O-antigen structure and surface hydrophobicity determines aggregate assembly type in Pseudomonas aeruginosa Bacteria live in spatially organized aggregates during chronic infections, where they adapt to the host environment, evade immune responses and resist therapeutic interventions. Although it is known that environmental factors such as polymers influence bacterial aggregation, it is not clear how bacterial adaptation during chronic infection impacts the formation and spatial organization of aggregates in the presence of polymers. Here we show that in an in vitro model of cystic fibrosis (CF) containing the polymers eDNA and mucin, O-specific antigen is a major factor in determining the formation of two distinct aggregate assembly types of Pseudomonas aeruginosa due to alterations in cell surface hydrophobicity. Our findings suggest that during chronic infection, interplay between cell surface properties and polymers in the environment may influence the formation and structure of bacterial aggregates, which would shed new light on the fitness costs and benefits of O-antigen production in environments such as CF lungs.

ImportanceDuring chronic infection, several factors contribute to the biogeography of microbial communities. Heterogeneous populations of Pseudomonas aeruginosa form aggregates in cystic fibrosis airways, however, the impact of this population heterogeneity on spatial organization and aggregate assembly is not well understood. In this study we found that changes in O-specific antigen determine the spatial organization of P. aeruginosa cells by altering the relative cell surface hydrophobicity. This finding suggests a role for O-antigen in regulating P. aeruginosa aggregate size and shape in cystic fibrosis airways.
A Drug-free, Self-destruction Strategy to Combat Bacterial Infections by Using the Intrinsically formed Magnetic Nanoparticles in Bacterial Pathogens The growing number of multiple drug resistant (MDR) bacteria and the dwindling pipeline of new antibiotics are driving us towards a  post-antibiotic era in which even common infections would become difficult to treat. To address this, an antibiotic-free strategy that can combat multiple bacteria is recommended. Most of the proposed approaches nevertheless have several limitations, including bacterial targeting. To overcome such limitations, the proposed strategy employs the bacterial machinery to self-destruct. Herein, the biosynthesis of magnetic nanoparticle (MNP) is reported for the first time in multiple pathogenic bacteria, including MDR bacteria. The intracellular MNPs composed of superparamagnetic zinc ferrites were formed in presence of iron and zinc precursors. Exposure of the treated bacteria/biofilms to an alternating magnetic field (AMF) exhibited hyperthermia (5-6{degrees}C) and a dramatic decrease in bacterial viability, suggesting the MNPs therapeutic potential. Likewise, the bacteria existing in vivo biosynthesize the MNPs by mining these elements from the host. To determine its therapeutic efficacy, the infected tissues were exposed directly to AMF. A 3-4 log reduction in bacterial burden, as compared to antibiotics treatment, confirmed the significance of using naturally existing MNPs to combat bacterial infections. The proposed broad-spectrum approach can therefore aid in overcoming the challenges facing anti-bacterial therapies.
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. Molecular switch between mammalian MLL complexes dictates response to Menin-MLL inhibition The chromatin adaptor Menin interacts with oncogenic fusion proteins encoded by MLL1-rearrangements (MLL1-r), and small molecules that disrupt these associations are currently in clinical trials for the treatment of leukemia. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacological, and biochemical approaches in mouse and human systems, we discovered a molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin modifying complexes that dictates response to Menin-MLL inhibitors. We show that MLL1-Menin safeguards leukemia survival by impeding binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the interaction between Menin and MLL1 leads to UTX-dependent transcriptional activation of a tumor suppressor gene-program that is crucial for a therapeutic response in murine and human leukemia. We establish the therapeutic relevance of this mechanism by showing that CDK4/6 inhibitors allow re-activation of this tumor-suppressor program in Menin-inhibitor insensitive leukemia cells, mitigating treatment resistance. The discovery of a molecular switch between MLL1-Menin and MLL3/4-UTX complexes on chromatin sheds light on novel functions of these evolutionary conserved epigenetic mediators and is particularly relevant to understand and target molecular pathways determining response and resistance in ongoing phase 1/2 clinical trials. The role of Kabuki Syndrome genes KMT2D and KDM6A in development: Analysis in Human sequencing data and compared to mice and zebrafish KMT2D and KDM6A are epigenetic regulators that have been implicated