones. Preliminary analysis of seismic reflection profiles suggest that the Tripartite Ridge is a very young feature which propagates into an older oceanic domain characterized by a significant sedimentary cover. By contrast, a very thin to absent sedimentary cover is observed about 100 km on both flanks of the South Pandora Ridge active axis. The magnetic anomaly profiles give evidence of long and continuous lineations, parallel to the South Pandora Ridge spreading axis. (Résumé d'auteur

BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations

A transition from fetal hemoglobin (HbF) to adult hemoglobin (HbA) normally occurs within a few months after birth. Increased production of HbF after this period of infancy ameliorates clinical symptoms of the major disorders of adult ß-hemoglobin: ß-thalassemia and sickle cell disease. The transcription factor BCL11A silences HbF and has been an attractive therapeutic target for increasing HbF levels; however, it is not clear to what extent BCL11A inhibits HbF production or mediates other developmental functions in humans. Here, we identified and characterized 3 patients with rare microdeletions of 2p15-p16.1 who presented with an autism spectrum disorder and developmental delay. Moreover, these patients all exhibited substantial persistence of HbF but otherwise retained apparently normal hematologic and immunologic function. Of the genes within 2p15-p16.1, only BCL11A was commonly deleted in all of the patients. Evaluation of gene expression data sets from developing and adult human brains revealed that BCL11A expression patterns are similar to other genes associated with neurodevelopmental disorders. Additionally, common SNPs within the second intron of BCL11A are strongly associated with schizophrenia. Together, the study of these rare patients and orthogonal genetic data demonstrates that BCL11A plays a central role in silencing HbF in humans and implicates BCL11A as an important factor for neurodevelopment

Magnetism, FeS colloids, and Origins of Life

A number of features of living systems: reversible interactions and weak bonds underlying motor-dynamics; gel-sol transitions; cellular connected fractal organization; asymmetry in interactions and organization; quantum coherent phenomena; to name some, can have a natural accounting via $physical$ interactions, which we therefore seek to incorporate by expanding the horizons of `chemistry-only' approaches to the origins of life. It is suggested that the magnetic 'face' of the minerals from the inorganic world, recognized to have played a pivotal role in initiating Life, may throw light on some of these issues. A magnetic environment in the form of rocks in the Hadean Ocean could have enabled the accretion and therefore an ordered confinement of super-paramagnetic colloids within a structured phase. A moderate H-field can help magnetic nano-particles to not only overcome thermal fluctuations but also harness them. Such controlled dynamics brings in the possibility of accessing quantum effects, which together with frustrations in magnetic ordering and hysteresis (a natural mechanism for a primitive memory) could throw light on the birth of biological information which, as Abel argues, requires a combination of order and complexity. This scenario gains strength from observations of scale-free framboidal forms of the greigite mineral, with a magnetic basis of assembly. And greigite's metabolic potential plays a key role in the mound scenario of Russell and coworkers-an expansion of which is suggested for including magnetism.Comment: 42 pages, 5 figures, to be published in A.R. Memorial volume, Ed Krishnaswami Alladi, Springer 201

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention

HLA-A Confers an HLA-DRB1 Independent Influence on the Risk of Multiple Sclerosis

A recent high-density linkage screen confirmed that the HLA complex contains the strongest genetic factor for the risk of multiple sclerosis (MS). In parallel, a linkage disequilibrium analysis using 650 single nucleotide polymorphisms (SNP) markers of the HLA complex mapped the entire genetic effect to the HLA-DR-DQ subregion, reflected by the well-established risk haplotype HLA-DRB1*15,DQB1*06. Contrary to this, in a cohort of 1,084 MS patients and 1,347 controls, we show that the HLA-A gene confers an HLA-DRB1 independent influence on the risk of MS (P = 8.4×10−10). This supports the opposing view, that genes in the HLA class I region indeed exert an additional influence on the risk of MS, and confirms that the class I allele HLA-A*02 is negatively associated with the risk of MS (OR = 0.63, P = 7×10−12) not explained by linkage disequilibrium with class II. The combination of HLA-A and HLA-DRB1 alleles, as represented by HLA-A*02 and HLA-DRB1*15, was found to influence the risk of MS 23-fold. These findings imply complex autoimmune mechanisms involving both the regulatory and the effector arms of the immune system in the triggering of MS

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photo-receptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.Foundation Fighting Blindness CanadaCanadian Institutes of Health ResearchNIHCharles University institutional programmesBIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development FundMinistry of Health of the Czech RepublicGraduate School of Life Sciences (University of Wuerzburg)Government of Canada through Genome CanadaOntario Genomics InstituteGenome QuebecGenome British ColumbiaMcLaughlin CentreCharles Univ Prague, Inst Inherited Metab Disorders, Fac Med 1, Prague 12000 2, Czech RepublicMcGill Univ, Dept Human Genet, Fac Med, Montreal, PQ H3A 0G1, CanadaGenome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, CanadaClin Res Inst Montreal, Cellular Neurobiol Res Unit, Montreal, PQ H2W 1R7, CanadaMcGill Univ, Montreal, PQ H3A 0G4, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, McGill Ocular Genet Lab, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Paediat Surg, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Human Genet, Montreal, PQ H3H 1P3, CanadaMcGill Univ, Ctr Hlth, Montreal Childrens Hosp, Dept Ophthalmol, Montreal, PQ H3H 1P3, CanadaUniv Alberta, Royal Alexandra Hosp, Dept Ophthalmol & Visual Sci, Edmonton, AB T5H 3V9, CanadaCharles Univ Prague, Inst Biol & Med Genet, Fac Med 1, Prague 12000 2, Czech RepublicBaylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USAUniversidade Federal de São Paulo, Dept Neurol, Div Gen Neurol, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol, Ataxia Unit, BR-04021001 São Paulo, BrazilNewcastle Univ, Inst Med Genet, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, EnglandUniversidade Federal de São Paulo, Dept Ophthalmol, BR-04021001 São Paulo, BrazilSo Gen Hosp, Dept Clin Genet, Glasgow G51 4TF, Lanark, ScotlandCardiff Univ, Sch Med, Inst Med Genet, Cardiff CF14 4XN, S Glam, WalesHadassah Hebrew Univ Med Ctr, Dept Ophthalmol, IL-91120 Jerusalem, IsraelOregon Hlth & Sci Univ, Oregon Inst Occupat Hlth Sci, Portland, OR 97239 USAUniv Wurzburg, Lehrstuhl Neurobiol & Genet, D-97074 Wurzburg, GermanyUniv Montreal, Dept Med, Montreal, PQ H3T 1P1, CanadaMcGill Univ, Dept Anat & Cell Biol, Div Expt Med, Montreal, PQ H3A 2B2, CanadaUniversidade Federal de São Paulo, Dept Neurol, Div Gen Neurol, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Neurol, Ataxia Unit, BR-04021001 São Paulo, BrazilUniversidade Federal de São Paulo, Dept Ophthalmol, BR-04021001 São Paulo, BrazilNIH: EY022356-01NIH: EY018571-05NIH: NS047663-09Charles University institutional programmes: PRVOUK-P24/LF1/3Charles University institutional programmes: UNCE 204011Charles University institutional programmes: SVV2013/266504BIOCEV-Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University, from the European Regional Development Fund: CZ.1.05/1.1.00/02.0109Ministry of Health of the Czech Republic: NT13116-4/2012Ministry of Health of the Czech Republic: NT14015-3/2013Ontario Genomics Institute: OGI-049Web of Scienc