Tibetan sheep highly susceptible to human plague, originates from marmots

In the Qinghai-Tibet plateau, one of the region’s highest risk areas for human plague, Himalayan marmots are the primary carriers of the infectious bacterium Y. pestis. Y. pestis infection can be transmitted to humans and other animals by the marmots’ parasitic fleas. In a new study recently published with PLOS Neglected Tropical Diseases, researchers determine that Tibetan sheep, who make up about one-third of China’s total sheep population, also carry this disease and can transmit it to humans.

Since the first documented marmot fatality caused by the biovar antique strain of Y. pestis in 1954, a total of 468 human plague cases with 240 deaths have been reported. To better understand local outbreaks, Wei Li of the CDC in China and colleagues, extracted the genomic DNA from 38 strains of Y. pestis isolated from Tibetan sheep, Himalayan marmots, and humans. Y. pestis isolated from Tibetan sheep and local marmots all were found to belong to the strain of human plague, biovar antique. Creating a phylogenetic tree of the isolated Y. pestis pathogen, researchers determined the disease transferred from Himalayan marmot to sheep to human. In addition, the genomic analysis of the Tibetan sheep-related strains revealed the strains have territory-specific characteristics. When there is no geographic barrier between adjacent areas, the pathogens isolated from adjacent areas grouped together.

The exact pathway of transmission of how the bacterium transmits still needs further study. However, researchers observed that Tibetan sheep have a habit of licking the bodies of dead rodents such as marmots, possibly as a means of ingesting micronutrients in the plateau. Transmission between marmot and sheep can also occur through fleas biting marmots and then carrying the disease onward. The transmission from sheep to human is associated with the skinning, butchering, and eating under-cooked sheep meat.

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Is Evolution of the Human Brain to Blame for Some Mental Disorders?

THURSDAY, Aug. 9, 2018 — Evolutionary changes in the human brain may be responsible for psychiatric illnesses such as schizophrenia and bipolar disorder, new research suggests.

The researchers identified long, noncoding stretches of DNA (called “repeat arrays”) in a gene that governs calcium transport in the brain. Their findings were published Aug. 9 in the American Journal of Human Genetics.

“Changes in the structure and sequence of these nucleotide arrays likely contributed to changes in CACNA1C function during human evolution and may modulate neuropsychiatric disease risk in modern human populations,” senior author David Kingsley said in a journal news release. Kingsley is a professor of developmental biology at Stanford University in California.

The study authors suggested that the findings could lead to improved treatment for patients with schizophrenia and bipolar disorder, which affect about 3 percent of people worldwide.

Classifying patients based on their repeat arrays may help identify those most likely to respond to current calcium channel drugs, which so far have produced mixed results, Kingsley said.

He added that more research is needed to determine whether patients with a genetic variation of CACNA1C have too much or too little calcium channel activity.

The repeat arrays in the CACNA1C gene occur only in humans. Kingsley said that suggests the arrays may have given humans an evolutionary advantage, even if they increased the risk of conditions such as schizophrenia and bipolar disorder.

More information

The U.S. National Institute of Mental Health has more on schizophrenia.

Posted: August 2018

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Evolutionary changes in the human brain may have led to bipolar disorder and schizophrenia

The same aspects of relatively recent evolutionary changes that make us prone to bad backs and impacted third molars may have generated long, noncoding stretches of DNA that predispose individuals to schizophrenia, bipolar disorder, and other neuropsychiatric diseases.

A study publishing August 9 in the American Journal of Human Genetics identifies an unusually lengthy array of tandem repeats found only within the human version of a gene governing calcium transport in the brain.

“Changes in the structure and sequence of these nucleotide arrays likely contributed to changes in CACNA1C function during human evolution and may modulate neuropsychiatric disease risk in modern human populations,” says senior author David Kingsley, professor of developmental biology at Stanford University.

