'Ardi' skull reveals links to human lineage

Jan. 6, 2014 — One of the most hotly debated issues in current human origins research focuses on how the 4.4 million-year-old African species Ardipithecus ramidus is related to the human lineage. "Ardi" was an unusual primate. Though it possessed a tiny brain and a grasping big toe used for clambering in the trees, it had small, humanlike canine teeth and an upper pelvis modified for bipedal walking on the ground.

Scientists disagree about where this mixture of features positions Ardipithecus ramidus on the tree of human and ape relationships. Was Ardi an ape with a few humanlike features retained from an ancestor near in time (between 6 and 8 million years ago, according to DNA evidence) to the split between the chimpanzee and human lines? Or was it a true relative of the human line that had yet to shed many signs of its remote tree-dwelling ancestry?

New research led by Arizona State University paleoanthropologist William Kimbel confirms Ardi's close evolutionary relationship to humans. Kimbel and his collaborators turned to the underside (or base) of a beautifully preserved partial cranium of Ardi. Their study revealed a pattern of similarity that links Ardi to Australopithecus and modern humans, but not to apes.

The research appears in the Jan. 6-10 online edition of Proceedings of the National Academy of Sciences. Kimbel is director of the ASU Institute of Human Origins, a research center of the College of Liberal Arts and Sciences in the School of Human Evolution and Social Change. Joining ASU's Kimbel as co-authors are Gen Suwa (University of Tokyo Museum), Berhane Asfaw (Rift Valley Research Service, Addis Ababa), Yoel Rak (Tel Aviv University) and Tim White (University of California at Berkeley).

White's field-research team has been recovering fossil remains of Ardipithecus ramidus in the Middle Awash research area, Ethiopia since the 1990s. The most recent study of the Ardi skull, led by Suwa, was published in Science in 2009, whose work (with the Middle Awash team) first revealed humanlike aspects of its base. Kimbel co-leads the team that recovered the earliest known Australopithecus skulls from the Hadar site, home of the "Lucy" skeleton, in Ethiopia.

"Given the very tiny size of the Ardi skull, the similarity of its cranial base to a human's is astonishing," says Kimbel.

The cranial base is a valuable resource for studying phylogenetic, or natural evolutionary relationships, because its anatomical complexity and association with the brain, posture and chewing system have provided numerous opportunities for adaptive evolution over time. The human cranial base, accordingly, differs profoundly from that of apes and other primates.

In humans, the structures marking the articulation of the spine with the skull are more forwardly located than in apes, where the base is shorter from front to back and the openings on each side for passage of blood vessels and nerves are more widely separated.

These shape differences affect the way the bones are arranged on the skull base, such that it is fairly easy to tell apart even isolated fragments of ape and human basicrania.

Ardi's cranial base shows the distinguishing features that separate humans and Australopithecus from the apes. Kimbel's earlier research (with collaborator Rak) had shown that these human peculiarities were present in the earliest known Australopithecus skulls by 3.4 million years ago.

The new work expands the catalogue of anatomical similarities linking humans, Australopithecus and Ardipithecus on the tree of life, and shows that the human cranial base pattern is at least a million years older than Lucy's species, A. afarensis.

Paleoanthropologists generally fall into one of two camps on the cause of evolutionary changes in the human cranial base. Was it the adoption of upright posture and bipedality that caused a shift in the poise of the head on the vertebral column? If so, does the humanlike cranial base of Ar. ramidus confirm postcranial evidence for partial bipedality in this species? Or, do the changes tell us about the shape of the brain (and of the base on which it sits), perhaps an early sign of brain reorganization in the human lineage? Both alternatives will need to be re-evaluated in light of the finding that Ardi does indeed appear to be more closely related to humans than to chimpanzees.

"The Ardi cranial base fills some important gaps in our understanding of human evolution above the neck," adds Kimbel. "But it also opens up a host of new questions . . . just as it should!"

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Alpine archaeology reveals high life through the ages

Sep. 25, 2013 — An international team of archaeologists led by experts from the University of York has uncovered evidence of human activity in the high slopes of the French Alps dating back over 8000 years.

The 14-year study in the Parc National des Eicrins in the southern Alps is one of the most detailed archaeological investigations carried out at high altitudes. It reveals a story of human occupation and activity in one of the world's most challenging environments from the Mesolithic to the Post-Medieval period.

The work included the excavation of a series of stone animal enclosures and human dwellings considered some of most complex high altitude Bronze Age structures found anywhere in the Alps.

