Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data

Content introduction:

• Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites


• Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data


• De novo assembly of haplotype-resolved genomes with trio binning


• An integrative tissue-network approach to identify and test human disease genes


• High-quality genome sequences of uncultured microbes by assembly of read clouds

1. Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites

The functions of many long noncoding RNAs (lncRNAs) in the human genome remain unknown owing to the lack of scalable loss-of-function screening tools. Ying Liu at Peking University in Beijing, China and her colleagues previously used pairs of CRISPR–Cas9 single guide RNAs (sgRNAs) for small-scale functional screening of lncRNAs4. Here they demonstrate genome-wide screening of lncRNA function using sgRNAs to target splice sites and achieve exon skipping or intron retention. Splice-site targeting outperformed a conventional CRISPR library in a negative selection screen targeting 79 ribosomal genes. Using a genome-scale library of splicing-targeting sgRNAs, they performed a screen covering 10,996 lncRNAs and identified 230 that are essential for cellular growth of chronic myeloid leukemia K562 cells. Screening GM12878 lymphoblastoid cells and HeLa cells with the same library identified cell-type-specific differences in lncRNA essentiality. Extensive validation confirmed the robustness of our approach.

Read more, please click https://www.nature.com/articles/nbt.4283

2. Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data

How intrinsic gene-regulatory networks interact with a cell's spatial environment to define its identity remains poorly understood. Qian Zhu at Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health in Massachusetts, USA and his colleagues developed an approach to distinguish between intrinsic and extrinsic effects on global gene expression by integrating analysis of sequencing-based and imaging-based single-cell transcriptomic profiles, using cross-platform cell type mapping combined with a hidden Markov random field model. They applied this approach to dissect the cell-type- and spatial-domain-associated heterogeneity in the mouse visual cortex region. Their analysis identified distinct spatially associated, cell-type-independent signatures in the glutamatergic and astrocyte cell compartments. Using these signatures to analyze single-cell RNA sequencing data, they identified previously unknown spatially associated subpopulations, which were validated by comparison with anatomical structures and Allen Brain Atlas images.



Read more, please click https://www.nature.com/articles/nbt.4260

3. De novo assembly of haplotype-resolved genomes with trio binning

Complex allelic variation hampers the assembly of haplotype-resolved sequences from diploid genomes. Sergey Koren at National Human Genome Research Institute in Maryland, USA and his colleagues developed trio binning, an approach that simplifies haplotype assembly by resolving allelic variation before assembly. In contrast with prior approaches, the effectiveness of their method improved with increasing heterozygosity. Trio binning uses short reads from two parental genomes to first partition long reads from an offspring into haplotype-specific sets. Each haplotype is then assembled independently, resulting in a complete diploid reconstruction. They used trio binning to recover both haplotypes of a diploid human genome and identified complex structural variants missed by alternative approaches. They sequenced an F1 cross between the cattle subspecies Bos taurus taurus and Bos taurus indicus and completely assembled both parental haplotypes with NG50 haplotig sizes of >20 Mb and 99.998% accuracy, surpassing the quality of current cattle reference genomes. They suggest that trio binning improves diploid genome assembly and will facilitate new studies of haplotype variation and inheritance.

Read more, please click https://www.nature.com/articles/nbt.4277

4. An integrative tissue-network approach to identify and test human disease genes

Effective discovery of causal disease genes must overcome the statistical challenges of quantitative genetics studies and the practical limitations of human biology experiments. Here Victoria Yao at Princeton University in New Jersey, USA and his colleagues developed diseaseQUEST, an integrative approach that combines data from human genome-wide disease studies with in silico network models of tissue- and cell-type-specific function in model organisms to prioritize candidates within functionally conserved processes and pathways. They used diseaseQUEST to predict candidate genes for 25 different diseases and traits, including cancer, longevity, and neurodegenerative diseases. Focusing on Parkinson's disease (PD), a diseaseQUEST-directed Caenhorhabditis elegans behavioral screen identified several candidate genes, which they experimentally verified and found to be associated with age-dependent motility defects mirroring PD clinical symptoms. Furthermore, knockdown of the top candidate gene, bcat-1, encoding a branched chain amino acid transferase, caused spasm-like 'curling' and neurodegeneration in C. elegans, paralleling decreased BCAT1 expression in PD patient brains. diseaseQUEST is modular and generalizable to other model organisms and human diseases of interest.

