Miracle-dz/UniFAR-FTUs huggingface dataset:
The trimmed-haplotype test for linkage disequilibrium.

Single-marker linkage-disequilibrium (LD) methods cannot fully describe disequilibrium in an entire chromosomal region surrounding a disease allele. With the advent of myriad tightly linked microsatellite markers, we have an opportunity to extend LD analysis from single markers to multiple-marker haplotypes. Haplotype analysis has increased statistical power to disclose the presence of a disease locus in situations where it correctly reflects the historical process involved. For maximum efficiency, evidence of LD ought to come not just from a single haplotype, which may well be rare, but in addition from many similar haplotypes that could have descended from the same ancestral founder but have been trimmed in succeeding generations. We present such an analysis, called the "trimmed-haplotype method. " We focus on chromosomal regions that are small enough that disequilibrium in significant portions of them may have been preserved in some pedigrees and yet that contain enough markers to minimize coincidental occurrence of the haplotype in the absence of a disease allele: perhaps regions 1-2 cM in length. In general, we could have no idea what haplotype an ancestral founder carried generations ago, nor do we usually have a precise chromosomal location for the disease-susceptibility locus. Therefore, we must search through all possible haplotypes surrounding multiple locations. Since such repeated testing obliterates the sampling distribution of the test, we employ bootstrap methods to calculate significance levels. Trimmed-haplotype analysis is performed on family data in which genotypes have been assembled into haplotypes. It can be applied either to conventional parent-affected-offspring triads or to multiplex pedigrees. We present a method for summarizing the LD evidence, in any pedigree, that can be employed in trimmed-haplotype analysis as well as in other methods.
Generation of Cashmere Goats Carrying an EDAR Gene Mutant Using CRISPR-Cas9-Mediated Genome Editing

In recent years, while the use of the clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) (CRISPR-Cas9) system for targeted genome editing has become a research hotspot, it has, to date, not proved adequate for genome editing in large mammals, such as goats. In this study, two opposite single-guide RNAs (sgRNAs) were designed for complete EDAR gene targeting in Cashmere goats, and co-transfected with a plasmid encoding Cas9 into goat fibroblasts. Among the 89 cell lines obtained through the cultivation of clonal cell lines, 62 were positive for EDAR gene targeting. Nine types of mutations were identified by sequencing analysis, and the mutation efficiency was 69.7%. Using one of these cell lines, EDAR gene-targeted Cashmere goat embryos were prepared by somatic cell cloning. Developed embryos were transferred to 79 Cashmere goat recipients, and, after a gestation period of five months six male EDAR gene-targeted Cashmere goats were born. Although only two of these goats survived, they had abnormal primary hair follicles and no hair on the top of their heads, which are the distinctive features of the EDAR gene-targeted Cashmere goats. Thus, this study provides a valuable animal model for future studies on EDAR gene-related phenotypes and hair follicle growth and development and shows that the CRISPR-Cas9 system can be used to edit genes in large mammals.
Q-Switched Pulse and Mode-Locked Pulse Generation From a Yb3+-Doped Fiber Laser Based on Bi2Se3

The Q-switched pulse and mode-locked pulse were investigated in an all-normal dispersion Yb-doped fiber laser (YDFL) based on the topological insulators (TIs) with mixing of polyvinyl alcohol (PVA) to produce Bi<sub>2</sub>Se<sub>3 </sub>/PVA film or deposition on the end facet of fiber to manufacture TI-compatible fiber. Through the dark Bi<sub> 2</sub>Se<sub>3</sub>/PVA films with large nonsaturable loss, the YDFL was operated in the Q-switched state. The repetition rate and the duration of the Q-switched pulses increased and declined, respectively, with the pump power to show 2.2 μs duration and 137.8 kHz repetition rate at the highest pump power. Moreover, the mode-locked pulses, with a 16 MHz repetition rate and 380 ps pulsewidth, were generated at high pump power by using the light Bi<sub>2</sub>Se<sub>3</sub>/PVA film. By means of a Bi<sub>2</sub>Se<sub>3</sub> compatible fiber, through optical deposition of the Bi<sub>2</sub>Se<sub>3</sub> nanoplatelets on the end facet of the fiber, the mode-locked YDFL was generated at low-threshold pump power and revealed more stabilized operation state up to two hours.
Do feasibility studies contribute to, or avoid, waste in research?

