Search

Ovarian cancer is the most lethal gynecological cancer with limited therapeutic options and a complex tumor microenvironment (TME). The TME provides signals that support ovarian cancer progression, and many of these signals are secreted by the fat-precursor cells of the nearby omentum, or omental preadipocytes. The omentum is a dynamic endocrine organ and during metastasis it is the first site of invasion with the largest tumor burden. While adipocytes have been shown to encourage cancer cell homing and provide metabolic support, the role of preadipocytes in tumorigenesis is unclear and warrants further investigation I have shown that preadipocytes are required for tumorigenesis of ovarian cancer cells when in low dilutions in a subcutaneous mouse model. Moreover, preadipocytes secrete factors that enhance tumor cell viability by increasing proliferation in nutrient-poor environments and enable increased colony formation at low dilution. RNA sequencing data indicate that ovarian cancer cells upregulate an extracellular matrix (ECM) gene program in the presence of secreted factors from preadipocytes, with increased expression of different collagen isoforms as well as members of the insulin-like growth factor binding protein (IGFBP) family. Within this dataset I discovered that IGFBP5 was the most upregulated gene in ovarian cancer cells co-cultured with preadipocytes, followed closely by COL1A2, COL6A2, FN1 and MMP2. The IGFBPs, including IGFBP5, regulate IGF-1, which is elevated in the cancer cells in co-culture and induces expression of COL1A2 and COL6A2, indicating a potential role for IGF-1 in regulating ECM remodeling in the TME. Interestingly, expression of IGFBP5 was found to increase between early and late stages of tumorigenesis, in contrast to the other ECM genes studied. In cells with IGFBP5 knockdown, the tumor growth rate decreased, indicating that increased IGFBP5 contributes to tumor growth in response to omental preadipocytes. This study proposes a new link between preadipocytes and ovarian cancer tumorigenesis via ECM remodeling and expression of IGFBP5, with implications for tumor metastasis.

Background Excessive repetitive behavior is a debilitating symptom of several neuropsychiatric disorders. Parvalbumin-positive inhibitory interneurons in the dorsal striatum have been linked to repetitive behavior, and a sizeable portion of these cells are surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures. Although PNNs have been associated with plasticity and neuropsychiatric disease, no previous studies have investigated their involvement in excessive repetitive behavior. Methods We used histochemistry and confocal imaging to investigate PNNs surrounding parvalbumin-positive cells in the dorsal striatum of four mouse models of excessive repetitive behavior (BTBR, Cntnap2, Shank3, prenatal valproate treatment). We then investigated one of these models, the BTBR mouse, in detail, with DiI labeling, in vivo and in vitro recordings, and behavioral analyses. We next degraded PNNs in the dorsomedial striatum (DMS) using the enzyme chondroitinase ABC and assessed dendritic spine density, electrophysiology, and repetitive behavior. Results We found a greater percentage of parvalbumin-positive interneurons with PNNs in the DMS of all four mouse models of excessive repetitive behavior compared to controls. In BTBR mice, we found fewer dendritic spines on medium spiny neurons (targets of parvalbumin-positive interneurons), and differences in neuronal oscillations as well as inhibitory postsynaptic potentials, compared to controls. Reduction of DMS PNNs in BTBR mice altered dendritic spine density and inhibitory responses, and normalized repetitive behavior. Discussion These findings suggest that cellular abnormalities in the DMS are associated with maladaptive repetitive behaviors and that manipulating PNNs can restore normal levels of repetitive behavior while altering DMS dendritic spines and inhibitory signaling.

Surface curvature both emerges from, and influences the behavior of, living objects at length scales ranging from cell membranes to single cells to tissues and organs. The relevance of surface curvature in biology is supported by numerous experimental and theoretical investigations in recent years. In this review, first, a brief introduction to the key ideas of surface curvature in the context of biological systems is given and the challenges that arise when measuring surface curvature are discussed. Giving an overview of the emergence of curvature in biological systems, its significance at different length scales becomes apparent. On the other hand, summarizing current findings also shows that both single cells and entire cell sheets, tissues or organisms respond to curvature by modulating their shape and their migration behavior. Finally, the interplay between the distribution of morphogens or micro-organisms and the emergence of curvature across length scales is addressed with examples demonstrating these key mechanistic principles of morphogenesis. Overall, this review highlights that curved interfaces are not merely a passive by-product of the chemical, biological, and mechanical processes but that curvature acts also as a signal that co-determines these processes. ispartof: ADVANCED MATERIALS vol:35 issue:13 ispartof: location:Germany status: Published online

This study describes the first finding of Salmonella enterica serotype Choleraesuis (Salmonella Choleraesuis) isolate harboring mobile colistin resistance (mcr)-3.1 obtained from human blood sample. The clinical relevant blood sample was collected during October 2018. The phenotypic identification and antimicrobial susceptibility testing (AST) were studied by using automate microbiology platform (Phoenix M50, BD), and in-depth characterization by whole genome sequencing. The phenotypic identification was reported Salmonella Choleraesuis. AST result demonstrated that this isolate had high minimum inhibitory concentrations (MICs) against colistin, fluoroquinolone, and cephalosporin III and IV, which are first-line antibiotic treatment choices for Gram-negative bacterial pathogen infections. This Salmonella Choleraesuis is harboring mcr-3.1 and presented a diversity carbapenemase including blaTEM and blactx-m-55. Regarding the multilocus sequence typing result, this Salmonella presented ST139 that related to the Choleraesuis variant sensu stricto. Swine is not the host specific for the Salmonella Choleraesuis since it also causes enteric and other diseases in human. Hence, the presence of the mobile plasmid colistin mcr-3.1 resistant gene in human sample is resulting to the public health concerns due to the fact that it is enable to transmit to other hosts and distribute into an environment.

