Strategies for developing protein tyrosine phosphatase inhibitors

Protein tyrosine phosphatases (PTPs) play vital roles in numerous cellular processes and are implicated in a growing number of human diseases, ranging from cancer to cardiovascular, immunological, infectious, neurological, and metabolic diseases. Here we present methods for developing small molecule inhibitors for these enzymes, starting with how to set up a high throughput chemical library screening for PTP inhibitors, how to confirm and prioritize hits, and how to circumnavigate possible pitfalls. Next, we present the relatively new hit generating method of in silico or virtual screening. We give an overview of existing software tools, describe how to choose and generate protein target structures and illustrate the procedure with examples. We then discuss how three-dimensional PTP structures can be analyzed in terms of their potential to bind small molecule inhibitors selectively over homologous proteins and how computer tools can be applied for lead optimization efforts. We finish with a perspective of how well these PTP inhibitors might perform as future drugs to treat human disease.     

The other cooperation problem: generating benefit

Understanding how cooperation evolves is central to explaining some core features of our biological world. Many important evolutionary events, such as the arrival of multicellularity or the origins of eusociality, are cooperative ventures between formerly solitary individuals. Explanations of the evolution of cooperation have primarily involved showing how cooperation can be maintained in the face of free-riding individuals whose success gradually undermines cooperation. In this paper I argue that there is a second, distinct, and less well explored, problem of cooperation that I call the generation of benefit. Focusing on how benefit is generated within a group poses a different problem: how is it that individuals in a group can (at least in principle) do better than those who remain solitary? I present several different ways that benefit may be generated, each with different implications for how cooperation might be initiated, how it might further evolve, and how it might interact with different ways of maintaining cooperation. I argue that in some cases of cooperation, the most important underlying “problem” of cooperation may be how to generate benefit, rather than how to reduce conflict or prevent free-riding.     

Discussion of errors and measuring strategies in morphometry using analysis of variance

Statistical techniques known as the analysis of variance make it possible for the morphologist to plan work in such a way as to get quantitative data with the greatest possible economy of effort. This paper explains how to decide how many measurements to make per micrograph, how many micrographs per tissue block or organ, and how many organs or individuals are necessary for getting an exactness of sufficient quality of the results. The examples furnished have been taken from measuring volume densities of mitochondria in heart muscle cells and from cell counting in lymph nodes. Finally we show, how to determine sample sizes, if we are interested in demonstration of significant differences between mean values.     

Zero tolerance ecology: improving ecological inference by modelling the source of zero observations

A common feature of ecological data sets is their tendency to contain many zero values. Statistical inference based on such data are likely to be inefficient or wrong unless careful thought is given to how these zeros arose and how best to model them. In this paper, we propose a framework for understanding how zero-inflated data sets originate and deciding how best to model them. We define and classify the different kinds of zeros that occur in ecological data and describe how they arise: either from 'true zero' or 'false zero' observations. After reviewing recent developments in modelling zero-inflated data sets, we use practical examples to demonstrate how failing to account for the source of zero inflation can reduce our ability to detect relationships in ecological data and at worst lead to incorrect inference. The adoption of methods that explicitly model the sources of zero observations will sharpen insights and improve the robustness of ecological analyses.     

An experimental analysis of design choices of multi-objective ant colony optimization algorithms

There have been several proposals on how to apply the ant colony optimization (ACO) metaheuristic to multi-objective combinatorial optimization problems (MOCOPs). This paper proposes a new formulation of these multi-objective ant colony optimization (MOACO) algorithms. This formulation is based on adding specific algorithm components for tackling multiple objectives to the basic ACO metaheuristic. Examples of these components are how to represent multiple objectives using pheromone and heuristic information, how to select the best solutions for updating the pheromone information, and how to define and use weights to aggregate the different objectives. This formulation reveals more similarities than previously thought in the design choices made in existing MOACO algorithms. The main contribution of this paper is an experimental analysis of how particular design choices affect the quality and the shape of the Pareto front approximations generated by each MOACO algorithm. This study provides general guidelines to understand how MOACO algorithms work, and how to improve their design.     

Compelling culture: The rhetoric of assimilation among Samoan migrants in the United States

Studies of assimilation tend to focus on whether or not members of a migrant group are adjusting to their new surroundings. This article inverts this focus, asking not how migrant groups adjust, but rather how migrant groups use the language of assimilation to explain generation gaps and other exigencies of migration. This inversion sheds light on the ways a migrant group's epistemological assumptions underlie their understandings of cultural identity, and shape how they might respond to dilemmas caused by migration. Building upon ethnographic fieldwork among Samoan migrants in the United States, the article explores how and why community workers use the rhetoric of assimilation to teach Samoan parents how to raise children in the US context.     

