From Utopia to Science: Challenges of Personalised Genomics Information for Health Management and Health Enhancement

From 1900 onwards, scientists and novelists have explored the contours of a future society based on the use of “anthropotechnologies” (techniques applicable to human beings for the purpose of performance enhancement ranging from training and education to genome-based biotechnologies). Gradually but steadily, the technologies involved migrated from (science) fiction into scholarly publications, and from “utopia” (or “dystopia”) into science. Building on seminal ideas borrowed from Nietzsche, Peter Sloterdijk has outlined the challenges inherent in this development. Since time immemorial, and at least since the days of Plato’s Academy, human beings have been interested in possibilities for (physical or mental) performance enhancement. We are constantly trying to improve ourselves, both collectively and individually, for better or for worse. At present, however, new genomics-based technologies are opening up new avenues for self-amelioration. Developments in research facilities using animal models may to a certain extent be seen as expeditions into our own future. Are we able to address the bioethical and biopolitical issues awaiting us? After analyzing and assessing Sloterdijk’s views, attention will shift to a concrete domain of application, namely sport genomics. For various reasons, top athletes are likely to play the role of genomics pioneers by using personalized genomics information to adjust diet, life-style, training schedules and doping intake to the strengths and weaknesses of their personalized genome information. Thus, sport genomics may be regarded as a test bed where the contours of genomics-based self-management are tried out

Improving physics‐based aftershock forecasts during the 2016–2017 Central Italy earthquake cascade

The 2016–2017 Central Apennines earthquake sequence is a recent example of how damages from subsequent aftershocks can exceed those caused by the initial mainshock. Recent studies reveal that physics‐based aftershock forecasts present comparable skills to their statistical counterparts, but their performance remains a controversial subject. Here we employ physics‐based models that combine the elasto‐static stress transfer with rate‐and‐state friction laws, and short‐term statistical Epidemic Type Aftershock Sequence (ETAS) models to describe the spatiotemporal evolution of the earthquake cascade. We then track the absolute and relative model performance using log‐likelihood statistics for a 1‐year horizon after the 24 August 2016 Mw = 6.0 Amatrice earthquake. We perform a series of pseudoprospective experiments by producing seven classes of Coulomb rate‐state (CRS) forecasts with gradual increase in data input quality and model complexity. Our goal is to investigate the influence of data quality on the predictive power of physics‐based models and to assess the comparative performance of the forecasts in critical time windows, such as the period following the 26 October Visso earthquakes leading to the 30 October Mw = 6.5 Norcia mainshock. We find that (1) the spatiotemporal performance of the basic CRS models is poor and progressively improves as more refined data are used, (2) CRS forecasts are about as informative as ETAS when secondary triggering effects from M3+ earthquakes are included together with spatially variable slip models, spatially heterogeneous receiver faults, and optimized rate‐and‐state parameters. After the Visso earthquakes, the more elaborate CRS model outperforms ETAS highlighting the importance of the static stress transfer for operational earthquake forecasting

The role of metacognition in self-critical rumination: an investigation in individuals presenting with low self-esteem

Background: No research, to date, has directly investigated the role of metacognition in self-critical rumination and low self-esteem. Aim: To investigate the presence of metacognitive beliefs about self-critical rumination; the goal of self-critical rumination and its stop signal; and the degree of detachment from intrusive self-critical thoughts. Method: Ten individuals reporting both a self-acknowledged tendency to judge themselves critically and having low self-esteem were assessed using metacognitive profiling, a semi-structured interview. Results: All participants endorsed both positive and negative metacognitive beliefs about self-critical rumination. Positive metacognitive beliefs concerned the usefulness of self-critical rumination as a means of improving cognitive performance and enhancing motivation. Negative metacognitive beliefs concerned the uncontrollability of self-critical rumination and its negative impact on mood, motivation and perception of self-worth. The primary goal of engaging in self-critical rumination was to achieve a better or clearer understanding of a given trigger situation or to feel more motivated to resolve it. However, only four participants were able to identify when this goal had been achieved, which was if the trigger situation were not to occur again. Participants unanimously stated that they were either unable to detach from their self-critical thoughts or could do so some of the time with varying degrees of success. More often than not, though, self-critical thoughts were viewed as facts, would rarely be seen as distorted or biased, and could take hours or days to dissipate. Conclusions: These findings provide preliminary evidence that specific facets of metacognition play a role in the escalation and perseveration of self-critical rumination

Regulation of pH by Carbonic Anhydrase 9 Mediates Survival of Pancreatic Cancer Cells With Activated KRAS in Response to Hypoxia.

