In order to probe the efficacy of new immune-intervention strategies in alopecia areata, the field can now choose from two mutually complementary mouse models.
Break through in biochemistry biotechnology[616]Dr.K Madhuri
The document discusses recent breakthroughs in biotechnology, biochemistry, and biology. Some key points include:
- Researchers have developed a device called the Moosy 32 eNose that can detect colon diseases by analyzing volatile compounds.
- Scientists have created human-pig embryos and developed an artificial womb to help extremely premature lambs survive.
- A new method called "cellular leapfrogging" allows mature cells like liver cells to be transformed into other cell types like neurons.
- CAR T-cell immunotherapy was approved for cancer treatment, engineering immune cells to target tumors.
- Advances could help address problems like malnutrition, crop failure, and extend human lifespans.
Receptor binding and antigenic site analysis of hemagglutinin gene fragments ...UniversitasGadjahMada
We reported a retrospective study on hemagglutinin (HA) gene fragments of Avian Influenza (AI) viruses recovered between 2010 to 2012, using reverse transcriptase polymerase chain reaction (RT-PCR) followed by sequencing. The results provide information about the receptor binding sites (RBS) and antigenic sites character of HA gene of AI viruses in Indonesia. Viral RNA was extracted from allantoic fluid of specific pathogen free (SPF) of chicken embryonated eggs inoculated by AI suspected samples. Amplification was performed by using H5 specific primers to produce amplification target of 544 bp. The resulting sequences were analyzed with MEGA-5 consisting of multiple alignment, deductive amino acid prediction, and phylogenetic tree analysis. The results showed that out of the 12 samples amplified using RT-PCR technique, only 7 were detected to be avian influenza serotype H5 viruses. Sequence analysis of AIV H5 positive samples, showed a binding preference towards avian type receptors. Antigenic site analysis is consistent with the previous report, however, the antigenic site B at position 189 showed that the residue had undergone mutation from arginine to methionine. Phylogenetic tree analysis showed that these viruses were clustered into clade 2.1.3. Our report supports the importance of the previous study of RBS and antigenic properties of HPAI H5N1 in Indonesia.
UTF-8''Final Assessing post-synaptic partners of Dentate Granule Cells in a M...Grant Pizzo
1) The document describes an experiment assessing how dentate granule cell (DGC) axon terminals and their post-synaptic partners change in a rat model of temporal lobe epilepsy (TLE).
2) The researcher induced seizures in rats using pilocarpine and later injected retroviruses to label dividing DGCs. Tissue was then analyzed to identify post-synaptic partners of DGCs using antibodies targeting interneurons and mossy cells.
3) Preliminary results showed that antibodies for GAD67 and GluR2 successfully labeled the correct cell types, but need further refinement, while an mGluR1/5 antibody did not label interneurons in the dentate gyrus
This document reports on a study that found adult hippocampal neural stem and progenitor cells (NSPCs) secrete significant amounts of vascular endothelial growth factor (VEGF), which plays an important role in maintaining the adult neurogenic niche. The study showed that NSPCs in the adult hippocampus express VEGF both in vivo and in vitro. Inducible knockout of VEGF specifically in NSPCs led to a 20-30% reduction in total hippocampal VEGF levels and impaired stem cell maintenance over time, demonstrating the functional relevance of NSPC-derived VEGF. These findings reveal that NSPCs act as a previously unknown secretory cell type that helps regulate the neurogenic niche through VEGF secretion.
This document summarizes a study identifying the genetic cause of Heimler syndrome (HS). Whole exome sequencing was performed on individuals from eight families with HS. Biallelic mutations in the peroxisome biogenesis genes PEX1 or PEX6 were identified in six families. These findings define HS as a mild peroxisome biogenesis disorder caused by hypomorphic PEX1 or PEX6 mutations, expanding the clinical spectrum of these genes.
The document describes malaria immunology and epidemiology studies conducted in Papua New Guinea between 2004-2017. It involved several cohort and intervention studies with observational cohorts of approximately 500-2000 individuals. The studies aimed to understand immunity targets and mechanisms to malaria in order to rationalize vaccine development. They examined both antibody and cellular immune responses. Key findings included that γδ T cells are a major source of IFNγ response and certain NK cell receptors are associated with risk of high density infections.
Break through in biochemistry biotechnology[616]Dr.K Madhuri
The document discusses recent breakthroughs in biotechnology, biochemistry, and biology. Some key points include:
- Researchers have developed a device called the Moosy 32 eNose that can detect colon diseases by analyzing volatile compounds.
- Scientists have created human-pig embryos and developed an artificial womb to help extremely premature lambs survive.
- A new method called "cellular leapfrogging" allows mature cells like liver cells to be transformed into other cell types like neurons.
- CAR T-cell immunotherapy was approved for cancer treatment, engineering immune cells to target tumors.
- Advances could help address problems like malnutrition, crop failure, and extend human lifespans.
Receptor binding and antigenic site analysis of hemagglutinin gene fragments ...UniversitasGadjahMada
We reported a retrospective study on hemagglutinin (HA) gene fragments of Avian Influenza (AI) viruses recovered between 2010 to 2012, using reverse transcriptase polymerase chain reaction (RT-PCR) followed by sequencing. The results provide information about the receptor binding sites (RBS) and antigenic sites character of HA gene of AI viruses in Indonesia. Viral RNA was extracted from allantoic fluid of specific pathogen free (SPF) of chicken embryonated eggs inoculated by AI suspected samples. Amplification was performed by using H5 specific primers to produce amplification target of 544 bp. The resulting sequences were analyzed with MEGA-5 consisting of multiple alignment, deductive amino acid prediction, and phylogenetic tree analysis. The results showed that out of the 12 samples amplified using RT-PCR technique, only 7 were detected to be avian influenza serotype H5 viruses. Sequence analysis of AIV H5 positive samples, showed a binding preference towards avian type receptors. Antigenic site analysis is consistent with the previous report, however, the antigenic site B at position 189 showed that the residue had undergone mutation from arginine to methionine. Phylogenetic tree analysis showed that these viruses were clustered into clade 2.1.3. Our report supports the importance of the previous study of RBS and antigenic properties of HPAI H5N1 in Indonesia.