Persons with human immunodeficiency virus (HIV) from NEAT022 study at high risk for cardiovascular disease showed high rates of hypertension. Switching to dolutegravir did not negatively impact on the incidence of hypertension relative to continuing protease inhibitors. Background Integrase inhibitors have been recently linked to a higher risk for hypertension. In NEAT022 randomized trial, virologically suppressed persons with human immunodeficiency virus (HIV, PWH) with high cardiovascular risk switched from protease inhibitors to dolutegravir either immediately (DTG-I) or after 48 weeks (DTG-D). Methods Primary endpoint was incident hypertension at 48 weeks. Secondary endpoints were changes in systolic (SBP) and diastolic (DBP) blood pressure; adverse events and discontinuations associated with high blood pressure; and factors associated with incident hypertension. Results At baseline, 191 (46.4%) participants had hypertension and 24 persons without hypertension were receiving antihypertensive medications for other reasons. In the 197 PWH (n = 98, DTG-I arm; n = 99, DTG-D arm) without hypertension or antihypertensive agents at baseline, incidence rates per 100 person-years were 40.3 and 36.3 (DTG-I) and 34.7 and 52.0 (DTG-D) at 48 (P = .5755) and 96 (P = .2347) weeks. SBP or DBP changes did not differed between arms. DBP (mean, 95% confidence interval) significantly increased in both DTG-I (+2.78 mmHg [1.07-4.50], P = .0016) and DTG-D (+2.29 mmHg [0.35-4.23], P = .0211) arms in the first 48 weeks of exposure to dolutegravir. Four (3 under dolutegravir, 1 under protease inhibitors) participants discontinued study drugs due to adverse events associated with high blood pressure. Classical factors, but not treatment arm, were independently associated with incident hypertension. Conclusions PWH at high risk for cardiovascular disease showed high rates of hypertension at baseline and after 96 weeks. Switching to dolutegravir did not negatively impact on the incidence of hypertension or blood pressure changes relative to continuing protease inhibitors.

This account presents information on all aspects of the biology of Salvia pratensis L. (Meadow Clary) that are relevant to understanding its ecological characteristics and behaviour. The main topics are presented within the standard framework of the Biological Flora of the British Isles: distribution, habitat, communities, responses to biotic factors, responses to environment, structure and physiology, phenology, floral and seed characters, herbivores and disease, history and conservation.Salvia pratensis is an erect, rosette-forming, perennial herb with a broad native distribution covering much of Europe—from the British Isles, Spain and Morocco in the west, across Europe into Asia, as far east as the Urals. In the British Isles, the species is nationally scarce, confined to a few south- to west-facing sites with calcareous soils in Southern England and one site in Wales. It is predominately found in unimproved pasture, hay meadows and grassy verges, but can occur on the fringes of scrub or woodland. Although the species is abundant in central Europe, changes to land management since the mid-20th century have resulted in fragmented and threatened populations in several European countries. It is cultivated as an ornamental, as is S. × sylvestris, the hybrid with S. nemorosa.Populations are typically gynodioecious, having both female (male-sterile) and hermaphrodite individuals at variable proportions. The species has a mixed mating system and is self-compatible via insect pollination, but predominantly outcrosses. Honeybees and bumblebees are abundant pollinators, but a diverse range of bee species and other insect species visit S. pratensis flowers. Inbreeding depression has been documented, presenting a conservation concern for small, fragmented populations.The species is the focus of conservation efforts and has been reintroduced to sites where it had become locally extinct in Britain. To sustain favourable habitat, site management should maintain low soil nutrient levels, and prevent scrub encroachment and the dominance of coarse grasses. The removal of sward by hay cutting or grazing after plants have flowered and set seed is advised, in addition to maintaining a degree of disturbance to provide bare patches of soil for seedling recruitment.

Bacillus pumilus SAFR-032, an endospore-forming bacterial strain, was investigated to determine its methylation pattern (methylome) change, compared to ground control, after direct exposure to space conditions onboard the International Space Station (ISS) for 1.5 years. The resulting ISS-flown and non-flown strains were sequenced using the Nanopore MinION and an in-house method and pipeline to identify methylated positions in the genome. Our analysis indicated genomic variants and m6A methylation increased in the ISS-flown SAFR-032. To complement the broader omics investigation and explore phenotypic changes, ISS-flown and non-flown strains were compared in a series of laboratory-based chamber experiments using an X-ray irradiation source (doses applied at 250, 500, 750, 1000 and 1250 Gy); results show a potentially higher survival fraction of ISS-flown DS2 at the two highest exposures. Taken together, results from this study document lasting changes to the genome by methylation, potentially triggered by conditions in spaceflight, with functional consequences for the resistance of bacteria to stressors expected on long-duration missions beyond low Earth orbit.

Major ecological disturbance events can provide opportunities to assess multispecies responses to upheaval. In particular, catastrophic disturbances that regionally extirpate habitat-forming species can potentially influence the genetic diversity of large numbers of codistributed taxa. However, due to the rarity of such disturbance events over ecological timeframes, the genetic dynamics of multispecies recolonization processes have remained little understood. Here, we use single nucleotide polymorphism (SNP) data from multiple coastal species to track the dynamics of cocolonization events in response to ancient earthquake disturbance in southern New Zealand. Specifically, we use a comparative phylogeographic approach to understand the extent to which epifauna (with varying ecological associations with their macroalgal hosts) share comparable spatial and temporal recolonization patterns. Our study reveals concordant disturbance-related phylogeographic breaks in two intertidal macroalgal species along with two associated epibiotic species (a chiton and an isopod). By contrast, two codistributed species, one of which is an epibiotic amphipod and the other a subtidal macroalga, show few, if any, genetic effects of palaeoseismic coastal uplift. Phylogeographic model selection reveals similar post-uplift recolonization routes for the epibiotic chiton and isopod and their macroalgal hosts. Additionally, codemographic analyses support synchronous population expansions of these four phylogeographically similar taxa. Our findings indicate that coastal paleoseismic activity has driven concordant impacts on multiple codistributed species, with concerted recolonization events probably facilitated by macroalgal rafting. These results highlight that high-resolution comparative genomic data can help reconstruct concerted multispecies responses to recent ecological disturbance.

In non-endemic settings, transfusion-transmitted malaria (TTM) is rare but potentially fatal and becoming more common with globalization. We present two pediatric cases that demonstrate donor screening using questionnaires is subject to error and that TTM should be considered with fever following numerous transfusions in children, particularly sickle cell patients.

