Active enhancers strengthen insulation by RNA-mediated CTCF binding at TAD boundaries Vertebrate genomes are partitioned into Topologically Associating Domains (TADs), which are typically bound by head-to-head pairs of CTCF binding sites. Transcription at TAD boundaries correlates with better insulation, however, it is not known whether the boundary transcripts themselves contribute to boundary function. Here we characterize boundary-associated RNAs genome-wide, focusing on the disease-relevant INK4a/ARF TAD. Using CTCF site deletions and boundary-associated RNA knockdowns, we observe that boundary-associated RNAs facilitate recruitment and clustering of CTCF at TAD borders. The resulting CTCF enrichment enhances TAD insulation, enhancer:promoter interactions and TAD gene expression. Importantly, knockdown of boundary-associated RNAs results in loss of boundary insulation function. Using enhancer deletions and CRISPRi of promoters we show that active TAD enhancers but not promoters induce boundary-associated RNA transcription, thus defining a novel class of regulatory enhancer RNAs.
Natural tolerance to transposition is associated with double-strand break repair and germ-cell differentiation Transposable elements (TE) are mobile genetic parasites whose unregulated activity in the germline causes DNA damage and sterility. While the regulation of TE mobilization by hosts is studied extensively, little is known about mechanisms that could allow germline cells to persist in the face of genotoxic stress imposed by active transposition. Such tolerance mechanisms are predicted to be beneficial when new TEs invade and host repression has not yet evolved. Here we use hybrid dysgenesis--a sterility syndrome of Drosophila caused by transposition of invading DNA transposons--to uncover genetic variants that confer tolerance to transposition. Using a panel of highly recombinant inbred lines of Drosophila melanogaster, we identified two linked quantitative trait loci (QTL), that determine tolerance in young and old females, respectively. Through transcriptomic and phenotypic comparisons, we provide evidence that young tolerant females exhibit enhanced repair of double-stranded breaks, explaining their ability to withstand high germline transposition rates. We furthermore identify the germline differentiation factor brat as an independent tolerance factor, whose activity may promote germline maintenance in aging dysgenic females. Together, our work reveals the diversity of potential tolerance mechanisms across development, as well as tolerant variants that may be beneficial in the context of P-element transposition.
Analysis of science journalism reveals gender and regional disparities in coverage Science journalism is a critical way in which the public can remain informed and benefit from new scientific findings. Such journalism also shapes the publics view of the current state of scientific findings and legitimizes experts. Those covering science can only cite and quote a limited number of sources. Sources may be identified by the journalists research or by recommendations by other scientists. In both cases, biases may influence who is identified and ultimately included as an expert. To analyze possible biases in science journalism, we analyzed 22,001 non-research articles published by Nature. We chose to analyze Nature non-research articles since its research articles provide a natural comparator. Our analysis considered two possible sources of disparity: gender and name origin. To explore these sources of disparity, we extracted cited authors names as well as extracted names of quoted speakers. While citations and quotations within a piece do not reflect the entire information-gathering process, they can provide insight into the demographics of visible sources. We then used the extracted names to predict gender and name origin of the cited authors and speakers.

In order to appropriately quantify the level of difference, we must identify a suitable reference set for comparison. We chose first and last authors within primary research articles in Nature and a subset of Springer Nature articles in the same time period as our comparator. In our analysis, we found a skew towards male quotation in Nature science journalism-related articles. However, quotation is trending toward equal representation at a faster rate than first and last authorship in academic publishing. Interestingly, we found that the gender disparity in Nature quotes was column-dependent, with the "Career Features" column reaching gender parity. Our name origin analysis found a significant over-representation of names with predicted Celtic/English origin and under-representation of names with a predicted East Asian origin. This finding was observed both in extracted quotes and journal citations, but dampened in citations. The LOTUS Initiative for Open Natural Products Research: Knowledge Management through Wikidata Contemporary bioinformatic and chemoinformatic capabilities hold promise to reshape knowledge management, analysis and interpretation of data in natural products research. Currently, reliance on a disparate set of non-standardized, insular, and specialized databases presents a series of challenges for data access, both within the discipline and for integration and interoperability between related fields. The fundamental elements of exchange are referenced structure-organism pairs that establish relationships between distinct molecular structures and the living organisms from which they were identified. Consolidating and sharing such information via an open platform has strong transformative potential for natural products research and beyond. This is the ultimate goal of the newly established LOTUS initiative, which has now completed the first steps toward the harmonization, curation, validation and open dissemination of 750,000+ referenced structure-organism pairs. LOTUS data is hosted on Wikidata and regularly mirrored on https://lotus.naturalproducts.net. Data sharing within the Wikidata framework broadens data access and interoperability, opening new possibilities for community curation and evolving publication models. Furthermore, embedding LOTUS data into the vast Wikidata knowledge graph will facilitate new biological and chemical insights. The LOTUS initiative represents an important advancement in the design and deployment of a comprehensive and collaborative natural products knowledge base.