Read more, please click https://www.nature.com/articles/nbt.4246

5. High-quality genome sequences of uncultured microbes by assembly of read clouds

Although shotgun metagenomic sequencing of microbiome samples enables partial reconstruction of strain-level community structure, obtaining high-quality microbial genome drafts without isolation and culture remains difficult. Here, Alex Bishara at Stanford University in California, USA and his colleagues present an application of read clouds, short-read sequences tagged with long-range information, to microbiome samples. They present Athena, a de novo assembler that uses read clouds to improve metagenomic assemblies. They applied this approach to sequence stool samples from two healthy individuals and compared it with existing short-read and synthetic long-read metagenomic sequencing techniques. Read-cloud metagenomic sequencing and Athena assembly produced the most comprehensive individual genome drafts with high contiguity (>200-kb N50, fewer than ten contigs), even for bacteria with relatively low (20×) raw short-read-sequence coverage. They also sequenced a complex marine-sediment sample and generated 24 intermediate-quality genome drafts (>70% complete, <10% contaminated), nine of which were complete (>90% complete, <5% contaminated). Their approach allows for culture-free generation of high-quality microbial genome drafts by using a single shotgun experiment.

Read more, please click https://www.nature.com/articles/nbt.4266

The Nobel Prize in Physiology or Medicine 1997

The Nobel Prize in Physiology or Medicine 1997 was awarded to Stanley B. Prusiner "for his discovery of Prions - a new biological principle of infection."

Stanley B. Prusiner

Born: 28 May 1942, Des Moines, IA, USA

Affiliation at the time of the award: University of California School of Medicine, San Francisco, CA, USA

Summary

The 1997 Nobel Prize in Physiology or Medicine is awarded to the American Stanley Prusiner for his pioneering discovery of an entirely new genre of disease-causing agents and the elucidation of the underlying principles of their mode of action. Stanley Prusiner has added prions to the list of well known infectious agents including bacteria, viruses, fungi and parasites. Prions exist normally as innocuous cellular proteins, however, prions possess an innate capacity to convert their structures into highly stabile conformations that ultimately result in the formation of harmful particles, the causative agents of several deadly brain diseases of the dementia type in humans and animals. Prion diseases may be inherited, laterally transmitted, or occur spontaneously. Regions within diseased brains have a characteristic porous and spongy appearance, evidence of extensive nerve cell death, and affected individuals exhibit neurological symptoms including impaired muscle control, loss of mental acuity, memory loss and insomnia. Stanley Prusiner’s discovery provides important insights that may furnish the basis to understand the biological mechanisms underlying other types of dementia-related diseases, for example Alzheimer’s disease, and establishes a foundation for drug development and new types of medical treatment strategies.

In 1972 Stanley Prusiner began his work after one of his patients died of dementia resulting from Creutzfeldt-Jakob disease (CJD). It had previously been shown that CJD, kuru, and scrapie, a similar disease affecting sheep, could be transmitted through extracts of diseased brains. There were many theories regarding the nature of the infectious agent, including one that postulated that the infectious agent lacked nucleic acid, a sensational hypothesis since at the time all known infectious agents contained the hereditary material DNA or RNA. Prusiner took up the challenge to precisely identify the infectious agent and ten years later in 1982 he and his colleagues successfully produced a preparation derived from diseased hamster brains that contained a single infectious agent. All experimental evidence indicated that the infectious agent was comprised of a single protein, and Prusiner named this protein a prion, an acronym derived from “proteinaceous infectious particle.” It should be noted that the scientific community greeted this discovery with great skepticism, however, an unwavering Prusiner continued the arduous task to define the precise nature of this novel infectious agent.



Please click https://www.nobelprize.org/prizes/medicine/1997/press-release/ for more detailed information.

Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data

Content introduction:

• Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites


• Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data


• De novo assembly of haplotype-resolved genomes with trio binning


• An integrative tissue-network approach to identify and test human disease genes


• High-quality genome sequences of uncultured microbes by assembly of read clouds

1. Genome-wide screening for functional long noncoding RNAs in human cells by Cas9 targeting of splice sites

The functions of many long noncoding RNAs (lncRNAs) in the human genome remain unknown owing to the lack of scalable loss-of-function screening tools. Ying Liu at Peking University in Beijing, China and her colleagues previously used pairs of CRISPR–Cas9 single guide RNAs (sgRNAs) for small-scale functional screening of lncRNAs4. Here they demonstrate genome-wide screening of lncRNA function using sgRNAs to target splice sites and achieve exon skipping or intron retention. Splice-site targeting outperformed a conventional CRISPR library in a negative selection screen targeting 79 ribosomal genes. Using a genome-scale library of splicing-targeting sgRNAs, they performed a screen covering 10,996 lncRNAs and identified 230 that are essential for cellular growth of chronic myeloid leukemia K562 cells. Screening GM12878 lymphoblastoid cells and HeLa cells with the same library identified cell-type-specific differences in lncRNA essentiality. Extensive validation confirmed the robustness of our approach.

