Utility of CRISPR/Cas9 systems in hematology research

Since the end of the 20th century, the development of novel approaches have emerged to manipulate experimental models of hematological disorders, so they would more accurately mirror what is observed in the clinic. Despite these technological advances, the characterization of crucial genes for benign or malignant hematological disorders remains challenging, mainly because of the dynamic nature of the hematopoietic system and the genetic heterogeneity of these disorders. To overcome this limitation, genome editing technologies have been developed to specifically manipulate the genome via deletion, insertion or modification of targeted loci. These technologies have swiftly progressed, allowing their common use to investigate genetic function in experimental hematology. Amongst them, homologous recombination (HR)-mediated targeting technologies have facilitated the manipulation of specific loci by generating knockout and knock-in models. Despite promoting significant advances in the understanding of the molecular mechanisms involved in hematology, these inefficient, time-consuming and labor-intensive approaches did not permit the development of cellular or animal models recapitulating the complexity of hematological disorders. In October 2016, Dr. Ben Ebert and Dr. Chad Cowan shared their knowledge and experiences with the utilization of CRISPR for models of myeloid malignancy, disease, and novel therapeutics. Here we provide an overview of the topics they covered including insights into the novel applications of the technique as well as its strengths and limitations

Carboxylate-Assisted C(sp^3)–H Activation in Olefin Metathesis-Relevant Ruthenium Complexes

The mechanism of C–H activation at metathesis-relevant ruthenium(II) benzylidene complexes was studied both experimentally and computationally. Synthesis of a ruthenium dicarboxylate at a low temperature allowed for direct observation of the C–H activation step, independent of the initial anionic ligand-exchange reactions. A first-order reaction supports an intramolecular concerted metalation–deprotonation mechanism with ΔG^(‡)_(298K) = 22.2 ± 0.1 kcal·mol^(–1) for the parent N-adamantyl-N′-mesityl complex. An experimentally determined ΔS^(‡) = −5.2 ± 2.6 eu supports a highly ordered transition state for carboxylate-assisted C(sp^3)–H activation. Experimental results, including measurement of a large primary kinetic isotope effect (k_(H)/k_(D) = 8.1 ± 1.7), agree closely with a computed six-membered carboxylate-assisted C–H activation mechanism where the deprotonating carboxylate adopts a pseudo-apical geometry, displacing the aryl ether chelate. The rate of cyclometalation was found to be influenced by both the electronics of the assisting carboxylate and the ruthenium ligand environment

Systematics of Cordiaceae in Argentina I: Taxonomic revision of the genus Cordia

La literatura taxonómica disponible para las especies argentinas de Cordia (Cordiaceae, Boraginales) dista de reflejar las relaciones filogenéticas del linaje tal y como se conoce en la actualidad. Estudios filogenéticos recientes evidencian que Patagonula americana y Saccellium lanceolatum se anidan dentro de Cordia y que cinco especies tradicionalmente circunscritas bajo Cordia deben ser consideradas bajo Varronia. Es por ello que en la presente contribución se comunica un tratamiento taxonómico actualizado de Cordia para la Argentina. Como resultado se provee de una sinonimia completa para las especies aceptadas, así como descripciones morfológicas, mapas de distribución geográfica, nombres comunes, una clave de identificación, usos, ilustraciones, fotografías y estimaciones de su estado de conservación. Adicionalmente, se designa un lectotipo para el nombre Cerdana alliodora y se evidencia por primera vez la presencia de Cordia trichotoma en la provincia de Formosa.The available taxonomic literature for Cordia species in Argentina (Cordiaceae, Boraginales) does not reflect the currently known phylogenetic relationships of the lineage. Recent studies evidence that Patagonula americana and Saccellium lanceolatum nest within Cordia, and that five species traditionally circumscribed under Cordia should be considered within Varronia. In this context, the present contribution provides an updated taxonomic treatment of Cordia in Argentina. Complete synonymy for all accepted species is provided, and morphological descriptions, geographic distribution maps, common names, an identification key, uses, illustrations, photographs and conservation status. Additionally, a lectotype is designated for the name Cerdana alliodora and Cordia trichotoma is recorded for the first time in Formosa province.Fil: Moroni, Pablo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: O'Leary, Nataly Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Botánica Darwinion. Academia Nacional de Ciencias Exactas, Físicas y Naturales. Instituto de Botánica Darwinion; ArgentinaFil: Nadra, Maria Gabriela. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán; ArgentinaFil: Miller, James S.. Missouri Botanical Garden; Estados Unido