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org.highwire.dtl.DTLVardef@184136borg.highwire.dtl.DTLVardef@16e0d6org.highwire.dtl.DTLVardef@30ae1org.highwire.dtl.DTLVardef@1bf4825_HPS_FORMAT_FIGEXP  M_FIG C_FIG FGF8-mediated signaling regulates tooth developmental pace during odontogenesis The developing human and mouse teeth constitute an ideal model system to study the regulatory mechanism underlying organ growth control due to the fact that their teeth share highly conserved and well-characterized developmental processes and their developmental tempo vary notably. In the current study, we manipulated heterogenous recombination between human and mouse dental tissues and demonstrate that the dental mesenchyme dominates the tooth developmental tempo and FGF8 could be a critical player during this developmental process. Forced activation of FGF8 signaling in the dental mesenchyme of mice promoted cell proliferation, prevented cell apoptosis via p38 and perhaps PI3K-Akt intracellular signaling, and impelled the transition of the cell cycle from G1- to S-phase in the tooth germ, resulting in the slowdown of the tooth developmental pace. Our results provide compelling evidence that extrinsic signals can profoundly affect tooth developmental tempo and the dental mesenchymal FGF8 could be a pivotal factor in controlling developmental pace in a non-cell-autonomous manner during mammalian odontogenesis. Reproduction in deep-sea vent shrimps is shaped by diet and phylogeny, with rhythms unlinked to surface production Variations in offspring production according to feeding strategies or food supply have been recognized in many animals from various ecosystems. Despite an unusual trophic structure based on non-photosynthetic primary production, these relationships remain largely under-studied in chemosynthetic ecosystems. Here, we use Rimicaris shrimps from deep-sea hydrothermal vents as a study case to explore relations between reproduction, diets and food supply in these environments. For that, we compared reproductive outputs of three congeneric shrimps differing by their diets. They inhabit vents located under oligotrophic waters of tropical gyres with opposed latitudes, allowing us to also examine the prevalence of phylogenetic vs environmental drivers in their reproductive rhythms. For this we used both our original data and a compilation of published observations on the presence of ovigerous females covering various seasons over the past 35 years. We report distinct egg production trends between Rimicaris species relying solely on chemosymbiosis - R. exoculata and R. kairei - and those relying on mixotrophy - R. chacei - where R. chacei produces broods with higher numbers of smaller eggs. Besides, our data and historical records suggest a reproductive period with substantial proportions of brooding females mostly between January and early April for all examined species whatever the region. Intriguingly, this periodicity does not correspond to seasonal variations in surface production with presence of brooding females during either boreal winter or austral summer. These observations contrast with the long-standing paradigm in deep-sea species for which periodic reproductive patterns have always been attributed to seasonal variations of photosynthetic production sinking from surface. Our results suggest the presence of intrinsic basis for biological rhythms in the deep sea, and bring to light the importance of having year-round observations in order to understand life history of vent animals. An AI-guided signature reveals the nature of the shared proximal pathways of host immune response in MIS-C and Kawasaki disease A significant surge in cases of multisystem inflammatory syndrome in children (MIS-C, also called Pediatric Inflammatory Multisystem Syndrome - PIMS) has been observed amidst the COVID-19 pandemic. MIS-C shares many clinical features with Kawasaki disease (KD), although clinical course and outcomes are divergent. We analyzed whole blood RNA sequences, serum cytokines, and formalin fixed heart tissues from these patients using a computational toolbox of two gene signatures, i.e., the 166-gene viral pandemic (ViP) signature, and its 20-gene severe (s)ViP subset that were developed in the context of SARS-CoV-2 infection and a 13-transcript signature previously demonstrated to be diagnostic for KD. Our analyses revealed that KD and MIS-C are on the same continuum of the host immune response as COVID-19. While both the pediatric syndromes converge upon an IL15/IL15RA-centric cytokine storm, suggestive of shared proximal pathways of immunopathogenesis, they diverge in other laboratory parameters and cardiac phenotypes. The ViP signatures also revealed unique targetable cytokine pathways in MIS-C, place MIS-C farther along in the spectrum in severity compared to KD and pinpoint key clinical (reduced cardiac function) and laboratory (thrombocytopenia and eosinopenia) parameters that can be useful to monitor severity. Large Bi-ethnic Study of Plasma Proteome Leads to Comprehensive Mapping of cis-pQTL and Models for Proteome-wide Association Studies Improved understanding of genetic regulation of proteome can facilitate the identification of causal mechanisms for complex traits. We analyzed data on 4,657 plasma proteins from 7,213 European American (EA) and 1,871 African American (AA) individuals from the ARIC study, and further replicated findings on 467 AA individuals from the AASK study. Here we identified 2,004 proteins in EA and 1,618 in AA, with majority overlapping, which showed associations with common variants in cis-regions. Availability of AA samples led to smaller credible sets and significant number of population-specific cis-pQTLs. Elastic-net produced powerful models for protein prediction in both populations. An application of proteome-wide association studies (PWAS) to serum urate and gout, implicated several proteins, including IL1RN, revealing the promise of the drug anakinra to treat acute gout flares. Our study demonstrates the value of large and diverse ancestry study for genetic mechanisms of molecular phenotypes and their relationship with complex traits. Pseudomonas aeruginosa C-terminal processing protease CtpA assembles into a hexameric structure that requires activation by a spiral-shaped lipoprotein binding partner Pseudomonas aeruginosa CtpA is a carboxyl terminal-processing protease that partners with the outer membrane lipoprotein LbcA to degrade at least five cell wall-associated proteins, four of which are cell wall hydrolases. This activity plays an important role in supporting P. aeruginosa virulence in a mouse model of acute pneumonia. However, almost nothing is known about the molecular mechanisms underlying CtpA and LbcA function. Here, we used structural analysis to show that CtpA alone assembles into an inactive hexamer comprising a trimer of dimers, which limits its substrate access and prevents nonspecific degradation. The adaptor protein LbcA is a right-handed open spiral with 11 tetratricopeptide repeats, which might wrap around a substrate to deliver it to CtpA for degradation. By structure-guided mutagenesis and functional assays, we also showed that the interfaces of the CtpA trimer-of-dimers, and an N-terminal helix of LbcA, are important for LbcA-mediated substrate degradation by CtpA both in vitro and in vivo. This work improves our understanding of the molecular mechanism of a CTP within the C-terminal processing peptidase-3 group.

IMPORTANCECarboxyl-terminal processing proteases (CTPs) are found in all three domains of life. In bacteria, some CTPs have been associated with virulence, raising the possibility that they could be theraputic targets. However, relatively little is known about their molecular mechanisms of action. In Pseudomonas aeruginosa, CtpA supports virulence by working in complex with the outer membrane lipoprotein LbcA to degrade cell wall hydrolases. Here, we report structure-function analyses of CtpA and LbcA, which reveals that CtpA assembles into an inactive hexamer comprising a trimer of dimers. LbcA is monomeric, with an N-terminal region important for binding to and activating CtpA, followed by a spiral structure composed of 11 tetratricopetide repeats, which could wrap around a substrate for delivery to CtpA. This work provides the first structure of a CTP-3 group member, revealing a unique mutimeric arrangement and insight into how this important proteolytic system functions. Nuclear Progestin Receptor Mediated Linkage of Blood Coagulation and Ovulation Ovulation is a dramatic remodeling process that includes rupture of blood capillaries and clotting, but coagulation is not thought to directly regulate this process. Herein, we report remarkable increases of coagulation factors V (f5, [~]3145-fold) and tissue factor (f3a, [~]120-fold) in zebrafish ovarian follicle cells during ovulation. This increase was mediated through the nuclear progestin receptor (Pgr), which is essential for ovulation in zebrafish, and was totally abolished in ovarian follicular cells from pgr-/- mutants. In addition, promoter activities of f5 and f3a were significantly enhanced by progestin (DHP) via Pgr. Similar regulation of human F5 promoter activity was induced via human PGRB, suggesting a conserved mechanism. Site-directed mutagenesis of the zebrafish f5 promoter further demonstrated a direct regulation of coagulation factors via progestin response elements. Moreover, a stark increase of erythrocytes occurred in capillaries meshed in wildtype preovulatory follicles but was absent in pgr-/- mutants. Interestingly, anticoagulants significantly inhibited ovulation both in vitro and in vivo, respectively. Furthermore, reduced fecundity was observed in f5+/- female zebrafish. Taken together, our study provides plausible evidence for