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We put things into a container to keep them organized and safe. In cells, the nucleus has a similar role: keeping DNA protected and intact within an enveloping membrane. But a new study by Salk Ins…
Source: Problems with nuclear membrane play role in leukemia, heart disease and aging disorders
We put things into a container to keep them organized and safe. In cells, the nucleus has a similar role: keeping DNA protected and intact within an enveloping membrane.
“Our research shows that, far from being a passive enclosure as many biologists have thought, the nuclear membrane is an active regulatory structure,” says Salk Professor Martin Hetzer, who is also holder of the Jesse and Caryl Philips Foundation chair. “Not only does it interact with portions of the genome to drive gene expression, but it can also contribute to disease processes when components are faulty.”
Using a suite of molecular biology technologies, the Salk team discovered that two proteins, which sit in the nuclear envelope, together with the membrane-spanning complexes they form, actively associate with stretches of DNA to trigger expression of key genes. Better understanding these higher-level functions could provide insight into diseases that appear to be related to dysfunctional nuclear membrane components, such as leukemia, heart disease and aging disorders.
Historically, the nuclear membrane’s main purpose was thought to be keeping the contents of the nucleus physically separated from the rest of the cell. Complexes of at least thirty different proteins, called nucleoporins, form gateways (pores) in the membrane, controlling what goes in or out. But as the Hetzer lab’s work on nucleoporins shows, these nuclear pore complexes (NPCs), beyond being mere gateways into the nucleus, have surprising regulatory effects on the DNA inside.
“Discovering that key regulatory regions of the genome are actually positioned at nuclear pores was very unexpected,” says Arkaitz Ibarra, a Salk staff scientist and first author of the paper. “And even more importantly, nuclear pore proteins are critical for the function of those genomic sites.”
Curious about all the regions of DNA with which nucleoporins potentially interact, the team turned to a human bone cancer cell line. The scientists used a molecular biology technique called DamID to pinpoint where two nucleoporins, Nup153 and Nup93, came into contact with the genome. Then they used several other sequencing techniques to understand which genes were being affected in those regions, and how.
The Salk team discovered that Nup153 and Nup93 interacted with stretches of the genome called super-enhancers, which are known to help determine cell identity. Since every cell in our body has the same DNA, what makes a muscle cell different from a liver cell or a nerve cell is which particular genes are turned on, or expressed, within that cell. In the Salk study, the presence of Nup153 and Nup93 was found to regulate expression of super-enhancer driven genes and experiments that silenced either protein resulted in abnormal gene expression from these regions. Further experiments in a lung cancer cell line validated the bone cancer line results: Nucleoporins in the NPC were found to interact with multiple super-enhancer regions to drive gene expression, while experiments that altered the NPC proteins made related gene expression faulty, even though the proteins still performed their primary role as gatekeepers in the cell membrane.
“It was incredible to find that we could perturb the proteins without affecting their gateway role, but still have nearby gene expression go awry,” says Ibarra.
“People have thought the nuclear membrane is just a protective barrier, which is maybe the reason why it evolved in the first place. But there are many more regulatory levels that we don’t understand. And it’s such an important area because so far, every membrane protein that has been studied and found to be mutated or mis-localized, seems to cause a human disease,” says Hetzer.
Bowel cancer or colorectal cancer patients experience depression before and for next 2 years after surgery. The Colorectal Wellbeing (CREW) study follows more than 1,000 people with colorectal canc…
Bowel cancer or colorectal cancer patients experience depression before and for next 2 years after surgery.
The Colorectal Wellbeing (CREW) study follows more than 1,000 people with colorectal cancer from before their surgery until five years afterwards. Results showed that people with colorectal cancer saw a reduction in affection, social interaction and practical and emotional support after surgery – and for up to two years afterwards.
