John Harris - US grants

orphan disease /drug;

The polymerization and sol-gel transformation of deoxyhemoglobin S will be inhibited by an unexplored mechanism in which the close approach of hemoglobin molecules necessary to initiate and propagate polymerization is prevented and the hemoglobin is allowed to remain fully functional. Peptides of the amino acid sequence present in the N-terminal portion of Band 3 of the human erythrocyte bind reversibly to hemoglobin A at the 2,3-DPG receptor locus. Binding to the deoxy conformation is much greater than to the oxy. The peptides extend deep into the cavity between the beta chains and, depending on length, protrude for varying distances beyond the confines of the tetrad. The interactions between fragments of the N-terminal cytoplasmic portion of Band 3 and hemoglobin S are comparable with those of hemoglobin A but the effect of such peptides on the polymerization of deoxy S has not been explored. It is postulated that 1) a 15 amino acid peptide of the same sequences as in the N-terminal cytoplasmic domain of Band 3 will enter the inter-betaS chain region a distance of 18 angstrom and protrude approximately 27 angstrom outside the molecule to occupy and occlude a hemispheric volume of 27 angstrom radius around the 2,3-DPG binding site of the betaS chains and 2) the protruding portion of the peptide will, by sheer bulk or by covering up specific interacting sites, prevent the 1-5 angstrom approaches that the surface beta 6 mutant and other contact areas must make to initiate polymerization. Additional steric impedance to hemoglobin S polymer formation may arise from 1) disordering of the beta chains in the 10-12 residues f the C-termini and in the 3 N-terminal amino acids before the A helix (Changes induced in hemoglobin A by the peptide), and 3) the formation of binary complexes of deoxyhemoglobin S molecules tethered together by the peptide in beta-to-beta chain apposition. These could not properly incorporate into the polymer. The peptides will be designed, synthesized, purified, and characterized: evaluation of reactions with hemoglobin will be by Csat, time-viscosity profile, physical properties of gel, P50, competitive binding with other polyanions, change in charge and M.W. The binding, reversibility, and steric interference will be optimized by varying the molar rations of peptide to hemoglobin, peptide length, amino acid sequence, an contour. Results will provide new data on nucleation, the polymerization reaction, and the structure of polymer and gel. A new class of inhibitors will be defined that may ultimately find applicability in controlling the intracellular polymerization basic to the pathophysiology and clinical manifestations of sickle cell disorders.

The beginnings of human use and control of fire has been an important concern for students of human origins since it is crucial for understanding early hominid cultural adaptation and development. Recently, traces of fire in early Pleistocene contexts have been reported at Koobi Fora, Kenya. However, archaeologists lack a methodology to distinguish whether these remains are naturally occurring or the result of human endeavors. To help remedy this situation, the student will conduct a series of actualistic experiments in Zaire and Kenya on the effects of campfires, tree stump fires and grass fires to see how they may be manifested physically and macroscopically in the range of sedimentary environments used by early hominids. The research will result in new methods and techniques to help determine the presence of fire in archaeological sites around the world.