in Kabuki Syndrome, a rare congenital birth defect with multiple tissue and organ abnormalities, including craniofacial and heart defects. Our previous study identified human families with mutations in the epigenetic modifiers KMT2D and KDM6A, which is implicated in 32% and 10% of Kabuki Syndrome patients respectively. To understand the connection to Kabuki syndrome patients, and the transcriptional targets of KMT2D and KDM6A in humans, we performed RNA sequencing (seq) of lymphoblastoid cells from Kabuki Syndrome patients carrying mutations in KMT2D and KDM6A. We identified 1995 significant changes in transcriptional targets for KMT2D and 1917 for KDM6A, as compared to control. When compared with RNA-seq datasets obtained from other mouse and zebrafish studies, our analysis revealed KMT2D mutations affect the expression of 76 orthologous genes across all three datasets. Similarliy, KDM6A afftects the expprssion of 7 orthologous genes across three datasets. Despite the differences in cell types, stages, and species in the comparison between the transcriptomic datasets, there are common gene expression changes associated with KMT2D and KDM6A mutations. qPCR on novel zebrafish mutants confirmed the differentially expression in KMT2D or KDM6A mutant backgrounds. Taken together, our results show that KMT2D and KDM6A regulate common and unique genes across humans, mice, and zebrafish for early craniofacial and cardiac development and this information contributes to the understanding of epigenetic dysregulation during development of Kabuki syndrome. A novel two-generation approach to the population dynamics of gregarious parasitoids Parasitoids, as important natural enemies, help maintain balance in natural ecosystems. Their population dynamics is generally predicted from the number of individuals. Here, using gregarious parasitoids as models, we show that this traditional approach omits one important parameter: the mothers manipulation of offspring fertility due to the clutch size-body size- fertility correlation. As a result of this correlation, when females deliberately adjust the number of offspring laid in a host, they determine not only the number but also the body sizes and reproductive potentials of those offspring. For the first time in the model species Anaphes flavipes, we determined the parasitoids offspring fertility from clutch size. Using this, we experimentally clarified the advantage of specific clutch size combinations and we show that identical fertility in the F1 generation can lead to distinctly different fertility values in the F2 generation. Even with the same number of hosts, lower fertility in the F1 generation can cause higher fertility in the F2 generation. Based on these results, we propose a novel two-generation approach which includes the clutch size-body size-fertility correlation. Our novel approach provides a new perspective for determining the individual fitness levels of gregarious parasitoids with new options for the modelling of parasitoid population dynamics. Avian haemosporidians (Plasmodium and Haemoproteus) status in selected bird groups (Old world Flycatchers, Warblers, Babblers, and Thrushes) of India and their phylogenetic relationships with other lineages of the world The avian haemosporidians (Plasmodium and Haemoproteus) are widely distributed and may affect the host populations from body damage at individual level to the extinction of a population. The knowledge about their status may help in future avifauna conservation plans. Hence, we examined the avian haemosporidians status, in selected bird groups (Old world Flycatchers, Warblers, Babblers, and Thrushes) of India, and their phylogenetic relationships with other known lineages of the world. We used the common genetic marker (Cytochrome b gene fragment of 479 bp) with information on the geographic distribution of parasite and host species available at MalAvi database. The prevalence of avian haemosporidians, from northern, eastern, and southern parts of India and phylogenetic genetic analysis of lineages was carried out to know the genetic relatedness among them at local and world level. The MCC tree revealed six Haemosporidian lineages in which one was common (H_MSP01) and five were unique (H_CYOPOL01, H_CHD01, H_CYORUB01, H_EUMTHA01, and P_GEOCIT01). The avian host richness Index was 2.0852. 