steroid regulation of coagulation factors, and a new hypothesis for blood clotting triggered ovulation in vertebrates. First Report of Lactoria cornuta from Karnataka, West coast of India, Role of tropical cyclones in Range Extension India is known for its rich biodiversity and is fortunate to have several endemic species from different classes of vertebrates. India is home to 7.5% of the global fish diversity, with 91 endemic species of ray finned fishes, the actinopterygians. Some fish species have never been reported until recently, one such example is the long-horned Cowfish (Ostracidae), best known for inhabiting only certain areas of the Indo-Pacific oceans. However, this fish has been reported from Bay of Bengal, Costs of Goa and Lakshadweep. This is the first time this fish has been found on the Coasts of Karnataka, west coast of India. Given its morphology, the migration seems highly improbable since it can only endure lethargic swimming. In this article, we have explored the role of other external forces that could have contributed to its range extension in the east and west coast of India. In this paper we are exploring the role of Super Cyclones as a vital force in determining the expansion of its range. The fact of collection longhorn cowfish for the first time from the coast of Karwar coincides with the passage of Cyclone Ockhi on the west coast of India this suggests the possible role of super cyclone in its range extension. A year later, another specimen was recovered from a location very close to the first, which indicates the successful establishment of Lacturia cornuta in its new environment. Related morphometric and meristic studies of our specimens are consistent with previous studies reported in the Bay of Bengal. Cooperation of two opposite flagella allows high-speed swimming and active turning in zoospores Phytophthora species cause diseases in a large variety of plants and represent a serious agricultural threat, leading, every year, to multibillion dollar losses. Infection occurs when these biflagellated zoospores move across the soil at their characteristic high speed and reach the roots of a host plant. Despite the relevance of zoospore spreading in the epidemics of plant diseases, characteristics of individual swimming of zoospores have not been fully investigated. It remains unknown about the characteristics of two opposite beating flagella during translation and turning, and the roles of each flagellum on zoospore swimming. Here, combining experiments and modeling, we show how these two flagella contribute to generate thrust when beating together, and identify the mastigonemes-attached anterior flagellum as the main source of thrust. Furthermore, we find that turning involves a complex active process, in which the posterior flagellum temporarily stops, while the anterior flagellum keeps on beating and changes its pattern from sinusoidal waves to power and recovery strokes, similar to Chlamydomonass breaststroke, to reorient its body to a new direction. Our study is a fundamental step towards a better understanding of the spreading of plant pathogens motile forms, and shows that the motility pattern of these biflagellated zoospores represents a distinct eukaryotic version of the celebrated "run-and-tumble" motility class exhibited by peritrichous bacteria. Greater spear nosed bats in Panama do not use social proximity to improve foraging efficiency Group foraging animals may change their spatial relationships in response to the resource landscape. The strength of social network ties across foraging groups could then reflect the energy balance of individual group members through their effect on foraging efficiency. Greater spear-nosed bats (Phyllostomus hastatus) live in social groups where unrelated females develop group-specific social calls, defend each others offspring, and are hypothesized to coordinate social foraging to feed on balsa flowers. To test if social groups forage together, and if this increases foraging efficiency, we tracked 18 individuals from three social groups of P. hastatus on Isla Colon, Panama using high frequency GPS for 1 - 3 days each. We found that individuals commuted alone but then joined group members in small foraging patches with high densities of flowering balsas, 25 km from their roost on the mainland. Proximity-based social network measures did not predict foraging efficiency or energy expenditure, but individuals with higher social associations spent more time outside of the cave. Individuals did not coordinate movement, but close proximity among individuals increased resting bout duration and synchrony, particularly when in the same patch. These results show that stronger social proximity associations were more closely tied to resting behavior, and indicate that factors other than increased feeding efficiency may structure network relationships of group members while foraging.