高校生物化学首堂课教学方法探索与实践

生物化学作为医学、生命科学等专业学生必修的一门学科基础课程,理论性强、概念抽象、内容较多、逻辑关系复杂,是教学难度相对较大的一门课程。本文通过阐述在首堂课授课过程中,从任课教师如何塑造良好的自身形象,如何形象生动地引入生物化学的研究内容,如何通过展现生物化学的魅力来激发学生的学习热情和兴趣,如何使用巧妙的方法学好这门课程,以及如何将课程思政理念融入到生物化学课程中等诸多方面,探讨了在授课过程中的一些教学方法和实践,以期改变生物化学课堂不受学生喜爱的现状,为生物化学课程教学改革提供一些思路和参考。     

Spectres of Seppo: the afterlives of Finland's nuclear waste experts

This article examines how Finland's nuclear waste repository safety assessment experts summoned memories of Seppo: a deceased colleague whose ‘spectre’ was said to still ‘haunt’ their workplace. First, it tracks how Seppo appeared in predecessor parables: cautionary tales told about his death, which conveyed value judgements about how experts ought to act, engage, and aspire. Second, it explores how Seppo's long-time ‘right-hand man’ Gustav still felt haunted by his colleague's affective intensities, scientific vision, and sharp tongue. This led Gustav to prod his workmates to reconsider how they modelled Finland's ecosystems many millennia into the future. Studying this ethnographically revealed how traces of Seppo's past life infused living experts with emotions, opened them to alternative futures, and spurred them to rethink their professional values. This article concludes by introducing expert afterlives as a temporal, epistemic, and affective nexus that can shape how technocratic projects are organized and how expert knowledge is made.     

Role of cell displacement, cell division, and fragment size in pattern formation during embryonic retinal regeneration in Xenopus

Studies on the regenerating vertebrate retina provide, for the first time, a detailed view of how cells respond to removal of 2/3 of the eyebud, how their displacements, new juxtapositions, and extra mitotic activity correlate with stable changes in the retinotectal projection. They provide insight into how retinal ganglion cells encode "position", and how they use this information to form specific neural connectivity patterns.     

A study of family communication space (Part I)--A preliminary study on how family communication is actually practiced

Housing science needs to concern itself with how to improve space for family communication because it plays an important role in human dwelling life. The purpose of this report (Parts I, II & III) is, hence, to elucidate various factors conditioning family communication, and spatial traits of the rooms where it is conducted, based on the survey of the households of students at women's junior colleges. Part I delves into what is specifically communicated within a family and how it is related with other living activities, by grasping how communication is practiced in everyday family life. A basic analysis is made as to how conscious a family members are of their mutual communication, and how rooms are used for it. It has become clear that family communication is closely related with meal-taking both behaviorally and spatially, and that different attitudes among a family members toward family communication cause different modes, and evaluations of it. It has proved to be necessary, for the further studies of family communication, to give an analytical perspective to an in-depth examination of how rooms in the target families are used and how every member views and evaluates their family communication.     

关于"探究问题"的课题开展及思考

“探究问题”的课题研究,让学生学会如何收集、处理和提取信息,如何运用相关知识分析和解决实际问题,如何与他人交流与合作,如何表述或展示研究的成果等等,达到学以致用的目的。     

Causation and causal inference for genetic effects

Over the past three decades, substantial developments have been made on how to infer the causal effect of an exposure on an outcome, using data from observational studies, with the randomized experiment as the golden standard. These developments have reshaped the paradigm of how to build statistical models, how to adjust for confounding, how to assess direct effects, mediated effects and interactions, and even how to analyze data from randomized experiments. The congruence of random transmission of alleles during meiosis and the randomization in controlled experiments/trials, suggests that genetic studies may lend themselves naturally to a causal analysis. In this contribution, we will reflect on this and motivate, through illustrative examples, where insights from the causal inference literature may help to understand and correct for typical biases in genetic effect estimates.     

Learning to recognize objects

Several aspects of systems for learning pattern or object recognition rules are discussed. First, how are recognition rules developed and to what extent is structural pattern information embedded into these recognition rules. Second, how are these rules applied to the recognition of complex patterns such as objects embedded in scenes and how is evidence from different rules combined into a single evidence vector. Third, how can learned rules be improved through performance evaluation and feedback to rule generation stages.     

The role of computation in modeling evolution

Artificial life uses computers and formal systems to model and explore the dynamics of evolution. A fundamental question for A-Life concerns the role of computation in these models, and how we are to interpret computer implementations that do not have actual contact with physical systems. In this paper I will discuss how models are seen to explain and predict in philosophy of science and how these ideas apply to A-Life. I will also explore how the notion of an epistemic cut, as defined by H. Pattee, can be realized in a computational model with an artificial physical world.     

The art of seeing and painting

The human urge to represent the three-dimensional world using two-dimensional pictorial representations dates back at least to Paleolithic times. Artists from ancient to modern times have struggled to understand how a few contours or color patches on a flat surface can induce mental representations of a three-dimensional scene. This article summarizes some of the recent breakthroughs in scientifically understanding how the brain sees that shed light on these struggles. These breakthroughs illustrate how various artists have intuitively understood paradoxical properties about how the brain sees, and have used that understanding to create great art. These paradoxical properties arise from how the brain forms the units of conscious visual perception; namely, representations of three-dimensional boundaries and surfaces. Boundaries and surfaces are computed in parallel cortical processing streams that obey computationally complementary properties. These streams interact at multiple levels to overcome their complementary weaknesses and to transform their complementary properties into consistent percepts. The article describes how properties of complementary consistency have guided the creation of many great works of art.     

