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Analysis of genes altered by the disease could provide targets for new treatments — ScienceDaily

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Analysis of genes altered by the disease could provide targets for new treatments -- ScienceDaily

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MIT researchers have performed the first comprehensive analysis of the genes that are expressed in individual brain cells of patients with Alzheimer’s disease. The results allowed the team to identify distinctive cellular pathways that are affected in neurons and other types of brain cells.

This analysis could offer many potential new drug targets for Alzheimer’s, which afflicts more than 5 million people in the United States.

“This study provides, in my view, the very first map for going after all of the molecular processes that are altered in Alzheimer’s disease in every single cell type that we can now reliably characterize,” says Manolis Kellis, a professor of computer science and a member of MIT’s Computer Science and Artificial Intelligence Laboratory and of the Broad Institute of MIT and Harvard. “It opens up a completely new era for understanding Alzheimer’s.”

The study revealed that a process called axon myelination is significantly disrupted in patients with Alzheimer’s. The researchers also found that the brain cells of men and women vary significantly in how their genes respond to the disease.

Kellis and Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, are the senior authors of the study, which appears in the May 1 online edition of Nature. MIT postdocs Hansruedi Mathys and Jose Davila-Velderrain are the lead authors of the paper.

Single-cell analysis

The researchers analyzed postmortem brain samples from 24 people who exhibited high levels of Alzheimer’s disease pathology and 24 people of similar age who did not have these signs of disease. All of the subjects were part of the Religious Orders Study, a longitudinal study of aging and Alzheimer’s disease. The researchers also had data on the subjects’ performance on cognitive tests.

The MIT team performed single-cell RNA sequencing on about 80,000 cells from these subjects. Previous studies of gene expression in Alzheimer’s patients have measured overall RNA levels from a section of brain tissue, but these studies don’t distinguish between cell types, which can mask changes that occur in less abundant cell types, Tsai says.

“We wanted to know if we could distinguish whether each cell type has differential gene expression patterns between healthy and diseased brain tissue,” she says. “This is the power of single-cell-level analysis: You have the resolution to really see the differences among all the different cell types in the brain.”

Using the single-cell sequencing approach, the researchers were able to analyze not only the most abundant cell types, which include excitatory and inhibitory neurons, but also rarer, non-neuronal brain cells such as oligodendrocytes, astrocytes, and microglia. The researchers found that each of these cell types showed distinct gene expression differences in Alzheimer’s patients.

Some of the most significant changes occurred in genes related to axon regeneration and myelination. Myelin is a fatty sheath that insulates axons, helping them to transmit electrical signals. The researchers found that in the individuals with Alzheimer’s, genes related to myelination were affected in both neurons and oligodendrocytes, the cells that produce myelin.

Most of these cell-type-specific changes in gene expression occurred early in the development of the disease. In later stages, the researchers found that most cell types had very similar patterns of gene expression change. Specifically, most brain cells turned up genes related to stress response, programmed cell death, and the cellular machinery required to maintain protein integrity.

Sex differences

The researchers also discovered correlations between gene expression patterns and other measures of Alzheimer’s severity such as the level of amyloid plaques and neurofibrillary tangles, as well as cognitive impairments. This allowed them to identify “modules” of genes that appear to be linked to different aspects of the disease.

“To identify these modules, we devised a novel strategy that involves the use of an artificial neural network and which allowed us to learn the sets of genes that are linked to the different aspects of Alzheimer’s disease in a completely unbiased, data-driven fashion,” Mathys says. “We anticipate that this strategy will be valuable to also identify gene modules associated with other brain disorders.”

The most surprising finding, the researchers say, was the discovery of a dramatic difference between brain cells from male and female Alzheimer’s patients. They found that excitatory neurons and other brain cells from male patients showed less pronounced gene expression changes in Alzheimer’s than cells from female individuals, even though those patients did show similar symptoms, including amyloid plaques and cognitive impairments. By contrast, brain cells from female patients showed dramatically more severe gene-expression changes in Alzheimer’s disease, and an expanded set of altered pathways.

“That’s when we realized there’s something very interesting going on. We were just shocked,” Tsai says.