The polymerization and sol-gel transformation of deoxyhemoglobin S will be inhibited by an unexplored mechanism in which the close approach of hemoglobin molecules necessary to initiate and propagate polymerization is prevented and the hemoglobin is allowed to remain fully functional. Peptides of the amino acid sequence present in the N-terminal portion of Band 3 of the human erythrocyte bind reversibly to hemoglobin A at the 2,3-DPG receptor locus. Binding to the deoxy conformation is much greater than to the oxy. The peptides extend deep into the cavity between the beta chains and, depending on length, protrude for varying distances beyond the confines of the tetrad. The interactions between fragments of the N-terminal cytoplasmic portion of Band 3 and hemoglobin S are comparable with those of hemoglobin A but the effect of such peptides on the polymerization of deoxy S has not been explored. It is postulated that 1) a 15 amino acid peptide of the same sequences as in the N-terminal cytoplasmic domain of Band 3 will enter the inter-betaS chain region a distance of 18 angstrom and protrude approximately 27 angstrom outside the molecule to occupy and occlude a hemispheric volume of 27 angstrom radius around the 2,3-DPG binding site of the betaS chains and 2) the protruding portion of the peptide will, by sheer bulk or by covering up specific interacting sites, prevent the 1-5 angstrom approaches that the surface beta 6 mutant and other contact areas must make to initiate polymerization. Additional steric impedance to hemoglobin S polymer formation may arise from 1) disordering of the beta chains in the 10-12 residues f the C-termini and in the 3 N-terminal amino acids before the A helix (Changes induced in hemoglobin A by the peptide), and 3) the formation of binary complexes of deoxyhemoglobin S molecules tethered together by the peptide in beta-to-beta chain apposition. These could not properly incorporate into the polymer. The peptides will be designed, synthesized, purified, and characterized: evaluation of reactions with hemoglobin will be by Csat, time-viscosity profile, physical properties of gel, P50, competitive binding with other polyanions, change in charge and M.W. The binding, reversibility, and steric interference will be optimized by varying the molar rations of peptide to hemoglobin, peptide length, amino acid sequence, an contour. Results will provide new data on nucleation, the polymerization reaction, and the structure of polymer and gel. A new class of inhibitors will be defined that may ultimately find applicability in controlling the intracellular polymerization basic to the pathophysiology and clinical manifestations of sickle cell disorders.

orphan disease /drug; hemolytic anemia; microcytic /hypochromic anemia; congenital hemolytic anemia; autoimmune hemolytic anemia; nutrition related tag;

Under the direction of Dr. John Harris, Mr. Michael Rogers will collect data for his doctoral dissertation. He will conduct archaeological survey and excavation in the region East of Lake Turkana in Kenya. He will focus his attention on a geological stratum known as the Okote Member and which dates to ca. 1.64-1.39 million years ago. Previous work has recovered both stone tools and associated faunal remains and thus demonstrated that this region was inhabited by early hominids. However little is known about the behavior of these early humans. Through a study both of the distribution of different kinds of lithic remains over space and of their association with faunal remains and each other, Mr. Rogers should gain insight into how activities were spaced over the landscape. This research is important for several reasons. First, it will increase our understanding of the emergence of modern humans. It is clear that behavior, and behavioral changes have played a major role in the development of our species yet for the earlier stages of this process, relatively little is known. Mr. Rogers' research will help to fill this gap. Secondly, this research will help to develop and refine techniques of archaeological analysis. The methods Mr. Rogers will use may be applicable in many time periods and many regions of the world. Finally this grant will help to train an extremely promising young scientist.

Harris Under the direction of Dr. John W. Harris, Ms. Paola Meneses will collect data for her doctoral dissertation. She will conduct archaeological fieldwork along the Umbeluzi and Changalane rivers in Southern Mozambique and analyze the resultant data. Previous work conducted by Ms. Meneses indicates that this area is rich in lithic remains associated with the Acheulean industry which covers the time span from ca. 1,250,000 to 125,000 years ago. The research consists of three parts. First a survey will be conducted to locate both surface and in situ materials. This will be followed by limited excavation to recover in place artifacts and to establish geological context. As part of this first stage, a geomorphological stages will be reconstructed and a chronological sequence will be developed. Secondly, lithic materials will be analyzed to determine formal attributes of the assemblages and to compare these with materials from South and Eastern Africa. Finally an experimental approach will be used to reconstruct the lithic manufacture process. On this basis it will be possible to map the distribution of lithic remains across the reconstructed landscapes and determine how these were used by Acheulean peoples. Africa provided the geographic cradle for humans and archaeologists wish to understand the processes which led to the emergence of both culturally and physically modern humans. Surprisingly little is known about the 1 million year plus time interval covered by the Acheulean and very few studies have employed modern analytic techniques. Ms. Meneses work will shed new light on how humans adapted during this interval. It will also provide data of interest to many archaeologists. Finally, this grant will assist in the training of a promising young archaeologist.

