Data on the effect of NbC inoculants on the elastic and microstructural evolution of LBP-DED IN718.

The use of inoculants added to precursor powder is a method of influencing grain growth during fabrication. Niobium carbide (NbC) particles have been added to IN718 gas atomised powder for additive manufacturing via laser-blown-powder directed-energy-deposition (LBP-DED). The collected data in this study reveals the effects of the NbC particles on the grain structure, texture and elastic properties, and oxidative properties of LBP-DED IN718 in the As-DED and heat-treated conditions. The microstructure was investigated using X-ray diffraction (XRD), scanning electron microscopy (SEM) coupled with electron backscattered diffraction (EBSD), and transmission electron microscopy (TEM) coupled with energy dispersive X-ray spectroscopy (EDS). Resonant ultrasound spectroscopy (RUS) was used to measure the elastic properties and phase transitions during standard heat treatments. Thermogravimetric analysis (TGA) is used to probe the oxidative properties at 650°C.

In situ study of sigma phase formation in Cr-Co-Ni ternary alloys at 800°C using the long duration experiment facility at Diamond Light Source.

The new long duration experiment facility on beamline I11 at Diamond Light Source has been used to study the kinetics of sigma phase formation in three Cr-Co-Ni alloys. Diffraction data acquired during in situ exposure at 800°C for 50 d showed progressive increases in the sigma fraction. This was accompanied by changes in the proportions of the other phases, which differed markedly between the alloys studied. These results demonstrate the capabilities of the long duration facility for the study of metallurgical phenomena over periods of months to years, a capability not previously available at a synchrotron source.

Peripheral CD4 loss of regulatory T cells is associated with persistent viraemia in chronic HIV infection.

Chronic HIV infection is associated with T cell abnormalities and altered effector function. Regulatory T cells (Treg) are CD4+ T cells that play a critical role in regulating the immune system. The impact of regulatory T cells on HIV infection and disease progression may be highly significant. We hypothesize that chronic antigenic stimulation from a persistent, high viraemic state may promote a population of Treg that contributes to HIV-associated immune dysfunction. We evaluated the pattern of Treg in chronically infected, HIV-positive individuals over a course of 6 months. Treg are depleted at a distinct rate from that of absolute CD4 cells and loss of Treg is slower in the presence of viral suppression. In vitro depletion of CD25+ CD4+ cells resulted in increased Gag-specific CD4 and CD8 responses. A significant correlation between ex vivo measurement of Treg and Gag-specific CD4 T cell responses was observed (r=-0 x 41, P=0 x 018) with a trend observed with Gag-specific CD8 T cell responses (P=0 x 07). The impact of HIV infection on the Treg population directly complicates the measured effect of Treg on the immune dysfunction although our data support the important role of Treg on modulating the effector T cell response in chronic infection.

Male strategies and Plio-Pleistocene archaeology.

Archaeological data are frequently cited in support of the idea that big game hunting drove the evolution of early Homo, mainly through its role in offspring provisioning. This argument has been disputed on two grounds: (1) ethnographic observations on modern foragers show that although hunting may contribute a large fraction of the overall diet, it is an unreliable day-to-day food source, pursued more for status than subsistence; (2) archaeological evidence from the Plio-Pleistocene, coincident with the emergence of Homo can be read to reflect low-yield scavenging, not hunting. Our review of the archaeology yields results consistent with these critiques: (1) early humans acquired large-bodied ungulates primarily by aggressive scavenging, not hunting; (2) meat was consumed at or near the point of acquisition, not at home bases, as the hunting hypothesis requires; (3) carcasses were taken at highly variable rates and in varying degrees of completeness, making meat from big game an even less reliable food source than it is among modern foragers. Collectively, Plio-Pleistocene site location and assemblage composition are consistent with the hypothesis that large carcasses were taken not for purposes of provisioning, but in the context of competitive male displays. Even if meat were acquired more reliably than the archaeology indicates, its consumption cannot account for the significant changes in life history now seen to distinguish early humans from ancestral australopiths. The coincidence between the earliest dates for Homo ergaster and an increase in the archaeological visibility of meat eating that many find so provocative instead reflects: (1) changes in the structure of the environment that concentrated scavenging opportunities in space, making evidence of their pursuit more obvious to archaeologists; (2) H. ergaster's larger body size (itself a consequence of other factors), which improved its ability at interference competition.

