Delineating biased ligand efficacy at 7TM receptors from an experimental perspective

During the last 10 years, the concept of “biased agonism” also called “functional selectivity” swamped the pharmacology of 7 transmembrane receptors and paved the way for developing signaling pathway-selective drugs with increased efficacy and less adverse effects. Initially thought to select the activation of only a subset of the signaling pathways by the reference agonist, bias ligands revealed higher complexity as they have been shown to stabilize variable receptor conformations that associate with distinct signaling events from the reference. Today, one major challenge relies on the in vitro determination of the bias and classification of these ligands, as a prerequisite for future in vivo and clinical translation. In this review, current experimental considerations for the bias evaluation related to choice of the cellular model, of the signaling pathway as well as of the assays are presented and discussed.     

Power Day: Addressing the Use and Abuse of Power in Medical Training

Problem: Medical student mistreatment, as well as patient and staff mistreatment by all levels of medical trainees and faculty, is still prevalent in U.S. clinical training. Largely missing in interventions to reduce mistreatment is acknowledgement of the abuse of power produced by the hierarchical structure in which medicine is practiced. Approach: Beginning in 2001, Yale School of Medicine has held annual “Power Day” workshops for third year medical students and advanced practice nursing students, to define and analyse power dynamics within the medical hierarchy and hidden curriculum using literature, guest speakers, and small groups. During rotations, medical students write narratives about the use of power witnessed in the wards. In response to student and small group leader feedback, workshop organizers have developed additional activities related to examining and changing the use of power in clinical teams. Outcome: Emerging narrative themes included the potential impact of small acts and students feeling “mute” and “complicit” in morally distressing situations. Small groups provided safe spaces for advice, support, and professional identity formation. By 2005, students recognized residents that used power positively with Power Day awards and alumni served as keynote speakers on the use of power in medicine. By 2010, departments including OB/GYN, surgery, psychiatry, and paediatrics, had added weekly team Power Hour discussions. Next Steps: The authors highlight barriers, benefits, and lessons learned. Barriers include the notion of clinical irrelevance and resistance to the word “power” due to perceived accusation of abuse. Benefits include promoting open dialogue about power, fostering inter-professional collaboration, rewarding positive role modelling by residents and faculty, and creating a network of trainee empowerment and leadership. Furthermore, faculty have started to ask that issues of power be addressed in a more transparent way at their level of the hierarchy as well.     

Apprehension and Pedagogy in Evolution Education

Instructors’ apprehensions and the decisions instructors make about pedagogy are often linked when it comes to teaching evolution. Whether it is the reticence of K-12 teachers that their instruction may affect their students’ religious beliefs detrimentally or that they may become caught up in some administrative, media, parental, or school political turmoil or whether it is the apprehension of college students who perceive that their religious beliefs are being explicitly challenged, such fears can be reduced by understanding their roots and by honing pedagogy in ways that reduce perceived threats. This article describes why it is prudent to address these often secretly held apprehensions and how to help instructors feel free to employ their best pedagogical methods to teach evolution without lingering fear. Some suggestions are given for pre-college and college instructors interested in combining effective pedagogy with as little perceived threat as possible. Methods are offered that allow instructors to focus on underlying scientific misconceptions even if those misconceptions are ultimately facilitated by non-scientific sources, while giving creationist or creationist-leaning students a chance to learn the appropriate scientific conceptions without their religious beliefs being explicitly threatened in a science course.     

Preaching to the choir or composing new verses? Toward a writerly climate literacy in introductory undergraduate biology

Climate change is one of the most pressing issues facing society today, yet a wide range of misconceptions exist in society about whether or why climate change is happening, what its consequences are, and what can be done to address it. Large introductory biology courses present an opportunity to teach a large number of students—some of whom may never take another course focused on climate, ecology, or the environment—about climate change. However, content knowledge alone may not be enough to prepare students to transform their knowledge into action. To begin understanding how content knowledge interacts with student constructions of climate change solutions, we administered and quantitatively analyzed a survey that examined student views of climate change and how they shifted with instruction during an undergraduate introductory biology course at a large Midwestern university. Almost all participants entered the course agreeing that climate change is occurring, and their certainty about the science of climate change increased after instruction. After taking the course, more participants described climate change as having more immediate impacts, reporting that climate change is already harming people and that climate change will harm them personally. However, both at the beginning and end of the course, participants tended to think that humans would either be unable or unwilling to reduce climate change. They were also more worried about climate change at the end of the course than they were before. Increased concern might result from students becoming more certain of the science and severity of climate change, while remaining pessimistic that humans will effectively act on climate change. This pattern suggests instructors have opportunities to modify curricula in ways that leave students with a greater sense of empowerment and efficacy; we suggest questions that instructors can ask themselves in order to modify their courses with this goal in mind.     

