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DOT1L is a histone H3 Lys79 methyltransferase whose activity is stimulated by histone H2B Lys120 ubiquitination, suggesting cross-talk between histone H3 methylation and H2B ubiquitination. Here, we present cryo-EM structures of DOT1L complexes with unmodified or H2B ubiquitinated nucleosomes, showing that DOT1L recognizes H2B ubiquitin and the H2A/H2B acidic patch through a C-terminal hydrophobic helix and an arginine anchor in DOT1L, respectively. Furthermore, the structures combined with single-molecule FRET experiments show that H2B ubiquitination enhances a noncatalytic function of the DOT1L-destabilizing nucleosome. These results establish the molecular basis of the cross-talk between H2B ubiquitination and H3 Lys79 methylation as well as nucleosome destabilization by DOT1L.

Background Although research participants are generally interested in receiving results from studies in which they participate, health researchers rarely communicate study findings to participants. The present study was designed to provide opportunity for a broad group of health researchers to describe their experiences and concerns related to sharing results (i.e. aggregate study findings) with research participants. Methods We used a mixed–methods concurrent triangulation design, relying on an online survey to capture health researchers’ experiences, perceptions and barriers related to sharing study results with participants. Respondents were health researchers who conduct research that includes the consent of human subjects and hold a current appointment at an accredited academic medical institution within the United States. For quantitative data, the analytic strategy focused on item-level descriptive analyses. For the qualitative data, analyses focused on a priori themes and emergent subthemes. Results Respondents were 414 researchers from 44 academic medical institutions; 64.5% reported that results should always be shared with participants, yet 60.8% of respondents could identify studies in which they had a leadership role where results were not shared. Emergent subthemes from researchers’ reasons why results should be shared included participant ownership of findings and benefits of results sharing to science. Reasons for not sharing included concerns related to participants’ health literacy and participants’ lack of desire for results. Across all respondents who described barriers to results sharing, the majority described logistical barriers. Conclusions Study findings contribute to the literature by documenting researchers’ perspectives and experiences about sharing results with research participants, which can inform efforts to improve results sharing. Most respondents indicated that health research results should always be shared with participants, although the extent to which many respondents described barriers to results sharing as well as reported reasons not to share results suggests difficulties with a one-size-fits-all approach to improving results sharing.

Here we show that translesion synthesis (TLS) opposite 1,N6-ethenodeoxyadenosine (εdA), which disrupts Watson–Crick base pairing, occurs via Polι/Polζ-, Rev1-, and Polθ-dependent pathways. The requirement of Polι/Polζ is consistent with the ability of Polι to incorporate nucleotide opposite εdA by Hoogsteen base pairing and of Polζ to extend synthesis. Rev1 polymerase and Polθ conduct TLS opposite εdA via alternative error-prone pathways. Strikingly, in contrast to extremely error-prone TLS opposite εdA by purified Polθ, it performs predominantly error-free TLS in human cells. Reconfiguration of the active site opposite εdA would provide Polθ the proficiency for error-free TLS in human cells.

Genomic imprinting is an epigenetic mechanism by which genes are expressed in a parental origin–dependent manner. We recently discovered that, like DNA methylation, oocyte-inherited H3K27me3 can also serve as an imprinting mark in mouse preimplantation embryos. In this study, we found H3K27me3 is strongly biased toward the maternal allele with some associated with DNA methylation–independent paternally expressed genes (PEGs) in human morulae. The H3K27me3 domains largely overlap with DNA partially methylated domains (PMDs) and occupy developmental gene promoters. Thus, our study not only reveals the H3K27me3 landscape but also establishes a correlation between maternal-biased H3K27me3 and PEGs in human morulae.

Formation of individualized sister chromatids is essential for their accurate segregation. In budding yeast, while most of the genome segregates at the metaphase to anaphase transition, resolution of the ribosomal DNA (rDNA) repeats is delayed. The timing and mechanism in human cells is unknown. Here we show that resolution of human rDNA occurs in anaphase after the bulk of the genome, dependent on tankyrase 1, condensin II, and topoisomerase IIα. Defective resolution leads to rDNA bridges, rDNA damage, and aneuploidy of an rDNA-containing acrocentric chromosome. Thus, temporal regulation of rDNA segregation is conserved between yeast and man and is essential for genome integrity.

