Ancient DNA: Methods,progress, and perspectives

The advent of the polymerase chain reaction as a standard molecular genetic technique and the demonstration that nucleic acids are routinely preserved in prehistoric material have led to a dramatic increase in molecular approaches to archaeological problems. These genetic approaches to long-standing problems in prehistory hold considerable promise to clarify issues of population origins, migrations, and settlement patterns, as well as ancestor/descendant relationships. The evolving methods for manipulating and analyzing ancient DNA (aDNA) are reviewed here, as are more recent applications of these methods to anthropologically relevant samples. In addition, new preliminary material is presented on mtDNA variation in Anasazi samples from the U.S. Southwest. The initial samples analyzed indicate similarity to contemporary populations of the Greater Southwest, as evidenced by the modest frequency of a 9bp deletion in Region V of the mtDNA molecule, and the possible absence of haplogroup D. © 1996 Wiley-Liss, Inc.     

A novel fMRI paradigm to dissociate the behavioral and neural components of mixed‐strategy decision making from non‐strategic decisions in humans

During competitive interactions, such as predator–prey or team sports, the outcome of one's actions is dependent on both their own choices and those of their opponents. Success in these rivalries requires that individuals choose dynamically and unpredictably, often adopting a mixed strategy. Understanding the neural basis of strategic decision making is complicated by the fact that it recruits various cognitive processes that are often shared with non‐strategic forms of decision making, such as value estimation, working memory, response inhibition, response selection, and reward processes. Although researchers have explored neural activity within key brain regions during mixed‐strategy games, how brain activity differs in the context of strategic interactions versus non‐strategic choices is not well understood. We developed a novel behavioral paradigm to dissociate choice behavior during mixed‐strategy interactions from non‐strategic choices, and we used task‐based functional magnetic resonance imaging (fMRI) to contrast brain activation. In a block design, participants competed in the classic mixed‐strategy game, “matching pennies,” against a dynamic computer opponent designed to exploit predictability in players’ response patterns. Results were contrasted with a non‐strategic task that had comparable sensory input, motor output, and reward rate; thus, differences in behavior and brain activation reflect strategic processes. The mixed‐strategy game was associated with activation of a distributed cortico‐striatal network compared to the non‐strategic task. We propose that choosing in mixed‐strategy contexts requires additional cognitive demands present to a lesser degree during the control task, illustrating the strength of this design in probing function of cognitive systems beyond core sensory, motor, and reward processes.     

The effect of apical foramen patency on condensation stresses

Abstract Mathematical models and computer-based engineering tools were used to evaluate the effect of a patent or closed apical foramen on stresses that are produced within gutta-percha during condensation. We examined a mathematical model of a tapered canal with a definite constriction and compared the results when the apical foramen was closed or open. When the canal was closed an almost constant stress was seen throughout the gutta-percha. When the foramen was open a sharp increase in lateral stress was observed in the apical portions of the canal. The constriction near the foramen caused the gutta-percha to be squeezed together and the stress was increased. This increases the likelihood that the gutta-percha is well adapted to the apical constriction. However, the stresses are also transferred to the surrounding dentin, resulting in a stress concentration near the apical foramen where the bulk of dentin is minimal.     

Immune responses and protection against vaginal infection after nasal or vaginal immunization with attenuated herpes simplex virus type-2

We compared nasal and vaginal immunizations using attenuated herpes simplex virus type-2 (HSV-2) for protection against vaginal infection with wild-type HSV-2. Mice were immunized once intranasally, intravaginally after progestin (DP) treatment, or intravaginally with scarification after oestradiol treatment. Compared with vaginal immunizations, nasal immunization did not increase immunoglobulin A (IgA) plasma cell numbers in the vagina or elicit a higher antiviral IgA titre in vaginal secretions. Both types of vaginal immunizations increased the number of immunoglobulin G (IgG) plasma cells in the vagina and the secretion/serum titre ratio of IgG antiviral antibody, indicating local production of virus-specific IgG in these groups. Cell-mediated immunity in the vagina, as indicated by memory T-cell secretion of interferon-gamma (IFN-gamma) in situ 20 hr after HSV-2 challenge, was essentially equivalent in the vaginally immunized groups but significantly lower in the nasal group, while lymphocyte recruitment to the vagina was similar in all three groups. All three immunizations protected all mice from neurological disease after challenge, but vaginal DP immunization induced the greatest immunity against reinfection of the vaginal epithelium.     