UTF-8''Final Assessing post-synaptic partners of Dentate Granule Cells in a M...Grant Pizzo
1) The document describes an experiment assessing how dentate granule cell (DGC) axon terminals and their post-synaptic partners change in a rat model of temporal lobe epilepsy (TLE).
2) The researcher induced seizures in rats using pilocarpine and later injected retroviruses to label dividing DGCs. Tissue was then analyzed to identify post-synaptic partners of DGCs using antibodies targeting interneurons and mossy cells.
3) Preliminary results showed that antibodies for GAD67 and GluR2 successfully labeled the correct cell types, but need further refinement, while an mGluR1/5 antibody did not label interneurons in the dentate gyrus
This document reports on a study that found adult hippocampal neural stem and progenitor cells (NSPCs) secrete significant amounts of vascular endothelial growth factor (VEGF), which plays an important role in maintaining the adult neurogenic niche. The study showed that NSPCs in the adult hippocampus express VEGF both in vivo and in vitro. Inducible knockout of VEGF specifically in NSPCs led to a 20-30% reduction in total hippocampal VEGF levels and impaired stem cell maintenance over time, demonstrating the functional relevance of NSPC-derived VEGF. These findings reveal that NSPCs act as a previously unknown secretory cell type that helps regulate the neurogenic niche through VEGF secretion.
This document summarizes a study identifying the genetic cause of Heimler syndrome (HS). Whole exome sequencing was performed on individuals from eight families with HS. Biallelic mutations in the peroxisome biogenesis genes PEX1 or PEX6 were identified in six families. These findings define HS as a mild peroxisome biogenesis disorder caused by hypomorphic PEX1 or PEX6 mutations, expanding the clinical spectrum of these genes.
The document describes malaria immunology and epidemiology studies conducted in Papua New Guinea between 2004-2017. It involved several cohort and intervention studies with observational cohorts of approximately 500-2000 individuals. The studies aimed to understand immunity targets and mechanisms to malaria in order to rationalize vaccine development. They examined both antibody and cellular immune responses. Key findings included that γδ T cells are a major source of IFNγ response and certain NK cell receptors are associated with risk of high density infections.
1. The study characterized antibody responses to Plasmodium falciparum invasion ligands EBA-140 and EBA-181 in individuals from malaria-endemic areas of Brazil and Cameroon.
2. Responses differed between populations, with African individuals strongly reacting to most EBA fragments while Brazilian individuals from Mato Grosso reacted weakly and those from the Amazon had elevated but lower responses than Africans.
3. When compared to responses against other malaria proteins, the Brazilian population appeared to have more variable ability to recognize P. falciparum invasion ligands, distinct from the African population.
The document summarizes new patent issues surrounding therapeutic antibodies. It discusses how antibodies have become a major class of therapeutic drugs and outlines key cases that have shaped patent law in this area. The document focuses on issues of enablement, written description, obviousness, and anticipation as the law has evolved to address emerging antibody technologies. It analyzes several important court cases and how they have impacted what can be claimed and whether certain claims have adequate support or are invalid. The document also raises questions about current issues like subgeneric claims and selection of antibody leads during research.
The prevalence of Copy Number Variation (CNV) on human chromosome 16p11.2, identified in approximately 1% of autism spectrum disorder (ASD) cases globally, was found to be 1.2% in an Australian ASD cohort. Bioinformatic analysis identified 13 of the 25 protein coding genes within the 16p11.2 region, including KCTD13, as significantly enriched in the nervous system. Experiments in mice found that suppression of Kctd13 led to impaired radial migration of cortical neurons and altered neuronal morphology, providing insight into how perturbations to KCTD13 expression via 16p11.2 microdeletion could influence brain development. Further experiments showed decreased cell proliferation and mitosis levels
Novel induction of alopecia areata in C3H/HeJ mice shows a potential role of previously unrecognized endogenous SSEA-positive myeloid cells in driving inflammatory cascade and hair loss mechanisms.
The document summarizes information about human granulocytic anaplasmosis (HGA), a tick-borne disease caused by the bacterium Anaplasma phagocytophilum. It was first reported in the United States in 1990. HGA symptoms include fever, headache, muscle aches, and fatigue. It can cause severe complications in some patients, such as respiratory failure and death. The disease is transmitted through tick bites and patients may experience symptoms 1-2 weeks after being bitten by an infected tick.
This document discusses genetic engineering and DNA technology. It explains that genetic engineering involves manipulating DNA from different organisms by splicing genes together or inserting select genes. This allows genes to be engineered for mass production in organisms like bacteria. Examples given include producing human insulin in E. coli and creating glowing plants. The document also discusses genetic modification of crops, animal cloning, stem cells, and debates around genetic engineering.
I. Computational analysis identified novel B- and T- cell epitopes from the glycoprotein and nucleoprotein of Ebola virus, including AIGLAWIPY, YDDDDDIPF, SQDTTIPDV, VSHLTTLAT, DLVLFDLDE, LRQLANETTT, and DYHKILTAGL.
II. A novel B-cell epitope was extracted from the 3D structure of Ebola glycoprotein bound to an antibody, and its sequence motifs were predicted by multiple algorithms.
III. An epitope from the nucleoprotein contained a conserved protein fingerprint that defines the WW domain-containing WAC protein, and a potential WW domain was
Researchers used zinc-finger nucleases (ZFNs) to generate knockout rats by targeting three genes - green fluorescent protein (GFP), Immunoglobulin M (IgM), and Rab38. ZFNs were microinjected into rat embryos to induce mutations in the target genes. Of 295 founder animals screened, 35 (12%) contained targeted mutations, including full knockout of the GFP transgene in some animals. Mutations were transmitted to offspring, demonstrating the ability of ZFNs to disrupt genes and induce heritable mutations in the rat genome. This technique allows for targeted genetic modification of the rat, an important model for studying human disease.
1. Organ transplantation is used to treat organs that are severely malformed or damaged, with rejection by the host immune system being a major obstacle.