Myocardin, a potent coactivator of serum response factor (SRF), competes with ternary complex factor (TCF) proteins for SRF binding to balance opposing mitogenic and myogenic gene programs in cardiac and smooth muscle. Here we identify a cardiac lncRNA transcribed adjacent to myocardin, named CARDINAL, which antagonizes SRF-dependent mitogenic gene transcription in the heart. CARDINAL-deficient mice show ectopic TCF/SRF-dependent mitogenic gene expression and decreased cardiac contractility in response to age and ischemic stress. CARDINAL forms a nuclear complex with SRF and inhibits TCF-mediated transactivation of the promitogenic gene c-fos, suggesting CARDINAL functions as an RNA cofactor for SRF in the heart.

Human SW872 preadipocyte conversion to mature adipocytes is associated with time‐dependent changes in differentiation markers' expression and with morphological changes accompanied by the accumulation of lipid droplets (LDs) as well as by increased mitochondriogenesis and mitochondrial membrane potential. Under identical conditions, the formation of reactive oxygen species (ROS) revealed with a general probe was significant at days 3 and 10 of differentiation and bearly detectable at day 6. NADPH oxidase (NOX)‐2 activity determined with an immunocytochemical approach followed a very similar pattern. There was no evidence of mitochondrial ROS (mROS), as detected with a selective fluorescence probe, at days 3 and 6, possibly due to the triggering of the Nrf‐2 antioxidant response. mROS were instead clearly detected at day 10, concomitantly with the accumulation of very large LDs, oxidation of both cardiolipin and thioredoxin 2, and decreased mitochondrial glutathione. In conclusion, the morphological and biochemical changes of differentiating SW872 cells are accompanied by the discontinuous formation of ROS derived from NOX‐2, increasingly implicated in adipogenesis and adipose tissue dysfunction. In addition, mROS formation was significant only in the late phase of differentiation and was associated with mitochondrial dysfunction.

Knowledge mobilization (KMb) is the communication process by which researchers engage with stakeholders to produce, co-produce, and share knowledge. The question of how researchers can better mobilize knowledge at each stage of the research process has become a matter of acute public and academic interest. Yet existing research indicates that researchers are often reticent to engage with non-academic stakeholders; studies have found many do not have the necessary time, skills, or resources. Furthermore, most research on KMb has focused on large institutions or a university context, despite the fact that Canada’s colleges also produce a significant proportion of Canadian research. This study investigated college researchers’ understandings of and approaches to KMb using in-depth, semi-structured interviews. Eleven participants representing six Canadian community colleges and polytechnic institutes were interviewed about their approaches to KMb and the institutional or systemic factors that influence how they perceive KMb and carry out KMb activities. Participants defined KMb as a complex, reciprocal process with the potential to elevate their field, solve problems, and inform important decisions. Key KMb facilitators identified by the participants included low professional pressure to publish academically, which freed up time and resources for non-traditional approaches to KMb; funding structures that incentivize effective and ongoing KMb; and strong collaborations with other college departments, especially communications and marketing. Barriers included challenges to academic freedom, long delays caused by institutional and legal oversight of KMb, and certain gaps in funding opportunities.

PurposeTo present social media (SoMe) platforms for surgeons, how these are used, with what impact, and their roles for research communication.MethodsA narrative review based on a literature search regarding social media use, of studies and findings pertaining to surgical disciplines, and the authors’ own experience.ResultsSeveral social networking platforms for surgeons are presented to the reader. The more frequently used, i.e., Twitter, is presented with details of opportunities, specific fora for communication, presenting tips for effective use, and also some caveats to use. Details of how the surgical community evolved through the use of the hashtag #SoMe4Surgery are presented. The impact on gender diversity in surgery through important hashtags (from #ILookLikeASurgeon to #MedBikini) is discussed. Practical tips on generating tweets and use of visual abstracts are presented, with influence on post-production distribution of journal articles through “tweetorials” and “tweetchats.” Findings from seminal studies on SoMe and the impact on traditional metrics (regular citations) and alternative metrics (Altmetrics, including tweets, retweets, news outlet mentions) are presented. Some concerns on misuse and SoMe caveats are discussed.ConclusionOver the last two decades, social media has had a huge impact on science dissemination, journal article discussions, and presentation of conference news. Immediate and real-time presentation of studies, articles, or presentations has flattened hierarchy for participation, debate, and engagement. Surgeons should learn how to use novel communication technology to advance the field and further professional and public interaction.