The research, published in Quaternary International, was led by Dr Kevin Walsh, landscape archaeologist at the University of York in partnership with Florence Mocci of the Centre Camille Julian, CNRS, Aix-en-Provence.

Dr Walsh explained: "High altitude landscapes of 2000 metres and above are considered remote and marginal. Many researchers had assumed that early societies showed little interest in these areas. This research shows that people, as well as climate, did have a role in shaping the Alpine landscape from as early as the Mesolithic period.

"It has radically altered our understanding of activity in the sub-alpine and alpine zones. It is also of profound relevance for the broader understanding of human-environment interactions in ecologically sensitive environments."

Excavations carried out by the team showed human activity shaped the Alpine landscape through the Bronze, Iron, Roman and Medieval ages as people progressed from hunting to more managed agricultural systems including the movement of livestock to seasonal alpine pastures, known as transhumant-pastoralism.

"The most interesting period is the Chalcolithic/Bronze Age when human activity, particularly to support pastoralism, really begins to dominate the landscape," said Dr Walsh. "The Bronze Age buildings we studied revealed the clear development of seasonal pastoralism that appears to have been sustained over many centuries with new enclosures added and evidence of tree clearing to create new grazing land.

"The evidence suggests the landscape was occupied over many centuries marking the start of a more sustained management of the alpine landscape and the development of the pastoral agricultural systems we see in the Alps today."

The study also uncovered evidence of Stone Age hunting camps in often inhospitable conditions in the upper reaches of the Alpine tree line at 2000 metres and above. Other finds included a Neolithic flint arrow head at 2475 metres, thought to be the highest altitude arrowhead discovered in the Alps.

The study was carried out by a team of British and French archaeologists and palaeoecologists. They surveyed over 300 sites across a number of valleys as well as studying pollen from cores taken from peat areas and lakes and carbonized wood remains

Initial fieldwork for the project started in 1998 followed by a series of further fieldwork expeditions into some of the most remote and spectacular landscapes in the national park.

"The nature of these landscapes and the fact that no-one had ever carried out fieldwork in these areas meant that we had to carry out numerous phases of work involving long treks over difficult ground and sometimes in challenging weather.

"The result of this work is that only now do we have a clear understanding of how these remote, beautiful areas were exploited by people over the millennia," said Dr Walsh.

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Molecular structure reveals how HIV infects cells

Sep. 12, 2013 — In a long-awaited finding, a team of Chinese and US scientists has determined the high-resolution atomic structure of a cell-surface receptor that most strains of HIV use to get into human immune cells. The researchers also showed where maraviroc, an HIV drug, attaches to cells and blocks HIV's entry.

"These structural details should help us understand more precisely how HIV infects cells, and how we can do better at blocking that process with next-generation drugs," said Beili Wu, PhD, professor at the Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences. Wu was the senior investigator for the study, which was published in Science Express on September 12, 2013.

The study, which focused on the CCR5 receptor, was supported by both US and Chinese research funding agencies. "International collaborations like this one are increasingly needed to solve big problems in science," said study co-author Raymond C. Stevens, PhD, a professor at The Scripps Research Institute (TSRI) in California. "Now that we have both human CXCR4 and CCR5 HIV co-receptor three-dimensional structures, it is likely we will see the next generation of HIV therapeutics."

A Major Target

The CCR5 receptor is one of the most sought-after targets for new anti-HIV drugs. Although the AIDS-causing virus was initially discovered to infect cells via another receptor, CD4, researchers found in 1996 that HIV infection also requires a co-receptor -- usually CCR5, which sits alongside CD4 on a variety of immune cells.

CCR5's importance to HIV infection is underscored by the fact that certain genetic variants of it can dramatically raise or lower HIV infection risk, as well as the speed of the disease process after infection. One shortened CCR5 variant, found in about 10 percent of Europeans, is not expressed at all on immune cell surfaces -- and people who produce only this variant are almost invulnerable to HIV infection.

Scientists therefore have sought to develop anti-HIV drugs that block the virus from binding to CCR5 or otherwise render the receptor inactive. Yet only a handful of CCR5-inhibiting compounds have been developed so far -- and no one knows exactly how they work. "One thing that we've lacked is a high-resolution molecular 'picture' of the CCR5 receptor structure that we can use for precise drug design," Wu said.

A Six-Year Quest

Wu came to the Stevens laboratory at TSRI in 2007 to conduct postdoctoral research on the two HIV co-receptors, CCR5 and the alternate HIV co-receptor CXCR4. A minority of HIV strains use CXCR4 instead of CCR5 as a co-receptor with CD4 for their initial infiltration of cells.

