medicine and health

ScienceDaily (Oct. 18, 2012) — Researchers at the Johns Hopkins Bloomberg School of Public Health have determined a new mechanism by which the mosquitoes' immune system can respond with specificity to infections with various pathogens, including the parasite that causes malaria in humans, using one single gene. Unlike humans and other animals, insects do not make antibodies to target specific infections. According to the Johns Hopkins researchers, mosquitoes use a mechanism known as alternative splicing to arrange different combinations of binding domains, encoded by the same AgDscam gene, into protein repertoires that are specific for different invading pathogens.

The researchers' findings were published October 18 in the journal Cell Host & Microbe and could lead to new ways to prevent the spread of a variety of mosquito born illnesses.

Mosquitoes and other insects use their primitive innate immune systems to successfully fight infections with a broad spectrum of viruses, bacteria, fungi and parasites, despite the lack of antibodies that are part of the more sophisticated human immune system. The effectiveness of the human immune system is to a large degree based on the ability to produce an enormous variety of antibodies containing different immunoglobulin domains that can specifically tag and label a pathogen for destruction. This great variety of pathogen-binding antibodies is achieved by combining different immunoglobulin gene segments and further mutate them through mechanisms called somatic recombination and hypermutation. While mosquitoes also have genes encoding immunoglobulin domains, they lack these specific mechanisms to achieve pathogen recognition diversity.

The Johns Hopkins researchers discovered a different way by which mosquitoes can combine immunoglobulin domains of a single gene called AgDscam (Anopheles gambiae Down Syndrome Cell Adhesion Molecule) to produce a variety of pathogen-binding proteins. The AgDscam gene is subjected to a mechanism called alternative splicing that combines different immunoglobulin domains into mature AgDscam proteins, depending on which pathogen has infected the mosquito. The researchers showed that this alternative splicing is guided by the immune signal transducing pathways (analogous to electrical circuits) that they previously demonstrated to activate defenses against different malaria parasites and other pathogens. While alternative splicing of the AgDscam gene does not nearly achieve the degree of pathogen recognition diversity of human antibodies, it does nevertheless vastly increase the variety of pathogen binding molecules.

"Using antibodies to fight infection is like fishing with a harpoon -- it's very targeted. The mosquito's innate immune system is more like fishing with a net -- it catches a bit of everything," explained George Dimopoulos, PhD, senior investigator of the study and professor with the Johns Hopkins Malaria Research Institute. "However, we discovered that immune pathway-guided alternative splicing of the AgDscam gene renders the mosquito's immune net, so to speak, more specific than previously suspected. The mosquito's immune system can come up with approximately 32,000 AgDscam protein combinations to target infections with greater specificity."

Dimopoulos and his group are developing a malaria control strategy based on mosquitoes that have been genetically modified to possess an enhanced immune defense against the malaria parasite Plasmodium. One obstacle to this approach is the great variety of Plasmodium strains that may interact somewhat differently with the mosquito's immune system.

"Some of these strains may not be detected by the engineered immune system proteins that mediate their killing. Our new discovery may provide the means to create genetically modified mosquitoes that can target a broader variety of parasite strains, like casting a net rather than shooting with a harpoon," said Dimopoulos.

Malaria kills more than 800,000 people worldwide each year. Many are children.

The research was supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Disease, the Calvin A. and Helen H. Lang Fellowship, and the Johns Hopkins Malaria Research Institute.

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The above story is reprinted from materials provided by Johns Hopkins Bloomberg School of Public Health.
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Journal Reference:

Yuemei Dong, Chris M. Cirimotich, Andrew Pike, Ramesh Chandra and George Dimopoulos. Anopheles NF-kB -Regulated Splicing Factors Direct Pathogen-Specific Repertoires of the Hypervariable Pattern Recognition Receptor AgDscam. Cell Host & Microbe, October 18, 2012

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Disclaimer: This article is not intended to provide medical advice, diagnosis or treatment. Views expressed here do not necessarily reflect those of ScienceDaily or its staff.