9.9%, prevalence of Haemosporidian infection was found in 111 DNA samples belonging to 6 host species. The Haemoproteus prevalence was found to be 9.0 % across five host species (Phylloscopus trochiloides, Cyornis poliogenys, C. hainanus dialilaemus, C. rubeculoides, Eumiyas thalassinus) and Plasmodium prevalence was 0.9% in Geokichla citrina. Spatial phylogeny at global level showed H_MSP01 lineage, found in different host species in India, was genetically related to H. pallidus lineages (COLL2 and PFC1) in parts of Africa, Europe, North America, Malaysia, and Philippines. The Plasmodium lineage (P_GEOCIT01) was related to PADOM16 in Egypt with poor sequence similarity (93.89%). The statistical analysis suggested that the haemosporidians host species distribution range was directly and significantly associated with the altitude, minimum temperature, and relative humidity. H_MSP01 distribution was in accordance with H. pallidus having a wide geographic and host range. A tool for assessing alignment of biomedical data repositories with open, FAIR, citation and trustworthy principles Increasing attention is being paid to the operation of biomedical data repositories in light of efforts to improve how scientific data is handled and made available for the long term. Multiple groups have produced recommendations for functions that biomedical repositories should support, with many using requirements of the FAIR data principles as guidelines. However, FAIR is but one set of principles that has arisen out of the open science community. They are joined by principles governing open science, data citation and trustworthiness, all of which are important aspects for biomedical data repositories to support. Together, these define a framework for data repositories that we call OFCT: Open, FAIR, Citable and Trustworthy. Here we developed an instrument using the open source PolicyModels toolkit that attempts to operationalize key aspects of OFCT principles and piloted the instrument by evaluating eight biomedical community repositories listed by the NIDDK Information Network (dkNET.org). Repositories included both specialist repositories that focused on a particular data type or domain, in this case diabetes and metabolomics, and generalist repositories that accept all data types and domains. The goal of this work was both to obtain a sense of how much the design of current biomedical data repositories align with these principles and to augment the dkNET listing with additional information that may be important to investigators trying to choose a repository, e.g., does the repository fully support data citation? The evaluation was performed from March to November 2020 through inspection of documentation and interaction with the sites by the authors. Overall, although there was little explicit acknowledgement of any of the OFCT principles in our sample, the majority of repositories provided at least some support for their tenets. Cross-species incompatibility between a DNA satellite and the Drosophila Spartan homolog poisons germline genome integrity Satellite DNA spans megabases of eukaryotic sequence and evolves rapidly. Paradoxically, satellite-rich genomic regions mediate strictly conserved, essential processes like chromosome segregation and nuclear structure. A leading resolution to this paradox posits that satellite DNA and satellite-associated chromosomal proteins coevolve to preserve these essential functions. We experimentally test this model of intra-genomic coevolution by conducting the first evolution-guided manipulation of both chromosomal protein and DNA satellite. The 359bp satellite spans an 11Mb array in D. melanogaster that is absent from its sister species, D. simulans. This species-specific DNA satellite colocalizes with the adaptively evolving, ovary-enriched protein, Maternal Haploid (MH)-the Drosophila homolog of Spartan. To determine if MH and 359 coevolve, we swapped the D. simulans version of MH ("MH[sim]") into D. melanogaster. MH[sim] triggers ovarian cell death, reduced ovary size, and loss of mature eggs. Surprisingly, the D. melanogaster mh null mutant has no such ovary phenotypes, suggesting that MH[sim] is toxic in a D. melanogaster background. Using both cell biology and genetics, we discovered that MH[sim] poisons oogenesis through a DNA damage pathway. Remarkably, deleting the D. melanogaster-specific 359 satellite array completely restores mh[sim] germline genome integrity and fertility, consistent with a history of coevolution between these two fast-evolving loci. Germline genome integrity and fertility are also restored by overexpressing Topoisomerase II (Top2), suggesting that MH[sim] interferes with Top2-mediated processing of 359. The observed 359-MH[sim] cross-species incompatibility supports a model under which ostensibly inert repetitive DNA and essential chromosomal proteins must coevolve to preserve germline genome integrity. In silico design of bioactive chimeric peptide from archaeal antimicrobial peptides Novel peptide therapeutics have been the cardinal part of modern-day research. Such therapies are being incorporated to prevent the adverse effects of globally emerging multi-drug resistant bacteria and various chronic human diseases which pose a great risk to the present world. In this study, we have designed a novel peptide therapy involving archaeal antimicrobial peptides. In silico predictions assign the peptide construct to be antigenic, non-allergenic, non-toxic and having stable physicochemical properties. The secondary and tertiary structures of the construct were predicted. The tertiary structure was refined for improving the quality of the predicted model. Computational tools predicted intracellular receptors in Escherichia coli, Klebsiella pneumoniae and the