People with inflammatory bowel disease (ulcerative colitis and Crohn’s disease) are at increased risk of colon cancer.[20] The risk increases the longer a person has the disease,[21] and the worse the severity of inflammation.[22] In these high risk groups, both prevention with aspirin and regular colonoscopies are recommended.[21]People with inflammatory bowel disease account for less than 2% of colon cancer cases yearly.[22] In those with Crohn’s disease 2% get colorectal cancer after 10 years, 8% after 20 years, and 18% after 30 years.[22] In those with ulcerative colitis approximately 16% develop either a cancer precursor or cancer of the colon over 30 years.[22]
Those with a family history in two or more first-degree relatives (such as a parent or sibling) have a two to threefold greater risk of disease and this group accounts for about 20% of all cases. A number of genetic syndromes are also associated with higher rates of colorectal cancer. The most common of these is hereditary nonpolyposis colorectal cancer (HNPCC or Lynch syndrome) which is present in about 3% of people with colorectal cancer.[15] Other syndromes that are strongly associated with colorectal cancer include Gardner syndrome,[23] and familial adenomatous polyposis (FAP). For people with these syndromes, cancer almost always occurs and makes up 1% of the cancer cases.[24] A total proctocolectomy may be recommended for people with FAP as a preventative measure due to the high risk of malignancy. Colectomy, removal of the colon, may not suffice as a preventative measure because of the high risk of rectal cancer if the rectum remains.[25]
Most deaths due to colon cancer are associated with metastatic disease. A gene that appears to contribute to the potential for metastatic disease, metastasis associated in colon cancer 1 (MACC1), has been isolated.[26] It is a transcriptional factor that influences the expression of hepatocyte growth factor. This gene is associated with the proliferation, invasion and scattering of colon cancer cells in cell culture, and tumor growth and metastasis in mice. MACC1 may be a potential target for cancer intervention, but this possibility needs to be confirmed with clinical studies.[27]
Epigenetic factors, such as abnormal DNA methylation of tumor suppressor promoters play a role in the development of colorectal cancer.[28]
Colorectal cancer is a disease originating from the epithelial cells lining the colon or rectum of the gastrointestinal tract, most frequently as a result of mutations in the Wnt signaling pathway that increase signaling activity. The mutations can be inherited or acquired, and most probably occur in the intestinal crypt stem cell.[29][30][31]The most commonly mutated gene in all colorectal cancer is the APC gene, which produces the APC protein. The APC protein prevents the accumulation of β-cateninprotein. Without APC, β-catenin accumulates to high levels and translocates (moves) into the nucleus, binds to DNA, and activates the transcription of proto-oncogenes. These genes are normally important for stem cell renewal and differentiation, but when inappropriately expressed at high levels, they can cause cancer. While APC is mutated in most colon cancers, some cancers have increased β-catenin because of mutations in β-catenin (CTNNB1) that block its own breakdown, or have mutations in other genes with function similar to APC such as AXIN1, AXIN2, TCF7L2, or NKD1.[32]
Beyond the defects in the Wnt signaling pathway, other mutations must occur for the cell to become cancerous. The p53 protein, produced by the TP53 gene, normally monitors cell division and kills cells if they have Wnt pathway defects. Eventually, a cell line acquires a mutation in the TP53 gene and transforms the tissue from a benign epithelial tumor into an invasive epithelial cell cancer. Sometimes the gene encoding p53 is not mutated, but another protective protein named BAX is mutated instead.[32]
According to The Cancer Genome Atlas Network, 16% of all CRC have been identified as hypermutated and among these, APC, TP53, KRAS, PIK3CA, FBXW7, SMAD4, TCF7L2 and NRAS were found to be the most frequently mutated genes. Moreover, CTNNB1 (β-catenin), SMAD2, FAM123B and SOX9 genes have also been found often mutated in CRC. Recent large scale sequencing analyses also have highlighted the predominance of large number of CRC patients carrying sequence variants in proteins involved in Wnt signaling pathway.
Identification of sequence variants in genes has advanced our understanding of how cancer develops, progresses and how these sequence variants can be targeted for a cure.
TP53, a well-known tumour suppressor gene that encodes p53, is frequently inactivated by mutation or deletion in most human tumours1, 2. A tremendous effort has been made to restore p53 activity in cancer therapies3, 4, 5, 6, 7. However, no effective p53-based therapy has been successfully translated into clinical cancer treatment owing to the complexity of p53 signalling. Here we demonstrate that genomic deletion of TP53 frequently encompasses essential neighbouring genes, rendering cancer cells with hemizygous TP53 deletion vulnerable to further suppression of such genes. POLR2A is identified as such a gene that is almost always co-deleted with TP53 in human cancers. It encodes the largest and catalytic subunit of the RNA polymerase II complex, which is specifically inhibited by α-amanitin8, 9. Our analysis of The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) databases reveals that POLR2A expression levels are tightly correlated with its gene copy numbers in human colorectal cancer. Suppression of POLR2A with α-amanitin or small interfering RNAs selectively inhibits the proliferation, survival and tumorigenic potential of colorectal cancer cells with hemizygous TP53loss in a p53-independent manner. Previous clinical applications of α-amanitin have been limited owing to its liver toxicity10. However, we found that α-amanitin-based antibody–drug conjugates are highly effective therapeutic agents with reduced toxicity11. Here we show that low doses of α-amanitin-conjugated anti-epithelial cell adhesion molecule (EpCAM) antibody lead to complete tumour regression in mouse models of human colorectal cancer with hemizygous deletion of POLR2A. We anticipate that inhibiting POLR2A will be a new therapeutic approach for human cancers containing such common genomic alterations.
http://www.nature.com/nature/journal/v520/n7549/full/nature14418.html
Methodology Esri uses the following methodology for Tapestry Segmentation: 2016 Tapestry Segmentation Methodology (PDF) 2015 Tapestry Segmentation Methodology (PDF) Tapestry Segment summaries The 6…
Source: Diversity of Americans – 67 types of people in the USA per ESRI
Esri uses the following methodology for Tapestry Segmentation:
The 67 distinct markets of Tapestry detail the diversity of the American population. Grouping the segments can simplify these differences by summarizing markets that share similar traits. There are 14 LifeMode groups and 6 Urbanization groups.