Background Zebrafish is a popular animal model used for high-throughput screening of chemical hazards, however, investigations of transcriptomic mechanisms of toxicity are still needed. Here, our goal was to identify genes and biological pathways that Aryl Hydrocarbon Receptor 2 (AHR2) Activators and flame retardant chemicals (FRCs) alter in developing zebrafish. Taking advantage of a compendium of phenotypically-anchored RNA sequencing data collected from 48-h post fertilization (hpf) zebrafish, we inferred a co-expression network that grouped genes based on their transcriptional response. Results Genes responding to the FRCs and AHR2 Activators localized to distinct regions of the network, with FRCs inducing a broader response related to neurobehavior. AHR2 Activators centered in one region related to chemical stress responses. We also discovered several highly co-expressed genes in this module, including cyp1a, and we subsequently show that these genes are definitively within the AHR2 signaling pathway. Systematic removal of the two chemical types from the data, and analysis of network changes identified neurogenesis associated with FRCs, and regulation of vascular development associated with both chemical classes. We also identified highly connected genes responding specifically to each class that are potential biomarkers of exposure. Conclusions Overall, we created the first zebrafish chemical-specific gene co-expression network illuminating how chemicals alter the transcriptome relative to each other. In addition to our conclusions regarding FRCs and AHR2 Activators, our network can be leveraged by other studies investigating chemical mechanisms of toxicity.

Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.

To determine microbial evolutionary strategies to low-pressure (LP; 5 kPa) growth, an environmental condition not experienced on Earth until ∼20 km in altitude, a previously described evolutionary ...

Neutrophils are characterized by a unique nuclear morphology, where the nucleus possesses a segmented multi-lobed form. During inflammation, neutrophils become activated and utilize their anti-microbial abilities. Neutrophil activation and extracellular trap formation are associated with the cell undergoing a change in nuclear morphology via delobing of the nucleus. While much work has been done concerning which parts of the activation pathway are required for NETosis, little is known about which portions of the activation pathway are involved with these morphology dynamics. Using quantitative image analysis, we established the promyelocyte HL-60 cell-line as a model system in which to study human neutrophil nuclear morphology dynamics and differentiated HL-60s as a model to investigate activation-induced nuclear morphological changes. We find that ATRA differentiated HL-60s and DMF differentiated HL-60s can be used to observe changes in the measured circularity of the nucleus induced by PMA and A23187 stimulation respectively. Using chemical inhibitors in differentiated HL-60 stimulation, it was discovered that NOX and NE activity are required for PMA-induced nuclear morphological change while MPO and PAD4 activity are not, and that PAD4 activity is required for A23187-induced nuclear morphological change. These findings demonstrate how factors that are known to contribute to NETosis also contribute to pre-NETosis neutrophil nuclear dynamics.

Herein we report on the most abundant and diverse fauna of Palaeozoic crinoids and blastoids collected from Mongolia to date. The fauna is from the Late Devonian (Famennian) Samnuuruul Formation in western Mongolia. The fauna consists of two genera of blastoids and twelve genera of crinoids—four genera of camerates, three genera of flexibles, one disparid genus, and four genera of cladids. The crinoids and blastoids were living on an active island arc complex in the Central Asian Orogenic Belt (CAOB) in a high physical stress environment with frequent and often voluminous pyroclastic eruptions. The Mongolian fauna is similar to coeval faunas collected from the Hongguleleng Formation in western China and supports the hypothesis that the CAOB was a biodiversity hotspot for Famennian echinoderms and a precursor to the very successful echinoderm communities that dominated Mississippian shallow-marine ecosystems globally. Three new taxa are described. Mongoliacrinus minjini, new genus and species, is the oldest member of the Acrocrinidae, previously known from the Mississippian and Pennsylvanian and the first occurrence of the family outside North America. Eutaxocrinus ariunai and Eutaxocrinus sersmaai are new species of the flexible crinoid Eutaxocrinus, a genus with a widespread distribution during the Early and Middle Devonian, which survived into the Lower Mississippian. It is restricted to the CAOB in the Late Devonian.

DNA methylation is a key epigenetic modification in vertebrate genomes known to be involved in the regulation of gene expression, X chromosome inactivation, genomic imprinting, chromatin structure, and control of transposable elements. DNA methylation is common to all eukaryote genomes, but we still lack a complete understanding of the variation in DNA methylation patterns on sex chromosomes and between the sexes in diverse species. To better understand sex chromosome DNA methylation patterns between different amniote vertebrates, we review literature that has analyzed the genome-wide distribution of DNA methylation in mammals and birds. In each system, we focus on DNA methylation patterns on the autosomes versus the sex chromosomes.

Biologists have long been intrigued by apparently predictable and repetitive evolutionary trajectories inferred across a variety of lineages and systems. In recent years, high-throughput sequencing analyses have started to transform our understanding of such repetitive shifts. While researchers have traditionally categorized such shifts as either "convergent" or "parallel," based on relatedness of the lineages involved, emerging genomic insights provide an opportunity to better describe the actual evolutionary mechanisms at play. A synthesis of recent genomic analyses confirms that convergence is the predominant driver of repetitive evolution among species, whereas repeated sorting of standing variation is the major driver of repeated shifts within species. However, emerging data reveal numerous notable exceptions to these expectations, with recent examples of de novo mutations underpinning convergent shifts among even very closely related lineages, while repetitive sorting processes have occurred among even deeply divergent taxa, sometimes via introgression. A number of very recent analyses have found evidence for both processes occurring on different scales within taxa. We suggest that the relative importance of convergent versus sorting processes depends on the interplay between gene flow among populations, and phylogenetic relatedness of the lineages involved.