human body to be possible binding targets of the construct. In silico docking of modelled peptide with predicted targets, showed prominent results against targets for complex human diseases and that of bacterial infections. The stability of those docked complexes was confirmed with computational studies of conformational dynamics. Certainly, the designed peptide could be a potent therapeutic against multi-drug resistant bacteria as well as several human diseases. Fission yeast polycystin Pkd2p promotes the cell expansion and antagonizes the Hippo pathway SIN Polycystins are conserved mechanosensitive channels whose mutations lead to the common human renal disorder ADPKD. Previously we discovered that the plasma membrane-localized fission yeast homologue Pkd2p is an essential protein required for cytokinesis, but the mechanism remains unclear. Here, we isolated a novel temperature-sensitive mutant pkd2-B42. Among its strong growth defects, the most unique was that many mutant cells often lost significant portion of their volume in just 5 minutes followed by a gradual recovery, a process that we termed Deflation. Unlike cell lysis, deflation did not result in the plasma membrane rupture and it occurred independently from the cell cycle progression. The tip extension of pkd2-B42 cells was 80% slower than the wild type and their turgor pressure was 50% lower. Both pkd2-B42 and the other mutant pkd2-81KD partially rescued the mutants of the yeast Hippo signaling pathway Septation Initiation Network, by preventing cell lysis, enhancing septum formation, and doubling the number of Sid2/Mob1 molecules at the spindle pole bodies. We conclude that Pkd2p promotes cell size expansion during interphase by regulating turgor pressure and antagonizes SIN during cytokinesis.

Summary statementMutations of polycystins lead to human genetic disorder ADPKD. We discovered that the fission yeast homologue Pkd2p promotes the cell expansion during interphase growth and antagonizes the Hippo pathway SIN during cytokinesis. Single cell profiling of functionally cured Chronic Hepatitis B patients reveals the emergence of activated innate and an altered adaptive immune response in the intra-hepatic environment Hepatitis B surface antigen (HBsAg) loss or functional cure (FC), is considered the desirable therapeutic outcome for chronic hepatitis B (CHB) patients. However, the immuno-pathological biomarkers and underlying mechanisms remain unclear. Here we present a comprehensive single cell-transcriptomic atlas together with immune-phenotyping of disease-associated cell states (DACS) isolated from intra-hepatic tissue and matched PBMCs of either CHB or FC patients. We find that the intra-hepatic environment displays specific cell identities and molecular signatures that are distinct from PBMCs. FC is associated with emergence of an altered adaptive immune response marked by CD4 cytotoxic T lymphocytes (CD4-CTLs), and an activated innate response represented by liver-resident natural killer (LR-NK) cells. Overall, these findings provide novel insights into immuno-pathological cell states associated with FC that could serve as prognostic biomarkers. TAK1 blockade as a therapy for retinal neovascularization Retinal neovascularization, or pathological angiogenesis in the retina, is a leading cause of blindness in developed countries. Transforming growth factor-{beta}-activated kinase 1 (TAK1) is a mitogen-activated protein kinase kinase kinase (MAPKKK) activated by TGF-{beta}1 and other pro-inflammatory cytokines. TAK1 is also a key mediator of inflammation, innate immune responses, apoptosis and tissue homeostasis and plays an important role in physiological angiogenesis. Its role in pathological angiogenesis, particularly in retinal neovascularization, remains unclear. We investigated the regulatory role of TAK1 in pathological angiogenesis in the retina. Transcriptome analysis of human retina featuring retinal neovascularization revealed enrichment of known TAK1-mediated signaling pathways. Selective inhibition of TAK1 activation by 5Z-7-oxozeaenol attenuated aberrant retinal angiogenesis in rats following oxygen-induced retinopathy. Transcriptome profiling revealed that TAK1 activation in human microvascular endothelial cells under TNF stimulation led to increase the gene expression related to cytokines and leukocyte-endothelial interaction, mainly through nuclear factor kappa B (NF{kappa}B) signaling pathways. These results reveal that inhibition of TAK1 signaling may have therapeutic value for the treatment of pathological angiogenesis in the retina. Cell-specific Bioorthogonal Tagging of Glycoproteins Altered glycosylation is an undisputed corollary of cancer development. Understanding these alterations is paramount but hampered by limitations underlying cellular model systems. For instance, the intricate interactions between tumour and host cannot be adequately recapitulated in monoculture of tumour-derived cell lines. More complex co-culture models usually rely on sorting procedures for proteome analyses and rarely capture the details of protein glycosylation. Here, we report a strategy termed Bio-Orthogonal Cell line-specific Tagging of Glycoproteins (BOCTAG). Cells are equipped by transfection with an artificial biosynthetic pathway that transforms bioorthogonally tagged sugars into the corresponding nucleotide-sugars. Only transfected cells incorporate bioorthogonal tags into glycoproteins in the presence of non-transfected cells. We employ BOCTAG as an imaging technique and to annotate cell-specific glycosylation sites in mass spectrometry-glycoproteomics. We demonstrate application in co-culture and mouse models, allowing for profiling of the glycoproteome as an important modulator of cellular function. 