2. There are different types of transplants based on how similar the donor and recipient are genetically, ranging from autographs within an individual to xenographs between species.
3. The most common form of allograft is blood transfusion.
This document discusses the use of CRISPR gene editing technology. It provides examples of how CRISPR has been used to cure diseases in animals and potentially humans, create customized cancer models and modify animal organs. It also describes how CRISPR can be applied in agriculture to develop drought-resistant and pest-resistant crops, as well as in industrial biotechnology settings. The document then explains how gene drives work to alter genes and spread them through populations using CRISPR. It calls for responsible development of this technology through community guidance, transparency and democratic decision making.
CRISPR is a gene editing technology that has many applications in medicine, agriculture, and the environment. It works by using guide RNA and Cas9 protein to edit genes. In medicine, it shows promise for treating diseases like HIV/AIDS, muscular dystrophy, and cancer. In agriculture and environment, CRISPR can be used to develop crops that are more nutritious, resistant to climate change and pests, helping reduce hunger and poverty. While the prospects for CRISPR are good, there are also ethical concerns to consider regarding its use and effects. The future of CRISPR is limitless but it should be applied cautiously.
This document discusses the potential benefits and risks of using CRISPR/Cas9 gene editing technology. Some key benefits discussed include its relatively low cost compared to other gene editing methods, its ability to efficiently and precisely edit genes, and recent successes using it to correct mutations that cause diseases like Duchenne Muscular Dystrophy in mice models. However, the document also notes potential risks like inducing unintended mutations, difficulties achieving a high enough editing rate, and risks of editing germline cells or human embryos. While promising for treating genetic diseases, the document argues that more research is still needed to minimize risks before clinical use, and that regulations will be important to guide its safe and ethical application.
Xenotransplantation involves transplanting organs or tissues from other animal species into humans as a way to address the shortage of human organs available for transplant. While research in this area is progressing, there are still concerns about immune rejection and the potential transmission of animal diseases to humans. Several biotech and pharmaceutical companies have active xenotransplantation programs focused on developing methods to prevent rejection and testing the use of pig organs in clinical trials. Regulatory agencies in the US and UK are providing oversight and guidance on clinical research in this emerging field.
1) In 2013, wheat stem rust outbreaks occurred in Ethiopia and parts of Western Europe for the first time in decades.
2) In Ethiopia, the variety "Digalu" was heavily affected, with some fields experiencing over 90% yield losses. Samples were collected and characterized, identifying the races TTKSK, JRCQC, and RRTTF.
3) In Western Europe, samples were collected from Germany and Denmark and characterized as the TKTT_ race, which had also been identified previously in the Middle East and North Africa.
This case report describes the first live birth resulting from pre-implantation genetic diagnosis (PGD) for Oculocutaneous Albinism type 1 (OCA1). A couple who were both carriers for OCA1 underwent two cycles of intracytoplasmic sperm injection with trophectoderm biopsy and next generation sequencing of the embryos. Two embryos were found to be normal and one was transferred, resulting in the live birth of a healthy baby boy without OCA1. This demonstrates the potential for PGD using trophectoderm biopsy and next generation sequencing to achieve successful pregnancies for couples at risk of passing on genetic diseases.
Transhumanismo y Mejoramiento Genético mediante CRISPRBioeticared
This document discusses CRISPR gene editing technology, including its origins and development, applications for therapeutic purposes, and debates around its use. It describes how CRISPR uses a guide RNA and Cas9 protein to cut DNA in a targeted way. While promising for treating genetic diseases, some argue its use in human embryos or germline cells raises safety and ethical issues due to risks of uncontrolled errors passing to future generations. Transhumanists support modifying the germline to induce enhanced traits, but this remains controversial.
Gene editing with CRISPR/Cas9: sorghum as a case studyapaari
This document summarizes a presentation on using CRISPR/Cas9 gene editing to improve sorghum. The presentation discusses using gene editing to increase grain size and protein content in sorghum, which could improve its use for animal feed. It describes ongoing research knocking out specific genes to increase grain size by over 10% and protein content by up to 24%. If successful, this could increase sorghum yields and protein per hectare for uses like poultry feed. The presentation notes that gene edited crops may not be classified as GMOs, depending on regulatory decisions, and outlines ongoing research using this technology in sorghum.
Defined tissue compartments of the hair follicle, namely the anagen hair bulb and the stem cell-harboring bulge
zone, enjoy a relative state of immune privilege. The protection and restoration of hair follicle immune privilege
remains the most fundamental prophylactic and therapeutic challenge in alopecia areata management.
1. T-cell infiltration is increased in the brains of transgenic mouse models of Alzheimer's disease-like cerebral amyloidosis compared to non-transgenic littermates. However, the infiltrating T-cells do not co-localize with amyloid plaques and produce less of the effector cytokine interferon-gamma.
2. Antigen-presenting cells in the brains of transgenic mice show an immature phenotype with accumulation of MHC-II in intracellular compartments, suggesting impaired antigen presentation.
3. The findings indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local T-cell activation and antigen presentation, which may contribute to amyloid accumulation in Alzheimer's disease progression.
1) WASp-deficient dendritic cells (DCs) show impaired activation of naive CD8+ T cells, especially at low antigen doses.
2) This is partly due to altered trafficking of antigen-bearing DCs from the periphery to lymph nodes. However, correcting DC migration does not fully rescue T cell activation.
3) In vitro and in vivo imaging revealed that cytoskeletal alterations in WASp-null DCs reduce their ability to form and maintain conjugates with naive CD8+ T cells in lymph nodes, contributing to defective T cell priming.
1. The study characterized antibody responses to Plasmodium falciparum invasion ligands EBA-140 and EBA-181 in individuals from malaria-endemic areas of Brazil and Cameroon.
2. Responses differed between populations, with African individuals strongly reacting to most EBA fragments while Brazilian individuals from Mato Grosso reacted weakly and those from the Amazon had elevated but lower responses than Africans.
3. When compared to responses against other malaria proteins, the Brazilian population appeared to have more variable ability to recognize P. falciparum invasion ligands, distinct from the African population.