In the context of avoiding research waste, the conduct of a feasibility study before a clinical trial should reduce the risk that further resources will be committed to a trial that is likely to ‘fail’. However, there is little evidence indicating whether feasibility studies add to or reduce waste in research. Feasibility studies funded by the National Institute for Health Research’s (NIHR) Research for Patient Benefit (RfPB) programme were examined to determine how many had published their findings, how many had applied for further funding for a full trial and the timeframe in which both of these occurred. A total of 120 feasibility studies which had closed by May 2016 were identified and each Principal Investigator (PI) was sent a questionnaire of which 89 responses were received and deemed suitable for analysis. Based on self reported answers from the PIs a total of 57 feasibility studies were judged as feasible, 20 were judged not feasible and for 12 it was judged as uncertain whether a full trial was feasible. The RfPB programme had spent approximately £19.5m on the 89 feasibility studies of which 16 further studies had been subsequently funded to a total of £16.8m. The 20 feasibility studies which were judged as not feasible potentially saved up to approximately £20m of further research funding which would likely to have not completed successfully. The average RfPB feasibility study took 31 months (range 18 to 48) to complete and cost £219,048 (range £72,031 to £326,830) and the average full trial funded from an RfPB feasibility study took 42 months (range 26 to 55) to complete and cost £1,163,996 (range £321,403 to £2,099,813). The average timeframe of feasibility study and full trial was 72 months (range 56 to 91), however in addition to this time an average of 10 months (range -7 to 29) was taken between the end of the feasibility study and the application for the full trial, and a further average of 18 months (range 13 to 28) between the application for the full trial and the start of the full trial. Approximately 58% of the 89 feasibility studies had published their findings with the majority of the remaining studies still planning to publish. Due to the long time frames involved a number of studies were still in the process of publishing the feasibility findings and/or applying for a full trial. Feasibility studies are potentially useful at avoiding waste and de-risking funding investments of more expensive full trials, however there is a clear time delay and therefore some potential waste in the existing research pathway.
Non-alcoholic fatty liver disease and insulin resistance: importance of risk factors and histological spectrum

Background Non-alcoholic fatty liver disease (NAFLD) has been associated with several metabolic conditions (MC) and secondary causes, but the relationship between insulin resistance (IR) and the underlying aetiology of NAFLD has not been extensively explored. Objective To determine the frequency of IR among NAFLD patients and to describe IR according to risk factors and histological findings of the disease. Methodology A case-series study of 64 patients with clinical and histological diagnosis of NAFLD. IR was calculated by homeostasis model assessment (HOMA) and IR was considered when HOMA ⩾3. Histological grades of NAFLD were: stage 1, steatosis isolated; stage 2, steatosis and inflammation; stage 3, steatosis and ballooning degeneration; stage 4, steatosis and fibrosis and/or Mallory bodies. Fibrosis was graded 0–4 (cirrhosis). Results IR was found in 21 (33%) patients. Among those with IR, 16 patients (76%) had associated MC and five patients (24%) had exposure to petrochemicals. The mean value of HOMA varied from 3.5 in NAFLD associated with MC to 1.6 in patients with exposure to petrochemicals (P<0.03). Waist circumference was the metabolic factor most strongly associated with IR (P<0.005). Steatohepatitis (NASH) was observed in 54 (84.3%) cases. The HOMA mean value was significantly higher in patients with advanced fibrosis. Conclusions IR occurred in 33% of the NAFLD patients, being more frequent among those with MC than among those with exposure to petrochemicals. The presence of IR in cases with advanced fibrosis suggests that it may influence the prognosis of NAFLD.
Valuation of Bond Illiquidity

