Preserving the impossible: conservation of soft-sediment hominin footprint sites and strategies for three-dimensional digital data capture.

Human footprints provide some of the most publically emotive and tangible evidence of our ancestors. To the scientific community they provide evidence of stature, presence, behaviour and in the case of early hominins potential evidence with respect to the evolution of gait. While rare in the geological record the number of footprint sites has increased in recent years along with the analytical tools available for their study. Many of these sites are at risk from rapid erosion, including the Ileret footprints in northern Kenya which are second only in age to those at Laetoli (Tanzania). Unlithified, soft-sediment footprint sites such these pose a significant geoconservation challenge. In the first part of this paper conservation and preservation options are explored leading to the conclusion that to 'record and digitally rescue' provides the only viable approach. Key to such strategies is the increasing availability of three-dimensional data capture either via optical laser scanning and/or digital photogrammetry. Within the discipline there is a developing schism between those that favour one approach over the other and a requirement from geoconservationists and the scientific community for some form of objective appraisal of these alternatives is necessary. Consequently in the second part of this paper we evaluate these alternative approaches and the role they can play in a 'record and digitally rescue' conservation strategy. Using modern footprint data, digital models created via optical laser scanning are compared to those generated by state-of-the-art photogrammetry. Both methods give comparable although subtly different results. This data is evaluated alongside a review of field deployment issues to provide guidance to the community with respect to the factors which need to be considered in digital conservation of human/hominin footprints

Normalizing Community Mask-Wearing: A Cluster Randomized Trial in Bangladesh

Background: A growing body of scientific evidence suggests that face masks can slow the spread of COVID-19 and save lives, but mask usage remains low across many parts of the world, and strategies to increase mask usage remain untested and unclear. Methods: We conducted a cluster-randomized trial of community-level mask promotion in rural Bangladesh involving 341,830 adults in 600 villages. We employed a series of strategies to promote mask usage, including free household distribution of surgical or cloth masks, distribution and promotion at markets and mosques, mask advocacy by Imams during Friday prayers, role modeling by local leaders, promoters periodically monitoring passers-by and reminding people to put on masks, village police accompanying those mask promoters, providing monetary rewards or certificates to villages if mask-wearing rate improves, public signaling of mask-wearing via signage, text message reminders, messaging emphasizing either altruistic or self-protection motives for mask-wearing, and extracting verbal commitments from households. The primary objective was to assess which of these interventions would increase proper (covering nose and mouth) wearing of face masks, and secondarily, whether mask promotion unintentionally creates moral hazard and decreases social distancing. This analysis is part of larger study evaluating the effect of mask-wearing on transmission of SARS-CoV-2. Results: There were 64,937 households in the intervention group and 64,183 households in the control group; study recruitment has ended. In the control group, proper mask-wearing was practiced by 13% of those observed across the study period. Free distribution of masks along with role modeling by community leaders produced only small increases in mask usage during pilot interventions. Adding periodic monitoring by mask promoters to remind people in streets and public places to put on the masks we provided increased proper mask-wearing by 29.0 percentage points (95% CI: 26.7% - 31.3%). This tripling of mask usage was sustained over all 10 weeks of surveillance, which includes a period after intervention activities ended. Physical distancing, measured as the fraction of individuals at least one arm’s length apart, also increased by 5.2 percentage points (95% CI: 4.2%-6.3%). Beyond the core intervention package comprised of free distribution and promotion at households/mosques/markets, leader endorsements plus periodic monitoring and reminders, several elements had no additional effect on mask wearing, including: text reminders, public signage commitments, monetary or non-monetary incentives, altruistic messaging or verbal commitments, or village police accompanying the mask promoters (the last not cross-randomized, but assessed in panel data). No adverse events were reported during the study period. Conclusions: Our intervention demonstrates a scalable and cost-effective method to promote mask adoption and save lives, and identifies a precise combination of intervention activities that were necessary. Comparisons between pilots shows that free mask distribution alone is not sufficient to increase mask-wearing, but adding periodic monitoring in public places to remind people to wear the distributed masks had large effects on behavior. The absence of any further effect of the village police suggests that the operative mechanism is not any threat of formal legal sanctions, but shame and people’s aversion to a light informal social sanction. The persistence of effects for 10 weeks and after the end of the active intervention period, as well as increases in physical distancing, all point to changes in social norms as a key driver of behavior change. Our cross-randomizations suggest that improved mask-wearing norms can be achieved without incentives that require costly monitoring, that aesthetic design choices and colors can influence mask-wearing, and that surgical masks with a substantially higher filtration efficiency can be a cost-effective alternative to cloth masks (1/3 the cost) and are equally or more likely to be worn. Implementing these interventions – including distribution of free masks, and the information campaign, reminders, encouragement – cost $2.30-$3.75 per villager, or between $8 and$13 per person adopting a mask. Combined with existing estimates of the efficacy of masks in preventing COVID-19 deaths, this implies that the intervention cost $28,000-$66,000 per life saved. Beyond reducing the transmission of COVID-19, mask distribution is likely to be a cost-effective strategy to prevent future respiratory disease outbreaks

The Impact of Community Masking on COVID-19: A Cluster Randomized Trial in Bangladesh