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. Relationship between shear wave velocity and muscle activation is inconsistent across different muscle types There is an increasing use of shear wave ultrasound elastography to quantify mechanical properties of muscles under various conditions such as changes muscle length and levels of activation in healthy and pathological muscle. However, little is known about the variability in shear wave velocity among muscles as most studies investigate one specific muscle. The purpose of this study was to determine if the relationship between SWV and muscle activation is consistent across muscles with different architectures: biceps brachii, tibialis anterior, and medial gastrocnemius, All measures were made at matching levels of activation and approximately at the optimal length for each muscle to control for length-dependent changes in the relationship between activation and force or stiffness. We also conducted a control experiment to determine how the passive force within a muscle alters the relationship between muscle activation and shear wave velocity. The relationship between shear wave velocity-squared and activation above 10% MVC differed across muscles, with biceps brachii and medial gastrocnemius showing a lower slope than tibialis anterior. Shear wave velocity-squared also differed between muscles at the shortest length (p<0.001) and the increase in shear wave velocity-squared with muscle lengthening also differed between muscle types (p = 0.005) Muscle-specific differences could not be explained by the architectural features such as pennation angle, fiber length, and physiological cross-sectional area. Our results demonstrate that there is not a unique relationship between muscle activation and shear wave velocity, highlighting the importance of understanding the many factors contributing to shear wave propagation in muscle before elastography can be used to make quantitative comparisons across muscle types. Diurnal activity budget and conservation implication of Hippopotamus amphibius at Bui National Park, Ghana Animals apportion time for their daily behavioral activities. We studied the activity budget of Hippopotamus amphibius at the Black Volta River in the Bui National Park, Ghana. We performed instantaneous scan sample using ground count survey between August 2020 to July 2021. We observed that H. amphibius spent most of their day time resting (54.75 %), followed by feeding (22.93 %), walking (19.2 %) and touching (3.12 %). We found significant difference in the time spent between the daily activities (H = 41.67; p < 0.0001). Except activities involving touching, we found no significant seasonal differences in feeding, resting and walking activities by H. amphibius. Understanding the behavioral activities of H. amphibius will enhance management and conservation of the animals. G Protein-Coupled Receptor-Ligand Dissociation Rates and Mechanisms from {tau}RAMD Simulations There is a growing appreciation of the importance of drug-target binding kinetics for lead optimization. For G protein-coupled receptors (GPCRs), which mediate signaling over a wide range of timescales, the drug dissociation rate is often a better predictor of in vivo efficacy than binding affinity, although it is more challenging to compute. Here, we assess the ability of the {tau}-Random Acceleration Molecular Dynamics ({tau}RAMD) approach to reproduce relative residence times and reveal dissociation mechanisms and the effects of allosteric modulation for two important membrane-embedded drug targets: the {beta}2-adrenergic receptor and the muscarinic acetylcholine receptor M2. The dissociation mechanisms observed in the relatively short RAMD simulations (in which molecular dynamics (MD) simulations are performed using an additional force with an adaptively assigned random orientation applied to the ligand) are in general agreement with much more computationally intensive conventional MD and metadynamics simulations. Remarkably, although decreasing the magnitude of the random force generally reduces the number of egress routes observed, the ranking of ligands by dissociation rate is hardly affected and agrees well with experiment. The simulations also reproduce changes in residence time due to allosteric modulation and reveal associated changes in ligand dissociation pathways.