The document summarizes new patent issues surrounding therapeutic antibodies. It discusses how antibodies have become a major class of therapeutic drugs and outlines key cases that have shaped patent law in this area. The document focuses on issues of enablement, written description, obviousness, and anticipation as the law has evolved to address emerging antibody technologies. It analyzes several important court cases and how they have impacted what can be claimed and whether certain claims have adequate support or are invalid. The document also raises questions about current issues like subgeneric claims and selection of antibody leads during research.
The prevalence of Copy Number Variation (CNV) on human chromosome 16p11.2, identified in approximately 1% of autism spectrum disorder (ASD) cases globally, was found to be 1.2% in an Australian ASD cohort. Bioinformatic analysis identified 13 of the 25 protein coding genes within the 16p11.2 region, including KCTD13, as significantly enriched in the nervous system. Experiments in mice found that suppression of Kctd13 led to impaired radial migration of cortical neurons and altered neuronal morphology, providing insight into how perturbations to KCTD13 expression via 16p11.2 microdeletion could influence brain development. Further experiments showed decreased cell proliferation and mitosis levels
Novel induction of alopecia areata in C3H/HeJ mice shows a potential role of previously unrecognized endogenous SSEA-positive myeloid cells in driving inflammatory cascade and hair loss mechanisms.
The document summarizes information about human granulocytic anaplasmosis (HGA), a tick-borne disease caused by the bacterium Anaplasma phagocytophilum. It was first reported in the United States in 1990. HGA symptoms include fever, headache, muscle aches, and fatigue. It can cause severe complications in some patients, such as respiratory failure and death. The disease is transmitted through tick bites and patients may experience symptoms 1-2 weeks after being bitten by an infected tick.
This document discusses genetic engineering and DNA technology. It explains that genetic engineering involves manipulating DNA from different organisms by splicing genes together or inserting select genes. This allows genes to be engineered for mass production in organisms like bacteria. Examples given include producing human insulin in E. coli and creating glowing plants. The document also discusses genetic modification of crops, animal cloning, stem cells, and debates around genetic engineering.
I. Computational analysis identified novel B- and T- cell epitopes from the glycoprotein and nucleoprotein of Ebola virus, including AIGLAWIPY, YDDDDDIPF, SQDTTIPDV, VSHLTTLAT, DLVLFDLDE, LRQLANETTT, and DYHKILTAGL.
II. A novel B-cell epitope was extracted from the 3D structure of Ebola glycoprotein bound to an antibody, and its sequence motifs were predicted by multiple algorithms.
III. An epitope from the nucleoprotein contained a conserved protein fingerprint that defines the WW domain-containing WAC protein, and a potential WW domain was
Researchers used zinc-finger nucleases (ZFNs) to generate knockout rats by targeting three genes - green fluorescent protein (GFP), Immunoglobulin M (IgM), and Rab38. ZFNs were microinjected into rat embryos to induce mutations in the target genes. Of 295 founder animals screened, 35 (12%) contained targeted mutations, including full knockout of the GFP transgene in some animals. Mutations were transmitted to offspring, demonstrating the ability of ZFNs to disrupt genes and induce heritable mutations in the rat genome. This technique allows for targeted genetic modification of the rat, an important model for studying human disease.
1. Organ transplantation is used to treat organs that are severely malformed or damaged, with rejection by the host immune system being a major obstacle.
2. There are different types of transplants based on how similar the donor and recipient are genetically, ranging from autographs within an individual to xenographs between species.
3. The most common form of allograft is blood transfusion.
This document discusses the use of CRISPR gene editing technology. It provides examples of how CRISPR has been used to cure diseases in animals and potentially humans, create customized cancer models and modify animal organs. It also describes how CRISPR can be applied in agriculture to develop drought-resistant and pest-resistant crops, as well as in industrial biotechnology settings. The document then explains how gene drives work to alter genes and spread them through populations using CRISPR. It calls for responsible development of this technology through community guidance, transparency and democratic decision making.
CRISPR is a gene editing technology that has many applications in medicine, agriculture, and the environment. It works by using guide RNA and Cas9 protein to edit genes. In medicine, it shows promise for treating diseases like HIV/AIDS, muscular dystrophy, and cancer. In agriculture and environment, CRISPR can be used to develop crops that are more nutritious, resistant to climate change and pests, helping reduce hunger and poverty. While the prospects for CRISPR are good, there are also ethical concerns to consider regarding its use and effects. The future of CRISPR is limitless but it should be applied cautiously.
This document discusses the potential benefits and risks of using CRISPR/Cas9 gene editing technology. Some key benefits discussed include its relatively low cost compared to other gene editing methods, its ability to efficiently and precisely edit genes, and recent successes using it to correct mutations that cause diseases like Duchenne Muscular Dystrophy in mice models. However, the document also notes potential risks like inducing unintended mutations, difficulties achieving a high enough editing rate, and risks of editing germline cells or human embryos. While promising for treating genetic diseases, the document argues that more research is still needed to minimize risks before clinical use, and that regulations will be important to guide its safe and ethical application.
Xenotransplantation involves transplanting organs or tissues from other animal species into humans as a way to address the shortage of human organs available for transplant. While research in this area is progressing, there are still concerns about immune rejection and the potential transmission of animal diseases to humans. Several biotech and pharmaceutical companies have active xenotransplantation programs focused on developing methods to prevent rejection and testing the use of pig organs in clinical trials. Regulatory agencies in the US and UK are providing oversight and guidance on clinical research in this emerging field.
1) In 2013, wheat stem rust outbreaks occurred in Ethiopia and parts of Western Europe for the first time in decades.
2) In Ethiopia, the variety "Digalu" was heavily affected, with some fields experiencing over 90% yield losses. Samples were collected and characterized, identifying the races TTKSK, JRCQC, and RRTTF.
3) In Western Europe, samples were collected from Germany and Denmark and characterized as the TKTT_ race, which had also been identified previously in the Middle East and North Africa.