CITATION: Czachur, M. V. et al. 2021. Opening the floor for discussion : a perspective on how scholars perceive attitudes to science in policymaking in South Africa. South African Journal of Science, 117(1/2):7948, doi:10.17159/sajs.2021/7948.

Ghrelin and its endogenous antagonist liver‐expressed antimicrobial peptide‐2 (LEAP‐2) are involved in GH secretion and glucose/lipids metabolism. LEAP‐2 expression in conditions of metabolic impairment may be upregulated, usually pairing with a concomitant reduction in ghrelin secretion. Adult growth hormone deficiency (aGHD) is characterized by insulin resistance, weight gain, and increased fat mass. Therefore, the primary endpoint of this cross‐sectional observational pilot study was to compare circulating LEAP‐2 and ghrelin levels in aGHD and healthy controls. Thirty patients were included in the study. Group A included adult GHD: 15 patients, 8 females, and 7 males. Median and interquartile range age of the group was 53 (41–57) years, while BMI was 27.1 (25–35) kg/m2. Group B was formed by 15 healthy controls (10 females and 5 males). Median and interquartile range age was 47 (36–57) years, while BMI 22.9 (20.8–33.1) kg/m2. They were evaluated for serum glucose and insulin, HOMA‐index, QUICKI‐index, total/LDL/HDL cholesterol, triglycerides, IGF‐1, ghrelin, and LEAP‐2. Ghrelin levels in the aGHD group were significantly lower than in healthy controls. In contrast, LEAP‐2 showed a trend toward higher levels, although the differences were not significant. However, the LEAP‐2/Ghrelin ratio was significantly higher in aGHD. No significant correlations between ghrelin and LEAP‐2 with BMI and HOMA index were found in aGHD population. However, a significant inverse correlation (r 2 = 0.15, p = .047) between BMI and ghrelin was evidenced when considering the whole population. Taken together, these results may suggest a body adaptation to a metabolic scenario typical of aGHD. The decrease in ghrelin production could prevent further weight gain and fat mass increase, although losing its secretagogue effect.

Here, we showed that the acetylation-defective p53-4KR mice, lacking the ability of cell cycle arrest, senescence, apoptosis, and ferroptosis, were tumor prone but failed to develop early-onset tumors. By identifying a novel p53 acetylation site at lysine K136, we found that simultaneous mutations at all five acetylation sites (p53-5KR) diminished its remaining tumor suppression function. Moreover, the embryonic lethality caused by the deficiency of mdm2 was fully rescued in the background of p535KR/5KR, but not p534KR/4KR background. p53-4KR retained the ability to suppress mTOR function but this activity was abolished in p53-5KR cells. Notably, the early-onset tumor formation observed in p535KR/5KR and p53-null mice was suppressed upon the treatment of the mTOR inhibitor. These results suggest that p53-mediated mTOR regulation plays an important role in both embryonic development and tumor suppression, independent of cell cycle arrest, senescence, apoptosis, and ferroptosis.

Vibrio cholerae is the causative agent of the diarrheal disease cholera, for which biofilm communities are considered to be environmental reservoirs. In endemic regions, and after algal blooms, which may result from phosphate enrichment following agricultural runoff, the bacterium is released from biofilms resulting in seasonal disease outbreaks. However, the molecular mechanism by which V. cholerae senses its environment and switches lifestyles from the biofilm‐bound state to the planktonic state is largely unknown. Here, we report that the major biofilm scaffolding protein RbmA undergoes autocatalytic proteolysis via a phosphate‐dependent induced proximity activation mechanism. Furthermore, we show that RbmA mutants that are defective in autoproteolysis cause V. cholerae biofilms to grow larger and mechanically stronger, correlating well with the observation that RbmA stability directly affects microbial community homeostasis and rheological properties. In conclusion, our biophysical study characterizes a novel phosphate‐dependent breakdown pathway of RbmA, while microbiological data suggest a new, sensory role of this biofilm scaffolding element.