Under the direction of Dr. Jack Harris, Mr. Brian Ludwig will collect data for his doctoral dissertation. He will study stone tool assemblages from a series of East African sites which date to between 2.5 and 1.5 million years ago. He will examine materials from the Gona and Omo sites in Ethiopia, Foobi Fora in Kenya and Olduvai Gorge in Tanzania. Measurements will be recorded on 29 variables based on strictly technological features found on flakes, angular fragments, cores and other reworked pieces. Mr. Ludwig is an experienced stone worker and he will also use replicative techniques to determine the processes by which these objects were produced. On this basis he will gain insight into the cognitive and manipulative abilities of the hominids who produced them and trace how these developed over time. The period between 2.5 and 1.5 years ago marked a major advance in hominid capabilities. At 2.5 million the archaeological record begins with the first flaked stone tools. A million years later hominids were producing standardized forms. The goal of this research is to determine how this process developed over time. Previous archaeological studies of these materials have focussed on `tool types` and attempted to sort materials into named categories. However such an approach gives little insight into their makers' cognitive and manipulative abilities. Mr. Ludwig's work will help to alleviate this situation. This research is important for several reasons. It will provide information of interest to many archaeologists. It will shed new light on the development of human cognitive abilities and assist in the training of a promising young archaeologist.

Harris Under the direction of Dr. John Harris, Mr Kyara Onesphor will collect data for his doctoral dissertation. He will conduct both field and laboratory analysis and study stone tool assemblages from sites located at Olduvai Gorge, Tanzania. He will focus on materials included in the Bed II geological strata which are significant because they document a major archaeological and physical transformation in human evolution. Stone tools recovered from this interval are made on a number of different raw materials and archaeologists wish to know what insight this variety might provide into early human behavior. Mr. Onesphor will analyze the tools by typology and by raw material. He will also conduct experiments to determine which kinds of raw materials are best suited to specific functions. He will then travel to Olduvai gorge, locate raw material sources, collect specimens and note the distances to archaeological sites. With the data thus collected he hopes to reconstruct aspects of the cognitive and land use systems of early hominids. The research will produce data of interest to many archaeologists. It will shed new light on the development of human capabilities and assist in the training of a promising young scientist.

Under the direction of Dr. J. W. K. Harris, Mr. David R. Braun will conduct his doctoral research on the ecology of stone artifacts in the time period known as the terminal Pliocene (~2 Ma). He will initiate excavations at new localities in the world famous Koobi Fora region known for its wealth of early human fossils and artifacts. These excavations will provide a comparison with one of the most exciting new finds in early human archaeology: Kanjera South. The site of Kanjera south has several thousand well-preserved bones and artifacts. With possible evidence of animal butchery and long distance transport of artifacts this site is on par with the Olduvai localities of Tanzania in its potential to elucidate early human behavior. Mr. Braun will compare interpretations of early human behaviors at these sites, as viewed through the window of lithic (stone tool) analysis. Lithics are a behavioral trace of the interface between early humans and their environments. Paleoenvironmental reconstructions at Koobi Fora paint a picture of a lake- and river-dominated ecosystem, with areas of swampy woodlands. Meanwhile, Kanjera is reconstructed as an open savannah grassland. A focus of Mr. Braun's analysis will be to compare the behaviors of early humans in the variable environments of the terminal Pliocene.

Mr. Braun's analysis of these artifacts will incorporate various new techniques to understand the importance of stone tools to these proto-humans. To determine the distances that early humans traveled to collect stones to make artifacts geochemical techniques (Energy Dispersive X-Ray Flourescence) will be used to link artifacts to rock outcrops. This analysis is the result of an important collaboration between American researchers and the Institute of Nuclear Science at the University of Nairobi. Furthermore, his analysis will incorporate digital imaging of stone artifacts. These techniques have not previously been employed on materials of such antiquity. Preliminary results from digital imaging analysis suggest evolution in early human ranging patterns and landscape use.
Crucial to an understanding of early human behavior is investigating the need and use of stone tools. Mr. Braun's analysis will approach stone artifacts using experimentally derived models to test theories of optimality in early human stone tool use. By applying an evolutionary ecological framework to the study of artifact assemblages in varying environments it is possible to further our understanding of the heterogeneity of early human behavior. The support of this project will provide vital new insights into the evolution of human behavior and further the career of a student committed to the study of African archaeology.