This case report describes the first live birth resulting from pre-implantation genetic diagnosis (PGD) for Oculocutaneous Albinism type 1 (OCA1). A couple who were both carriers for OCA1 underwent two cycles of intracytoplasmic sperm injection with trophectoderm biopsy and next generation sequencing of the embryos. Two embryos were found to be normal and one was transferred, resulting in the live birth of a healthy baby boy without OCA1. This demonstrates the potential for PGD using trophectoderm biopsy and next generation sequencing to achieve successful pregnancies for couples at risk of passing on genetic diseases.
Transhumanismo y Mejoramiento Genético mediante CRISPRBioeticared
This document discusses CRISPR gene editing technology, including its origins and development, applications for therapeutic purposes, and debates around its use. It describes how CRISPR uses a guide RNA and Cas9 protein to cut DNA in a targeted way. While promising for treating genetic diseases, some argue its use in human embryos or germline cells raises safety and ethical issues due to risks of uncontrolled errors passing to future generations. Transhumanists support modifying the germline to induce enhanced traits, but this remains controversial.
Gene editing with CRISPR/Cas9: sorghum as a case studyapaari
This document summarizes a presentation on using CRISPR/Cas9 gene editing to improve sorghum. The presentation discusses using gene editing to increase grain size and protein content in sorghum, which could improve its use for animal feed. It describes ongoing research knocking out specific genes to increase grain size by over 10% and protein content by up to 24%. If successful, this could increase sorghum yields and protein per hectare for uses like poultry feed. The presentation notes that gene edited crops may not be classified as GMOs, depending on regulatory decisions, and outlines ongoing research using this technology in sorghum.
Defined tissue compartments of the hair follicle, namely the anagen hair bulb and the stem cell-harboring bulge
zone, enjoy a relative state of immune privilege. The protection and restoration of hair follicle immune privilege
remains the most fundamental prophylactic and therapeutic challenge in alopecia areata management.
1. T-cell infiltration is increased in the brains of transgenic mouse models of Alzheimer's disease-like cerebral amyloidosis compared to non-transgenic littermates. However, the infiltrating T-cells do not co-localize with amyloid plaques and produce less of the effector cytokine interferon-gamma.
2. Antigen-presenting cells in the brains of transgenic mice show an immature phenotype with accumulation of MHC-II in intracellular compartments, suggesting impaired antigen presentation.
3. The findings indicate that cerebral amyloidosis promotes T-cell infiltration but interferes with local T-cell activation and antigen presentation, which may contribute to amyloid accumulation in Alzheimer's disease progression.
1) WASp-deficient dendritic cells (DCs) show impaired activation of naive CD8+ T cells, especially at low antigen doses.
2) This is partly due to altered trafficking of antigen-bearing DCs from the periphery to lymph nodes. However, correcting DC migration does not fully rescue T cell activation.
3) In vitro and in vivo imaging revealed that cytoskeletal alterations in WASp-null DCs reduce their ability to form and maintain conjugates with naive CD8+ T cells in lymph nodes, contributing to defective T cell priming.
AA is not necessarily a single disease entity, but rather a stereotypic hair follicle damage response pattern that can be triggered by various pathogenic mechanisms. In some patients with autoreactive T cells, AA represents an autoimmune disease (AAA), while in others it may occur in response to stress, infection, or dysbiosis without specific autoimmunity. The classic AA clinical presentation arises when hair follicle immune privilege collapses during the growth (anagen) phase, attracting inflammatory cells that secrete IFNγ and induce premature regression (catagen). While causal therapy targeting autoreactive T cells may be possible for AAA, symptomatic therapies aiming to protect immune privilege and repair follicle damage are generally beneficial across AA variants.
This document describes a case study of a 5-year-old female Argentine patient with a mutation in the CD25 gene resulting in CD25 deficiency. Key findings include chronic inflammatory lung disease (follicular bronchiolitis), eczema, infections, extremely low levels of regulatory T cells, and a homozygous missense mutation (c.122a>c; p.Y41S) in the CD25αR gene. The mutation is predicted to compromise protein function and cause immune dysregulation similar to IPEX syndrome. CD25 deficiency should be considered in patients presenting with these clinical and laboratory features to facilitate early diagnosis and treatment.
Ld b 145 geni mutanti_2014-11-18 jamora - ricerca scientifica 3laboratoridalbasso
This document discusses the role of the transcription factor Snail in wound healing and fibrosis. It finds that overexpression of Snail in the epidermis of mice induces dermal fibrosis through increased secretion of spondin-2/mindin by keratinocytes. Spondin-2 then activates dermal fibroblasts by stimulating the NF-kB pathway, leading to increased expression of genes associated with myofibroblast differentiation and extracellular matrix production. This establishes a paracrine signaling mechanism from epidermal Snail to induce dermal fibrosis through spondin-2.
This document summarizes research on using humanized mouse models to study inflammatory skin diseases. Humanized mouse models are generated by transplanting human tissues like skin, immune cells, or organs into immunodeficient mouse strains. This allows the study of human immune cell trafficking and interactions in vivo. Models have been used to investigate processes like T-cell migration and recruitment to skin, as well as test potential anti-inflammatory therapies. Specifically, combining transplants of human immune cells and skin into mice has provided insights into allograft rejection and the effects of immunosuppressants. Overall, humanized mouse models offer advantages over traditional models and clinical research for developing treatments of inflammatory skin disorders and other immunological diseases.
This document summarizes a study that screened an antibody library to identify antibodies that could induce protective immune responses by targeting dendritic cells. The screening identified an antibody against CD36, a receptor expressed on CD8α+ dendritic cells. The antibody was linked to the model antigen OVA and shown to deliver the antigen for both MHC class I and II processing in vitro and in vivo. Immunization with the anti-CD36-OVA antibody induced robust activation of naive CD4+ and CD8+ T cells and differentiation of primed CD8+ T cells into long-term effector cytotoxic T lymphocytes. Vaccination protected against tumor growth in a tumor-specific antigen model. Targeting CD36 was qualitatively different than targeting DEC
This document summarizes combined immunodeficiency (CID), a disorder characterized by defects in the production or maturation of T cells and/or B cells, leaving the body without necessary immunity. There are two main types of CID - mutagenic defects due to genetic mutations and enzyme deficiencies from lack of enzymes. Mutagenic CIDs can be autosomal recessive or X-linked. Treatments discussed include bone marrow transplantation, gene therapy, passive antibody administration, and enzyme replacement.