Thinking Big or Small: Does Mental Abstraction Affect Social Network Organization?

Four studies examined how mental abstraction affects how people perceive their relationships with other people, specifically, how these relationships may be categorized in social groups. We expected that individuals induced to think abstractly would report fewer more global social groups, compared to those induced to think concretely, who would report more specific groups. However, induced abstract mindset did not affect how people structured their social groups (Study 2–4), despite evidence that the mindset manipulation changed the level of abstraction in their thoughts (Study 3) and evidence that it changed how people structured groups for a control condition (household objects, Study 4). Together, these studies suggest that while the way people organize their relationships into groups is malleable; cognitive abstraction does not seem to affect how people categorize their relationships into social groups.     

Future directions in disturbance research

The major questions identified for future research are: what determines patterns of human disturbance; how can we determine population-level responses to disturbance; are there general rules for predicting how important disturbance will be; how important are disturbance-derived ecological traps; what is the interaction between predation and disturbance; when does habituation occur; how do physiological responses to disturbance affect population size; what is the evidence for changes in access impacting upon populations; what are the positive consequences of access to the countryside; how important is habitat-specific disturbance; which measures reduce human impact and how can large-scale planning minimize the impact of disturbance?     

The role of seasonal timing and phenological shifts for species coexistence

Shifts in the phenologies of coexistence species are altering the temporal structure of natural communities worldwide. However, predicting how these changes affect the structure and long‐term dynamics of natural communities is challenging because phenology and coexistence theory have largely proceeded independently. Here, I propose a conceptual framework that incorporates seasonal timing of species interactions into a well‐studied competition model to examine how changes in phenologies influence long‐term dynamics of natural communities. Using this framework I demonstrate that persistence and coexistence conditions strongly depend on the difference in species’ mean phenologies and how this difference varies across years. Consequently, shifts in mean and interannual variation in relative phenologies of species can fundamentally alter the outcome of interactions and the potential for persistence and coexistence of competing species. These effects can be predicted by how per‐capita effects scale with differences in species’ phenologies. I outline how this approach can be parameterized with empirical systems and discuss how it fits within the context of current coexistence theory. Overall, this synthesis reveals that phenology of species interactions can play a crucial yet currently understudied role in driving coexistence and biodiversity patterns in natural systems and determine how species will respond to future climate change.     

How the spatial scales of dispersal, competition, and environmental heterogeneity interact to affect coexistence

Spatial coexistence depends on a variety of biological and physical processes, and the relative scales of these processes may promote or suppress coexistence. We model plant competition in a spatially varying environment to show how shifting scales of dispersal, competition, and environmental heterogeneity affect coexistence. Spatial coexistence mechanisms are partitioned into three types: the storage effect, nonlinear competitive variance, and growth-density covariance. We first describe how the strength of each of these mechanisms depends on covariances between population densities and between population densities and the environment, and we then explain how changes in the scales of dispersal, competition, and environmental heterogeneity should affect these covariances. Our quantitative approach allows us to show how changes in the scales of biological and physical processes can shift the relative importance of different classes of spatial coexistence mechanisms and gives us a more complete understanding of how environmental heterogeneity can enable coexistence. For example, we show how environmental heterogeneity can promote coexistence even when competing species have identical responses to the environment.     

Spatially balanced sampling and ground‐level imagery for vegetation monitoring on reclaimed well pads

Land reclamation associated with natural gas development has become increasingly important to mitigate land surface disturbance in western North America. Since well pads occur on sites with multiple land use and ownership, the progress and outcomes of these efforts are of interest to multiple stakeholders including industry, practitioners and consultants, regulatory agents, private landowners, and the scientific community. Reclamation success criteria often vary within, and among, government agencies and across land ownership type. Typically, reclamation success of a well pad is judged by comparing vegetation cover from a single transect on the pad to a single transect in an adjacent reference site and data are collected by a large number of technicians with various field monitoring skills. We utilized “SamplePoint” image analysis software and a spatially balanced sampling design, called balanced acceptance sampling, to demonstrate how spatially explicit quantitative data can be used to determine if sites are meeting various reclamation success criteria and used chi‐square tests to show how sites in vegetation percent cover differ from a statistical standpoint. This method collects field data faster than traditional methods. We demonstrate how quantitative and spatially explicit data can be utilized by multiple stakeholders, how it can improve upon current reference site selection, how it can satisfy reclamation monitoring requirements for multiple regulatory agencies, how it may help improve future seed mix selection, and discuss how it may reduce costs for operations responsible for reclamation and how it may reduce observer bias.