Host phenology can drive the evolution of intermediate virulence strategies in some parasites AO_SCPLOWBSTRACTC_SCPLOWThe traditional mechanistic trade-offs resulting in a negative correlation between transmission and virulence are the foundation of nearly all current theory on the evolution of parasite virulence. Several ecological factors have been shown to modulate the optimal virulence strategies predicted from mechanistic trade-off models, but these ecological factors have not yet been shown to be sufficient to explain the intermediate virulence strategies observed in any natural system. The timing of seasonal activity, or phenology, is a common factor that influences the types and impact of many ecological interactions but is difficult to incorporate into virulence evolution studies. We develop a mathematical model of a disease system with seasonal host activity to study the evolutionary consequences of host phenology on the virulence of obligate-killer parasite. Results from this model demonstrated that seasonal host activity is sufficient to drive the evolution of intermediate parasite virulence in some types of natural disease systems, even when a traditional mechanistic trade-off between transmission and virulence is not assumed in the modeling framework. The optimal virulence strategy in these systems can be determined by both the duration of the host activity period as well as the variation in the host emergence timing. Parasites with low virulence strategies are favored in environments with long host activity periods and in environments in which hosts emerge synchronously. The results demonstrate that host phenology can be sufficient to select for intermediate optimal virulence strategies, providing an alternative mechanism to account for virulence evolution in some natural systems.
The origins and drivers of Neotropical diversity The origins and evolution of the outstanding Neotropical biodiversity are still debated. A comprehensive understanding is hindered by the lack of deep-time comparative data across wide phylogenetic and ecological contexts. Here, we evaluate four evolutionary scenarios assuming different diversification trajectories and drivers of Neotropical diversification, and assess their variation across Neotropical regions and taxa. Our analysis of 150 phylogenies (12,512 species) of seed plants and tetrapods reveals that Neotropical diversity has mostly expanded through time (70% of the clades), while scenarios of saturated and declining diversity also account for 21% and 9% of Neotropical diversity, respectively. We identify five biogeographic areas that represent distinctive units of long-term Neotropical evolution (Pan-Amazonia, Dry Diagonal, Bahama-Antilles, Galapagos, and an  elsewhere region) and find that diversity dynamics do not differ across these areas, suggesting no geographic structure in long-term Neotropical diversification. In contrast, diversification dynamics differ substantially across taxa: plant diversity mostly expanded through time (88%), while a substantial fraction (43%) of tetrapod diversity accumulated at a slower pace or declined toward the present. These opposite evolutionary patterns may reflect different capacities for plants and tetrapods to cope with climate change, with potential implications for future adaptation and ecosystem resilience.
The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance FTSJ1 is a conserved human 2-O-methyltransferase (Nm-MTase) that modifies several transfer RNAs (tRNAs) at position 32 and the wobble position 34 in the AntiCodon Loop (ACL). Its loss of function has been linked to Non-Syndromic X-Linked Intellectual Disability (NSXLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear. Here we report a novel FTSJ1 pathogenic variant from a NSXLID patient. Using blood cells derived from this patient and other affected individuals carrying FTSJ1 mutations, we performed an unbiased and comprehensive RiboMethSeq analysis to map the ribose methylation (Nm) on all tRNAs and identify novel targets. In addition, we performed a transcriptome analysis in these cells and found that several genes previously associated with intellectual disability and cancers were deregulated. We also found changes in the miRNA population that suggest potential cross-regulation of some miRNAs with these key mRNA targets. Finally, we show that differentiation of FTSJ1-depleted human neuronal progenitor cells (NPC) into neurons displays long and thin spine neurites compared to control cells. These defects are also observed in Drosophila and are associated with long term memory deficit in this organism. Altogether, our study adds insight into FTSJ1 pathologies in human by the identification of novel FTSJ1 targets and the defect in neuron morphology. Quercetin handles cellular oxidant / antioxidant systems and mitigates immunosenescence hallmarks in human PBMCs: an in vitro study Immunosenescence, oxidative stress, and low vaccine efficacy are important symptoms of aging. The goal of our study was to see if quercetin had anti-aging and stimulating effects on PBMC immune cells in vitro. In the presence of concanavalin a, PBMCs were isolated from healthy elderly and young people and cultured in a complete RPMI-1640 medium supplemented with quercetin. Cell proliferation was assessed using the MTT colorimetric assay after a 48-hour incubation period. Spectrophophotometric assays were used to assess oxidative biomarkers (PC, MDA, and GSH). The ELISA method was used to determine the amount of IL-2 released. A Griess reagent was used to investigate iNOS activity. When compared to young control cells, aged PBMCs had lower proliferation potency, lower IL-2 and NO release, and higher MDA and PC levels. Importantly, quercetin-treated aged PBMCs have a high proliferative response comparable to young cells, restored iNOS activity, and increased levels of GSH antioxidant defences. In comparison to untreated aged PBMCs, treated PBMCs have lower lipo-oxidative damage but higher PC levels. Quercetin may be used as a promising dietary vaccinal adjuvant in the elderly, it has significant effects in reducing immunosenescence hallmarks, as well as mitigating the lipo-oxidative stress in PBMCs cells.

