title: The climate benefits of yield increases in genetically engineered crops

abstract: The benefits of genetically engineered (GE) crops are systematically underestimated because previous studies did not incorporate the reduction in greenhouse gas (GHG) emissions associated with yield increases. We estimate this impact using the carbon opportunity cost of land use. Our results suggest that the GHG emissions reductions from the yield increases in GE crops are substantial and should be included in future analyses.


title: The seasonal dynamics of bud dormancy in grapevine suggest a regulated checkpoint prior to acclimation

abstract:
Grapevine (Vitis vinifera L.) displays wide plasticity to climate and seasonality, ranging from strongly deciduous to evergreen. Understanding the physiology of decisions to grow or quiesce is critical for improved crop management, prediction, and the adaptability of production to alternative climate scenarios. The perenniating bud (N+2) is a major economic unit and focus of study. Here we investigated the physiology and transcriptome of cv. Merlot buds grown in a temperate maritime climate from summer to spring in two consecutive years. The changes in bud respiration, hydration and internal tissue oxygen data were consistent with the transcriptome data. ABA-responsive gene processes prevailed upon the transition to a deep metabolic and cellular quiescence in the bud during autumn. Light, together with hypoxia and redox signalling presided over the resumption of nuclear and cellular growth in the transition to spring. Comparisons with transcriptome data from bud burst studies revealed a number of regulatory candidates for the orderly resumption of growth in spring, including components that may integrate light and temperature signalling. Importantly however, the bud burst forcing data, which is widely used as a measure of bud dormancy, were not consistent with the physiological and transcription data. We hypothesise the existence of a physiological checkpoint following bud set in summer, which if not met results in extreme quiescence. Collectively this is the most integrated developmental dataset of the latent bud of cultivated grapevine, and establishes a platform for systems approaches to study seasonal plasticity.

One sentence summaryPhysiology and transcriptome data provide strong evidence of a regulatory checkpoint prior to acclimation and dormancy in latent grapevine buds.

category: plant biology


title: An integrated strategy reveals complex glycosylation of erythropoietin using top-down and bottom-up mass spectrometry

abstract: The characterization of glycoproteins, like erythropoietin, is challenging due to the structural micro- and macro-heterogeneity of the protein glycosylation. This study presents an in-depth strategy for glycosylation analysis of a first-generation erythropoietin (epoetin beta), including a developed top-down mass spectrometric workflow for N-glycan analysis, bottom-up mass spectrometric methods for site-specific N-glycosylation and a LC-MS approach for O-glycan identification. Permethylated N-glycans, peptides and enriched glycopeptides of erythropoietin were analyzed by nanoLC-MS/MS and de-N-glycosylated erythropoietin was measured by LC-MS, enabling the qualitative and quantitative analysis of glycosylation and different glycan modifications (e.g., phosphorylation and O-acetylation). Extending the coverage of our newly developed Python script to phosphorylated N-glycans enabled the identification of 140 N-glycan compositions (237 N-glycan structures) from erythropoietin. The site-specificity of N-glycans was revealed at glycopeptide level by pGlyco software using different proteases. In total, 215 N-glycan compositions were identified from N-glycan and glycopeptide analysis. Moreover, LC-MS analysis of de-N-glycosylated erythropoietin species identified two different O-glycan compositions, based on the mass shifts between non-O-glycosylated and O-glycosylated species. This integrated strategy allows the in-depth glycosylation analysis of a therapeutic glycoprotein to understand its pharmacological properties and improving the manufacturing processes.

category: biochemistry


title: Accommodating site variation in neuroimaging data using hierarchical and Bayesian models

abstract:
AO_SCPLOWBSTRACTC_SCPLOWThe potential of normative modeling to make individualized predictions from neuroimaging data has enabled inferences that go beyond the case-control approach. However, site effects are often confounded with variables of interest in a complex manner and can bias estimates of normative models, which has impeded the application of normative models to large multi-site neuroimaging data sets. In this study, we suggest accommodating for these site effects by including them as random effects in a hierarchical Bayesian model. We compared the performance of a linear and a non-linear hierarchical Bayesian model in modeling the effect of age on cortical thickness. We used data of 570 healthy individuals from the ABIDE (autism brain imaging data exchange) data set in our experiments. In addition, we used data from individuals with autism to test whether our models are able to retain clinically useful information while removing site effects. We compared the proposed single stage hierarchical Bayesian method to several harmonization techniques commonly used to deal with additive and multiplicative site effects using a two stage regression, including regressing out site and harmonizing for site with ComBat, both with and without explicitly preserving variance related to age and sex as biological variation of interest. In addition, we made predictions from raw data, in which site has not been accommodated for. The proposed hierarchical Bayesian method showed the best predictive performance according to multiple metrics. Beyond that, the resulting z-scores showed little to no residual site effects, yet still retained clinically useful information. In contrast, performance was particularly poor for the regression model and the ComBat model in which age and sex were not explicitly modeled. In all two stage harmonization models, predictions were poorly scaled, suffering from a loss of more than 90 % of the original variance. Our results show the value of hierarchical Bayesian regression methods for accommodating site variation in neuroimaging data, which provides an alternative to harmonization techniques. While the approach we propose may have broad utility, our approach is particularly well suited to normative modelling where the primary interest is in accurate modelling of inter-subject variation and statistical quantification of deviations from a reference model.

1 HighlightsO_LIDevelopment and presentation of normative modeling approach based on hierarchical Bayesian modeling that can be applied to large multi-site neuroimaging data sets.
C_LIO_LIComparison of performance of Hierarchical Bayesian model including site as predictor to several common ways to harmonize for multi-site effects.
C_LIO_LIPresentation of normative modeling as site correction tool.
C_LI

category: bioinformatics


title: Accommodating site variation in neuroimaging data using normative and hierarchical Bayesian models


title: Multiplatform Computational Analysis of Mast Cells in Adrenocortical Carcinoma Tumor Microenvironment

abstract:
IntroductionImmunotherapeutic response failure of adrenocortical carcinomas (ACC) highlights a need for novel strategies targeting immune cell populations in the tumor microenvironment (TME) to overcome tumor resistance and enhance therapeutic response. A recent study explored a new link between tumor mast cell (MC) infiltration and improved outcomes in patients with ACC. We further dissect the role of MC in TME of ACC by examining the tumor MC expression signatures and MC activity within TME to provide additional insight into potential novel immunotherapeutic targets.

MethodsUsing CIBERSORTx computational immunogenomic deconvolution algorithm to analyze ACC tumor gene mRNA expression data (TCGA, N=79), we estimated the abundance of tumor immune infiltrating MC, and assessed prognostic potential of MC signaling genes as pro- or anti- tumor signatures, as well as the impact on overall (OS) and disease-free (DFS) survival.

ResultsWe stratified MC signaling genes with survival prognostic values (OS, DFS, p<0.05) into anti-tumor (ALOX5, CCL2, CCL5, CXCL10, HDC, IL16, TNF, TPSAB1, VEGFD) and pro-tumor (CXCL1, CXCL3, CXCL8, IL4, IL13, PTGS3, TNSF4, VEGFD) groups. Anti-tumor MC signature, as the predominant phenotype, was associated with improved OS and DFS.

ConclusionThe deconvolution analysis of TCGA data identified MC infiltration in ACC microenvironment as predominantly associated with anti-tumor activity. Future studies stemming from our findings may help define the role of MC in TME and the impact on patient survival in patients with ACC. Modulation of tumor MC infiltration may serve as a potential target for novel synergistic immunotherapies for the treatment and improved survival of patients with ACC.

category: cancer biology


title: A comprehensive urine proteome database generated from patients with various renal conditions and prostate cancer

abstract: Urine proteins can serve as viable biomarkers for diagnosing and monitoring various diseases. A comprehensive urine proteome database, generated from a variety of urine samples with different disease conditions, can serve as a reference resource for facilitating discovery of potential urine protein biomarkers. Herein, we present a urine proteome database generated from multiple datasets using 2D LC-MS/MS proteome profiling of urine samples from healthy individuals (HI), renal transplant patients with acute rejection (AR) and stable graft (STA), patients with non-specific proteinuria (NS), and patients with prostate cancer (PC). A total of ~28,000 unique peptides spanning ~2,200 unique proteins were identified with a false discovery rate of <0.5% at the protein level. Over one third of the annotated proteins were plasma membrane proteins and another one third were extracellular proteins according to gene ontology analysis. Ingenuity Pathway Analysis of these proteins revealed 349 potential biomarkers. Surprisingly, 43% (167) of all known cluster of differentiation (CD) proteins were identified in the various human urine samples. Interestingly, following comparisons with five recently published urine proteome profiling studies, which applied similar approaches, there are still ~400 proteins which are unique to this current study. These may represent potential disease-associated proteins. Among them, several proteins such as myoglobin, serpin B3, renin receptor, and periostin have been reported as pathological markers for renal failure and prostate cancer, respectively. Taken together, our data should provide valuable information for future discovery and validation studies of urine protein biomarkers for various diseases.

category: systems biology


title: Effects of physical, chemical, and biological ageing on the mineralization of pine wood biochar by a 	Streptomyces isolate

abstract:
If biochar is to be used for carbon (C) management, we must understand how ageing affects biochar C mineralization. Here, we incubated aged and unaged eastern white pine wood biochar produced at 350 and 550 {degrees}C with a Streptomyces isolate, a putative biochar-decomposing microbe. Ageing was simulated via exposure to (a) alternating freeze-thaw and wet-dry cycles (physical ageing), (b) concentrated hydrogen peroxide (chemical ageing) and (c) nutrients and microorganisms (biological ageing). Elemental composition and surface chemistry (Fourier Transform Infrared spectroscopy) of biochar samples were compared before and after ageing. Ageing significantly increased biochar C mineralization in the case of physically aged 350 {degrees}C biochar (p < 0.001). Among 350 {degrees}C biochars, biochar C mineralization was positively correlated with an increase in O/C ratio (R2 = 0.78) and O-containing functional groups (R2 = 0.73) post-ageing, suggesting that surface oxidation during ageing enhanced biochar degradation by the isolate. However, in the case of 550 {degrees}C biochar, ageing did not result in a significant change in biochar C mineralization (p > 0.05), likely due to lower surface oxidation and high condensed aromatic C content. These results have implications for the use of biochar for long term C storage in soils.