TABLE OF CONTENTS GRAPHIC

O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/449151v2_ufig1.gif" ALT="Figure 1">
View larger version (43K):
org.highwire.dtl.DTLVardef@743dcdorg.highwire.dtl.DTLVardef@1857381org.highwire.dtl.DTLVardef@62359aorg.highwire.dtl.DTLVardef@1ad38a3_HPS_FORMAT_FIGEXP  M_FIG C_FIG Exploitation of the genetic variability in the genotype of Egyptian Wheat by studding Molecular Markers, Molecular Docking and Nano Composites. Regulation of leaf and stem rust This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author. Creatine transporter deficient rat model show motor dysfunction, cerebellar alterations and muscle creatine deficiency without muscle atrophy Creatine (Cr) is a nitrogenous organic acid and plays roles as fast phosphate energy buffer to replenish ATP, osmolyte, antioxidant, neuromodulator, and as a compound with anabolic and ergogenic properties in muscle. Cr is taken from the diet or endogenously synthetized by the enzymes AGAT and GAMT, and specifically taken up by the transporter SLC6A8. Loss-of-function mutations in the genes encoding for the enzymes or the transporter cause Cerebral Creatine Deficiency Syndromes (CCDS). CCDS are characterized by brain Cr deficiency, intellectual disability with severe speech delay, behavioral troubles, epilepsy and motor dysfunction. Among CCDS, the X-linked Cr transporter deficiency (CTD) is the most prevalent with no efficient treatment so far. Different animal models of CTD show reduced brain Cr levels, cognitive deficiencies and together they cover other traits similar to those of patients. However, motor function was poorly explored in CTD models and some controversies in the phenotype exist in comparison with CTD patients. Our recently described Slc6a8Y389C knock-in (KI) rat model of CTD showed mild impaired motor function, morphological alterations in cerebellum, reduced muscular mass, Cr deficiency and increased guanidinoacetate content in muscle, although no consistent signs of muscle atrophy. Our results indicate that such motor dysfunction co-occurred with both nervous and muscle dysfunction, suggesting that muscle strength and performance as well as neuronal connectivity might be affected by this Cr deficiency in muscle and brain. Higher-order effects, continuous species interactions, and trait evolution shape microbial spatial dynamics The assembly and maintenance of microbial diversity in natural communities, despite the abundance of toxin-based antagonistic interactions, presents major challenges for biological understanding. A common framework for investigating such antagonistic interactions involve cyclic dominance games with pairwise interactions. The incorporation of higher-order interactions in such models permits increased levels of microbial diversity, especially in communities where antibiotic producing, sensitive, and resistant strains co-exist. However, most such models involve a small number of discrete species, assume a notion of pure cyclic dominance, and focus on low mutation rate regimes, none of which well represents the highly interlinked, quickly evolving, and continuous nature of microbial phenotypic space. Here, we present an alternative vision of spatial dynamics for microbial communities based on antagonistic interactions--one in which a large number of species interact in continuous phenotypic space, are capable of rapid mutation, and engage in both direct and higher-order interactions mediated by production of and resistance to antibiotics. Focusing on toxin production, vulnerability, and inhibition among species, we observe highly divergent patterns of diversity and spatial community dynamics. We find that species interaction constraints (rather than mobility) best predict spatiotemporal disturbance regimes, whereas community formation time, mobility, and mutation size best explain patterns of diversity. We also report an intriguing relationship among community formation time, spatial disturbance regimes, and diversity dynamics. This relationship, which suggests that both higher-order interactions and rapid evolution are critical for the origin and maintenance of microbial diversity, has broad-ranging links to the maintenance of diversity in other systems.