The possible role of “sibling neurite bias” in the coordination of neurite extension,branching, and survival

In this review we consider a novel mechanism, “sibling neurite bias,” which may explain aspects of the coordination of elongation, branching, and resorption among different neurites growing from the same neuronal cell body. In this model, growing neurites which incorporate structural precursors at higher rates would deplete the cellular pool of precursors available to their “sibling” neurites; neurites would compete for survival, but in addition they would bias each other's behavior during active growth. Evidence is reviewed that “sibling neurite bias” may contribute to the establishment and stabilization of specific neural connections. Specific examples examined include the loss of polyinnervation at the developing neuromuscular junction, contextual mapping in the retino-tectal system, and selective neurite growth patterns and synaptic connections in nerve tissue culture model systems.     

A critique of the “ultra‐high risk” and “transition” paradigm

The transdiagnostic expression of psychotic experiences in common mental disorder (anxiety/depression/substance use disorder) is associated with a poorer prognosis, and a small minority of people may indeed develop a clinical picture that meets criteria for schizophrenia. However, it appears neither useful nor valid to observe early states of multidimensional psychopathology in young people through the “schizo”‐prism, and apply misleadingly simple, unnecessary and inefficient binary concepts of “risk” and “transition”. A review of the “ultra‐high risk” (UHR) or “clinical high risk” (CHR) literature indicates that UHR/CHR samples are highly heterogeneous and represent individuals diagnosed with common mental disorder (anxiety/depression/substance use disorder) and a degree of psychotic experiences. Epidemiological research has shown that psychotic experiences are a (possibly non‐causal) marker of the severity of multidimensional psychopathology, driving poor outcome, yet notions of “risk” and “transition” in UHR/CHR research are restrictively defined on the basis of positive psychotic phenomena alone, ignoring how baseline differences in multidimensional psychopathology may differentially impact course and outcome. The concepts of “risk” and “transition” in UHR/CHR research are measured on the same dimensional scale, yet are used to produce artificial diagnostic shifts. In fact, “transition” in UHR/CHR research occurs mainly as a function of variable sample enrichment strategies rather than the UHR/CHR “criteria” themselves. Furthermore, transition rates in UHR/CHR research are inflated as they do not exclude false positives associated with the natural fluctuation of dimensional expression of psychosis. Biological associations with “transition” thus likely represent false positive findings, as was the initial claim of strong effects of omega‐3 polyunsatured fatty acids in UHR samples. A large body of UHR/CHR intervention research has focused on the questionable outcome of “transition”, which shows lack of correlation with functional outcome. It may be more productive to consider the full range of person‐specific psychopathology in all young individuals who seek help for mental health problems, instead of “policing” youngsters for the transdiagnostic dimension of psychosis. Instead of the relatively inefficient medical high‐risk approach, a public health perspective, focusing on improved access to a low‐stigma, high‐hope, small scale and youth‐specific environment with acceptable language and interventions may represent a more useful and efficient strategy.     

Leading Students to Investigate Diffusion as a Model of Brine Shrimp Movement

Integrating experimental biology laboratory exercises with mathematical modeling can be an effective tool to enhance mathematical relevance for biologists and to emphasize biological realism for mathematicians. This paper describes a lab project designed for and tested in an undergraduate biomathematics course. In the lab, students follow and track the paths of individual brine shrimp confined in shallow salt water in a Petri dish. Students investigate the question, “Is the movement well characterized as a 2-dimensional random walk?” Through open, but directed discussions, students derive the corresponding partial differential equation, gain an understanding of the solution behavior, and model brine shrimp dispersal under the experimental conditions developed in class. Students use data they collect to estimate a diffusion coefficient, and perform additional experiments of their own design tracking shrimp migration for model validation. We present our teaching philosophy, lecture notes, instructional and lab procedures, and the results of our class-tested experiments so that others can implement this exercise in their classes. Our own experience has led us to appreciate the pedagogical value of allowing students and faculty to grapple with open-ended questions, imperfect data, and the various issues of modeling biological phenomena.     