PB1 functions as the catalytic subunit of influenza virus RNA polymerase complex and plays an essential role in viral RNA transcription and replication. To determine plasticity in the PB1 enzymatic site and map catalytically important residues, 658 mutants were constructed, each with one to seven mutations in the enzymatic site of PB1. The polymerase activities of these mutants were quantified using a minigenome assay, and polymerase activity-associated residues were identified using sparse learning. Results showed that polymerase activities are affected by the residues not only within the conserved motifs, but also across the inter-motif regions of PB1, and the latter are primarily located at the base of the palm domain, a region that is conserved in avian PB1 but with high sequence diversity in swine PB1. Our results suggest that mutations outside the PB1 conserved motifs may affect RNA replication and could be associated with influenza virus host adaptation.

Social memory dysfunction is an especially devastating symptom of many neuropsychiatric disorders, which makes understanding the cellular and molecular processes that contribute to such abnormalities important. Evidence suggests that the hippocampus, particularly the CA2 region, plays an important role in social memory. We sought to identify potential mechanisms of social memory dysfunction in the hippocampus by investigating features of neurons, glia, and the extracellular matrix (ECM) of BTBR mice, an inbred mouse strain with deficient social memory. The CA2 is known to receive inputs from dentate gyrus adult-born granule cells (abGCs), neurons known to participate in social memory, so we examined this cell population and found fewer abGCs, as well as fewer axons from abGCs in the CA2 of BTBR mice compared to controls. We also found that BTBR mice had fewer pyramidal cell dendritic spines, in addition to fewer microglia and astrocytes, in the CA2 compared to controls. Along with diminished neuronal and glial elements, we found atypical perineuronal nets (PNNs), specialized ECM structures that regulate plasticity, in the CA2 of BTBR mice. By diminishing PNNs in the CA2 of BTBR mice to control levels, we observed a partial restoration of social memory. Our findings suggest that the CA2 region of BTBR mice exhibits multiple cellular and extracellular abnormalities and identify atypical PNNs as one mechanism producing social memory dysfunction, although the contribution of reduced abGC afferents, pyramidal cell dendritic spine, and glial cell numbers remains unexplored.

Malaria remains a public health problem in Thailand, especially along its borders where highly mobile populations can contribute to persistent transmission. This study aimed to determine resistant genotypes and phenotypes of 112 Plasmodium falciparum isolates from patients along the Thai-Cambodia border during 2013–2015. The majority of parasites harbored a pfmdr1-Y184F mutation. A single pfmdr1 copy number had CVIET haplotype of amino acids 72–76 of pfcrt and no pfcytb mutations. All isolates had a single pfk13 point mutation (R539T, R539I, or C580Y), and increased % survival in the ring-stage survival assay (except for R539I). Multiple copies of pfpm2 and pfcrt-F145I were detected in 2014 (12.8%) and increased to 30.4% in 2015. Parasites containing either multiple pfpm2 copies with and without pfcrt-F145I or a single pfpm2 copy with pfcrt-F145I exhibited elevated IC90 values of piperaquine. Collectively, the emergence of these resistance patterns in Thailand near Cambodia border mirrored the reports of dihydroartemisinin-piperaquine treatment failures in the adjacent province of Cambodia, Oddar Meanchey, suggesting a migration of parasites across the border. As malaria elimination efforts ramp up in Southeast Asia, host nations militaries and other groups in border regions need to coordinate the proposed interventions.

Understanding the forces that shape species distributions is increasingly important in a fast-changing world. Although major disturbance events can adversely affect natural populations, they can also present new opportunities, for example by opening up habitat for colonization by other lineages. Following extensive geographic sampling, we use genomic data to infer a range extension following disturbance for an ecologically important intertidal macroalgal species. Specifically, we genotyped 288 southern bull kelp (Durvillaea) plants from 28 localities across central New Zealand. All specimens from the North Island were expected to be D. antarctica, but unexpectedly 10 samples from four sites were identified as D. poha. Extensive sampling from the northern South Island (105 samples at five locations) confirmed the absence of D. poha north of the Kaikōura Peninsula. The North Island specimens of D. poha therefore reveal a biogeographic disjunction, some 150 km northeast of the nearest (South Island) population of this species. Based on strong geographic correspondence between these North Island samples and historic disturbance, we infer that tectonic upheaval, particularly earthquake-generated landslides, likely extirpated local D. antarctica and created an opportunity for a northward range expansion event by D. poha. Close phylogenomic relationships between this new North Island population and South Island samples support a geologically recent northward expansion, rather than a deeper evolutionary origin. These findings indicate the potential of large-scale disturbances to facilitate sudden biogeographic range expansions, and they emphasize the ability of genomic analyses with fine-scale sampling to reveal long-lasting signatures of past disturbance, dispersal, and colonization.

The Psylloidea (Hemiptera) comprise ~4,000 species of small sap-feeding insects known as psyllids or jumping plant-lice. We summarize species composition of the nonnative psyllid fauna in North America and review detection records, current distributions, host use, life histories, and geographical sources. Forty-six species are considered to be nonnative accounting for ~10% of the known North American psyllid fauna. The family Psyllidae is overrepresented in the pool of exotics (52% of exotic species) relative to global psyllid diversity, whereas Triozidae (at 11% of exotic species) is underrepresented. Records of initial detection range from the 1832 detection of a European pear psyllid to the 2016 detection of a Ficus specialist from Asia. Many species exhibit discontinuous distributions in North America presumably caused by multiple introductions or by secondary spread of established populations. Host plants of nonnative species are almost exclusively trees and shrubs. The factor most correlated with introduction is presence of hosts from the psyllid’s native region. Virtually all host plants in North America have been imported intentionally for human-related use, with initial importation beginning in the 1500s and 1600s. Arrival of host plants in North America often preceded psyllid detection or arrival by decades or centuries. There has been almost no spillover by psyllids onto native plant species reflecting the narrow host range of Psylloidea. A glaring exception is the recent damaging colonization of a native Fraxinus closely related to the psyllid’s European Fraxinus host. Biological and geographical traits correlated with arrival and establishment of nonnative psyllids have shifted through time. Temperate Europe was the source of the earliest arriving species, with initial detection records primarily in New England and eastern Canada. In contrast, recent arrivals are mostly Myrtaceae- and Fabaceae-feeding species from the Neotropics or Australia, with detection records limited mostly to Florida or California. Early-arriving, temperate zone species exhibit a formal winter diapause while recent arrivals from the Neotropics and Australia appear to reproduce more-or-less continuously.