SynopsisThis study highlights the impact of ageing on the microbial mineralization of biochar, which can affect its long-term C storage capacity.

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category: ecology


title: Cytogenetic events in the endosperm of amphiploid Avena maroccana x A. longiglumis

abstract: This study analysed cytogenetic events occurring in the syncytial endosperm of the Avena maroccana Gand. x Avena longiglumis Dur. amphiploid, which is a product of two wild species having different genomes. Selection through the elimination of chromosomes and their fragments, including those translocated, decreased the level of ploidy in the endosperm below the expected 3n, leading to the modal number close to 2n. During intergenomic translocations, fragments of the heterochromatin-rich C-genome were transferred to the A and Al genomes. Terminal and non-reciprocal exchanges dominated, whereas other types of translocations, including microexchanges, were less common. Using two probes and by counterstaining with DAPI, the A. longiglumis and the rare exchanges between the A and Al genomes were detected by GISH. The large discontinuity in the probe labelling in the C chromosomes demonstrated inequality in the distribution of repetitive sequences along the chromosome and probable intragenomic rearrangements. In the nucleus, the spatial arrangement of genomes was non-random and showed a sectorial-concentric pattern, which can vary during the cell cycle, especially in the less stable tissue like the hybrid endosperm.

category: genetics


title: Gene dosage effects of polyA track engineered hypomorphs

abstract: The manipulation of gene activity through the creation of hypomorphic mutants has been a long-standing tool in examining gene function. Our previous studies have indicated that hypomorphic mutants could be created by inserting cis-regulatory sequences composed of consecutive adenosine nucleotides called polyA tracks. Here we use polyA tracks to create hypomorphic mutants and functional characterization of membrane, secretory and endogenous proteins. Insertion of polyA tracks into the sequences of interleukin-2 and membrane protein CD20 results in a programmable reduction of mRNA stability and attenuation of protein expression regardless of the presence of signaling sequence. Likewise, CRISPR/Cas9 targeted insertion of polyA tracks in the coding sequence of endogenous human genes AUF1 and TP53 results in a programmable reduction of targeted protein and mRNA levels. Functional analyses of AUF1 engineered hypomorphs indicate a direct correlation between AUF1 gene levels and the stability of AUF1-regulated mRNAs. Hypomorphs of TP53 affect the expression of the target genes differentially depending upon the severity of the hypomorphic mutation. Finally, decreases in TP53 protein affect the same cellular pathways in polyA track engineered cells as in cancer cells, indicating these variants biological relevance. These results highlight this technologys power to create predictable, stable hypomorphs in recombinant or endogenous genes in combination with CRISPR/Cas9 engineering tools.


title: TemplateFlow: a community archive of imaging templates and atlases for improved consistency in neuroimaging

abstract: Reference anatomies of the brain and corresponding atlases play a central role in experimental neuroimaging workflows and are the foundation for reporting standardized results. The choice of such references --i.e., templates-- and atlases is one relevant source of methodological variability across studies, which has recently been brought to attention as an important challenge to reproducibility in neuroscience. TemplateFlow is a publicly available framework for human and nonhuman brain models. The framework combines an open database with software for access, management, and vetting, allowing scientists to distribute their resources under FAIR --findable, accessible, interoperable, reusable-- principles. TemplateFlow supports a multifaceted insight into brains across species, and enables multiverse analyses testing whether results generalize across standard references, scales, and in the long term, species, thereby contributing to increasing the reliability of neuroimaging results.

category: neuroscience


title: TemplateFlow: FAIR-sharing of multi-scale, multi-species brain models


title: Prediction of adverse drug reactions associated with drug-drug interactions using hierarchical classification

abstract: Adverse drug reactions (ADRs) associated with drug-drug interactions (DDIs) represent a significant threat to public health. Unfortunately, most conventional methods for prediction of DDI-associated ADRs suffer from limited applicability and/or provide no mechanistic insight into DDIs. In this study, a hierarchical machine learning model was created to predict DDI-associated ADRs and pharmacological insight thereof for any drug pair. Briefly, the model takes drugs chemical structures as inputs to predict their target, enzyme, and transporter (TET) profiles, which are subsequently utilized to assess occurrences of ADRs, with an overall accuracy of ~91%. The robustness of the model for ADR classification was validated with DDIs involving three widely prescribed drugs. The model was then applied for interstitial lung disease (ILD) associated with DDIs involving atorvastatin, identifying the involvement of multiple targets, enzymes, and transporters in ILD. The model presented here is anticipated to serve as a versatile tool for enhancing drug safety.


title: Optimized CRISPR tools and site-directed transgenesis in Culex quinquefasciatus mosquitoes for gene drive development.

abstract: Culex mosquitoes are a global vector for multiple human and animal diseases, including West Nile virus, lymphatic filariasis, and avian malaria, posing a constant threat to public health, livestock, companion animals, and endangered birds. While rising insecticide resistance has threatened the control of Culex mosquitoes, advances in CRISPR genome-editing tools have fostered the development of alternative genetic strategies such as gene drive systems to fight disease vectors. However, though gene-drive technology has quickly progressed in other mosquitoes, advances have been lacking in Culex. Here, we developed a Culex-specific Cas9/gRNA expression toolkit and used site-directed homology-based transgenesis to generate and validate a Culex quinquefasciatus Cas9-expressing line. We showed that gRNA scaffold variants improve transgenesis efficiency in both Culex and Drosophila and boost gene-drive performance in the fruit fly. These findings support future technology development to control Culex mosquitoes and provide valuable insight for improving these tools in other species.

category: synthetic biology


title: Cholinergic calcium responses in cultured antennal lobe neurons of the migratory locust

abstract: Locusts are advantageous organisms to elucidate mechanisms of olfactory coding at the systems level. Sensory input is provided by the olfactory receptor neurons of the antenna, which send their axons into the antennal lobe. So far, cellular properties of neurons isolated from the circuitry of the olfactory system, such as transmitter-induced calcium responses, have not been studied. Biochemical and immunocytochemical investigations have provided evidence for acetylcholine as classical transmitter of olfactory receptor neurons. Here, we characterize cell cultured projection and local interneurons of the antennal lobe by cytosolic calcium imaging to cholinergic stimulation. We bulk loaded the indicator dye Cal-520 AM in dissociated culture and recorded calcium transients after applying cholinergic agonists and antagonists. The majority of projection and local neurons respond with increases in calcium levels to activation of both nicotinic and muscarinic receptors. In local interneurons, we reveal interactions lasting over minutes between intracellular signaling pathways, mediated by muscarinic and nicotinic receptor stimulation. The present investigation is pioneer in showing that Cal-520 AM readily loads Locusta migratoria neurons, making it a valuable tool for future research in locust neurophysiology, neuropharmacology, and neurodevelopment.


title: Contribution of quasi-fibrillar superstructures in peroxide quenching by collagen peptides derived from fish processing by-products and their application as natural food additives

abstract: This study attempts to identify the significant role played by the secondary structure of collagen-derived peptides that are involved in lipid peroxide quenching in food products. Collagen was extracted from the skin of Perch and swim bladder of Rohu at 45-78% efficiency. It was identified as type-I based on a high molecular weight (110kDa) and its ion-exchange elution profile. The collagen samples were enzymatically hydrolyzed and collagen hydrolysate (CH) was extracted with an efficiency of 0.67-0.74g/g of collagen. The CH samples displayed a molecular weight in the range of 8.2-9.7kDa and exhibited a higher abundance of charges resulting in higher solubility. The structural studies revealed that the CH peptides existed in polyproline-II helix and formed a mimic-triple helix in a wide range of pH. In neutral and alkaline pH, the mimic helices joined to form a hierarchical quasi-fibrillar network that was smaller than collagen fibrils but also more dynamic. The CH exhibited >95% degradation in 15h through simulated digestion. The CH were able to decrease peroxide formation by 84.5-98.9% in commercially available cod liver and almond oil and increased the shelf life of soya bean oil by a factor of 5 after 6 months of storage. The addition of CH to cultured cells quenched peroxide ions generated in situ and decreased stressor activity by a factor of 12. The reason behind the high efficacy of CH was deciphered to be the proximal charge stabilization by the quasi-fibrillar network, which allowed efficient peroxide quenching and long-term stability.


title: Seasonal Abundance and Spatial Pattern of Distribution of Liriomyza trifolii (Diptera: Agromyzidae) and Its Parasitoid on Bean and Squash in South Florida.

abstract: American serpentine leafminer, Liriomyza trifolii, is a polyphagous insect pest that feeds on a wide range of vegetable and ornamental plants around the world. To develop an effective IPM program, information on the seasonal field distribution and population dynamics of leafminer and its parasitoids is very important. Therefore, seasonal abundances and spatial distributions of, L. trifolii on snap bean and squash were studied during four crop growing periods between 2013 to 2015 in Homestead, Florida. The mean numbers of mines, larvae, pupae, emerged adults, and parasitoids on snap bean were highest at 2 weeks after planting during all four growing periods. Whereas, the mean numbers of mines, larvae, pupae, emerged adults, and parasitoids on squash were highest at 3 weeks after planting during all four growing periods. L. trifolii distributions tended to be aggregated (1 < b/{beta}) on snap bean at 2 weeks after planting during all four growing periods but had uniform (1 > b/{beta}) distributions on squash at 2 weeks after planting during all four growing periods. Similar results were seen on the distribution of leafminer parasitoids on both bean and squash.