Background & Aims Most pancreatic ductal adenocarcinomas (PDACs) express an activated form of KRAS, become hypoxic and dysplastic, and are refractory to chemo and radiation therapies. To survive in the hypoxic environment, PDAC cells upregulate enzymes and transporters involved in pH regulation, including the extracellular facing carbonic anhydrase 9 (CA9). We evaluated the effect of blocking CA9, in combination with administration of gemcitabine, in mouse models of pancreatic cancer. Methods We knocked down expression of KRAS in human (PK-8 and PK-1) PDAC cells with small hairpin RNAs. Human and mouse (KrasG12D/Pdx1-Cre/Tp53/RosaYFP) PDAC cells were incubated with inhibitors of MEK (trametinib) or extracellular signal-regulated kinase (ERK), and some cells were cultured under hypoxic conditions. We measured levels and stability of the hypoxia-inducible factor 1 subunit alpha (HIF1A), endothelial PAS domain 1 protein (EPAS1, also called HIF2A), CA9, solute carrier family 16 member 4 (SLC16A4, also called MCT4), and SLC2A1 (also called GLUT1) by immunoblot analyses. We analyzed intracellular pH (pHi) and extracellular metabolic flux. We knocked down expression of CA9 in PDAC cells, or inhibited CA9 with SLC-0111, incubated them with gemcitabine, and assessed pHi, metabolic flux, and cytotoxicity under normoxic and hypoxic conditions. Cells were also injected into either immune-compromised or immune-competent mice and growth of xenograft tumors was assessed. Tumor fragments derived from patients with PDAC were surgically ligated to the pancreas of mice and the growth of tumors was assessed. We performed tissue microarray analyses of 205 human PDAC samples to measure levels of CA9 and associated expression of genes that regulate hypoxia with outcomes of patients using the Cancer Genome Atlas database. Results Under hypoxic conditions, PDAC cells had increased levels of HIF1A and HIF2A, upregulated expression of CA9, and activated glycolysis. Knockdown of KRAS in PDAC cells, or incubation with trametinib, reduced the posttranscriptional stabilization of HIF1A and HIF2A, upregulation of CA9, pHi, and glycolysis in response to hypoxia. CA9 was expressed by 66% of PDAC samples analyzed; high expression of genes associated with metabolic adaptation to hypoxia, including CA9, correlated with significantly reduced survival times of patients. Knockdown or pharmacologic inhibition of CA9 in PDAC cells significantly reduced pHi in cells under hypoxic conditions, decreased gemcitabine-induced glycolysis, and increased their sensitivity to gemcitabine. PDAC cells with knockdown of CA9 formed smaller xenograft tumors in mice, and injection of gemcitabine inhibited tumor growth and significantly increased survival times of mice. In mice with xenograft tumors grown from human PDAC cells, oral administration of SLC-0111 and injection of gemcitabine increased intratumor acidosis and increased cell death. These tumors, and tumors grown from PDAC patient-derived tumor fragments, grew more slowly than xenograft tumors in mice given control agents, resulting in longer survival times. In KrasG12D/Pdx1-Cre/Tp53/RosaYFP genetically modified mice, oral administration of SLC-0111 and injection of gemcitabine reduced numbers of B cells in tumors. Conclusions In response to hypoxia, PDAC cells that express activated KRAS increase expression of CA9, via stabilization of HIF1A and HIF2A, to regulate pH and glycolysis. Disruption of this pathway slows growth of PDAC xenograft tumors in mice and might be developed for treatment of pancreatic cancer

Accounting for quality improvement during the conduct of embedded pragmatic clinical trials within healthcare systems: NIH Collaboratory case studies

Embedded pragmatic clinical trials (ePCTs) and quality improvement (QI) activities often occur simultaneously within healthcare systems (HCSs). Embedded PCTs within HCSs are conducted to test interventions and provide evidence that may impact public health, health system operations, and quality of care. They are larger and more broadly generalizable than QI initiatives, and may generate what is considered high-quality evidence for potential use in care and clinical practice guidelines. QI initiatives often co-occur with ePCTs and address the same high-impact health questions, and this co-occurrence may dilute or confound the ability to detect change as a result of the ePCT intervention. During the design, pilot, and conduct phases of the large-scale NIH Collaboratory Demonstration ePCTs, many QI initiatives occurred at the same time within the HCSs. Although the challenges varied across the projects, some common, generalizable strategies and solutions emerged, and we share these as case studies. KEY LESSONS: Study teams often need to monitor, adapt, and respond to QI during design and the course of the trial. Routine collaboration between ePCT researchers and health systems stakeholders throughout the trial can help ensure research and QI are optimally aligned to support high-quality patient-centered care