Practical abstractQuercetin is a common dietary polyphenol found in fruits and vegetables that is well known for its antioxidant activity in radical scavenging and anticancer properties characterized by immune system stimulation. In vitro, quercetin boosts immune responses in the elderly and reduces immunosenescence symptoms, according to our findings. As a result, this molecule could be a safe and promising vaccine adjuvant for boosting immunity and reducing aging complications in immune cells as well as reducing oxidative stress in PBMC cells. Structural basis for Nirmatrelvir in vitro efficacy against SARS-CoV-2 variants The COVID-19 pandemic continues to be a public health threat with emerging variants of SARS-CoV-2. Nirmatrelvir (PF-07321332) is a reversible, covalent inhibitor targeting the main protease (Mpro) of SARS-CoV-2 and the active protease inhibitor in PAXLOVID (nirmatrelvir tablets and ritonavir tablets). We evaluated the in vitro catalytic activity and in vitro potency of nirmatrelvir against the main protease (Mpro) of prevalent variants of concern (VOC) or variants of interest (VOI): Alpha (, B.1.1.7), Beta ({beta}, B.1.351), Delta ({delta}, B1.617.2), Gamma ({gamma}, P.1), Lambda ({lambda}, B.1.1.1.37/C37), Omicron (o, B.1.1.529) as well as the original Washington or wildtype strain. These VOC/VOI carry prevalent mutations at varying frequencies in the Mpro specifically for: , {beta},{gamma} (K90R), {lambda} (G15S) and o (P132H). In vitro biochemical enzymatic assay characterization of the enzyme kinetics of the mutant Mpros demonstrate that they are catalytically comparable to wildtype. Nirmatrelvir has similar potency against each mutant Mpro including P132H that is observed in the Omicron variant with a Ki of 0.635 nM as compared to a Ki of 0.933nM for wildtype. The molecular basis for these observations were provided by solution-phase structural dynamics and structural determination of nirmatrelvir bound to the o, {lambda} and {beta} Mpro at 1.63 - 2.09 [A] resolution. These in vitro data suggest that PAXLOVID has the potential to maintain plasma concentrations of nirmatrelvir many-fold times higher than the amount required to stop the SARS-CoV-2 VOC/VOI, including Omicron, from replicating in cells (1). 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. Worldwide analysis of reef surveys sorts coral taxa by (adaptive) response to heat stress Coral reefs around the world are under threat due to widespread decline of hard corals caused by anomalous heat waves. Different coral taxa are known to have different sensitivities to heat. However, little is known about how long-term effects of heat exposure differ between coral taxa, nor in particular how such effects might drive adaptive processes. Here, we combined worldwide reef survey data with remotely sensed thermal anomalies to evaluate how local rates of taxa-specific coral cover were associated with heat stress. We found a negative association between coral cover and heat stress: weaker for massive and encrusting Poritidae, for meandroid Favidae and Mussidae; and stronger for branching, tabular and corymbose Acroporidae. Additionally, we found that coral cover decline driven by recent heat stress (measured as the year before a survey) was mitigated by long-term past heat (measured since 1985) in branching, tabular and corymbose Acroporidae and Pocilloporidae, but not in Poritidae, Favidae and Mussidae. This mitigation of coral decline was not observed under the effect of short-term past heat (measured during the two previous years), suggesting that these presumptive adaptive processes are the result of evolutionary adaptation, rather than of physiological acclimatization. We finally queried the Coral Trait Database to characterize morphological, physiological and reproductive traits of different taxa showing similar heat-responses. Further genomics studies should confirm the evolutionary origin of such divergent adaptive responses to heat stress. Contribution Evenness: A functional redundancy metric sensitive to trait stability in microbialcommunities The concept of functional redundancy has received considerable attention in both the macroecology and microbial ecology literature. As a result, multiple metrics of functional redundancy have been proposed. These vary in how they weight trait levels, species abundance, functional richness, and species richness. Here we present a new functional redundancy metric tailored for community-aggregated traits, which are traits that are quantified at the community level and can be quantitatively partitioned among species. We call this metric Contribution Evenness (CE) because it measures how evenly species contribute to a community-aggregated trait. As CE is an evenness measurement, it ranges from 0 and 1, where 0 corresponds to a single species contributing to a community-aggregated trait and 1 corresponds to all species contributing equally. Using in silico simulations of species extinctions, we demonstrate that CE reflects the stability of an ecosystem function to species extinction, a hypothesized ecological consequence of functional redundancy. As a positive control and to illustrate how CE can be used with sequence data, we analyzed the functional redundancy of eight nitrogen-transforming pathways using 2,631 metagenome-assembled genomes from 47 marine sites. CE for marine nitrogen cycle marker genes was consistent with our qualitative understanding of which nitrogen pathways are most functionally redundant in the ocean. We found that, on average, the NH4+ assimilation pathway was the most functionally redundant (0.44 {+/-} 0.08) while dissimilatory nitrate reduction was the least redundant (0.005 {+/-} 0.005). As demonstrated here, CE provides a promising framework for measuring trait stability in microbiomes. Potent but transient immunosuppression of T-cells is a general feature of CD71+ erythroid cells CD71+ erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. Here, we show that in mice early-stage CECs expand in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). In the spleens of anemic mice, CECs expansion-induced L-arginine depletion suppresses T-cell responses. In humans with anemia, CECs expand and express ARG1 and ARG2 that suppress T-cells IFN-{gamma} production. Moreover, bone marrow CECs from healthy human donors suppress T-cells proliferation. CECs differentiated from peripheral blood mononuclear cells potently suppress T-cell activation, proliferation, and IFN-{gamma} production in an ARG- and ROS-dependent manner. These effects are the most prominent for early-stage CECs (CD71highCD235adim cells). The suppressive properties disappear during erythroid differentiation as more differentiated CECs and mature erythrocytes lack significant immunoregulatory properties. Our studies provide a novel insight into the role of CECs in the immune response regulation.

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/427109v2_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@136fbd8org.highwire.dtl.DTLVardef@d05d00org.highwire.dtl.DTLVardef@189baceorg.highwire.dtl.DTLVardef@1472b2b_HPS_FORMAT_FIGEXP  M_FIG C_FIG Improving localization precision via restricting biomolecule confined stochastic motion in SMLM Single-molecule localization microscopy (SMLM) boosts its applications when combined with the studies of cells, in which nanometer-sized biomolecules are irresolvable due to diffraction limit unless being subjected to SMLM. Although being well immobilized, given the nanometer sizes of biological molecules, they are still capable of movement stochastically around their immobilized sites. The influence of such motion on image quality and possible improvements have not yet been systematically investigated. Here, we accessed the biomolecule stochastic motion in SMLM by calculating the displacements between different localizations from the same molecule in single-molecule samples of Alexa Fluor-647-conjugated oligonucleotides. We found that, for most molecules, localization displacements at random frame intervals are remarkably larger than those between temporally neighbouring frames despite of drift correction, showing that biomolecule stochastic motion is involved in SMLM. Furthermore, the localization displacements were observed to increase with frame intervals and then saturate, suggesting biomolecule stochastic motion is confined within a finite area. Moreover, we showed that the localization precision is deteriorated by enlarging molecule sizes and improved by sample post-fixation. This study reveals confined stochastic motion of biomolecules increase localization uncertainty in SMLM, and improved localization precision can be achieved via restricting biomolecule stochastic motion. Neural excitability and sensory input determine intensity perception with opposing directions in initial cortical responses Perception of sensory information is determined by stimulus features (e.g., intensity) and instantaneous neural states (e.g., excitability). Commonly, it is assumed that both are reflected similarly in evoked brain potentials, that is, higher evoked activity leads to a stronger percept of a stimulus. We tested this assumption in a somatosensory discrimination task in humans, simultaneously assessing (i) single-trial