Lay SummarySocial foraging can increase foraging efficiency on hard-to-find food sources. Miniaturized high-frequency GPS allowed us to test this on groups of greater spear-nosed bats. We estimated food intake rates, energy expenditure, and the strength of bat social relationships. In contrast to our expectations, we did not find a relationship between bat social relationships and energy expenditure or foraging efficiency. However, bats took longer resting breaks when group members were close. Why these bats commute 25 km individually across the ocean to then forage near each other thus requires further investigation. Extensive characterization of HIV-1 reservoirs reveals links to plasma viremia before and during analytical treatment interruption The HIV-1 reservoir is composed of cells harboring latent proviruses that are capable of contributing to viremia upon antiretroviral treatment (ART) interruption. Although this reservoir is known to be maintained by clonal expansion, the contribution of large, infected cell clones to residual viremia and viral rebound remains underexplored. Here, we conducted an extensive analysis on four ART-treated individuals who underwent an analytical treatment interruption (ATI). We performed subgenomic (V1-V3 env), near full-length proviral and integration site sequencing, and used multiple displacement amplification to sequence both the integration site and provirus from single HIV-infected cells. We found eight proviruses that could phylogenetically be linked to plasma virus obtained before or during the ATI. This study highlights a role for HIV-infected cell clones in the maintenance of the replication-competent reservoir and suggests that infected cell clones can directly contribute to rebound viremia upon ATI. 3D Echo Planar Time-resolved Imaging (3D-EPTI) for ultrafast multi-parametric quantitative MRI Multi-parametric quantitative MRI has shown great potential to improve the sensitivity and specificity of clinical diagnosis and to enhance our understanding of complex brain processes, but suffers from long scan time especially at high spatial resolution. To address this long-standing challenge, we introduce a novel approach, termed 3D Echo Planar Time-resolved Imaging (3D-EPTI), which significantly increases the acceleration capacity of MRI sampling, and provides high acquisition efficiency for multi-parametric MRI. This is achieved by exploiting the spatiotemporal correlation of MRI data at multiple timescales through new encoding strategies within and between efficient continuous readouts. Specifically, an optimized spatiotemporal CAIPI encoding within the readouts combined with a radial-block sampling strategy across the readouts enables an acceleration rate of 800 folds in the k-t space. A subspace reconstruction was employed to resolve thousands of artifact-free high-quality multi-contrast images spaced at a time interval of ~1 ms. We have demonstrated the ability of 3D-EPTI to provide robust and repeatable whole-brain simultaneous T1, T2, T2*, PD and B1+ mapping at high isotropic resolution within minutes (e.g., 1-mm isotropic resolution in 3 minutes), and to enable submillimeter multi-parametric imaging to study detailed brain structures.

HighlightsO_LIUltra-fast acquisition for 3D multi-parametric quantitative MRI.
C_LIO_LISimultaneous T1 T2 T2* PD and B1+ mapping.
C_LIO_LI3-minute scan at 1-mm isotropic resolution with whole-brain coverage.
C_LIO_LIMulti-parametric mapping at 700-m isotropic resolution in 10 minutes.
C_LIO_LIRepeatable quantification and cortical-depth analysis.
C_LI Sex differences in behavioral responding and dopamine release during Pavlovian learning Learning associations between cues and rewards requires the mesolimbic dopamine system. The dopamine response to cues signals differences in reward value in well-trained animals. However, these value-related dopamine responses are absent during early training sessions when cues signal differences in the reward rate. These findings suggest cue-evoked dopamine release conveys differences between outcomes only after extensive training, though it is unclear if this is unique to when cues signal differences in reward rate, or if this is also evident when cues signal differences in other value-related parameters such as reward size. To address this, we utilized a Pavlovian conditioning task in which one audio cue was associated with a small reward (one pellet) and another audio cue was associated with a large reward (three pellets). We performed fast-scan cyclic voltammetry to record changes in dopamine release in the nucleus accumbens of male and female rats throughout learning. While female rats exhibited higher levels of conditioned responding, a faster latency to respond, and elevated post-reward head entries relative to male rats, there were no sex differences in the dopamine response to cues. Multiple training sessions were required before cue-evoked dopamine release signaled differences in reward size. Reward-evoked dopamine release scaled with reward size, though females displayed lower reward-evoked dopamine responses relative to males. Conditioned responding related to the decrease in the peak reward-evoked dopamine response and not to cue-evoked dopamine release. Collectively these data illustrate sex differences in behavioral responding as well as in reward-evoked dopamine release during Pavlovian learning. ALLOPURINOL BLOCKS THE AORTIC ANEURYSM IN A MOUSE MODEL OF MARFAN SYNDROME VIA REDUCING AORTIC OXIDATIVE STRESS 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

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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 A novel Boolean network inference strategy to model early hematopoiesis aging Hematopoietic stem cell (HSC) aging is a multifactorial event that leads to changes in HSC properties and function. These changes are intrinsically coordinated and affect the early hematopoiesis, involving hematopoietic stem and progenitor cells (HSPCs). The objective of this work is to better understand the mechanisms and factors controlling these changes. We have therefore developed an original strategy to construct a Boolean network of genes explaining the priming and homeostasis of HSCs (graphical abstract). Based on our previous scRNA-seq data, we performed an exhaustive analysis of the transcriptional network and identified active transcription modules or regulons along the differentiation trajectory of selected HSPC states. This global view of transcriptional regulation led us to focus on 15 components, 13 selected TFs (Tal1, Fli1, Gata2, Gata1, Zfpm1, Egr1, Junb, Ikzf1, Myc, Cebpa, Bclaf1, Klf1, Spi1) and 2 complexes regulating the ability of HSC to cycle (CDK4/6 - Cyclin D and CIP/KIP). We then defined the connections controlling the differentiation dynamics of HSC states and constructed an influence graph between the TFs involved in the dynamics by mixing observations from our scRNA-seq data and knowledge from the literature. Then, using answer set programming (ASP) and in silico perturbation analysis, we obtained a Boolean model which is the solution of a Boolean satisfiability problem. Finally, perturbation of the model based on age-related changes revealed important regulations, such as the overactivation of Egr1 and Junb or the loss of Cebpa activation by Gata2, which were found to be relevant for the myeloid bias of aged HSC. Our work shows the efficiency of the combination of manual and systematic methods to elaborate a Boolean model. The developed strategy led to the proposal of new regulatory mechanisms underlying the differentiation bias of aged HSCs, explaining the decreased transcriptional priming of HSCs to all mature cell types except megakaryocytes. Beneficial effects of novel strains of Aureobasidium pullulans produced 1,3-1,6 β-glucans on non-esterified fatty acid levels in diabetic KKAy mice Obesity, metabolic syndrome, associated lipotoxicity and its cascade of events contribute to the majority of the burden related to non-communicable diseases globally. Preventive lifestyle changes aside, several beneficial effects have been reported in type II diabetes mellitus and dyslipidaemia patients with biological response modifier glucans (BRMG) produced as an exopolysaccharide by Aureobasidium pullulans. In this study, we compared two strains (AFO-202 and N-163) that produce beta glucans in alleviating lipotoxicity. This study was performed in obese diabetic mice model of KK-Ay mice, in four groups with six subjects in each group - Group 1: sacrificed on Day 0 for baseline values; Group 2: control (drinking water); Group 3: AFO-202 beta glucan--200 mg/kg/day; Group 4: N-163 beta glucan--300 mg/kg/day. The animals in groups 2-4 had the test solutions administered by gavage once daily for 28 consecutive days. Biochemical analyses were conducted of blood glucose, triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol and non-esterified fatty acids (NEFA). Group 4 (N-163) had the lowest NEFA levels, as compared to the other groups, and marginally decreased triglyceride levels. The groups had no significant differences in blood glucose, HbA1c, triglycerides, or LDL and HDL cholesterol. N-163 produced by A. pullulans decreased NEFA in a diabetic mice model in 28 days. These results, although modest, warrant further in-depth research into lipotoxicity and associated inflammatory cascades in both healthy and disease affected subjects to develop novel strategies for prevention and management. A Hierarchy of Biomolecular Proportional-Integral-Derivative Feedback Controllers for Robust Perfect Adaptation and Dynamic Performance Proportional-Integral-Derivative (PID) feedback controllers have been the most widely used controllers in industry for almost a century due to their good performance, simplicity, and ease of tuning. Motivated by their success in various engineering disciplines, PID controllers recently found their way into synthetic biology, where the design of feedback molecular control systems has been identified as an important goal. In this paper, we consider the mathematical realization of PID controllers via biomolecular interactions. We propose an array of topologies that offer a compromise between simplicity and high performance. We first demonstrate that different Proportional-Integral (PI) controllers exhibit different capabilities for enhancing the dynamics and reducing variance (cell-to-cell variability). Next, we introduce several derivative controllers that are realized based on incoherent feedforward loops acting in a feedback configuration. Alternatively, we show that differentiators can be realized by placing molecular integrators in a negative feedback loop--an arrangement that can then be augmented by PI components to yield PID feedback controllers. We demonstrate that the derivative component can be exploited for enhancing system stability, dramatically increasing the molecular control systems dynamic performance, and for reducing the noise effect on the output of interest. The PID controller features are established through various deterministic and stochastic analyses as well as numerical simulations. Finally, we provide an experimental demonstration using a recently developed hybrid setup, the cyberloop, where the controller is implemented in silico to control a biological genetic circuit in vivo. The large array of novel biomolecular PID controllers introduced here forms a basis for the design and construction of advanced high-performance biomolecular control systems that robustly regulate the dynamics of living systems. Visualizing functional human profilin in cells and in vitro applications Profilin is an essential regulator of actin and microtubule dynamics and therefore a critical control point for the normal division, motility, and morphology of cells. Most studies of profilin have focused on biochemical investigations using purified protein because high cellular concentrations present challenges for conventional imaging modalities. In addition, past studies that employed direct labeling or conventional fusion protein strategies compromised different facets of profilin function. We engineered two versions of tagged profilin that retain native activities with respect to phosphoinositide lipids, actin monomers, formin-mediated actin assembly, and microtubule polymerization. mApple-profilin-1 directly binds to dimers of tubulin (kD = 1.7 {micro}M) and the microtubule lattice (kD = 10 {micro}M) to stimulate microtubule assembly. In cells, Halo-tagged profilin-1 fully rescues profilin-1(-/-) cells from knockout-induced perturbations to cell shape, actin filament architecture, and microtubule arrays. In cells expressing Halo-profilin, we visualized a subset of individual molecules of profilin-1 by titrating fluorescent Halo-ligands. Further, we combined this imaging approach with specific function-disrupting point-mutants in profilin to visualize dynamic profilin associated with microtubules in live-cells. Thus, these tagged profilins are reliable tools for studying the dynamic interactions of profilin with actin or microtubules in live-cell or in vitro applications. Teosinte mexicana introgression modulates phosphatidylcholine levels and maize flowering time Native Americans domesticated maize (Zea mays ssp. mays) from lowland teosinte parviglumis (Zea mays ssp.parviglumis) in the warm Mexican southwest and brought it to the highlands of Mexico and South America where it was exposed to lower temperatures that imposed strong selection on flowering time. Phospholipids are important metabolites in plant responses to low-temperature and phosphorus availability, and have been suggested to influence flowering time. Here, we combined linkage mapping with genome scans to identify High PhosphatidylCholine 1 (HPC1), a gene that encodes a phospholipase A1 enzyme, as a major driver of phospholipid variation in highland maize. Common garden experiments demonstrated strong genotype-by-environment interactions associated with variation at HPC1, with the highland HPC1 allele leading to higher fitness in highlands, possibly by hastening flowering. The highland maize HPC1 variant resulted in impaired function of the encoded protein due to a polymorphism in a highly conserved sequence. A meta-analysis across HPC1 orthologs indicated a strong association between the identity of the amino acid at this position and optimal growth in prokaryotes. Mutagenesis of HPC1 via genome editing validated its role in regulating phospholipid metabolism. Finally, we showed that the highland HPC1 allele entered cultivated maize by introgression from the wild highland teosinte Zea mays ssp. mexicana and has been maintained in maize breeding lines from the Northern US, Canada and Europe. Thus, HPC1 introgressed from teosinte mexicana underlies a large metabolic QTL that modulates phosphatidylcholine levels and has an adaptive effect at least in part via induction of early flowering time. Analyses of symbiotic bacterial communities in the plant pest Bemisia tabaci reveal high prevalence of Candidatus Hemipteriphilus asiaticus on the African continent AO_SCPLOWBSTRACTC_SCPLOWMicrobial symbionts are widespread in insects and some of them have been associated to adaptive changes. Primary symbionts (P-symbionts) have a nutritional role that allows their hosts to feed on unbalanced diets (plant sap, wood, blood). Most of them have undergone genome reduction, but their genomes still retain genes involved in pathways that are necessary to synthesize the nutrients that their hosts need. However, in some P-symbionts, essential pathways are incomplete and secondary symbionts (S-symbionts) are required to complete parts of their degenerated functions. The P-symbiont of the phloem sap-feeder Bemisia tabaci, Candidatus Portiera aleyrodidarium, lacks genes involved in the synthesis of vitamins, cofactors, and also of some essential amino-acids. Seven S-symbionts have been detected in the B. tabaci species complex. Phenotypic and genomic analyses have revealed various effects, from