Systemic hematologic effects of PEG-rHuMGDF-induced megakaryocyte hyperplasia in mice

PEG-rHuMGDF injected daily in normal mice causes a rapid dose-dependent increase in megakaryocytes and platelets. At the same time that platelet numbers are increased, the mean platelet volume (MPV) and platelet distribution width (PDW) can be either decreased, normal, or increased depending on the dose and time after administration. Thus, PEG-rHuMGDF at a low dose causes decreases in MPV and PDW, MGDF at an intermediate dose causes an initial increase followed by a decrease in MPV and PDW, and PEG-rHuMGDF at higher doses causes an increase in MPV and PDW followed by a gradual normalization of these platelet indices. In addition to the expected thrombocytosis after 7 to 10 days of daily injection of high doses of PEG-rHuMGDF, a transient decrease in peripheral red blood cell numbers and hemoglobin is noted accompanied in the bone marrow by megakaryocytic hyperplasia, myeloid hyperplasia, erythroid and lymphoid hypoplasia, and deposition of a fine network of reticulin fibers. Splenomegaly, an increase in splenic megakaryocytes, and extramedullary hematopoiesis accompany the hematologic changes in the peripheral blood and marrow to complete a spectrum of pathologic features similar to those reported in patients with myelofibrosis and megakaryocyte hyperplasia. However, all the PEG-rHuMGDF-initiated hematopathology including the increase in marrow reticulin is completely and rapidly reversible upon the cessation of administration of PEG-rHuMGDF. Thus, transient hyperplastic proliferation of megakaryocytes does not cause irreversible tissue injury. Furthermore, PEG-rHuMGDF completely ameliorates carboplatin-induced thrombocytopenia at a low-dose that does not cause the hematopathology associated with myelofibrosis.     

Systemic antibacterial activity of novel synthetic cyclic peptides

Cyclic peptides with an even number of alternating d,l-alpha-amino acid residues are known to self-assemble into organic nanotubes. Such peptides previously have been shown to be stable upon protease treatment, membrane active, and bactericidal and to exert antimicrobial activity against Staphylococcus aureus and other gram-positive bacteria. The present report describes the in vitro and in vivo pharmacology of selected members of this cyclic peptide family. The intravenous (i.v.) efficacy of six compounds with MICs of less than 12 microg/ml was tested in peritonitis and neutropenic-mouse thigh infection models. Four of the six peptides were efficacious in vivo, with 50% effective doses in the peritonitis model ranging between 4.0 and 6.7 mg/kg against methicillin-sensitive S. aureus (MSSA). In the thigh infection model, the four peptides reduced the bacterial load 2.1 to 3.0 log units following administration of an 8-mg/kg i.v. dose. Activity against methicillin-resistant S. aureus was similar to MSSA. The murine pharmacokinetic profile of each compound was determined following i.v. bolus injection. Interestingly, those compounds with poor efficacy in vivo displayed a significantly lower maximum concentration of the drug in serum and a higher volume of distribution at steady state than compounds with good therapeutic properties. S. aureus was unable to easily develop spontaneous resistance upon prolonged exposure to the peptides at sublethal concentrations, in agreement with the proposed interaction with multiple components of the bacterial membrane canopy. Although additional structure-activity relationship studies are required to improve the therapeutic window of this class of antimicrobial peptides, our results suggest that these amphipathic cyclic d,l-alpha-peptides have potential for systemic administration and treatment of otherwise antibiotic-resistant infections.