The stories we tell and are told, the images we see and share, the ways we communicate find new paths and come to expression in new forms of networks, other agoras (to borrow Foley’s terminology) and at a faster pace. Nonetheless, we ought to examine what the novelty of contemporary storytelling consists in when it conquers digital forms and environments. Likewise, the digital brings us new tools and possibilities of access to data – but how much have our disciplines, methods, approaches and concepts actually transformed and changed? And how much have we assessed the capacity of adaptation of our disciplines for embracing the study of what takes place online and in relation to the digital? From this vantage point, this paper gives particular attention to the footprints and the traceability of our doings and our data in order to highlight the flows, continuity and ruptures of what we do and tell. Based on examples from a variety of contexts, I illustrate how our quest for renewal, novelty and innovation is strongly anchored in, subjected to and depends upon our habits, old-fashioned ways and ability to observe the world around us. Further, I argue that in research like in storytelling, the value of vintage equals the value of novelty and originality. Las historias que contamos y nos cuentan, las imágenes que vemos y compartimos, las formas en que nos comunicamos, encuentran nuevos caminos y se expresan en nuevas formas de redes, otras ágoras (para tomar prestada la terminología de Foley) y a un ritmo más rápido. No obstante, conviene examinar en qué consiste la novedad de la narración contemporánea cuando conquista formas y entornos digitales. Del mismo modo, lo digital nos brinda nuevas herramientas y posibilidades de acceso a los datos, pero ¿cuánto se han transformado y cambiado realmente nuestras disciplinas, métodos, enfoques y conceptos? Y ¿cuánto hemos valorado la capacidad de adaptación de nuestras disciplinas para emprender el estudio de lo que ocurre en línea y en relación con lo digital? Desde este punto de vista, este trabajo presta especial atención a las huellas y la trazabilidad de nuestra actividad y de nuestros datos, para resaltar los flujos, la continuidad y los cambios en lo que hacemos y contamos. Basándome en ejemplos procedentes de una gran variedad de contextos, ilustro cómo nuestra búsqueda de renovación, novedad e innovación está fuertemente anclada, sujeta y depende de nuestros hábitos, costumbres y de la capacidad de observar el mundo que nos rodea. Además, sostengo que tanto en la investigación como en la narración de historias, el valor de lo antiguo es igual al valor de la novedad y la originalidad. Alternative title: "Huella digital y trazabilidad narrativa/Huella narrativa y trazabilidad digital"

With the ongoing rise of coronavirus disease 2019 (COVID-19) pandemic across the globe, interests in COVID-19 antibody testing, also known as a serology test has grown, as a way to measure how far the infection has spread in the population and to identify individuals who may be immune. Recently, many countries reported their population based antibody titer study results. South Korea recently reported their third antibody formation rate, where it divided the study between the general population and the young male youths in their early twenties. As previously stated, these simple point estimates may be misinterpreted without proper estimation of standard error and confidence intervals. In this article, we provide an updated 95% confidence intervals for COVID-19 antibody formation rate for the Korean population using asymptotic, exact and Bayesian statistical estimation methods. As before, we found that the Wald method gives the narrowest interval among all asymptotic methods whereas mid p-value gives the narrowest among all exact methods and Jeffrey's method gives the narrowest from Bayesian method. The most conservative 95% confidence interval estimation shows that as of 00:00 November 23, 2020, at least 69,524 people were infected but not confirmed. It also shows that more positive cases were found among the young male in their twenties (0.22%), three times that of the general public (0.051%). This thereby calls for the quarantine authorities' need to strengthen quarantine managements for the early twenties in order to find the hidden infected people in the population.

As the knowledge society paradigm and its emphasis on knowledge as socioeconomic capital grows, the importance of subtle, collective sharing of ‘blue skies’ academic theories is sidelined. Non-expert voices are largely marginalized in these discussions of what academic knowledge is or should be. In order to bridge gaps between academia and laypeople, and basic research and impact, this study explored how Canadian laypeople construed the popularity of academic theories across domains of physical sciences, social sciences, and the humanities, and related those perceptions to a novel measure of diffusion. An integrated mixed-methods research design was framed by a constructionist philosophy and a conceptual framework rooted in Diffusion of Innovations literature, re-conceptualizing academic theories as constructed innovations. Ninety academic theories were input into Google Trends, which provided data regarding the frequency with which Canadians searched theory terms. This was used as a measure of initial diffusion. Repertory grids were produced with the completion of online interviews with fifteen Canadian laypeople, which captured the qualities of academic theories that they understood as being related to popularity. Qualitative analyses revealed that Canadian laypeople had complex, mixed feelings about whether theories were beneficial or irrelevant. Cluster analyses identified themes of ‘the nature of discussion’, ‘benefits’, ‘acceptance of the best knowledge’, ‘explanation of something meaningful’, ‘understandability’, ‘physically verification’, ‘scientific proof’, ‘religious belief’, and ‘applied use’ as being used by laypeople to contrast the popularity of academic theories, the first three of which were most closely related to the initial diffusion of theories. Overall, the conceptual framework of innovations attributes from Diffusion of Innovations literature proved to be a fruitful application.

