Gene-centric functional dissection of human genetic variation uncovers regulators of hematopoiesis

Genome-wide association studies (GWAS) have identified thousands of variants associated with human diseases and traits. However, the majority of GWAS-implicated variants are in non-coding regions of the genome and require in depth follow-up to identify target genes and decipher biological mechanisms. Here, rather than focusing on causal variants, we have undertaken a pooled loss-of-function screen in primary hematopoietic cells to interrogate 389 candidate genes contained in 75 loci associated with red blood cell traits. Using this approach, we identify 77 genes at 38 GWAS loci, with most loci harboring 1-2 candidate genes. Importantly, the hit set was strongly enriched for genes validated through orthogonal genetic approaches. Genes identified by this approach are enriched in specific and relevant biological pathways, allowing regulators of human erythropoiesis and modifiers of blood diseases to be defined. More generally, this functional screen provides a paradigm for gene-centric follow up of GWAS for a variety of human diseases and traits

Search for Charmless Two-body Baryonic Decays of B Mesons

We report the results of a search for the rare baryonic decays $B^0 \to p\bar{p}$, $\Lambda\bar{\Lambda}$, and $B^+ \to p\bar{\Lambda}$. The analysis is based on a data set of $31.7\times 10^6 B\bar{B}$ events collected by the Belle detector at the KEKB $e^+e^-$ collider. No statistically significant signals are found, and we set branching fraction upper limits ${\mathcal B}(B^0 \to p\bar{p}) < 1.2 \times 10^{-6}$, ${\mathcal B}(B^0 \to \Lambda\bar{\Lambda}) < 1.0 \times 10^{-6}$, and ${\mathcal B}(B^+ \to p\bar{\Lambda}) < 2.2 \times 10^{-6}$ at the 90% confidence level.Comment: 6 pages, 4 figures and 1 table. Submitted to Phys. Rev. D Rapid Communication

Using microphone arrays to investigate microhabitat selection by declining breeding birds

Understanding the microhabitat preferences of animals can help managers to develop better conservation and recovery strategies but this is challenging. Traditional methods are limited by cost, accuracy and human resources. In this study, we investigated avian microhabitat preferences using microphone arrays that are capable of accurately locating vocalizing birds. Our objective was to identify the microhabitat associations of two common species in steep population decline, the Boreal Chickadee Poecile hudsonicus and the Cape May Warbler Setophaga tigrina. We deployed 68 eight‐channel arrays at random locations in Labrador, Canada, during the 2016 avian breeding season. We returned in 2017 to the 18 array locations where the target species had been detected the previous year and characterized the microhabitat at the exact locations where they had been detected. We also characterized the microhabitat at randomly determined control locations. Results show that Boreal Chickadees select trees with greater diameter‐at‐breast‐height that are surrounded by greater stem density. We did not find evidence that Cape May Warblers exhibit microhabitat selection during song production. The study shows that microphone arrays are an effective tool for identifying preferred microhabitat that could be incorporated into future conservation or recovery strategies

Development of time domain behanioural non-linear models for microwave devices and ICS from vectorial large-signal measurements and simulations

We have developed a procedure to determine a behavioural non-linear model for microwave devices and ICs that is directly based on vectorial large-signal measurements. For the examples of a HEMT and an amplifier IC, we represent the terminal currents in the time domain by a dynamic model that is fitted to the embedded terminal voltages

A Genome-wide CRISPR Death Screen Identifies Genes Essential for Oxidative Phosphorylation.

Oxidative phosphorylation (OXPHOS) is the major pathway for ATP production in humans. Deficiencies in OXPHOS can arise from mutations in either mitochondrial or nuclear genomes and comprise the largest collection of inborn errors of metabolism. At present we lack a complete catalog of human genes and pathways essential for OXPHOS. Here we introduce a genome-wide CRISPR "death screen" that actively selects dying cells to reveal human genes required for OXPHOS, inspired by the classic observation that human cells deficient in OXPHOS survive in glucose but die in galactose. We report 191 high-confidence hits essential for OXPHOS, including 72 underlying known OXPHOS diseases. Our screen reveals a functional module consisting of NGRN, WBSCR16, RPUSD3, RPUSD4, TRUB2, and FASTKD2 that regulates the mitochondrial 16S rRNA and intra-mitochondrial translation. Our work yields a rich catalog of genes required for OXPHOS and, more generally, demonstrates the power of death screening for functional genomic analysis

Bromodomain Inhibitors Correct Bioenergetic Deficiency Caused by Mitochondrial Disease Complex I Mutations

Contains fulltext : 172050.pdf (publisher's version ) (Closed access

Activation-induced cytidine deaminase targets DNA at sites of RNA polymerase II stalling by interaction with Spt5

Activation-induced cytidine deaminase (AID) initiates antibody gene diversification by creating U:G mismatches. However, AID is not specific for antibody genes; Off-target lesions can activate oncogenes or cause chromosome translocations. Despite its importance in these transactions little is known about how AID finds its targets. We performed an shRNA screen to identify factors required for class switch recombination (CSR) of antibody loci. We found that Spt5, a factor associated with stalled RNA polymerase II (Pol II) and single stranded DNA (ssDNA), is required for CSR. Spt5 interacts with AID, it facilitates association between AID and Pol II, and AID recruitment to its Ig and non-Ig targets. ChIP-seq experiments reveal that Spt5 colocalizes with AID and stalled Pol II. Further, Spt5 accumulation at sites of Pol II stalling is predictive of AID-induced mutation. We propose that AID is targeted to sites of Pol II stalling in part via its association with Spt5