In this article, the authors present an easily applicable option-theoretical approach to quantifying liquidity spreads of bonds. Following Longsta [1995], they describe the value of liquidity as that of exotic options. After valuing these lookback options in a framework with interest rate uncertainty, this approach yields liquidity spreads for bonds that cannot be traded continuously. The liquidity spreads show plausible properties: they are humped-shaped functions of the maturity and increase with the interest rate volatility. Liquidity spreads depend on the distribution of possible trading dates but are independent of the short rate. Regarding German Jumbo Pfandbrief market data, they find several parallels between theoretical and empirical liquidity spreads, while credit risk has nearly no explanatory power.
Effect of Transport Time, Temperature, and Concentration on the Survival of Group B Streptococci in Amies Transport Medium

ABSTRACT The impact of transport time and temperature on survival of group B streptococci (GBS) in Amies transport medium was evaluated. Viability of 10 or more CFU of GBS was maintained for 4 days at 24 or 3°C. However, there was a significant decrease in viability for GBS held at 30°C for 4 days.
Glutathione S-transferase A1-1-catalysed conjugation of bay and fjord region diol epoxides or polycyclic aromatic hydrocarbons with glutathione.

Mammalian metabolism of polycyclic aromatic hydrocarbons results in the formation of vicinal diol epoxides (existing as enantiomeric pairs of two diastereomers) considered as important ultimate carcinogens if the oxirane ring is located in a bay or fjord region of the parent hydrocarbon. In the present study, individual stereoisomers of the bay region diol epoxides of chrysene, dibenz[a,h]-anthracene and benzo[a]pyrene, as well as of the fjord region diol epoxides of benzo[c]phenanthrene, benzo[c]chrysene and benzo[g]chrysene, have been incubated with glutathione (GSH) in the presence or absence of human glutathione S-transferase isoenzyme GST A1-1, a class Alpha enzyme. The formation of GSH conjugates was determined and quantified by HPLC. The results demonstrate that the GST A1-1 isoenzyme catalyzes the formation of GSH conjugates of all diol epoxides tested, although a marked variation in catalytic efficiency (>20-fold) was observed. With both bay and fjord region anti-diol epoxides a significant preference for conjugation of the enantiomer with the R configuration at the benzylic position of the oxirane ring was noted. Among the syn diastereomers of the fjord region diol epoxides a similar substrate enantioselectivity was noted, i.e. the enantiomer with the corresponding R configuration was again preferentially conjugated. In contrast, for the bay region syn-diol epoxides this substrate selectivity was reversed, resulting in a preference for the enantiomer with the S configuration. The chemically more reactive syn diastereomers were in general better substrates for GST A1-1 than the corresponding anti diastereomers. However, a comparison between different diol epoxide diastereomers revealed no obvious correlation between chemical reactivity of the compounds and catalytic efficiencies. Furthermore, no significant correlation between diol epoxide lipophilicity and catalytic efficiency was observed. It is suggested that stereochemical factors, including the size and the geometry of the aromatic ring system and the preferred conformation of the diol epoxide, are involved as the major determinant for the rate of catalysis by GST A1-1.
Sustainable Graduation from Social Protection Programmes

Efforts to reduce extreme poverty by assisting poor people to cross income or asset thresholds are receiving increasing attention in social protection programming. Livelihood-promoting interventions aim to reduce vulnerability, so that participants can manage moderate risk and ‘graduate’ from social protection provision. This article elaborates the theory of change underpinning the notion of graduation and explores the range of enabling and constraining factors that facilitate or undermine this change process, drawing on case studies from Bangladesh, Ethiopia and Rwanda. The authors distinguish ‘threshold’ graduation from ‘sustainable’ graduation and argue that multiple factors operating beyond the household level — such as market conditions, community investment and scale effects — have significant implications for the graduation potential of social protection programmes.
Belief Reward Shaping in Reinforcement Learning

