Single molecule studies reveal branched pathways for activator-dependent assembly of RNA polymerase II pre-initiation complexes RNA polymerase II (Pol II) transcription reconstituted from purified factors suggests pre-initiation complexes (PICs) can assemble by sequential incorporation of factors at the TATA box. However, these basal transcription reactions are generally independent of activators and co-activators. To study PIC assembly under more realistic conditions, we used single-molecule microscopy to visualize factor dynamics during activator-dependent reactions in nuclear extracts. Surprisingly, Pol II, TFIIF, and TFIIE can pre-assemble on enhancer-bound activators before loading into PICs, and multiple Pol II complexes can bind simultaneously to create a localized cluster. Unlike TFIIF and TFIIE, TFIIH binding is singular and dependent on the basal promoter. Activator-tethered factors exhibit dwell times on the order of seconds. In contrast, PICs can persist on the order of minutes in the absence of nucleotide triphosphates, although TFIIE remains unexpectedly dynamic even after TFIIH incorporation. Our kinetic measurements lead to a new branched model for activator-dependent PIC assembly.

HIGHLIGHTSSingle molecule microscopy reveals unexpected dynamics of RNA Pol II and GTFs

Multiple Pol IIs cluster on UAS/enhancer-bound activators before binding the core promoter

Pol II, TFIIF, and TFIIE, but not TFIIH, can pre-assemble at the UAS/enhancer

Activators increase the rates of Pol II and GTF association with DNA

eTOC BlurbSingle-molecule microscopy experiments by Baek et al. show that RNA polymerase II and basal transcription factors TFIIF and TFIIE preassemble on UAS/enhancer-bound activators, poised for loading into initiation complexes with TFIIH at the core promoter. Transcription activators kinetically enhance factor recruitment, creating a localized cluster of polymerases at the UAS/enhancer.
Erythropoietin supplementation ameliorates the immunological and hematological deficiencies of lysinuric protein intolerance in mice SLC7A7 encodes for y+LAT1, a cationic amino acid transporter expressed on the basolateral membrane of epithelial cells and macrophages. Mutations in human SLC7A7 cause lysinuric protein intolerance (LPI), a rare autosomal disorder with a variety of clinical symptoms. Citrulline and a low protein diet are widely used to treat the main symptoms of LPI; however, the hematological and immunological abnormalities in LPI remain poorly understood and difficult to manage by established treatments. Here, we show that erythropoietin levels are significantly diminished in mice lacking Slc7a7, which reduces the number of erythroblast precursors, resulting in mature red blood cells with a smaller mean corpuscular volume. Ex vivo analysis demonstrated that erythrocytes from Slc7a7-deficient mice were phagocytosed more by bone marrow-derived macrophages. Gene expression analysis of sorted red pulp macrophages (RPMs) from Slc7a7-deficient mice indicated that this cell population had higher erythrophagocytic activity, but preserved heme catabolic activity. The increase in erythrophagocytosis resulted in iron accumulation in macrophages and tissues, and ultimately led to RPM apoptosis. Surprisingly, ablation of Slc7a7 in myeloid cells failed to trigger tissue iron accumulation or changes in the RPM population, indicating that the expression of this gene in macrophages is not key for the development of iron accumulation in tissue. Finally, restoration of serum erythropoietin levels in Slc7a7-deficient mice re-established normal erythropoiesis and erythrophagocytosis and prevented the accumulation of iron in tissues. Thus, erythropoietin has a fundamental role in the immune-hematological alterations of LPI in mice, revealing a new crucial role for this hormone in this disease.
First evidence of in vitro cytotoxic effects of marine microlitter on Merluccius merluccius and Mullus barbatus, two Mediterranean commercial fish species Marine litter is composed mainly of plastics and is recognized as a serious threats to marine ecosystems. Ecotoxicological approaches have started elucidating the potential severity of microplastics (MPs) in controlled laboratory studies with pristine materials but no information exist on marine environmental microlitter as a whole. Here, we characterized the litter in the coastal Northern Tyrrhenian sea and in the stomach of two fish species of socio-economic importance, and exposed primary cell cultures of mucosal and lymphoid organs to marine microlitter for evaluating possible cytotoxic effects. An average of 0.30 {+/-} 0.02 microlitter items m-3 was found in water samples. FT-IR analysis revealed that plastic particles, namely HDPE, polyamide and polypropylene were present in 100% and 83.3% of Merluccius merluccius and Mullus barbatus analyzed, which overall ingested 14.67 {+/-} 4.10 and 5.50 {+/-} 1.97 items/individual, respectively. Moreover, microlitter was confirmed as a vector of microorganisms. Lastly, the apical end-point of viability was found to be significantly reduced in splenic cells exposed in vitro to two microlitter conditions. Considering the role of the spleen in the mounting of adaptive immune responses, our results warrant more in-depth investigations for clarifying the actual susceptibility of these two species to anthropogenic microlitter.

HighlightsO_LI0.30 {+/-} 0.02 microlitter items m-3 were found at the surface of coastal Northern Tyrrhenian sea
C_LIO_LI14.67 {+/-} 4.10 and 5.50 {+/-} 1.97 items/individual were retrieved from the stomach of hakes and mullets
C_LIO_LIThe ingested microlitter contained plastic items
C_LIO_LIMicrolitter was validated as a carrier of bacteria, fungi and flagellates
C_LIO_LISplenic cells exposed to two microlitter conditions for 72 hours suffered cytotoxicity
C_LI Enhancers regulate 3' end processing activityto control expression of alternative 3'UTR isoforms Multi-UTR genes are widely transcribed but show cell type-specific 3'UTR isoform expression. As transcriptional enhancers regulate mRNA expression, we investigated if they also regulate mRNA isoform expression. Deletion of an endogenous enhancer of a multi-UTR gene did not impair transcript production but prevented a switch in 3'UTR isoform expression. Also, the same enhancers are able to increase transcript production in the context of single-UTR gene promoters, but they increase 3' end processing activity when paired with multi-UTR gene promoters. We show that transcription factors regulate processing activity of weak polyadenylation sites to control cell type-specific alternative 3'UTR isoform expression of widely expressed genes. A novel sodium signaling complex regulates uterine activity Depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential is necessary for the transition of the uterus from a quiescent state to a contractile state. The molecular mechanisms involved in this transition are not completely understood. Here, we report a novel coupled system between the Na+-activated K+ channel (SLO2.1) and the non-selective Na+ leak channel (NALCN) which determines the MSMC membrane potential. We show that SLO2.1 currents are activated by an inward Na+ leak current carried by the NALCN channel leading to MSMC hyperpolarization. These results show an unanticipated role for the Na+ leak currents in activating a negative feedback system countering the excitable effects of Na+ currents. This is a novel role for the NALCN channel in which Na+ acts as an intracellular signaling molecule. In fact, we report here that the net effect of Na+ entry through NALCN channels is a hyperpolarization of the MSMCs plasma membrane because of the activation of SLO2.1 K channel. Importantly, we also report that a decrease in NALCN/SLO2.1 activity triggers both Ca2+ entries through VDCCs, promoting myometrial contraction. Consistently, with a functional coupling, our data show that NALCN and SLO2.1 are in proximity to one another in human MSMCs. We propose that the spatial arrangement of SLO2.1 and NALCN permits these channels to functionally interact in order to regulate human MSMC membrane potential and cell excitability to modulate uterine contractile activity. Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: the Multi-Targeting Drug DREAM Challenge A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets ( polypharmacology). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.

Author SummaryMany modern drugs are developed with the goal of modulating a single cellular pathway or target. However, many drugs are, in fact,  dirty; they target multiple cellular pathways or targets. This phenomenon is known as multi-targeting or polypharmacology. While some strive to develop  cleaner therapeutics that eliminate secondary targets, recent work has shown that multi-targeting therapeutics have key advantages for a variety of diseases. However, while multi-targeting drugs that affect a precisely-defined profile of targets may be more effective, it is difficult to computationally predict which molecules have desirable target profiles. Here, we report the results of a competitive crowdsourcing project (the Multi-Targeting Drug DREAM Challenge), where we challenged participants to predict chemicals that have desired target profiles for cancer and neurodegenerative disease. Propelling and perturbing appendages together facilitate strenuous ground self-righting Terrestrial animals must self-right when overturned on the ground, but this locomotor task is strenuous. To do so, the discoid cockroach often pushes its wings against the ground to begin a somersault which rarely succeeds. As it repeatedly attempts this, the animal probabilistically rolls to the side to self- right. During winged self-righting, the animal flails its legs vigorously. Here, we studied whether wing opening and leg flailing together facilitate strenuous ground self-righting. Adding mass to increase hind leg flailing kinetic energy increased the animals self-righting probability. We then developed a robot with similar strenuous self-righting behavior and used it as a physical model for systematic experiments. The robots self-righting probability increased with wing opening and leg flailing amplitudes. A potential energy landscape model revealed that, although wing opening did not generate sufficient kinetic energy to overcome the high pitch potential energy barrier to somersault, it reduced the barrier for rolling, facilitating the small kinetic energy from leg flailing to probabilistically overcome it to self-right. The model also revealed that the stereotyped body motion during self-righting emerged from physical interaction of the body and appendages with the ground. Our work demonstrated the usefulness of potential energy landscape for modeling self-righting transitions.

Impact statementAnimals can, and robots should, use different types of appendages together to propel and perturb themselves to self-right when overturned, a strenuous yet crucial locomotor task. Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. Allopurinol Blocks The Formation And Progression Of Aortic Aneurysm In A Mouse Model Of Marfan Syndrome BackgroundThe pathogenesis and progression of aortic aneurysm in Marfan syndrome (MFS) involves dysregulated TGF-{beta} and nitric oxide signaling, altered hemodynamics, and biomechanical forces. Increasing evidence indicates that redox stress participates in MFS aortopathy, though its contribution is not well established. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mice aortic samples. Here we address the contribution of xanthine oxidoreductase (XOR), which is transcribed as dehydrogenase (XDH) and then post-translationally modified to oxidase (XO), catabolizing mainly purines into uric acid and ROS.

Methods and ResultsWe report that in MFS patients, XOR protein levels increased in aortic samples. In MFS mice (Fbn1C1041G/+), XOR mRNA transcripts augmented in the aorta of young but not older MFS mice. Moreover, the enzymatic activity of XO form increased with respect to XDH. The administration of the XOR inhibitor allopurinol (ALO) blocked the progression of aortic root aneurysm in MFS mice. ALO was also protective when administrated before the appearance of aneurysm. MFS-induced elastic fiber fragmentation, fibrotic remodeling, nuclear translocation of pNRF2, and increased 3-nitrotyrosine levels in the aortic tunica media as well as endothelial dysfunction were all prevented by allopurinol. The large overproduction of H2O2 in MFS aorta did not occur in allopurinol-treated mice whose uric acid plasma levels remained unaltered.

ConclusionsThis study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and supports a clinical trial for ALO in the pharmacological treatment of MFS aortopathy.

GRAPHICAL ABSTRACT

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=146 SRC="FIGDIR/small/464182v3_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@eab02aorg.highwire.dtl.DTLVardef@1d3b39eorg.highwire.dtl.DTLVardef@1b54d0forg.highwire.dtl.DTLVardef@1d61ad0_HPS_FORMAT_FIGEXP  M_FIG C_FIG An mRNA SARS-CoV-2 vaccine employing Charge-Altering Releasable Transporters with a TLR-9 agonist induces neutralizing antibodies and T cell memory The SARS-CoV-2 pandemic has necessitated the rapid development of prophylactic vaccines. Two mRNA vaccines have been approved for emergency use by the FDA and have demonstrated extraordinary effectiveness. The success of these mRNA vaccines establishes the speed of development and therapeutic potential of mRNA. These authorized vaccines encode full-length versions of the SARS-CoV-2 spike protein. They are formulated with Lipid Nanoparticle (LNP) delivery vehicles that have inherent immunostimulatory properties. Different vaccination strategies and alternative mRNA delivery vehicles would be desirable to ensure flexibility of future generations of SARS-CoV-2 vaccines and the development of mRNA vaccines in general.

Here, we report on the development of an alternative mRNA vaccine approach using a delivery vehicle called Charge-Altering Releasable Transporters (CARTs). Using these inherently nonimmunogenic vehicles we can tailor the vaccine immunogenicity by inclusion of co-formulated adjuvants such as oligodeoxynucleotides with CpG motifs (CpG-ODN). Mice vaccinated with the mRNA-CART vaccine developed therapeutically relevant levels of RBD-specific neutralizing antibodies in both the circulation and in the lung bronchial fluids. In addition, vaccination elicited strong and long lasting RBD-specific TH1 T cell responses including CD4+ and CD8+ T cell memory. A network approach to genetic circuit designs As genetic circuits become more sophisticated, the size and complexity of data about their designs increases. This data captured goes beyond monolithic genetic sequences and towards circuit modularity and functional details, which are beneficial for analyzing circuit performance and establishing design automation techniques. However, the accessibility, visualisation and usability of design data (and metadata) have received relatively little attention to date. Here, we present a method to turn circuit designs into networks and showcase its potential to enhance the utility of design data. Since networks are dynamic structures, initial graphs can be interactively shaped into sub-networks of relevant information based on requirements such as abstraction, hierarchy and protein interactions. Additionally, several visual changes can be applied, such as colouring or clustering nodes based on types (e.g., genes or promoters), resulting in easier comprehension from a user perspective. This approach allows circuit designs to be coupled to other networks, such as metabolic pathways or implementation protocols captured in graph-like formats. Therefore, we advocate using networks to structure, access and improve synthetic biology information. The effect of resource depletion on the thermal response of mosquito population fitness The temperature-dependencies of life history traits are increasingly being used to predict how climatic warming will affect vector-borne disease dynamics, partially by affecting the abundance dynamics of the vector population. Such predictions generally arise from mathematical models that incorporate the temperature dependence of traits measured under laboratory conditions. These temperature-trait relationships are typically estimated from juvenile populations reared under optimal resource conditions, even though natural populations experience intermittent resource depletion. Using laboratory experiments on the mosquito Aedes aegypti, combined with a stage-structured population model, we show that resource depletion in the juvenile habitat can significantly depress the vectors maximal population growth rate (rm) across the entire temperature range, cause it to peak at a lower temperature, and narrow its thermal niche width. Our results provide compelling evidence for future studies to consider resource depletion when predicting the effects of global change on vector-borne disease transmission, disease vectors and other arthropods. Hippocampal sharp wave-ripples and the associated sequence replay emerge from structured synaptic interactions in a network model of area CA3 Hippocampal place cells are activated sequentially as an animal explores its environment. These activity sequences are internally recreated ("replayed"), either in the same or reversed order, during bursts of activity (sharp wave-ripples; SWRs) that occur in sleep and awake rest. SWR-associated replay is thought to be critical for the creation and maintenance of long-term memory. In order to identify the cellular and network mechanisms of SWRs and replay, we constructed and simulated a data-driven model of area CA3 of the hippocampus. Our results show that the chain-like structure of recurrent excitatory interactions established during learning not only determines the content of replay, but is essential for the generation of the SWRs as well. We find that bidirectional replay requires the interplay of the experimentally confirmed, temporally symmetric plasticity rule, and cellular adaptation. Our model provides a unifying framework for diverse phenomena involving hippocampal plasticity, representations, and dynamics, and suggests that the structured neural codes induced by learning may have greater influence over cortical network states than previously appreciated. Chimeric spike mRNA vaccines protect against Sarbecovirus challenge in mice The emergence of SARS-CoV in 2003 and SARS-CoV-2 in 2019 highlights the need to develop universal vaccination strategies against the broader Sarbecovirus subgenus. Using chimeric spike designs, we demonstrate protection against challenge from SARS-CoV, SARS-CoV-2, SARS-CoV-2 B.1.351, bat CoV (Bt-CoV) RsSHC014, and a heterologous Bt-CoV WIV-1 in vulnerable aged mice. Chimeric spike mRNAs induced high levels of broadly protective neutralizing antibodies against high-risk Sarbecoviruses. In contrast, SARS-CoV-2 mRNA vaccination not only showed a marked reduction in neutralizing titers against heterologous Sarbecoviruses, but SARS-CoV and WIV-1 challenge in mice resulted in breakthrough infection. Chimeric spike mRNA vaccines efficiently neutralized D614G, UK B.1.1.7., mink cluster five, and the South African B.1.351 variant of concern. Thus, multiplexed-chimeric spikes can prevent SARS-like zoonotic coronavirus infections with pandemic potential.

SentenceChimerized RBD, NTD, and S2 spike mRNA-LNPs protect mice against epidemic, zoonotic, and pandemic SARS-like viruses Heterologous autoimmunity and prokaryotic immune defense Some prokaryotes possess CRISPR-Cas systems that provide adaptive immunity to viruses guided by DNA segments called spacers acquired from invading phage. However, the patchy incidence and limited memory breadth of CRISPR-Cas systems suggest that their fitness benefits are offset by costs. Here, we propose that cross-reactive CRISPR targeting can lead to heterologous autoimmunity, whereby foreign spacers guide self-targeting in a spacer-length dependent fashion. Balancing antiviral defense against autoimmunity predicts a scaling relation between spacer length and CRISPR repertoire size. We find evidence for this scaling through comparative analysis of sequenced prokaryotic genomes, and show that this association also holds at the level of CRISPR types. In contrast, the scaling is absent in strains with nonfunctional CRISPR loci. Finally, we demonstrate that stochastic spacer loss can explain variations around the scaling relation, even between strains of the same species. Our results suggest that heterologous autoimmunity is a selective factor shaping the evolution of CRISPR-Cas systems. If Research is Not the Evidence, What is it? The Lack of Research Citations in Health Vlogs Doctor-influencers have the knowledge needed to understand scientific research, and they have the social media popularity to share it with large audiences. In this article, I explore the treatment of evidence in vlogs by Egyptian doctor-influencers: how they present it and what they use instead of it. I answer the following questions: 1) How do doctor-influencers present evidence on social media? 2) If evidence is not the research, then what is it? The data was collected through in-depth interviews with 12 Egyptian doctor-influencers from different specializations; two focus groups; and a critical discourse analysis of 48 of the influencers most popular and most engaging videos. I found that the doctor-influencers cited academic research only in the videos about medical controversies, new treatments, misinformation, or common medical mistakes. In most of their videos, the Egyptian doctor-influencers scarcely referred to medical research. This is because they believe that their audiences would not understand evidence due to their low educational attainment, weak research skills, and the language barrier (as most medical research is published in English rather than Arabic). These findings highlight the challenges of communicating science in societies with a low level of education. In these settings, communicators may need to move beyond mediating research studies on social media and instead focus on simplifying, translating, and connecting evidence-based information to the cultural context. LazySampling and LinearSampling: Fast Stochastic Sampling of RNA Secondary Structure with Applications to SARS-CoV-2 Many RNAs fold into multiple structures at equilibrium. The classical stochastic sampling algorithm can sample secondary structures according to their probabilities in the Boltzmann ensemble, and is widely used. However, this algorithm, consisting of a bottom-up partition function phase followed by a top-down sampling phase, suffers from three limitations: (a) the formulation and implementation of the sampling phase are unnecessarily complicated; (b) the sampling phase repeatedly recalculates many redundant recursions already done during the partition function phase; (c) the partition function runtime scales cubically with the sequence length. These issues prevent stochastic sampling from being used for very long RNAs such as the full genomes of SARS-CoV-2. To address these problems, we first adopt a hypergraph framework under which the sampling algorithm can be greatly simplified. We then present three sampling algorithms under this framework, among which the LazySampling algorithm is the fastest by eliminating redundant work in the sampling phase via on-demand caching. Based on LazySampling, we further replace the cubic-time partition function by a linear-time approximate one, and derive LinearSampling, an end-to-end linear-time sampling algorithm that is orders of magnitude faster than the standard one. For instance, LinearSampling is 176x faster (38.9s vs. 1.9h) than Vienna RNAsubopt on the full genome of Ebola virus (18,959 nt). More importantly, LinearSampling is the first RNA structure sampling algorithm to scale up to the full-genome of SARS-CoV-2 without local window constraints, taking only 69.2 seconds on its reference sequence (29,903 nt). The resulting sample correlates well with the experimentally-guided structures. On the SARS-CoV-2 genome, LinearSampling finds 23 regions of 15 nt with high accessibilities, which are potential targets for COVID-19 diagnostics and drug design.

See code: https://github.com/LinearFold/LinearSampling Genome editing excisase origins illuminated by somatic genome of Blepharisma Massive DNA excision occurs regularly in ciliates, ubiquitous microbial eukaryotes with somatic and germline nuclei in the same cell. Tens of thousands of internally eliminated sequences (IESs) scattered throughout a copy of the ciliate germline genome are deleted during development of the streamlined somatic genome. Blepharisma represents one of the two earliest diverging ciliate classes, and, unusually, has dual pathways of somatic nuclear development, making it ideal for investigating the functioning and evolution of these processes. Here, we report the somatic genome assembly of Blepharisma stoltei strain ATCC 30299 (41 Mb), arranged as numerous alternative telomere-capped minichromosomes. This genome encodes eight PiggyBac transposase homologs liberated from transposons. All are subject to purifying selection, but just one, the putative IES excisase, has a complete catalytic triad. We propose PiggyBac homologs were ancestral excisases that enabled evolution of extensive, natural genome editing. An Evolutionary Process Without Variation and Selection Natural selection successfully explains how organisms accumulate adaptive change despite that traits acquired over a lifetime are eliminated at the end of each generation. However, in some domains that exhibit cumulative, adaptive change--e.g., cultural evolution, and earliest life--acquired traits are retained; these domains do not face the problem that Darwins theory was designed to solve. Lack of transmission of acquired traits occurs when germ cells are protected from environmental change, due to a self-assembly code used in two distinct ways: (i) actively interpreted during development to generate a soma, and (ii) passively copied without interpretation during reproduction to generate germ cells. Early life and cultural evolution appear not to involve a self-assembly code used in these two ways. We suggest that cumulative, adaptive change in these domains is due to a lower-fidelity evolutionary process, and model it using Reflexively Autocatalytic and Foodset-generated networks. We refer to this more primitive evolutionary process as Self-Other Reorganisation (SOR) because it involves internal self-organising and self-maintaining processes within entities, as well as interaction between entities. SOR encompasses learning but in general operates across groups. We discuss the relationship between SOR and Lamarckism, and illustrate a special case of SOR without variation. Lower limb in sprinters with larger relative mass but not larger normalized moment of inertia Inhomogeneous muscle hypertrophy in response to daily motor executions is a morphological adaptation in humans. Inhomogeneous morphological adaptation would change the mass distribution, which in turn may affect the mechanical difficulty in moving from an inertia perspective; however, the morphological adaptation from the inertia perspective has not been examined. Here we show no corresponding differences in the normalized mass and normalized moment of inertia between the sprinters and the untrained non-sprinters. We analyzed the fat- and water-separated magnetic resonance images from the lower limbs of 11 male sprinters (100 m best time of 10.44-10.83 s) and 12 untrained non-sprinters. The lower-limb relative mass was significantly larger in sprinters (18.7{+/-}0.7% body mass) than in non-sprinters (17.6{+/-}0.6% body mass), while the normalized moment of inertia of the lower limb around the hip in the anatomical position was similar between them (0.044{+/-}0.002 vs. 0.042{+/-}0.002 [a. u.]). The thigh relative mass in sprinters (12.9{+/-}0.4% body mass) was significantly larger than that in non-sprinters (11.9{+/-}0.4% body mass), whereas the shank and foot relative masses were similar. We revealed that the adaptation to sprinting in humans does not relatively increase the mechanical difficulty to swing the lower limb in terms of inertia, even though the lower-limb mass increases, reflecting muscular hypertrophy. This is suggested to be one of the significant advantages of human morphology for adaptability to explosive motor tasks.

NEW & NOTEWORTHYWe compared the lower-limb inertia properties between male sprinters and untrained non-sprinters by using the fat- and water-separated magnetic resonance images. Sprinters had lower limbs with a larger relative mass but not a larger normalized moment of inertia than non-sprinters. We suggest one of the practical advantages of human morphological characteristics for their adaptation to explosive motor tasks, which provides a novel perspective to the literature for understanding human morphological adaptability. Somatic mutations of activated signaling genes, transcription factors, or tumor suppressors are a precondition for leukemic transformation from myelodysplastic syndromes: a sequencing analysis of 64 paired samples The transformation biology of secondary AML from MDS is still not fully understood. Here, we performed a large cohort of paired sequences including target, whole-exome and single cell sequencing to search AML transformation-related mutations (TRM). The results showed that fifty-five out of the 64 (85.9%) patients presented presumptive TRM involving activated signaling, transcription factors, or tumor suppressors. Most of TRM (63.6%, 35 cases) emerged at the leukemia transformation point. All five of the remaining nine patients analyzed by paired whole exome sequencing showed TRM which are not included in the reference targets. Single-cell sequencing indicated that the activated cell signaling route was related to TRM which take place prior to phenotypic development. Of note, defined TRM was limited to a small set of genes (less than ten, in the order: NRAS/KRAS, CEBPA, TP53, FLT3, RUNX1, CBL, PTPN11 and WT1, accounted for 91.0% of the mutations). In conclusion, somatic mutations involving in activated signaling, transcription factors, or tumor suppressors appeared to be a precondition for AML transformation from myelodysplastic syndromes. The TRM may be considered as new therapy targets. Untargeted metabolomic analyses reveal the diversity and plasticity of the specialized metabolome in seeds of different Camelina sativa genotypes Despite the essential role of Specialized Metabolites (SMs) in the interaction of plants with the environment, studying the ability of crop seeds to produce these protective compounds has been neglected. Furthermore, seeds produce a myriad of SMs providing an interesting model to investigate their diversity and plasticity. Camelina sativa gained a lot of interest in the past few years as rustic oil seed crop. A characterization of seed SM landscapes in six camelina genotypes grown in the field and harvested during five growing seasons has been undertaken in this work. This allowed a comprehensive annotation of seed SMs combining analyses that cluster SMs based on their chemical structures and co-accumulation patterns. These data showed broad effects of the environment on the stimulation of the seed-specialized metabolome. Among well annotated compounds, flavonols were identified as the metabolic class characterised by high plasticity, revealing significant variable accumulation according to the year and/or the genotype. Lastly, a deeper characterisation of primary metabolites and lipids in two selected genotypes has been performed. We showed that, in addition to flavonols, alkaloids and glucosinolates displayed a higher phenotypic plasticity with respect to most of the primary metabolites, including some sugars and major storage compounds such as fatty acids, proteins and most lipid classes (e.g. DAG, TAG), but similar plasticity compared to free aminoacids and carboxylic acids. This work highlighted major and unexplored effects of the environment on the seed specialized metabolome demonstrating that seeds exhibit a dynamic and plastic metabolism, with an impact on seed quality.

Significance statementSeeds produce a myriad of Specialized Metabolites (SMs) with an essential role in the interaction of plants with the environment. We characterized SM landscapes, primary metabolites and lipid composition in the seeds of camelina genotypes grown in the open field in five consecutive growing seasons. Our results showed the predominant effect of the environment on the regulation of the seed - specialized metabolome, with a potential impact on seed quality of camelina that may also occur in other oilseed crops. The Temporal Statistics of Musical Rhythm across Western Genres: An Amplitude Modulation Phase Hierarchy Model Statistical learning by the human brain plays a core role in the development of cognitive systems like language and music. Both music and speech have structured inherent rhythms, however the acoustic sources of these rhythms are debated. Theoretically, rhythm structures in both systems may be related to a novel set of acoustic statistics embedded in the amplitude envelope, statistics originally revealed by modelling childrens nursery rhymes. Here we apply similar modelling to explore whether the amplitude modulation (AM) timescales underlying rhythm in music match those in child-directed speech (CDS). Utilising AM-driven phase hierarchy modelling previously applied to infant-directed speech (IDS), adult-directed speech (ADS) and CDS, we test whether the physical stimulus characteristics that yield speech rhythm in IDS and CDS describe rhythm in music. Two models were applied. One utilized a low-dimensional representation of the auditory signal adjusted for known mechanisms of the human cochlear, and the second utilized probabilistic amplitude demodulation, estimating the modulator (envelope) and carriers using Bayesian inference. Both models revealed a similar hierarchically-nested temporal modulation structure across Western musical genres and instruments. Core bands of AM and spectral patterning matched prior analyses of IDS and CDS, and music showed strong phase dependence between slower bands of AMs, again matching IDS and CDS. This phase dependence is critical to the perception of rhythm. Control analyses modelling other natural sounds (wind, rain, storms, rivers) did not show similar temporal modulation structures and phase dependencies. We conclude that acoustic rhythm in language and music has a shared statistical basis. Computation of the mitochondrial age distribution along the axon length We describe a compartmental model of mitochondrial transport in axons, which we apply to compute mitochondrial age at different distances from the soma. The model predicts that the average mitochondrial age at the tip of an axon with a length of 1 cm is approximately 22 hours. The mitochondria are youngest closest to the soma and their age scales approximately linearly with distance from the soma. To the best of the authors knowledge, this is the first attempt to predict the spatial distribution of mitochondrial age within an axon. A sensitivity study of the mean age of mitochondria to various model parameters is also presented. Quantifying the Morphology and Mechanisms of Cancer Progression in 3D in-vitro environments: Integrating Experiments and Multiscale Models Mathematical models of cancer growth have become increasingly more accurate both in the space and time domains. However, the limited amount of data typically available has resulted in a larger number of qualitative rather than quantitative studies. In the present study, we provide an integrated experimental-computational framework for the quantification of the morphological characteristics and the mechanistic modelling of cancer progression in 3D environments. The proposed framework allows for the calibration of multiscale, spatiotemporal models of cancer growth using state-of-the-art 3D cell culture data, and their validation based on the resulting experimental morphological patterns. Its implementation enabled us to pursue two goals; first, the quantitative description of the morphology of cancer progression in 3D cultures, and second, the relation of tumour morphology with underlying biophysical mechanisms that govern cancer growth and migration. We applied this framework to the study of the spatiotemporal progression of Triple Negative Breast Cancer cells cultured in Matrigel scaffolds, and validated the hypothesis of chemotactic migration using a multiscale Keller-Segel model. The results revealed transient, non-random spatial distributions of cancer cells that consist of clustered, and dispersion patterns. The proposed model was able to describe the general characteristics of the experimental observations and suggests that cancer cells exhibited chemotactic migration and accumulation, as well as random motion during the examined time period of development. To our knowledge, this is the first time that a multiscale model is used to quantify the relationship between the spatial patterns and the underlying mechanisms of cancer growth in 3D environments. Reconstructing SNP Allele and Genotype Frequencies from GWAS Summary Statistics The emergence of genomewide association studies (GWAS) has led to the creation of large repositories of human genetic variation, creating enormous opportunities for genetic research and worldwide collaboration. Methods that are based on GWAS summary statistics seek to leverage such records, overcoming barriers that often exist in individual-level data access while also offering significant computational savings. Here, we propose a novel framework that can reconstruct allelic and genotypic counts/frequencies for each SNP from case-control GWAS summary statistics. Our framework is simple and efficient without the need of any complicated underlying assumptions. Illustrating the great potential of this framework we also propose three summary-statistics-based applications implemented in a new software package (ReACt): GWAS meta-analysis (with and without sample overlap), case-case GWAS, and, for the first time, group polygenic risk score (PRS) estimation. We evaluate our methods against the current state-of-the-art on both synthetic data and real genotype data and show high performance in power and error control. Our novel group PRS method based on summary statistics could not be achieved prior to our proposed framework. We demonstrate here the potential applications and advantages of this approach. Our work further highlights the great potential of summary-statistics-based methodologies towards elucidating the genetic background of complex disease and opens up new avenues for research.