title: Comparative Chromatin Dynamics of Stem Cell Differentiation in Human and Rat

abstract: Differentiation of cell types homologous between species are controlled by conserved networks of regulatory elements driving gene expression. In order to identify conservation of gene expression and chromatin accessibility during cell differentiation in two different species. We collected a daily time-course of gene expression and chromatin accessibility in rat and human to quantify conserved and species-specific chromatin dynamics during embryonic stem cell differentiation to definitive endoderm (DE) as well as to neuronal progenitor cells (NPC). We identify shared and cell-type specific transient differentiation markers in each species, including key transcription factors that may regulate differentiation into each cell-type and their candidate cis-regulatory elements (cCREs). Our analysis shows that DE differentiation has higher conservation of gene expression and chromatin accessibility than NPC differentiation. We provide the first global comparison of transcriptional complexity and chromatin dynamics between human and rat for DE and NPC differentiation.

category: genomics


title: Predicting behavior from eye movement and whisking asymmetry

abstract: Navigation through complex environments requires motor planning, motor preparation and the coordination between multiple sensory motor modalities. For example, the stepping motion when we walk is coordinated with motion of the torso, arms, head and eyes. In rodents, movement of the animal through the environment is often coordinated with whisking. Here we trained head fixed mice, navigating a floating Airtrack plus maze, to overcome their directional preference and use cues indicating the direction of movement expected in each trial. Once cued, mice had to move backward out of a lane, then turn in the correct direction, and enter a new lane. In this simple paradigm, as mice begin to move backward, they position their whiskers asymmetrically: whiskers on one side of the face protract, and on the other side they retract. This asymmetry reflected the turn direction. Additionally, on each trial, mice move their eyes conjugately in the direction of the upcoming turn. Not only do they move their eyes, but saccadic eye movement is coordinated with the asymmetric positioning of the whiskers. Our analysis shows that the asymmetric positioning of the whiskers predicts the direction of turn that mice will make at an earlier stage than eye movement does. We conclude that, when mice move or plan to move in complex real-world environments, their motor plan and behavioral state can be read out in the movement of both their whiskers and eyes.


title: Optimal Linkage Disequilibrium Splitting

abstract: A few algorithms have been developed for splitting the genome in nearly independent blocks of linkage disequilibrium. Due to the complexity of this problem, these algorithms rely on heuristics, which makes them sub-optimal. Here we develop an optimal solution for this problem using dynamic programming. This is now implemented as function snp_ldplit as part of R package bigsnpr.


title: Anti-diabetic effects of Holarrhena antidysentrica extracts: Results from a Longitudinal Meta-analysis

abstract:
BackgroundHolarrhena antidysenterica (HA), a twining shrub belonging to the Apocynaceae family is found in tropical regions of Africa and over a large part of Asia including India, Philippines and Malayan Peninsula. In Indian traditional system of medicine, HA has been used to treat gastric ailments, for wound healing and also to improve glycaemic control. Glucose lowering activity of HA root, bark, seed, leaf and fruit extract in different parts of India as well as in Chinese traditional medicine is widely reported.

PurposeIn the meta-analysis reported in this article, we summarize glucose-lowering effects of HA extracts from different plant parts as reported in multiple studies involving animal models of diabetes. Our analysis helps to quantify the glucose-lowering effect of HA in comparison with standard diabetes drugs. The analysis also sheds light on differential efficacy levels of HA extracted from different plant parts.

Study designThe meta-analysis was carried out following PRISMA guidelines. Literature was searched to identify studies published between years 2011 to 2019 reporting glucose-lowering effects of HA extract on rodent models of diabetes.

MethodsLongitudinal meta-analysis was carried out on time-course data extracted from selected studies to calculate standardized mean change of glucose value from day 1 to days 7, 14 and 21 post-treatment by HA extract or standard anti-diabetic drug. Subgroup analysis was carried out for studies reporting effects of HA on leaf and seed extracts. Standardized mean difference in levels of cholesterol, triglycerides and serum total protein between treatment and control groups were also assessed.

ResultsWe shortlisted nine articles to be used for this meta-analysis. Summarized standardized mean changes of glucose value between day 1 and day 21 post-treatment indicated glucose-lowering effects of HA extracts to be marginally lower but comparable to that of standard anti-diabetic drugs like Glibenclamide or Sitagliptin. However, subgroup analysis revealed seed extracts of HA to be more potent than leaf extracts or even standard drugs. Effects of the extract on levels of cholesterol, triglyceride and serum total protein was also commensurate with its glucose-lowering property.

ConclusionsOur results, summarized over multiple studies, present a clear quantitative assessment of the anti-diabetic property of HA, in particular the seed extracts compared to standard anti-diabetic drugs. Further differential analysis of the seed extracts will be useful to arrive at a herbal formulation with superior anti-diabetic property and possibly lesser side effects than chemical entities.


title: Photoperiod shapes aluminium tolerance in plants

abstract:
Aluminium is a limiting factor for crop productivity in acidic soils (pH [≤] 5.5). Since acid soil distribution on Earth cannot adequately explain the differential Al tolerance across the plant kingdom, we investigated photoperiod effects on plant Al tolerance. We observed that with increasing distance from the equator, Al tolerance disappears, suggesting a relationship with the photoperiod. Long-day (LD) species are generally more Al-sensitive than short-day (SD) species, whereas genetic conversion of tomato for SD growth boosts Al tolerance. Reduced Al tolerance correlates with DNA-checkpoint activation under LD. DNA-checkpoint-related genes are under positive selection in Arabidopsis accessions from regions with shorter days, suggesting photoperiod acts as a selective barrier for Al tolerance. Our findings revealed that diel regulation and genetic diversity affect Al tolerance, suggesting that day-length orchestrates Al tolerance.

One-Sentence SummaryAluminum is a major constraint for crop yield worldwide. We reveal that photoperiod acts as a barrier for Al tolerance in plants.


title: Multi-channel 4D parametrized Atlas of Macro- and Microstructural Neonatal Brain Development

abstract:
Structural and diffusion MRI provide complimentary anatomical and microstructural characterization of early brain maturation. The existing models of the developing brain in time include only either structural or diffusion channels. Furthermore, there is a lack of tools for combined analysis of structural and diffusion MRI in the same reference space.

In this work we propose methodology to generate multi-channel (MC) continuous spatio-temporal parametrized atlas of brain development based on MC registration driven by both T2-weighted and orientation distribution functions (ODF) channels along with the Gompertz model (GM) fitting of the signals and spatial transformations in time. We construct a 4D MC atlas of neonatal brain development during 38 to 44 week PMA range from 170 normal term subjects from developing Human Connectomme Project. The resulting atlas consists of fourteen spatio-temporal microstructural indices and two parcellation maps delineating white matter tracts and neonatal transient structures. We demonstrate applicability of the atlas for quantitative region-specific comparison of 140 term and 40 preterm subjects scanned at the term-equivalent age. We show multi-parametric microstructural differences in multiple white matter regions, including the transient compartments. The atlas and software will be available after publication of the article.


title: Using a Human Circulation Mathematical Model to Simulate the Effects of Hemodialysis and Therapeutic Hypothermia.

abstract:
BackgroundThe human blood circulation is an intricate process regulated by multiple biophysical factors. Our patients often suffer from renal disease and atrial fibrillation, and are given treatments such as therapeutic hypothermia, exercise, and hemodialysis. In this work, a hemodynamic mathematical model of human circulation coupled to a representative dialysis machine is developed and used to explore causal mechanisms of our recent clinical observations.

MethodsAn ordinary differential equation model consisting of human whole body circulation, baroreflex control, and a hemodialysis machine was implemented. Experimentally informed parameter alterations were used to implement hemodialysis and therapeutic hypothermia. By means of parameter perturbation, four model populations encompassing baseline, dialysed, hypothermia treated, and simultaneous dialysed with hypothermia were generated. In model populations, multiple conditions including atrial fibrillation, exercise, and renal failure were simulated. The effects of all conditions on clinically relevant non-invasive measurables such as heart rate and blood pressure were quantified. A parameter sensitivity analysis was implemented to rank model output influencing parameters in the presented model.

ResultsResults were interpreted as alterations of the respective populations mean values and standard deviations of the clinical measurables, both in relation to the baseline population. A clinical measurables smaller standard deviation (in comparison to baseline population) was interpreted as a stronger association between a given clinical measure and the corresponding underlying process, which may permit the use of deducing one by observation of the other.

The modelled dialysis was observed to increase systolic blood pressure, vessel shear, and heart rate. Therapeutic hypothermia was observed to reduce blood pressure as well as the intra-population standard deviation (heterogeneity) of blood flow in the large (aorta) and small (kidney) vasculature. Therapeutic hypothermia reduced shear in vessels, suggesting a potential benefit with respect to endothelial dysfunction and maintenance of microcirculatory blood flow. The action of therapeutic hypothermia under conditions such as atrial fibrillation, exercise, and renal failure was to reduce total blood flow, which was applicable in all simulated populations. Therapeutic hypothermia did not affect the dialysis function, but exercise improved the efficacy of dialysis by facilitating water removal.

ConclusionsThis study illuminates some mechanisms of action for therapeutic hypothermia. It also suggests clinical measurables that may be used as surrogates to diagnose underlying diseases such as atrial fibrillation.

category: biophysics


title: IN VITRO ANTI-VIRAL ACTIVITY OF HEXETIDINE (BACTIDOL) ORAL MOUTHWASH AGAINST HUMAN CORONAVIRUS OC43 ANDINFLUENZA A (H1N1) VIRUS

abstract:
Mouthwashes are used to decrease oral cavity microbial load due to their antiseptic properties. Hexetidine is a broad-spectrum antiseptic used for minor infections of mucous membranes, and in particular as a 0.1% mouthwash for local infections and oral hygiene.

This study determined the anti-viral activity of the mouthwash hexetidine (Bactidol(R)), specifically in reducing viral concentration of Human Coronavirus OC43 (HCoV OC43; ATCC(R) VR-1558) and Influenza A virus (IAV H1N1; clinical strain) in Vero 6 and MDCK cell cultures respectively, using in-vitro suspension assay (ASTM E-1052-11) designed to evaluate virucidal property of microbicides like hexetidine.