Significance StatementPersistently diverse microbial communities are one of biologys great puzzles. Using a novel continuous trait space modeling framework that accommodates high mutation rates, elevated species richness, and direct and higher-order antagonistic species interactions, we find that two parameters characterizing mutation size and mobility best explain patterns of microbial diversity. Moreover, community formation time (the duration of the transient phase in community assembly) provides an unexpectedly clear guide to the diversity profiles of the resulting communities. These discoveries showcase how complex, antagonistic interactions mediated by the production of, inhibition of, and vulnerability to toxins (antibiotics) can shape microbial communities, allowing for extraordinarily high levels of diversity and temporal persistence. Pathways of savannization in a mesic African savanna-forest mosaic following an extreme fire O_LIFires in savannas limit tree cover, thereby promoting flammable grass accumulation and fuelling further frequent fires. Meanwhile, forests and thickets form dense canopies that reduce C4-grass fuel loads and creating a humid microclimate, thereby excluding fires under typical climatic conditions.
C_LIO_LIHowever, extreme fires occasionally burn into these closed-canopy systems. Although these rare fires cause substantial tree mortality and can make repeat fires more likely, the long-term consequences of an extreme fire for closed canopy vegetation structure and potential to convert to savanna (hereafter "savannization") remain largely unknown.
C_LIO_LIHere, we analysed whether an extreme fire could, alone, alter species composition, vegetation structure, and fire regimes of closed-canopy ecosystems in an intact savanna-forest-thicket mosaic, or whether successive fires after an initial extreme fire were necessary to trigger a biome transition between from forest to savanna.
C_LIO_LIWe found that forests that only burned once recovered, whereas those that burned again following an initial extreme fire transitioned from closed-canopy forests towards open, grassy savannas.
C_LIO_LIWhile thickets had less tree mortality in fires than forests, repeat fires nonetheless precipitated a transition towards savannas.
C_LIO_LIColonization of the savanna tree community lagged behind the grass community, but also began to transition.
C_LI

SynthesisOur results suggest that rare extreme fires, followed by repeated burning can indeed result in savannization in places where savanna and forest represent alternative stable states. A novel nongenetic murine model of hyperglycemia and hyperlipidemia-associated aggravated atherosclerosis ObjectiveAtherosclerosis, the main pathology underlying cardiovascular diseases is accelerated in diabetic patients. Genetic mouse models require breeding efforts which are time-consuming and costly. Our aim was to establish a new nongenetic model of inducible metabolic risk factors that mimics hyperlipidemia, hyperglycemia, or both and allows the detection of phenotypic differences dependent on the metabolic stressor(s).

Methods and ResultsWild-type mice were injected with gain-of-function PCSK9D377Y (proprotein convertase subtilisin/kexin type 9) mutant adeno-associated viral particles (AAV) and streptozotocin and fed either a high-fat diet (HFD) for 12 or 20 weeks or a high-cholesterol/high-fat diet (Paigen diet, PD) for 8 weeks. To evaluate atherosclerosis, two different vascular sites (aortic sinus and the truncus of the brachiocephalic artery) were examined in the mice. Combined hyperlipidemic and hyperglycemic (HGHCi) mice fed a HFD or PD displayed characteristic features of aggravated atherosclerosis when compared to hyperlipidemia (HCi HFD or PD) mice alone. Atherosclerotic plaques of HGHCi HFD animals were larger, showed a less stable phenotype (measured by the increased necrotic core area, reduced fibrous cap thickness, and less -SMA-positive area) and had more inflammation (increased plasma IL-1{beta} level, aortic pro-inflammatory gene expression, and MOMA-2-positive cells in the BCA) after 20 weeks of HFD. Differences between the HGHCi and HCi HFD models were confirmed using RNA-seq analysis of aortic tissue, revealing that significantly more genes were dysregulated in mice with combined hyperlipidemia and hyperglycemia than in the hyperlipidemia-only group. The HGHCi-associated genes were related to pathways regulating inflammation (increased Cd68, iNos, and Tnfa expression) and extracellular matrix degradation (Adamts4 and Mmp14). When comparing HFD with PD, the PD aggravated atherosclerosis to a greater extent in mice and showed plaque formation after 8 weeks. Hyperlipidemic and hyperglycemic mice fed a PD (HGHCi PD) showed less collagen (Sirius red) and increased inflammation (CD68-positive cells) within aortic plaques than hyperlipidemic mice (HCi PD). HGHCi-PD mice represent a directly inducible hyperglycemic atherosclerosis model compared with HFD-fed mice, in which atherosclerosis is severe by 8 weeks.