excitatory post-synaptic currents inferred from short-latency somatosensory evoked potentials (SEP), (ii) pre-stimulus alpha oscillations (8-13 Hz), and (iii) peripheral nerve measures. Fluctuations of neural excitability shaped the perceived stimulus intensity already during the very first cortical response (at [~]20 ms) yet demonstrating opposite neural signatures as compared to the effect of presented stimulus intensity. We reconcile this discrepancy via a common framework based on modulations of electro-chemical membrane gradients linking neural states and responses, which calls for reconsidering conventional interpretations of brain potential magnitudes in stimulus intensity encoding. The obstacles and potential clues of prime editing applications in tomato, a dicot plant Precision genome editing is highly desired for crop improvement. The recently emerged CRISPR/Cas technology offers great potential applications in precision plant genome engineering. A prime editing (PE) approach combining a reverse transcriptase (RT) with a Cas9 nickase and a "priming" extended guide RNA has shown a high frequency for precise genome modification in mammalian cells and several plant species. Nevertheless, the applications of the PE approach in dicot plants are still limited and inefficient. We designed and tested prime editors for precision editing of a synthetic sequence in a transient assay and for desirable alleles of 10 loci in tomato by stable transformation. Our data obtained by targeted deep sequencing also revealed only low PE efficiencies in both the tobacco and tomato systems. Further assessment of the activities of the PE components uncovered potential reasons for the inefficiency of the PE complexes. Modifying the pegRNA sequences by shortening or introducing mismatches to the primer binding sequences (PBS) in order to reduce their melting temperatures (Tm) did not enhance the PE efficiency at the SlBMP21, SlALC and SlALS1 loci. Our data show challenges of PE approach in tomato, indicating a further improvement of the PE system for the successful applications such as use of improved expression systems. Our work provides an important clue for the successful application of the PE approach in crop improvement. New insights into tomato CLE peptide repertoire and perception mechanisms Precision in sensing the environmental cues and adjusting the growth and the physiology of the root system are necessary for plant robustness. Plants achieve their phenotypic plasticity by tightly controlling and buffering developmental decisions. In addition to the classical plant hormones that mediate plant development and stress responses, the CLE peptides constitute an additional crucial level of regulation. While the CLV3-CLV1 module appears to be highly conserved to control the proliferation of the shoot apical meristem stem cells, we do not yet fully understand the function of the additional CLE genes and whether they act in a similar way across the plant species, including tomato. Due to the small gene size and high sequence variability, it is extremely difficult to precisely annotate CLE genes in plant genomes. Here we present our analysis of the CLE family in tomato, based on a combination of iterative tBLASTn and Hidden-Markov-Model (HMM), which allowed us to identify thirty-seven new SlCLEs in addition to the fifteen reported previously. We could confirm the biological activities of selected SlCLEs in suppressing root meristematic cell divisions. We show that root response is mediated by SlCLAVATA2, indicating the conservation of CLE perception mechanism.

One-sentence summaryUsing a combination of iterative tBLASTn and Hidden-Markov-Model approaches, we uncovered 37 new tomato CLE genes predominantly expressed in roots, and we showed a conserved effect on root meristem arrest, that was SlCLAVATA2-dependent.

HighlightsO_LIWe applied a combined approach of iterative tBLASTn and Hidden-Markov-Model to identify fifty-two tomato SlCLE genes, including thirty-seven new genes
C_LIO_LIAll identified genes encode for pre-propeptides with a single CLE-domain containing conserved residues similar to Arabidopsis
C_LIO_LIAnalyzing the publicly available RNAseq datasets, we could confirm the expression of SlCLE genes that was often associated specifically with root or shoot, a certain developmental stage of the fruit, or with drought stress conditions
C_LIO_LIRemarkably, the majority of SlCLE genes are predominantly expressed in the root tissues
C_LIO_LIWe showed the conserved inhibitory effect on the root meristem and columella cells division for the selected SlCLE peptides that were SlCLAVATA2-dependent.