Study results indicated that hexetidine was able to reduce infectivity of HCoV OC43 and IAV H1N1 at 25%, 50% and 100% concentrations by more than 80% at 15- and 30-seconds exposure times. One hundred percent (100%) concentration of hexetidine was found to be cytotoxic to MDCK cell line used for IAV H1N1 propagation. Hexetidine-treated cell lines achieved >80% survival rate for MDCK and Vero E6 at a contact time of 15 seconds and 30 seconds (which are the approximate times of gargling with hexetidine mouthwash).

The anti-viral activity of hexetidine mouthwash against other more virulent or pathogenic coronaviruses like SARS-CoV-2 can be explored further.

category: microbiology


title: Unbiased profiling of CRISPR RNA-guided transposition products by long-read sequencing

abstract: Bacterial transposons propagate through either non-replicative (cut-and-paste) or replicative (copy-and-paste) pathways, depending on how the mobile element is excised from its donor source. In the well-characterized E. coli transposon Tn7, a heteromeric TnsA-TnsB transposase directs cut-and-paste transposition by cleaving both strands at each transposon end during the excision step. Whether a similar pathway is involved for RNA-guided transposons, in which CRISPR-Cas systems confer DNA target specificity, has not been determined. Here, we apply long-read, population-based whole-genome sequencing (WGS) to unambiguously resolve transposition products for two evolutionarily distinct transposon types that employ either Cascade or Cas12k for RNA-guided DNA integration. Our results show that RNA-guided transposon systems lacking functional TnsA primarily undergo copy-and-paste transposition, generating cointegrate products that comprise duplicated transposon copies and insertion of the vector backbone. Finally, we report natural and engineered transposon variants encoding a TnsAB fusion protein, revealing a novel strategy for achieving RNA-guided transposition with fewer molecular components.

category: molecular biology


title: Cholinergic signalling at the body wall neuromuscular junction couples to distal inhibition of feeding in C. elegans

abstract: Complex biological functions within organisms are frequently orchestrated by systemic communication between tissues. In the model organism C. elegans, the pharyngeal and body wall neuromuscular junctions are two discrete structures that control feeding and locomotion, respectively. These distinct tissues are controlled by separate, well-defined neural circuits. Nonetheless, the emergent behaviours, feeding and locomotion, are coordinated to guarantee the efficiency of food intake. We show that pharmacological hyperactivation of cholinergic transmission at the body wall muscle reduces the rate of pumping behaviour. This was evidenced by a systematic screening of the cholinesterase inhibitor aldicarbs effect on the rate of pharyngeal pumping on food in mutant worms. The screening revealed that the key determinant of the inhibitory effect of aldicarb on pharyngeal pumping is the L-type nicotinic acetylcholine receptor expressed in body wall muscle. This idea was reinforced by the observation that selective hyperstimulation of the body wall muscle L-type receptor by the agonist levamisole inhibited pumping. Overall, our results reveal that body wall cholinergic transmission controls locomotion and simultaneously couples a distal inhibition of feeding.


title: A bacteriophage cocktail significantly reduces Listeria monocytogenes without deleterious impact on the commensal gut microbiota under simulated gastro-intestinal conditions

abstract: In this study, we examined the effect of a bacteriophage cocktail (tentatively designated FOP, for Foodborne Outbreak Pill) on the levels of Listeria monocytogenes in simulated small intestine, large intestine, and Caco-2 model systems. We found that FOP survival during simulated passage of the upper gastrointestinal was dependent on stomach pH, and that FOP robustly inhibited L. monocytogenes levels with effectiveness comparable to antibiotic treatment (ampicillin) under simulated ilium and colon conditions. FOP did not inhibit the commensal bacteria, whereas ampicillin treatment led to dysbiosis-like conditions. FOP was also more effective than antibiotic in protecting Caco-2 cells from adhesion and invasion by L. monocytogenes, while not triggering an inflammatory response. Our data suggest that FOP may provide a robust protection against L. monocytogenes should the bacterium enter the human gastrointestinal tract (e.g., by consumption of contaminated food), without deleterious impact on the commensal bacteria.


title: Melanoma cells adopt features of both mesenchymal and amoeboid migration within confining channels

abstract: For metastasis to occur, cancer cells must traverse a range of tissue environments. In part, this is accomplished by cells adjusting their migration mode to one that is best suited to the environment. Melanoma cells have been shown to be particularly plastic, frequently using both mesenchymal and amoeboid (bleb-based) modes of migration. It has been demonstrated that 2D confinement will promote the transition from mesenchymal to bleb-based migration. However, if melanoma cells similarly transition to bleb-based migration in response to 3D confinement, such as within narrow channels, is unknown. Here, using micro-fabricated channels, we demonstrate that melanoma cells adopt features of both mesenchymal and bleb-based migration. In narrow (8 m; height and width) channels coated with fibronectin, ~50% of melanoma cells were found to use either mesenchymal or bleb-based migration modes. In contrast, the inhibition of Src family kinases or coating channels with BSA, completely eliminated any features of mesenchymal migration. Detailed comparisons of migration parameters revealed that blebbing cells, particularly in the absence of adhesions, were faster than mesenchymal cells. In contrast to what has been previously shown under conditions of 2D confinement, pharmacologically inhibiting Arp2/3 promoted a fast filopodial-based mode of migration. Accordingly, we report that melanoma cells adopt a unique range of phenotypes under conditions of 3D confinement.

category: cell biology


title: Competition in depleting resource environments shapes the thermal response of mosquito population fitness

abstract: The temperature-dependencies of life history traits are increasingly being used to predict how climatic warming will affect vector-borne disease dynamics, partially by affecting the abundance dynamics of the vector population. Such predictions generally arise from mathematical models that incorporate the temperature dependence of traits measured under laboratory conditions. These temperature-trait relationships are typically estimated from juvenile populations reared under optimal resource conditions, even though natural populations experience intermittent resource depletion. Using laboratory experiments on the mosquito Aedes aegypti, combined with a stage-structured population model, we show that resource depletion in the juvenile habitat can significantly depress the vectors maximal population growth rate (rm) across the entire temperature range, cause it to peak at a lower temperature, and narrow its thermal niche width. Our results provide compelling evidence for future studies to consider resource depletion when predicting the effects of global change on vector-borne disease transmission, disease vectors and other arthropods.


title: The effect of resource depletion on the thermal response of mosquito population fitness


title: Exon 9 LEPR Gene SNP Polymorphism of Hybrid Chickens F2 Kambro Crossbreeds of female F1 Kambro with male F1 Kambro

abstract: The implementation of the T-ARMS PCR method in the detection of single nucleotide polymorphisms (SNPs) in the LEPR gene in chicken DNA samples has never been conducted. This research aims to design a specific protocol for exon 9 LEPR gene SNPs detection and detect LEPR gene expression or LEPR SNPs in Pelung chicken samples, F1 Pelung, Layer, Broiler Cobb 500, F1 Kambro chicken and F2 Kambro chicken using the T-ARMS PCR method. Determination of LEPR gene correlation degree on Body Weight (BT) and Egg Productivity (PT) in F1 Kambro population and F2 Kambro. Qualitative phenotype parameters showed six groups of segregated phenotypes compared to F1 Kambro chicken. Growth of F2 Kambro chicken weight reached 753.36 {+/-} 155.31 grams in 8 weeks was not significant for F1 Kambro chicken due to inbreeding depression (Fx = 25%, IR = 4.925%) and transversion of A LEPR allele mutations. Specific protocol detection of exon 9 LEPR gene SNPs using the T-ARMS PCR method can detect C127A LEPR mutations with IP: OP ratio 10:1 pmol / {micro}M, chicken DNA template concentration of 100 ng / {micro}L with annealing temperature of 55.7{degrees} C / 30s. The transversion mutation of C127A of LEPR exon 9 SNP were detected in DNA samples of F1 Kambro hens (80%), F2 Kambro roosters (20%), Broiler Cobb 500 hens (75%). The mutations were not detected in Layer, Pelung Blirik Hitam chicken and F1 Pelung populations.


title: Hydrogels Containing Gradients in Vascular Density Reveal Dose-Dependent Role of Angiocrine Cues on Stem Cell Behavior

abstract: Biomaterials that replicate patterns of microenvironmental signals from the stem cell niche offer the potential to refine platforms to regulate stem cell behavior. While significant emphasis has been placed on understanding the effects of biophysical and biochemical cues on stem cell fate, vascular-derived or angiocrine cues offer an important alternative signaling axis for biomaterial-based stem cell platforms. Elucidating dose-dependent relationships between angiocrine cues and stem cell fate are largely intractable in animal models and two-dimensional cell culture. In this study, we leverage microfluidic mixing devices to generate three-dimensional hydrogels containing lateral gradients in vascular density alongside murine hematopoietic stem cells (HSCs). Regional differences in vascular density can be generated via embossed gradients in cell, matrix, or growth factor density. HSCs co-cultured alongside vascular gradients reveal spatial patterns of HSC phenotype in response to angiocrine signals. Notably, decreased Akt signaling in high vessel density regions led to increased expansion of lineage-positive hematopoietic cells. This approach offers a combinatorial tool to rapidly screen a continuum of microenvironments with varying vascular, biophysical, and biochemical cues to reveal the influence of local angiocrine signals on HSC fate.

category: bioengineering


title: Clinically Validated Model Predicts the Effect of Intratumoral Heterogeneity on Overall Survival for Non-Small Cell Lung Cancer (NSCLC) Patients

abstract:
PurposeWe demonstrate the importance of considering intratumoral heterogeneity and the development of resistance during fractionated radiotherapy when the same dose of radiation is delivered for all fractions (Fractional Equivalent Dosing FED).