Is there a weekend bias in clutch-initiation dates from citizen science? Implications for studies of avian breeding phenology

Accurate phenology data, such as the timing of migration and reproduction, is important for understanding how climate change influences birds. Given contradictory findings among localized studies regarding mismatches in timing of reproduction and peak food supply, broader-scale information is needed to understand how whole species respond to environmental change. Citizen science—participation of the public in genuine research—increases the geographic scale of research. Recent studies, however, showed weekend bias in reported first-arrival dates for migratory songbirds in databases created by citizen-science projects. I investigated whether weekend bias existed for clutch-initiation dates for common species in US citizen-science projects. Participants visited nests on Saturdays more frequently than other days. When participants visited nests during the laying stage, biased timing of visits did not translate into bias in estimated clutch-initiation dates, based on back-dating with the assumption of one egg laid per day. Participants, however, only visited nests during the laying stage for 25 % of attempts of cup-nesting species and 58 % of attempts in nest boxes. In some years, in lieu of visit data, participants provided their own estimates of clutch-initiation dates and were asked “did you visit the nest during the laying period?” Those participants who answered the question provided estimates of clutch-initiation dates with no day-of-week bias, irrespective of their answer. Those who did not answer the question were more likely to estimate clutch initiation on a Saturday. Data from citizen-science projects are useful in phenological studies when temporal biases can be checked and corrected through protocols and/or analytical methods.     

Confronting a “Big Huge Gaping Wound”: Emotion and Anxiety in a Cultural Sensitivity Course for Psychiatry Residents

In his seminal volume From Anxiety to Method in the Behavioral Sciences, George Devereux suggests that any therapeutic or scientific engagement with another human being inevitably will be shaped by one’s own expectations, assumptions, and reactions. If left unacknowledged, such unspoken and unconscious influences have the capacity to torpedo the interaction; if subjected to critical reflection, however, they can yield insights of great interpretive value and practical significance. Taking these reflections on counter-transference as point of departure, this article explores how a range of unacknowledged assumptions can torpedo good faith efforts to engender “cultural sensitivity” in a required course for American psychiatry residents. The course examined in this paper has been taught for seven successive years by a pair of attending psychiatrists at a longstanding New England residency training program. Despite the instructors’ good intentions and ongoing experimentation with content and format, the course has failed repeatedly to meet either residents’ expectations or, as the instructors bravely acknowledged, their own. The paper draws upon a year-long ethnographic study, conducted in the late 2000s during the most recent iteration of the course, which involved observation of course sessions, a series of interviews with course instructors, and pre- and post-course interviews with the majority of participating residents. By examining the dynamics of the course from the perspectives of both clinician-instructors and resident-students, the paper illuminates how classroom-based engagement with the clinical implications of culture and difference can run awry when the emotional potency of these issues is not adequately taken into account.     

Digital gestützte Biodiversitätsexkursionen

Digitally supported excursions focusing on biodiversity The current study was conceived in order to constructively counteract the lack of essential experiences of nature and biodiversity knowledge of students. It combines the three fields “biodiversity”, “education” and “biology instruction“ outside the classroom in a context of environmental education in the Thuringian nature reserve Schiefergebirge/Obere Saale with regard to education as a necessary condition for any planned protection of biodiversity worldwide. The pedagogical proceeding focusing the concept of biodiversity was developed for biology instruction outside the classroom by integrating digital media into the learning process in a constructive way. On the basis of a ten-step procedure, biologically based GPS tours (“biotracks”) were created and tested in practice. For this purpose, two student excursions were designed: the first for grade 7 students in the vicinity of Heberndorf, the second for grade 9 students in the Bleilochstausee region. The results of the knowledge tests and records of the excursion journals from both groups indicate positive effects on studentś biodiversity knowledge. The pre-post questionnaires of the grade 7 students reveal the positive effects of biotracks on studentś attitudes and intentional behavior with respect to biodiversity.     

The construction of Mendel's laws

While “Mendel's Laws” are generally taught as natural facts, they are actually pedagogical constructions, which originated in a series of lectures at Princeton in 1916. What accounts for their popularity?     

