Biggest Unanswered Questions Research Articles

Research and academic output evaluation for career initiation or progression: Critical issues for Health Professionals

In current times, much stress is being laid on the evaluation of research productivity of researchers or faculty in addition to the academic qualifications and experience for the purposes of recruitment, promotion, and research grant funding. Over the years, several quantitative indices have been devised for this purpose. Some of these indices such as h-index, impact factor and e-index are being extensively used by research organizations, universities, accreditation bodies and funding agencies for basic scientists as well as health professionals. In the absence of any formal training, these parameters or their advantages and shortcomings may not be well understood by the health professionals, especially in the early stages of their careers and sometimes, even by the evaluators. A big unanswered question is the validity of the same criteria for health professionals as are applicable for the basic science researchers. Since health professional undertaking research assignments are neither adequately trained in basic research nor can they comprehend these indices well, the same yardstick to evaluate these two widely different groups of researchers often places the health professionals at a disadvantage. This paper aims to highlight certain vital issues related to the application of research productivity indicators for recruitment and career progression of health care professionals.

Connecting primitive phase separation to biotechnology, synthetic biology, and engineering

One aspect of the study of the origins of life focuses on how primitive chemistries assembled into the first cells on Earth and how these primitive cells evolved into modern cells. Membraneless droplets generated from liquid-liquid phase separation (LLPS) are one potential primitive cell-like compartment; current research in origins of life includes study of the structure, function, and evolution of such systems. However, the goal of primitive LLPS research is not simply curiosity or striving to understand one of life’s biggest unanswered questions, but also the possibility to discover functions or structures useful for application in the modern day. Many applicational fields, including biotechnology, synthetic biology, and engineering, utilize similar phase-separated structures to accomplish specific functions afforded by LLPS. Here, we briefly review LLPS applied to primitive compartment research and then present some examples of LLPS applied to biomolecule purification, drug delivery, artificial cell construction, waste and pollution management, and flavor encapsulation. Due to a significant focus on similar functions and structures, there appears to be much for origins of life researchers to learn from those working on LLPS in applicational fields, and vice versa, and we hope that such researchers can start meaningful cross-disciplinary collaborations in the future.

Sticking together: Harnessing cadherin biology for tissue engineering

Directing cell behavior and building a tissue for therapeutic impact is the main goal of regenerative medicine, for which scientists need to modulate the interaction of cells with biomaterials. The focus of the field thus far has been on the incorporation of cues from the extracellular matrix but we propose that scientists take lessons from cell–cell adhesion proteins, more specifically cadherin biology, as these proteins make multicellularity possible. In this perspective, we re-examine cadherins through the lens of a tissue engineer for the purpose of advancing regenerative medicine. Furthermore, we summarize exciting developments in biomaterials inspired by cadherins and discuss some challenges and opportunities for the future. Statement of significanceTissue engineers need tools to direct cell behavior. To date, tissue engineers have designed many sophisticated materials to positively influence cell behavior but are faced with the challenge where these materials sometimes work and sometimes fail. This uncertainty is a big unanswered question that challenges the community. We propose that tissue engineering could be more successful if they would take lessons from cell–cell adhesion proteins, more specifically cadherin biology. In the article, we discuss key structural and functional characteristics that make cadherins ideal for tissue engineering approaches. Furthermore, by providing a state-of-the-art overview of exemplary studies that have used cadherins to influence cell behavior, we show tissue engineers that they already have the tools necessary to incorporate this knowledge.

Sensory cilia act as a specialized venue for regulated extracellular vesicle biogenesis and signaling

Ciliary extracellular vesicle (EV) shedding is evolutionarily conserved. In Chlamydomonas and C.elegans, ciliary EVs act as signaling devices.1-3 In cultured mammalian cells, ciliary EVs regulate ciliary disposal but also receptor abundance and signaling, ciliary length, and ciliary membrane dynamics.4-7 Mammalian cilia produce EVs from the tip and along the ciliary membrane.8,9 This study aimed to determine the functional significance of shedding at distinct locations and to explore ciliary EV biogenesis mechanisms. Using Airyscan super-resolution imaging in living C.elegans animals, we find that neuronal sensory cilia shed TRP polycystin-2 channel PKD-2::GFP-carrying EVs from two distinct sites: the ciliary tip and the ciliary base. Ciliary tip shedding requires distal ciliary enrichment of PKD-2 by the myristoylated coiled-coil protein CIL-7. Kinesin-3 KLP-6 and intraflagellar transport (IFT) kinesin-2 motors are also required for ciliary tip EV shedding. A big unanswered question in the EV field is how cells sort EV cargo. Here, we show that two EV cargoes- CIL-7 and PKD-2-localized and trafficked differently along cilia and were sorted to different environmentally released EVs. In response to mating partners, C.elegans males modulate EV cargo composition by increasing the ratio of PKD-2 to CIL-7 EVs. Overall, our study indicates that the cilium and its trafficking machinery act as a specialized venue for regulated EV biogenesis and signaling.