Under the direction of Dr. John Harris, Ms Purity Kiura will collect data for her doctoral dissertation. Her project is a study over the annual cycle by direct observation and stable isotope analysis of the food consumption of three groups of people with different subsistence strategies (the Dassanetch, Gabra and El-molo) living today to the East of Lake Turkana in Northern Kenya. The ultimate goal of this study is to provide an interpretive framework for investigating the subsistence strategies and diet of people believed to have occupied the region during the last 10,000 years (Holocene period). These three modern groups are not direct analogues for the Holocene peoples but do have diets similar to those proposed in the region by prior researchers. However, if by direct observations, including the analysis of food residues discarded in garbage pits, and by the study of stable isotope signatures of modern peoples that these are found to be discrete, then it may be possible to identify similar subsistence strategies in the regions Holocene record.

Ms Kiura and her field assistants will conduct daily observations and interviews of the people's dietary behavior (food types, processing, preparing and sharing) while at the same time they will document the food remains that are discarded in garbage pits through the people's food processing and consumption activities. Stable carbon and nitrogen isotope analysis to determine the food types consumed will be carried out on the people's hair, bone and teeth from the animals consumed by the people, and also the plants eaten by these animals. Daily weather observations (i.e. rain, humidity, temperature and wind patterns) will also be recorded to provide seasonal changes in the region.

The data collected here will have broad implications beyond setting up a base for the study of the Holocene people's subsistence strategies. The data will also provide novel information on the dietary activities through the annual cycle of three modern groups of people that are poorly studied. Plants and animals in the region are poorly understood and this project will therefore provide very important information to plant physiologists, mammalogists, paleontologists and others. Daily weather records will also prove important to all scientists interested in the region's seasonal changes and effects on the overall environment.

Under the direction of Dr. J.W.K. Harris, Jack McCoy will conduct extensive field survey and excavation of 2 million year old sediment deposits at Koobi Fora in Northern Kenya. This doctoral dissertation project is designed to identify, characterize and describe archaeological occurrences principally through the proxy of hominid (early human) modified fossil bone exhibiting evidence of meat consumption and stone tool use. Using stone tools to process a carcass for meat and marrow produces distinctive modification marks (cut marks, percussion marks) on fresh bone. These marks are often preserved on the bone as it becomes fossilized. Evidence (stone tools and cut marked fossil bone) of an established pattern of this novel new meat consumption behavior prior to 2.3 million years ago has been discovered to the north in Ethiopia and only a short distance to the west at Lokalalei in Kenya. And yet, at Koobi Fora, where the fossil remains of over three dozen hominids (genera: Australopithecus & Homo) have been recovered from Upper Burgi (2.2-1.9 million years old) exposures virtually nothing is known of hominid behavior, ecology, or material culture during this period. Extensive paleontological and archaeological research previously conducted at Koobi Fora did not focus on archaeological traces from the Upper Burgi period; a pivotal time in hominid evolution.

Koobi Fora encompasses an area of over 3,000 square kilometers. Approximately 1,000 square kilometers are exposed ancient deposits spanning the last 4 million years. Because of the unique nature and vast lateral extent of the exposures, a large variety of ancient landscapes and habitats can be identified in the sediments. The selection of widely separated areas of investigation makes it possible, utilizing modified bone and stone tools as markers on the landscape, to develop a regional view of hominid activities and movements during this time period. Recognition of the distribution patterns of these markers across widely different geographic locations and paleoenvironments will allow one to address theoretical questions of hominid habitat preference, as well as changes in diet and behavior which have not been addressed elsewhere at this early stage of human evolution. Significantly, this research goes beyond the discovery and initial description of the archaeological traces and examines the circumstances that made stone tools adaptive at the onset of a novel new hominid behavior (carnivory) that would eventually become habitual. It is expected that this research will become part of a long term basin-wide comparative study that will address the changing nature of the earliest archaeological record in the Turkana Basin over time.