Photocatalytic oxidation of NOx gases using TiO2: a surface spectroscopic approach.

The bandgap of solid-state TiO2 (3.2 eV) enables it to be a useful photocatalyst in the ultraviolet (lambda < 380 nm) region of the spectrum. A clean TiO2 surface in the presence of sunlight therefore enables the removal of harmful NOx gases from the atmosphere by oxidation to nitrates. These properties, in addition to the whiteness, relative cheapness and non-toxicity, make TiO2 ideal for the many de-NOX catalysts that are currently being commercially exploited both in the UK and Japan for concrete paving materials in inner cities. There is need, however, for further academic understanding of the surface reactions involved. Hence, we have used surface specific techniques, including X-ray photoelectron spectroscopy and Raman spectroscopy, to investigate the NOx adsorbate reaction at the TiO2 substrate surface.

Definition of an optimal cytotoxic T lymphocyte epitope in the latently expressed Kaposi's sarcoma-associated herpesvirus kaposin protein.

Cytotoxic T lymphocytes (CTL) recognize and kill virus-infected cells and contribute to immunologic control of viral replication. For many herpesviruses (e.g., Epstein-Barr and cytomegalovirus), virus-specific CTL responses can be readily detected in infected persons, but CTL responses against Kaposi's sarcoma-associated herpesvirus (KSHV) appear to be weak and remain poorly characterized. Using a human leukocyte antigen (HLA) binding motif-based epitope prediction algorithm, we identified 37 HLA-A*0201 binding peptides from 8 KSHV open-reading frames (ORFs). After in vitro stimulation of peripheral blood mononuclear cells from KSHV-infected persons, CTL responses against 1 peptide in the KSHV kaposin protein (ORF K12) were detected in 2 HLA-A*0201-positive subjects. The optimal CTL epitope was identified by HLA restriction analysis and peptide titration assays. These data describe a latent phase viral gene product targeted by CTL that may be relevant for KSHV immunopathogenesis.

Inhibition of human NK cell-mediated cytotoxicity by exposure to ammonium chloride.

Ammonium-chloride-containing solutions (AC) are routinely used to lyse red blood cells during preparation of PBMC. Although exposure to AC has been described to affect the ultrastructural appearance of large granular lymphocytes and to temporarily inhibit cytolytic activity of PBMC preparations, the cellular basis of this phenomenon has not been studied. Here, the inhibitory effect of AC on human CTL and NK-mediated cytotoxicity has been analyzed in 4-h 51Cr-release assays. The results show that NK killing of K562 leukemia cells and xenogeneic endothelial cells is inhibited by AC exposure. The effect is dose-dependent and reversible, because recovery of cytotoxicity is observed within 15 h of re-culturing. AC does not reduce the viability of NK cells and the inhibitory effect is not mediated by the exhaustive release of granzymes upon AC treatment. In contrast, antigen-specific CTL killing of EBV-transformed B-lymphoblastoid cell lines and xenogeneic PHA lymphoblasts was less sensitive to AC and data are presented suggesting that FasL-induced apoptosis is not inhibited by AC. In conclusion, perforin-mediated NK killing is AC-sensitive whereas CTL killing and FasL-mediated killing appear to be AC-resistant. Therefore, AC represents a powerful tool to study different mechanisms of cell-mediated cytotoxicity and may be helpful in assessing antigen-specific CTL cytotoxicity without the influence of NK cell-mediated background killing.

Hadza meat sharing.

In most human foraging societies, the meat of large animals is widely shared. Many assume that people follow this practice because it helps to reduce the risk inherent in big game hunting. In principle, a hunter can offset the chance of many hungry days by exchanging some of the meat earned from a successful strike for shares in future kills made by other hunters. If hunting and its associated risks of failure have great antiquity, then meat sharing might have been the evolutionary foundation for many other distinctively human patterns of social exchange. Here we use previously unpublished data from the Tanzanian Hadza to test hypotheses drawn from a simple version of this argument. Results indicate that Hadza meat sharing does not fit the expectations of risk-reduction reciprocity. We comment on some variations of the "sharing as exchange" argument; then elaborate an alternative based partly on the observation that a successful hunter does not control the distribution of his kill. Instead of family provisioning, his goal may be to enhance his status as a desirable neighbor. If correct, this alternative argument has implications for the evolution of men's work.

Impaired CTL recognition of cells latently infected with Kaposi's sarcoma-associated herpes virus.