Mendelian randomization in health research: Using appropriate genetic variants and avoiding biased estimates

Mendelian randomization methods, which use genetic variants as instrumental variables for exposures of interest to overcome problems of confounding and reverse causality, are becoming widespread for assessing causal relationships in epidemiological studies. The main purpose of this paper is to demonstrate how results can be biased if researchers select genetic variants on the basis of their association with the exposure in their own dataset, as often happens in candidate gene analyses. This can lead to estimates that indicate apparent “causal” relationships, despite there being no true effect of the exposure. In addition, we discuss the potential bias in estimates of magnitudes of effect from Mendelian randomization analyses when the measured exposure is a poor proxy for the true underlying exposure. We illustrate these points with specific reference to tobacco research.     

Giving More to Humans than to Animals in Need? A Behavioral Measure of Animal–Human Continuity in Large-scale Surveys

Survey research on attitudes and behavior toward animals is affected by the hypothetical character of behavioral measurements and socially desirable responses. Drawing on previous research in the fields of environmental behavior and behavioral economics, we combined the advantages of incentivized behavioral experiments and large-scale surveys by asking 2,299 participants in “dictator games” to allocate 10 euros between a charity for poverty reduction and themselves, as well as between a charity for animal protection and themselves (presented in counterbalanced order, with 200 allocations paid to the charities and participants). On average, participants donated approximately 70% of the 10 euros to each charity but donated slightly more money (0.42 euros) for poverty reduction than animal protection. Interestingly, participants allocated the same amount of money to the first charity (whether for humans or animals), but their second allocation depended on the charity and indicated an anthropocentric bias (i.e., higher allocations to poverty reduction than animal protection). Women donated more for animal protection than men, and stronger pro-animal attitudes were associated with higher donations for animal protection. We also found a positive effect of a “social desirability” scale on incentivized donations. In sum, our study finds that participants gave more to humanitarian than animal charities. However, this difference is less than fifty cents and, consequently, minor in magnitude.     

Testing the predictions of sex allocation hypotheses in dimorphic,cooperatively breeding riflemen

Evolutionary theory predicts that parents should invest equally in the two sexes. If one sex is more costly, a production bias is predicted in favour of the other. Two well‐studied causes of differential costs are size dimorphism, in which the larger sex should be more costly, and sex‐biased helping in cooperative breeders, in which the more helpful sex should be less costly because future helping “repays” some of its parents’ investment. We studied a bird species in which both processes should favor production of males. Female riflemen Acanthisitta chloris are larger than males, and we documented greater provisioning effort in more female‐biased broods indicating they are likely costlier to raise. Riflemen are also cooperative breeders, and males provide more help than females. Contrary to expectations, we observed no male bias in brood sex ratios, which did not differ significantly from parity. We tested whether the lack of a population‐wide pattern was a result of facultative sex allocation by individual females, but this hypothesis was not supported either. Our results show an absence of adaptive patterns despite a clear directional hypothesis derived from theory. This appears to be associated with a suboptimal female‐biased investment ratio. We conclude that predictions of adaptive sex allocation may falter because of mechanistic constraint, unrecognized costs and benefits, or weak selection.     

A comment on “Novel scavenger removal trials increase wind turbine-caused avian fatality estimates”

In a recent paper, Smallwood et al. (2010) conducted a study to compare their “novel” approach to conducting carcass removal trials with what they term the “conventional” approach and to evaluate the effects of the different methods on estimated avian fatality at a wind power facility in California. A quick glance at Table 3 that succinctly summarizes their results and provides estimated fatality rates and 80% confidence intervals calculated using the 2 methods reveals a surprising result. The confidence intervals of all of their estimates and most of the conventional estimates extend below 0. These results imply that wind turbines may have the capacity to create live birds. But a more likely interpretation is that a serious error occurred in the calculation of either the average fatality rate or its standard error or both. Further evaluation of their methods reveals that the scientific basis for concluding that “many estimates of scavenger removal rates prior to [their] study were likely biased low due to scavenger swamping” and “previously reported estimates of avian fatality rates … should be adjusted upwards” was not evident in their analysis and results. Their comparison to conventional approaches was not applicable, their statistical models were questionable, and the conclusions they drew were unsupported. © 2013 The Wildlife Society.     