From July 2021 eLife will only review manuscripts already published as preprints, and will focus its editorial process on producing public reviews to be posted alongside the preprints.

It has been assumed that the suprachiasmatic nucleus (SCN) synchronizes peripheral circadian oscillators. However, this has never been convincingly shown, since biochemical time series experiments are not feasible in behaviorally arrhythmic animals. By using long-term bioluminescence recording in freely moving mice, we show that the SCN is indeed required for maintaining synchrony between organs. Surprisingly, however, circadian oscillations persist in the livers of mice devoid of an SCN or oscillators in cells other than hepatocytes. Hence, similar to SCN neurons, hepatocytes can maintain phase coherence in the absence of Zeitgeber signals produced by other organs or environmental cycles.

Trichinella zimbabwensis naturally infects a variety of reptilian and wild mammalian hosts in South Africa. Attempts have been made to experimentally infect piranha fish with T. zimbabwensis and T. papuae without success. Tigerfish (Hydrocynus vittatus) and African sharp tooth catfish (Clarias gariepinus) are accomplished predators cohabiting with Nile crocodiles (Crocodylus niloticus) and Nile monitor lizards (Varanus niloticus) in southern Africa and are natural hosts of T. zimbabwensis. To assess the infectivity of T. zimbabwensis to these two hosts, 24 African sharp tooth catfish (mean live weight 581.75 ± 249.71 g) randomly divided into 5 groups were experimentally infected with 1.0 ± 0.34 T. zimbabwensis larvae per gram (lpg) of fish. Forty-one tigerfish (mean live weight 298.6 ± 99.3 g) were randomly divided for three separate trials. An additional 7 tigerfish were assessed for the presence of natural infection as controls. Results showed no adult worms or larvae of T. zimbabwensis in the gastrointestinal tract and body cavities of catfish sacrificed at day 1, 2 and 7 post-infection (p.i.). Two tigerfish from one experimental group yielded 0.1 lpg and 0.02 lpg of muscle tissue at day 26 p.i. and 28 p.i., respectively. No adult worms or larvae were detected in the fish from the remaining groups sacrificed at day 7, 21, 28, 33 and 35 p.i. and from the control group. Results from this study suggest that tigerfish could sustain T. zimbabwensis under specific yet unknown circumstances.

While changes in MeCP2 dosage cause Rett syndrome (RTT) and MECP2 duplication syndrome (MDS), its transcriptional regulation is poorly understood. Here, we identified six putative noncoding regulatory elements of Mecp2, two of which are conserved in humans. Upon deletion in mice and human iPSC-derived neurons, these elements altered RNA and protein levels in opposite directions and resulted in a subset of RTT- and MDS-like behavioral deficits in mice. Our discovery provides insight into transcriptional regulation of Mecp2/MECP2 and highlights genomic sites that could serve as diagnostic and therapeutic targets in RTT or MDS.

Mutations in the estrogen receptor α (ERα) occur in endocrine-resistant metastatic breast cancer. However, a major gap persists with the lack of genetically tractable immune competent mouse models to study disease. Hence, we developed a Cre-inducible murine model expressing a point-activated ESR1Y541S (ESR1Y537S in humans) driven by its endogenous promoter. Germline expression of mutant ESR1Y541S reveals dramatic developmental defects in the reproductive organs, mammary glands, and bones of the mice. These observations provide critical insights into the tissue-specific roles of ERα during development and highlights the potential use of our model in further developmental and cancer studies.

Prezentácia z webinára pre STU o vývoji vedeckej komunikácie, Open Access a Open Science.