The document discusses mast cell activation syndrome (MCAS), including the development and classification of mast cells, clinical manifestations of MCAS, diagnostic criteria for MCAS under various consensus guidelines from 2010 to 2022, and treatments for MCAS. MCAS is diagnosed based on recurrent symptoms affecting multiple organ systems as well as elevated mast cell mediators that respond to treatments targeting mast cell mediators. Diagnostic criteria have evolved over time to rely more on clinical symptoms and treatment response compared to specific mast cell marker thresholds.
Neonatal CD8+ T cells have a distinct gene expression and epigenetic profile compared to adult CD8+ T cells. Neonatal cells show lower expression of genes involved in T cell receptor signaling and cytotoxicity. In contrast, neonatal cells express higher levels of genes related to cell cycle and innate immunity. Functional studies confirm that neonatal CD8+ T cells proliferate more, are less cytotoxic, and express antimicrobial peptides and reactive oxygen species, consistent with an innate immune response bias. This distinctive profile may explain neonates' vulnerability to infection.
This study aimed to determine if mutations in the human cystatin M/E gene (CST6) contribute to harlequin ichthyosis (HI) by sequencing the entire coding region and intron-exon boundaries of CST6 in 11 patients with HI. No mutations were found in CST6, indicating it is not a major gene for types 1 and 2 HI. However, cystatin M/E protein expression was normal in patient tissues by immunohistochemistry, suggesting regulatory or noncoding mutations were unlikely. While CST6 does not appear to cause HI, further study of its role in skin differentiation and other skin disorders may provide insights into cornification pathways.
1) The study examined CD4+ T cells in the central nervous system (CNS) of mice during experimental allergic encephalomyelitis (EAE), both during active disease and remission.
2) Flow cytometry analysis revealed a 30-fold reduction in the number of CD4+ T cells in the CNS of mice in remission compared to those with active EAE.
3) However, the CD4+ T cells that remained in the CNS during remission maintained an activated memory/effector phenotype, suggesting remission is not due to downregulation of T cell function.
Presentation by Michael A. Brehm, Ph.D., Assistant Professor, Diabetes Center of Excellence, Program in Molecular Medicine, University of Massachusetts Medical School, at the JDRF New England Chapter's 14th Annual Spring Research Briefing on Tuesday, April 9, 2013.
Different pathways might drive the inflammation in alopecia areata and clinical trials utilizing narrow-targeted
therapeutics will be able to elucidate the role of each cytokine pathway in the disease phenotype.
1) Influenza infection exerts prominent inflammatory and thrombotic effects on atherosclerotic plaques in aged Apo E-deficient mice. Approximately one third of the mice showed increased plaque inflammation and some died 4-10 days after influenza inoculation.
2) A protocol was tested using cytokines and SPIO nanoparticles to enhance macrophage homing to plaques in Apo E-deficient mice. Mice that received cytokines prior to SPIO injection showed more iron-labeled macrophages in plaques compared to controls.
3) The results suggest that influenza infection exacerbates plaque inflammation in mice and cytokines may account for some of the effects of influenza on atherosclerosis. Longer studies are needed to determine the full
Similar to Pros and Cons of the C3H HeJ versus the Humanized Mouse Model (20)
Dr. Angela Christiano presented an update on genetic and immunological studies in alopecia areata. Her research is focused on defining the genetic basis of alopecia areata to clarify how the disease develops—a key initial step toward creating novel therapies. Dr. Christiano is the Richard and Mildred Rhodebeck Professor of Dermatology, Genetics and Development, Vice Chair for Basic Science Research in Dermatology, and Director of the Center for Human Genetics at Columbia University.
Dr. Leslie Castelo-Soccio presented an overview of what parents need to know about alopecia areata in children and adolescents, including the differences between pediatric and adult patients, and the risks and benefits of current and evolving off-label treatment options. Dr. Castelo-Soccio is Assistant Professor of Pediatrics and Dermatology at the University of Pennsylvania School of Medicine and head of the Pediatric Hair Clinic and Director of Research in Pediatric Dermatology at the Children’s Hospital of Philadelphia. Her clinical and academic research focus is on pediatric hair disorders.
Dr. Maria Hordinsky presented an overview of key things adults need to know about alopecia areata, including the risks and benefits of current and evolving off-label treatment options. Dr. Hordinsky is Professor and Head of the Department of Dermatology at the University of Minnesota. She is recognized for her clinical expertise in alopecia areata and hair diseases.
Dr. Natasha Mesinkovska, NAAF’s Chief Scientific Officer, presented the latest progress of NAAF’s Treatment Development Program and how your involvement is critical to developing treatments for alopecia areata. In addition to overseeing NAAF’s research efforts, Dr. Mesinkovska is Director of Clinical Research in Dermatology at the University of California Irvine.
Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.
This document summarizes the key discussion points from a breakout group at a genetics, immunology, and therapeutic targets conference. The group discussed that while some new targets have been identified for alopecia areata, more exploration is needed into other potential targets, cell types, and signaling pathways. Questions remain about how to better stratify and select patients for current and new treatments. Additional resources are needed, including more funding for immunological and genetic studies, as well as research into the hair follicle biology and environmental factors. The North American Alopecia Areata Foundation can help by continuing to support exploratory research ideas, driving drug development, and convening research summits to define research priorities.
This document summarizes the discussions from a health economics and burden of disease breakout group on alopecia areata. The group discussed questions that still need answers around how alopecia areata impacts work, income, mental health, and patients' life courses. They also identified the need for partnerships to measure clinically relevant outcomes, better database access, and connections between stakeholders. The group suggested the North American Alopecia Areata Foundation could help fund research to address practice gaps, identify patients for research, and coordinate among pharmaceutical companies and payers.
