Biological AFM: where we come from--where we are--where we may go

Biological atomic force microscopy (AFM) is a fast growing and advancing field. This review's objective is to overview the state of the art and to retrace achievements of biological AFM as presented by past and present research, and wishes to give a (subjective) outlook where AFM may go in the upcoming years. The following areas of interest are discussed: High-resolution imaging, cell imaging, single molecule force spectroscopy, cell mechanical measurements, combined AFM instrumentation, and AFM instrumentation. Of all these topics, particular representative examples are shown, each of them standing for a variety of achievements by many research groups.     

Do we age because we have mitochondria?

The process of aging remains a great riddle. Production of reactive oxygen species (ROS) by mitochondria is an inevitable by-product of respiration, which has led to a hypothesis proposing the oxidative impairment of mitochondrial components (e.g., mtDNA, proteins, lipids) that initiates a vicious cycle of dysfunctional respiratory complexes producing more ROS, which again impairs function. This does not exclude other processes acting in parallel or targets for ROS action in other organelles than mitochondria. Given that aging is defined as the process leading to death, the role of mitochondria-based impairments in those organ systems responsible for human death (e.g., the cardiovascular system, cerebral dysfunction, and cancer) is described within the context of “garbage” accumulation and increasing insulin resistance, type 2 diabetes, and glycation of proteins. Mitochondrial mass, fusion, and fission are important factors in coping with impaired function. Both biogenesis of mitochondria and their degradation are important regulatory mechanisms stimulated by physical exercise and contribute to healthy aging. The hypothesis of mitochondria-related aging should be revised to account for the limitations of the degradative capacity of the lysosomal system. The processes involved in mitochondria-based impairments are very similar across a large range of organisms. Therefore, studies on model organisms from yeast, fungi, nematodes, flies to vertebrates, and from cells to organisms also add considerably to the understanding of human aging.     

Melanoma: Where we are and where we go

Melanoma is known as an aggressive tumor which shows an increasing incidence and poor prognosis in the metastatic phase. Hence, it seems that diagnosis and effective management (including early diagnosis, choosing of the effective therapeutic platform, caring, and training of patients for early detection) are major aspects of melanoma therapy. Early detection of melanoma is a key point for melanoma therapy. There are various diagnosis options such as assessing of biopsy, imaging techniques, and biomarkers (i.e., several proteins, polymorphism, and liquid biopsy). Among the various biomarkers, assessing circulating tumor cells, cell-free DNAs, cell-free RNAs, and microRNAs (miRNAs) have emerged as powerful diagnosis tools for melanoma patients. Deregulations of these molecules are associated with melanoma pathogenesis. After detection of melanoma, choosing of effective therapeutic regimen is a key step for recovery of melanoma patients. Several studies indicated that various therapeutic approaches including surgery, immunotherapy, systematic therapy, radiation therapy and antibodies therapy could be used as potential therapeutic candidates for melanoma therapy. Caring for melanoma patients is one of the important components of melanoma therapy. Caring and training for melanoma patients could contribute to better monitoring of patients in response to various therapeutic options. Here, we summarized various diagnosis approaches such as assessing biopsy, imaging techniques, and utilization of various biomarkers (i.e., proteins, CTCs, cfDNAs, and miRNAs) as a diagnostic biomarker for detection and monitoring patients with melanoma. Moreover, we highlighted various therapeutic options and caring aspects in patients with melanoma.     

When we increase diversity in academia,we all win

Increasing diversity in academia is not just a matter of fairness but also improves science. It is up to individual scientists and research organisations to support underrepresented minorities. Subject Categories: S&S: Economics & Business, S&S: Ethics