On a broader perspective, this project has the potential to confirm the usefulness of modified fossil bone as an unequivocal proxy for stone tool use. If fossil bone fragments with a modification signature indicative of hominid activity have visibility in the geological record then it will become possible to identify hominid presence and behavior patterns where no stone tool evidence (traditional archaeological record) is known to exist. Stone tools from Gona in Ethiopia, dated at 2.6 million years old, presently define the onset of the archaeological record. Testable hypotheses about hominid behavior prior to 2.6 million years ago can only be formulated if the hominids can be located on the ancient landscape. Cut marked bone and percussion fractured shaft fragments may provide that opportunity and could become the basis of a new paradigm from which to investigate the true onset of the archaeological record.

DESCRIPTION (provided by applicant): The overall goal of this project is to design a new generation of fully implantable flexible substrate microelectrode array probes to record neural activity from behaving rodents. In existing approaches, the behaving rodents are either tethered or encumbered by external devices strapped to their bodies. A fully implantable unit would allow improved characterization of brain function via neural recordings in rats in an unrestrained condition. The proposed device is a battery powered electronic chip that utilizes the state-of- the-art integrate-and-fire (IF) representation and proven protocols: microwire array, flexible substrate, and wireless communication. What makes this implantable specification possible is anew IF sampling principle that is able to reduce both the power dissipation and the necessary bandwidth to transmit high-resolution data. We anticipate that it is possible to build an implant that uses less than 2mW of total power dissipation to record, amplify, encode and transmit wirelessly 16 channels of field potentials and extracellular action for 72-96 hours depending on the data rates. An external signal reconstruction algorithm will output neural data with at least 40dB accuracy (better on high amplitude signal regions) at a 20 kHz sampling rate. In order to design, characterize, build and test in vivo the Florida Wireless Implantable Recording Electrodes (FWIRE), we specifically propose: 1. To design, fabricate in VLSI, test in vivo and formulate system specifications for an ultra low power 16- channel amplifier with pulsed output based on the novel integrate-and-fire sampling scheme. The overall power consumption of this subsystem will be below 1mW. 2. To design an ultra-power (1mW), low-bandwidth (500Kpulses/sec) wireless link and integrate the multiple modules (electrodes, integrate-and-fire amplifiers, communication link) into an implantable package using a flexible substrate. 3. To study in vivo the characteristics of FWIRE during the full duration of the implantable probe development. Bottlenecks in the design will be anticipated, found, and corrected;system performance will be fully characterized.

Recently about half of an associated hominin (human ancestors and extinct relatives) upper limb skeleton and several layers of sediment containing hominin and other animal footprints were discovered at a 1.5 million-year old site (FwJj14) in Kenya. This award continues the fieldwork on this important discovery. Its goals are to 1) recover more of the newly-discovered associated hominin skeleton likely belonging to the extinct human relative, Paranthropus boisei; 2) excavate, scan, and analyze three footprint layers at FwJj14E, including two layers with hominin footprints; and 3) excavate, scan and analyze a footprint layer at GaJi10 that also preserves hominin prints. These discoveries offer a unique opportunity to test long-standing hypotheses, ask novel questions, and dramatically improve our understanding of hand and upper limb anatomy, bipedal gait, behavior, and environmental context of sympatric hominins during this critical time in human evolutionary history.

This project offers a number of measurable broader impacts for the scientific community by fostering interdisciplinary and international collaboration, improving training of African scholars, and improving ethnic representation in paleoanthropology in the US. The data as well as 3D scan data of footprints will be available to the National Museum of Kenya, other scholars, and the Human Origins Database, soon-to-be publicly accessible through the Smithsonian National Museum of Natural History. This project will strengthen international (US-Kenya-South Africa-UK) and, within the US, inter-institutional (George Washington University-James Madison University-Smithsonian Institution-Rutgers University) collaborations. Furthermore, this project demonstrates a strong commitment to train US students from groups underrepresented (e.g., African-American, Hispanic) in paleoanthropology, as well as graduate students from Kenya and South Africa.

With National Science Foundation support Mr. J.S. Reti will analyze artifact assemblages from two important human evolutionary sites: Koobi Fora, Northern Kenya and Olduvai Gorge, Tanzania. Both Koobi Fora and Olduvai Gorge are renowned for their stone tool and fossil assemblages from the earliest recognized stone tool industry, known as the Oldowan. Though research into early human behavior via stone (lithic) artifacts has a long history, traditional analytical methods have focused on the potential functional utility of these artifacts, often without substantiated or quantified evidence. Other research has classified these lithic implements into cultural groups, thus making an explicit statement regarding how stone tools are behaviorally related.