So far, it is unclear why this discrepancy exists. The sex difference was particularly stark in oligodendrocytes, which produce myelin, so the researchers performed an analysis of patients’ white matter, which is mainly made up of myelinated axons. Using a set of MRI scans from 500 additional subjects from the Religious Orders Study group, the researchers found that female subjects with severe memory deficits had much more white matter damage than matched male subjects.

More study is needed to determine why men and women respond so differently to Alzheimer’s disease, the researchers say, and the findings could have implications for developing and choosing treatments.

“There is mounting clinical and preclinical evidence of a sexual dimorphism in Alzheimer’s predisposition, but no underlying mechanisms are known. Our work points to differential cellular processes involving non-neuronal myelinating cells as potentially having a role. It will be key to figure out whether these discrepancies protect or damage the brain cells only in one of the sexes — and how to balance the response in the desired direction on the other,” Davila-Velderrain says.

The researchers are now using mouse and human induced pluripotent stem cell models to further study some of the key cellular pathways that they identified as associated with Alzheimer’s in this study, including those involved in myelination. They also plan to perform similar gene expression analyses for other forms of dementia that are related to Alzheimer’s, as well as other brain disorders such as schizophrenia, bipolar disorder, psychosis, and diverse dementias.

The research was funded by the National Institutes of Health, the JBP Foundation, and the Swiss National Science Foundation.

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Imo Governor’s aide visits Oziza FM Staff, Ogechi Iwu in hospital

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Imo Governor’s aide visits Oziza FM  Staff, Ogechi Iwu in hospital

The Chief Press Secretary and Media Adviser to Governor Hope Uzodimma of Imo State, Mr. Oguwike Nwachuku has visited Mr. Ogechi Iwu, a journalist with Osiza FM.

The media man is hospitalized at the Federal Medical Centre (FMC), Owerri over complications from diabetes that led to his right leg being amputated.

Mr. Nwachuku said the visit was to show solidarity on behalf of Governor Uzodimma to his professional colleague, assuring him of their prayers, particularly that of his principal, and the prayers of Mr. Iwu’s numerous friends and well wishers who are touched by his plight.

“I am here on behalf of my principal to associate with him in this time of health challenge and to encourage him not to see the sickness as a death sentence.”

Oge Iwu at fmc

L-R: Chief Akaraonye, Mr. Oguwike Nwachuku with Ogechi Iwu during the visit

Mr. Nwachuku urged Mr. Iwu to continue in the high spirit he saw him and trust God for his total recovery “because healing is a thing of mind and when a sick person is in high spirit the patient gets recovered quickly.”

The spokesman of the Governor promised to bring the plight of the journalist to the attention of his principal, and assured that the Governor will, in his usual manner of one with milk of human sympathy, show concern over Iwu’s plight.

Earlier, Mr. Iwu thanked the CPS/Media Adviser, the State Chairman of NUJ, Imo State, Chief Christopher Akaraonye and other journalists who were on the entourage, for coming to identify with him on his sick bed, and assured that God in his infinite mercy will quicken his recovery.

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Lessons from the Melee in Mali

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Lessons from the Melee in Mali

Just a couple of days ago, former president of Nigeria, Dr. Goodluck Jonathan, penned an assuring message on his successful mediation trips – leading the ECOWAS fact-finding and resolution team to Mali. The ink is still wet on that page when we however, woke up to the news of a coup in Mali. Whether it is Gambia, Guinea, Sudan, name them, Africa seems to be on the back foot when it comes to democratic gains. Is this a recurring narrative?

Mali should be another stark reminder to other African governments especially Nigeria that when an ineffective, out of touch and repressive government is about to come to an end, it always happens suddenly, not gradually. The tempo always builds up but from the inside, presenting a false calm exterior. Then like a landslide, it unexpectedly gives; the whole mountain comes crumbling as can be seen happening right now in Mali.

Seething resentments towards kleptocratic African governments always showcase themselves at the fall. African governments are miles behind, regarding the yearnings of their people and just like it happened in the ’60’s and ’70’s during our independence and subsequent coups and counter coups, Africa – led by its yearning youths connected globally through technology and the internet –is again bursting at the seams for legitimacy, effective leadership, direction and global integration.

