Bovid mortality patterns from Kanjera South, Homa Peninsula, Kenya and FLK-Zinj, Olduvai Gorge, Tanzania: Evidence for habitat mediated variability in Oldowan hominin hunting and scavenging behavior

The archaeological record has documented Oldowan hominin occupation of habitats ranging from open grasslands to riparian forest by 2.0 Ma. Despite this we have a poor understanding of whether hominin foraging behavior varied in different environmental settings. We compared bovid mortality profiles from the two largest Oldowan zooarchaeological samples, one from a grassland (Excavation 1, Kanjera South, Kenya) and another from a woodland (FLK Zinj, Olduvai Gorge, Tanzania) with bovid mortality samples created by African carnivores in different habitats. Kanjera hominins frequently had early access, likely through hunting, to small (size 1 ≤ 23 kg and size 2 = 24–112 kg) juvenile bovids, creating a mortality pattern similar to that created by grassland dwelling carnivores. Kanjera hominins had more mixed access to large (size 3 = 113–340 kg), often juvenile, bovids and frequently scavenged heads. In contrast, previous work has shown that the few small bovids at FLK-Zinj were predominantly older individuals. Prime adults dominated the FLK-Zinj large bovid sample, leading to a mortality pattern similar to that created by carnivores occupying more closed habitats. Variation in bovid body size and mortality profiles between these archaeological assemblages may reflect the challenges of acquiring fauna in open versus closed habitats with a simple hunting toolkit. The heterogeneous woodland habitat of FLK-Zinj would have provided more opportunities to ambush prey, whereas on grasslands with more limited concealment opportunities Kanjera hominins focused their efforts on vulnerable juvenile prey, some likely acquired after short chases

Old stones’ song—second verse: use-wear analysis of rhyolite and fenetized andesite artifacts from the Oldowan lithic industry of Kanjera South, Kenya

This paper investigates Oldowan hominin behavioral ecology through use-wear analysis of artifacts from Kanjera South, Western Kenya. It extends development of our experimental use-wear reference collection and analysis of use-wear on the well preserved and unweathered Oldowan tools from this site to include rhyolite, a non-local material of similar durability to previously studied quartz and quartzite tools, and fenetized andesite, a local material with considerably less durability. Variability in rhyolite and fenetized andesite texture, inclusions, and matrix required enhancement of previous methods so we combine the use of stereoscopic, metallographic, and scanning electron microscopy in this study. This study allows us to begin exploration of the links between specific artifactual raw materials and the materials they were used to process. Data assembled so far suggest that tools fashioned from non-local and local stone were, with one possible exception, used to process similar materials. Additionally, experiments carried out with replicas of tools made of rhyolite and fenetized andesite confirm interpretation of reduction sequences that tools made of less durable local material had a shorter use-life and were used expediently compared to the more durable non-local quartz, quartzite, and rhyolite. These new data improve our understanding, of the functional needs, behavioral solutions, and cognitive capacities of Oldowan hominins. Finally, these data show how use-wear analysis, combined with lithic raw material and lithic technology, can be a powerful means for evaluating two key points for human evolution: long-term memory, and planning

Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3

The mechanisms by which stressful life events increase the risk of relapse in recovering cocaine addicts are not well understood. We previously reported that stress, via elevated corticosterone, potentiates cocaine-primed reinstatement of cocaine seeking following self-administration in rats and that this potentiation appears to involve corticosterone-induced blockade of dopamine clearance via the organic cation transporter 3 (OCT3). In the present study, we use a conditioned place preference/reinstatement paradigm in mice to directly test the hypothesis that corticosterone potentiates cocaine-primed reinstatement by blockade of OCT3. Consistent with our findings following self-administration in rats, pretreatment of male C57/BL6 mice with corticosterone (using a dose that reproduced stress-level plasma concentrations) potentiated cocaine-primed reinstatement of extinguished cocaine-induced conditioned place preference. Corticosterone failed to re-establish extinguished preference alone but produced a leftward shift in the dose–response curve for cocaine-primed reinstatement. A similar potentiating effect was observed upon pretreatment of mice with the non-glucocorticoid OCT3 blocker, normetanephrine. To determine the role of OCT3 blockade in these effects, we examined the abilities of corticosterone and normetanephrine to potentiate cocaine-primed reinstatement in OCT3-deficient and wild-type mice. Conditioned place preference, extinction and reinstatement of extinguished preference in response to low-dose cocaine administration did not differ between genotypes. However, corticosterone and normetanephrine failed to potentiate cocaine-primed reinstatement in OCT3-deficient mice. Together, these data provide the first direct evidence that the interaction of corticosterone with OCT3 mediates corticosterone effects on drug-seeking behavior and establish OCT3 function as an important determinant of susceptibility to cocaine use