Common ailments such as lower back, knee, and foot problems are likely due to the transition to walking upright; impacted wisdom teeth may be tied to humans’ smaller jaws and recent changes in diet. Kingsley hypothesizes that the prevalence of neurological diseases in modern humans may stem from recent evolutionary changes in genes controlling brain size, connectivity, and function.

Bipolar disorder and schizophrenia affect more than 3 percent of the population worldwide.

Missing data

Tandem repeats are repeated lengths of DNA occurring either inside or outside a gene’s coding sequence. They have been hypothesized to explain individual-to-individual variations in complex neurological functions and may act as “tuning knobs” for modulating gene expression. The tandem repeats may affect CACNA1C function—even when the coding region of the gene itself is free of mutations.

Most genetic studies focus on how simple letter substitutions in the DNA code cause disease. Yet 15 years after the human genome was mapped, regions of the human genome are still largely unexplored, missing, or understudied, Kingsley says. In particular, large regions of repeated sequence can be difficult to propagate in bacteria and to assemble correctly. Many of these regions also vary substantially between individuals and may contribute to key phenotypic traits and disease susceptibilities in humans and other organisms.

After identifying a large discrepancy between the standard human reference genome and levels of DNA sequence reads coming from a key calcium channel gene previously linked to psychiatric disease, Kingsley and Stanford colleagues Janet Song and Craig Lowe carried out further studies of 181 human cell lines and postmortem brain tissue samples. They found lengthy stretches of DNA—ten to a hundred times longer and more complex than expected—containing many variant nucleotide base pairs embedded in a noncoding region of the CACNA1C gene.

Different versions of the highly repeated sequences showed different abilities to activate gene expression and were tightly linked to genetic markers of bipolar disease and schizophrenia disease susceptibility in humans. Such “hidden variants” may illuminate the risk of psychiatric disease among patients whose DNA profile is otherwise unremarkable, he says.

Kingsley, a Howard Hughes Medical Institute investigator, says classifying patients based on their repeat arrays may help identify those most likely to respond to existing calcium channel drugs. These medications have produced mixed results to date, he notes, and further study is needed to clarify whether patients with a genetic variation of CACNA1C have too much or too little calcium channel activity. “We hope genotype-based drug targeting will lead to improved future treatments,” he says.

Evolutionary byproducts

Kingsley says the large structural arrays found in the CACNA1C gene are unique to humans, raising the question of whether we derived an evolutionary advantage from this expanded genetic sequence—even though it apparently increased our susceptibility to neuropsychiatric disease.

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New protocol produces large numbers of mature human podocytes, enabling kidney disease modeling, drug discovery

Human stem cells are of great interest in the fields of regenerative medicine and medical research because they reproduce indefinitely and can differentiate into every other cell type found in the body. While stem cells naturally occur in very few places in the adult body, induced pluripotent stem cells (iPS cells) can be produced directly from adult cells, and offer the potential for a patient to one day have a limitless source of personalized cells to replace those lost to damage or disease.

Previous work from the Wyss Institute at Harvard University established a protocol for producing human kidney podocytes (a type of cell that helps filter blood in the kidneys) from iPS cells with greater than 90% efficiency, and used those podocytes in a Glomerulus Chip that can recreate in vitro the specialized tissue structure and molecular filtration found in the glomerulus of the human kidney.

Now, using that protocol, Wyss researchers have shown that the differentiated cells exhibit transcriptomic and protein expression profiles that match those of mature podocytes—a feat that no other method has so far been able to achieve. This confirmation of mature podocytes gives kidney researchers across the scientific community a tool for investigating human kidney development, function, and disease; these cells also could potentially be delivered as a cell therapy for kidney diseases in the future. The research is reported in Nature Protocols.