"Her goal from the beginning was to determine the structures and understand the functions of these two HIV co-receptors and she was very determined which was inspiring," said Stevens.

Wu spent her postdoctoral years focusing on CXCR4, which posed fewer technical challenges than CCR5. Her landmark study of the CXCR4 structure was published in Science in 2010. After moving back to China to start her own laboratory at SIMM, she returned to the "unfinished business" of the CCR5 structure.

Both CCR5 and CXCR4 belong to a large family of cell receptors known as G protein-coupled receptors (GPCRs). GPCRs are notoriously hard to produce in useful amounts for structural analysis. With their floppy structures, they are also very hard to coax into the ordered, solid lineups of individual molecules -- "crystals" -- needed for structure determination by X-ray crystallography. Eventually, however, with help from insights gained during the CXCR4 project, Wu, as a new professor, and her young team of students used a novel "fusion partner" molecule that would hold CCR5 proteins together enough to form usable crystals, together with efforts of computational modeling, compound synthesis and cell signaling assays from Drs. Hualiang Jiang, Hong Liu and Xin Xie's groups at SIMM, which led to the structure determination of CCR5.

As in most receptor-structure projects, Wu and her colleagues further stabilized CCR5 with a compound that is known to bind to it, in this case the Pfizer drug maraviroc (sold under the brand name SelzentryR or CelsentriR outside the US). Marketed for HIV infection since 2007, maraviroc grabs hold of CCR5 in a way that prevents HIV from using the receptor to get into cells. "Maraviroc was thought to lock CCR5 into an inactive conformation, and so we wanted to 'see' that conformation at high resolution," said Wu.

The resulting crystallography data provided that fine-grained picture of CCR5's HIV-resistant conformation. The data also revealed maraviroc's precise binding site on CCR5 -- a site from which the drug molecule clearly influences how the receptor works, even though it is separate from the sites on the receptor that are thought to be used by HIV. The maraviroc binding site is also different from the site used by CCR5's natural binding-partners, a set of immune proteins called chemokines. Maraviroc thus appears to work against HIV indirectly -- not by physically blocking the virus, but by locking the receptor structure into an HIV-insensitive conformation.

"Structural details can offer tremendous insight into how proteins and drugs work, also aiding the development of therapeutic agents," said Peter Preusch, PhD, of the National Institute of General Medical Sciences, which helped fund the research along with another component of the National Institutes of Health, the National Institute of Allergy and Infectious Diseases. "This study provides knowledge about the interactions between maraviroc and CCR5, a target for anti-HIV therapy, that helps us understand how the drug works at the molecular level and could enable further explorations of HIV biology and approaches to improve drugs targeting such interactions."

Useful Insights

Comparison of the CCR5 structure with the previously determined CXCR4 structure also provided hints about an important aspect of HIV evolution during infections. Most HIV infections start by using only CCR5 as a co-receptor for cell entry, but in time the virus often switches its co-receptor usage from CCR5 to CXCR4. That opens up more cell types to HIV infection, and the further spread of the virus inside the body is liable to speed up the disease progression towards full-blown AIDS and death.

The new data suggest that the distinction between CCR5 and CXCR4 as co-receptors for HIV infection boils down to relatively subtle differences in structural shapes and electric charge distributions in the HIV binding region -- differences that will be of interest to HIV drug developers.

"Knowing the CXCR4 structure and now the CCR5 structure at this level of detail should accelerate the development of drugs that can block HIV by using both of these co-receptors," said Wu.

She and her colleagues now plan to follow up with structural studies of CCR5 and CXCR4 in complex with the HIV envelope protein gp120 and CD4 to obtain even more informative pictures of the process of viral infection.

Soon after the structure determination of CCR5, SIMM performed structure-based drug design and has obtained several drug lead compounds with more potent antiviral efficacies than maraviroc, which further proves the importance of CCR5 structure on the development of HIV theraputics.

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Reveals the genetic causes of childhood leukemia.

For the first time, a genetic link specific childhood leukemia risk has been identified, according to the team of researchers from the Memorial Sloan-Kettering Cancer Center, St. Jude children's research hospital and Washington University （ affiliate Fred Hutchinson Cancer Research Center ）, and other institutions. Discovery is reported in the online journal Nature Genetics.

Learn to read the full text of the press release.

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Among the research institutions in NCI funding, all over the United States that current cancer specifies 68 as a Center. Based at research universities, these facilities are cancer's origin and development of intense laboratory research wide range, the scientists from NCI support many home. Cancer Center program is also focused on cross-cutting research, population Sciences, and clinical research please. Center for research results are often at the forefront of cancer research.

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