C_LI Decoding the porcine developing spatial processing system and production of human entorhinal stellate cell-like cells by a direct programming approach. Classic studies investigating how and when the entorhinal cortex (component of the memory processing system of the brain) develops have been based on traditional thymidine autoradiography and histological techniques. In this study, we take advantage of modern technologies to trace at a high resolution, the cellular complexity of the developing porcine medial entorhinal cortex by using single-cell profiling. The postnatal medial entorhinal cortex comprises 4 interneuron, 3 pyramidal neuron and 2 stellate cell populations which emerge from intermediate progenitor and immature neuron populations. We discover four MGE-derived interneurons and one CGE-derived interneuron population as well as several IN progenitors. We also identify two oligodendrocyte progenitor populations and three populations of oligodendrocytes. We perform a proof-of-concept experiment demonstrating that porcine scRNA-seq data can be used to develop novel protocols for producing human entorhinal cells in-vitro. We identified six transcription factors (RUNX1A1, SOX5, FOXP1, MEF2C, TCF4, EYA2) important in neurodevelopment and differentiation from one RELN+ stellate cell population. Using a lentiviral vector approach, we reprogrammed human induced pluripotent stem cells into stellate cell-like cells which expressed RELN, SATB2, LEF1 and BCL11B. Our findings contribute to the understanding of the formation of the brains cognitive memory and spatial processing system and provides proof-of-concept for the production of entorhinal cells from human pluripotent stem cells in-vitro. A biochemically-realisable relational model of the self-manufacturing cell As shown by Hofmeyr, the processes in the living cell can be divided into three classes of efficient causes that produce each other, so making the cell closed to efficient causation, the hallmark of an organism. They are the enzyme catalysts of covalent metabolic chemistry, the intracellular milieu that drives the supramolecular processes of chaperone-assisted folding and self-assembly of polypeptides and nucleic acids into functional catalysts and transporters, and the membrane transporters that maintain the intracellular milieu, in particular its electrolyte composition. Each class of efficient cause can be modelled as a relational diagram in the form of a mapping in graph-theoretic form, and a minimal model of a self-manufacturing system that is closed to efficient causation can be constructed from these three mappings using the formalism of relational biology. This Fabrication-Assembly or (F,A)-system serves as an alternative to Robert Rosens replicative Metabolism-Repair or (M,R)-system, which has been notoriously problematic to realise in terms of real biochemical processes. A key feature of the model is the explicit incorporation of formal cause, which arrests the infinite regress that plagues all relational models of the cell. The (F,A)-system is extended into a detailed relational model of the self-manufacturing cell that has a clear biochemical realisation. This (F,A) cell model allows the interpretation and visualisation of concepts such as the metabolism and repair components of Rosens (M,R)-system, John von Neumanns universal constructor, Howard Pattees symbol-function split via the symbol-folding transformation, Marcello Barbieris genotype-ribotype-phenotype ontology, and Tibor Gantis chemoton. 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. NUCLEAR RETENTION OF LEPTIN/UPD2 REGULATES ORGANISMAL RESILIENCE TO NUTRIENT EXTREMES Adipokines released from the adipocytes function as a systemic adipometer; they impinge on neural circuits to signal nutrient status. On starvation, adipokines must be retained to signal energy deficit; else, it significantly reduces starvation survival. But how fat cells retain adipokines is unclear. Here, we demonstrate that Atg8, a cell-intrinsic autophagy factor, regulates the starvation-induced acute retention of the Leptin Drosophila ortholog Upd2. We show that on starvation, as a direct consequence of Atg8s lipidation, Upd2 accumulates in the nucleus. We illustrate that Upd2s nuclear retention is critical to fat mobilization and increased starvation resilience. Furthermore, nuclear Upd2 promotes the expression of a secreted innate immune gene signature. This hints at an unanticipated connection between adipokine nuclear retention and increased innate immunity. In conclusion, we propose that, during starvation, Atg8s role is not just limited to autophagy but is critical for withholding adipokines in the nucleus to promote starvation resilience.

GRAPHICAL ABSTRACT

O_FIG O_LINKSMALLFIG WIDTH=178 HEIGHT=200 SRC="FIGDIR/small/428913v5_ufig1.gif" ALT="Figure 1">
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org.highwire.dtl.DTLVardef@1826425org.highwire.dtl.DTLVardef@17cca52org.highwire.dtl.DTLVardef@1c70ac7org.highwire.dtl.DTLVardef@94a024_HPS_FORMAT_FIGEXP  M_FIG C_FIG O_LIIn fed state Upd2 requires Atg8 for nuclear exit and cytosolic localization.
C_LIO_LIAtg8s lipidation on starvation results in Upd2s nuclear accumulation.
C_LIO_LIUpd2 nuclear retention on starvation increases fat mobilization and post-starvation hunger.
C_LIO_LIOn starvation Upd2 nuclear retention increases expression of a secreted innate immune signature.