Before settling on their final cell type, iPS cells differentiate into “progenitor” cells, which can themselves become multiple cell types. Those that are destined to become podocytes first differentiate into nephron progenitor-like cells. While these cells can be used as a proxy for human cells in research, mature cells are of much greater use to researchers and clinicians, as they more closely mimic the cells found in adult organs. In order to produce mature podocytes, Samira Musah, Ph.D., a former Postdoctoral Fellow in the laboratory of Founding Director Donald Ingber, M.D., Ph.D who is currently an Assistant Professor of Biomedical Engineering at Duke University, first created nephron progenitor-like cells from iPS cells, and then exposed them to a new cell culture medium containing a cocktail of five molecules that had been previously shown to play key roles in kidney development and function in vivo. This in vitro differentiation protocol resulted in cells that grew the long “foot” processes and expressed the genes that are the hallmarks of mature podocytes.

“Our method’s ability to produce mature human podocytes from iPS cells with high yield and without the need for subpopulation selection or genetic manipulations offers researchers and clinicians a robust, renewable source of kidney cells for scientific and medical studies,” said Musah, who is also a Dean’s Postdoctoral Fellow at Harvard Medical School.

There are many valuable uses for this protocol of mature podocyte generation, including investigating the steps involved in the differentiation of podocytes from their progenitor cells (a process which remains largely unknown), studying the source and progression of various kidney diseases including podocytopathies and glomerulosclerosis, and establishing in vitro systems for kidney drug testing and discovery, such as the Glomerulus Chip. The researchers also hypothesize that mature human iPS cell-derived podocytes could one day be used as an injectable form of cell therapy for diseases that are characterized by podocyte loss or dysfunction.

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First human scanned with next-generation 3-D colour medical scanner

The first human has been scanned with a revolutionary new 3D colour medical scanner invented in New Zealand by father and son scientists from the Universities of Canterbury and Otago.

The MARS spectral x-ray scanner will revolutionise medical imaging globally – and as a result the diagnosis and treatment of diseases such as cancer and heart disease – because it provides far greater detail of the body’s chemical components.

In the next few months, Christchurch orthopaedic and rheumatology patients will be scanned by the machine in a world-first clinical trial.

Father and son scientists Professors Phil and Anthony Butler invented the MARS spectral x-ray scanner. Professor Phil Butler is a physicist working at the University of Canterbury. His son Anthony is a radiologist and Professor at both the Universities of Otago and Canterbury.

The Butlers adapted technology used by the European Organization for Nuclear Research (CERN) in the hunt for the ‘God particle’ into a medical scanner.

The MARS CT scanner produces images with significantly improved diagnostic information. It measures the x-ray spectrum to produce colour images instead of black-and-white ones, and shows different components of body parts such as fat, water, calcium, and disease markers.

Small versions of the scanner that can house tissue samples are already in use in research institutions around the world. The first human has now been scanned through a larger form of the scanner. Professor Phil Butler was the first person to be scanned. His ankle and wrist were imaged.

The next step in development is an imminent clinical trial where orthopaedic and rheumatology patients from Christchurch will be scanned. This will allow the MARS team to compare the images produced by their scanner with the technology currently used in New Zealand hospitals.

The Butlers and their growing team of scientists have been supported over the past decade of developing the machine by the Universities of Otago and Canterbury; the Ministry of Business, Innovation and Employment; and GE Healthcare. MARS Bioimaging Ltd (MBI) has commercialised the product.

Professor Anthony Butler says after a decade in development it is really exciting to have reached a point where it’s clear the technology could be used for routine patient care. 

“X-ray spectral information allows health professionals to measure the different components of body parts such as fat, water, calcium, and disease markers. Traditional black-and-white x-rays only allow measurement of the density and shape of an object,” Professor Anthony Butler says.

“So far researchers have been using a small version of the MARS scanner to study cancer, bone and joint health, and vascular diseases that cause heart attacks and strokes. In all of these studies, promising early results suggest that when spectral imaging is routinely used in clinics it will enable more accurate diagnosis and personalisation of treatment.”

Professor Butler says CERN’s Medipix3 technology sets the machine apart diagnostically because its small pixels and accurate energy resolution mean it can get images no other imaging tool can.

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