Toward a personalized approach to psychotherapy outcome and the study of therapeutic change.

Toward a personalized approach to psychotherapy outcome and the study of therapeutic change.

Nutritional Regulation of the Sae Two-Component System by CodY in Staphylococcus aureus.

Staphylococcus aureus subverts innate defenses during infection in part by killing host immune cells to exacerbate disease. This human pathogen intercepts host cues and activates a transcriptional response via the S. aureus exoprotein expression (SaeR/SaeS [SaeR/S]) two-component system to secrete virulence factors critical for pathogenesis. We recently showed that the transcriptional repressor CodY adjusts nuclease (nuc) gene expression via SaeR/S, but the mechanism remained unknown. Here, we identified two CodY binding motifs upstream of the sae P1 promoter, which suggested direct regulation by this global regulator. We show that CodY shares a binding site with the positive activator SaeR and that alleviating direct CodY repression at this site is sufficient to abrogate stochastic expression, suggesting that CodY represses sae expression by blocking SaeR binding. Epistasis experiments support a model that CodY also controls sae indirectly through Agr and Rot-mediated repression of the sae P1 promoter. We also demonstrate that CodY repression of sae restrains production of secreted cytotoxins that kill human neutrophils. We conclude that CodY plays a previously unrecognized role in controlling virulence gene expression via SaeR/S and suggest a mechanism by which CodY acts as a master regulator of pathogenesis by tying nutrient availability to virulence gene expression.IMPORTANCE Bacterial mechanisms that mediate the switch from a commensal to pathogenic lifestyle are among the biggest unanswered questions in infectious disease research. Since the expression of most virulence genes is often correlated with nutrient depletion, this implies that virulence is a response to the lack of nourishment in host tissues and that pathogens like S. aureus produce virulence factors in order to gain access to nutrients in the host. Here, we show that specific nutrient depletion signals appear to be funneled to the SaeR/S system through the global regulator CodY. Our findings reveal a strategy by which S. aureus delays the production of immune evasion and immune-cell-killing proteins until key nutrients are depleted.

A £2 billion boost for the NHS

overspend by some £2.5 billion next year; it also begs the question of how much of the cash might be needed to plug an overall deficit this year. Paul Baumann, NHS England’s chief financial officer, told the Commons Health Select Committee in November, that achieving overall financial balance this year is ‘absolutely on the knife edge.’ So the headline figure may not prove to be quite what it seems, and it is likely to take a few weeks—if not a few months—to work out where the announcement really leaves the service. One should not, however, be over curmudgeonly. The money is also, the chancellor said, ‘a down payment on the NHS’s on long term plan’—in other words, on October’s Five Year Forward View. A down payment does at least imply that there will be more to come at some point, and it is a measure of the success of the Five Year Forward View that politicians of all parties have, at least on the face of it, adopted it as their own; or as a credible way forward for the service in times of continued austerity. Simon Stevens, Chief Executive of NHS England, unsurprisingly, welcomed the cash, saying it would ‘kick start transformation’—and the really big question is how far it will provide at least some room for manoeuvre to do that. The Five Year Forward View posited half-a-dozen or so models for getting hospitals, primary and community care to work together in a more integrated fashion. It is a model for providing a better service, and hopefully a more cost-effective one, for those patients who form the biggest current challenge to health services—people with multiple conditions, and most notably the frail elderly, who end up too often and too unnecessarily in hospital. The Five Year Forward View did not, in so many words, adopt the idea of a ‘transformation fund’ to get these up and running. But it did contain an implicit recognition that some may involve double running costs to build a new service before an old one closes down. Stevens raised that idea in his health select committee evidence, saying that NHS England will be looking at ‘the case for freeing up some of the cash from day to day operations in order to lever in some of these new models.’ Quite how they are to be brought into existence, with what degree of central support, was the big unanswered question in the Five Year Forward View. Quite how the extra cash will help with that is the big unanswered question that lies behind the announcement of additional money. BJHCM Nick Timmins, senior fellow at the Institute for Government and the King’s Fund examines George Osborne’s announcement of £2 billion extra funding for the NHS A £2 billion boost for the NHS

