Some People Infected with HIV Naturally Produce Antibodies, Clinical Trials For New AIDS Vaccines..

Researchers have identified an immunogen that can activate a certain subset of B cells to release broadly neutralizing antigens against HIV and titled as "HIV-1 broadly neutralizing antibody precursor B cells revealed by germline-targeting immunogen."

Some people infected with HIV naturally produce antibodies that effectively neutralize many strains of the rapidly mutating virus, and scientists are working to develop a vaccine capable of inducing such "broadly neutralizing" antibodies that can prevent HIV infection.

An emerging vaccine strategy involves immunizing people with a series of different engineered HIV proteins as immunogens to teach the immune system to produce broadly neutralizing antibodies against HIV. This strategy depends on the ability of the first immunogen to bind and activate special cells, known as broadly neutralizing antibody precursor B cells, which have the potential to develop into broadly neutralizing antibody-producing B cells.

A research team has now found that the right precursor ("germline") cells for one kind of HIV broadly neutralizing antibody are present in most people, and has described the design of an HIV vaccine germline-targeting immunogen capable of binding those B cells. The findings by scientists from The Scripps Research Institute (TSRI), the International AIDS Vaccine Initiative (IAVI) and the La Jolla Institute for Allergy and Immunology were published in Science on March 25.

"We found that almost everybody has these broadly neutralizing antibody precursors, and that a precisely engineered protein can bind to these cells that have potential to develop into HIV broadly neutralizing antibody-producing cells, even in the presence of competition from other immune cells," said the study's lead author, William Schief, TSRI professor and director, Vaccine Design of the IAVI Neutralizing Antibody Center at TSRI, in whose lab the engineered HIV vaccine protein was developed.

The body's immune system contains a large pool of different precursor B cells so it can respond to a wide variety of pathogens. But that also means that precursor B cells able to recognize a specific feature on a virus surface are exceedingly rare within the total pool of B cells.

"The challenge for vaccine developers is to determine if an immunogen can present a particular viral surface in a way that distinct B cells can be activated, proliferate and be useful," said study co-author Shane Crotty, professor at the La Jolla Institute. "Using a new technique, we were able to show -- well in advance of clinical trials -- that most humans actually have the right B cells that will bind to this vaccine candidate. It is remarkable that protein design can be so specific as to 'find' one in a million cells, demonstrating the feasibility of this new vaccine strategy."

The work offers encouraging insights for a planned Phase 1 clinical trial to test a nanoparticle version of the engineered HIV vaccine protein, the "eOD-GT8 60mer." "The goal of the clinical study will be to test safety and the ability of this engineered protein to elicit the desired immune response in humans that would look like the start of broadly neutralizing antibody development," Schief said. "Data from this new study was also important for designing the clinical trial, including the size and the methods of analysis."

In June, scientists from TSRI, IAVI and The Rockefeller University reported that the eOD-GT8 60mer produced antibody responses in mice that showed some of the traits necessary to recognize and inhibit HIV. If the eOD-GT8 60mer performs similarly in humans, additional boost immunogens are thought to be needed to ultimately induce broadly neutralizing antibodies that can block HIV.

The new work also provides a method for researchers to assess whether other new vaccine proteins can bind their intended precursor B cells. This method is a valuable tool in the design of more targeted and effective vaccines against AIDS, providing the ability to vet germline-targeting immunogens before testing them in large, time-consuming and costly clinical trials.

Looking at blood donated by healthy volunteers, the scientists found B cells that were capable of creating "VRC01-class" antibodies that recognized a critical surface patch, or epitope, of HIV. VRC01-class broadly neutralizing antibodies are a group of antibodies isolated from different individuals that appear to have developed in a very similar way, and it has been hypothesized that the starting VRC01-class B cells were very similar in the different people. The eOD-GT8 60mer is designed to engage these precursor B cells to initiate HIV broadly neutralizing antibody development.

EMBRYO DEVELOPMENT: Some Cells Are More Equally Than Other Cells Even At Four-Cell Stage...

THIS IS A FOUR-CELL STAGE EMBRYO.