There has been a large body of research on diversity in the workplace—in both academic and non‐academic settings—that highlights the benefits of an inclusive workplace. This is perhaps most clearly visible in industry where the rewards are immediate: A study by McKinsey showed that companies with a more diverse workforce perform better financially and by substantial margins, compared to their respective national industry medians (https://www.mckinsey.com/business-functions/organization/our-insights/why-diversity-matters#).It is easy to measure success in financial terms, but since there is no similar binary metric for research performance (https://sfdora.org), it is harder to quantify the rewards of workplace diversity in academic research. However, research shows that diversity actually provides research groups with a competitive edge in other quantifiable terms, such as citation counts (Powell, 2018), and the scientific process obviously benefits from diversity in perspectives. Bringing together individuals with different ways of thinking will allow us to solve more challenging scientific problems and lead to better decision‐making and leadership. Conversely, there is a direct cost to bias in recruitment, tenure, and promotion processes. When such processes are affected by bias—whether explicit or implicit—the whole organization is losing by not tapping into the wider range of skills and assets that could otherwise have been brought to the workplace. Promoting diversity in academia is therefore not simply an issue of equity, which in itself is a sufficient reason, but also a very practical question: how do we create a better work environment for our organization, both in terms of collegiality and in terms of performance?Notwithstanding the fact that there is now substantial awareness of the importance of diversity and that significant work is being invested into addressing the issue, the statistics do not look good. Despite a substantial improvement at the undergraduate and graduate student levels in the EU, women remain significantly underrepresented in research at the more senior levels (Directorate‐General for Research and Innovation European Commission, 2019). In addition, the lion’s share of diversity efforts, at least in Sweden where I work, is frequently focused on gender. Gender is clearly important, but other diversity axes with problematic biases deserve the same attention. As one example, while statistics on ethnic diversity is readily available for US Universities (Davis & Fry, 2019), this information is much harder to find in Europe. While there is an increased awareness of diversity at the student level, this does not necessarily translate into initiatives to support faculty diversity (Aragon & Hoskins, 2017). There are examples of progress and concrete actions on these fronts, including the Athena Swan Charter (https://www.ecu.ac.uk/equality-charters/athena-swan/), the more recent Race Equality Charter (https://www.advance-he.ac.uk/charters/race-equality-charter), and the EMBO journals that regularly analyze their decisions for gender bias. However, progress remains frustratingly slow. In 2019, the World Economic Forum suggested that, at the current rate of progress, the global gender gap will take 108 years to close (https://www.weforum.org/reports/the-global-gender-gap-report-2018). I worry that it may take even longer for other diversity axes since these receive far less attention.It is clear that there is a problem, but what can we do to address it? Perhaps one of the single most important contributions we can make as faculty is to address the implicit (subconscious) biases we all carry. Implicit bias will manifest itself in many ways: gender, ethnicity, socioeconomic status, or disability, just to mention a few. These are the easily identifiable ones, but implicit bias also extends to, for example, professional titles (seniority level), institutional affiliation and even nationality. These partialities affect our decision‐making—for example, in recruitment, tenure, promotion, and evaluation committees—and how we interact with each other.The “Matilda effect” (Rossiter, 1993), which refers to the diminishment of the value of contributions made by female researchers, is now well recognized, and it is not unique to gender (Ross, 2014). When we diminish the contributions of our colleagues, it affects how we evaluate them in competitive scenarios, and whether we put them forward for grants, prizes, recruitment, tenure, and so on. In the hypercompetitive environment that is academia today, even small and subtle injuries can tremendously amplify their negative impact on success, given the current reward system that appears to favor “fighters” over “collaborators”. Consciously working to correct for this, stepping back to rethink our first assessment, is imperative.Women and other minorities also frequently suffer from imposter syndrome, which can impact self‐confidence and make members of these groups less likely to self‐promote in the pursuit of prestigious funding, awards, and competitive career opportunities. This effect is further amplified by a globally mobile academic workforce who, when moving to new cultural contexts (whether locally or internationally), can be unaware of the unwritten rules that guide a department’s work environment and decision‐making processes. Here, mentoring can play a tremendous role in reducing barriers to success; however, for such mentorship to be productive, mentors need to be aware of the specific challenges faced by minorities in academia, as well as their own implicit biases (Hinton et al, 2020).Other areas where we, as individual academics, can contribute to a more diverse work environment include meeting cultures and decision‐making. Making sure that the members of decision‐making bodies have diverse composition so that a variety of views are represented is an important first step. One complication to bear in mind though is that implicit biases are not limited to individuals outside the group: A new UN report shows that almost 90% of people—both men and women—carry biases against women, which in turn is what contributes to the glass‐ceiling effect (United Nations Development Program, 2020). However, equally important is inclusiveness in the meeting culture. Studies from the business world show that even high‐powered women often struggle to speak up and be heard at meetings, and the onus for solving this is often passed back onto themselves. The same holds true for other minority groups, and in an academic setting, it extends to seminars and conferences. The next time you plan a meeting, think about the setting and layout. Who gets to talk? Why? Is the distribution of time given to participants representative of the composition of the meeting participants? If not, why not?As a final example of personal action, we can take: language matters (Ås, 1978). Even without malicious intent, there can be a big gap between what we say and mean, and how it comes across to the recipient. Some examples of this are given by Harrison and Tanner (Harrison & Tanner, 2018), who discuss microagressions in an academic setting and the underlying message one might be unintentionally sending. Microaggressions, when built up over a long period of time, and coming from different people, can significantly impact someone’s confidence and sense of self‐worth. Taking a step back and thinking about why we choose the language, we do is a vital part of creating an inclusive work environment.Addressing diversity challenges in academia is a highly complex multi‐faceted topic that is impossible to do justice in a short opinion piece. This is, therefore, just a small set of examples: By paying attention to our own biases and thinking carefully about how we interact with those around us, both in terms of the language we use and the working environments we create, we can personally contribute to improving both recruitment and retention of a diverse academic workforce. In addition, it is crucial to break the culture of silence and to speak up when we see others committing micro‐ or not so microaggressions or otherwise contributing to a hostile environment. There is a substantial amount of work that needs to be done, at both the individual and organization levels, before we have a truly inclusive academic environment. However, this is not a reason to not do it, and if each of us contributes, we can accelerate this change to a better and more equitable future, while all winning from the benefits of diversity.     

What we talk about when we talk about access deficits

Semantic impairments have been divided into storage deficits, in which the semantic representations themselves are damaged, and access deficits, in which the representations are intact but access to them is impaired. The behavioural phenomena that have been associated with access deficits include sensitivity to cueing, sensitivity to presentation rate, performance inconsistency, negative serial position effects, sensitivity to number and strength of competitors, semantic blocking effects, disordered selection between strong and weak competitors, correlation between semantic deficits and executive function deficits and reduced word frequency effects. Four general accounts have been proposed for different subsets of these phenomena: abnormal refractoriness, too much activation, impaired competitive selection and deficits of semantic control. A combination of abnormal refractoriness and impaired competitive selection can account for most of the behavioural phenomena, but there remain several open questions. In particular, it remains unclear whether access deficits represent a single syndrome, a syndrome with multiple subtypes or a variable collection of phenomena, whether the underlying deficit is domain-general or domain-specific, whether it is owing to disorders of inhibition, activation or selection, and the nature of the connection (if any) between access phenomena in aphasia and in neurologically intact controls. Computational models offer a promising approach to answering these questions.     

What we talk about when we talk with medical students

In this article, we review how we interact with medical students in our efforts to teach blood pressure regulation and systemic cardiovascular control along with related elements of respiratory and exercise physiology. Rather than provide a detailed lecture with key facts, we attempted to outline our approach to teaching integrative cardiovascular physiology to medical students, which includes five major themes. First, focus on questions versus answers and facts. We believe that this offers both the learner and teacher a number of advantages. Second, avoid teaching dogma in the name of clarity (i.e., heavy focus on teaching "facts" that have not yet been fully investigated). This is especially important because of the way knowledge evolves over time. Third, include laboratory-based experiences in human integrative physiology. Fourth, provide students with intellectual frameworks versus a list of "facts" to serve as a platform for question generation. Finally, focus on the role of integration and regulatory redundancy in physiology and the idea that physiology is a narrative that can help. In this article, we discuss the philosophy behind the themes outlined above and argue that questions, and not answers, are where the action is for both research and education.     

Neuroscience: what we cannot model, we do not understand

To understand computations in neuronal circuits, a model of a small patch of cortex has been developed that can describe the firing regime in the visual system remarkably well.     

What we can and what we cannot see with extracellular multielectrodes

Extracellular recording is an accessible technique used in animals and humans to study the brain physiology and pathology. As the number of recording channels and their density grows it is natural to ask how much improvement the additional channels bring in and how we can optimally use the new capabilities for monitoring the brain. Here we show that for any given distribution of electrodes we can establish exactly what information about current sources in the brain can be recovered and what information is strictly unobservable. We demonstrate this in the general setting of previously proposed kernel Current Source Density method and illustrate it with simplified examples as well as using evoked potentials from the barrel cortex obtained with a Neuropixels probe and with compatible model data. We show that with conceptual separation of the estimation space from experimental setup one can recover sources not accessible to standard methods.     

Anticipation in lynch syndrome: where we are where we go

Lynch syndrome (LS) is the most common form of inherited predisposition to develop cancer mainly in the colon and endometrium but also in other organ sites. Germline mutations in DNA mismatch repair (MMR) gene cause the transmission of the syndrome in an autosomal dominant manner. The management of LS patients is complicated by the large variation in age at cancer diagnosis which requires these patients to be enrolled in surveillance protocol starting as early as in their second decade of life. Several environmental and genetic factors have been proposed to explain this phenotypic heterogeneity, but the molecular mechanisms remain unknown. Although the presence of genetic anticipation in Lynch syndrome has been suspected since 15 years, only recently the phenomenon has been increasingly reported to be present in different cancer genetic syndromes including LS. While the biological basis of earlier cancer onset in successive generations remains poorly known, recent findings point to telomere dynamics as a mechanism significantly contributing to genetic anticipation in Lynch syndrome and in other familial cancers. In this review, we summarize the clinical and molecular features of Lynch syndrome, with a particular focus on the latest studies that have investigated the molecular mechanisms of genetic anticipation.     

The origin of life: what we know,what we can know and what we will never know

The origin of life (OOL) problem remains one of the more challenging scientific questions of all time. In this essay, we propose that following recent experimental and theoretical advances in systems chemistry, the underlying principle governing the emergence of life on the Earth can in its broadest sense be specified, and may be stated as follows: all stable (persistent) replicating systems will tend to evolve over time towards systems of greater stability. The stability kind referred to, however, is dynamic kinetic stability, and quite distinct from the traditional thermodynamic stability which conventionally dominates physical and chemical thinking. Significantly, that stability kind is generally found to be enhanced by increasing complexification, since added features in the replicating system that improve replication efficiency will be reproduced, thereby offering an explanation for the emergence of life''s extraordinary complexity. On the basis of that simple principle, a fundamental reassessment of the underlying chemistry–biology relationship is possible, one with broad ramifications. In the context of the OOL question, this novel perspective can assist in clarifying central ahistoric aspects of abiogenesis, as opposed to the many historic aspects that have probably been forever lost in the mists of time.