Bacterial porin disrupts mitochondrial membrane potential and sensitizes host cells to apoptosis

The bacterial PorB porin, an ATP-binding beta-barrel protein of pathogenic Neisseria gonorrhoeae, triggers host cell apoptosis by an unknown mechanism. PorB is targeted to and imported by host cell mitochondria, causing the breakdown of the mitochondrial membrane potential (delta psi m). Here, we show that PorB induces the condensation of the mitochondrial matrix and the loss of cristae structures, sensitizing cells to the induction of apoptosis via signaling pathways activated by BH3-only proteins. PorB is imported into mitochondria through the general translocase TOM but, unexpectedly, is not recognized by the SAM sorting machinery, usually required for the assembly of beta-barrel proteins in the mitochondrial outer membrane. PorB integrates into the mitochondrial inner membrane, leading to the breakdown of delta psi m. The PorB channel is regulated by nucleotides and an isogenic PorB mutant defective in ATP-binding failed to induce delta psi m loss and apoptosis, demonstrating that dissipation of delta psi m is a requirement for cell death caused by neisserial infection

Risk factors for childhood malnutrition in Roma settlements in Serbia

<p>Abstract</p> <p>Background</p> <p>Children living in Roma settlements in Central and Eastern Europe face extreme levels of social exclusion and poverty, but their health status has not been well studied. The objective of this study was to elucidate risk factors for malnutrition in children in Roma settlements in Serbia.</p> <p>Methods</p> <p>Anthropometric and sociodemographic measures were obtained for 1192 Roma children under five living in Roma settlements from the 2005 Serbia Multiple Indicator Cluster Survey. Multiple logistic regression was used to relate family and child characteristics to the odds of stunting, wasting, and underweight.</p> <p>Results</p> <p>The prevalence of stunting, wasting, and underweight was 20.1%, 4.3%, and 8.0%, respectively. Nearly all of the children studied fell into the lowest quintile of wealth for the overall population of Serbia. Children in the lowest quintile of wealth were four times more likely to be stunted compared to those in the highest quintile, followed by those in the second lowest quintile (AOR = 2.1) and lastly by those in the middle quintile (AOR = 1.6). Children who were ever left in the care of an older child were almost twice as likely to stunted as those were not. Children living in urban settlements showed a clear disadvantage with close to three times the likelihood of being wasted compared to those living in rural areas. There was a suggestion that maternal, but not paternal, education was associated with stunting, and maternal literacy was significantly associated with wasting. Whether children were ever breastfed, immunized or had diarrhoeal episodes in the past two weeks did not show strong correlations to children malnutrition status in this Roma population.</p> <p>Conclusions</p> <p>There exists a gradient relationship between household wealth and stunting even within impoverished settlements, indicating that among poor and marginalized populations socioeconomic inequities in child health should be addressed. Other areas on which to focus future research and public health intervention include maternal literacy, child endangerment practices, and urban settlements.</p

Disease-specific composite measures for psoriatic arthritis are highly responsive to a Janus kinase inhibitor treatment that targets multiple domains of disease