Read more, please click https://www.nature.com/articles/nbt.4283

2. Identification of spatially associated subpopulations by combining scRNAseq and sequential fluorescence in situ hybridization data

How intrinsic gene-regulatory networks interact with a cell's spatial environment to define its identity remains poorly understood. Qian Zhu at Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health in Massachusetts, USA and his colleagues developed an approach to distinguish between intrinsic and extrinsic effects on global gene expression by integrating analysis of sequencing-based and imaging-based single-cell transcriptomic profiles, using cross-platform cell type mapping combined with a hidden Markov random field model. They applied this approach to dissect the cell-type- and spatial-domain-associated heterogeneity in the mouse visual cortex region. Their analysis identified distinct spatially associated, cell-type-independent signatures in the glutamatergic and astrocyte cell compartments. Using these signatures to analyze single-cell RNA sequencing data, they identified previously unknown spatially associated subpopulations, which were validated by comparison with anatomical structures and Allen Brain Atlas images.



Read more, please click https://www.nature.com/articles/nbt.4260

3. De novo assembly of haplotype-resolved genomes with trio binning

Complex allelic variation hampers the assembly of haplotype-resolved sequences from diploid genomes. Sergey Koren at National Human Genome Research Institute in Maryland, USA and his colleagues developed trio binning, an approach that simplifies haplotype assembly by resolving allelic variation before assembly. In contrast with prior approaches, the effectiveness of their method improved with increasing heterozygosity. Trio binning uses short reads from two parental genomes to first partition long reads from an offspring into haplotype-specific sets. Each haplotype is then assembled independently, resulting in a complete diploid reconstruction. They used trio binning to recover both haplotypes of a diploid human genome and identified complex structural variants missed by alternative approaches. They sequenced an F1 cross between the cattle subspecies Bos taurus taurus and Bos taurus indicus and completely assembled both parental haplotypes with NG50 haplotig sizes of >20 Mb and 99.998% accuracy, surpassing the quality of current cattle reference genomes. They suggest that trio binning improves diploid genome assembly and will facilitate new studies of haplotype variation and inheritance.

Read more, please click https://www.nature.com/articles/nbt.4277

4. An integrative tissue-network approach to identify and test human disease genes

Effective discovery of causal disease genes must overcome the statistical challenges of quantitative genetics studies and the practical limitations of human biology experiments. Here Victoria Yao at Princeton University in New Jersey, USA and his colleagues developed diseaseQUEST, an integrative approach that combines data from human genome-wide disease studies with in silico network models of tissue- and cell-type-specific function in model organisms to prioritize candidates within functionally conserved processes and pathways. They used diseaseQUEST to predict candidate genes for 25 different diseases and traits, including cancer, longevity, and neurodegenerative diseases. Focusing on Parkinson's disease (PD), a diseaseQUEST-directed Caenhorhabditis elegans behavioral screen identified several candidate genes, which they experimentally verified and found to be associated with age-dependent motility defects mirroring PD clinical symptoms. Furthermore, knockdown of the top candidate gene, bcat-1, encoding a branched chain amino acid transferase, caused spasm-like 'curling' and neurodegeneration in C. elegans, paralleling decreased BCAT1 expression in PD patient brains. diseaseQUEST is modular and generalizable to other model organisms and human diseases of interest.

Read more, please click https://www.nature.com/articles/nbt.4246

5. High-quality genome sequences of uncultured microbes by assembly of read clouds

Although shotgun metagenomic sequencing of microbiome samples enables partial reconstruction of strain-level community structure, obtaining high-quality microbial genome drafts without isolation and culture remains difficult. Here, Alex Bishara at Stanford University in California, USA and his colleagues present an application of read clouds, short-read sequences tagged with long-range information, to microbiome samples. They present Athena, a de novo assembler that uses read clouds to improve metagenomic assemblies. They applied this approach to sequence stool samples from two healthy individuals and compared it with existing short-read and synthetic long-read metagenomic sequencing techniques. Read-cloud metagenomic sequencing and Athena assembly produced the most comprehensive individual genome drafts with high contiguity (>200-kb N50, fewer than ten contigs), even for bacteria with relatively low (20×) raw short-read-sequence coverage. They also sequenced a complex marine-sediment sample and generated 24 intermediate-quality genome drafts (>70% complete, <10% contaminated), nine of which were complete (>90% complete, <5% contaminated). Their approach allows for culture-free generation of high-quality microbial genome drafts by using a single shotgun experiment.