Face Recognition based on a Hybrid Meta-heuristic Feature Selection Algorithm

For the past few years, a number of new face recognition techniques have been proposed. Always it is a big unanswered question among face recognition researchers about which method or technique will have better performance. In this study an approach to recognize known faces based on Eigen vectors and a hybrid Meta-heuristic feature selection algorithm is proposed. The eigenvectors which are covariance matrix of the face images together describes the difference between face images. Face recognition problem is viewed as a two dimensional recognition problem. Initially the face images are projected in to face space and using Principal component analysis the eigenvectors with high Eigenvalues are extracted to reduce the dimension of the feature vector. Further to select the best feature vectors which increase the classification accuracy is selected by using a hybrid metaheuristic algorithm using Genetic algorithm (GA) and Bacteria Foraging Optimization (BFO). In this study the Support vector machine (SVM) and Back propagation neural network (BPNN) are used for classification. The classifiers are trained and tested separately using the frontal face images taken from AT&T database. The SVM and BPNN produces an average classification accuracy of 82.6% and 83.28% respectively.

Pricing for retail electricity

A big unanswered question in the power industry is how the future demand for energy will be met. As the rate of energy usage increases at an average of 2.3 per cent per year, demand management is one means of dealing with the increasing demands for energy. Pricing that varies for critical peak demand periods and discounted the rest of the time is one means of dealing with the increasing demands for energy. The next frontier for the revenue management and pricing practice will be helping the retail energy providers develop more efficient rate designs or dynamic pricing programs.

Alanine-shaving Mutagenesis to Determine Key Interfacial Residues Governing the Assembly of a Nano-cage Maxi-ferritin

The fundamental process of protein self-assembly is governed by protein-protein interactions between subunits, which combine to form structures that are often on the nano-scale. The nano-cage protein, bacterioferritin from Escherichia coli, a maxi-ferritin made up of 24 subunits, was chosen as the basis for an alanine-shaving mutagenesis study to discover key amino acid residues at symmetry-related protein-protein interfaces that control protein stability and self-assembly. By inspection of these interfaces and "virtual alanine scanning," nine mutants were designed, expressed, purified, and characterized using transmission electron microscopy, size exclusion chromatography, dynamic light scattering, native PAGE, and temperature-dependent CD. Many of the selected amino acids act as hot spot residues. Four of these (Arg-30, which is located at the two-fold axis, and Arg-61, Tyr-114, and Glu-128, which are located at the three-fold axis), when individually mutated to alanine, completely shut down detectable solution formation of 24-mer, favoring a cooperatively folded dimer, suggesting that they may be oligomerization "switch residues." Furthermore, two residues, Arg-30 and Arg-61, when changed to alanine form mutants that are more thermodynamically stable than the native protein. This investigation into the structure and energetics of this self-assembling nano-cage protein not only can act as a jumping off point for the eventual design of novel protein nano-structures but can also help to understand the role that structure plays on the function of this important class of proteins.

Mathematics in Accounting as a Big Unanswered Question

Mathematics has been employed in accounting for centuries. It was included in the double entry system in the Luca Pacioli’s mathematics book but has not, so far, received appropriate attention in the development of modern accounting. The expanded accounting equation employed nowadays is considered a black-box, and there have been no significant improvements to the equation. This paper outlines the importance of the accounting equation in identifying the limitations of current accounting standards, particularly the definition of the elements of financial statements. Furthermore, this paper argues that the approach employed in the definitions of the elements of financial statements should be on the basis of information-base, instead of the use either the balance sheet or the income statement approach. Finally, the paper suggests that the application of mathematics in accounting be dealt with so that accounting will make a significant contribution to the academic world.