The eLife Early-Career Advisory Group (ECAG), an international group of early-career researchers committed to improving research culture, calls for radical changes at eLife and other journals to address racism in the scientific community and to make science more diverse and inclusive. Fil: Mehta, Devang. University of Alberta; Canadá Fil: Bediako, Yaw. University Of Ghana; Ghana Fil: De Winde, Charlotte M.. Colegio Universitario de Londres; Reino Unido Fil: Ebrahimi, Hedyeh. No especifíca; Fil: Fernández, Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires - Instituto Partner de la Sociedad Max Planck; Argentina Fil: Ilangovan, Vinodh. University Aarhus; Dinamarca Fil: Paz Quezada, Carolina. Universidad Bernardo O'higgins; Chile Fil: Riley, Julia L.. Dalhousie University Halifax; Canadá Fil: Saladi, Shyam M.. California Institute of Technology; Estados Unidos Fil: Tay, Andy. No especifíca; Fil: Weissgerber, Tracey. No especifíca

On the 17th February 2020, British Library and RAND Europe convened a roundtable discussion on the future of research outputs. Since the workshop we have all been challenged by the profound changes to our lives and research caused by COVID-19, a crisis which re-focused a worldwide research effort in search of a vaccine and effective drugs, and which, among other things, brought into sharp relief the importance of rapid sharing of research data, but also importance of communicating research to the widest possible public. This makes this discussion even more relevant when considering the future of research outputs. The aim of the workshop was to explore the issues and implications for different actors in the sector e.g. researchers, universities, libraries and funders presenting recent research and facilitating a discussion with the group.

Kynurenic acid (KynA) levels link peripheral metabolic status to neural functions including learning and memory. Since neural KynA levels dampen learning capacity, KynA reduction has been proposed as a therapeutic strategy for conditions of cognitive deficit such as neurodegeneration. While KynA is generated locally within the nervous system, its precursor, kynurenine (Kyn), is largely derived from peripheral resources. The mechanisms that import Kyn into the nervous system are poorly understood. Here, we provide genetic, anatomical, biochemical, and behavioral evidence showing that in C. elegans an ortholog of the human LAT1 transporter, AAT-1, imports Kyn into sites of KynA production.

In this paper, we present few technical notes about the distance distribution paradigm for Mosaab-metric using 1, 2, and 3 grams feature extraction techniques to analyze composite data points in high dimensional feature spaces. This technical analysis will help the specialist in bioinformatics and biotechnology to deeply explore the biodiversity of influenza virus genome as a composite data point. Various technical examples are presented in this paper, in addition, the integrated statistical learning pipeline to process segmented genomes of influenza virus is illustrated as sequential-parallel computational pipeline.

Introduction Predatory journals harm the integrity of science as principles of ‘good scientific practice’ are bypassed by omitting a proper peer-review process. Therefore, we aimed to explore the awareness of predatory journals among oncologists. Methods An online survey among oncologists working in Germany or Austria of various professional surroundings was conducted between October 2018 and April 2019. Results One hundred and eighty-eight participants (55 women (29.2%), 128 men (68.1%)) completed the questionnaire. 41 (21.8%) participants indicated to work in a hospital, 24 (12.8%) in private practice and 112 (59.6%) in a university hospital. 98.9% of participants indicated to actively read scientific articles and consider them in clinical decision-making (96.3%). 90.4% of participants indicated to have scientific experience by publishing papers in journals with peer-review system. The open-access system was known by 170 (90.4%), predatory journals by 131 (69.7%) and Beall’s list by 52 participants (27.7%). Predatory journals were more likely to be known by participants with a higher number of publications (p

Mitochondrial function requires the coordinated expression of dozens of gene products from the mitochondrial genome and hundreds from the nuclear genomes. The systems that emerge from these interactions convert the food we eat and the oxygen we breathe into energy for life, while regulating a wide range of other cellular processes. These facts beg the question of whether the gene‐by‐gene interactions (G x G) that enable mitochondrial function are distinct from the gene‐by‐environment interactions (G x E) that fuel mitochondrial activity. We examine this question using a Drosophila model of mitonuclear interactions in which experimental combinations of mtDNA and nuclear chromosomes generate pairs of mitonuclear genotypes to test for epistatic interactions (G x G). These mitonuclear genotypes are then exposed to altered dietary or oxygen environments to test for G x E interactions. We use development time to assess dietary effects, and genome wide RNAseq analyses to assess hypoxic effects on transcription, which can be partitioned in to mito, nuclear, and environmental (G x G x E) contributions to these complex traits. We find that mitonuclear epistasis is universal, and that dietary and hypoxic treatments alter the epistatic interactions. We further show that the transcriptional response to alternative mitonuclear interactions has significant overlap with the transcriptional response to alternative oxygen environments. Gene coexpression analyses suggest that these shared genes are more central in networks of gene interactions, implying some functional overlap between epistasis and genotype by environment interactions. These results are discussed in the context of evolutionary fitness, the genetic basis of complex traits, and the challenge of achieving precision in personalized medicine. © 2018 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 70(12):1275–1288, 2018