Read more, please click https://www.nature.com/articles/nbt.4266

The Nobel Prize in Physiology or Medicine 1998

The Nobel Prize in Physiology or Medicine 1998 was awarded jointly to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system."

Nobelist	Born	Died	Affiliation at the time of the award
Robert F. Furchgott	4 June 1916, Charleston, SC, USA	19 May 2009, Seattle, WA, USA	SUNY Health Science Center, Brooklyn, NY, USA
Louis J. Ignarro	31 May 1941, Brooklyn, NY, USA		University of California School of Medicine, Los Angeles, CA, USA
Ferid Murad	14 September 1936, Whiting, IN, USA		University of Texas Medical School at Houston, Houston, TX, USA

Background

Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.

It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.

Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.
– When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.
– When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.
– When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.

Please click https://www.nobelprize.org/prizes/medicine/1998/press-release/ for more detailed information.

 

The Nobel Prize in Physiology or Medicine 1998

The Nobel Prize in Physiology or Medicine 1998 was awarded jointly to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system."

Nobelist	Born	Died	Affiliation at the time of the award
Robert F. Furchgott	4 June 1916, Charleston, SC, USA	19 May 2009, Seattle, WA, USA	SUNY Health Science Center, Brooklyn, NY, USA
Louis J. Ignarro	31 May 1941, Brooklyn, NY, USA		University of California School of Medicine, Los Angeles, CA, USA
Ferid Murad	14 September 1936, Whiting, IN, USA		University of Texas Medical School at Houston, Houston, TX, USA

Background

Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.

It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.

Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.
– When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.
– When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.
– When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.

Please click https://www.nobelprize.org/prizes/medicine/1998/press-release/ for more detailed information.

 

The Nobel Prize in Physiology or Medicine 1998

The Nobel Prize in Physiology or Medicine 1998 was awarded jointly to Robert F. Furchgott, Louis J. Ignarro and Ferid Murad "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system."

Nobelist	Born	Died	Affiliation at the time of the award
Robert F. Furchgott	4 June 1916, Charleston, SC, USA	19 May 2009, Seattle, WA, USA	SUNY Health Science Center, Brooklyn, NY, USA
Louis J. Ignarro	31 May 1941, Brooklyn, NY, USA		University of California School of Medicine, Los Angeles, CA, USA
Ferid Murad	14 September 1936, Whiting, IN, USA		University of Texas Medical School at Houston, Houston, TX, USA

Background

Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.

It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.

Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.
– When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.
– When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.
– When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.

Please click https://www.nobelprize.org/prizes/medicine/1998/press-release/ for more detailed information.

 

Targeted neurotechnology restores walking in humans with spinal cord injury

Content introduction:

• TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle


• Targeted neurotechnology restores walking in humans with spinal cord injury


• DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells


• Shared and distinct transcriptomic cell types across neocortical areas


• De novo NAD+ synthesis enhances mitochondrial function and improves health

1. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle
A dominant histopathological feature in neuromuscular diseases, including amyotrophic lateral sclerosis and inclusion body myopathy, is cytoplasmic aggregation of the RNA-binding protein TDP-43. Although rare mutations in TARDBP—the gene that encodes TDP-43—that lead to protein misfolding often cause protein aggregation, most patients do not have any mutations in TARDBP. Therefore, aggregates of wild-type TDP-43 arise in most patients by an unknown mechanism. Here Thomas O. Vogler at University of Colorado in Boulder, USA and his colleagues show that TDP-43 is an essential protein for normal skeletal muscle formation that unexpectedly forms cytoplasmic, amyloid-like oligomeric assemblies, which they call myo-granules, during regeneration of skeletal muscle in mice and humans. Myo-granules bind to mRNAs that encode sarcomeric proteins and are cleared as myofibres mature. Although myo-granules occur during normal skeletal-muscle regeneration, myo-granules can seed TDP-43 amyloid fibrils in vitro and are increased in a mouse model of inclusion body myopathy. Therefore, increased assembly or decreased clearance of functionally normal myo-granules could be the source of cytoplasmic TDP-43 aggregates that commonly occur in neuromuscular disease.