The persistent puzzle of the geographic patterning of cardiovascular disease

It has long been known that health is geographically patterned (Jones and Moon, 1987). In fact, “place” has been a key dimension of epidemiology since its origins. Descriptive epidemiology emphasizes differences in disease distribution across places because it may provide important etiologic clues. Cardiovascular disease mortality, and in particular coronary heart disease (CHD) and stroke, vary markedly across and within countries (Lloyd-Jones et al., 2009). In the United States, there are up to two-fold differences in stroke and CHD mortality across states (Lloyd-Jones et al., 2009). Yet our ignorance about the reasons for these differences is surprising, especially given our knowledge of major heart disease and stroke risk factors. Together with the causes of trends over time – topic of debate and research in itself – the causes of geographic variations remain one of the big unanswered questions in cardiovascular disease epidemiology. In this issue of Preventive Medicine, Howard et al. (G.C.M. Howard, Prineas R., Howard VJ., Moy CS, Sullivan LM, D'Agistino RB, McLure LA, Pulley LV, Safford MM) use unique data collected as part of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national study of geographic variations in stroke, to investigate the extent to which established heart disease and stroke risk factors explain geographic variations in stroke and heart disease mortality. They construct summary aggregate measures of the Framingham Coronary Heart Disease Risk Score and the Framingham Stroke Risk Score for US states and investigate correlations between scores and corresponding mortality rates, between stroke and heart disease scores, and between stroke and heart disease mortality rates. As expected, each of these scores is positively associated with the corresponding mortality rate at the state level, with stronger correlations observed for CHD than for stroke. They find that CHD and stroke mortality rates are not correlated, suggesting that the etiologic processes leading to each outcome are distinct and could involve different sets of factors. In contrast the Framingham heart and stroke risk scores are positively correlated with each other. From this pattern of results (weak associations between CHD and stroke mortality but strong associations between scores) the authors infer that the risk factor components of the FRS do not explain the geographic variation in store and CHD mortality rates. The correlational results reported by Howard et al. are compatible with the possibility that geographic differences are not explained by risk factors, but they also have limitations. If risk factors are important contributors tomortality differences, the geographic patterning of risk factor scores should mirror the geographic patterning of mortality

Panel on Big Unanswered Questions in Accounting—Genesis

n recent years, prominent accounting scholars speaking at the annual meetings of the American Accounting Association AAA have bemoaned the state of accounting inquiry. The main thrust of the criticisms is that accounting researchers increasingly pursue very small and arrow questions that do not advance professional knowledge. For instance, at the 2006 AAA nnual Meeting, Demski 2007 and Fellingham 2007 questioned whether accounting was even n academic discipline. In a plenary address at the 2006 AAA Annual Meeting, Hopwood 2007 rgued that accounting researchers were shrinking their research boundaries and that the “top hree” U.S. accounting journals are increasingly unlikely to publish truly innovative research. hese commentators agree that “innovation is close to nonexistent” and that “our research is argely derivative, bifurcated, and far from foundational” Demski 2007 . Fellingham 2007 poses he challenge, “What big intellectual ideas have accounting researchers contributed to the niversity?” One reason senior researchers might feel that we are making little progress is that accounting esearchers do not share a common research goal such as particle physicists do in their quest for Grand Unified Theory of the fundamental forces. If we are to make big intellectual contributions o the academy, it would probably help to identify the big unanswered questions that we could ollectively attack, and then work on finding the tools to answer these questions rather than hoosing only the questions that our current research methods can address. At least this is one Imagined World of Accounting,” consistent with the theme of the 2007 AAA Annual Meeting. To elp identify these big-picture questions, I offered to moderate a panel discussion on this topic. But who would make good panelists? Galenson 2005 argues that important innovative ontributions tend to be made by either experimental Old Masters like Rembrandt and Alfred itchcock or conceptual Young Geniuses like Picasso and James Joyce. Berlin 1953 argues that mportant thinkers tend to be either hedgehogs who are guided by one defining idea such as Plato nd Hegel, or foxes who draw on a wide variety of experiences such as Aristotle and Shakespeare. hese perspectives suggest that an ideal panel would consist of innovative accounting researchers ho are at different career stages, some of whom regularly cross methodological and disciplinary arriers while others specialize in a particular research stream. Greg Waymire chair requested the AA Annual Meeting Planning Committee to suggest potential panelists. Greg Waymire, Shyam under AAA’s president , and I then invited several scholars whose research we admire, while rying to balance the coverage of research methodologies, research styles, career stages, panel size,