Genetic 'signatures' of early-stage embryos confirm that our development begins to take shape as early as the second day after conception, when we are a mere four cells in size, according to new research. Although they seem to be identical, the cells of the two day-old embryo are already beginning to display subtle differences.

Once an egg has been fertilised by a sperm, it divides several times, becoming a large free-floating ball of stem cells. At first, these stem cells are 'totipotent', the state at which a stem cell can divide and grow and produce everything--every single cell of the whole body and the placenta, to attach the embryo to the mother's womb. The stem cells then change to a 'pluripotent' state, in which their development is restricted to generating the cells of the whole body, but not the placenta. However, the point during development at which cells begin to show a preference for becoming a specific cell type is unclear.

Now, in a study published in the journal Cell, scientists at the University of Cambridge and the European Bioinformatics Institute (EMBL-EBI) suggests that as early as the four-cell embryo stage, the cells are indeed different.

The researchers used the latest sequencing technologies to model embryo development in mice, looking at the activity of individual genes at a single cell level. They showed that some genes in each of the four cells behaved differently. The activity of one gene in particular, Sox21, differed the most between cells; this gene forms part of the 'pluripotency network'. The team found when this gene's activity was reduced, the activity of a master regulator that directs cells to develop into the placenta increased.

"We know that life starts when a sperm fertilises an egg, but we're interested in when the important decisions that determine our future development occur," says Professor Magdalena Zernicka-Goetz from the Department of Physiology, Development and Neuroscience at the University of Cambridge. "We now know that even as early as the four-stage embryo - just two days after fertilisation - the embryo is being guided in a particular direction and its cells are no longer identical."

Dr John Marioni of EMBL-EBI, the Wellcome Trust Sanger Institute and the Cancer Research UK Cambridge Institute, adds: "We can make use of powerful sequencing tools to deepen our understanding of the molecular mechanisms that drive development in individual cells. Because of these high-resolution techniques, we are now able to see the genetic and epigenetic signatures that indicate the direction in which early embryonic cells will tend to travel."

Reaction Believed Harmful For Photosynthesis is Now Proved Beneficial...

Researchers have demonstrated that photo inhibition of photo-system I, which reduces the effectiveness of photosynthesis, is actually a plant's self-defense mechanism against more extensive harm.

Plants use energy from the Sun to convert carbon dioxide and water into carbohydrates that act as the building blocks and energy sources for life. Oxygen is produced as a by-product of photosynthesis. However, this also causes secondary reactions that slow photosynthesis.

"Photosynthesis has developed in conditions where the atmosphere's oxygen content was low and its carbon dioxide content high. When photosynthetic organisms became the dominant life form around the world, the atmosphere's oxygen content rose, after which its secondary reactions have become a problem for photosynthesis," says University Lecturer of Molecular Plant Biology Mikko Tikkanen from the University of Turku. Tikkanen also works in the Academy of Finland's Centre of Excellence in Molecular Biology of Primary Producers.

Despite having developed safety mechanisms against secondary reactions, plants cannot avoid damage completely. An intriguing observation was that the damage alters the function of photosystem I. Instead of forwarding electrons from water splitting photosystem II, a damaged photosystem I begins to dissipate excess excitation energy as heat and stops producing NADPH molecules, which is its normal function.

"We proved that altering the function is a way to protect the photosynthetic apparatus from more extensive damage. Damage initiates a series of changes, where the direction of light energy is turned towards damaged photosystem I centres. This reduces the risk of damage to photosystem II and curtails the electron flow towards photosystem I, which stops the damage, Tikkanen explains.

In photosynthesis, photosystem II oxidises water into electrons, hydrogen protons and oxygen, whereas photosystem I uses electrons to produce high energy NADPH. The damage referred to as photoinhibition has been thought to be a detrimental reaction that should be avoided. It was thought, among other things, to reduce profits from crops.

"It was previously believed that photosystem II and photosystem I worked in series but rather independently in converting light energy into chemical form. Our new research demonstrates that photosystems form a functional pair in that damage to one protects the other from more extensive damage," Tikkanen says.

An understanding of the roles of photosynthesis' different photosystems is important with regard to understanding the evolution of the photosynthesis mechanism.