ConclusionWe established a nongenetically inducible mouse model allowing comparative analyses of atherosclerosis in HCi and HGHCi conditions and its modification by diet, allowing analyses of multiple metabolic hits in mice. Dissociable plasticity of the nucleus basalis of Meynert in early and late blind individuals Plasticity in the brain is differentially affected by age of blindness onset. One possible, but not yet identified mechanism is that the cholinergic signals originating from the nucleus basalis of Meynert may underlie differential extent of plasticity in early and late blind individuals. This prospect is based on the fact that the nucleus basalis of Meynert modulates cortical processes such as plasticity and sensory encoding and that the degree of cross-modal plasticity varies depending on the age of blindness onset. However, this question yet remains largely unclear. Here, we tested whether the early and late blind individuals develop dissociable plasticity in the nucleus basalis of Meynert using multi-parametric magnetic resonance imaging. We found the relatively preserved volumetric size and cerebrovascular reactivity, but significant disruption in the white matter integrity of the nucleus basalis of Meynert in both early and late blind individuals. Critically, despite its reduction in the white matter integrity, the nucleus basalis of Meynert of early blind individuals presented greater global and network functional connectivity including visual, language, and default-mode networks. Such changes in the functional connectivity were not observed in the late-blind individuals. Further, less duration of the visual experience was associated with greater global and network functional connectivity. These results indicate that the nucleus basalis of Meynert is differentially involved in the plasticity of early and late blind individuals - a similar amount of reduction in microstructural integrity in early and late blind individuals, but stronger and more widespread functional connectivity of the NBM in the early blind individuals. Our findings suggest that the nucleus basalis of Meynert may develop greater cholinergic influence on the cortex of early blind individuals. Such change may explain why early blind individuals present stronger and more widespread cross-modal plasticity during non-visual tasks compared to late blind individuals. An adaptive teosinte mexicana introgression modulates phosphatidylcholine levels and is associated with 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. A Physiometric Investigation of Inflammatory Composites: Comparison of A Priori Aggregates, Empirically-identified Factors, and Individual Proteins Most research testing the association between inflammation and health outcomes (e.g., heart disease, diabetes, depression) has focused on individual proteins; however, some studies have used summed composites of inflammatory markers without first investigating dimensionality. Using two different samples (MIDUS-2: N = 1,255 adults, MIDUS-R: N = 863 adults), this study investigates the dimensionality of eight inflammatory proteins (C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor- (TNF-), fibrinogen, E-selectin, and intercellular adhesion molecule (ICAM)-1) and compared the resulting factor structure to a) an "a priori"/tau-equivalent factor structure in which all inflammatory proteins equally load onto a single dimension (comparable to the summed composites) and b) proteins modeled individually (i.e., no latent variable) in terms of model fit, replicability, reliability, and their associations with health outcomes. An exploratory factor analysis indicated a two-factor structure (Factor 1: CRP and fibrinogen; Factor 2: IL-8 and IL-10) in MIDUS-2 and was replicated in MIDUS-R. Results did not clearly indicate whether the empirically-identified factor structure or the individual proteins modeled without a latent variable had superior model fit, but both strongly outperformed the "a priori"/tau-equivalent structure (which did not achieve acceptable model fit in any models). Modeling the empirically-identified factors and individual proteins (without a latent factor) as outcomes of medical diagnoses resulted in comparable conclusions. However, modeling individual proteins resulted in findings more robust to correction for multiple comparisons despite more conservative adjustments. Further, reliability for all latent variables was poor. These results indicate that modeling inflammation as a unidimensional construct equally associated with all available proteins does not fit the data well. Instead, individual inflammatory proteins or, potentially (if empirically supported and biologically-plausible) empirically-identified inflammatory factors should be used in accordance with theory.