Kaposi's sarcoma-associated herpes virus (KSHV) is a recently identified human gamma2-herpesvirus associated with Kaposi's sarcoma, primary effusion lymphoma, and Castleman's disease. We reasoned that CTL responses may provide host defense against this virus, and consequently, KSHV may have evolved strategies to evade the CTL-mediated immune surveillance. In this study six B cell lines latently infected with KSHV were found to express reduced levels of HLA class I surface molecules compared with B cell lines transformed by the related gamma-herpesvirus EBV. KSHV-infected cells also required higher concentrations of soluble peptides to induce efficient CTL-mediated lysis than control cell lines and were unable to process and/or present intracellularly expressed Ag. Incubation of the KSHV-infected cell lines with high concentrations of soluble HLA class I binding peptides did not restore the deficient HLA class I surface expression. To assess the underlying mechanisms of these phenomena, TAP-1 and TAP-2 gene expression was analyzed. While no attenuation in TAP-2 expression was observed, TAP-1 expression was significantly reduced in all KSHV cell lines compared with that in controls. These results indicate that KSHV can modulate HLA class I-restricted Ag presentation to CTL, which may allow latently infected cells to escape CTL recognition and persist in the infected host.

Effect of ornidazole on fertility of male rats: inhibition of a glycolysis-related motility pattern and zona binding required for fertilization in vitro.

The effects of the male antifertility agent ornidazole on glycolysis as a prerequisite for fertilization were investigated in rats. Antifertility doses of ornidazole inhibited glycolysis within mature spermatozoa as determined from the lack of glucose utilization, reduced acidosis under anaerobic conditions and reduced glycolytic enzyme activity. As a consequence, cauda epididymidal spermatozoa from ornidazole-fed rats were unable to fertilize rat oocytes in vitro, with or without cumulus cells, which was not due to transfer of an inhibitor in epididymal fluid with the spermatozoa. Under IVF conditions, binding to the zona pellucida was reduced in spermatozoa from ornidazole-fed males and the spermatozoa did not undergo a change in swimming pattern, which was observed in controls. The block to fertilization could be explained by the disruption of glycolysis-dependent events, since reduced binding to the zona pellucida and a lack of kinematic changes were demonstrated by control spermatozoa in glucose-free media in the presence of respiratory substrates. The importance of glycolysis for binding to, and penetration of, the zona pellucida, and hyperactivation in rats is discussed in relation to the glycolytic production of ATP in the principal piece in which local deprivation of energy may explain the reduced force of spermatozoa from ornidazole-fed males.

Efficient processing of the immunodominant, HLA-A*0201-restricted human immunodeficiency virus type 1 cytotoxic T-lymphocyte epitope despite multiple variations in the epitope flanking sequences.

Immune escape from cytotoxic T-lymphocyte (CTL) responses has been shown to occur not only by changes within the targeted epitope but also by changes in the flanking sequences which interfere with the processing of the immunogenic peptide. However, the frequency of such an escape mechanism has not been determined. To investigate whether naturally occurring variations in the flanking sequences of an immunodominant human immunodeficiency virus type 1 (HIV-1) Gag CTL epitope prevent antigen processing, cells infected with HIV-1 or vaccinia virus constructs encoding different patient-derived Gag sequences were tested for recognition by HLA-A*0201-restricted, p17-specific CTL. We found that the immunodominant p17 epitope (SL9) and its variants were efficiently processed from minigene expressing vectors and from six HIV-1 Gag variants expressed by recombinant vaccinia virus constructs. Furthermore, SL9-specific CTL clones derived from multiple donors efficiently inhibited virus replication when added to HLA-A*0201-bearing cells infected with primary or laboratory-adapted strains of virus, despite the variability in the SL9 flanking sequences. These data suggest that escape from this immunodominant CTL response is not frequently accomplished by changes in the epitope flanking sequences.

Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection.

Cellular immune responses are thought to be an important antiviral host defense, but the relationship between virus-specific T-helper and cytotoxic-T-lymphocyte (CTL) responses has not been defined. To investigate a potential link between these responses, we examined functional human immunodeficiency virus type 1 (HIV-1)-specific memory CTL precursor frequencies and p24-specific proliferative responses in a cohort of infected untreated persons with a wide range of viral loads and CD4 cell counts. Levels of p24-specific proliferative responses positively correlated with levels of Gag-specific CTL precursors and negatively correlated with levels of plasma HIV-1 RNA. These data linking the levels of HIV-specific CTL with virus-specific helper cell function during chronic viral infection provide cellular immunologic parameters to guide therapeutic and prophylactic vaccine development.

Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy.

Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38(+) activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.

Grandmothering and the evolution of homo erectus.

Despite recent, compelling challenge, the evolution of Homo erectus is still commonly attributed to big game hunting and/or scavenging and family provisioning by men. Here we use a version of the "grandmother" hypothesis to develop an alternative scenario, that climate-driven adjustments in female foraging and food sharing practices, possibly involving tubers, favored significant changes in ancestral life history, morphology, and ecology leading to the appearance, spread and persistence of H. erectus. Available paleoclimatic, environmental, fossil and archaeological data are consistent with this proposition; avenues for further critical research are readily identified. This argument has important implications for widely-held ideas about the recent evolution of long human lifespans, the prevalence of male philopatry among ancestral hominids, and the catalytic role of big game hunting and scavenging in early human evolution.

Persistent HIV-1-specific CTL clonal expansion despite high viral burden post in utero HIV-1 infection.

To address the issue of clonal exhaustion in humans, we monitored HLA class I-restricted, epitope-specific CTL responses in an in utero HIV-1-infected infant from 3 mo through 5 years of age. Serial functional CTL precursor assays demonstrated persistent, vigorous, and broadly directed HIV-1 specific CTL activity with a dominant response against an epitope in HIV-1 Gag-p17 (SLYNTVATL, aa 77-85). A clonal CTL response directed against the immunodominant, HLA-A*0201-restricted epitope was found to persist over the entire observation period, as shown by TCR analysis of cDNA libraries generated from PBMC. The analysis of autologous viral sequences did not reveal any escape mutations within the targeted epitope, and viral load measurement indicated ongoing viral replication. Furthermore, inhibition of viral replication assays indicated that the epitope was properly processed from autologous viral protein. These data demonstrate that persistent exposure to high levels of viral Ag does not necessarily lead to clonal exhaustion and that epitope-specific clonal CTL responses induced within the first weeks of life can persist for years without inducing detectable viral escape variants.

Lack of strong immune selection pressure by the immunodominant, HLA-A*0201-restricted cytotoxic T lymphocyte response in chronic human immunodeficiency virus-1 infection.

Despite detailed analysis of the HIV-1-specific cytotoxic T lymphocyte response by various groups, its relation to viral load and viral sequence variation remains controversial. We analyzed HLA-A*0201 restricted cytotoxic T lymphocyte responses in 17 HIV-1-infected individuals with viral loads ranging from < 400 to 221,000 HIV RNA molecules per milliliter of plasma. In 13 out of 17 infected subjects, CTL responses against the SLYNTVATL epitope (p17 Gag; aa 77-85) were detectable, whereas two other HLA-A*0201 restricted epitopes (ILKEPVHGV, IV9; and VIYQYMDDL, VL9) were only recognized by six and five individuals out of 17 individuals tested, respectively. Naturally occurring variants of the SL9 epitope were tested for binding to HLA-A*0201 and for recognition by specific T cell clones generated from five individuals. Although these variants were widely recognized, they differed by up to 10,000-fold in terms of variant peptide concentrations required for lysis of target cells. A comparison of viral sequences derived from 10 HLA-A*0201-positive individuals to sequences obtained from 11 HLA-A*0201-negative individuals demonstrated only weak evidence for immune selective pressure and thus question the in vivo efficacy of immunodominant CTL responses present during chronic HIV-1 infection.

Grandmothering, menopause, and the evolution of human life histories.

Long postmenopausal lifespans distinguish humans from all other primates. This pattern may have evolved with mother-child food sharing, a practice that allowed aging females to enhance their daughters' fertility, thereby increasing selection against senescence. Combined with Charnov's dimensionless assembly rules for mammalian life histories, this hypothesis also accounts for our late maturity, small size at weaning, and high fertility. It has implications for past human habitat choice and social organization and for ideas about the importance of extended learning and paternal provisioning in human evolution.

Women's reproductive cancers in evolutionary context.