Background: Mask usage remains low across many parts of the world during the COVID- 19 pandemic, and strategies to increase mask-wearing remain untested. Our objectives were to identify strategies that can persistently increase mask-wearing and assess the impact of increasing mask-wearing on symptomatic SARS-CoV-2 infections. Methods: We conducted a cluster-randomized trial of community-level mask promotion in rural Bangladesh from November 2020 to April 2021 (N=600 villages, N=342,126 adults). We cross-randomized mask promotion strategies at the village and household level, including cloth vs. surgical masks. All intervention arms received free masks, information on the importance of masking, role modeling by community leaders, and in-person reminders for 8 weeks. The control group did not receive any interventions. Neither participants nor field staff were blinded to intervention assignment. Outcomes included symptomatic SARS-CoV-2 seroprevalence (primary) and prevalence of proper mask-wearing, physical distancing, and symptoms consistent with COVID-19 (secondary). Mask-wearing and physical distancing were assessed through direct observation at least weekly at mosques, markets, the main entrance roads to villages, and tea stalls. At 5 and 9 weeks follow-up, we surveyed all reachable participants about COVID-related symptoms. Blood samples collected at 10-12 weeks of follow-up for symptomatic individuals were analyzed for SARS-CoV-2 IgG antibodies. Results: There were 178,288 individuals in the intervention group and 163,838 individuals in the control group. The intervention increased proper mask-wearing from 13.3% in control villages (N=806,547 observations) to 42.3% in treatment villages (N=797,715 observations) (adjusted percentage point difference = 0.29 [0.27, 0.31]). This tripling of mask usage was sustained during the intervention period and two weeks after. Physical distancing increased from 24.1% in control villages to 29.2% in treatment villages (adjusted percentage point difference = 0.05 [0.04, 0.06]). After 5 months, the impact of the intervention faded, but mask-wearing remained 10 percentage points higher in the intervention group. The proportion of individuals with COVID-like symptoms was 7.62% (N=13,273) in the intervention arm and 8.62% (N=13,893) in the control arm. Blood samples were collected from N=10,952 consenting, symptomatic individuals. Adjusting for baseline covariates, the intervention reduced symptomatic seroprevalence by 9.3% (adjusted prevalence ratio (aPR) = 0.91 [0.82, 1.00]; control prevalence 0.76%; treatment prevalence 0.68%). In villages randomized to surgical masks (n = 200), the relative reduction was 11.2% overall (aPR = 0.89 [0.78, 1.00]) and 34.7% among individuals 60+ (aPR = 0.65 [0.46, 0.85]). No adverse events were reported. Conclusions: Our intervention demonstrates a scalable and effective method to promote mask adoption and reduce symptomatic SARS-CoV-2 infections. Trial registration: ClinicalTrials.gov Identifier: NCT04630054 Funding: GiveWell.or

Effect of Chemical Mutagens and Carcinogens on Gene Expression Profiles in Human TK6 Cells

Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes), we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose–response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti-) apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control

Bone regeneration: current concepts and future directions

Bone regeneration is a complex, well-orchestrated physiological process of bone formation, which can be seen during normal fracture healing, and is involved in continuous remodelling throughout adult life. However, there are complex clinical conditions in which bone regeneration is required in large quantity, such as for skeletal reconstruction of large bone defects created by trauma, infection, tumour resection and skeletal abnormalities, or cases in which the regenerative process is compromised, including avascular necrosis, atrophic non-unions and osteoporosis. Currently, there is a plethora of different strategies to augment the impaired or 'insufficient' bone-regeneration process, including the 'gold standard' autologous bone graft, free fibula vascularised graft, allograft implantation, and use of growth factors, osteoconductive scaffolds, osteoprogenitor cells and distraction osteogenesis. Improved 'local' strategies in terms of tissue engineering and gene therapy, or even 'systemic' enhancement of bone repair, are under intense investigation, in an effort to overcome the limitations of the current methods, to produce bone-graft substitutes with biomechanical properties that are as identical to normal bone as possible, to accelerate the overall regeneration process, or even to address systemic conditions, such as skeletal disorders and osteoporosis

Genetic Evidence Implicates the Immune System and Cholesterol Metabolism in the Aetiology of Alzheimer's Disease

Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches

Mycobacterium tuberculosis lineage 4 comprises globally distributed and geographically restricted sublineages

Generalist and specialist species differ in the breadth of their ecological niches. Little is known about the niche width of obligate human pathogens. Here we analyzed a global collection of Mycobacterium tuberculosis lineage 4 clinical isolates, the most geographically widespread cause of human tuberculosis. We show that lineage 4 comprises globally distributed and geographically restricted sublineages, suggesting a distinction between generalists and specialists. Population genomic analyses showed that, whereas the majority of human T cell epitopes were conserved in all sublineages, the proportion of variable epitopes was higher in generalists. Our data further support a European origin for the most common generalist sublineage. Hence, the global success of lineage 4 reflects distinct strategies adopted by different sublineages and the influence of human migration.We thank S. Lecher, S. Li and J. Zallet for technical support. Calculations were performed at the sciCORE scientific computing core facility at the University of Basel. This work was supported by the Swiss National Science Foundation (grants 310030_166687 (S.G.) and 320030_153442 (M.E.) and Swiss HIV Cohort Study grant 740 to L.F.), the European Research Council (309540-EVODRTB to S.G.), TB-PAN-NET (FP7-223681 to S.N.), PathoNgenTrace projects (FP7-278864-2 to S.N.), SystemsX.ch (S.G.), the German Center for Infection Research (DZIF; S.N.), the Novartis Foundation (S.G.), the Natural Science Foundation of China (91631301 to Q.G.), and the National Institute of Allergy and Infectious Diseases (5U01-AI069924-05) of the US National Institutes of Health (M.E.)

Correction: genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

[This corrects the article on p. e13950 in vol. 5.]. Background: Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology: We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings: We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance: Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches