The hop downy mildew pathogen Pseudoperonospora humuli

Pseudoperonospora humuli is an obligate biotrophic oomycete that causes downy mildew, one of the most devastating diseases of cultivated hop, Humulus lupulus. Downy mildew occurs in all production areas of the crop in the Northern Hemisphere and Argentina. The pathogen overwinters in hop crowns and roots, and causes considerable crop loss. Downy mildew is managed by sanitation practices, planting of resistant cultivars, and fungicide applications. However, the scarcity of sources of host resistance and fungicide resistance in pathogen populations complicates disease management. This review summarizes the current knowledge on the symptoms of the disease, life cycle, virulence factors, and management of hop downy mildew, including various forecasting systems available in the world. Additionally, recent developments in genomics and effector discovery, and the future prospects of using such resources in successful disease management are also discussed.TaxonomyClass: Oomycota; Order: Peronosporales; Family: Peronosporaceae; Genus: Pseudoperonospora; Species: Pseudoperonospora humuli.Disease symptomsThe disease is characterized by systemically infected chlorotic shoots called “spikes". Leaf symptoms and signs include angular chlorotic lesions and profuse sporulation on the abaxial side of the leaf. Under severe disease pressure, dark brown discolouration or lesions are observed on cones. Infected crowns have brown to black streaks when cut open. Cultivars highly susceptible to crown rot may die at this phase of the disease cycle without producing shoots. However, foliar symptoms may not be present on plants with systemically infected root systems.Infection processPathogen mycelium overwinters in buds and crowns, and emerges on infected shoots in spring. Profuse sporulation occurs on infected tissues and sporangia are released and dispersed by air currents. Under favourable conditions, sporangia germinate and produce biflagellate zoospores that infect healthy tissue, thus perpetuating the infection cycle. Though oospores are produced in infected tissues, their role in the infection cycle is not defined.ControlDowny mildew on hop is managed by a combination of sanitation practices and timely fungicide applications. Forecasting systems are used to time fungicide applications for successful management of the disease.Useful Websites https://content.ces.ncsu.edu/hop‐downy‐mildew (North Carolina State University disease factsheet), https://www.canr.msu.edu/resources/michigan‐hop‐management‐guide (Michigan Hop Management Guide), http://uspest.org/risk/models (Oregon State University Integrated Plant Protection Center degree‐day model for hop downy mildew), https://www.usahops.org/cabinet/data/Field‐Guide.pdf (Field Guide for Integrated Pest Management in Hops).     

Reply to Bronstein and Vinogradov

The response by the author. Subject Categories: S&S: Economics & Business, S&S: Ethics

I thank Michael Bronstein and Sophia Vinogradov for their interest and comments. I would like to respond to a few of their points.First, I agree with the authors that empirical studies should be conducted to validate any approaches to prevent the spread of misinformation before their implementation. Nonetheless, I think that the ideas I have proposed may be worth further discussion and inspire empirical studies to test their effectiveness.Second, the authors warn that informing about the imperfections of scientific research may undermine trust in science and scientists, which could result in higher vulnerability to online health misinformation (Roozenbeek et al, 2020; Bronstein & Vinogradov, 2021). I believe that transparency about limitations and problems in research does not necessarily have to diminish trust in science and scientists. On the contrary, as Veit et al put it, “such honesty… is a prerequisite for maintaining a trusting relationship between medical institutions (and practitioners) and the public” (Veit et al, 2021). Importantly, to give an honest picture of scientific research, information about its limitations should be put in adequate context. In particular, the public also should be aware that “good science” is being done by many researchers; we do have solid evidence of effectiveness of many medical interventions; and efforts are being taken to address the problems related to quality of research.Third, Bronstein and Vinogradov suggest that false and dangerous information should be censored. I agree with the authors that “[c]ensorship can prevent individuals from being exposed to false and potentially dangerous ideas” (Bronstein & Vinogradov, 2021). I also recognize that some information is false beyond any doubt and its spread may be harmful. What I am concerned about are, among others, the challenges related to defining what is dangerous and false information and limiting censorship only to this kind of information. For example, on what sources should decisions to censor be based and who should make such decisions? Anyone, whether an individual or an organization, with a responsibility to censor information will likely not only be prone to mistakes, but also to abuses of power to foster their interests. Do the benefits we want to achieve by censorship outweigh the potential risks?Fourth, we need rigorous empirical studies examining the actual impact of medical misinformation. What exactly are the harms we try to protect against and what is their scale? This information is necessary to choose proportionte and effective measures to reduce the harms. Bronstein and Vinogradov give an example of a harm which may be caused by misinformation—an increase in methanol poisoning in Iran. Yet, as noticed by the authors, misinformation is not the sole factor in this case; there are also cultural and other contexts (Arasteh et al, 2020; Bronstein & Vinogradov, 2021). Importantly, the methods of studies exploring the effects of misinformation should be carefully elaborated, especially when study participants are asked to self‐report. A recent study suggests that some claims about the prevalence of dangerous behaviors, such as drinking bleach, which may have been caused by misinformation are largely exaggerated due to the presence of problematic respondents in surveys (preprint: Litman et al, 2021).Last but not least, I would like to call attention to the importance of how veracity of information is determined in empirical studies on misinformation. For example, in a study of Roozenbeek et al, cited by Bronstein and Vinogradov, the World Health Organization (WHO) was used as reliable source of information, which raises questions. For instance, Roozenbeek et al (2020) used a statement “the coronavirus was bioengineered in a military lab in Wuhan” as an example of false information, relying on the judgment of the WHO found on its “mythbusters” website (Roozenbeek et al, 2020). Yet, is there a solid evidence to claim that this statement is false? At present, at least some scientists declare that we cannot rule out that the virus was genetically manipulated in a laboratory (Relman, 2020; Segreto & Deigin, 2020). Interestingly, the WHO also no longer excludes such a possibility and has launched an investigation on this issue (https://www.who.int/health‐topics/coronavirus/origins‐of‐the‐virus, https://www.who.int/emergencies/diseases/novel‐coronavirus‐2019/media‐resources/science‐in‐5/episode‐21‐‐‐covid‐19‐‐‐origins‐of‐the‐sars‐cov‐2‐virus); the information about the laboratory origin of the virus being false is no longer present on the WHO “mythbusters” website (https://www.who.int/emergencies/diseases/novel‐coronavirus‐2019/advice‐for‐public/myth‐busters). Against this backdrop, some results of the study by Roozenbeek et al (2020) seem misleading. In particular, the perception of the reliability of the statement about bioengineered virus by study participants in Roozenbeek et al (2020) does not reflect the susceptibility to misinformation, as intended by the researchers, but rather how the respondents perceive reliability of uncertain information.I hope that discussion and research on these and related issues will continue.     

The Data Governance Act and the EU's move towards facilitating data sharing

The implementation of the EU General Data Protection Regulation (GDPR) has had significant impacts on biomedical research, often complicating data sharing among researchers. The recently announced proposal for a new EU Data Governance Act is a promising step towards facilitating data sharing, if it can interplay well with the GDPR.Subject Categories: S&S: Ethics

The EU General Data Protection Regulation (GDPR) has affected biomedical research, often complicating data sharing. The recently announced proposal for a new EU Data Governance Act, is a promising step towards facilitating data sharing.

In an attempt to improve and increase data sharing in the EU and to optimize the re‐use of personal and non‐personal data, the European Commission has recently announced the proposal for a new EU Data Governance Act (https://ec.europa.eu/digital‐single‐market/en/news/proposal‐regulation‐european‐data‐governance‐data‐governance‐act). If approved, it will enable the creation and regulation of “secure spaces” where various types of data, including health data, can be shared and re‐used for both commercial and altruistic purposes, including scientific research. The Data Governance Act, within the framework of a European Strategy for Data, (https://ec.europa.eu/info/sites/info/files/communication‐european‐strategy‐dat‐19feb2020_en.pdf), would address some of the shortcomings and drawbacks of the current regulatory framework which holds back sharing and re‐using data for biomedical research purposes.While the proposed Act would apply to all types of personal and non‐personal data, the increasing demand for sharing health data has most likely been a major rationale for this new legislation of data governance. Notably, sharing health and genetic data for scientific research entails an extra layer of complexity, owing to concerns over data protection and privacy when sharing sensitive personal data. Vice versa, there are also concerns in the scientific community over the negative impact of regulatory restrictions on sharing health data in data‐driven biomedical research. The pressing question here is how far the EU’s proposed legislative and policy framework can offset either concerns?     

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.     

Comparative Analysis of Pdf-Mediated Circadian Behaviors Between Drosophila melanogaster and D. virilis

PAR proteins (partitioning defective) are major regulators of cell polarity and asymmetric cell division. One of the par genes, par-1, encodes a Ser/Thr kinase that is conserved from yeast to mammals. In Caenorhabditis elegans, par-1 governs asymmetric cell division by ensuring the polar distribution of cell fate determinants. However the precise mechanisms by which PAR-1 regulates asymmetric cell division in C. elegans remain to be elucidated. We performed a genomewide RNAi screen and identified six genes that specifically suppress the embryonic lethal phenotype associated with mutations in par-1. One of these suppressors is mpk-1, the C. elegans homolog of the conserved mitogen activated protein (MAP) kinase ERK. Loss of function of mpk-1 restored embryonic viability, asynchronous cell divisions, the asymmetric distribution of cell fate specification markers, and the distribution of PAR-1 protein in par-1 mutant embryos, indicating that this genetic interaction is functionally relevant for embryonic development. Furthermore, disrupting the function of other components of the MAPK signaling pathway resulted in suppression of par-1 embryonic lethality. Our data therefore indicates that MAP kinase signaling antagonizes PAR-1 signaling during early C. elegans embryonic polarization.ASYMMETRIC cell division, a process in which a mother cell divides in two different daughter cells, is a fundamental mechanism to achieve cell diversity during development. We use the early embryo of Caenorhabditis elegans as a model system to study asymmetric cell division. The C. elegans one-cell embryo divides asymmetrically along its anteroposterior axis, generating two cells of different sizes and fates: the larger anterior daughter cell will generate somatic tissues while the smaller posterior daughter cell will generate the germline (Sulston et al. 1983).A group of proteins called PAR proteins (partitioning defective) is required for asymmetric cell division in C. elegans (Kemphues et al. 1988). Depletion of any of the seven par genes (par-1 to -6 and pkc-3) leads to defects in asymmetric cell division and embryonic lethality (Kemphues et al. 1988; Kirby et al. 1990; Tabuse et al. 1998; Hung and Kemphues 1999; Hao et al. 2006). PAR-3 and PAR-6 are conserved proteins that contain PDZ-domains and form a complex with PKC-3 (Etemad-Moghadam et al. 1995; Izumi et al. 1998; Tabuse et al. 1998; Hung and Kemphues 1999). This complex becomes restricted to the anterior cortex of the embryo in response to spatially defined actomyosin contractions occurring in the embryo upon fertilization (Goldstein and Hird 1996; Munro et al. 2004). The posterior cortex of the embryo that becomes devoid of the anterior PAR proteins is occupied by the RING protein PAR-2 and the Ser/Thr kinase PAR-1 (Guo and Kemphues 1995; Boyd et al. 1996; Cuenca et al. 2003). Once polarized, the anterior and posterior PAR proteins mutually exclude each other from their respective cortices (Etemad-Moghadam et al. 1995; Boyd et al. 1996; Cuenca et al. 2003; Hao et al. 2006). Loss of function of the gene par-1, as opposed to loss of most other par genes, results in embryos that exhibit only subtle effects on the polarized cortical domains occupied by the other PAR proteins (Cuenca et al. 2003). However defects in this gene are associated with a more symmetric division in size, an aberrant distribution of cell fate specification markers, altered cell fates of the daughter cells of the embryo, and ultimately embryonic lethality (Kemphues et al. 1988; Guo and Kemphues 1995).PAR-1 controls asymmetric cell division and cell fate specification by regulating the localization of the two highly similar CCCH-type zinc-finger proteins MEX-5 and MEX-6 (referred to as MEX-5/6). MEX-5 and MEX-6 are 70% identical in their amino acid sequence and fulfill partially redundant functions in the embryo (Schubert et al. 2000). In wild-type animals, endogenous MEX-5 and GFP fusions of MEX-6 localize primarily to the anterior of the embryo while both proteins are evenly distributed in par-1 mutant embryos (Schubert et al. 2000; Cuenca et al. 2003). This suggests that in wild-type animals, PAR-1 acts in part by restricting MEX-5 and MEX-6 to the anterior of the embryo. The precise mechanism of this regulation is not known, but an elegant study performed for MEX-5 indicates that differential protein mobility in the anterior and posterior cytoplasm of the one-cell embryo contributes to this asymmetry (Tenlen et al. 2008). While increased mobility in the posterior of the one-cell embryo correlates with a par-1- and par-4-dependent phosphorylation on MEX-5, the kinase directly phosphorylating MEX-5 remains to be identified (Tenlen et al. 2008).Some of the phenotypes associated with loss of par-1 function are dependent on the function of mex-5 and mex-6. First, loss of function of par-1 leads to a decreased stability and aberrant localization of the posterior cell fate specification marker PIE-1, a protein that is usually inherited by the posterior daughter cell in wild-type animals and ensures the correct specification of the germline (Mello et al. 1996; Seydoux et al. 1996). This decreased stability is dependent on mex-5/6 function as PIE-1 levels are restored, albeit with symmetrical distribution, in mex-6(RNAi); mex-5(RNAi); par-1(b274) embryos (Schubert et al. 2000; Cuenca et al. 2003; Derenzo et al. 2003). Second, embryos lacking par-1 function exhibit decreased amounts of P granules in the one-cell embryo, while these markers are present in mex-6(pk440); mex-5(zu199); par-1(RNAi) embryos of comparable age (Cheeks et al. 2004). Third, in par-1(RNAi) one-cell embryos the posterior cortical domain occupied by the polarity protein PAR-2 is extended anteriorly, when compared to wild-type embryos (Cuenca et al. 2003). This anterior extension is rescued in embryos deficient for both par-1 and mex-5/6 (Cuenca et al. 2003). Taken together, these results indicate that par-1 acts in the embryo—at least in part—by regulating the localization and/or activity of the proteins MEX-5 and MEX-6. However, it remains unclear whether other proteins can modulate PAR-1 function to affect MEX-5/6 activity.To gain insight into the mechanisms of par-1 function in the embryo, we sought to identify genes that act together with par-1 during embryonic development. We performed an RNAi-based screen for genetic interactors of the temperature-sensitive allele par-1(zu310), using the embryonic lethal phenotype of this mutant as a readout. This method has proven successful in previous screens to identify genes involved in early embryonic processes (Labbé et al. 2006; O''Rourke et al. 2007). We were able to identify six genes that, upon disruption of their function, suppress the embryonic lethal phenotype of par-1 mutant embryos. One of these genes is mpk-1, the C. elegans homolog of the highly conserved MAP kinase ERK. Closer analysis subsequently showed that reduction of function of mpk-1 not only increases viability of par-1 mutant embryos, but also reverts several polarity phenotypes associated with loss of function of par-1. Our data indicate that mpk-1 antagonizes par-1 activity to regulate polarization and asymmetric cell divisions in the early embryo.     

Soybean anthracnose caused by Colletotrichum species: Current status and future prospects

Soybean (Glycine max) is one of the most important cultivated plants worldwide as a source of protein‐rich foods and animal feeds. Anthracnose, caused by different lineages of the hemibiotrophic fungus Colletotrichum, is one of the main limiting factors to soybean production. Losses due to anthracnose have been neglected, but their impact may threaten up to 50% of the grain production.TaxonomyWhile C. truncatum is considered the main species associated with soybean anthracnose, recently other species have been reported as pathogenic on this host. Until now, it has not been clear whether the association of new Colletotrichum species with the disease is related to emerging species or whether it is due to the undergoing changes in the taxonomy of the genus.Disease symptomsTypical anthracnose symptoms are pre‐ and postemergence damping‐off; dark, depressed, and irregular spots on cotyledons, stems, petioles, and pods; and necrotic laminar veins on leaves that can result in premature defoliation. Symptoms may evolve to pod rot, immature opening of pods, and premature germination of grains.ChallengesAs accurate species identification of the causal agent is decisive for disease control and prevention, in this work we review the taxonomic designation of Colletotrichum isolated from soybean to understand which lineages are pathogenic on this host. We also present a comprehensive literature review of soybean anthracnose, focusing on distribution, symptomatology, epidemiology, disease management, identification, and diagnosis. We consider the knowledge emerging from population studies and comparative genomics of Colletotrichum spp. associated with soybean providing future perspectives in the identification of molecular factors involved in the pathogenicity process.Useful websiteUpdates on Colletotrichum can be found at http://www.colletotrichum.org/.All available Colletotrichum genomes on GenBank can be viewed at http://www.colletotrichum.org/genomics/.     

Open Labware: 3-D Printing Your Own Lab Equipment

The introduction of affordable, consumer-oriented 3-D printers is a milestone in the current “maker movement,” which has been heralded as the next industrial revolution. Combined with free and open sharing of detailed design blueprints and accessible development tools, rapid prototypes of complex products can now be assembled in one’s own garage—a game-changer reminiscent of the early days of personal computing. At the same time, 3-D printing has also allowed the scientific and engineering community to build the “little things” that help a lab get up and running much faster and easier than ever before.Applications of 3-D printing technologies (Fig. 1A, Box 1) have become as diverse as the types of materials that can be used for printing. Replacement parts at the International Space Station may be printed in orbit from durable plastics or metals, while back on Earth the food industry is starting to explore the same basic technology to fold strings of chocolate into custom-shaped confectionary. Also, consumer-oriented laser-cutting technology makes it very easy to cut raw materials such as sheets of plywood, acrylic, or aluminum into complex shapes within seconds. The range of possibilities comes to light when those mechanical parts are combined with off-the-shelf electronics, low-cost microcontrollers like Arduino boards [1], and single-board computers such as a Beagleboard [2] or a Raspberry Pi [3]. After an initial investment of typically less than a thousand dollars (e.g., to set-up a 3-D printer), the only other materials needed to build virtually anything include a few hundred grams of plastic (approximately US$30/kg), cables, and basic electronic components [4,5].Open in a separate windowFig 1Examples of open 3-D printed laboratory tools. A ₁, Components for laboratory tools, such as the base for a micromanipulator [18] shown here, can be rapidly prototyped using 3-D printing. A _2, The printed parts can be easily combined with an off-the-shelf continuous rotation servo-motor (bottom) to motorize the main axis. B ₁, A 3-D printable micropipette [8], designed in OpenSCAD [19], shown in full (left) and cross-section (right). B ₂, The pipette consists of the printed parts (blue), two biro fillings with the spring, an off-the-shelf piece of tubing to fit the tip, and one screw used as a spacer. B ₃, Assembly is complete with a laboratory glove or balloon spanned between the two main printed parts and sealed with tape to create an airtight bottom chamber continuous with the pipette tip. Accuracy is ±2–10 μl depending on printer precision, and total capacity of the system is easily adjusted using two variables listed in the source code, or accessed via the “Customizer” plugin on the thingiverse link [8]. See also the first table.

Box 1. Glossary

Open source

A collective license that defines terms of free availability and redistribution of published source material. Terms include free and unrestricted distribution, as well as full access to source code/blueprints/circuit board designs and derived works. For details, see http://opensource.org.

Maker movement

Technology-oriented extension of the traditional “Do-it-Yourself (DIY)” movement, typically denoting specific pursuits in electronics, CNC (computer numerical control) tools such as mills and laser cutters, as well as 3-D printing and related technologies.

3-D printing

Technology to generate three-dimensional objects from raw materials based on computer models. Most consumer-oriented 3-D printers print in plastic by locally melting a strand of raw material at the tip (“hot-end”) and “drawing” a 3-D object in layers. Plastic materials include Acrylnitrile butadiene styrene (ABS) and Polylactic acid (PLA). Many variations of 3-D printers exist, including those based on laser-polymerization or fusion of resins or powdered raw materials (e.g., metal or ceramic printers).

Arduino boards

Inexpensive and consumer-oriented microcontroller boards built around simple processors. These boards offer a variety of interfaces (serial ports, I2C and CAN bus, etc.), μs-timers, and multiple general-purpose input-output (GPIO) pins suitable for running simple, time-precise programs to control custom-built electronics.

Single board computers

Inexpensive single-board computers capable of running a mature operating system with graphical-user interface, such as Linux. Like microcontroller boards, they offer a variety of hardware interfaces and GPIO pins to control custom-built electronics.It therefore comes as no surprise that these technologies are also routinely used by research scientists and, especially, educators aiming to customize existing lab equipment or even build sophisticated lab equipment from scratch for a mere fraction of what commercial alternatives cost [6]. Designs for such “Open Labware” include simple mechanical adaptors [7], micropipettes (Fig. 1B) [8], and an egg-whisk–based centrifuge [9] as well as more sophisticated equipment such as an extracellular amplifier for neurophysiological experiments [10], a thermocycler for PCR [11], or a two-photon microscope [12]. At the same time, conceptually related approaches are also being pursued in chemistry [13–15] and material sciences [16,17]. See also

Membrane protein biogenesis by the EMC

Recent cryo‐EM‐based models reveal how the ER membrane protein complex may accomplish insertion of protein transmembrane domains with limited hydrophobicity.

Insertion of strongly hydrophobic TMDs into the ER membrane is mediated by the Sec61 complex for co‐translational insertion and the GET complex for post‐translational insertion of tail‐anchors (Volkmar & Christianson, 2020). By contrast, the EMC inserts TMDs of limited hydrophobicity, frequently located at the N‐ or C‐termini of proteins, and is involved in biogenesis of multi‐spanning membrane proteins (Volkmar & Christianson, 2020).The EMC is highly conserved (Wideman, 2015). In vertebrates, ten subunits have been identified (EMC1‐10), two of which, EMC8 and EMC9, are homologous and the result of a vertebrate‐specific gene duplication (Wideman, 2015). In Saccharomyces cerevisiae, EMC8 has been lost (Wideman, 2015). Only EMC3 displays clear homology to other membrane protein insertases, the Oxa1 family (Wideman, 2015; Volkmar & Christianson, 2020). This family includes YidC, which inserts TMDs into the bacterial cytoplasmic membrane, usually in cooperation with the Sec61‐homologous SecYEG channel (Volkmar & Christianson, 2020). Their association, along with the SecDF ancillary complex, forms a holo‐translocon capable of protein secretion and TMD insertion, with striking similarities to the EMC complex (Martin et al, 2019).Recent work by Pleiner et al (2020) presented a 3.4 Å cryo‐EM structure of the human EMC purified via a GFP‐tag on EMC2 and incorporated into a phospholipid nanodisc. The complex is formed by nine proteins (EMC1‐8, EMC10) (Pleiner et al, 2020). EMC8 and EMC9 are structurally similar, and their association with EMC2 is mutually exclusive (O''Donnell et al, 2020). Of the 12 TMDs, nine constitute the pseudosymmetric central ordered core, with a basket‐shaped cytosolic vestibule formed primarily by alpha‐helices of the EMC3 and EMC6 TMDs and cytosolic EMC2 (Fig 1A; Pleiner et al, 2020). The L‐shaped lumenal domain of the EMC consists mostly of beta‐sheets (Fig 1A; Pleiner et al, 2020), flanked by a conspicuous and conserved amphipathic alpha‐helix of EMC1 sealing the vestibule at the interface between the membrane and the ER lumen, together with another smaller amphipathic helix contributed by EMC3 (Fig 1A; Pleiner et al, 2020). In the ER lumen, the two 8‐bladed propellers of EMC1 contact six of the eight other subunits and stabilize the entire complex (Fig 1A; Pleiner et al, 2020). Beta‐sandwiches of EMC7 and EMC10 are anchored to the EMC1 lumenal domain (Fig 1A; Pleiner et al, 2020). In the cytosol, the tetratricopeptide repeat (TPR) spiral of EMC2 forms a cup underneath the partially hydrophilic vestibule in the membrane between the TMDs of EMC3 and EMC6, bridging the cytosolic ends of TMDs of EMC1, 3 and 5 (Fig 1A; Pleiner et al, 2020). Cytosolic EMC8 is bound to the opposite face of EMC2 (Fig 1A).Open in a separate windowFigure 1Comparison of the structures of human and yeast EMC(A) Cryo‐EM 3D map of the human (emdb‐21929) and yeast (emdb‐21587) EMC, showing front and back views with individual subunits coloured. Membrane position, obtained from the OPM database, is shown by grey discs. (B) Close‐up view of the EMC cavity formed by EMC3 and EMC6. Left, shown in a hydrophobicity surface pattern. Right, surface representation overlapped with the TMDs of EMC3 and EMC6. EMC4, flexible and with a gate function at the substrate‐binding place, is shown in pink in the yeast representation. EMC4 is not visible at the atomic EMC human structure, although is observed as a weak density at the human model, accompanied by TMs of EMC7 and EMC10 (Pleiner et al, 2020). (C) The yeast EMC following > 5 µs of CG‐MD simulation. The protein is shown as surface and coloured as per Pleiner et al (2020). The computed densities of waters and phospholipid tails and phosphates are shown as blue, yellow and lime green densities, sliced to bisect the cavity for clarity. Right, inset of the EMC cavity. Methods: CG‐MD simulations were built using PDB 6WB9 in a solvated symmetric POPC/POPE/cholesterol membrane and run in the Martini forcefield as described in Martin et al (2019). 3 µs unrestrained simulations were run, followed by 2.5 µs backbone restrained simulation for density calculation, done using VolMap in VMD (Humphrey et al, 1996).The 3.0 Å cryo‐EM structure of the yeast EMC presented by Bai and colleagues shows a very similar overall organization (Bai et al, 2020). Here, purification was via a 3xFLAG‐tag on EMC5, and the structure of the 8‐subunit complex (without EMC8/9) was visualized in detergent solution (Bai et al, 2020). The yeast complex has twelve TMDs like the human EMC, but unlike the human structure, EMC4 in yeast has three TMDs that are clearly visible (Bai et al, 2020). They are angled in the membrane pointing away from the complex at the cytosolic end (Fig 1A), and Bai et al (2020) propose that TMDs of EMC4, EMC3 and EMC6 form a substrate‐binding pocket similar to that of YidC. As in the human EMC, there are two amphipathic helices (EMC1 and EMC3) at the membrane/lumen interface (Fig 1A; Bai et al, 2020). In the ER lumen, yeast EMC1 only has one 8‐bladed beta‐propeller, to which the beta‐sandwiches of EMC7 and EMC10 are anchored (Fig 1A; Bai et al, 2020). In the cytosol, EMC2 bridges EMC3, 4 and 5, and its TPR repeats form a cup underneath the vestibule similar to human EMC2 (Fig 1A; Bai et al, 2020).The authors propose that insertion of a partially hydrophilic TMD by the yeast EMC is mechanistically similar to insertion by bacterial YidC (Bai et al, 2020). Yeast EMC is proposed to bind substrate between TMD2 of EMC3 and TMD2 of EMC4 in a pocket with polar and positively charged amino acids at either end and hydrophobic amino acids in the centre (Fig 1B; Bai et al, 2020). Much has been made of a conserved positive region within the EMC complex here, present in an equivalent position also in YidC (Kumazaki et al, 2014): It is claimed to be important for the incorporation of more‐hydrophilic TMDs and perhaps responsible for the “positive‐inside” orientation rule (von Heijne, 1992). Yeast and human EMC3 contain a specific R31 and R26 residue, respectively, conserved also in YidC and important for function of the EMC, as well as for YidC in Gram‐positive, but interestingly not Gram‐negative, bacteria (Chen et al, 2014; Pleiner et al, 2020; Bai et al, 2020). Another interesting feature, also conserved with YidC, is the flexibility of the TMDs flanking the substrate‐binding pocket, critical for EMC entry of substrates (Bai et al, 2020).In the human EMC, methionine residues in a cytosolic loop of EMC3 act as a substrate bait (Pleiner et al, 2020). Polar and charged residues within the substrate‐binding groove guide the lumenal domain across the membrane, facilitated by local membrane thinning (Pleiner et al, 2020; Fig 1B). The positive charges within the substrate‐binding site exclude signal peptides and enforce the “positive‐inside rule” (von Heijne, 1992; Pleiner et al, 2020). Flexible TMDs of EMC4, EMC7 and EMC10 forming a “lateral gate” of the substrate‐binding groove allow sampling of the bilayer by the substrate TMD (Pleiner et al, 2020). As the shortened TMDs of EMC3 and EMC6 cannot stably bind the substrate TMD, they favour its release into the bilayer (Pleiner et al, 2020). The EMC1 beta‐propeller(s) may recruit additional protein maturation factors in the ER lumen (Pleiner et al, 2020; Bai et al, 2020) or bind the Sec61 channel to allow cooperation between the two insertases (Bai et al, 2020).Arguably, the most interesting feature of the EMC complex is the location of a large interior cavity with distinctive hydrophilic character, which likely aids TMD insertion (Fig 1B). We ran a coarse‐grained molecular dynamics (CG‐MD) simulation of the yeast EMC structure, which highlights a profound perturbation of the phospholipid bilayer in the EMC interior cavity (Fig 1C). Here, a deep gorge forms in the cytoplasmic leaflet of the bilayer, allowing the cavity to become flooded with water (Fig 1C). Note the location of the lipid head groups here (lime green), which presumably define the site of amphipathic TMD insertion. The incursion of phospholipids into the centre of the EMC complex is a feature shared by the bacterial holo‐translocon (Martin et al, 2019) and perhaps by all membrane protein insertases. The shape and character of the EMC cavity presumably dictate its predisposition for less hydrophobic TMDs; it would be interesting to see whether the cavities of different insertases are similarly tailored to suit their substrates.     

Restraining CDK1–cyclin B activation: PP2A on the cUSP(7)

USP7 inhibitors are gaining momentum as a therapeutic strategy to stabilize p53 through their ability to induce MDM2 degradation. However, these inhibitors come with an unexpected p53‐independent toxicity, via an unknown mechanism. In this issue of The EMBO Journal, Galarreta et al report how inhibition of USP7 leads to re‐distribution of PP2A from cytoplasm to nucleus and an increase of deleterious CDK1‐dependent phosphorylation throughout the cell cycle, revealing a new regulatory mechanism for the progression of S‐phase cells toward mitosis to maintain genomic integrity.Subject Categories: Cell Cycle, Post-translational Modifications, Proteolysis & Proteomics

Recent work reveals untimely activation of mitotic cyclin‐dependent kinase as a molecular basis for p53‐independent cell toxicity of USP7 deubiquitinase inhibitors.

The G2‐M transition in the eukaryotic cell cycle is a critical point to ensure that cells with damaged DNA are unable to enter the mitotic phase. This checkpoint is highly regulated by a number of kinases, including ATR, ATM and WEE1, and ends upon activation of the CDK1–cyclin B1 kinase complex (Visconti et al, 2016). Since premature activation of CDK1–cyclin B1 causes replication fork collapse, DNA damage, apoptosis, and mitotic catastrophe (Szmyd et al, 2019 and references therein), restricting CDK1–cyclin B1 activity prior to mitosis is key to maintaining genomic integrity.A body of recent work has suggested that the deubiquitinase USP7 is a master regulator of genomic integrity; it is required for DNA replication in numerous ways, including indirect regulation of cyclin A2 during the S‐phase, origin firing, and replication fork progression. USP7 also regulates mitotic entry by stabilizing PLK1, another kinase which is highly active in the M phase and ensures proper alignment of chromatids prior to segregation. Notably, USP7 inhibitors have become an attractive cancer therapeutic strategy based on their ability to trigger degradation of MDM2, and thereby stabilize p53 (Valles et al, 2020). However, there is growing evidence of USP7 inhibitor‐related toxicity that is not mediated through p53 (Lecona et al, 2016; Agathanggelou et al, 2017), indicating that USP7 inhibitors impact other cellular processes. Therefore, Galarreta et al (2021) investigated the potential functional relationship between USP7 and CDK1, given the role of both factors in regulating the cell cycle.Through a series of in vitro experiments, the authors confirmed that five USP7 inhibitors induce premature mitotic kinase activity, including increased MPM2 signal (indicative of mitosis‐specific phosphorylation events) and phosphorylation of histone H3 Ser10 (H3S10P) in all cells, regardless of where they are in the cell cycle. To determine whether USP7 affects CDK1 during the cell cycle, Galarreta et al (2021) demonstrate that cell lines treated with USP7 inhibitors exhibit reduced levels of inhibitory Tyr‐15 phosphorylation on CDK1 and increased cyclin B1 presence in the nucleus, suggesting activation of the CDK1–cyclin B1 complex. Furthermore, treatment with the CDK1 inhibitor RO3306 rescues the USP7 inhibitor‐dependent increase of mitotic activity.These observations suggest that CDK1 has the potential to catalyze mitosis‐specific phosphorylation irrespective of cell cycle phase and that cells rely on USP7‐specific deubiquitination to suppress or reverse premature CDK1 activity. Surprisingly, despite the nuclear localization of cyclin B and decrease in inhibitory CDK1 Tyr‐15 phosphorylation, USP7 inhibitors failed to drive cells into mitosis. How might this be? Nuclear localization of cyclin B normally occurs just minutes before the onset of mitosis and nuclear envelope breakdown (Santos et al, 2012), yet the nucleus remains intact following USP7 inhibition. Moreover, the decrease in Tyr‐15 phosphorylation suggests the ATR‐ and WEE1‐dependent G2/M checkpoint is inactivated by USP7 inhibition. Do these data hint at the presence of an additional, unknown regulatory mechanism controlling mitotic entry independent of the G2/M checkpoint and nuclear localization of the CDK1–cyclin B complex?To determine whether CDK1 is the driver of USP7 inhibitor toxicity, Galarreta et al exposed cells to CDK1 inhibitors and observed a reduction in apoptosis. Furthermore, CDK1 inhibitors promote cell survival in cells treated with three structurally unrelated USP7 inhibitors. Finally, CDC25A‐deficient mouse embryonic stem cells, which constitutively express low levels of CDK1, resist USP7 inhibition. Together, these data suggest that the USP7 inhibitor‐dependent toxicity is the result of CDK1‐mediated cell death. The authors note that the phosphatase PP2A is an antagonist for CDK1 in addition to being a candidate USP7 substrate (Lecona et al, 2016; Wlodarchak & Xing, 2016), and thus, they turned their attention to elucidating the connection between USP7 and PP2A. Combining biochemical and immunofluorescence studies, Galarreta et al (2021) demonstrate that USP7 interacts with two subunits of PP2A, and this interaction increases in response to USP7 inhibition. Inhibiting USP7 furthermore triggers PP2A re‐localization from the cytoplasm to the nucleus and increases the phosphorylation levels of PP2A substrates, such as AKT and PRC1. DT‐061, a chemical activator of PP2A, reduces CDK1 phosphorylation events, suggesting that PP2A deregulation is a key mediator of USP7 inhibitor‐related toxicity. Using phosphoproteomics to analyze cells treated with a USP7 inhibitor or PP2A‐inhibiting okadaic acid, the authors reveal that both treatments share a significant number of altered phosphorylated targets—especially those related to mitosis, the cell cycle, and epitopes with a CDK‐dependent motif. Thus, the effects of USP7 inhibitors on CDK1 appear to be mediated through PP2A localization to the nucleus.These unexpected findings raise several questions that potentially impact the current view of cell cycle regulation. For example, how does USP7 regulate PP2A localization and is this important for reversing CDK1‐dependent phosphorylation of mitotic substrates prior to mitosis? Does PP2A accumulation in the nucleus explain the failure of USP7‐inhibited cells to enter mitosis despite cyclin B1 nuclear localization? A role for ubiquitin signaling as a regulator of CDK1 in interphase cells has not been reported, and accordingly, new investigations will be needed to unravel the mechanisms by which USP7 controls PP2A localization.Another important question that arises is whether or not CDK1 has sufficient basal activity to phosphorylate numerous mitotic proteins independent of cell cycle phase. The observation that USP7 and PP2A act to prevent the improper accumulation of CDK1‐dependent phosphorylation even in G1 phase cells suggests this to be the case. Alternatively, USP7 activity may be required to prevent abnormal pairing of CDK1 with a cyclin that is ubiquitously expressed across the cell cycle. If so, more research will be needed to uncover how ubiquitin signaling ensures CDK1 only pairs with cyclin A and cyclin B once they accumulate later in the cell cycle.Interestingly, USP7 inhibition also causes a rapid loss in DNA synthesis of S‐phase cells, prompting the authors to perform a time course experiment to decipher the order of events following treatment (i.e., does CDK1 activation precede or follow termination of DNA replication?). High‐throughput microscopy and flow cytometry analysis reveal an immediate reduction of DNA replication, an increase of CDK1 activity, and elevated DNA damage before a detectable increase in H3S10P. Long‐term exposure of USP7 inhibitors leads to DNA damage restricted only to cells with corresponding high levels of H3S10P and MPM2. Overall, these results illustrate how inhibition of USP7 activates CDK1, disrupting DNA replication and inducing DNA damage (Fig 1).Open in a separate windowFigure 1USP7 regulates CDK1In untreated cells, CDK1 is suppressed by USP7 and PP2A, and CDK1‐cyclin B is only active during the G2/M transition. In response to treatment, USP7 facilitates PP2A localization to the nucleus. This allows CDK1 to initiate premature mitotic activity throughout the cell cycle, resulting in increased DNA damage and cellular toxicity.The finding that USP7 inhibitors caused a rapid shutdown of DNA replication brings to mind the recent findings by several groups, that CDK1 activation occurs concomitantly with the S/G2 transition and that premature CDK1 activation in S‐phase terminates replication (Akopyan et al, 2014; Lemmens et al, 2018; Saldivar et al, 2018; Deng et al, 2019; Branigan et al, 2021). According to these studies, coupling of CDK1 activation to the S/G2 transition is regulated by ATR‐CHK1 signaling, a pathway activated by DNA replication to restrain CDK1 through Tyr‐15 phosphorylation. Galarreta et al''s observation that USP7 inhibition overrides ATR‐CHK1 (i.e., Tyr‐15 phosphorylation) highlights the fundamental importance of ubiquitin signaling, and potentially PP2A localization, for ensuring proper S‐to‐M progression and genome maintenance. Ultimately, the mechanistic details of Galarreta et al''s observations remain to be elucidated, and undoubtedly, their findings will inspire future investigations. Moreover, their discovery may lead to a new strategy targeting CDK1 to mitigate unwanted toxicities in the clinic.     

A Novel Cholinergic Action of Alcohol and the Development of Tolerance to That Effect in Caenorhabditis elegans

The Prp43 DExD/H-box protein is required for progression of the biochemically distinct pre-messenger RNA and ribosomal RNA (rRNA) maturation pathways. In Saccharomyces cerevisiae, the Spp382/Ntr1, Sqs1/Pfa1, and Pxr1/Gno1 proteins are implicated as cofactors necessary for Prp43 helicase activation during spliceosome dissociation (Spp382) and rRNA processing (Sqs1 and Pxr1). While otherwise dissimilar in primary sequence, these Prp43-binding proteins each contain a short glycine-rich G-patch motif required for function and thought to act in protein or nucleic acid recognition. Here yeast two-hybrid, domain-swap, and site-directed mutagenesis approaches are used to investigate G-patch domain activity and portability. Our results reveal that the Spp382, Sqs1, and Pxr1 G-patches differ in Prp43 two-hybrid response and in the ability to reconstitute the Spp382 and Pxr1 RNA processing factors. G-patch protein reconstitution did not correlate with the apparent strength of the Prp43 two-hybrid response, suggesting that this domain has function beyond that of a Prp43 tether. Indeed, while critical for Pxr1 activity, the Pxr1 G-patch appears to contribute little to the yeast two-hybrid interaction. Conversely, deletion of the primary Prp43 binding site within Pxr1 (amino acids 102–149) does not impede rRNA processing but affects small nucleolar RNA (snoRNA) biogenesis, resulting in the accumulation of slightly extended forms of select snoRNAs, a phenotype unexpectedly shared by the prp43 loss-of-function mutant. These and related observations reveal differences in how the Spp382, Sqs1, and Pxr1 proteins interact with Prp43 and provide evidence linking G-patch identity with pathway-specific DExD/H-box helicase activity.     

Biodiversity 2030: a road paved with good intentions: The new EU Commission's biodiversity Strategy risks to remain an empty husk without proper implementation

The EU''s Biodiversity Strategy for 2030 makes great promises about halting the decline of biodiversity but it offers little in terms of implementation. Subject Categories: S&S: Economics & Business, Ecology, S&S: Ethics

Earth is teeming with a stunning variety of life forms. Despite hundreds of years of exploration and taxonomic research, and with 1.2 million species classified, we still have no clear picture of the real extent of global biodiversity, with estimates ranging from 3 to 100 million species. A highly quoted—although not universally accepted—study predicted some 8.7 million species, of which about 2.2 million are marine (Mora et al, 2011). Although nearly any niche on the surface of Earth has been colonized by life, species richness is all but evenly distributed. A large share of the known species is concentrated in relatively small areas, especially in the tropics (Fig 1). Ultimately, it is the network of the interactions among life forms and the physical environment that make up the global ecosystem we call biosphere and that supports life itself.Open in a separate windowFigure 1Biological hotspots of the worldA total of 36 currently recognized hotspots make up < 3% of the planet''s land area but harbor half of the world''s endemic plant species and 42% of all terrestrial vertebrates. Overall, hotspots have lost more than 80% of their original extension. Credit: Richard J. Weller, Claire Hoch, and Chieh Huang, 2017, Atlas for the End of the World, http://atlas‐for‐the‐end‐of‐the‐world.com/. Reproduced with permission.Driven by a range of complex and interwoven causes–such as changes in land and sea use, habitat destruction, overexploitation of organisms, climate change, pollution, and invasive species–biodiversity is declining at an alarming pace. A report by the Intergovernmental Science‐Policy Platform on Biodiversity and Ecosystem Services (IPBES) issued a clear warning: “An average of around 25 per cent of species in assessed animal and plant groups are threatened, suggesting that around 1 million species already face extinction, many within decades, unless action is taken to reduce the intensity of drivers of biodiversity loss. Without such action, there will be a further acceleration in the global rate of species extinction, which is already at least tens to hundreds of times higher than it has averaged over the past 10 million years” (IPBES, 2019) (Fig 2). Although focused on a smaller set of organisms, a more recent assessment by WWF has reached similar conclusions. Their Living Planet Index, that tracks the abundance of thousands of populations of mammals, birds, fish, reptiles, and amphibians around the world, shows a stark decline in monitored populations (WWF, 2020). As expected, the trend of biodiversity decline is not homogeneous with tropical areas paying a disproportionately high price, mostly because of unrestrained deforestation and exploitation of natural resources.Open in a separate windowFigure 2The global, rapid decline of biodiversity(A) Percentage of species threatened with extinction in taxonomic groups that have been assessed comprehensively, or through a “sampled” approach, or for which selected subsets have been assessed by the IUCN Red List of Threatened Species. Groups are ordered according to the best estimate, assuming that data‐deficient species are as threatened as non‐data deficient species. (B) Extinctions since 1500 for vertebrate groups. (C) Red List Index of species survival for taxonomic groups that have been assessed for the IUCN Red List at least twice. A value of 1 is equivalent to all species being categorized as Least Concern; a value of zero is equivalent to all species being classified as Extinct. Data for all panels from www.iucnredlist.org. Reproduced from (IPBES, 2019), with permission.

Driven by a range of complex and interwoven causes […] biodiversity is declining at an alarming pace.

Against this dire background, the EU has drafted a Biodiversity Strategy 2030, an ambitious framework aimed to tackling the key reasons behind biodiversity loss. The plan hinges around a few main elements, such as the establishment of protected areas for at least 30% of Europe''s lands and seas (Fig 3); a significant increase of biodiversity‐rich landscape features on agricultural land by establishing buffer zones like hedges and fallow fields; halting and reversing the decline of pollinators; and planting 3 billion trees by 2030 (https://ec.europa.eu/info/strategy/priorities‐2019‐2024/european‐green‐deal/actions‐being‐taken‐eu/eu‐biodiversity‐strategy‐2030_en). The budget for implementing these measures was set at €20 billion per year.Open in a separate windowFigure 3Natura 2000, the EU''s network of protected areasIn 2019, 18% of land in the EU was protected as Natura 2000, with the lowest share of protected land in Denmark (8%) and the highest in Slovenia (38%). In 2019, the largest national network of terrestrial Natura 2000 sites was located in Spain, covering 138,111 km², followed by France (70,875 km²) and Poland (61,168 km²). Reproduced from Eurostat: https://ec.europa.eu/eurostat/statistics‐explained/index.php?title=Main_Page “Nature is vital for our physical and mental wellbeing, it filters our air and water, it regulates the climate and it pollinates our crops. But we are acting as if it didn''t matter, and losing it at an unprecedented rate”, said Virginijus Sinkevičius, Commissioner for the Environment, Oceans and Fisheries, at the press launch of the new EU action (https://ec.europa.eu/commission/presscorner/detail/en/ip_20_884). “This new Biodiversity Strategy builds on what has worked in the past, and adds new tools that will set us on a path to true sustainability, with benefits for all. The EU''s aim is to protect and restore nature, to contribute to economic recovery from the current crisis, and to lead the way for an ambitious global framework to protect biodiversity around the planet”.Environmental groups and other stakeholders have welcomed the EU''s pledge in principle. “This is a unique opportunity to shape a new society in harmony with nature”, applauded Wetlands International. “We must not forget that the biodiversity and climate crisis is a much bigger and persistent challenge for humanity than COVID‐19”, (https://europe.wetlands.org/news/welcoming‐the‐eu‐biodiversity‐strategy‐for‐2030/). EuroNatur, a foundation focused on conservation, stated that the goals set out by the new strategy provide a strong basis for improving the state of nature in the EU (www.euronatur.org).Alongside the voices of praise, however, many have expressed concerns that the strategy could turn into a little more than a wish list. “The big issue of the strategy is that while setting a goal for financial funds, the EU does not specify where the money is supposed to come from. It only says it should include ‘EU funds and national and private funding’”, commented the European Wilderness Society, an environmental advocacy non‐profit organization headquartered in Tamsweg, Austria. “Goals are important, but do not create change without an organized and sustainable implementation. It''s a good and ambitious document, but what is also obvious is the lack of strategy of how to implement it, and a lack of discussion of why previous documents of this type failed” (https://wilderness‐society.org/ambitious‐eu‐biodiversity‐strategy‐2030/).

Alongside the voices of praise, however, many have expressed concerns that the strategy could turn into a little more than a wish list.

The Institute for European Environmental Policy (IEEP) is on the same page. The sustainability think‐tank based in Brussels and London noted that the outgoing EU 2020 biodiversity strategy showed major implementation problems, especially because of lack of engagement at national level and of ad hoc legislation supporting the meeting of key targets. Therefore, “[it] can be argued that a legally binding approach to the biodiversity governance framework is urgently needed unless Member States and other key stakeholders can show greater intrinsic ownership to deliver on agreed objectives”, (https://ieep.eu/news/first‐impressions‐of‐the‐eu‐biodiversity‐strategy‐to‐2030). In addition, IEEP remarked that money is an issue, since the €20 billion figure appears more as an estimate than a certified obligation.“The intentions of the Commission are good and the strategy contains a number of measures and targets that can really make a difference. However, implementation depends critically on the member states and experiences with the Common Agricultural Policy the past decade or so have taught us that many of them are more interested in short‐term economic objectives than in safeguarding the natural wealth of their country for future generations”, commented David Kleijn, an ecologist and nature conservation expert at the Wageningen University, the Netherlands. “I think it is important that we now have an ambitious Biodiversity Strategy but at the same time I have little hope that we will be able to achieve its objectives”.

I think it is important that we now have an ambitious Biodiversity Strategy but at the same time I have little hope that we will be able to achieve its objectives.

There is further criticism against specific measures, such as the proposal of planting 3 billion trees. “To have lots of trees planted in an area does not necessarily translate into an increase of biodiversity. Biodiverse ecosystems are the result of million years of complex multi‐species interactions and evolutionary processes, which are not as easy to restore”, explained plant ecologist Susana Gómez‐González, from the University of Cádiz, Spain. Planting a large number of trees is a too simplistic approach for saving European forests from the combined effects of excessive anthropic pressure and climate change, and could even have detrimental effects (see Box 1). More emphasis should be placed instead in reducing tree harvesting in sensitive areas and in promoting natural forest renewal processes (Gómez‐González et al, 2020). “For a biodiversity strategy, increasing the number of trees, or even increasing the forest area, should not be an objective; priority should be given to the conservation and restoration of natural ecosystems, forests and non‐forests”, Gómez‐González said.In other cases, it could be difficult, if not impossible, to reach some of the goals because of lack of information. For example, one of the roadmap''s targets is to restore at least 25,000 km of Europe''s rivers back to free‐flowing state. However, the number of barriers dispersed along European rivers will probably prevent even getting close to the mark. An international research team has collected detailed information on existing instream barriers for 147 rivers in 36 European countries, coming up with the impressive figure of over 1.2 million obstacles that inevitably impact on river ecosystems, affecting the transport and dispersion of aquatic organisms, nutrients, and sediments (Belletti et al, 2020). Existing inventories mainly focused on dams and other large barriers, while, in fact, a large number of artificial structures are much smaller, such like weirs, locks, ramps, and fords. As a result, river fragmentation has been largely underestimated, and the models used to plan flow restoration might be seriously flawed. “To avoid ‘death by a thousand cuts’, a paradigm shift is necessary: to recognize that although large dams may draw most of the attention, it is the small barriers that collectively do most of the damage. Small is not beautiful”, concluded the authors (Belletti et al, 2020).

Box 1: Why many trees don''t (always) make a forestForests are cathedrals of biodiversity. They host by far the largest number of species on land, which provide food and essential resources for hundreds of millions of people worldwide. However, forests are disappearing and degrading at an alarming pace. The loss of these crucial ecosystems has given new impulses to a variety of projects aimed at stopping this devastation and possibly reversing the trend.Once it is gone, can you rebuild a forest? Many believe the answer is yes, and the obvious solution is to plant trees. Several countries have thus launched massive tree‐planting programs, notably India and Ethiopia, where 350 million trees have been planted in single day (https://www.unenvironment.org/news‐and‐stories/story/ethiopia‐plants‐over‐350‐million‐trees‐day‐setting‐new‐world‐record). The World Economic Forum has set up its own One Trillion Tree initiative (https://www.1t.org/) “to conserve, restore, and grow one trillion trees by 2030”. Launched in January last year at Davos, 1t.org was conceived as a platform for governments, companies and NGOs/civil society groups to support the UN Decade on Ecosystem Restoration (2021–2030). The initiative has been christened by renowned naturalist Jane Goodall, who commented: “1t.org offers innovative technologies which will serve to connect tens of thousands of small and large groups around the world that are engaged in tree planting and forest restoration”, (https://www.weforum.org/agenda/2020/01/one‐trillion‐trees‐world‐economic‐forum‐launches‐plan‐to‐help‐nature‐and‐the‐climate/).However, things are way more complicated than they appear: large‐scale tree planting schemes are rarely a viable solution and can even be harmful. “[A] large body of literature shows that even the best planned restoration projects rarely fully recover the biodiversity of intact forests, owing to a lack of sources of forest‐dependent flora and fauna in deforested landscapes, as well as degraded abiotic conditions resulting from anthropogenic activities”, commented Karen Holl from the University of Caliornia, Santa Cruz, and Pedro Brancalion from the University of São Paulo (Holl & Brancalion, 2020). A common problem of tree plantations, for example, is the low survival rate of seedlings, mostly because the wrong tree species are selected and due to poor maintenance after planting. Moreover, grasslands and savannas, which are often targeted for establishing new forests, are themselves treasure troves of biodiversity. Ending indiscriminate deforestation, improving the protection of existing forests, and promoting their restoration would therefore be a more efficient strategy to preserve biodiversity in the shorter term. If tree planting is indeed necessary, it should be well planned by selecting the right areas for reforestation, using suitable tree species that can maximize biodiversity, and involving local populations to maintain the plantations, Holl and Brancalion argue (Holl & Brancalion, 2020).

…even the best planned restoration projects rarely fully recover the biodiversity of intact forests, owing to a lack of sources of forest‐dependent flora and fauna in deforested landscapes…

The health of soil, where a high proportion of biodiversity is hosted, is another problem the new strategy should address in a more focused manner. “In my opinion, the EU Biodiversity Strategy is already a leap forward in terms of policy interest in soils in general and in soil biodiversity in particular. Compared with other nations/regions of the world, Europe is by far in the forefront regarding this issue”, commented Carlos António Guerra at the German Centre for Integrative Biodiversity Research (iDiv) in Leipzig, Germany, and Co‐leader of the Global Soil Biodiversity Observation Network (https://geobon.org/bons/thematic‐bon/soil‐bon/). “Nevertheless, the connection between soil biodiversity and ecological functions needs further commitments. Soils allow for horizontal integration of several policy agendas, from climate to agriculture and, very importantly, nature conservation. This is not explicit in the EU Biodiversity Strategy in regard to soils”. It remains to be seen if EU restoration plan will emphasize soil biodiversity, or consider it as a mere side effect of other initiatives, Guerra added. “A soil nature conservation plan should be proposed”, he said. “Only such a plan, that implies that current and future protected areas have to consider, describe and protect their soil biodiversity would make a significant push to help protect such a valuable resource”.More generally, research shows that the current paradigm of protection must be shifted to prevent further losses to biodiversity. In fact, an analysis of LIFE projects—a cornerstone of EU nature protection—found that conservation efforts are extremely polarized and strongly taxonomically biased (Mammola et al, 2020). From 1992 to 2018, investment in vertebrates was sixfold higher than that for invertebrates, with birds and mammals alone accounting for 72% of the targeted species and 75% of the total budget. In relative terms, investment per species for vertebrates has been 468 times higher than for invertebrates (Fig 4). There is no sound scientific reasoning behind this uneven conservation attention, but just popularity. “[T]he species covered by a greater number of LIFE projects were also those which attracted the most interest online, suggesting that conservation in the EU is largely driven by species charisma, rather than objective features”, the researchers wrote (Mammola et al, 2020).Open in a separate windowFigure 4Taxonomic bias in EU fauna protection effortsBreakdown of the number of projects (A) and budget allocation (B) across main animal groups covered by the LIFE projects (n = 835). (C) The most covered 30 species of vertebrates (out of 410) and invertebrates (out of 78) in the LIFE projects analyzed (n = 835). The vertical bar represents monetary investment and the blue scatter line the number of LIFE projects devoted to each species. Reproduced from (Mammola et al, 2020), with permission.     

Mycobiota dysbiosis: a new nexus in intestinal tumorigenesis

While there is growing evidence that perturbation of the gut microbiota can result in a variety of pathologies including gut tumorigenesis, the influence of commensal fungi remains less clear. In this issue, Zhu et al (2021) show that mycobiota dysbiosis stimulates energy metabolism changes in subepithelial macrophages promoting colon cancer via enhancing innate lymphoid cell activity. These findings provide insights into a role of the gut flora in intestinal carcinogenesis and suggest opportunities for adjunctive antifungal or immunotherapeutic strategies to prevent colorectal cancer.Subject Categories: Cancer, Immunology, Metabolism

Recent work reports a role for the commensal gut flora in driving aberrant host immunity and malignant cytokine signaling.

There is growing evidence for an important role for the microbiota in influencing tumorigenesis (Helmink et al, 2019). It is now well documented that gut microbiota represents a highly diverse polymicrobial population of bacteria, fungi, viruses, and protozoa. Recent evidence highlights involvement of the bacterial component of the gut microbiota in protection or enhancement of colorectal tumorigenesis. In contrast, the importance of the mycobiota is less well understood although recently suggested to promote pancreatic oncogenesis and colitis‐associated colon cancer (CAC) (Wang et al, 2018; Aykut et al, 2019). Therefore, gut fungi may play a role in the development of other gastro‐intestinal cancer types, such as CRC. Notably, there is emerging evidence suggesting that mycobiota imbalance modulates immune cells and can trigger inflammatory bowel disease (IBD) (Richard & Sokol, 2019).Here, Zhu et al (2021) provide new insight into the association between mycobiota dysbiosis, immunomodulation, and tumorigenesis in the mouse gut (Fig 1).Open in a separate windowFigure 1Dectin‐3 deficiency induces fungal dysbiosis and tumorigenesis in mice by orchestrating immune cell metabolism and cytokine signalingIn the gut of wild‐type mice, the natural population of the commensal yeast Candida albicans is detected by the Dectin‐3 receptor located on the subepithelial macrophage cell surface. This recognition allows macrophages to maintain gut homeostasis by exerting an antifungal activity. In Dectin‐3‐deficient mice, the mycobiota becomes disrupted and aberrantly increased populations of C. albicans emerge. Elevated C. albicans load triggers increased glycolysis in macrophages and interleukin‐7 (IL‐7) secretion. Macrophage‐derived IL‐7 finally induces IL‐22 secretion by group‐3 innate lymphoid cells that in turn promote tumor cell proliferation in the gut epithelium.The current study (Zhu et al, 2021) is based on previous observations suggesting that human pathogenic fungi are recognized by the C‐type lectin receptor Dectin‐3. This led Zhu et al (2021) to test whether the mycobiota influenced gut tumor formation and is linked to immune recognition mediated by Dectin‐3. First, the authors demonstrated that mice lacking the Dectin‐3 receptor had increased colonic tumorigenesis in response to the azoxymethane (AOM) and dextran sodium sulfate (DSS). This was evident histologically in marked differences in tumor number, size, and burden in Dectin‐3‐deficient mice. Of note, immunohistochemical staining revealed that the lack of Dectin‐3 induced gut tumor formation by triggering epithelial cell proliferation rather than preventing cell apoptosis. In fact, first insight into the impact of microbes in CAC was suggested by the observation that co‐housed WT and Dectin‐3‐deficient mice displayed no difference in tumorigenesis. The pivotal role of the microbiota was then underlined in fecal transplantation experiments. Chemically induced germ‐free mice that received feces from Dectin‐3 tumor‐bearing mice displayed exacerbated tumor development compared to wild‐type controls. In addition, the fungal burden was specifically increased in tumor‐bearing Dectin‐3‐deficient animals. Deep profiling of the mycobiota alterations demonstrated an increase in a single yeast species, i.e., Candida albicans, that normally behaves as commensal in the gut (Papon et al, 2013; Wilson, 2019). Preliminary experiments suggested that the increased burden of C. albicans in Dectin‐3‐deficient tumor‐bearing mice is due to impaired antifungal killing by macrophages. Consistently, elevated C. albicans populations triggered glycolysis and inflammatory IL‐7 secretion from lamina propria macrophages, suggesting that Dectin‐3 deficiency‐induced fungal dysbiosis resulted in modulation of gut macrophage metabolism, promoting tumorigenesis. Exploring the molecular and cellular mechanisms that linked macrophage‐derived IL‐7 secretion and CRC development, Zhu et al (2021) showed in vitro that IL‐7 produced by subepithelial macrophages induced IL‐22 secretion by group‐3 innate lymphoid cells (ILC3s). In turn, up‐regulation of IL‐22 in Dectin‐3‐deficient mice contributed to the oncogenesis seen in these animals. Finally, a detailed analysis of tumor tissues collected from 172 patients with CRC showed correlation and poorer clinical outcome in patients with decreased expression of Dectin‐3, but increased expression of IL‐22 and mycobiota burden, although they did not directly link this to the presence of C. albicans in these patients.Overall, Zhu et al (2021) define a new cell paradigm linking mycobiota dysbiosis, macrophage energy metabolism, and innate lymphoid cell function to tumor development in the mouse gut. In this context, this study also sheds additional light on a new role of ILC3s, a recently described type of lymphoid effectors (Serafini et al, 2015). Indeed, ILC3s have been shown in the present article to act as cornerstone cells orchestrating cytokine‐regulated tumorigenesis in the gut. Beyond these pathophysiological considerations, the study opens up new opportunities for developing adjunctive antifungal or immunotherapeutic strategies for the prevention of high morbidity in CRC. Importantly, this enlightening article provides firm evidence that colonic C. albicans populations promote metabolic reprogramming in lamina propria macrophages and tumor cell formation. Metabolic reprogramming has been observed with other fungi, such as Aspergillus fumigatus, which induces metabolic rewiring of alveolar macrophages in the lung epithelium (Gonçalves et al, 2020). In line, the report by Zhu et al (2021) adds to previous work suggesting that mycobiota promotes pancreatic oncogenesis via activation of mannose‐binding lectins (Aykut et al, 2019). Mycobiota dysbiosis therefore stands out as an important new field of investigation in cancer research that is ripe for future exploration.     

USP26: a genetic risk factor for sperm X‐Y aneuploidy

Segregation of the largely non‐homologous X and Y sex chromosomes during male meiosis is not a trivial task, because their pairing, synapsis, and crossover formation are restricted to a tiny region of homology, the pseudoautosomal region. In humans, meiotic X‐Y missegregation can lead to 47, XXY offspring, also known as Klinefelter syndrome, but to what extent genetic factors predispose to paternal sex chromosome aneuploidy has remained elusive. In this issue, Liu et al (2021) provide evidence that deleterious mutations in the USP26 gene constitute one such factor.Subject Categories: Cell Cycle, Development & Differentiation, Molecular Biology of Disease

Analyses of Klinefelter syndrome patients and Usp26‐deficient mice have revealed a genetic influence on age‐dependent sex chromosome missegregation during male meiosis.

Multilayered mechanisms have evolved to ensure successful X‐Y recombination, as a prerequisite for subsequent normal chromosome segregation. These include a distinct chromatin structure as well as specialized proteins on the pseudoautosomal region (Kauppi et al, 2011; Acquaviva et al, 2020). Even so, X‐Y recombination fails fairly often, especially in the face of even modest meiotic perturbations. It is perhaps not surprising then that X‐Y aneuploidy—but not autosomal aneuploidy—in sperm increases with age (Lowe et al, 2001; Arnedo et al, 2006), as does the risk of fathering sons with Klinefelter syndrome (De Souza & Morris, 2010).Klinefelter syndrome is one of the most common aneuploidies in liveborn individuals (Thomas & Hassold, 2003). While most human trisomies result from errors in maternal chromosome segregation, this is not the case for Klinefelter syndrome, where the extra X chromosome is equally likely to be of maternal or paternal origin (Thomas & Hassold, 2003; Arnedo et al, 2006). Little is known about genetic factors in humans that predispose to paternal XY aneuploidy, i.e., that increase the risk of fathering Klinefelter syndrome offspring. The general notion has been that paternally derived Klinefelter syndrome arises stochastically. However, fathers of Klinefelter syndrome patients have elevated rates of XY aneuploid sperm (Lowe et al, 2001; Arnedo et al, 2006), implying a persistent defect in spermatogenesis in these individuals rather than a one‐off meiotic error.To identify possible genetic factors contributing to Klinefelter syndrome risk, Liu et al (2021) performed whole‐exome sequencing in a discovery cohort of > 100 Klinefelter syndrome patients, followed by targeted sequencing in a much larger cohort of patients and controls, as well as Klinefelter syndrome family trios. The authors homed in on a mutational cluster (“mutated haplotype”) in ubiquitin‐specific protease 26 (USP26), a testis‐expressed gene located on the X chromosome. Effects of this gene’s loss of function (Usp26‐deficient mice) on spermatogenesis have recently been independently reported by several laboratories and ranged from no detectable fertility phenotype (Felipe‐Medina et al, 2019) to subfertility/sterility associated with both meiotic and spermiogenic defects (Sakai et al, 2019; Tian et al, 2019). With their Klinefelter syndrome cohort findings, Liu et al (2021) also turned to Usp26 null mice, paying particular attention to X‐Y chromosome behavior and—unlike earlier mouse studies—including older mice in their analyses. They found that Usp26‐deficient animals often failed to achieve stable pairing and synapsis of X‐Y chromosomes in spermatocytes, produced XY aneuploid sperm at an abnormally high frequency, and sometimes also sired XXY offspring. Importantly, these phenotypes only occurred at an advanced age: XY aneuploidy was seen in six‐month‐old, but not two‐month‐old Usp26‐deficient males. Moreover, levels of spindle assembly checkpoint (SAC) proteins also reduced in six‐month‐old males. Thus, in older Usp26 null mice, the combination of less efficient X‐Y pairing and less stringent SAC‐mediated surveillance of faithful chromosome segregation allows for sperm aneuploidy, providing another example of SAC leakiness in males (see Lane & Kauppi, 2019 for discussion).Liu et al’s analyses shed some light on what molecular mechanisms may be responsible for the reduced efficiency of X‐Y pairing and synapsis in Usp26‐deficient spermatocytes. USP26 codes for a deubiquitinating enzyme that has several substrates in the testis. Because USP26 prevents degradation of these substrates, their levels should be downregulated in Usp26 null testes. Liu et al (2021) show that USP26 interacts with TEX11, a protein required for stable pairing and normal segregation of the X and Y chromosomes in mouse meiosis (Adelman & Petrini, 2008). USP26 can de‐ubiquitinate TEX11 in vitro, and in Usp26 null testes, TEX11 was almost undetectable. It is worth noting that USP26 has several other known substrates, including the androgen receptor (AR), and therefore, USP26 disruption likely contributes to compromised spermatogenesis via multiple mechanisms. For example, AR signaling‐dependent hormone levels are misregulated in Usp26 null mice (Tian et al, 2019).The sex chromosome phenotypes observed in Usp26 null mice predict that men with USP26 mutations may be fertile, but producing XY aneuploid sperm at an abnormally high frequency, and that spermatogenic defects should increase with age (Fig 1). These predictions were testable, because the mutated USP26 haplotype, present in 13% of Klinefelter syndrome patients, was reasonably common also in fertile men (7–10%). Indeed, sperm XY aneuploidy was substantially higher in fertile men with the mutated USP26 haplotype than in those without USP26 mutations. Some mutation carriers produced > 4% aneuploid sperm. Moreover, age‐dependent oligospermia was also found associated with the mutated USP26 haplotype.Open in a separate windowFigure 1Mutated USP26 as genetic risk factor for age‐dependent X‐Y defects in spermatogenesisMouse genetics demonstrate that deleterious USP26 mutations lead to less‐efficient X‐Y pairing and recombination with advancing age. Concomitant decrease of spindle assembly checkpoint (SAC) protein levels leads to less‐efficient elimination of metaphase I spermatocytes that contain misaligned X and Y chromosomes. This allows for the formation of XY aneuploid sperm in older individuals and subsequently increased age‐dependent risk for fathering Klinefelter syndrome (KS) offspring, two correlates also observed in human USP26 mutation carriers. At the same time, oligospermia/subfertility also increases with advanced age in both Usp26‐deficient mice and USP26 mutation‐carrying men, tempering Klinefelter syndrome offspring risk but also decreasing fecundity.As indicated by its prevalence in the normal control population, the USP26 mutated haplotype is not selected against in the human population. With > 95% of sperm in USP26 mutation carriers having normal haploid chromosomal composition, the risk of producing (infertile) Klinefelter syndrome offspring remains modest, likely explaining why USP26 mutant alleles are not eliminated. Given that full Usp26 disruption barely affects fertility of male mice during their prime reproductive age (Felipe‐Medina et al, 2019; Tian et al, 2019; Liu et al, 2021), there is little reason to assume strong negative selection against USP26 variants in humans. USP26 as the first‐ever genetic risk factor predisposing to sperm X‐Y aneuploidy and paternal origin Klinefelter syndrome offspring in humans, as uncovered by Liu et al, may be just one of many. 90% of Liu et al’s Klinefelter syndrome cases were not associated with USP26 mutations. But even in the age of genomics, discovery of Klinefelter syndrome risk factors is not straightforward, since most sperm of risk mutation carriers will not be XY aneuploid and thus not give rise to Klinefelter syndrome offspring. In addition, as Usp26 null mice demonstrate, both genetic and non‐genetic modifiers impact on penetrance of the XY aneuploidy phenotype: Spermatogenesis in the absence of Usp26 was impaired in the DBA/2 but not the C57BL/6 mouse strain background (Sakai et al, 2019), and in older mice, there was substantial inter‐individual variation in the severity of the X‐Y defect (Liu et al, 2021). In human cohorts, genetic and non‐genetic modifiers are expected to blur the picture even more.Future identification of sex chromosome aneuploidy risk factors has human health implications beyond Klinefelter syndrome. Firstly, XXY incidence is not only relevant for Klinefelter syndrome livebirths—it also contributes to stillbirths and spontaneous abortions, at a 4‐fold higher rate than to livebirths (Thomas & Hassold, 2003). Secondly, persistent meiotic X‐Y defects can, over time, result in oligospermia and even infertility. Since the mean age of first‐time fathers is steadily rising and currently well over 30 years in many Western countries, age‐dependent spermatogenic defects will be of ever‐increasing clinical relevance.