This document summarizes a breakout group report on clinical outcome assessments for alopecia. It discusses several existing assessment measures, including the SALT Score, ALODEX Score, and Lesional Density Score. It notes that these measures have limitations and do not fully capture new areas of hair loss or incremental increases in density. The report identifies questions around defining meaningful response from both investigator and patient perspectives. It also outlines resources needed, such as tools to assess eyebrows/lashes, training for SALT scoring, and developing an overall assessment measure. The group recommends NAAF continue efforts to develop new outcome measures through stakeholder collaboration.
Discussion of the immune privilege collapse model of alopecia areata pathogenesis, available evidence to support this hypothetical scenario, and promising avenues for future investigation.
The FDA plans to prioritize improvements in the quality of demographic subgroup data collection, reporting and analysis, encourages greater participation of diverse patients, and supports the transparency of subgroup data. To this end, ways to recruit, engage, educate, and study those of diverse backgrounds to alopecia areata trials will be discussed.
Measuring willingness to pay in patients with alopecia areata to gauge their willingness to pay out of pocket for a cure or control of their condition.
The document summarizes research on identifying genetic risk factors for alopecia areata. It describes analyzing genetic data from over 700 patients to identify 64 candidate genes and 701 variants potentially involved in monogenic causes. Pathway analysis found these genes enriched for extracellular matrix functions. Further studies will validate co-segregation of variants in families and test for genetic burden using exome data from 10,000 controls. The research aims to elucidate pathogenesis by studying extracellular matrix integrity and signaling in patient samples.
Expert clinicians and patients with alopecia areata were interviewed to develop a new outcome measure called the Alopecia Areata Investigator Global Assessment (AA-IGATM) to evaluate treatment success in clinical trials. Through iterative development and feedback, the measure was refined to a 5-grade scale assessing scalp hair loss from 0-100%. Both clinicians and patients agreed that regrowing hair to the 21-49% range defined as the 'Limited' category would be considered a clinically meaningful treatment success for patients originally having ≥50% scalp hair loss. The finalized AA-IGATM incorporates input from experienced clinicians and patients to capture what constitutes meaningful improvement from both perspectives.
Report on the progress of NAAF’s Patient-Reported Outcome (PRO) Consortium to develop a single, consensus-defined PRO instrument that can be shared across industry partners and other ongoing initiatives to incorporate the voice of the patient in alopecia areata research.
Bruce Patsner is an Oncologist and has served as Director of North American Operations for Legacy Healthcare since 2017; he is based in Boston, Massachusetts.
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Pros and Cons of the C3H HeJ versus the Humanized Mouse Model
1. Skin Research Laboratory,
The B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology,
Haifa, Israel
Human Scalp Skin Xenotransplants in Androgenetic
AlopeciaPre-clinical research in Vivo: Pros and Cons of the
C3H/HeJ versus Humanized Mouse Model
Human skin grafts on animal models
Amos Gilhar, M.D.
2. In our opinion both models should be usedBochenska K et al. J. Mol. Sci. 2017
Murine models
of Psoriasis
According to the literature there are 11 models for vitiligo
19 for Atopic Dermatitis, more than 20 for psoriasis
but 2 for Alopecia Areata
1. The C3H/HeJ is used widely, whereas
2. The humanized mice (no NK , T and B cells) is used in only one Lab.
3. Normal Human
scalp skin/SCID*
mice injected
with IL-2
enriched PBMCs
C3H/HeJ
with skin
graft-
induced
hair loss
Animal
Model
+Regrowth
<3%
Sudden hair loss with temporarily hair regrowth.
++Spontaneous hair growth
++Mononuclear infiltrate around and within the hair bulb.
++Peri- and intrafollicular- CD8+ T-cells
+NANKG2D and NKG2D- ligands
++Major histocompatibility complex (MHC) I and II
-+The hair loss pattern is categorize to focal and diffuse pattern
Table 1
AA criteria in the animal models
Similarities and differences between the C3H/HeJ & humanized mouse model
Gilhar A et al Autoimmun Rev. 2016
4. C3H/HeJ with skin graft-induced hair loss AA humanized mouse model
Easy to use Housed together. Do not require specific pathogen-free
conditions.
Technical expertise is required, complicated
Convenient and cheap Relatively inexpensive, convenient model of AA. Expensive
Grooming induced hair loss Grooming and scratching behaviors None
Potential for pre-clinical drug
screening
With limited value due to murine-specific disease
pathology.
Can be used widely due to its reliance on healthy human donor tissue
and human disease pathology
Disadvantages The histological feature is not specific for AA:
The inflammatory cells are also observed above the hair
bulb, CD4+ cells dominants over CD8 + cells
CTLA4 polymorphisms, is not adequately represented.
MICA is strikingly absent in mice (only 27% amino-acid
identity with human MICA).
Difficulty in obtaining sufficient clinical material
Require a pathogen-free environment for maintenance
Absence of genetic background
Advantages Has yielded tremendous insight into the pathogenesis and
treatment of AA
Specific histological feature: around and within the hair bulb as in
human AA
CD8+ cells dominants over CD4 + cells as in human AA
5. Differences between non-conventional T cells populations among human versus mice should be taken into
account when using mice as preclinical models of human disease.