Panel on Big Unanswered Questions in Accounting—Synopsis

Panel on Big Unanswered Questions in Accounting—Synopsis

Three Patterns in Need of a Unified Theory

ow earnings affect stock price, how earnings are formed from underlying events and management actions, and how pay affects performance are questions that have been prominent in the research agendas of many accounting scholars. Among the results of this xtensive research effort are three striking empirical regularities: 1 stock returns are an S-shaped unction of earnings; 2 the distribution of earnings is lumpy around benchmarks; and 3 pay for op executives is an increasing convex function of stock price. To my mind, these findings suggest big unanswered question in accounting: Why are stock prices, earnings, and pay packages elated in these ways? Because price, earnings, and pay are interrelated, a good theory ought to mply relationships among these variables that are consistent with the patterns schematized in igure 1. We have some explanations for these regularities in isolation and even a few explanaions that address two of them simultaneously, but no model I know persuasively comprehends hem all. Some elements in Figure 1 bear emphasizing: First, the “divots” in the distribution of firms’ eported earnings lie just above a variety of salient benchmarks. Second, at least one divot lies in he region of steepest slope in the S-shaped relationship between the unexpected component of arnings and the contemporaneous price response. Finally, compensation contracts are smooth unctions of stock price. To illustrate some inadequacies of partial explanations, consider the argument that caps and oors in managers’ compensation contracts lead them to distort reported earnings in the neighborood of the kinks in the pay schedule. While kinks may indeed induce divots, this line of reasonng begs the theoretical question of why kinked compensation contracts are optimal and the mpirical question of whether kinks are prevalent enough to drive the divot. On the latter point, tock-based compensation is widespread and obviously imposes no cap. Another difficulty that

The Profitability of Risk Arbitrage in Mergers and Acquisitions

If and why M&A arbitrageurs earn risk adjusted excess returns is a big unanswered question in the M&A literature. The goal of this study is to examine the risk and return relation of M&A arbitrageurs in different idiosyncratic and systematic environments. On one hand, deal characteristics create idiosyncratic risk for arbitrageurs by affecting the ex-ante probability of deal success. On the other hand, market liquidity conditions affect speculative spreads, which is the source of these arbitrageurs' profit. For example, when the market experienced the credit crunch in mid 2007, speculative spreads widened up dramatically. But both of these risks have not been taken into account in previous literature when examining M&A arbitrageurs` return. In this article, we empirically examine this risk and return relationship by considering both idiosyncratic and systematic risk including market liquidity risk. Our empirical study shows that deal characteristics, for example, the medium of payment, affects risk characteristics of these arbitrageurs' portfolios. Also, both idiosyncratic risk captured by the probability of deal success and market liquidity proxy by VIX affects M&A arbs' return. More importantly, after considering the liquidity risk they are bearing, M&A arbs are not making excess return. This article contributes to the existing research on M&A arbitrage in two aspects. First, we provide evidence that M&A arbitrageurs bear both idiosyncratic risk and systematic liquidity risk. Second, we examine how excess return (a3B1) is related to different idiosyncratic and systematic market environments and shows that M&A arbs are not earning excess return.

What is the Actual Economic Role of Financial Reporting?

SYNOPSIS: This short essay is based on a presentation at the panel discussion on “Big Unanswered Questions in Accounting” at the 2007 American Accounting Association Annual Meeting. It poses the question: “What is the actual economic role of financial reporting?” and discusses why this question is important, why it is unanswered, and what types of inventive research design are needed to help answer it. Examples are given of the types of questions involved.

What is the Actual Economic Role of Financial Reporting?

This short essay is based on a presentation at the panel discussion on Big Unanswered Questions in at the American Accounting Association Meetings in 2007. It poses the question what is the actual economic role of financial reporting? and discusses why this is an important question, why it is unanswered, and the types of inventive research design needed to help answer it. Examples of the types of questions involved are given.

The early settlement of North America: the Clovis era

Part I. Fluted Points and the Peopling of the Americas: 1.1. Introduction 1.2. Fin de siecle paradigm-busting, or what's at stake in the debate about the colonizing of North America? 1.3. How do archaeologists address the big unanswered questions about Fluted-Point-Makers? Part II. What is Clovis? The Archaeological Record: 2.1. Introduction 2.2. Clovis archaeological footprints, region by region 2.3. Knowledge and guesswork about the late Pleistocene 2.4. Defining Clovis: is it a culture? 2.5. The course of regional developments: the megamammal connection Part III. Clovis Archaeological Culture: 3.1. Introduction 3.2. Clovis-era technology 3.3. Clovis-era megamammal bone-breakage 3.4. Clovis-era artwork, decorative work, 'symbolic' objects Part IV. The Old and New World Patterns Compared: 4.1. Dispersals and diffusions: old world Upper Paleolithic and new world Clovis 4.2. The American Upper Paleolithic Part V. Figures in the Landscape: Foraging in the Clovis Era: 5.1. Introduction 5.2. Archaeological evidence about hunting and gathering in megamammal landscapes 5.3. Why hunt megamammals? Why not hunt megamammals? Conclusions from Part V. Figures in the Landscapes: Part VI. Colonizing Foragers: 6.1. Introduction 6.2. Colonization theory. Conclusions from Part VI: Complexity in Clovis dispersals Part VII. Unified Conclusions about the Clovis Era: 7.1. Introduction 7.2. The end.