C_LI A MALDI-TOF assay identifies nilotinib as an inhibitor of inflammation in acute myeloid leukaemia Inflammatory responses are important in cancer, particularly in the context of monocyte-rich aggressive myeloid neoplasm. We developed a label-free cellular phenotypic drug discovery assay to identify anti-inflammatory drugs in human monocytes derived from acute myeloid leukaemia (AML), by tracking several biological features ionizing from only 2,500 cells using matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry. A proof-of-concept screen showed that the BCR-ABL inhibitor nilotinib, but not the structurally similar imatinib, blocks inflammatory responses. In order to identify the cellular (off-)targets of nilotinib, we performed thermal proteome profiling (TPP). Unlike imatinib, nilotinib and other later generation BCR-ABL inhibitors inhibit the p38-MK2/3 signalling axis which suppressed the expression of inflammatory cytokines, cell adhesion and innate immunity markers in activated human monocytes derived from AML. Thus, our study provides a tool for the discovery of new anti-inflammatory drugs, which could contribute to the treatment of inflammation in myeloid neoplasms and other diseases.

Key PointsLabel-free cell-based assay identifies new anti-inflammatory drugs using MALDI-TOF MS. Nilotinib reduces inflammation by inhibition of MAPK14-MK2/3 signalling axis in AML. Effects of a 33-ion sequential beam galactic cosmic ray analog on male mouse behavior and evaluation of CDDO-EA as a radiation countermeasure In long-term spaceflight, astronauts will face unique cognitive loads and social challenges which will be complicated by communication delays with Earth. It is important to understand the central nervous system (CNS) effects of deep spaceflight and the associated unavoidable exposure to galactic cosmic radiation (GCR). Rodent studies show single- or simple-particle combination exposure alters CNS endpoints, including hippocampal-dependent behavior. An even better Earth-based simulation of GCR is now available, consisting of a 33-beam (33-GCR) exposure. However, the effect of whole-body 33-GCR exposure on rodent behavior is unknown, and no 33-GCR CNS countermeasures have been tested. Here astronaut-age-equivalent (6mo-old) C57BL/6J male mice were exposed to 33-GCR (75cGy, a Mars mission dose). Pre-/during/post-Sham or 33-GCR exposure, mice received a diet containing a  vehicle formulation alone or with the antioxidant/anti-inflammatory compound CDDO-EA as a potential countermeasure. Behavioral testing beginning 4mo post-irradiation suggested radiation and diet did not affect measures of exploration/anxiety-like behaviors (open field, elevated plus maze) or recognition of a novel object. However, in 3-Chamber Social Interaction (3-CSI), CDDO-EA/33-GCR mice failed to spend more time exploring a holder containing a novel mouse vs. a novel object (empty holder), suggesting sociability deficits. Also, Vehicle/33-GCR and CDDO-EA/Sham mice failed to discriminate between a novel stranger vs. familiarized stranger mouse, suggesting blunted preference for social novelty. CDDO-EA given pre-/during/post-irradiation did not attenuate the 33-GCR-induced blunting of preference for social novelty. Future elucidation of the mechanisms underlying 33-GCR-induced blunting of preference for social novelty will improve risk analysis for astronauts which may in-turn improve countermeasures. Sarcoplasmic reticulum calcium handling in young DBA/2J vs C57BL/10 mdx models of Duchenne muscular dystrophy The DBA/2J (D2) mdx mouse has emerged as a more severe model of Duchenne muscular dystrophy when compared to the traditional C57BL/10 (C57) mdx mouse. Here, we questioned whether sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) function would differ in muscles from young D2 and C57 mdx mice. In gastrocnemius muscles, both D2- and C57 mdx mice exhibited signs of impaired Ca2+ uptake, however, this was more severe in D2 mdx mice. Maximal SERCA activity was lowered only in D2 mdx gastrocnemius muscles and not C57 mdx muscles. Furthermore, in the left ventricle and diaphragm, Ca2+ uptake was impaired in C57 mdx muscles with lowered rates of Ca2+ uptake compared with C57 WT mice, whereas in muscles from D2 mdx mice, rates of Ca2+ uptake were unattainable due to the severe impairments in their ability to transport Ca2+. Overall, our study demonstrates that SERCA function is drastically impaired in young D2 mdx mice. Intermittent compression increases flow through a gel: a mechanical model perhaps relevant to flow of cerebrospinal fluid Exchange of molecules between cerebrospinal fluid (CSF) and brain cells contributes to brain function and protection from dementia. Despite widespread acceptance of the  glymphatic theory, the route by which CSF is brought close enough to the neural tissue for solutes to be exchanged by extracellular diffusion is not entirely clear. Exogenous molecules injected into CSF are observed to reach the basement lamina that surrounds the