The elitist old folks at the helm, unable to catch up and belligerent towards inclusive prosperity and development, are using their incumbent powers and minions to thwart the wishes of the people but for how long?

After the World War II, the world is again witnessing an unprecedented degree of untold suffering and death at peacetime, as a result of human disaster, but in Africa. It seems like the world rebuilt itself and moved on without us. How did we get here? How did we get left behind? First we started the blame game with the effect of slave trade, then the shackles of colonialism, yet Eastern countries have come out of both and are prosperous regardless.

China and the rest of the block are another testament that most of our arguments though with their merits, don’t hold water in their entirety. We are the makers of our destinies.
The origin of Mali’s problems, like every other Africa country, is government sectarianism – where a people in power skew electoral outcomes to favor themselves and their minions. This always led to widespread corruption, mismanagement of the economy, worsening security situations and exacerbating communal violence consequently.

For Mali, it started on June 5 when thousands of people went on street protest against the hijacked outcome of the parliamentary elections which took place on March 25. It turned deadly and 11 people were killed. As it is, regional security is threatened, at a time when COVID-19 and economic positions of these countries, indeed the whole world, are in tatters.

Whether it is Nigeria, Congo, Somalia, Kenya, name it, the problem is the same. When responsibility is alienated from governance, it breeds impunity which leads to corruption.

Like cancer, this corruption feeds and sustains itself by permeating all democratic institutions in its bid to replicate, validate and perpetuate itself, thus adulterating the electoral process which ultimately leads to political disintegration with the people seen as the enemy.

Our present crop of leaders has worked constitutions and political structures to such an extent that they sit home and predict electoral and judicial outcomes to the last digit.

This begs the question, is democracy working for Africa and if it doesn’t, what works? At times like this, we as Africans, should look inwards and take stock of how far we have come with the advent of constitutional democracy, where we have lost it and what should be done. The Chinese have found their formula, the Russians too. We too must find our path to an all inclusive, sustainable and prosperous future.

By Iboro Otu

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BAN ON THE CANAANLAND ADORATION (ALIAS E-DEY WORK) MINISTRY AND WITHDRAWAL OF FACULTY FROM REV. FR. MAGNUS EBERE SDV

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BAN ON THE CANAANLAND ADORATION (ALIAS E-DEY WORK) MINISTRY AND WITHDRAWAL OF FACULTY FROM REV. FR. MAGNUS EBERE SDV

To the Clergy, Religious and Laity of
Ahiara Diocese.

Dear people of God!

Compliments of the season: peace and joy!

As bishop, it is my duty to uphold authentic gospel values, sound Catholic traditions in worship and defend the teaching of the Catholic Church on faith and morals. It is also my responsibility to ensure that it is transmitted to the faithful in its purity and integrity in my area of pastoral jurisdiction.

Having established that there are serious abuses in the administration of the sacraments and sacramentals in the Canaanland Adoration Ministry a.k.a E-Dey Work as well as many other practices in the Adoration Ministry which are contrary to the teachings and traditions of the Catholic Church, I withdrew the Faculties of the Diocese of Ahiara from Fr. Magnus Ebere a priest of the Society of Divine Vocation (SDV), who started the Adoration Ministry without the required permission from an ecclesiastical authority. Consequently, he can no longer legitimately carry out priestly ministry such as preaching, celebration of the Mass, hearing confessions and administration of the other Sacraments and Sacramentals in the Diocese of Ahiara.

Nevertheless, Fr. Magnus has continued his private Ministry at his Centre in Onicha Ezinihitte in the Diocese of Ahiara in gross disobedience to me the bishop and also his Superior General in Rome who has also directed him to stop his Adoration Ministry. I hereby state that the Catholic Church has nothing to do with his Ministry. Accordingly, the faithful of Ahiara Catholic Diocese and other Dioceses are hereby warned to desist from attending the Ministry of a defiant priest, who has no respect for Church authority and Church law. Those who attend his private Ministry do so at their own spiritual peril.

God bless you!

Sincerely yours

Lucius Iwejuru Ugorji
Apostolic Administrator of Ahiara Diocese

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