The oncogene KRAS not only promotes the tumorigenesis of pancreatic cancers but also is required for the malignant progression and metastasis of these cancers. Many methods have been explored to influence the malignant biological behavior of these cancers by targeting mutant KRAS. The ornithine decarboxylase/antizyme (ODC/AZ) system is another protein degradation pathway that exists in nature. The formation of an ODC and protein substrate complex through direct combination can promote its degradation by the 26S proteasome without ubiquitination, and this process can be catalyzed by AZ. In this study, we designed and reconstructed a chimeric fusion protein (named RC‐ODC). The engineered fusion protein RC‐ODC was confirmed to interact with the mutant KRAS oncoprotein in a co‐immunoprecipitation assay, and the introduction of both RC‐ODC and AZ resulted in degradation of the exogenous and endogenous mutant KRAS oncoprotein at the post‐translational level independent of ubiquitination in vitro. Along with a decreased KRAS level, suppression of PANC‐1 cell proliferation was detected in vitro and in vivo, and meanwhile downregulation of phosphorylated extracellular signal‐regulated kinase 1/2 (ERK1/2) was also observed. Targeted degradation of the KRAS oncoprotein through the ODC/AZ pathway at the post‐translational level may reflect a more effective future therapeutic strategy for pancreatic cancer patients. © 2018 The Authors. IUBMB Life published by Wiley Periodicals,Inc. on behalf of International Union of Biochemistry and Molecular Biology, 71(1):57–65, 2019

Summary Ketamine, though widely used in pediatric anesthesia, may induce cortical neurotoxicity in young patients. This study focused on an in vitro model of rat brain embryonic stem cell (ESC)‐derived neurons to investigate the effects of microRNA‐107 (miR‐107) on ketamine‐induced neural injury. Rat brain ESCs were proliferated in vitro and differentiated toward neuronal fate. Ketamine induced neural injury in ESC‐derived neurons was inspected by TUNEL and neurite growth assays. Ketamine‐induce aberrant miR‐107 expression was examined by qRT‐PCR. MiR‐107 was downregulated in ESCs through lentiviral transduction. Its effect on ketamine‐induced neural injury in ESC‐derived neurons was then examined. Potential downstream target of miR‐107, brain derived neurotrophin factor (BDNF), was inspected by dual‐luciferase reporter assay and qRT‐PCR. BDNF was knocked down, through siRNA transfection, in NSCs to investigate its functional involvement in miR‐107 mediated neural protection in ketamine‐injured NSC‐derived neurons. Ketamine induced apoptosis, neurite degeneration, and upregulated miR‐107 in NSC‐derived neurons. Lentivirus‐mediated miR‐107 downregulation attenuated ketamine‐induced neural injury. BDNF was proven to be directly and inversely regulated by miR‐107 in NSC‐derived neurons. SiRNA‐mediated BDNF inhibition reversed the protective effect of miR‐107 downregulation on ketamine injury in NSC‐derived neurons. MiR‐107 / BDNF was demonstrated to be an important epigenetic signaling pathway in regulating ketamine‐induced neural injury in cortical neurons. © 2018 The Authors. IUBMB Life published by Wiley Periodicals,Inc. on behalf of International Union of Biochemistry and Molecular Biology., 71(1):20–27, 2019