dense capillary network. Transport of solutes by diffusion along the basement lamina, a gel of macromolcules about 100 nm thick, would be too slow; bulk flow in a static geometry would require unphysiologically high pressures. However, it is known that the pulsation of blood aids transport of CSF, and we hypothesized that this is because the pulsation intermittently squeezes the pericapillary lamina. In a primitive mimicry, we have tested whether intermittent squeezing increases flow through an agar gel. In all but one of 216 tests, pulsation caused a reversible increase, sometimes by a factor of 100 or more. The enhancement was greatest for frequencies 5-11 Hz and, over the tested range of pressure heads (20 - 50 cmH2O), was greatest for the lowest pressure. The results suggest a reason why exercise slows the aging of the brain. Modeling microRNA-driven post-transcriptional regulation by using exon-intron split analysis (EISA) in pigs The contribution of microRNAs (miRNAs) to mRNA regulation has often been explored by post hoc selection of downregulated genes and determining whether they harbor binding sites for miRNAs of interest. This approach, however, does not discriminate whether these mRNAs are also downregulated at the transcriptional level. Here, we have characterized the transcriptional and post-transcriptional changes of mRNA expression in two porcine tissues: gluteus medius muscle of fasted and fed Duroc gilts and adipose tissue of lean and obese Duroc-Gottingen minipigs. Exon-intron split analysis (EISA) of RNA-seq data allowed us to identify downregulated mRNAs with high post-transcriptional signals in fed or obese states, and we assessed whether they harbor binding sites for upregulated miRNAs in any of these two physiological states. We found 26 downregulated mRNAs with high post-transcriptional signals in the muscle of fed gilts and 21 of these were predicted targets of upregulated miRNAs also in the fed state. For adipose tissue, 44 downregulated mRNAs in obese minipigs displayed high post-transcriptional signals, and 25 of these were predicted targets of miRNAs upregulated in the obese state. These results suggest that the contribution of miRNAs to mRNA repression is more prominent in the skeletal muscle system. Finally, we identified several genes that may play relevant roles in the energy homeostasis of the pig skeletal muscle (DKK2 and PDK4) and adipose (SESN3 and ESRRG) tissues. By differentiating transcriptional from post-transcriptional changes in mRNA expression, EISA provides a valuable view about the regulation of gene expression, complementary to canonical differential expression analyses. First detection of herpesvirus and prevalence of mycoplasma infection in free-ranging Hermann s tortoises (Testudo hermanni), and in potential pet vectors AO_SCPLOWBSTRACTC_SCPLOWTwo types of pathogens cause highly contagious upper respiratory tract diseases (URTD) in Chelonians: testudinid herpesviruses (TeHV) and a mycoplasma (Mycoplasma agassizii). In captivity, these infections are frequent and can provoke outbreaks. Pet trade generates international flow of tortoises, often without sanitary checking; individuals intentionally or accidentally released in the wild may spread pathogens. A better understanding of the transmission of infectious agents from captivity to wild tortoises is needed. Many exotic individuals have been introduced in populations of the endangered western Hermanns tortoise (Testudo hermanni hermanni), notably spur-thighed tortoises (Testudo graeca). We assessed the presence of TeHV and mycoplasma in native western Hermanns tortoises and in potential pet vectors in south-eastern France. Using a large sample (N=572 tortoises), this study revealed, by PCR, the worrying presence of herpesvirus in 7 free-ranging individuals (3 sub-populations). Additionally, Mycoplasma agassizii was detected, by PCR, in 15 of the 18 populations sampled with a frequency ranging from 3.4% (1 of 29 tortoises) to 25% (3 of 12 tortoises). Exotic spur-thighed tortoises showed high frequency of mycoplasma infection in captivity (18.2%) and in individuals (50%) found in native Hermanns tortoise sub-populations, suggesting that this species could be a significant vector. The paucity of information of TeHV on European tortoise URTD in natural settings, especially in combination with mycoplasma, prompts for further studies. Indeed, sick tortoises remain concealed and may not be easily detected in the field. Our results indicate a good health for most infected tortoise but it should be screened in the field as well as in captivity. Standardized genome-wide function prediction enables comparative functional genomics: a new application area for Gene Ontologies in plants BackgroundGenome-wide gene function annotations are useful for hypothesis generation and for prioritizing candidate genes potentially responsible for phenotypes of interest. We functionally annotated the genes of 18 crop plant genomes across 14 species using the GOMAP pipeline.

