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

The Nobel Prize in Physiology or Medicine 1999

The Nobel Prize in Physiology or Medicine 1999 was awarded to Günter Blobel "for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell."

Günter Blobel Facts:

Günter Blobel

Born: 21 May 1936, Waltersdorf (now Niegoslawice), Germany (now Poland)

Died: 18 February 2018, New York, NY, USA

Affiliation at the time of the award: Rockefeller University, New York, NY, USA

Summary
A large number of proteins carrying out essential functions are constantly being made within our cells. These proteins have to be transported either out of the cell, or to the different compartments – the organelles – within the cell. How are newly made proteins transported across the membrane surrounding the organelles, and how are they directed to their correct location?

These questions have been answered through the work of this year’s Nobel Laureate in Physiology or Medicine, Dr Günter Blobel, a cell and molecular biologist at the Rockefeller University in New York. Already at the beginning of the 1970s he discovered that newly synthesized proteins have an intrinsic signal that is essential for governing them to and across the membrane of the endoplasmic reticulum, one of the cell’s organelles. During the next twenty years Blobel characterized in detail the molecular mechanisms underlying these processes. He also showed that similar “address tags”, or “zip codes”, direct proteins to other intracellular organelles.

The principles discovered and described by Günter Blobel turned out to be universal, operating similarly in yeast, plant, and animal cells. A number of human hereditary diseases are caused by errors in these signals and transport mechanisms. Blobel’s research has also contributed to the development of a more effective use of cells as “protein factories” for the production of important drugs.



Please click https://www.nobelprize.org/prizes/medicine/1999/press-release/ for more detailed information.

 

The Nobel Prize in Physiology or Medicine 1999

The Nobel Prize in Physiology or Medicine 1999 was awarded to Günter Blobel "for the discovery that proteins have intrinsic signals that govern their transport and localization in the cell."

Günter Blobel Facts:

Günter Blobel

Born: 21 May 1936, Waltersdorf (now Niegoslawice), Germany (now Poland)

Died: 18 February 2018, New York, NY, USA

Affiliation at the time of the award: Rockefeller University, New York, NY, USA

Summary
A large number of proteins carrying out essential functions are constantly being made within our cells. These proteins have to be transported either out of the cell, or to the different compartments – the organelles – within the cell. How are newly made proteins transported across the membrane surrounding the organelles, and how are they directed to their correct location?

These questions have been answered through the work of this year’s Nobel Laureate in Physiology or Medicine, Dr Günter Blobel, a cell and molecular biologist at the Rockefeller University in New York. Already at the beginning of the 1970s he discovered that newly synthesized proteins have an intrinsic signal that is essential for governing them to and across the membrane of the endoplasmic reticulum, one of the cell’s organelles. During the next twenty years Blobel characterized in detail the molecular mechanisms underlying these processes. He also showed that similar “address tags”, or “zip codes”, direct proteins to other intracellular organelles.

The principles discovered and described by Günter Blobel turned out to be universal, operating similarly in yeast, plant, and animal cells. A number of human hereditary diseases are caused by errors in these signals and transport mechanisms. Blobel’s research has also contributed to the development of a more effective use of cells as “protein factories” for the production of important drugs.



Please click https://www.nobelprize.org/prizes/medicine/1999/press-release/ for more detailed information.

 

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

• A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans


• In utero priming of highly functional effector T cell responses to human malaria


• Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3


• Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling


• The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.



Read more, please click http://stke.sciencemag.org/content/11/553/eaat5916

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

• A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans


• In utero priming of highly functional effector T cell responses to human malaria


• Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3


• Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling


• The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.



Read more, please click http://stke.sciencemag.org/content/11/553/eaat5916

The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Content introduction:

• A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans


• In utero priming of highly functional effector T cell responses to human malaria


• Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3


• Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling


• The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

1. A dysbiotic microbiome triggers TH17 cells to mediate oral mucosal immunopathology in mice and humans

Periodontitis is one of the most common human inflammatory diseases, yet the mechanisms that drive immunopathology and could be therapeutically targeted are not well defined. Here, Nicolas Dutzan at NIH in Bethesda, USA and his colleagues demonstrate an expansion of resident memory T helper 17 (TH17) cells in human periodontitis. Phenocopying humans, TH17 cells expanded in murine experimental periodontitis through local proliferation. Unlike homeostatic oral TH17 cells, which accumulate in a commensal-independent and interleukin-6 (IL-6)–dependent manner, periodontitis-associated expansion of TH17 cells was dependent on the local dysbiotic microbiome and required both IL-6 and IL-23. TH17 cells and associated neutrophil accumulation were necessary for inflammatory tissue destruction in experimental periodontitis. Genetic or pharmacological inhibition of TH17 cell differentiation conferred protection from immunopathology. Studies in a unique patient population with a genetic defect in TH17 cell differentiation established human relevance for our murine experimental studies. In the oral cavity, human TH17 cell defects were associated with diminished periodontal inflammation and bone loss, despite increased prevalence of recurrent oral fungal infections. Their study highlights distinct functions of TH17 cells in oral immunity and inflammation and paves the way to a new targeted therapeutic approach for the treatment of periodontitis.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat0797