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease

The structural maintenance of chromosomes (SMC) family of proteins supports mitotic proliferation, meiosis, and DNA repair to control genomic stability. Impairments in chromosome maintenance are linked to rare chromosome breakage disorders. Here, we have identified a chromosome breakage syndrome associated with severe lung disease in early childhood. Four children from two unrelated kindreds died of severe pulmonary disease during infancy following viral pneumonia with evidence of combined T and B cell immunodeficiency. Whole exome sequencing revealed biallelic missense mutations in the NSMCE3 (also known as NDNL2) gene, which encodes a subunit of the SMC5/6 complex that is essential for DNA damage response and chromosome segregation. The NSMCE3 mutations disrupted interactions within the SMC5/6 complex, leading to destabilization of the complex. Patient cells showed chromosome rearrangements, micronuclei, sensitivity to replication stress and DNA damage, and defective homologous recombination. This work associates missense mutations in NSMCE3 with an autosomal recessive chromosome breakage syndrome that leads to defective T and B cell function and acute respiratory distress syndrome in early childhood

ELL’s science meaning making in multimodal inquiry: a case-study in a Hong Kong bilingual school

This paper reports on a multimodal teaching approach delivered to grade 5 elementary students in a bilingual school in Hong Kong, as part of a larger research study aimed at supporting English Language Learners (ELLs) in science class. As language demands of reading, writing and talking science place additional challenges on ELLs, there is much research interest in exploring the use of multiple modes of communication beyond the dominant use of verbal and written language. Research has shown that students develop a better scientific understanding of natural phenomena by using and alternating between a variety of representations. Yet, questions remain as to what meanings ELLs make during a multimodal discourse and, in turn, how such discourse provides support to ELLs in learning science. Drawing on social semiotics, which theorizes language as a meaning making resource comprising a range of modes (e.g. gestures and diagrams), we used a case-study approach to examine how a multimodal instructional approach provided 10 students with multiple avenues to make sense of science learning. Video recordings (capturing gestures, speech and model manipulation) and student works (drawing and writing) were collected during nine inquiry science lessons, which encompassed biology, physics and chemistry science units. Multimodal transcription allowed discourse to be analysed at a fine-grain level which, together with analysis of student works, indicated that the multimodal instructional approach provided the necessary inquiry opportunities and variety of language experiences for ELLs to build science understandings. Analysis also revealed how the affordances of modes attributed to the meaning making potentials for the ELLs and how they provided alternate communication avenues in which new meanings could be made. The findings from this study have implications for ELLs learning science within the growing multilingual Asia-Pacific region

Effects of Feeding Increasing Standardized Ileal Digestible Lysine on Growth Performance of 26- to 300-lb PIC Line 800-Sired Pigs

The objective of this study was to evaluate the growth performance and economic returns of PIC 800 × 1050 pigs fed increasing SID Lys from approximately 26 to 300 lb. Pens of pigs were blocked by BW and randomly assigned to 1 of 5 dietary treatments in a randomized complete block design with 26 pigs per pen and 16 pens per treatment. Pens were provided 1 of 5 dietary treatments with increasing SID Lys at 85, 93, 100, 107, and 115% of current PIC recommendations within 6 different phases. Two base diets containing low Lys and high Lys were blended to meet target SID Lys levels for each treatment diet within phase. For the overall experimental period (d 0 to 143), feeding increasing SID Lys improved (linear, P ≤ 0.007) ADG and F/G, but did not impact ADFI (P \u3e 0.10). For carcass characteristics, a tendency (linear, P = 0.067) for increased HCW of pigs that were provided increasing SID Lys was observed. However, there was no evidence for differences (P \u3e 0.10) across treatments in carcass yield, backfat depth, loin depth, or carcass lean percentage. Increasing SID Lys of the diets increased (linear, P \u3c 0.001) feed cost and feed cost per lb of gain. There was no evidence of difference (P \u3e 0.10) in revenue for either ingredient price scenario, thus, feeding increasing levels of SID Lys reduced (linear, P \u3c 0.001) income over feed cost (IOFC) in both scenarios. The linear model (LM) served as the best fit for both growth and economic parameters. The LM model predicted maximum ADG and minimal F/G at levels greater than 115% of PIC’s current SID Lys recommendations. For IOFC, the LM model predicted maximum profitability at or below 85% of PIC’s current Lys recommendations. In conclusion, the optimal SID Lys level for PIC 800 × 1050 pigs from 26- to 300-lb depends upon the response criteria, with growth performance maximized at levels at or above 115% of PIC’s recommendation for SID Lys; however, economic responses were maximized at or below 85% of PIC’s current SID Lys recommendations