There are several distinct subsets of γδ T cells in mice and humans, but mouse and human subsets notably have different TCR use, antigen reactivity and
patterns of tissue homing
Godfrey et al. Nature Immunology, 2015
Mouse models have failed to account for the natural diversity in human immune responses. As a result,
insights gained in the lab may be lost in translation
Konrad Buscher et al. Nature Communications, 2017
Differences between immune system of human & mice
There is growing concern that laboratory mice do not reflect relevant aspects of the human immune system,
which may account for failures to translate disease treatments
Beura et al. Nature , 2016 from bench to bedside
6. Foxp3
Vδ2TCR
ע37%
Increased level of γδTreg
γ/δTregs
γδTregs are the predominant
regulatory T cells and have more
potent immunosuppressive activity
than CD4+ or CD8+ Tregs
Hu G, et al. Oncoimmunology 2017
Gu Y, et al. J Immunol Methods 2014
Feng Y, et al. Nature 2015
Hu y, et al. Hematol Oncol. 2017
Humanized
model
TGF-β INF-γ
Gilhar et al. unpublished
High levels of TGF-β and low of IFN-ƴ in γδTreg
Humanized
model
Human
AA
Human
Scalp
Skin
Humanized
AA
model
Green –Keratin 15
Normal HF of
normal scalp skin
AA HF
Presence of γ/δTregs
among stem cells in the bulge area
7. High levels of intracellular IL-10 & TGF-β in γδTreg
Co-culture of CD8+NKG2D+ cells with γδTreg cells
Human HF organ culture
Effect of IL-10 and TGFβ on HFs co-culture
with CD8/NKG2D cells
IFN-γTGF-β
%Catagen
Control CD8/
71%
44% %43%43
p<0.01
CD8/NKG2D cells
TGFβ IL-10 TGFβ/
IL10
8. Induction of psoriatic skin by ILC3+ cells
Normal Skin Graft
l
Psoriatic Induced Graft
Keren ….Gilhar et al . JACI , 2018
PSORIASIS CAN BE INDUCED by
pure ILC3 without the
involvement TH17
Normal
scalp skin
AA scalp skin graft
Normal scalp
skin graft
AA
scalp skin
Normal
scalp skin
N
o
r
m
a
l
s
Increased number of ILC1 in AA patients
A study to determine the role of ILC1 in AA
9. Kv1.3 blocker,
PAP-1
suppresses AA
development in
human skin
grafts
Ecopic HLA-DR
Non - responder graft Responder graft
No R
No DR
Gilhar et al. J Invest Dermatol. 2013
Kv1.3 blockers
preferentially
suppress
autoreactive
CCR7− effector
memory T cells
Additional Therapeutic Targets for AA Need to be Identified and Explored
Gilhar, Keren. Paus . Lancet- accepted for publication
The Humanized mice can be used as a pre clinical drug screening
10. Schafer PH, et al . Br J Pharmacol. 2010
Apremilast in a model of psoriasis
Preclinical modeling of atopic dermatitis
Apremilast on Humanized Mice for Psoriasis and Atopic Dermatitis
Remission of Established Atopic Dermatitis
Predicting the exact efficacy of
apremilast as was observed later on
in clinical trials
11. A comparative study: Therapeutic Effect of Apremilast versus
Tofacitinib
Mice were randomly divided into three groups:
(i) Control (0.5% methylcellulose, bid) (n=5)
(ii) Treated orally with Apremilast (5 mg/kg/day,bid) (n=5).
(iii) Treated orally with Tofacininib (10 mg/kg, bid) (n=5).
Control Apremilast Tofacitinib
Therapeutic effect
Apremilast Versus Tofacitinib
A comparative study
Treatments of Apremilast and Tofacitinib were given to
humanized mice with ongoing alopecia from day 45 after
injections of NKG2D enriched cells, till day 105. .
Tofacitini
b
Control
Gilhar et al. unpublished
12. Agent
1
Montarolo et al. demonstrated protective but not therapeutic effect in EAE mice. PLOS ONE, 2014
Protective but not Therapeutic Effect of Apremilat in Mice
Preventive Non-therapeutic
Potent enough
Treatment
Not potent enough
t
13. Increased number of NKT/IL-10 in humanized AA mice
following treatment with α-GalCer
IL-10
IL-10
IL-10
IL-10
Double
staining
Double
staining
NKT
cells
Double
staining
NKT
cells
NKT
cells
NKT
cells
Double
staining
Ghraieb … Gilhar , J Autoimmun. 2018
14. MeannumberofIL10+/NKT+cells
(per0.5mm2)
AA patient
Human alopecia
areata
AA likeNormal skin
Humanized
mouse model
AA like/GalCer
treatment
Healthy
volunteer
p=0.05
P<0.05
P<0.05
P<0.005
Mean number of NKT10 cells in lesional areas of AA patients and humanized mouse model
α-GalCer Induced Expansion of
NKT10
Ghraieb … Gilhar , J Autoimmun. 2018
o
15. Normal scalp skin before
induction of hair loss
Induction of AA
skinday 60))graft
Hair growth on AA induced graft /rIL-10 day
day105))treatment
Therapeutic Effect of IL-10
and
α-Gal-Cer in AA mouse Model
Hair growth on AA induced graft /α-Gal-Cer
Ghraieb … Gilhar , J Autoimmun. 2018
16. Meanhairnumber(pergraft)
Before
injection
30-40d after
injection
50-60d after
treatment
Treatment
starts
Treatment
ends
16-30d after
stopping
treatment
Before injection 50- 60d of treatment
Treatment starts Treatment ends
Normal scalp skin
grafts bearing hair
AA-Induction
Therapeutic effect
of α-GalCer
Reappearance
of AA
30-40d after injection 16-30 after stopping treatment
Reappearance of AA Following Sopping Treatment With α-GalCer
Reappearance
of AA
conclusion
The study demonstrated
the role of NKT and
NKT10 in AA
Ghraieb … Gilhar , J Autoimmun. 2018 Ghraieb … Gilhar , J Autoimmun. 2018
The regulatory effect is
achieved not only by
Tregs
17. Our very preliminary experiments demonstrated
•Effects of Kv1.3 blocker and α-GaLcer (NKT10)
•A significant difference between therapeutic effect of Tofacitinib VS Apremilast
•Non-conventional T cells may play a role in AA and thus
may serve as future therapeutic targets
Summary
18. Laboratory Staff
Aviad Keren , PhD
Nadia Smirnov , B A
Natalia Kaplun, M D
Gil Kaufman, PhD
Rimma Laufer, MD
Amal Ghraieb , MSc
Prof. Y. Ullmann
Rambam Medical
Center, Israel
Prof. A. Shemer
Sheba Medical
Center, Israel
Prof. Y. Refaeli,
University of Colorado, Denver
Prof. M. David
Beilinson Medical
Center, Israel
Prof. R. Paus
University of Manchester,UK
& University of Miami, USA
Nira Goldstein, BA
Prof. A. Schrum, PhD
Columbia, Missouri