Reproductive experiences for women in today's affluent Western nations differ from those of women in hunting and gathering societies, who continue the ancestral human pattern. These differences parallel commonly accepted reproductive risk factors for cancers of the breast, endometrium and ovary. Nutritional practices, exercise requirements, and body composition are nonreproductive influences that have been proposed as additional factors affecting the incidence of women's cancers. In each case, these would further increase risk for women in industrialized countries relative to forager women. Lifestyles and reproductive patterns new from an evolutionary perspective may promote women's cancers. Calculations based on a theoretical model suggest that, to age 60, modern Western women have a breast cancer risk as much as 100 times that of preagricultural women.

Demography of the Hadza, an increasing and high density population of Savanna foragers.

This is a report on the demography of the Hadza, a population of East African hunter-gatherers. In it, we describe the results of a census, and our estimation of age structure, survivorship, mean age of women at childbearing, number of live children, total population size and density, and rate of change since 1967. We show that relevant measures fit closely the stable population model North 6 chosen by Dyson to represent Hadza demography in the 1960s. We compare aspects of Hadza demography with surrounding non-Hadza and with the !Kung. Among other things, we find that the Hadza have a higher population density, higher fertility, and a faster population growth rate than do the !Kung. These demographic differences are consistent with our expectations, which were based on differences in the costs and benefits of foraging in the two regions. We also show that Hadza demographic parameters display remarkable consistency over the past 20 years. Since neighboring populations have been encroaching on the area used by the Hadza, and Hadza foragers have been subject to interludes of externally imposed settlement, this consistency is surprising. We discuss some of the implications.

PIP: The research objective was to obtain demographic information of the Hadza, hunter-gatherers from the Eastern Rift Valley, southeast of Lake Eyasi in eastern Africa, in 1985. The aim was to gain insight into their reproductive strategies and how local ecology affects the population. Fertility is assumed to increase where it is more difficult to feed offspring. Comparisons are made to the ]Kung reproductive model. Demographic data were obtained in a 1985 census among 36 camps plus 2 villages in eastern-Hadza-occupied territory in the Eastern Rift Valley. Previous demographic surveys in 1966-67 and 1977 and the Tanzanian Census of 1978 for neighboring populations were important as independent checks on the accuracy of family compositions and age structure. Null hypotheses were tested: that the 1985 data fit the model chosen by Dyson in 1967, or that the data fit the model chosen by Howell for the ]Kung. Data were collected on 1) the age structure of the population, 2) survivorship of people counted in the 1967 census, 3) the mean age of childbearing for mothers of small babies in 1985 and previous censuses, 4) the number of live children/women by age, and 5) calculation of the total population in 1967. 719 eastern Hadza were recorded for 1985 and density was calculated as .30/km squared of .74/sq mile. Density varies locally and with the seasons. With villagers excluded, the density is .24/km squared or .61/sq mile. The methods for constructing the age structure involved fitting a 3-term polynomial regression of individuals of known age against the distribution of all individuals by age rank, and estimating ages of reach rank with a regression equation. The results were not different from the 1967 data; age structure does vary with location. Mortality was closer to Dyson's North 6 stable population model, but very close to Howell's estimates for the ]Kung. The mean age of childbearing was 30.9 years which is later than the ]Kung. The findings support Dyson's conclusions, and reflect higher density, higher fertility (6.15 vs. 4.7), and higher rates of growth than the ]Kung. Bush-living Hadza were even more different from the bush-living ]Kung. A number of explanations for the differences are explored.

Hunting income patterns among the Hadza: big game, common goods, foraging goals and the evolution of the human diet.

The assumption that large mammal hunting and scavenging are economically advantageous to hominid foragers is examined in the light of data collected among the Hadza of northern Tanzania. Hadza hunters disregard small prey in favour of larger forms (mean adult mass greater than or equal to 40 kg). Here we report experimental data showing that hunters would reduce their mean rates if they included small animals in the array they target. Still, daily variance in large animal hunting returns is high, and the risk of failure correspondingly great, significantly greater than that associated with small game hunting and trapping. Sharing large kills reduces the risk of meatless days for big game hunters, and obviates the problem of storing large amounts of meat. It may be unavoidable if large carcasses cannot be defended economically against the demands of other consumers. If so, then large prey are common goods. A hunter may gain no consumption advantage from his own big game acquisition efforts. We use Hadza data to model this 'collective action' problem, and find that an exclusive focus on large game with extensive sharing is not the optimal strategy for hunters concerned with maximizing their own chances of eating meat. Other explanations for the emergence and persistence of this practice must be considered.