Researchers explore how the brain perceives direction and location

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ScienceDaily (Oct. 19, 2012) — The Who asked "who are you?" but Dartmouth neurobiologist Jeffrey Taube asks "where are you?" and "where are you going?" Taube is not asking philosophical or theological questions. Rather, he is investigating nerve cells in the brain that function in establishing one's location and direction.

Taube, a professor in the Department of Psychological and Brain Sciences, is using microelectrodes to record the activity of cells in a rat's brain that make possible spatial navigation -- how the rat gets from one place to another -- from "here" to "there." But before embarking to go "there," you must first define "here."

Survival Value

"Knowing what direction you are facing, where you are, and how to navigate are really fundamental to your survival," says Taube. "For any animal that is preyed upon, you'd better know where your hole in the ground is and how you are going to get there quickly. And you also need to know direction and location to find food resources, water resources, and the like."

Not only is this information fundamental to your survival, but knowing your spatial orientation at a given moment is important in other ways, as well. Taube points out that it is a sense or skill that you tend to take for granted, which you subconsciously keep track of. "It only comes to your attention when something goes wrong, like when you look for your car at the end of the day and you can't find it in the parking lot," says Taube.

Perhaps this is a momentary lapse, a minor navigational error, but it might also be the result of brain damage due to trauma or a stroke, or it might even be attributable to the onset of a disease such as Alzheimer's. Understanding the process of spatial navigation and knowing its relevant areas in the brain may be crucial to dealing with such situations.

The Cells Themselves

One critical component involved in this process is the set of neurons called "head direction cells." These cells act like a compass based on the direction your head is facing. They are located in the thalamus, a structure that sits on top of the brainstem, near the center of the brain.

He is also studying neurons he calls "place cells." These cells work to establish your location relative to some landmarks or cues in the environment. The place cells are found in the hippocampus, part of the brain's temporal lobe. They fire based not on the direction you are facing, but on where you are located.

Studies were conducted using implanted microelectrodes that enabled the monitoring of electrical activity as these different cell types fired.

Taube explains that the two populations -- the head direction cells and the place cells -- talk to one another. "They put that information together to give you an overall sense of 'here,' location wise and direction wise," he says. "That is the first ingredient for being able to ask the question, 'How am I going to get to point B if I am at point A?' It is the starting point on the cognitive map."

The Latest Research

Taube and Stephane Valerio, his postdoctoral associate for the last four years, have just published a paper in the journal Nature Neuroscience, highlighting the head direction cells. Valerio has since returned to the Université Bordeaux in France.

The studies described in Nature Neuroscience discuss the responses of the spatial navigation system when an animal makes an error and arrives at a destination other than the one targeted -- its home refuge, in this case. The authors describe two error-correction processes that may be called into play -- resetting and remapping -- differentiating them based on the size of error the animal makes when performing the task.

When the animal makes a small error and misses the target by a little, the cells will reset to their original setting, fixing on landmarks it can identify in its landscape. "We concluded that this was an active behavioral correction process, an adjustment in performance," Taube says. "However, if the animal becomes disoriented and makes a large error in its quest for home, it will construct an entirely new cognitive map with a permanent shift in the directional firing pattern of the head direction cells." This is the "remapping."

Taube acknowledges that others have talked about remapping and resetting, but they have always regarded them as if they were the same process. "What we are trying to argue in this paper is that they are really two different, separate brain processes, and we demonstrated it empirically," he says. "To continue to study spatial navigation, in particular how you correct for errors, you have to distinguish between these two qualitatively different responses."

Taube says other investigators will use this distinction as a basis for further studies, particularly in understanding how people correct their orientation when making navigational errors.

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The above story is reprinted from materials provided by Dartmouth College. The original article was written by Joseph Blumberg.
Note: Materials may be edited for content and length. For further information, please contact the source cited above.