Speciation is frequently initiated but rarely completed, a phenomenon hypothesized to arise due to the failure of nascent lineages to persist. Although a failure to persist often has ecological causes, key gaps exist between ecological and evolutionary theories that, if filled, would clarify when and why speciation succeeds or fails. Here, we apply ecological coexistence theory to show how the alignment between different forms of niche opportunity and niche use shape the initiation, progression, and completion of speciation. Niche evolution may drive coexistence or competitive exclusion, and an ability to coexist ecologically may help or hinder speciation. Our perspective allows progress towards unifying the origin and maintenance of species diversity across the tree of life.

Cyclic dinucleotide (cdN) second messengers are essential for bacteria to sense and adapt to their environment. These signals were first discovered with the identification of 3'-5', 3'-5' cyclic di-GMP (c-di-GMP) in 1987, a second messenger that is now known to be the linchpin signaling pathway modulating bacterial motility and biofilm formation. In the past 15 years, three more cdNs were uncovered: 3'-5', 3'-5' cyclic di-AMP (c-di-AMP) and 3'-5', 3'-5' cyclic GMP-AMP (3',3' cGAMP) in bacteria and 2'-5', 3'-5' cyclic GMP-AMP (2',3' cGAMP) in eukaryotes. We now appreciate that bacteria can synthesize many varieties of cdNs from every ribonucleotide, and even cyclic trinucleotide (ctN) second messengers have been discovered. Here we highlight our current understanding of c-di-GMP and c-di-AMP in bacterial physiology and focus on recent advances in 3',3' cGAMP signaling effectors, its role in bacterial phage response, and the diversity of its synthase family.

Purpose Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown. Methods We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD. Results We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways. Conclusion The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.

Background Patient-derived airway cells differentiated at Air Liquid Interface (ALI) are valuable models for Cystic fibrosis (CF) precision therapy. Different culture expansion methods have been established to extend expansion capacity of airway basal cells, while retaining functional airway epithelium physiology. Considerable variation in response to CFTR modulators is observed in cultures even within the same CFTR genotype and despite the use of similar ALI culture techniques. We aimed to address culture expansion method impact on differentiation. Methods Nasal epithelial brushings from 14 individuals (CF=9; non-CF=5) were collected, then equally divided and expanded under conditional reprogramming culture (CRC) and feeder-serum-free “dual-SMAD inhibition” (SMADi) methods. Expanded cells from each culture were differentiated with proprietary PneumaCult™-ALI media. Morphology (Immunofluorescence), global proteomics (LC-MS/MS) and function (barrier integrity, cilia motility, and ion transport) were compared in CRCALI and SMADiALI under basal and CFTR corrector treated (VX-809) conditions. Results No significant difference in the structural morphology or baseline global proteomics profile were observed. Barrier integrity and cilia motility were significantly different, despite no difference in cell junction morphology or cilia abundance. Epithelial Sodium Channels and Calcium-activated Chloride Channel activity did not differ but CFTR mediated chloride currents were significantly reduced in SMADiALI compare to their CRCALI counterparts. Conclusion Alteration of cellular physiological function in vitro were more prominent than structural and differentiation potential in airway ALI. Since initial expansion culture conditions significantly influence CFTR activity, this could lead to false conclusions if data from different labs are compared against each other without specific reference ranges.

Background Homozygous and compound heterozygous variants in glucocerebrosidase (GBA) can cause Gaucher disease (GD), whereas heterozygous variants increase the risk of developing Parkinson's disease (PD). GD patients display altered peripheral immune proteins. However, it is unknown if these are altered in GBA carriers with PD. Objectives To determine whether plasma cytokines and immune biomarkers associated with GD are also altered in GBA carriers with or without PD. Methods Inflammatory cytokines and established GD biomarkers, ferritin, CD162, CCL18, and chitotriosidase (28 biomarkers) were measured in GBA pathogenic variant carriers with (n = 135) and without (n = 83) PD, and non-carriers with (n = 75) and without PD (n = 77). Results PD patients with biallelic pathogenic variants in GBA had elevated plasma levels of ferritin, CCL18, and MIP1α. These biomarkers were not elevated in heterozygous GBA carriers. Conclusion GD plasma biomarkers are not promising candidates for stratifying the risk for PD in carriers of heterozygous GBA pathogenic variants. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Reelin plays a key role in neuronal migration and lamination in the cortex and hippocampus. Animal studies have shown that reelin expression decreases with age. The aim of this study was to evaluate the expression of reelin in all layers of the human hippocampal formation across three age groups. We used immunohistochemistry in formalin fixed and paraffin embedded hippocampal tissue from infants (1-10 months; n = 9), children (4-10 years; n = 4), and adults (45-60 years; n = 6) to stain for reelin. Expression was quantified (measured as the number of positive reelin cells/mm2 ) in the granule cell layer of the dentate gyrus (DG), the molecular layer of the dentate gyrus (ML), the hippocampal fissure (HF), stratum lacunosum moleculare (SLM), CA4/Hilus and the stratum pyramidale layer of CA3, CA2, and CA1. Expression of reelin was highest in the HF irrespective of age, followed by the SLM and ML. Minimal to no expression was seen in the stratum pyramidale layer of CA1-3. With age, reelin expression decreased and was statistically significant from infancy to childhood in the HF (p = .02). This study confirms that reelin expression decreases with age in the human hippocampus, and shows for the first time that the major decrease occurs between infancy and early childhood.