Materials and MethodsA mathematical model was developed with the following parameters: a starting population of 1011 non-small cell lung cancer (NSCLC) tumor cells, 48-hour doubling time, and cell death per the linear-quadratic (LQ) model with  and {beta} values derived from RSI/{beta}, in a previously described gene expression based model that estimates  and {beta}. To incorporate both inter- and intratumor radiation sensitivity, RSI/{beta} output for each patient sample is assumed to represent an average value in a gamma distribution with the bounds set to -50% and +50% of RSI/b. Therefore, we assume that within a given tumor there are subpopulations that have varying radiation sensitivity parameters that are distinct from other tumor samples with a different mean RSI/{beta}. A simulation cohort (SC) comprised of 100 lung cancer patients with available RSI/{beta} (patient specific  and {beta} values) was used to investigate 60Gy in 30 fractions with fractionally equivalent dosing (FED). A separate validation cohort (VC) of 57 lung cancer patients treated with radiation with available local control (LC), overall survival (OS), and tumor gene expression was used to clinically validate the model. Cox regression was used to test for significance to predict clinical outcomes as a continuous variable in multivariate analysis (MVA). Finally, the VC was used to compare FED schedules with various altered fractionation schema utilizing a Kruskal-Wallis test. This was examined using the end points of end of treatment log cell count (LCC) and by a parameter described as mean log kill efficiency (LKE) defined as: O_FD O_INLINEFIG[Formula 1]C_INLINEFIGM_FD(1)C_FD

ResultsCox regression analysis on LCC for the VC demonstrates that, after incorporation of intratumoral heterogeneity, LCC has a linear correlation with local control (p = 0.002) and overall survival (p =< 0.001). Other suggested treatment schedules labeled as High Intensity Treatment (HIT) with a total 60Gy delivered over 6 weeks have a lower mean LCC and an increased LKE compared to standard of care 60Gy delivered in FED in the VC.

ConclusionWe find that LCC is a clinically relevant metric that is correlated with local control and overall survival in NSCLC. We conclude that 60Gy delivered over 6 weeks with altered HIT fractionation leads to an enhancement in tumor control compared to FED when intratumoral heterogeneity is considered.


title: Epigenetic changes with age primes mammary luminal epithelia for cancer initiation

abstract: Aging causes molecular changes that manifest as stereotypical phenotypes yet aging-associated diseases progress only in certain individuals. At lineage-specific resolution, we show how stereotyped and variant responses are integrated in mammary epithelia. Age-dependent directional changes in gene expression and DNA methylation (DNAm) occurred almost exclusively in luminal cells and implicated genome organizers SATB1 and CTCF. DNAm changes were robust indicators of aging luminal cells, and were either directly (anti-)correlated with expression changes or served as priming events for subsequent dysregulation, such as demethylation of ESR1-binding regions in DNAm-regulatory CXXC5 in older luminal cells and luminal-subtype cancers. Variance-driven changes in the transcriptome of both luminal and myoepithelial lineages further contributed to age-dependent loss of lineage fidelity. The pathways affected by transcriptomic and DNAm changes during aging are commonly linked with breast cancer, and together with the differential variability found across individuals, influence aging-associated cancer susceptibility in a subtype-specific manner.


title: In vitro efficacy of Artemisia extracts against SARS-CoV-2

abstract: Traditional medicines based on herbal extracts have been proposed as affordable treatments for patients suffering from coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Teas and drinks containing extracts of Artemisia annua and Artemisia afra have been widely used in Africa in efforts to prevent and fight COVID-19 infections. We sought to study the ability of different A. annua and A. afra extracts and the Covid-Organics drink produced in Madagascar to inhibit SARS-CoV-2 and feline coronavirus (FCoV) replication in vitro. Several extracts as well as Covid-Organics inhibit SARS-CoV-2 and FCoV replication at concentrations that did not affect cell viability. It remains unclear whether peak plasma concentrations in humans can reach levels needed to inhibit viral replication following consumption of teas or Covid-Organics. Clinical studies are required to evaluate the utility of these drinks for COVID-19 prevention or treatment in patients.

category: pharmacology and toxicology


title: Comparison of library preparation and sequencing depths for direct sequencing of Bordetella pertussis positive samples

abstract:
Whooping cough, or pertussis, is a highly transmissible respiratory infection caused by Bordetella pertussis. Due to the high burden of pertussis, vaccine programmes were introduced internationally and in Australia since the 1950s. This has resulted in a significant decrease of pertussis infections. However, since the 1990s the number of pertussis notifications has increased considerably. Currently circulating B. pertussis strains differ in vaccine antigen composition compared to strains that circulated in the pre-vaccination era. These genetic differences are thought to contribute, in part, to the re-emergence of pertussis in Australia and around the world. Whole genome sequencing (WGS) can resolve minute differences in circulating strains and provides unparalleled resolution of vaccine antigens. This high-resolution snapshot can provide clues that enable more targeted public health interventions. However, pertussis is primarily diagnosed with culture-independent diagnostic assays which offer fast turnaround result times and reduced laboratory costs, eliminating the need to culture isolates. Current WGS methods require a cultured isolate, resulting in an absence of B. pertussis genome sequences in the post vaccination era. This scarcity has, in turn, limited understanding of currently circulating strains and respective vaccine antigen compositions.

Recent advancements of WGS technologies have allowed direct sequencing of clinical specimens without the need for a cultured isolate. However, recovering reliable sequence data from clinical samples of low bacterial load infections such as B. pertussis is a pressing challenge. We sought to increase the yield of B. pertussis sequences direct from a clinical sample by evaluating widely available WGS library preparation methods.

We report that the Illumina DNA prep library preparation kit combined with deep sequencing allowed the detection of important surveillance information such as allelic variations in the B. pertussis vaccine antigens. Further, our method generates high coverage over the 23S ribosomal RNA of B. pertussis enabling macrolide resistance to be easily determined. Overall, this method can improve surveillance of B. pertussis, by monitoring changes in vaccine antigens, detecting antimicrobial resistance and guiding Public Health control interventions.


title: Distribution of Panama's narrow-range trees: are there hot-spots?

abstract:
BackgroundTree species with narrow ranges are a conservation concern because heightened extinction risk accompanies their small populations. Assessing risks for these species is challenging, however, especially in tropical flora where their sparse populations seldom appear in traditional plots and inventories. Here, we utilize instead large scale databases that combine tree records from many sources to test hypotheses about where the narrow-range tree species of Panama are concentrated.

MethodsAll individual records were collected from public databases, and the range size of each tree species found in Panama was estimated as a polygon around all its locations. Rare species were defined as those with ranges < 20,000 km2. We divided Panama into geographic regions and elevation zones and counted the number of individual records and the species richness in each, separating rare species from all other species.

ResultsThe proportion of rare species peaked at elevations above 2000 m, reaching 17.3% of the species recorded. At lower elevation across the country, the proportion was 6-11%, except in the dry Pacific region, where it was 1.5%. Wet forests of the Caribbean coast had 8.4% rare species, slightly higher than other regions. The total number of rare species, however, peaked at mid-elevation, not high elevation, because total species richness was highest there.

ConclusionsHigh elevation forests of west Panama have higher endemicity of trees than all low-elevation regions. Dry forests had the lowest endemicity. This supports the notion that montane forests of Central America should be a conservation focus, however, given generally higher diversity at low- to mid-elevation, lowlands are also important habitats for rare species.


title: Flexible analysis of TSS mapping data and detection of TSS shifts with TSRexploreR

abstract: Heterogeneity in transcription initiation has important consequences for transcript stability and translation, and shifts in transcription start site (TSS) usage are prevalent in various disease and developmental contexts. Accordingly, numerous methods for global TSS profiling have been developed, including our recently published Survey of TRanscription Initiation at Promoter Elements with high-throughput sequencing (STRIPE-seq), a method to profile transcription start sites (TSSs) on a genome-wide scale with minimal cost and time. In parallel to our development of STRIPE-seq, we built TSRexploreR, an R package for end-to-end analysis of TSS mapping data. TSRexploreR provides functions for TSS and TSR detection, normalization, correlation, visualization, and differential TSS/TSR analysis. TSRexploreR is highly interoperable, accepting the data structures of TSS and TSR sets generated by several existing tools for processing and alignment of TSS mapping data, such as CAGEr for Cap Analysis of Gene Expression (CAGE) data. Lastly, TSRexploreR implements a novel approach for the detection of shifts in TSS distribution.


title: Regulatory adenylnucleotide-mediated binding of the PII-like protein SbtB to the cyanobacterial bicarbonate transporter SbtA is controlled by the cellular energy state

abstract: Cyanobacteria have evolved one of the most powerful CO2 concentrating mechanisms (CCM), supporting high photosynthetic rates with limiting inorganic carbon (Ci), which makes their CCM a desirable system for integration into higher plant chloroplasts to enhance photosynthetic yield. The CCM is driven by active Ci uptake, facilitated by bicarbonate transporters and CO2 pumps, which locally elevates the CO2 concentration and carboxylation rate of the primary CO2 fixing enzyme, Rubisco, inside cytoplasmic micro-compartments (carboxysomes). Ci uptake responds allosterically to Ci supply and light, but the molecular signals and regulators of protein function are unknowns. Functional analyses of sodium-dependent bicarbonate transporters classified as SbtA in E. coli support the hypothesis that SbtA activity is negatively regulated through association with its cognate PII-like SbtB protein. Here, we demonstrate that the association of SbtA with SbtB from two phylogenetically distant species, Cyanobium sp. PCC7001 and Synechococcus elongatus PCC7942, depends on the relative amounts of ATP or cAMP compared to ADP or AMP. Higher ATP over ADP or AMP ratios decreased the formation of SbtA:SbtB complexes, consistent with a sensory response to the cellular adenylate energy charge (AEC=[ATP + 0.5 ADP]/[ATP+ADP+AMP]) and the different binding affinities of these adenylates to SbtB protein trimers. Based on evidence for adenylate ligand-specific conformation changes for the SbtB protein trimer of Cyanobium sp. PCC7001, we propose a role for SbtB as a curfew protein locking SbtA into an inactive state as safe-guard against energetically futile and physiologically disadvantageous activation during prolonged low cellular AEC and photosynthetically unfavourable conditions.


