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The go-to-market cheat code : the secret to unlocking B2B growth
\"In The Go-to-Market Cheat Code: The Secret to Unlocking B2B Growth, award-winning entrepreneur Justin Gray and seasoned executive Josh Wagner deliver a research-rich and example-based exploration of why trust and relationships are the true foundation of every thriving business, and how you can build, maintain, and leverage trust in your own business dealings to gain an edge over competitors. This book avoids flash-in-the-pan trends and focuses instead on timeless proven principles that can help you scale your organization to the next level.\"-- Provided by publisher.
BOOK
Variant calling and benchmarking in an era of complete human genome sequences
Genetic variant calling from DNA sequencing has enabled understanding of germline variation in hundreds of thousands of humans. Sequencing technologies and variant-calling methods have advanced rapidly, routinely providing reliable variant calls in most of the human genome. We describe how advances in long reads, deep learning, de novo assembly and pangenomes have expanded access to variant calls in increasingly challenging, repetitive genomic regions, including medically relevant regions, and how new benchmark sets and benchmarking methods illuminate their strengths and limitations. Finally, we explore the possible future of more complete characterization of human genome variation in light of the recent completion of a telomere-to-telomere human genome reference assembly and human pangenomes, and we consider the innovations needed to benchmark their newly accessible repetitive regions and complex variants.Variant calling is the process of identifying genetic variants, which is important for characterizing population genetic diversity and for identifying disease-associated variants in clinical sequencing projects. In this Review, the authors discuss the state-of-the-art in variant calling, focusing on challenging types of genetic variants, advances in both sequencing technologies and computational pipelines, and benchmarking strategies to assess the robustness of variant-calling strategies.
Journal Article
Pizzasaurus Rex
After inventing a device that allows Rex Raditude, the Pizzasaurus, to enter his dimension, Jeremy Duderman finds himself on the frontline when Rex is followed by Emperor Buzzkill and his horde of minions.
Book
XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia
Biallelic mutations in human
XRCC1
are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia.
Cerebellar ataxia link to mutant XRCC1
This paper shows that mutated forms of human XRCC1, a scaffold protein involved in DNA single-strand break repair, are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. In cells from a patient with an
XRCC1
−/−
mutation, rates of break repair are reduced and the single-strand break sensor protein PARP1 is hyperactivated, resulting in abnormally high levels of cellular ADP-ribose. Genetic deletion of Parp1 in
Xrcc1
-defective mice prevents the accumulation of excessive ADP-ribose and rescues the loss of cerebellar neurons and cerebellar ataxia. These findings point to PARP1 as a possible therapeutic target in DNA strand break repair-defective disease.
XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair
1
,
2
. Here we show that biallelic mutations in the human
XRCC1
gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in
XRCC1
exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP
3
,
4
,
5
and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of
Parp1
rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in
Xrcc1
-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
Journal Article
An open resource for accurately benchmarking small variant and reference calls
Benchmark small variant calls are required for developing, optimizing and assessing the performance of sequencing and bioinformatics methods. Here, as part of the Genome in a Bottle (GIAB) Consortium, we apply a reproducible, cloud-based pipeline to integrate multiple short- and linked-read sequencing datasets and provide benchmark calls for human genomes. We generate benchmark calls for one previously analyzed GIAB sample, as well as six genomes from the Personal Genome Project. These new genomes have broad, open consent, making this a ‘first of its kind’ resource that is available to the community for multiple downstream applications. We produce 17% more benchmark single nucleotide variations, 176% more indels and 12% larger benchmark regions than previously published GIAB benchmarks. We demonstrate that this benchmark reliably identifies errors in existing callsets and highlight challenges in interpreting performance metrics when using benchmarks that are not perfect or comprehensive. Finally, we identify strengths and weaknesses of callsets by stratifying performance according to variant type and genome context.
Genome in a Bottle Consortium presents a high-confidence dataset for benchmarking small variant calls in human genomes.
Journal Article
Assembly and annotation of an Ashkenazi human reference genome
Background
Thousands of experiments and studies use the human reference genome as a resource each year. This single reference genome, GRCh38, is a mosaic created from a small number of individuals, representing a very small sample of the human population. There is a need for reference genomes from multiple human populations to avoid potential biases.
Results
Here, we describe the assembly and annotation of the genome of an Ashkenazi individual and the creation of a new, population-specific human reference genome. This genome is more contiguous and more complete than GRCh38, the latest version of the human reference genome, and is annotated with highly similar gene content. The Ashkenazi reference genome, Ash1, contains 2,973,118,650 nucleotides as compared to 2,937,639,212 in GRCh38. Annotation identified 20,157 protein-coding genes, of which 19,563 are > 99% identical to their counterparts on GRCh38. Most of the remaining genes have small differences. Forty of the protein-coding genes in GRCh38 are missing from Ash1; however, all of these genes are members of multi-gene families for which Ash1 contains other copies. Eleven genes appear on different chromosomes from their homologs in GRCh38. Alignment of DNA sequences from an unrelated Ashkenazi individual to Ash1 identified ~ 1 million fewer homozygous SNPs than alignment of those same sequences to the more-distant GRCh38 genome, illustrating one of the benefits of population-specific reference genomes.