Centuries of intense surface melt on Larsen C Ice Shelf

Following a southward progression of ice-shelf disintegration along the Antarctic Peninsula, Larsen C Ice Shelf is the focus of ongoing investigation regarding its future stability. The ice shelf is known to be experience surface melt, and commonly features surface meltwater ponds. Here, we use a flowline model and a firn density model to date and interpret observations of melt-affected ice layers found within five 90?m boreholes distributed across the ice shelf. We find that units of ice within the boreholes, which have densities exceeding those expected under normal compaction metamorphism, correspond to two climatic warm periods within the last 300 years on the Antarctic Peninsula. The more recent warm period, from the 1960s onwards, has generated distinct sections of dense ice in two boreholes in Cabinet Inlet, close to the Antarctic Peninsula mountains ? a region currently affected by f?hn winds. Previous work has classified these layers as refrozen pond ice, requiring large quantities of mobile liquid water to form. Our flowline model shows that, whilst preconditioning of the ice began in the late 1960s, it was probably not until the early 1990s that twentieth-century ponding began. The earlier warm period occurred during the 18th century and resulted in two additional sections of anomalously dense ice deep within the boreholes. The first, in one of the Cabinet Inlet boreholes, consists of ice characteristic of refrozen ponds and must have formed in an area currently featuring ponding. The second, in a mid-shelf borehole, formed at the same time in an area which now experiences significant annual melt. Further south on the shelf, the boreholes sample ice that is of an equivalent age but which does not exhibit the same degree of melt influence. This west?east and north?south gradient in past melt distribution resembles current spatial patterns of surface melt intensity. Using flowlines to trace the advection and submergence of continental ice identified in boreholes, we demonstrate that, even by the time the ice reaches the calving front, only the upper 40 to 50?% of the shelf is composed of meteoric ice accumulated on the shelf. This vertical composition implies that basal crevasses must be confined within continental and/or basally accreted ice, and therefore will be unaffected by current climate-induced firn compactionauthorsversio

Carotid intimal-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors

BACKGROUND: Surrogate measures for cardiovascular disease events have the potential to increase greatly the efficiency of clinical trials. A leading candidate for such a surrogate is the progression of intima-media thickness (IMT) of the carotid artery; much experience has been gained with this endpoint in trials of HMG-CoA reductase inhibitors (statins). METHODS AND RESULTS: We examine two separate systems of criteria that have been proposed to define surrogate endpoints, based on clinical and statistical arguments. We use published results and a formal meta-analysis to evaluate whether progression of carotid IMT meets these criteria for HMG-CoA reductase inhibitors (statins). IMT meets clinical-based criteria to serve as a surrogate endpoint for cardiovascular events in statin trials, based on relative efficiency, linkage to endpoints, and congruency of effects. Results from a meta-analysis and post-trial follow-up from a single published study suggest that IMT meets established statistical criteria by accounting for intervention effects in regression models. CONCLUSION: Carotid IMT progression meets accepted definitions of a surrogate for cardiovascular disease endpoints in statin trials. This does not, however, establish that it may serve universally as a surrogate marker in trials of other agents

The Function Biomedical Informatics Research Network Data Repository

The Function Biomedical Informatics Research Network (FBIRN) developed methods and tools for conducting multi-scanner functional magnetic resonance imaging (fMRI) studies. Method and tool development were based on two major goals: 1) to assess the major sources of variation in fMRI studies conducted across scanners, including instrumentation, acquisition protocols, challenge tasks, and analysis methods, and 2) to provide a distributed network infrastructure and an associated federated database to host and query large, multi-site, fMRI and clinical datasets. In the process of achieving these goals the FBIRN test bed generated several multi-scanner brain imaging data sets to be shared with the wider scientific community via the BIRN Data Repository (BDR). The FBIRN Phase 1 dataset consists of a traveling subject study of 5 healthy subjects, each scanned on 10 different 1.5 to 4 Tesla scanners. The FBIRN Phase 2 and Phase 3 datasets consist of subjects with schizophrenia or schizoaffective disorder along with healthy comparison subjects scanned at multiple sites. In this paper, we provide concise descriptions of FBIRN’s multi-scanner brain imaging data sets and details about the BIRN Data Repository instance of the Human Imaging Database (HID) used to publicly share the data

Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10 -8). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events

Весовые соотношения тимуса и надпочечников у антенатально погибших плодов

ТИМУСНАДПОЧЕЧНИКИтимомегалиядети первого года жизнидети раннего возрастаМЛАДЕНЕЦ, СМЕРТНОСТЬЭНДОКРИННОЙ СИСТЕМЫ БОЛЕЗНИСМЕРТНОСТЬ ДЕТСКАЯсиндром внезапной детской смерт