Background Newly emerged mutations within the Plasmodium falciparum chloroquine resistance transporter (PfCRT) can confer piperaquine resistance in the absence of amplified plasmepsin II (pfpm2). In this study, we estimated the prevalence of co-circulating piperaquine resistance mutations in P. falciparum isolates collected in northern Cambodia from 2009 to 2017. Methods The sequence of pfcrt was determined for 410 P. falciparum isolates using PacBio amplicon sequencing or whole genome sequencing. Quantitative polymerase chain reaction was used to estimate pfpm2 and pfmdr1 copy number. Results Newly emerged PfCRT mutations increased in prevalence after the change to dihydroartemisinin-piperaquine in 2010, with >98% of parasites harboring these mutations by 2017. After 2014, the prevalence of PfCRT F145I declined, being outcompeted by parasites with less resistant, but more fit PfCRT alleles. After the change to artesunate-mefloquine, the prevalence of parasites with amplified pfpm2 decreased, with nearly half of piperaquine-resistant PfCRT mutants having single-copy pfpm2. Conclusions The large proportion of PfCRT mutants that lack pfpm2 amplification emphasizes the importance of including PfCRT mutations as part of molecular surveillance for piperaquine resistance in this region. Likewise, it is critical to monitor for amplified pfmdr1 in these PfCRT mutants, as increased mefloquine pressure could lead to mutants resistant to both drugs.

The identification of functional genetic variants and associated candidate genes linked to feed efficiency may help improve selection for feed efficiency in dairy cattle, providing economic and environmental benefits for the dairy industry. This study used RNA-sequencing data obtained from liver tissue from 9 Holstein cows [n = 5 low residual feed intake (RFI), n = 4 high RFI] and 10 Jersey cows (n = 5 low RFI, n = 5 high RFI), which were selected from a single population of 200 animals. Using RNA-sequencing, 3 analyses were performed to identify: (1) variants within low or high RFI Holstein cattle; (2) variants within low or high RFI Jersey cattle; and (3) variants within low or high RFI groups, which are common across both Holstein and Jersey cattle breeds. From each analysis, all variants were filtered for moderate, modifier, or high functional effect, and co-localized quantitative trait loci (QTL) classes, enriched biological processes, and co-localized genes related to these variants, were identified. The overlapping of the resulting genes co-localized with functional SNP from each analysis in both breeds for low or high RFI groups were compared. For the first two analyses, the total number of candidate genes associated with moderate, modifier, or high functional effect variants fixed within low or high RFI groups were 2,810 and 3,390 for Holstein and Jersey breeds, respectively. The major QTL classes co-localized with these variants included milk and reproduction QTL for the Holstein breed, and milk, production, and reproduction QTL for the Jersey breed. For the third analysis, the common variants across both Holstein and Jersey breeds, uniquely fixed within low or high RFI groups were identified, revealing a total of 86,209 and 111,126 functional variants in low and high RFI groups, respectively. Across all 3 analyses for low and high RFI cattle, 12 and 31 co-localized genes were overlapping, respectively. Among the overlapping genes across breeds, 9 were commonly detected in both the low and high RFI groups (INSRR, CSK, DYNC1H1, GAB1, KAT2B, RXRA, SHC1, TRRAP, PIK3CB), which are known to play a key role in the regulation of biological processes that have high metabolic demand and are related to cell growth and regeneration, metabolism, and immune function. The genes identified and their associated functional variants may serve as candidate genetic markers and can be implemented into breeding programs to help improve the selection for feed efficiency in dairy cattle.

Research on gut microbiota has increased in popularity over the past decade, with evidence associating different dietary habits with changes in the makeup of the rich ecosystem of microorganisms that performs a variety of functions and induces a range of health effects, within and well beyond the gastrointestinal tract. Similarly, intermittent fasting (IF), an umbrella term describing various regimens of periods of voluntary abstinence from food and drink, has classically been associated with favourable impacts on cardiovascular risk factors, body weight, circadian biology, and, more recently, the gut health..The objective of this PRISMA systematic review was to summarize the peer-reviewed literature of clinical trials related to the impact of IF regimens on the gut microbiota. A MEDLINE search was conducted using PubMed and the keywords “intermittent fasting”, “gut microbiota”, “microbes”, and others. Whilst the field is still in its infancy, an emerging body of evidence suggests beneficial effects of IF on the health of the gut through increasing the microbial diversity and abundance, with possible clinical implications related to improving the immune function and ameliorating the metabolic status. Further research in larger clinical trials is warranted before practical recommendations for the public health can be made.

Within the hypothalamic paraventricular nucleus (PVN), estrogen receptor (ER) β and other gonadal hormone receptors play a role in central cardiovascular processes. However, the influence of sex and age on the cellular and subcellular relationships of ERβ with ERα, G-protein ER (GPER1), as well as progestin and androgen receptors (PR and AR) in the PVN is uncertain. In young (2- to 3-month-old) females and males, ERβ-enhanced green fluorescent protein (EGFP) containing neurons were approximately four times greater than ERα-labeled and PR-labeled nuclei in the PVN. In subdivisions of the PVN, young females, compared to males, had: (1) more ERβ-EGFP neurons in neuroendocrine rostral regions; (2) fewer ERα-labeled nuclei in neuroendocrine and autonomic projecting medial subregions; and (3) more ERα-labeled nuclei in an autonomic projecting caudal region. In contrast, young males, compared to females, had approximately 20 times more AR-labeled nuclei, which often colocalized with ERβ-EGFP in neuroendocrine (approximately 70%) and autonomic (approximately 50%) projecting subregions. Ultrastructurally, in soma and dendrites, PVN ERβ-EGFP colocalized primarily with extranuclear AR (approximately 85% soma) and GPER1 (approximately 70% soma). Aged (12- to 24-month-old) males had more ERβ-EGFP neurons in a rostral neuroendocrine subregion compared to aged females and females with accelerated ovarian failure (AOF) and in a caudal autonomic subregion compared to post-AOF females. Late-aged (18- to 24-month-old) females compared to early-aged (12- to 14-month-old) females and AOF females had fewer AR-labeled nuclei in neuroendrocrine and autonomic projecting subregions. These findings indicate that gonadal steroids may directly and indirectly influence PVN neurons via nuclear and extranuclear gonadal hormone receptors in a sex-specific manner.