This project seeks to quantify and statistically identify the behaviors utilized by Oldowan-producing hominins to produce Oldowan lithic artifacts. Identification of specific production behaviors will allow for direct comparisons between Oldowan assemblages to determine if early human populations were practicing behaviorally uniform strategies to make stone tools or if there were divergent behaviors, which might be interpreted as early cultural differences. In order to assess what behaviors are necessary to make early stone tools, Oldowan artifacts will be replicated by the researcher and each lithic flake that is removed will have an empirically determined technological behavior associated with it. The author has experimentally identified five prerequisite behaviors associated with Oldowan stone tool production and these behaviors will form the foundation for behavioral comparisons. Replicated assemblages are measured on twelve technological features and statistically analyzed to determine which features reliably separate flakes produced via different behaviors. Archaeological assemblages from Koobi Fora and Olduvai Gorge can then be measured against the known replicated assemblages so as to determine if similar and/or different behaviors were utilized to produce them. Significantly, this research is the first to directly compare the Oldowan assemblages of Koobi Fora and Olduvai Gorge. Comparison will yield important information as to specific cultural differences between early humans and will provide insight as to how these populations differentially addressed adaptive problems concerning technology.

This research will have broader impacts on both archaeological and educational communities. Archaeologically, this project will construct a methodology, termed Behavioral Lithic Analysis, which will provide a foundation for data sharing and site comparison for archaeologists. Educationally, this project will train undergraduate students in lithic analytical techniques and provide a training opportunity for several Kenyan and Tanzanian graduate students. The raw material collection phase of this research will overlap with an archaeological field school in Kenya and will provide specific instruction to students regarding early hominin procurement strategies and production techniques.

The main goals of this paleoanthropology field and lab project, awarded to Brian Richmond and colleagues, are to 1) recover more of a newly-discovered associated fossil human skeleton possibly belonging to the extinct species Paranthropus boisei, and perform detailed analyses of the fossil anatomy to improve our understanding of the evolution of the human upper limb and hand; 2) excavate, document, and analyze multiple layers of fossil human footprints at sites in Kenya; 3) conduct surveys and excavations to find new footprint layers in targeted areas and to document the paleo-environmental and archeological contexts of the sites.

Fossil human skeletons and footprints are among the rarest and most informative discoveries relating to human evolution. Recent research has unearthed both, along with stone tools and fossilized butchered bones, at a site complex (FwJj14) dating to 1.51-1.53 million years ago near Ileret, Kenya. The research team also discovered fossilized footprint layers, ranging in age from 1.4-1.5 million years ago, near site GaJi10 at Koobi Fora, Kenya. This award funds fieldwork to recover more of the fossil human skeleton and footprints, and data on their ancient ecological setting. These discoveries offer a unique opportunity to test long-standing hypotheses, ask novel questions, and dramatically improve our understanding of the evolution of human upper limb and hand anatomy, walking gait, ancient human behavior, and the environmental contexts of several extinct human species living in the Lake Turkana area 1.5 million years ago, a critical time in human evolutionary history.

This project offers a number of measurable broader impacts for the scientific community by fostering interdisciplinary and international collaboration, improving minority representation in paleoanthropology in the US and improving training of African scholars.. The researchers will make data from this project, including 3D maps of footprints available to the National Museum of Kenya (NMK) for curation, and to other scholars directly and via online-accessible databases (e.g., fossil animal data in the Turkana Database, and 3D digital footprint surfaces on the Human Origins Program website at the Smithsonian's NMNH). Many fossil footprint surfaces are fragile and subject to rapid erosion; our project will document and, when appropriate, collect and preserve at the NMK these irreplaceable resources. This project will strengthen international (US-Kenya-South Africa) and, within the US, inter-institutional (GW-JHU-Smithsonian-Rutgers) collaborations. Furthermore, this project takes very seriously its commitment to train US students from groups underrepresented (e.g., African-American, Hispanic) in paleoanthropology, as well as graduate students from Kenya and South Africa.