A key challenge in many reinforcement learning problems is delayed rewards, which can significantly slow down learning. Although reward shaping has previously been introduced to accelerate learning by bootstrapping an agent with additional information, this can lead to problems with convergence. We present a novel Bayesian reward shaping framework that augments the reward distribution with prior beliefs that decay with experience. Formally, we prove that under suitable conditions a Markov decision process augmented with our framework is consistent with the optimal policy of the original MDP when using the Q-learning algorithm. However, in general our method integrates seamlessly with any reinforcement learning algorithm that learns a value or action-value function through experience. Experiments are run on a gridworld and a more complex backgammon domain that show that we can learn tasks significantly faster when we specify intuitive priors on the reward distribution.
Native oligomeric human immunodeficiency virus type 1 envelope glycoprotein elicits diverse monoclonal antibody reactivities

We synthesized and purified a recombinant human immunodeficiency virus type 1 (HIV-1) envelope (Env) glycoprotein, lacking the gp120/gp41 cleavage site as well as the transmembrane domain, that is secreted principally as a stable oligomer. Mice were immunized with separated monomeric and oligomeric HIV-1 Env glycoproteins to analyze the repertoire of antibody responses to the tertiary and quaternary structure of the protein. Hybridomas were generated and assayed for reactivity by immunoprecipitation of nondenatured Env protein. A total of 138 monoclonal antibodies (MAbs) were generated and cloned, 123 of which were derived from seven animals immunized with oligomeric Env. Within this group, a significant response was obtained against the gp41 ectodomain; 49 MAbs recognized epitopes in gp41, 82% of which were conformational. The influence of conformation on gp120 antigenicity was less pronounced, with 40% of the anti-gp120 MAbs binding to conformational epitopes, many of which blocked CD4 binding. Surprisingly, less than 7% of the MAbs derived from mice immunized with oligomeric Env recognized the V3 loop. In addition, MAbs to linear epitopes in the C-terminal domain of gp120 were not obtained, suggesting that this region of the protein may be partially masked in the oligomeric molecule. A total of 15 MAbs were obtained from two mice immunized with monomeric Env. Nearly half of these recognized the V3 loop, suggesting that this region may be a less predominant epitope in the context of oligomeric Env than in monomeric protein. Thus, immunization with oligomeric Env generates a large proportion of antibodies to conformational epitopes in both gp120 and gp41, many of which may be absent from monomeric Env.
Lipopolysaccharide‐induced microglial activation induces learning and memory deficits without neuronal cell deathin rats

We used lipopolysaccharide (LPS) to activate microglia that play an important role in the brain immune system. LPS injected into the rat hippocampus CA1 region activated microglial cells resulting in an increased production of interleukin (IL)‐1β and tumor necrosis factor (TNF)‐α in the hippocampus during the initial stage of treatment. Immunostaining for IL‐1β was increased at 6 hr after LPS injection. IL‐1β‐immunopositive cells were co‐localized with immunostaining for CD11b. Subacute treatment with LPS by the same route for 5 days caused long‐term activation of microglia and induced learning and memory deficits in animals when examined with a step‐through passive avoidance test, but histochemical analysis showed that neuronal cell death was not observed under these experimental conditions. The increased expression of the heme oxygenase‐1 (HO‐1) gene, an oxidative stress maker, was observed. However, the genetic expression of brain‐derived neurotrophic factor (BDNF) and its receptor, TrkB, decreased during the course of LPS treatment. We found decreases in [3H]MK801 binding in the hippocampus CA1 region by LPS‐treatment for 5 days. The data shows that glutamatergic transmission was attenuated in the LPS‐treated rats. These results suggest that long‐term activation of microglia induced by LPS results in a decrease of glutamatergic transmission that leads to learning and memory deficits without neuronal cell death. The physiologic significance of these findings is discussed. © 2006 Wiley‐Liss, Inc.
The factor structure of financial markets: a simulation study of the Italian case

This article develops a new information criterion for the analysis of the factor structure of financial markets. The new proposal is obtained by resorting to a Monte Carlo experiment, which allows one to evaluate the behaviour of different information criteria by a priori knowing the true number of unobservable factors. The financial markets factor structure is found to be different from those suggested by traditional factor analysis methods, and for the Italian stock market in particular, only two or three factors are signalled.
Heart vs hard drive: Children learn more from a human tutor than a social robot