reproductive manipulation to fitness benefits, notably some of them have complementary metabolic capabilities to Candidatus Portiera aleyrodidarium, suggesting that their presence may be obligatory. In order to get the full picture of the symbiotic community of this pest, we investigated, through metabarcoding approaches, the symbiont content of individuals from Burkina Faso, a West African country where B. tabaci induces severe crop damage. While no new putative B. tabaci S-symbiont was identified, Candidatus Hemipteriphilus asiaticus, a symbiont only described in B. tabaci populations from Asia, was detected for the first time on this continent. Phylogenetic analyses however reveal that it is a different strain than the reference found in Asia. Specific diagnostic PCRs showed a high prevalence of these S-symbionts and especially of Candidatus Hemipteriphilus asiaticus in different genetic groups. These results suggest that Candidatus Hemipteriphilus asiaticus may affect the biology of B. tabaci and provide fitness advantage in some B. tabaci populations. Phenotypic heterogeneity driven by plasticity of the intermediate EMT state governs disease progression and metastasis in breast cancer The Epithelial-to-Mesenchymal Transition (EMT) is a developmental cellular program frequently coopted by cancer cells1 and is a key contributor to both heterogeneity in solid tumors2-4 and later stage chemo-resistance and metastasis5,6. Rather than being a switch from an epithelial to a mesenchymal state, increasing evidence points to the existence of intermediate EMT states, wherein cells co-express both epithelial and mesenchymal traits7-13. Multiple stable intermediate EMT states possessing unique characteristics exist across the EMT spectrum7,8,14,15, contributing to the complex heterogeneity of tumors to promote metastasis16. While much work has been carried out identifying and characterizing EMT-inducing transcription factors17-20, the transcriptional and epigenetic networks responsible for the stability and maintenance of the midpoints along the EMT spectrum are poorly defined. In addition, there are currently no approaches to identifying and quantifying intermediate EMT subpopulations within patient tumors to evaluate their prognostic significance. Using clonally isolated derivatives of the SUM149PT breast cancer cell line, we systematically interrogate how each EMT state independently contributes to heterogeneity and influences metastatic progression, uncovering the role of RUNX2 in stabilizing certain intermediate states. Using SUM149PT-derived tumors as a training set, we develop an entropy-based model to quantify phenotypic heterogeneity and EMT status. Remarkably, the majority of cell states captured in the SUM149PT model are represented in a selection of patient tumors, laying the foundation for quantification of epithelial-mesenchymal heterogeneity and understanding the role of the intermediate EMT state in tumor progression. 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. Polycystin promotes renal fibrosis through EZH2 Autosomal polycystic kidney disease (ADPKD) is caused by mutations in PKD1or PKD2 gene, which encodes polycystin-1 or polycystin-2 respectively. Paradoxically, polycystins are up-regulated in human ADPKD kidneys and overexpression of polycystin-1 even induced renal cyst formation in mice, suggesting that up-regulation of polycystin is pathogenic. In this study, we determined the role of polycystin in renal fibrosis and explored its underlying mechanisms. We found that the expression of polycystin-1 or polycystin-2 was positively correlated with the expression of collagen-I in the kidney of three different fibrotic mouse models. Pharmaceutical inhibition or genetic knockout of polycystin-2 reduced the expression of pro-fibrotic markers in fibrotic kidneys of two animal models. Moreover, conditional knockout of Pkd1 gene attenuated renal fibrosis in two mouse models. Enhancer of Zeste homolog 2 (EZH2) is a methyltransferase which plays important role in renal fibrosis. We found that EZH2 was positively correlated with the expression of polycystins in fibrotic kidneys. Conditional knockout of the Ezh2 attenuated the anti-fibrotic responses induced by Pkd1 deletion in fibrotic kidneys.

In conclusion, polycystins are up-regulated in injured kidneys and polycystins promote renal fibrosis through up-regulation of EZH2 in fibrotic kidneys, suggesting that renal fibrosis in polycystic kidneys is not the direct effect of PKD gene mutations.

SignificanceMutations of polycystins cause autosomal polycystic kidney disease (ADPKD) which is associated with increased renal fibrosis in cystic kidneys. However, the role of polycystin in renal fibrosis remains unclear. Here, we showed that the expression of polycystins is positively correlated with the development of renal fibrosis in injured kidneys. Pharmaceutical inhibition or genetic deletion of polycystin-2 attenuated renal fibrosis in fibrotic kidneys. Moreover, genetic deletion of polycystin-1 inhibited renal fibrosis in two different animal models. Finally, we showed that ablation of the methyltransferase EZH2 mitigated the anti-fibrotic effect of polycystin-1 deletion in fibrotic kidneys. We conclude that polycystin promotes through EZH2 and renal fibrosis in cystic kidney is not the direct effect of PKD gene mutations.