Background: The multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints. Methods: Oral Psoriatic Arthritis triaL (OPAL) Broaden was a 12-month study of tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to at least one conventional synthetic disease-modifying anti-rheumatic drug; OPAL Beyond was a 6-month study of patients with inadequate response to TNFi. Patients with active PsA received tofacitinib 5 or 10 mg doses twice daily (BID), adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only), or placebo advancing at month 3 to tofacitinib 5 or 10 mg BID. The disease-specific composites were Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Change from baseline in composite endpoints was also assessed for minimal disease activity (MDA) responders versus non-responders. Results: Overall, 422 patients from OPAL Broaden and 394 patients from OPAL Beyond were treated. The mean changes from baseline to month 3 for tofacitinib 5 mg BID, tofacitinib 10 mg BID (standard error; effect size) were OPAL Broaden: PASDAS, −2.0 (0.14; 1.73), −2.4 (0.14; 2.4); DAPSA, −20.2 (1.72; 0.9), −24.4 (1.73; 1.23); and CPDAI, −2.9 (0.34; 1.03), −4.2 (0.36; 1.53); OPAL Beyond: PASDAS, −1.9 (0.14; 1.53), −2.1 (0.14; 1.84); DAPSA, −22.5 (1.67; 0.81), −21.0 (1.70; 0.84); and CPDAI, −3.3 (0.31; 1.41), −3.4 (0.31; 1.45). Greater changes from baseline to month 3 (P ≤0.05) were seen with both doses of tofacitinib versus placebo for all endpoints except CPDAI for tofacitinib 5 mg BID in OPAL Broaden. Effect sizes generally increased from 3 to 6 months. Mean changes from baseline were greater in MDA responders than MDA non-responders for all composite endpoints across all time points and treatments. Conclusions: This analysis suggests that disease-specific composite measures are appropriate for evaluating treatment efficacy on multiple disease domains in PsA. Trial registration: OPAL Broaden: ClinicalTrials.gov Identifier: NCT01877668, first posted June 12, 2013; OPAL Beyond: ClinicalTrials.gov Identifier: NCT01882439, first posted June 20, 2013

Geochronology and physical context of Oldowan site formation at Kanjera South, Kenya.

Oldowan sites in primary geologic context are rare in the archaeological record. Here we describe the depositional environment of Oldowan occurrences at Kanjera South, Kenya, based on field descriptions and granulometric analysis. Excavations there have recovered a large Oldowan artefact sample as well as the oldest substantial sample of archaeological fauna. The deposits at Kanjera South consist of 30 m of fluvial, colluvial, and lacustrine sediments. Magneto- and bio-stratigraphy indicate the Kanjera South Member of the Kanjera Formation was deposited between 2.3 and 1.92 million years ago (Ma), with 2.0 Ma being a likely age for the archaeological occurrences. Oldowan artefacts and associated fauna were deposited in the colluvial and alluvial silts and sands of Beds KS-1 to KS-3, in the margins of a lake basin. Field descriptions and granulometric analysis of the sediment fine fraction indicates sediments from within the main archaeological horizon were emplaced as a combination of tractional and hyperconcentrated flows with limited evidence of debris flow deposition. This style of deposition is unlikely to significantly erode or disturb the underlying surface and therefore promotes preservation of surface archaeological accumulations. Hominins were repeatedly attracted to the site locale, and rapid sedimentation, minimal bone weathering, and an absence of bone or artefact rounding further indicate that fossils and artefacts were quickly buried

Mathematical model of a telomerase transcriptional regulatory network developed by cell-based screening: analysis of inhibitor effects and telomerase expression mechanisms

Cancer cells depend on transcription of telomerase reverse transcriptase (TERT). Many transcription factors affect TERT, though regulation occurs in context of a broader network. Network effects on telomerase regulation have not been investigated, though deeper understanding of TERT transcription requires a systems view. However, control over individual interactions in complex networks is not easily achievable. Mathematical modelling provides an attractive approach for analysis of complex systems and some models may prove useful in systems pharmacology approaches to drug discovery. In this report, we used transfection screening to test interactions among 14 TERT regulatory transcription factors and their respective promoters in ovarian cancer cells. The results were used to generate a network model of TERT transcription and to implement a dynamic Boolean model whose steady states were analysed. Modelled effects of signal transduction inhibitors successfully predicted TERT repression by Src-family inhibitor SU6656 and lack of repression by ERK inhibitor FR180204, results confirmed by RT-QPCR analysis of endogenous TERT expression in treated cells. Modelled effects of GSK3 inhibitor 6-bromoindirubin-3′-oxime (BIO) predicted unstable TERT repression dependent on noise and expression of JUN, corresponding with observations from a previous study. MYC expression is critical in TERT activation in the model, consistent with its well known function in endogenous TERT regulation. Loss of MYC caused complete TERT suppression in our model, substantially rescued only by co-suppression of AR. Interestingly expression was easily rescued under modelled Ets-factor gain of function, as occurs in TERT promoter mutation. RNAi targeting AR, JUN, MXD1, SP3, or TP53, showed that AR suppression does rescue endogenous TERT expression following MYC knockdown in these cells and SP3 or TP53 siRNA also cause partial recovery. The model therefore successfully predicted several aspects of TERT regulation including previously unknown mechanisms. An extrapolation suggests that a dominant stimulatory system may programme TERT for transcriptional stability