Conclusions
The Ash1 genome is presented as a reference for any genetic studies involving Ashkenazi Jewish individuals.
Journal Article
Traumatic Brain Injury in Mice Induces Acute Bacterial Dysbiosis Within the Fecal Microbiome
The secondary injury cascade that is activated following traumatic brain injury (TBI) induces responses from multiple physiological systems, including the immune system. These responses are not limited to the area of brain injury; they can also alter peripheral organs such as the intestinal tract. Gut microbiota play a role in the regulation of immune cell populations and microglia activation, and microbiome dysbiosis is implicated in immune dysregulation and behavioral abnormalities. However, changes to the gut microbiome induced after acute TBI remains largely unexplored. In this study, we have investigated the impact of TBI on bacterial dysbiosis. To test the hypothesis that TBI results in changes in microbiome composition, we performed controlled cortical impact (CCI) or sham injury in male 9-weeks old C57BL/6J mice. Fresh stool pellets were collected at baseline and at 24 h post-CCI. 16S rRNA based microbiome analysis was performed to identify differential abundance in bacteria at the genus and species level. In all baseline vs. 24 h post-CCI samples, we evaluated species-level differential abundances via clustered and annotated operational taxonomic units (OTU). At a high-level view, we observed significant changes in two genera after TBI,
, and
. At the species-level, we found significant decreases in three species (
, and
, and significant increases in two additional species (
, and
. These results pinpoint critical changes in the genus-level and species-level microbiome composition in injured mice compared to baseline; highlighting a previously unreported acute dysbiosis in the microbiome after TBI.
Journal Article
The GIAB genomic stratifications resource for human reference genomes
Despite the growing variety of sequencing and variant-calling tools, no workflow performs equally well across the entire human genome. Understanding context-dependent performance is critical for enabling researchers, clinicians, and developers to make informed tradeoffs when selecting sequencing hardware and software. Here we describe a set of “stratifications,” which are BED files that define distinct contexts throughout the genome. We define these for GRCh37/38 as well as the new T2T-CHM13 reference, adding many new hard-to-sequence regions which are critical for understanding performance as the field progresses. Specifically, we highlight the increase in hard-to-map and GC-rich stratifications in CHM13 relative to the previous references. We then compare the benchmarking performance with each reference and show the performance penalty brought about by these additional difficult regions in CHM13. Additionally, we demonstrate how the stratifications can track context-specific improvements over different platform iterations, using Oxford Nanopore Technologies as an example. The means to generate these stratifications are available as a snakemake pipeline at
https://github.com/usnistgov/giab-stratifications
. We anticipate this being useful in enabling precise risk-reward calculations when building sequencing pipelines for any of the commonly-used reference genomes.
The GIAB genomic stratification resource defines challenging regions in three commonly used human genome references, including the first complete human genome (CHM13). These help understand strengths and weaknesses of sequencing and analysis methods.
Journal Article
Nutraceuticals Synergistically Promote Osteogenesis in Cultured 7F2 Osteoblasts and Mitigate Inhibition of Differentiation and Maturation in Simulated Microgravity
Microgravity is known to impact bone health, similar to mechanical unloading on Earth. In the absence of countermeasures, bone formation and mineral deposition are strongly inhibited in Space. There is an unmet need to identify nutritional countermeasures. Curcumin and carnosic acid are phytonutrients with anticancer, anti-inflammatory, and antioxidative effects and may exhibit osteogenic properties. Zinc is a trace element essential for bone formation. We hypothesized that these nutraceuticals could counteract the microgravity-induced inhibition of osteogenic differentiation and function. To test this hypothesis, we cultured 7F2 murine osteoblasts in simulated microgravity (SMG) in a Random Positioning Machine in the presence and absence of curcumin, carnosic acid, and zinc and evaluated cell proliferation, function, and differentiation. SMG enhanced cell proliferation in osteogenic medium. The nutraceuticals partially reversed the inhibitory effects of SMG on alkaline phosphatase (ALP) activity and did not alter the SMG-induced reduction in the expression of osteogenic marker genes in osteogenic medium, while they promoted osteoblast proliferation and ALP activity in the absence of traditional osteogenic media. We further observed a synergistic effect of the intermix of the phytonutrients on ALP activity. Intermixes of phytonutrients may serve as convenient and effective nutritional countermeasures against bone loss in space.
Journal Article