2. In utero priming of highly functional effector T cell responses to human malaria

Malaria remains a significant cause of morbidity and mortality worldwide, particularly in infants and children. Some studies have reported that exposure to malaria antigens in utero results in the development of tolerance, which could contribute to poor immunity to malaria in early life. However, the effector T cell response to pathogen-derived antigens encountered in utero, including malaria, has not been well characterized. Here, Pamela M. Odorizzi at University of California in San Francisco, USA and his colleagues assessed the frequency, phenotype, and function of cord blood T cells from Ugandan infants born to mothers with and without placental malaria. They found that infants born to mothers with active placental malaria had elevated frequencies of proliferating effector memory fetal CD4+ T cells and higher frequencies of CD4+ and CD8+ T cells that produced inflammatory cytokines. Fetal CD4+ and CD8+ T cells from placental malaria–exposed infants exhibited greater in vitro proliferation to malaria antigens. Malaria-specific CD4+ T cell proliferation correlated with prospective protection from malaria during childhood. These data demonstrate that placental malaria is associated with the generation of proinflammatory malaria-responsive fetal T cells. These findings add to our current understanding of fetal immunity and indicate that a functional and protective pathogen-specific T cell response can be generated in utero.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat6176

3. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3

A primary barrier to the success of T cell–recruiting bispecific antibodies in the treatment of solid tumors is the lack of tumor-specific targets, resulting in on-target off-tumor adverse effects from T cell autoreactivity to target-expressing organs. To overcome this, Dionysos Slaga at Genentech Inc in South San Francisco, USA and his colleagues developed an anti-HER2/CD3 T cell–dependent bispecific (TDB) antibody that selectively targets HER2-overexpressing tumor cells with high potency, while sparing cells that express low amounts of HER2 found in normal human tissues. Selectivity is based on the avidity of two low-affinity anti-HER2 Fab arms to high target density on HER2-overexpressing cells. The increased selectivity to HER2-overexpressing cells is expected to mitigate the risk of adverse effects and increase the therapeutic index. Results included in this manuscript not only support the clinical development of anti-HER2/CD3 1Fab–immunoglobulin G TDB but also introduce a potentially widely applicable strategy for other T cell–directed therapies. The potential of this discovery has broad applications to further enable consideration of solid tumor targets that were previously limited by on-target, but off-tumor, autoimmunity.

Read more, please click http://stm.sciencemag.org/content/10/463/eaat5775

4. Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling

In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. Ganlan Bian at Fourth Military Medical University in Xi’an, China and his colleagues identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Their results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.

Read more, please click http://stke.sciencemag.org/content/11/553/eaat1470

5. The Src family kinase Fgr is a transforming oncoprotein that functions independently of SH3-SH2 domain regulation

Fgr is a member of the Src family of nonreceptor tyrosine kinases, which are overexpressed and constitutively active in many human cancers. Fgr expression is restricted to myeloid hematopoietic cells and is markedly increased in a subset of bone marrow samples from patients with acute myeloid leukemia (AML). Here, Kexin Shen at University of Pittsburgh School of Medicine in Pittsburgh, USA and his colleagues investigated the oncogenic potential of Fgr using Rat-2 fibroblasts that do not express the kinase. Expression of either wild-type or regulatory tail-mutant constructs of Fgr promoted cellular transformation (inferred from colony formation in soft agar), which was accompanied by phosphorylation of the Fgr activation loop, suggesting that the kinase domain of Fgr functions independently of regulation by its noncatalytic SH3-SH2 region. Unlike other family members, recombinant Fgr was not activated by SH3-SH2 domain ligands. However, hydrogen-deuterium exchange mass spectrometry data suggested that the regulatory SH3 and SH2 domains packed against the back of the kinase domain in a Src-like manner. Sequence alignment showed that the activation loop of Fgr was distinct from that of all other Src family members, with proline rather than alanine at the +2 position relative to the activation loop tyrosine. Substitution of the activation loop of Fgr with the sequence from Src partially inhibited kinase activity and suppressed colony formation. Last, Fgr expression enhanced the sensitivity of human myeloid progenitor cells to the cytokine GM-CSF. Because its kinase domain is not sensitive to SH3-SH2–mediated control, simple overexpression of Fgr without mutation may contribute to oncogenic transformation in AML and other blood cancers.



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The Nobel Prize in Physiology or Medicine 2000

The Nobel Prize in Physiology or Medicine 2000 was awarded jointly to Arvid Carlsson, Paul Greengard and Eric R. Kandel "for their discoveries concerning signal transduction in the nervous system."

Nobelist	Born	Died	Affiliation at the time of the award
Arvid Carlsson	25 January 1923, Uppsala, Sweden	29 June 2018, Gothenburg, Sweden	Göteborg University, Gothenburg, Sweden
Paul Greengard	11 December 1925, New York, NY, USA		Rockefeller University, New York, NY, USA
Eric R. Kandel	7 November 1929, Vienna, Austria		Columbia University, New York, NY, USA

Summary

In the human brain there are more than hundred billion nerve cells. They are connected to each other through an infinitely complex network of nerve processes. The message from one nerve cell to another is transmitted through different chemical transmitters. The signal transduction takes place in special points of contact, called synapses. A nerve cell can have thousands of such contacts with other nerve cells.

The three Nobel Laureates in Physiology or Medicine have made pioneering discoveries concerning one type of signal transduction between nerve cells, referred to as slow synaptic transmission. These discoveries have been crucial for an understanding of the normal function of the brain and how disturbances in this signal transduction can give rise to neurological and psychiatric diseases. These findings have resulted in the development of new drugs.



More details, please click The Nobel Prize in Physiology or Medicine 2000.