Read more, please click https://www.nature.com/articles/s41586-018-0665-2

2. Targeted neurotechnology restores walking in humans with spinal cord injury
Spinal cord injury leads to severe locomotor deficits or even complete leg paralysis. Here Fabien B. Wagner at Swiss Federal Institute of Technology (EPFL) in Lausanne, Switzerland and his colleagues introduce targeted spinal cord stimulation neurotechnologies that enabled voluntary control of walking in individuals who had sustained a spinal cord injury more than four years ago and presented with permanent motor deficits or complete paralysis despite extensive rehabilitation. Using an implanted pulse generator with real-time triggering capabilities, they delivered trains of spatially selective stimulation to the lumbosacral spinal cord with timing that coincided with the intended movement. Within one week, this spatiotemporal stimulation had re-established adaptive control of paralysed muscles during overground walking. Locomotor performance improved during rehabilitation. After a few months, participants regained voluntary control over previously paralysed muscles without stimulation and could walk or cycle in ecological settings during spatiotemporal stimulation. These results establish a technological framework for improving neurological recovery and supporting the activities of daily living after spinal cord injury.



Read more, please click https://www.nature.com/articles/s41586-018-0649-2

3. DYNLL1 binds to MRE11 to limit DNA end resection in BRCA1-deficient cells

Limited DNA end resection is the key to impaired homologous recombination in BRCA1-mutant cancer cells. Here, using a loss-of-function CRISPR screen, Yizhou Joseph He at Harvard Medical School in Boston, USA and his colleagues identify DYNLL1 as an inhibitor of DNA end resection. The loss of DYNLL1 enables DNA end resection and restores homologous recombination in BRCA1-mutant cells, thereby inducing resistance to platinum drugs and inhibitors of poly(ADP-ribose) polymerase. Low BRCA1 expression correlates with increased chromosomal aberrations in primary ovarian carcinomas, and the junction sequences of somatic structural variants indicate diminished homologous recombination. Concurrent decreases in DYNLL1 expression in carcinomas with low BRCA1 expression reduced genomic alterations and increased homology at lesions. In cells, DYNLL1 limits nucleolytic degradation of DNA ends by associating with the DNA end-resection machinery (MRN complex, BLM helicase and DNA2 endonuclease). In vitro, DYNLL1 binds directly to MRE11 to limit its end-resection activity. Therefore, they infer that DYNLL1 is an important anti-resection factor that influences genomic stability and responses to DNA-damaging chemotherapy.

Read more, please click https://www.nature.com/articles/s41586-018-0670-5
4. Shared and distinct transcriptomic cell types across neocortical areas
The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here Bosiljka Tasic at Allen Institute for Brain Science in Seattle, USA and his colleagues analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. They define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, they match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Their study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Read more, please click https://www.nature.com/articles/s41586-018-0654-5

5. De novo NAD+ synthesis enhances mitochondrial function and improves health
Nicotinamide adenine dinucleotide (NAD+) is a co-substrate for several enzymes, including the sirtuin family of NAD+-dependent protein deacylases. Beneficial effects of increased NAD+ levels and sirtuin activation on mitochondrial homeostasis, organismal metabolism and lifespan have been established across species. Here Elena Katsyuba at École Polytechnique Fédérale de Lausanne in Lausanne, Switzerland and his colleagues show that α-amino-β-carboxymuconate-ε-semialdehyde decarboxylase (ACMSD), the enzyme that limits spontaneous cyclization of α-amino-β-carboxymuconate-ε-semialdehyde in the de novo NAD+ synthesis pathway, controls cellular NAD+ levels via an evolutionarily conserved mechanism in Caenorhabditis elegans and mouse. Genetic and pharmacological inhibition of ACMSD boosts de novo NAD+ synthesis and sirtuin 1 activity, ultimately enhancing mitochondrial function. They also characterize two potent and selective inhibitors of ACMSD. Because expression of ACMSD is largely restricted to kidney and liver, these inhibitors may have therapeutic potential for protection of these tissues from injury. In summary, they identify ACMSD as a key modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis in kidney and liver.

Read more, please click https://www.nature.com/articles/s41586-018-0645-6