There is need for effective and affordable vaccines against SARS-CoV-2 to tackle the ongoing pandemic. In this study, we describe a protein nanoparticle vaccine against SARS-CoV-2. The vaccine is based on the display of coronavirus spike glycoprotein receptor-binding domain (RBD) on a synthetic virus-like particle (VLP) platform, SpyCatcher003-mi3, using SpyTag/SpyCatcher technology. Low doses of RBD-SpyVLP in a prime-boost regimen induce a strong neutralising antibody response in mice and pigs that is superior to convalescent human sera. We evaluate antibody quality using ACE2 blocking and neutralisation of cell infection by pseudovirus or wild-type SARS-CoV-2. Using competition assays with a monoclonal antibody panel, we show that RBD-SpyVLP induces a polyclonal antibody response that recognises key epitopes on the RBD, reducing the likelihood of selecting neutralisation-escape mutants. Moreover, RBD-SpyVLP is thermostable and can be lyophilised without losing immunogenicity, to facilitate global distribution and reduce cold-chain dependence. The data suggests that RBD-SpyVLP provides strong potential to address clinical and logistic challenges of the COVID-19 pandemic., Vaccines for SARS-COV-2 are needed in the ongoing pandemic. Here the authors characterize a vaccine candidate that presents the receptor-binding domain (RBD) of SARS-CoV-2 spike protein on a synthetic VLP platform using SpyTag/SpyCatcher technology and show immunogenicity of a prime-boost regimen in mice and pigs.

Nutrient recycling by consumers can strongly impact nutrient availability for autotrophic and heterotrophic microbes, thus impacting functions such as primary production and decomposition. Filter-feeding freshwater mussels form dense, multispecies assemblages in aquatic ecosystems and have been shown to play a critical role in nutrient cycling. Mussel excretion can enhance benthic primary production and influence algal species composition. However, the role of mussels in brown or detritus-based food webs and species-specific differences has received considerably less attention. Here, using mesocosm experiments, we assessed how three species of freshwater mussels that occupy three different phylogenetic tribes influenced benthic algal accrual, ecosystem metabolism, cotton strip decomposition, leaf litter (Acer saccharum) decomposition, and litter-associated fungal biomass measured as ergosterol. Additionally, we measured mussel excretion and biodeposition rates and assessed the stoichiometry (C:N, C:P, and N:P) of the benthic algae, cotton strips, and leaf litter. In comparison to controls without mussels, generally, mussel treatments had higher benthic algal biomass composed of more diatoms, higher gross primary productivity and net ecosystem production rates, and higher cotton strip tensile strength loss, but there was not a difference in ecosystem respiration rates, leaf litter decomposition rates, or fungal biomass. Benthic algae had lower C:N and higher N:P in mussel treatment tanks and cotton strip C:N was lower in mesocosms with mussels. Our results suggest that nutrient regeneration by mussels most strongly regulates green food webs, with some impacts to brown food webs, suggesting that consumers have interactive effects on microbial functioning in freshwaters.

Recent genomic analyses have highlighted parallel divergence in response to ecological gradients, but the extent to which altitude can underpin such repeated speciation remains unclear. Wing reduction and flight loss have apparently evolved repeatedly in montane insect assemblages and have been suggested as important drivers of hexapod diversification. We test this hypothesis using genomic analyses of a widespread wing-polymorphic stonefly species complex in New Zealand. We identified over 50,000 polymorphic genetic markers generated across almost 200 Zelandoperla fenestrata stonefly specimens using a newly generated plecopteran reference genome, to reveal widespread parallel speciation between sympatric full-winged and wing-reduced ecotypes. Rather than the existence of a single, widespread, flightless taxon (Zelandoperla pennulata), evolutionary genomic data reveal that wing-reduced upland lineages have speciated repeatedly and independently from full-winged Z. fenestrata. This repeated evolution of reproductive isolation between local ecotype pairs that lack mitochondrial DNA differentiation suggests that ecological speciation has evolved recently. A cluster of outlier single-nucleotide polymorphisms detected in independently wing-reduced lineages, tightly linked in an approximately 85 kb genomic region that includes the developmental “supergene” doublesex, suggests that this “island of divergence” may play a key role in rapid ecological speciation. [Ecological speciation; genome assembly; genomic island of differentiation; genotyping-by-sequencing; incipient species; plecoptera; wing reduction.]

Coronavirus disease 19 (COVID-19) caused by infection with a novel severe acute respiratory syndrome virus -2 (SARS-CoV2) has evolved into a pandemic and a global public health emergency. The viral genomics, host cellular factors, and interactions are critical for establishing a viral infection and developing a related disease. This paper aims to provide an overview of viral genomics and discuss host cellular factors so far identified to be involved with the disease susceptibility. The novel pathogen is a beta coronavirus and one of seven that cause diseases to humans. It is a single strand positive-sense RNA genome virus that encodes 27 proteins, including the structural Spike protein that binds to host cell surface receptors and is a key for viral entry, and 16 nonstructural proteins play a critical role in viral replication and virulence. While the angiotensin-converting enzyme, ACE2 receptor, and the proteases TMPRSS2 and furin are established as necessary for viral entry, host factors CD147, Cathepsins, DPP4, GRP78, L-SIGN, DC-SIGN, Sialic acid, and Plasmin(ogen) may also play a role in the viral entry. The Spike protein and nonstructural proteins, and various host factors working together may contribute to the infection kinetics, high infectivity, rapid transmission, and a spectrum of clinical manifestations of COVID-19. More importantly, they can serve as potential targets in developing strategies for therapeutical prevention and intervention.