Summary The mitochondrial DNA of diplonemid and kinetoplastid protists is known for its suite of bizarre features, including the presence of concatenated circular molecules, extensive trans‐splicing and various forms of RNA editing. Here we report on the existence of another remarkable characteristic: hyper‐inflated DNA content. We estimated the total amount of mitochondrial DNA in four kinetoplastid species (Trypanosoma brucei, Trypanoplasma borreli, Cryptobia helicis, and Perkinsela sp.) and the diplonemid Diplonema papillatum. Staining with 4′,6‐diamidino‐2‐phenylindole and RedDot1 followed by color deconvolution and quantification revealed massive inflation in the total amount of DNA in their organelles. This was further confirmed by electron microscopy. The most extreme case is the ∼260 Mbp of DNA in the mitochondrion of Diplonema, which greatly exceeds that in its nucleus; this is, to our knowledge, the largest amount of DNA described in any organelle. Perkinsela sp. has a total mitochondrial DNA content ~6.6× greater than its nuclear genome. This mass of DNA occupies most of the volume of the Perkinsela cell, despite the fact that it contains only six protein‐coding genes. Why so much DNA? We propose that these bloated mitochondrial DNAs accumulated by a ratchet‐like process. Despite their excessive nature, the synthesis and maintenance of these mtDNAs must incur a relatively low cost, considering that diplonemids are one of the most ubiquitous and speciose protist groups in the ocean. © 2018 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology., 70(12):1267–1274, 2018

MYC enhances protein synthesis by regulating genes involved in ribosome biogenesis and protein translation. Here, we show that MYC-induced protein translation is mediated by the transcription factor aryl hydrocarbon receptor (AHR), which is induced by MYC in colonic cells. AHR promotes protein synthesis by activating the transcription of genes required for ribosome biogenesis and protein translation, including OGFOD1 and NOLC1. Using surface sensing of translation (SUnSET) to measure global protein translation, we found that silencing AHR or its targets diminishes protein synthesis. Therefore, targeting AHR or its downstream pathways could provide a novel approach to limit biomass production in MYC-driven tumors.

The CNS of the protovertebrate Ciona intestinalis contains a single cluster of dopaminergic (DA) neurons, the coronet cells, which have been likened to the hypothalamus of vertebrates. Whole-embryo single-cell RNA sequencing (RNA-seq) assays identified Ptf1a as the most strongly expressed cell-specific transcription factor (TF) in DA/coronet cells. Knockdown of Ptf1a activity results in their loss, while misexpression results in the appearance of supernumerary DA/coronet cells. Photoreceptor cells and ependymal cells are the most susceptible to transformation, and both cell types express high levels of Meis. Coexpression of both Ptf1a and Meis caused the wholesale transformation of the entire CNS into DA/coronet cells. We therefore suggest that the reiterative use of functional manipulations and single-cell RNA-seq assays is an effective means for the identification of regulatory cocktails underlying the specification of specific cell identities.

Skin biopsy is an important procedure for a correct diagnosis of varying skin conditions, from inflammatory to neoplastic diseases. Nevertheless, some authors still consider this procedure a high risk in patients affected by leg ulcers (LUs) and prefer reserving it for selected cases [1].

Tomato Dicer-like2 (slDCL2) is a key component of resistance pathways against potato virus X (PVX) and tobacco mosaic virus (TMV). It is also required for production of endogenous small RNAs, including miR6026 and other noncanonical microRNAs (miRNAs). The slDCL2 mRNAs are targets of these slDCL2-dependent RNAs in a feedback loop that was disrupted by target mimic RNAs of miR6026. In lines expressing these RNAs, there was correspondingly enhanced resistance against PVX and TMV. These findings illustrate a novel miRNA pathway in plants and a crop protection strategy in which miRNA target mimicry elevates expression of defense-related mRNAs.

Loss of function of the DIS3L2 exoribonuclease is associated with Wilms tumor and the Perlman congenital overgrowth syndrome. LIN28, a Wilms tumor oncoprotein, triggers the DIS3L2-mediated degradation of the precursor of let-7, a microRNA that inhibits Wilms tumor development. These observations have led to speculation that DIS3L2-mediated tumor suppression is attributable to let-7 regulation. Here we examine new DIS3L2-deficient cell lines and mouse models, demonstrating that DIS3L2 loss has no effect on mature let-7 levels. Rather, analysis of Dis3l2-null nephron progenitor cells, a potential cell of origin of Wilms tumors, reveals up-regulation of Igf2, a growth-promoting gene strongly associated with Wilms tumorigenesis. These findings nominate a new potential mechanism underlying the pathology associated with DIS3L2 deficiency.