Experiences and lessons learned from two virtual,hands-on microbiome bioinformatics workshops

In October of 2020, in response to the Coronavirus Disease 2019 (COVID-19) pandemic, our team hosted our first fully online workshop teaching the QIIME 2 microbiome bioinformatics platform. We had 75 enrolled participants who joined from at least 25 different countries on 6 continents, and we had 22 instructors on 4 continents. In the 5-day workshop, participants worked hands-on with a cloud-based shared compute cluster that we deployed for this course. The event was well received, and participants provided feedback and suggestions in a postworkshop questionnaire. In January of 2021, we followed this workshop with a second fully online workshop, incorporating lessons from the first. Here, we present details on the technology and protocols that we used to run these workshops, focusing on the first workshop and then introducing changes made for the second workshop. We discuss what worked well, what didn’t work well, and what we plan to do differently in future workshops.     

Biased signaling: A viable strategy to drug ghrelin receptors for the treatment of obesity

Obesity is a global burden and a chronic ailment with damaging overall health effects. Ghrelin, an octanoylated 28 amino acid peptide hormone, is secreted from the oxyntic mucosa of the stomach. Ghrelin acts on regions of the hypothalamus to regulate feeding behavior and glucose homeostasis through its G protein-coupled receptor. Recently, several central pathways modulating the metabolic actions of ghrelin have been reported. While these signaling pathways can be inhibited or activated by antagonists or agonists, they can also be discriminatingly activated in a “biased” response to impart different degrees of activation in distinct pathways downstream of the receptor. Here, we review recent ghrelin biased signaling findings as well as characteristics of ghrelin hormone and its receptors pertinent for biased signaling. We then evaluate the feasibility for ghrelin receptor biased signaling as a strategy for the development of effective pharmacotherapy in obesity treatment.     

“Active” and “passive” ecological restoration strategies in meta‐analysis

One of the means of creating a more robust methodology for ecological restoration involves reducing the gap between ecological theory and restoration practices. A common strategy to do so is using meta‐analysis to understand key drivers of restoration outcomes. “Active” and “passive” is a dichotomy often used to separate restoration strategies in such meta‐analyses. We investigate previously raised concerns about selection bias and subjective categorization of strategies. We promote a paired experimental design in future empirical research and propose the use of three categories of restoration strategy in lieu of “passive” and “active” to alleviate inconsistency in definitions and categorization.     

Plastic,inquisitive roots and intelligent plants in the light of some new vistas in plant biology

Abstract

Metaphors, such as those used in the title of this article, are often useful for the comprehension of specialised topics in plant biology. A brief attempt is made to elucidate one of these metaphors, plant “intelligence”, as it relates to the plastic responses of roots and root systems to their environment. Tropisms and nastic movements of root apices are two expressions of an inherent plasticity of form exhibited by roots. In soil, roots are exposed to multiple stimuli, many of which can potentially elicit such movements. Hence, a key question is how roots respond to and process the different stimuli which simultaneously reach their surfaces. Assuming that roots always use the same site along their length to express their movement responses, and that they also use an auxin‐based information‐transduction pathway, the most evident choices for the processing of stimuli are that roots either prioritise the various incoming stimuli and respond only to the strongest or they amalgamate stimuli and mount an averaged compromise response to all of them. The proposal that plants may be “intelligent”, especially in respect to their plastic growth responses, is one that draws upon knowledge of this faculty from animal biology. Also implied is that plants and animals are sufficiently similar to share usage of this term “intelligence”. But an alternative view is that plants and animals are sufficiently different and so intelligence is an unfitting term. Following the line of enquiry into creative evolution initiated by Henri Bergson, plants can be viewed differently to animals. The tendency of plants is towards instinctive behaviour rather than intelligent behaviour.     

Sustaining the development and implementation of student-centered teaching nationally: the importance of a community of practice

Although the idea of using a workshop to educate potential users about a set of materials or techniques is not new, the workshops described here go beyond simple dissemination and create ongoing communities of practice that support widespread and sustained improvement in the biochemistry classroom. The degree to which pedagogical innovations improve student learning on a national level depends on how broadly they are disseminated and how they are implemented and sustained. Workshops can be effective in disseminating ideas and techniques, but they often fail to sustain implementation. This paper describes Core Collaborators Workshops (CCWs) that were specifically designed for biochemistry faculty to improve the quality of active learning materials, support faculty in transforming their classrooms, and disseminate these efforts nationally. This CCW model proved very effective to date as shown by the fact that, 8 months after the last CCW, all workshop participants reported using at least some of the instructional materials discussed during the workshop. In addition, participants remarked that the superior community building and direct mentoring available through the CCWs greatly increased their confidence in implementing this new curricular approach and has made them more likely to act as leaders themselves.