title: Microbial tryptophan catabolism affects the vector competence of Anopheles

abstract: The influence of microbiota on mosquito physiology and vector competence is becoming increasingly clear but our understanding of interactions between microbiota and mosquitoes still remains incomplete. Here we show that gut microbiota of Anopheles stephensi, a competent malaria vector, participates mosquito tryptophan metabolism. Elimination of microbiota by antibiotics treatment leads to the accumulation of tryptophan (Trp) and its metabolites, kynurenine (Kyn), 3-hydroxykynurenine (3-HK) and xanthurenic acid (XA). Of these, 3-HK impairs the structure of peritrophic matrix (PM), thereby promoting Plasmodium berghei infection. Among the major gut microbiota in An. stephensi, Pseudomonas alcaligenes plays a role in catabolizing 3-HK as revealed by whole genome sequencing and LC-MS metabolic analysis. The genome of P. alcaligenes encodes kynureninase (KynU) that is responsible for the conversion of 3-HK to 3-Hydroxyanthranilic acid (3-HAA). Mutation of this gene abrogates the ability of P. alcaligenes to metabolize 3-HK, which in turn abolishes its role on PM protection. Colonization of An. stephensi with KynU mutated P. alcaligenes fails to protect mosquitoes against parasite infection as effectively as those with wild type bacterium. In summary, we identify an unexpected function of gut microbiota in controlling mosquito tryptophan metabolism with the major consequences on vector competence.


title: SecSel, a new software tool for conservation prioritization that is applicable to ordinal-scale data for multiple biodiversity features

abstract: SecSel, a protected-area prioritization tool, has been developed to help design areas that efficiently protect multiple features, including conservation of biodiversity and use of ecosystem services. The prioritization by SecSel is based on evaluation of the local units of each feature. The evaluation metrics should be quantitative but need not be ratio scale. The minimum requirement of the input data is that they are ordinal. The conservation target is the number of local units with high values of each feature to be protected in the area. SecSel can handle conflicts among features, including conflicts between conservation and utilization of land or specific ecosystem functions. Before the selection procedure, one of a conflicting pair of features in a site is discarded. That decision is based on the dispensability of the local unit to fulfilling the conservation target of each feature. SecSel also considers the cost of including each site in the protected area and the compactness of the area in terms of total boundary length or the distance to the nearest site. To demonstrate the functionality of Secsel, we used it to design land use in an alpine region of northern Japan where conservation of alpine vegetation and its recreational use are important considerations.


title: Coding of chromatic spatial contrast by macaque V1 neurons

abstract: Color perception relies on spatial comparisons of chromatic signals, but how the brain performs these comparisons is poorly understood. Here, we show that many V1 neurons compare signals across their receptive fields (RF) using a common principle. We estimated the spatial-chromatic RFs of each neuron, and then measured neural selectivity to customized colored edges that were sampled using a novel closed-loop technique. We found that many double-opponent (DO) cells, which have spatially and chromatically opponent RFs, responded to chromatic contrast as a weighted sum, akin to how simple cells respond to luminance contrast. Other neurons integrated chromatic signals non-linearly, confirming that linear signal integration is not an obligate property of V1 neurons. The functional similarity of DO and simple cells suggests a common underlying neural circuitry, promotes the construction of image-computable models for full-color image representation, and sheds new light on V1 complex cells.


title: Attention to speech: Mapping distributed and selective attention systems

abstract:
Daily life is full of situations where many people converse at the same time. Under these noisy circumstances, individuals can employ different listening strategies to deal with the abundance of sounds around them. In this fMRI study we investigated how applying two different listening strategies - Selective vs. Distributed attention - affects the pattern of neural activity. Specifically, in a simulated  cocktail party paradigm, we compared brain activation patterns when listeners attend selectively to only one speaker and ignore all others, versus when they distribute their attention and attempt to follow two or four speakers at the same time. Results indicate that the two attention types activate a highly overlapping, bilateral fronto-temporal-parietal network of functionally connected regions. This network includes auditory association cortex (bilateral STG/STS) and higher-level regions related to speech processing and attention (bilateral IFG/insula, right MFG, left IPS). Within this network, responses in specific areas were modulated by the type of attention required. Specifically, auditory and speech-processing regions exhibited higher activity during Distributed attention, whereas fronto-parietal regions were activated more strongly during Selective attention. This pattern suggests that a common perceptual-attentional network is engaged when dealing with competing speech-inputs, regardless of the specific task at hand. At the same time, local activity within nodes of this network varies when implementing different listening strategies, reflecting the different cognitive demands they impose. These results nicely demonstrate the systems flexibility to adapt its internal computations to accommodate different task requirements and listener goals.

Significance StatementHearing many people talk simultaneously poses substantial challenges for the human perceptual and cognitive systems. We compared neural activity when listeners applied two different listening strategy to deal with these competing inputs: attending selectively to one speaker vs. distributing attention among all speakers. A network of functionally connected brain regions, involved in auditory processing, language processing and attentional control was activated when applying both attention types. However, activity within this network was modulated by the type of attention required and the number of competing speakers. These results suggest a common  attention to speech network, providing the computational infrastructure to deal effectively with multi-speaker input, but with sufficient flexibility to implement different prioritization strategies and to adapt to different listener goals.


title: Attentional Modulations of Alpha Power Are Sensitive to the Task-relevance of Auditory Spatial Information

abstract: The topographical distribution of oscillatory power in the alpha band is known to vary depending on the current focus of spatial attention. Here, we investigated to what extend univariate and multivariate measures of post-stimulus alpha power are sensitive to the required spatial specificity of a task. To this end, we varied the perceptual load and the spatial demand in an auditory search paradigm. A centrally presented sound at the beginning of each trial indicated the to-be-localized target sound. This spatially unspecific pre-cue was followed by a sound array, containing either two (low perceptual load) or four (high perceptual load) simultaneously presented lateralized sound stimuli. In separate task blocks, participants were instructed either to report whether the target was located on the left or the right side of the sound array (low spatial demand) or to indicate the exact target location (high spatial demand). Univariate alpha lateralization magnitude was neither affected by perceptual load nor by spatial demand. However, an analysis of onset latencies revealed that alpha lateralization emerged earlier in low (vs. high) perceptual load trials as well as in low (vs. high) spatial demand trials. Finally, we trained a classifier to decode the specific target location based on the multivariate alpha power scalp topography. A comparison of decoding accuracy in the low and high spatial demand conditions suggests that the amount of spatial information present in the scalp distribution of alpha-band power increases as the task demands a higher degree of spatial specificity. Altogether, the results offer new insights into how the dynamic adaption of alpha-band oscillations in response to changing task demands is associated with post-stimulus attentional processing.


title: Id4 is required for normal ependymal cell development

abstract: Ependymal cells are radial glia-derived multiciliated cells lining the lateral ventricles of the brain and spinal cord. Correct development and coordinated cilia beating is essential for proper cerebrospinal fluid flow (CSF) and neurogenesis modulation. Dysfunctions of ependymal cells were associated with transcription factor deregulation. Here we provide evidence that the transcriptional regulator Id4 is involved in ependymal cell development and maturation. We observed that Id4-deficient mice display altered ependymal cytoarchitecture, decreased ependymal cell number, altered CSF flow and enlarged ventricles. Our findings open the way for a potential role of Id4 in ependymal cell development and/or motor cilia function.

category: developmental biology


title: Synaptotagmin-like protein 2a regulates lumen formation via Weibel-Palade body apical secretion of angiopoietin-2 during angiogenesis

abstract:
ObjectiveVascular lumen formation requires the redistribution of intracellular proteins to instruct apico-basal polarity, thereby enforcing maturation of both luminal and basal domains. In the absence of proper apical signaling, lumen formation can be distorted leading to lumen collapse and cessation of blood flow. Synaptotagmin-like protein-2a (Slp2a) has been implicated in apical membrane signaling; however, the role of Slp2a in vascular lumen formation has never been assessed.

Approach and ResultsOur results demonstrate that Slp2a is required for vascular lumen formation. Using a 3- dimensional sprouting assay, sub-cellular imaging, and zebrafish blood vessel development we establish that Slp2a resides at the apical membrane acting as a tether for Rab27a that decorates Weibel-Palade bodies (WPBs). Unique to endothelial tissue, we show that Slp2a regulates exocytic activity of WPBs, thus regulating release of WPB contents into the luminal space during angiogenesis. Angiopoietin-2 is a Tie-2 receptor ligand that is selectively released from WPB secretory granules. We identify a critical role for angiopoietin-2 in regulating endothelial lumenization and show that in the absence of Slp2a, WPB contents cannot fuse with the apical membrane. This disrupts the release of angiopoietin-2 and blocks Tie-2 signaling necessary for proper lumen formation.

ConclusionsOur results demonstrate a novel requirement of Slp2a for vascular lumen formation. Moreover, we show that Slp2a is required for the exocytic release of WPB secretory granule cargo during vascular lumen development, and thus is a core upstream component of the WPB secretory pathway. Furthermore, we provide evidence that WPB-housed angiopoietin-2 is required for vascular lumen formation.

HIGHLIGHTSO_LISynaptotagmin-like protein-2a (Slp2a) is required for vascular lumen formation via its interaction with Rab27a and Weibel Palade Body secretory granules.
C_LIO_LISlp2a is recruited to the apical membrane where it regulates secretion of Weibel Palade Body components into the luminal space.
C_LIO_LIIn the absence of Slp2a, Weibel Palade Body-housed angiopoietin-2 ligand cannot be exocytosed, this impedes activation of Tie-2 signaling required for lumen biogenesis.
C_LIO_LIKnockout of Slp2a or Tie-2 in zebrafish blunts the formation of vascular lumens during angiogenic development.
C_LI


title: The Metabesity Factor HMG20A Potentiates Astrocyte Survival and Reactivity Preserving Neuronal Integrity

abstract:
RationaleWe recently demonstrated that the  Metabesity factor HMG20A regulates islet beta-cell functional maturity and adaptation to physiological stress such as pregnancy and pre-diabetes. HMG20A also dictates central nervous system (CNS) development via inhibition of the LSD1/CoREST complex but its expression pattern and function in adult brain remains unknown. Herein we sought to determine whether HMG20A is expressed in the adult CNS, specifically in hypothalamic astrocytes that are key in glucose homeostasis and whether similar to islets, HMG20A potentiates astrocyte function in response to environmental cues.