Combining PPI with qualitative research to engage ‘harder-to-reach’ populations: service user groups as co-applicants on a platform study for a trial

Abstract Background: Patient and public involvement (PPI) in all research studies is recommended from the earliest point and in as many stages as possible. Qualitative research is also recommended in the early stages of designing. complex intervention trials. Combining both together might enable inclusion of ‘harder-to-reach’ perspectives from the target population(s), particularly when the research is intended for their benefit. However, the interface between PPI and qualitative research has received little attention. Methods: In a multi-disciplinary, mixed methods study to inform the design of incentive trials for smoking cessation in pregnancy and breastfeeding, we combined PPI and qualitative research, with some overlap. Mother and baby groups from two geographically separate disadvantaged areas, with diverse experiences of the smoking and breastfeeding, but no training or previous involvement in research, were recruited as PPI research grant co-applicants. An iterative partnership approach facilitated involvement in research conduct and design across all project phases. Group PPI members were also invited to contribute to more formal qualitative data collection, as and when indicated by the research questions, and emerging analysis. Results: We engaged with ‘harder-to-reach’ women in mother and baby group settings, rather than in academic or home environments. These settings were relaxed and informal, which facilitated rapport-building, disclosures of unexpected information and maintained trust. 21 women participated in standard PPI activities: feedback on study protocols and documents; piloting questionnaires and interview schedules. PPI members voiced some different perspectives from those captured within the qualitative dataset. 19 participated in focused qualitative research. Novel aspects were audio recorded PPI discussions, which contributed qualitative data; first, to interpret systematic review findings and construct intervention vignettes for use in the qualitative research; second, to assist with recruitment to improve sample diversity in the formal qualitative dataset; and third, to translate theory and findings presented in a researcher generated logic model into a lay tool. This had face validity for potential trial participants and used the metaphor of a ladder. Conclusions: Combining and overlapping PPI and qualitative research added ‘harder-to-reach’ contributions, sample diversity, trust and engagement in creative approaches beyond what could be achieved through PPI or qualitative research alone. (350/350

Proposal for a method to estimate nutrient shock effects in bacteria

Plating methods are still the golden standard in microbiology; however, some studies have shown that these techniques can underestimate the microbial concentrations and diversity. A nutrient shock is one of the mechanisms proposed to explain this phenomenon. In this study, a tentative method to assess nutrient shock effects was tested. Findings To estimate the extent of nutrient shock effects, two strains isolated from tap water (Sphingomonas capsulata and Methylobacterium sp.) and two culture collection strains (E. coli CECT 434 and Pseudomonas fluorescens ATCC 13525) were exposed both to low and high nutrient conditions for different times and then placed in low nutrient medium (R2A) and rich nutrient medium (TSA). The average improvement (A.I.) of recovery between R2A and TSA for the different times was calculated to more simply assess the difference obtained in culturability between each medium. As expected, A.I. was higher when cells were plated after the exposition to water than when they were recovered from high-nutrient medium showing the existence of a nutrient shock for the diverse bacteria used. S. capsulata was the species most affected by this phenomenon. This work provides a method to consistently determine the extent of nutrient shock effects on different microorganisms and hence quantify the ability of each species to deal with sudden increases in substrate concentration. <br/