LifeMode groups represent markets that share a common experience—born in the same generation or immigration from another country—or a significant demographic trait, like affluence. Tapestry Segments are classified into 14 LifeMode groups. Click a link to view a PDF summary:
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LifeMode |
Segment ID and Name (PDF) |
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LifeMode 1 Affluent Estates
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LifeMode 2 Upscale Avenues
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LifeMode 3 Uptown Individuals
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LifeMode 4 Family Landscapes
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LifeMode 5 GenXurban
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LifeMode 6 Cozy Country Living
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LifeMode 7 Ethnic Enclaves
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LifeMode 8 Middle Ground
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LifeMode 9 Senior Styles
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LifeMode 10 Rustic Outposts
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LifeMode 11 Midtown Singles
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LifeMode 12 Hometown
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LifeMode 13 Next Wave
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LifeMode 14 Scholars and Patriots
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| All Segment Summaries |
All Segment Summaries (88 MB) |
Tapestry groups are also available as Urbanization summary groups, in which markets share similar locales, from the urban canyons of the largest cities to the rural lanes of villages or farms. Tapestry Segments are classified into 6 Urbanization groups. Click a link to view a PDF summary:
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Urbanization |
Segment ID and Name (PDF) |
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Principal Urban Centers
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Urban Periphery
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Metro Cities
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Suburban Periphery
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Semirural
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Rural
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Photo post by @momdancer40.
Source: Google reveals what people really think about parts of North America
Anxiety risk scale and Senior care The above anxiety risk scale is used by doctors to evaluate behavior health issues especially in older adults as brought about by trauma, sickness, chronic…
The above anxiety risk scale is used by doctors to evaluate behavior health issues especially in older adults as brought about by trauma, sickness, chronic stress, death in the family, being divorced or widowed, other health issues.
For 24/7 Alzheimer care in the bay area, call 408-854-1883 or email motherhealth@gmail.com
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In the future, predictive medicine can help us be more proactive.
Predictive medicine is a field of medicine that entails predicting the probability of disease and instituting preventive measures in order to either prevent the disease altogether or significantly decrease its impact upon the patient (such as by preventing mortality or limiting morbidity).[1] While different prediction methodologies exist, such as genomics, proteomics, and cytomics, the most fundamental way to predict future disease is based on genetics. Although proteomics and cytomics allow for the early detection of disease, much of the time those detect biological markers that exist because a disease process has already started. However, comprehensive genetic testing (such as through the use of DNA arrays or full genome sequencing) allows for the estimation of disease risk years to decades before any disease even exists, or even whether a healthy fetus is at higher risk for developing a disease in adolescence or adulthood. Individuals who are more susceptible to disease in the future can be offered lifestyle advice or medication with the aim of preventing the predicted illness.
Current genetic testing guidelines supported by the health care professionals discourage purely predictive genetic testing of minors until they are competent to understand the relevancy of genetic screening so as to allow them to participate in the decision about whether or not it is appropriate for them.[2] Genetic screening of newborns and children in the field of predictive medicine is deemed appropriate if there is a compelling clinical reason to do so, such as the availability of prevention or treatment as a child that would prevent future disease.
Why the need for complete DNA sequence at 50yrs of age?
This is the time that there is some damage in our DNA structure as a result of the environment, health issues and aging. We can use this genetic information to predict any health issues in the coming years.
Email motherhealth@gmail.com for gene-based diet for older adults and for senior concierge in the bay area.
Coming soon is our website http://www.avatarcare.net to bring precision medicine, predictive medicine and telemedicine to all.
by Connie Dello Buono A coworker cannot absorb iron in her diet because of one gene, MTHFR. As a result, she had been having chronic pain in the past. I recommended that she adds vinegar in her die…
Source: Gene-based diet
by Connie Dello Buono
A coworker cannot absorb iron in her diet because of one gene, MTHFR. As a result, she had been having chronic pain in the past. I recommended that she adds vinegar in her diet since vinegar helps in the absorption of minerals in whole foods.
Most of us as we age have poor absorption of important nutrients in the whole foods that we eat, so we have to chew more and eat whole foods rich in digestive enzymes (in papaya and pineapple) and add probiotics (acidophilus, pickled veggies) in our diet.
Many mental health issues arise because of the unfriendly bacteria in our guts, so we have to eat more whole foods and avoid processed foods and sugar. And add probiotics supplementation or eat pickled veggies.
When our genes tell us that we are prone to infection or sensitive to allergens, we have to up our intake of Vitamin C rich foods and zinc.
When our genes tell us that we tend to have skin sensitivities, we need to take care of our liver with more greens, liver detox diet rich in Vit C (lemons, ginger) and less on preservatives and toxic substances in our environment.
Many of our genes can all tell us that we are prone to weakened tissues, we then up our intake of red colored greens or whole foods as they are rich in nutrients to strengthen our membranes and tissues.
And more to come…
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