MethodsHMG20A expression profile was assessed by quantitative PCR (RT-PCR) and/or immunofluorescence in: 1) the hypothalamus of mice exposed or not to a high-fat diet, 2) human blood leukocytes and adipose tissue obtained from healthy or diabetic individuals 3) primary mouse hypothalamic astrocytes exposed to either high glucose or palmitate. To investigate the function and regulatory mechanism of HMG20A, RNA-seq and cell metabolic parameters were performed on astrocytes treated or not with a siHMG20A. The regulatory function of HMG20A on astrogliosis was also assessed pharmacologically using ORY1001. Astrocyte-mediated neuronal survival was evaluated using conditioned media from siHMG20A-treated astrocytes.

ResultsWe show that Hmg20a is predominantly expressed in hypothalamic astrocytes, the main nutrient-sensing cell type of the brain. Hmg20A expression was upregulated in diet-induced obesity and glucose intolerant mice, correlating with increased transcript levels of Gfap and Il1b indicative of inflammation and astrogliosis. Expression levels were also increased in adipose tissue of obese non-diabetic individuals as compared to obese diabetic patients. HMG20A silencing in astrocytes resulted in repression of inflammatory, cholesterol biogenesis and epithelial-to-mesenchymal transition pathways with a concomitant increase in apoptosis and reduced mitochondrial bioenergetics. Motoneuron viability was also hindered in HMG20A-depleted astrocyte-derived conditioned media. Astrogliosis was induced using ORY1001, a pharmacological inhibitor of the LSD1/CoREST complex, mimicking the effect of HMG20A.

ConclusionHMG20A coordinates the astrocyte polarization state. Under physiological pressure such as obesity and insulin resistance that induces low grade inflammation, HMG20A expression is increased to induce astrogliosis in an attempt to preserve the neuronal network and glucose homeostasis. Nonetheless, a chronic metabesity state or functional mutations will result in lower levels of HMG20A, failure to promote astrogliosis and increase susceptibility of neurons to stress-mediated apoptosis. Such effects could be therapeutically reversed by ORY1001-induced astrogliosis.


title: Neurological mechanism of sensory deficits after developmental exposure to non-dioxin-like polychlorinated biphenyls (PCBs)

abstract: The most abundant polychlorinated biphenyl (PCB) congeners found in the environment and in humans are neurotoxic. This is of particular concern for early life stages because the exposure of the more vulnerable developing nervous system to chemicals can result in neurobehavioral disorders. To uncover currently unknown links between PCB target mechanisms and neurobehavioral deficits, we investigated the effects of the non-dioxin-like (NDL) congener PCB153 on neuronal morphology and synaptic transmission linked to the proper execution of a sensorimotor response using zebrafish as a vertebrate model. Zebrafish that were exposed during development to concentrations similar to those found in human cord blood and PCB contaminated sites showed a delay in startle response. A similar delay was observed for other NDL congeners but not for the potent dioxin-like congener PCB126. Morphological and biochemical data demonstrate that while exposure to PCB153 induced swelling of afferent sensory neurons, the disruption of dopaminergic and GABAergic signaling is the dominant mechanism associated with motor movement. The effects on important and broadly conserved signaling mechanisms in vertebrates suggest that NDL PCBs may contribute to neurodevelopmental abnormalities in humans and, with the startle response being critical for the survival of fish, to evolutionary adaptation in wildlife.


title: Neurological mechanism of sensory deficits after developmental exposure to non-dioxin-like polychlorinated biphenyls (PCBs) in zebrafish larvae


title: The genome of the CTG(Ser1) yeast  Scheffersomyces stipitis  is plastic

abstract: Microorganisms need to adapt to environmental changes, and genome plasticity can lead to rapid adaptation to hostile environments by increasing genetic diversity. Here, we investigate genome plasticity in the CTG(Ser1) yeast Scheffersomyces stipitis, an organism with an enormous potential for second-generation biofuel production. We demonstrate that S. stipitis has an intrinsically plastic genome and that different S. stipitis isolates have genomes with distinct chromosome organisation. Real-time evolution experiments show that S. stipitis genome plasticity is common and rapid as extensive genomic changes with fitness benefits are detected following in vitro evolution experiments. Hybrid MinION Nanopore and Illumina genome sequencing identifies retrotransposons as major drivers of genome diversity. Indeed, the number and position of retrotransposons is different in different S. stipitis isolates, and retrotransposon-rich regions of the genome are sites of chromosome rearrangements. Our findings provide important insights into the adaptation strategies of the CTG (Ser1) yeast clade and have critical implications in the development of second-generation biofuels. These data highlight that genome plasticity is an essential factor to be considered for the development of sustainable S. stipitis platforms for second-generation biofuels production.


title: Magnetically stimulated cryogels to enhance osteogenic and chondrogenic differentiaton of stem cells

abstract:
Cells can respond to the physical stimulus that comes from their micro-environments. There are several strategies to alter cell behavior. Several tissues like bone and cartilage, which are the point of interest of regenerative medicine, are under significant degrees of mechanical stress in real life. Within this stress, the arising mechanotransduction effect may trigger several behavioral responses on cells. As a novel and efficient way, magnetic nanoparticles can be used to make such a mechanotransductive effect on cells.

In this study, pre-functionalized Fe3O4 superparamagnetic magnetite nanoparticles were synthesized and used to fabricate gelatin-based magnetic cryogels. Cell growth, tissue-specific metabolic activities, differentiation potential to the bone, and cartilage under static magnetic field at different magnetic field strength (1000-4000G) were investigated. Results indicated that there was a better induction in considerable higher magnetic field among all others and magnetic cryogels helps to mediate mesenchymal stem cell behaviour, promote their growth and induce osteogenic and chondrogenic differentiation.


title: Nets-within-nets for modeling emergent patterns in ontogeneticprocesses

abstract:
Ontogenesis is the development of an organism from its earliest stage to maturity, including homeostasis maintenance throughout adulthood despite environmental perturbations. Almost all cells of a multicellular organism share the same genomic information. Nevertheless, phenotypic diversity and complex supra-cellular architectures emerge at every level, starting from tissues and organs. This is possible thanks to a robust and dynamic interplay of regulative mechanisms.

To study ontogenesis, it is necessary to consider different levels of regulation, both genetic and epigenetic. Each cell undergoes a specific path across a landscape of possible regulative states affecting both its structure and its functions during development. This paper proposes using the Nets-Within-Nets formalism, which combines Petri Nets simplicity with the capability to represent and simulate the interplay between different layers of regulation connected by non-trivial and context-dependent hierarchical relations.

In particular, this work introduces a modeling strategy based on Nets-Within-Nets that can model several critical processes involved in ontogenesis. Moreover, it presents a case study focusing on the first phase of Vulval Precursor Cells specification in C. Elegans. The case study shows that the proposed model can simulate the emergent morphogenetic pattern corresponding to the observed developmental outcome of that phase, in both the physiological case and different mutations. The model presented in the results section is available online at https://github.com/sysbio-polito/NWN_CElegans_VPC_model/


title: Decoupling alignment strategy from feature quantification using a standard alignment incidence data structure

abstract:
SummaryThe abundance of genomic feature such as gene expression is often estimated from observed total number of alignment incidences in the targeted genome regions. We introduce a generic data structure and associated file format for alignment incidence data so that method developers can create novel pipelines comprising models, each optimal for read alignment, post-alignment QC, and quantification across multiple sequencing modalities.

Availability and Implementationalntools software is freely available at https://github.com/churchill-lab/alntools under MIT license.

Contactkb.choi@jax.org or gary.churchill@jax.org


title: Virus relatedness predicts susceptibility in novel host species

abstract:
Virus host shifts are a major source of outbreaks and emerging infectious diseases, and predicting the outcome of novel host and virus interactions remains a key challenge for virus research. The evolutionary relationships between host species can explain variation in transmission rates, virulence, and virus community composition between hosts, but the potential for different viruses to interact with host species effects has yet to be established. Here, we measure correlations in viral load of four Cripavirus isolates across experimental infections of 45 Drosophilidae host species. We find positive correlations between every pair of viruses tested, suggesting that broadly susceptible host clades could act as reservoirs and donors for certain types of viruses. Additionally, we find evidence of genotype-by-genotype interactions between viruses and host species, highlighting the importance of both host and virus traits in determining the outcome of virus host shifts. More closely related viruses tended to be more strongly correlated, providing tentative evidence that virus evolutionary relatedness may be a useful proxy for determining the likelihood of novel virus emergence, which warrants further research.