"When the roles are recognised, we will no longer use the wrong methods in an effort to increase the effectiveness of photosynthesis. New data helps us see the problem points for the development of artificial photosynthesis," Tikkanen says.

The research article was published in the scientific journalNature Plants........

MALARIA HAS ITS ROOTS IN BIRD HOSTS

Extensive testing of malarial DNA found in birds, bats and other small mammals from five East African countries revealed that malaria has its roots in bird hosts. It then spread from birds to bats and on to other mammals.

A new study reveals a new hypothesis on the evolution of hundreds of species of malaria -- including the form that is deadly to humans.

A study published this week in the journal Molecular Phylogenetics and Evolutionreveals a new hypothesis on the evolution of hundreds of species of malaria -- 

Extensive testing of malarial DNA found in birds, bats and other small mammals from five East African countries revealed that malaria has its roots in bird hosts. It then spread from birds to bats and on to other mammals.

"We can't begin to understand how malaria spread to humans until we understand its evolutionary history," said lead author Holly Lutz, a doctoral candidate in the fields of Ecology and Evolutionary Biology and Population Medicine and Diagnostic Sciences at Cornell University. "In learning about its past, we may be better able to understand the effects it has on us."

Lutz and her colleagues took blood samples from hundreds of East African birds, bats, and other small mammals and screened the blood for the parasites. When they found malaria, they took samples of the parasites' DNA and sequenced it to identify mutations in the genetic code. From there, Lutz determined how different malaria species are related based on differences in their genetic code. Having large sample sizes from many species was key.

"Trying to determine the evolutionary history of malaria from just a few specimens would be like trying to reconstruct the bird family tree when you only know about eagles and canaries," explained Lutz. "There's still more to discover, but this is the most complete analysis of its kind for malaria to date."

Humans cannot contract malaria directly from birds or bats. And while the study doesn't have direct implications for malaria treatment in humans, co-author and Field Museum Curator of Mammals Bruce Patterson noted, "Malaria is notoriously adaptive to treatment, and its DNA holds a host of secrets about how it's able to change and evolve. Having a better understanding of its evolutionary history could help scientists anticipate its future."

NEW STUDY SHOWS "CONTROLLING FAT PRODUCTION" IN THE BODY

New research suggests that combining bone marrow or stem cell transplant technology with genetic engineering could result in tailor made fat storing cells with desirable functions.

Move over diet and exercise, a new weight control method is in the works and it involves manipulating the production of fat cells at their source. A new research report published in the March 2016 issue of The FASEB Journal shows that at least some human fat cells are actually produced from stem cells that originate in bone marrow. As a result, scientists hope to one-day manipulate the type or quantity of fat cells created to ultimately reduce the risk of diseases impacted by the prevalence of unhealthy fat, such as cardiovascular disease, types 2 diabetes, high blood pressure, sleep apnea, asthma, pulmonary hypertension, gall bladder disease, kidney disease, some cancers, and perhaps obesity itself.

"Our study suggests that it may be the type of fat-storing cells produced in our bodies that determines risk for disease, rather than the amount of fat," said Dwight J. Klemm, Ph.D., a researcher involved in the work from the University of Colorado Anschutz Medical Campus in Aurora, Colorado. "This paradigm highlights the possibility of new strategies to prevent and reverse fat-related chronic disease by controlling the production of different types of fat-storing cells."

To make their discovery, Klemm and colleagues recruited human subjects who received bone marrow transplants for clinical reasons from a different human donor many months before the study. A small sample of fat tissue was removed from just under the skin next to the belly button. The DNA from the fat cells in the tissue sample was evaluated to determine if it came from the person who donated the bone marrow or the transplant recipient. They found the presence of donor DNA, which indicated that some of the fat cells had grown from cells that originated in the transplanted bone marrow. Previous research with mice indicates that fat-storing cells produced from bone marrow stem cells may be particularly harmful because they produce substances that promote inflammation and hinder the ability of other cells to respond to insulin.

"This research may help unravel many of the mysteries associated with weight gain, weight loss, and the effects that excessive fat has on the body," said Thoru Pederson, Ph.D., Editor-in-Chief of The FASEB Journal. "The more we learn about this interesting discovery, the closer we are toward shutting down the harmful effects of fat cells at the source."