ObjectivePrognosis of patients with advanced oesophagogastric adenocarcinoma (mEGAC) is poor and molecular determinants of shorter or longer overall survivors are lacking. Our objective was to identify molecular features and develop a prognostic model by profiling the genomic features of patients with mEGAC with widely varying outcomes.DesignWe profiled 40 untreated mEGACs (20 shorter survivors 36 months) with whole-exome sequencing (WES) and RNA sequencing and performed an integrated analysis of exome, transcriptome, immune profile and pathological phenotypes to identify the molecular determinants, developing an integrated model for prognosis and comparison with The Cancer Genome Atlas (TCGA) cohorts.ResultsKMT2C alterations were exclusively observed in shorter survivors together with high level of intratumour heterogeneity and complex clonal architectures, whereas the APOBEC mutational signatures were significantly enriched in longer survivors. Notably, the loss of heterozygosity in chromosome 4 (Chr4) was associated with shorter survival and ‘cold’ immune phenotype characterised by decreased B, CD8, natural killer cells and interferon-gamma responses. Unsupervised transcriptomic clustering revealed a shorter survivor subtype with distinct expression features (eg, upregulated druggable targets JAK2, MAP3K13 and MECOM). An integrated model was then built based on clinical variables and the identified molecular determinants, which significantly segregated shorter and longer survivors. All the above features and the integrated model have been validated independently in multiple TCGA cohorts.ConclusionThis study discovered novel molecular features prognosticating overall survival in patients with mEGAC and identified potential novel targets in shorter survivors.

Migrating adult Pacific salmon (Oncorhynchus spp.) are sensitive to warm water (>18 °C), with a range of consequences from decreased spawning success to early mortality. We examined the proportion of Yukon River Chinook salmon (O. tshawytscha) exhibiting evidence of heat stress to assess the potential that high temperatures contribute to freshwater adult mortality in a northern Pacific salmon population. Water temperatures greater than 18 °C have occurred almost annually in the Yukon River and correspond with low population abundance since the 1990s. Using gene transcription products and heat shock protein 70 biomarkers validated by field experiment, we identified heat stress in half of Chinook salmon examined (54%, n = 477) across three mainstem locations and three tributaries in 2016–2017. Biomarkers tracked wide variation in water temperature (14–23 °C) within a tributary. The proportion of salmon with heat stress differed between years at four of the six locations, with more prevalent heat stress in the warmer year. This work demonstrates that warming water temperatures are currently affecting northern populations of Pacific salmon.

Rationale: Little is known in contemporary cystic fibrosis (CF) cohorts about the outcomes after new Burkholderia species infections.Objectives: To evaluate the changing epidemiology and clinical o...

Selective breeding and genetic modification have been the cornerstone of animal agriculture. However, the current strategy of breeding animals over multiple generations to introgress novel alleles is not practical in addressing global challenges such as climate change, pandemics, and the predicted need to feed a population of 9 billion by 2050. Consequently, genome editing in zygotes to allow for seamless introgression of novel alleles is required, especially in cattle with long generation intervals. We report for the first time the use of CRISPR-Cas genome editors to introduce novel PRNP allelic variants that have been shown to provide resilience towards human prion pandemics. From one round of embryo injections, we have established six pregnancies and birth of seven edited offspring, with two founders showing >90% targeted homology-directed repair modifications. This study lays out the framework for in vitro optimization, unbiased deep-sequencing to identify editing outcomes, and generation of high frequency homology-directed repair–edited calves.

Background Hibernation is a physiological state exploited by many animals exposed to prolonged adverse environmental conditions associated with winter. Large changes in metabolism and cellular function occur, with many stress response pathways modulated to tolerate physiological challenges that might otherwise be lethal. Many studies have sought to elucidate the molecular mechanisms of mammalian hibernation, but detailed analyses are lacking in reptiles. Here we examine gene expression in the Australian central bearded dragon (Pogona vitticeps) using mRNA-seq and label-free quantitative mass spectrometry in matched brain, heart and skeletal muscle samples from animals at late hibernation, 2 days post-arousal and 2 months post-arousal. Results We identified differentially expressed genes in all tissues between hibernation and post-arousal time points; with 4264 differentially expressed genes in brain, 5340 differentially expressed genes in heart, and 5587 differentially expressed genes in skeletal muscle. Furthermore, we identified 2482 differentially expressed genes across all tissues. Proteomic analysis identified 743 proteins (58 differentially expressed) in brain, 535 (57 differentially expressed) in heart, and 337 (36 differentially expressed) in skeletal muscle. Tissue-specific analyses revealed enrichment of protective mechanisms in all tissues, including neuroprotective pathways in brain, cardiac hypertrophic processes in heart, and atrophy protective pathways in skeletal muscle. In all tissues stress response pathways were induced during hibernation, as well as evidence for gene expression regulation at transcription, translation and post-translation. Conclusions These results reveal critical stress response pathways and protective mechanisms that allow for maintenance of both tissue-specific function, and survival during hibernation in the central bearded dragon. Furthermore, we provide evidence for multiple levels of gene expression regulation during hibernation, particularly enrichment of miRNA-mediated translational repression machinery; a process that would allow for rapid and energy efficient reactivation of translation from mature mRNA molecules at arousal. This study is the first molecular investigation of its kind in a hibernating reptile, and identifies strategies not yet observed in other hibernators to cope stress associated with this remarkable state of metabolic depression. Electronic supplementary material The online version of this article (10.1186/s12864-019-5750-x) contains supplementary material, which is available to authorized users.

The marsupial inactive X chromosome expresses a long noncoding RNA (lncRNA) called Rsx that has been proposed to be the functional analog of eutherian Xist. Despite the possibility that Xist and Rsx encode related functions, the two lncRNAs harbor no linear sequence similarity. However, both lncRNAs harbor domains of tandemly repeated sequence. In Xist, these repeat domains are known to be critical for function. Using k-mer based comparison, we show that the repeat domains of Xist and Rsx unexpectedly partition into two major clusters that each harbor substantial levels of nonlinear sequence similarity. Xist Repeats B, C, and D were most similar to each other and to Rsx Repeat 1, whereas Xist Repeats A and E were most similar to each other and to Rsx Repeats 2, 3, and 4. Similarities at the level of k-mers corresponded to domain-specific enrichment of protein-binding motifs. Within individual domains, protein-binding motifs were often enriched to extreme levels. Our data support the hypothesis that Xist and Rsx encode similar functions through different spatial arrangements of functionally analogous protein-binding domains. We propose that the two clusters of repeat domains in Xist and Rsx function in part to cooperatively recruit PRC1 and PRC2 to chromatin. The physical manner in which these domains engage with protein cofactors may be just as critical to the function of the domains as the protein cofactors themselves. The general approaches we outline in this report should prove useful in the study of any set of RNAs.