Effects of Standardized Ileal Digestible Threonine to Lysine Ratio on Growth Performance of PIC Line 337 × 1050 Pigs

The objective of this research was to evaluate the impact of varying SID Thr:Lys ratios on growth performance, removals, and mortality rates of late-nursery, grower, and finishing PIC 337 × 1050 pigs. In each experiment, pens of pigs were blocked by BW and randomly assigned to 1 of 5 dietary treatments in a randomized complete block design with 19 to 27 pigs per pen and 8, 7, and 7 replications per treatment in Exp. 1, 2, and 3, respectively. In Exp. 1, 987 pigs (initially 26.0 ± 0.70 lb) were used from 26 to 54 lb. In Exp. 2, 875 pigs (initially 95.5 ± 1.17 lb) were used from 95 to 155 lb. In Exp. 3, 824 pigs (initially 224.4 ± 1.85 lb) were used from 224 to 297 lb. Pens were randomly assigned to 1 of 5 dietary treatments with increasing SID Thr:Lys ratios at 53, 58, 62, 65, and 68% in Exp. 1 and 2, and 56.5, 60, 64, 68, and 72.5% in Exp. 3. Diets were corn-soybean meal-based. Diets with the lowest and highest Thr:Lys ratios were blended to achieve the target SID Thr:Lys treatments in each experiment. Between experiments, all pens of pigs were placed on a common diet for 23 (Exp. 1 and 2) and 32 d (Exp. 2 and 3) to provide opportunity for compensatory growth prior to initiation of the next experiment. In Exp. 1 (26 to 54 lb), ADG and final BW increased linearly (P ≤ 0.006) while ADFI, Thr intake/d, and Thr intake/kg of gain increased quadratically (P ≤ 0.001). Overall, F/G improved (quadratic, P ≤ 0.001) as Thr:Lys ratio increased. Additionally, Lys intake/d increased (quadratic, P \u3c 0.001) while Lys intake/ kg of gain decreased (quadratic, P\u3c 0.001) with increasing Thr:Lys ratio. The quadratic polynomial (QP) model predicted greater than 68% SID Thr:Lys was required for ADG from 26 to 54 lb, while a QP model suggested that minimum F/G was achieved at 62.1% SID Thr:Lys. In Exp. 2 (95 to 155 lb), ADG, final BW, Thr intake/d, and Thr intake/kg of gain increased (linear, P ≤ 0.05) and F/G improved (linear, P = 0.030) as dietary Thr:Lys increased. Moreover, Lys intake/kg of gain decreased (linear, P = 0.023) with increasing Thr:Lys ratio. For model analysis, QP models suggested optimum ADG and F/G were achieved at levels greater than 68% SID Thr:Lys. However, similar fitting broken-line quadratic (BLQ) and broken-line linear (BLL) models predicted no further improvement to F/G and ADG beyond 61 and 67% SID Thr:Lys, respectively. In Exp. 3 (224 to 297 lb), increasing SID Thr:Lys increased (linear, P ≤ 0.001) Thr intake/d and Thr intake/kg of gain. In addition, increasing SID Thr:Lys ratios tended (P ≤ 0.086) to quadratically increase (P≤ 0.086) ADFI and BW of pigs at the second marketing event. However, no other response criteria were impacted (P ≥ 0.10) by dietary Thr:Lys. Due to a lack of ADG and F/G responses, prediction models were not developed. In summary, these results suggest the optimal SID Thr:Lys level for 26- to 54-lb pigs is 62.1% for feed efficiency and greater than 68% for ADG. From 95 to 155 lb, the requirement was predicted at or above 61 and 67% SID Thr:Lys for F/G and ADG, respectively. However, with the variation in response criteria in Exp. 3 (224 to 297 lb), we were unable to statistically define a requirement estimate