The field of Human-Robot Interaction (HRI) is increasingly exploring the use of social robots for educating children. Commonly, non-academic audiences will ask how robots compare to humans in terms of learning outcomes. This question is also interesting for social roboticists as humans are often assumed to be an upper benchmark for social behaviour, which influences learning. This paper presents a study in which learning gains of children are compared when taught the same mathematics material by a robot tutor and a non-expert human tutor. Significant learning occurs in both conditions, but the children improve more with the human tutor. This difference is not statistically significant, but the effect sizes fall in line with findings from other literature showing that humans outperform technology for tutoring. We discuss these findings in the context of applying social robots in child education.
Domesticating Radical Rant and Rage: An Exploration of the Consequences of Environmental Shareholder Resolutions on Corporate Environmental Performance

This article examines the effect of social shareholder activism on one of the most visible aspects of corporate social behavior, namely corporate pollution management practice. Social shareholder activism is a distinct form of social movement that engages firms “in the suites. ” We theorize the effect of social shareholder activism using three social movement mechanisms: (a) disruption of routines, (b) reframing of issues using extant institutional logics, and (c) mobilization of relevant third-party constituents. Our empirical analysis using 13-year panel data of 58 public corporations strongly confirm the positive effect of environmental shareholder resolutions on the targeted firm’s pollution management practice. We have also found that certain firms targeted by social shareholder activism are more likely to respond positively to the demands than others. In particular, firms that can potentially incur higher disruption costs and are more dependent on reputation for critical resources such as larger firms as well as firms in industries that are closer to end-user consumers are more likely to concede to the demands from shareholder activists.
Targeting Research for Poverty Reduction in Marginal Areas of Rural Syria

Agricultural research in marginal dry areas can contribute to reducing poverty through the development of technological, institutional and policy options for poor farmers. Such research should address diversified opportunities and development pathways. This article analyses the diversity of livelihood strategies of rural people living in the Khanasser Valley in northwestern Syria, an area that is typical of marginal drylands. It proposes an operational classification of households based on their different livelihood strategies, applying an integrated methodology within a Sustainable Livelihoods framework. Households are classified into three clusters: agriculturists, labourers and pastoralists. The article examines the diversity of livelihoods involved, and considers where and how research should be directed to have greatest impact on poverty. Given that rural households are not homogeneous but dynamic entities, with diverse assets, capabilities and opportunities, the definition of household typologies can help to target development research. The article concludes that while agriculturists benefit most, poor labourers with enough land can also gain from pro-poor agricultural research. The poorest households with little land, and pastoralists, benefit little or only indirectly.
NO-REGRET DYNAMICS CONVERGING TO NASH EQUILIBRIUM IN SELF-PLAY

We study the limit behavior and performance of no-regret dynamics in general game theoretic settings. We design protocols that achieve both good regret and equilibration guarantees in general games. In terms of arbitrary no-regret dynamics we establish a strong equivalence between them and coarse correlated equilibria. We examine structured game settings where stronger properties can be established for no-regret dynamics and coarse correlated equilibria. In congestion games, as we decrease the size of agents, coarse correlated equilibria become closely concentrated around the unique equilibrium flow of the nonatomic game. Moreover, we compare best/worst case no-regret learning behavior to best/worst case Nash in small games. We study these ratios both analytically and experimentally. These ratios are small for 2 × 2 games, become unbounded for slightly larger games, and exhibit strong anticorrelation.
Pulsed injection locking dynamics of passively mode-locked external-cavity semiconductor laser systems for all-optical clock recovery

The performance characteristics of a pulse injection locked, passively mode-locked (PML) external-cavity semiconductor laser system for all-optical clock recovery are investigated in detail. It is important to characterize the clock recovery dynamics to understand the fundamental capabilities and limitations of the clock recovery system. It is experimentally shown that these devices offer robust clock recovery with low phase and amplitude noise, low injected data power requirements, large frequency locking bandwidth, large phase tracking bandwidth, short lockup time, long dephasing time and immunity to bit-pattern-effects. Harmonic clock generation and subharmonic clock generation are demonstrated for data-rate conversion applications.