ResultsBy comparison to existing GO annotation datasets, GOMAP-generated datasets cover more genes, contain more GO terms, and produce datasets similar in quality (based on precision and recall metrics using existing gold standards as the basis for comparison). From there, we sought to determine whether the datasets across multiple species could be used together to carry out comparative functional genomics analyses in plants. To test the idea and as a proof of concept, we created dendrograms of functional relatedness based on terms assigned for all 18 genomes. These dendrograms were compared to well-established species-level evolutionary phylogenies to determine whether trees derived were in agreement with known evolutionary relationships, which they largely are. Where discrepancies were observed, we determined branch support based on jack-knifing then removed individual annotation sets by genome to identify the annotation sets causing unexpected relationships.

ConclusionsGOMAP-derived functional annotations used together across multiple species generally retain sufficient biological signal to recover known phylogenetic relationships based on genome-wide functional similarities, indicating that comparative functional genomics across species based on GO data hold promise for generating novel hypotheses about comparative gene function and traits. A general role for MIA3/TANGO1 in secretory pathway organization and function. Complex machinery is required to drive secretory cargo export from the endoplasmic reticulum, an essential process in eukaryotic cells. In vertebrates, the Mia3 gene encodes two major forms of Transport ANd Golgi Organization Protein 1 (TANGO1S and TANGO1L). Here, using genome engineering of human cells, light microscopy, secretion assays, genomics, and proteomics we show that disruption of the longer form, TANGO1L, results in relatively minor defects in secretory pathway organization and function including limited impacts on procollagen secretion. In contrast, loss of both long and short forms results in major defects in cell organization and secretion. These include a failure to maintain the localization of ERGIC53 and SURF4 to the ER-Golgi Intermediate Compartment and dramatic changes to the ultrastructure of the ER-Golgi interface. Disruption of TANGO1 expression also causes significant changes in early secretory pathway gene and protein expression. Disruption of both TANGO1L and TANGO1S expression impairs secretion not only of large proteins, including procollagens, but of all types of secretory cargo including small soluble proteins. Our data support a general role for Mia3/TANGO1 in maintaining both secretory pathway structure and function in vertebrate cells. Development of an in-situ printing system with human platelet lysate-based bio-adhesive to treat corneal perforation PurposeCorneal perforation is a clinical emergency. Tissue glue to seal the perforation, and supplementary topical medication represents existing standard treatment. Previously, our group developed a transparent human platelet lysate (hPL)-based biomaterial that showed good cell compatibility and accelerated corneal epithelial cells healing in-vitro. This study aims to develop a novel treatment method for corneal perforation using this biomaterial.

MethodsRheometry was used to measure the hPL-based biomaterial behaviour at room and corneal surface temperatures. Its adhesiveness to porcine skin and burst pressure limit were also measured. Based on rheological behaviour, a hand-held biopen was developed to extrude it onto the cornea. An animal trial (5 New Zealand white rabbits) to compare impact of the biomaterial and cyanoacrylate glue (control group) on a 2mm perforation was conducted to evaluate safety and efficacy.

ResultsThe hPL-based biomaterial showed higher adhesiveness compared to commercial fibrin glue and withstood burst pressure approximately 6.4x higher than routine intraocular pressure. Treatment rabbits had lower pain scores and faster recovery, despite generating similar scar-forming structure compared to controls. No secondary corneal ulcer was generated in rabbits treated with the bio-adhesive.

ConclusionsThis study reports a novel in-situ printing system capable of delivering a hPL-based, transparent bio-adhesive and successfully treating small corneal perforations. Bio-adhesive-treated rabbits recovered faster and required no additional analgesia. Both groups showed scarred corneal tissue after healing, however no infection and inflammation was observed by 3 weeks. The delivery system was easy to use and may represent an alternative treatment for corneal perforation.

HighlightsO_LIThis study presents a novel in situ printing system to treat corneal perforation
C_LIO_LIThe system is comprised of a human platelet lysate-based bio-adhesive and a pen-like hand held delivery system
C_LIO_LIMechanical tests showed our transparent bio-adhesive has a higher adhesiveness compared to existing treatments and burst pressure threshold approximately 6.4 times higher than normal intraocular pressure.
C_LIO_LIIn vivo rabbit trial showed that compared to cyanoacrylate glue, the bio-adhesive was safer, faster healing and led to less pain in rabbits.
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