Journal Reference:

Stephane Valerio, Jeffrey S Taube. Path integration: how the head direction signal maintains and corrects spatial orientation. Nature Neuroscience, 2012; 15 (10): 1445 DOI: 10.1038/nn.3215

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Tissue-engineered kidneys: Researchers make important strides

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ScienceDaily (Oct. 18, 2012) — With a worldwide shortage of kidneys for patients who need kidney transplants, researchers are diligently working to find ways to engineer new kidney tissue from a patient's own cells or another source. They've come a step closer to realizing that goal with a breakthrough described in an upcoming Journal of the American Society of Nephrology (JASN) study. The advance could lead to more options for individuals with kidney failure, as well as better tools for understanding kidney diseases and how to treat them.

Investigators can produce tissues similar to immature kidneys from simple suspensions of embryonic kidney cells, but they have been unsuccessful at growing more mature kidney tissues in the lab because the kidneys' complicated filtering units do not form without the support of blood vessels.

Now, from suspensions of single kidney cells, Christodoulos Xinaris PhD (Mario Negri Institute for Pharmacological Research) and his colleagues have for the first time constructed "organoids" that can be integrated into a living animal and carry out kidney functions including blood filtering and molecule reabsorption. Key to their success was soaking the organoids in a solution containing molecules that promote blood vessel formation, then injecting these molecules into the recipient animals after the organoids were implanted below the kidneys. The organoids continued to mature and were viable for three to four weeks after implantation.

"The ability to build functional renal tissue starting from suspensions of single cells represents a considerable step toward the practical goal of engineering renal tissues suitable for transplantation and offers the methodological basis for a number of investigative and therapeutic applications," said Dr. Xinaris. For example, disease-related genes could be introduced into an organoid to help researchers study the mechanisms of complex kidney diseases and to perform a preliminary screening of new drugs to treat them.

Study co-authors include Valentina Benedetti, BiolSciD, Paola Rizzo, BiolSciD, Mauro Abbate, MD, Daniela Corna, Nadia Azzolini, Sara Conti, BSc, Mathieu Unbekand, PhD, Jamie A. Davies, PhD, Marina Morigi PhD, Ariela Benigni, PhD, and Giuseppe Remuzzi, MD.

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The above story is reprinted from materials provided by American Society of Nephrology (ASN), via Newswise.
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Journal Reference:

Christodoulos Xinaris, Valentina Benedetti, Paola Rizzo, Mauro Abbate, Daniela Corna, Nadia Azzollini, Sara Conti, Mathieu Unbekandt, Jamie A. Davies, Marina Morigi, Ariela Benigni, and Giuseppe Remuzzi. In Vivo Maturation of Functional Renal Organoids Formed from Embryonic Cell Suspensions. Journal of the American Society of Nephrology, 2012; DOI: 10.1681/ASN.2012050505

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Friday, October 19, 2012

Researchers study 'ACT TIL' approach to treating metastatic melanoma

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ScienceDaily (Oct. 17, 2012) — Researchers at Moffitt Cancer Center have carried out a clinical trial in which patients with metastatic melanoma were given chemotherapy and an immunotherapy of adoptive cell transfer (ACT) with tumor infiltrating lymphocytes (TIL). Tumor tissues were surgically removed from patients, minced and grown in culture. The treatment combined chemotherapy, then ACT with TIL, followed by interleukin-2 (IL-2). The combination therapy drew a high response rate from some patients.

The study appears in the October issue of the Journal of Immunotherapy.

"Our purpose was to demonstrate the feasibility of performing TIL growth and the efficacy of ACT TIL therapy using techniques developed at the National Cancer Institute," said Amod Sarnaik, M.D., assistant member of the Cutaneous Oncology Department at Moffitt. "Combining chemotherapy with ACT and high dose IL-2 resulted in a 38 percent objective response rate in patients with metastatic melanoma."

"Although our clinical study successfully met its goal of demonstrating that ACT TIL therapy could be offered to advanced melanoma patients, strategies to improve on its feasibility and efficacy are under way," said Shari A. Pilon-Thomas, Ph.D., assistant member of the Immunology Program at Moffitt. "Combination therapies that enhance the proliferation and function of TIL are being explored."

A second-generation ACT TIL trial is enrolling patients at Moffitt.

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