Impact SummaryMany new infectious diseases are caused by viruses jumping into novel host species. Estimating the probability that jumps will occur, what the characteristics of new viruses will be, and how they are likely to evolve after jumping to new host species are major challenges. To solve these challenges, we require a detailed understanding of the interactions between different viruses and hosts, or metrics that can capture some of the variation in these interactions. Previous studies have shown that the evolutionary relationships between host species can be used to predict traits of infections in different hosts, including transmission rates and the damage caused by infection. However, the potential for different viruses to influence the patterns of these host species effects has yet to be determined. Here, we use four viruses of insects in experimental infections across 45 different fruit fly host species to begin to answer this question. We find similarities in the patterns of replication and persistence between all four viruses, suggesting susceptible groups of related hosts could act as reservoirs and donors for certain types of virus. However, we also find evidence that different virus genotypes interact in different ways with some host species. Viruses that were more closely related tended to behave in similar ways, and so we suggest that virus evolutionary relatedness may prove to be a useful metric for predicting the traits of novel infections and should be explored further in future studies.

category: evolutionary biology


title: Between virus correlations in the outcome of infection across host species: evidence of virus genotype by host species interactions


title: Shared long-term and short-term memory representational formats in occipital and parietal cortex

abstract: Current theories propose that the short-term retention of information in working memory (WM) and the recall of information from long-term memory (LTM) are supported by overlapping neural mechanisms in occipital and parietal cortex. Both are thought to rely on reinstating patterns of sensory activity evoked by the perception of the remembered item. However, the extent of the shared representations between WM and LTM are unclear, and it is unknown how WM and LTM representations may differ across cortical regions. We designed a spatial memory task that allowed us to directly compare the representations of remembered spatial information in WM and LTM. Critically, we carefully matched the precision of behavioral responses in these tasks. We used fMRI and multivariate pattern analyses to examine representations in (1) retinotopic cortex and (2) lateral parietal cortex (LPC) regions previously implicated in LTM. We show that visual memories were represented in a sensory-like code in both tasks across retinotopic regions in occipital and parietal cortex. LPC regions also encoded remembered locations in both WM and LTM, but in a format that differed from the sensory-evoked activity. These results suggest a striking correspondence in the format of WM and LTM representations across occipital and parietal cortex. On the other hand, we show that activity patterns in nearly all parietal regions, but not occipital regions, contained information that could discriminate between WM trials and LTM trials. Our data provide new evidence for theories of memory systems and the representation of mnemonic content.


title: Human cytomegalovirus blocks canonical TGFβ signaling during lytic infection to limit induction of type I interferons

abstract:
Human cytomegalovirus (HCMV) microRNAs (miRNAs) significantly rewire host signaling pathways to support the viral lifecycle and regulate host cell responses. Here we show that SMAD3 expression is regulated by HCMV miR-UL22A and contributes to the IRF7-mediated induction of type I IFNs and IFN-stimulated genes (ISGs) in human fibroblasts. Addition of exogenous TGF{beta} interferes with the replication of a miR-UL22A mutant virus in a SMAD3-dependent manner in wild type fibroblasts, but not in cells lacking IRF7, indicating that downregulation of SMAD3 expression to limit IFN induction is important for efficient lytic replication. These findings uncover a novel interplay between SMAD3 and innate immunity during HCMV infection and highlight the role of viral miRNAs in modulating these responses.

Author SummaryCells trigger the interferon (IFN) response to induce the expression of cellular genes that limit virus replication. In turn, viruses have evolved numerous countermeasures to avoid the effects of IFN signaling. Using a microRNA (miRNA) mutant virus we have uncovered a novel means of regulating the IFN response during human cytomegalovirus (HCMV) infection. Lytic HCMV infection induces the production of TGF{beta}, which binds to the TGF{beta} receptor and activates the receptor-associated SMAD SMAD3. SMAD3, together with IRF7, induces the expression of IFN{beta} and downstream IFN-stimulated genes in human fibroblasts. To counteract this, HCMV miR-UL22A, along with other HCMV gene products, directly targets SMAD3 for downregulation. Infection of fibroblasts with a miR-UL22A mutant virus results in enhanced type I IFN production in a SMAD3-dependent manner and the virus is impaired for growth in the presence of TGF{beta}, but only when both SMAD3 and IRF7 are present, highlighting the unique interaction between TGF{beta} and innate immune signaling.


title: Complex Activity and Short-term Memories in Reciprocally Connected Cerebral Organoids

abstract: Macroscopic axonal connections in the human brain distribute information and neuronal activity across the brain. Although brain organoid technologies have recently provided novel avenues to investigate human brain function by replicating small neuronal networks of the brain in vitro, functionality of the macroscopic connections between distant regions has not been investigated with organoids. Here, we describe the neural activity of human cerebral organoids reciprocally connected by a bundle of axons. The connected organoids produced significantly more intense and complex oscillatory activity than conventional cerebral organoids. Optogenetic manipulations revealed that the connected organoids could respond to external stimuli and maintain the elevated frequency of neuronal activity for a short term, indicating that the connected organoids exhibit plasticity as a neuronal network. Our findings highlight functional importance of inter-regional connections and suggest that connected organoids can be used as a powerful tool for investigating the development and functions of macroscopic circuits in the human brain. can allow researchers to develop and test compounds to modulate activity of in vitro neuronal network models in unprecedented ways.


title: Advanced Complexity and Plasticity of Neural Activity in Reciprocally Connected Human Cerebral Organoids


title: Demands of visual processing hierarchy shape laminar compartmentalization of attention modulation of luminance contrast in area V4

abstract: Contrast is a key feature of the visual scene that aids object recognition. Attention has been shown to selectively enhance the responses to low contrast stimuli in visual area V4, a critical hub that sends projections both up and down the visual hierarchy. Veridical encoding of contrast information is a key computation in early visual areas, while later stages encode higher level features that benefit from improved sensitivity to low contrast. How area V4 meets these distinct information processing demands in the attentive state is not known. We found that attentional modulation of contrast responses in area V4 is cortical layer and cell-class specific. Putative excitatory neurons in the superficial output layers that project to higher areas show enhanced boosting of low contrast information. On the other hand, putative excitatory neurons of deep output layers that project to early visual areas exhibit contrast-independent scaling. Computational modeling revealed that such layer-wise differences may result from variations in spatial integration extent of inhibitory neurons. These findings reveal that the nature of interactions between attention and contrast in V4 is highly compartmentalized, in alignment with the demands of the visual processing hierarchy.


title: Laminar compartmentalization of attention modulation in area V4 aligns with the demands of visual processing hierarchy in the cortex


title: Osmolarity-regulated swelling initiates egg activation in Drosophila

abstract:
Egg activation is a series of highly coordinated processes that prepare the mature oocyte for embryogenesis. Typically associated with fertilisation, egg activation results in many downstream outcomes, including the resumption of the meiotic cell cycle, translation of maternal mRNAs and cross-linking of the vitelline membrane. While some aspects of egg activation, such as initiation factors in mammals and environmental cues in sea animals, have been well-documented, the mechanics of egg activation in insects are less well understood. For many insects, egg activation can be triggered independently of fertilisation. In Drosophila melanogaster, egg activation occurs in the oviduct resulting in a single calcium wave propagating from the posterior pole of the oocyte.

Here we use physical manipulations, genetics and live imaging to demonstrate the requirement of a volume increase for calcium entry at egg activation in mature Drosophila oocytes. The addition of water, modified with sucrose to a specific osmolarity, is sufficient to trigger the calcium wave in the mature oocyte and the downstream events associated with egg activation. We show that the swelling process is regulated by the conserved osmoregulatory channels, aquaporins (AQPs) and DEGenerin/Epithelial Na+ (DEG/ENaC) channels. Furthermore, through pharmacological and genetic disruption, we reveal a concentration-dependent requirement of Trpm channels to transport calcium, most likely from the perivitelline space, across the plasma membrane into the mature oocyte.

Our data establishes osmotic pressure as the mechanism that initiates egg activation in Drosophila and is consistent with previous work from evolutionarily distant insects, including dragonflies and mosquitos, and shows remarkable similarities to the mechanism of egg activation in some plants.


title: The role of Dectin-1 signaling in altering tumor immune microenvironment in the context of aging

abstract: An increased accumulation of immune-dysfunction-associated CD4+Foxp3+ regulatory T cells (Tregs) is observed in aging oral mucosa during infection. Here we studied the function of Tregs during oral cancer development in aging mucosa. First, we found heightened proportions of Tregs and myeloid-derived suppressor cells (MDSC) accumulating in mouse and human oral squamous cell carcinoma (OSCC) tissues. Using the mouse 4-Nitroquinoline 1-oxide(4-NQO) oral carcinogenesis model, we found that tongues of aged mice displayed increased propensity for epithelial cell dysplasia, hyperplasia, and accelerated OSCC development, which coincided with significantly increased abundance of IL-1{beta}, Tregs, and MDSC in tongues. Partial depletion of Tregs reduced tumor burden. Moreover, fungal abundance and dectin-1 signaling were elevated in aged mice suggesting a potential role for dectin-1 in modulating immune environment and tumor development. Confirming this tenet, dectin-1 deficient mice showed diminished IL-1{beta}, reduced infiltration of Tregs and MDSC in the tongues, as well as slower progression and reduced severity of tumor burden. Taken together, these data identify an important role of dectin-1 signaling in establishing the intra-tumoral immunosuppressive milieu and promoting OSCC tumorigenesis in the context of aging.

category: immunology


title: Neural entrainment facilitates duplets: Frequency-tagging differentiates musicians and non-musicians when they tap to the beat

abstract:
Motor coordination to an isochronous beat improves when it is subdivided into equal intervals. Here, we study if this subdivision benefit (i) varies with the kind of subdivision, (ii) is enhanced in individuals with formal musical training, and (iii), is an inherent property of neural oscillations. We recorded electroencephalograms of musicians and non-musicians during: (a) listening to an isochronous beat, (b) listening to one of 4 different subdivisions, (c) listening to the beat again, and (d) listening and tapping the beat with the same subdivisions as in (b). We found that tapping consistency and neural entrainment in condition (d) was enhanced in non-musicians for duplets (1:2) compared to the other types of subdivisions. Musicians showed overall better tapping performance and were equally good at tapping together with duplets, triplets (1:3) and quadruplets (1:4), but not with quintuplets (1:5). This group difference was reflected in enhanced neural responses in the triplet and quadruplet conditions. Importantly, for all participants, the neural entrainment to the beat and its first harmonic (i.e. the duplet frequency) increased after listening to each of the subdivisions (c compared to a). Since these subdivisions are harmonics of the beat frequency, the observed preference of the brain to enhance the simplest subdivision level (duplets) may be an inherent property of neural oscillations. In sum, a tapping advantage for simple binary subdivisions is reflected in neural oscillations to harmonics of the beat, and formal training in music can enhance it.

Highlights- The neural entrainment to periodic sounds only differs between musicians and non-musicians when they perform a predictive sensorimotor synchronization task.
- After listening to a subdivided beat, the frequencies related to the beat and its first harmonic are enhanced in the EEG, likely stabilizing the perception of the beat.
- There is a natural advantage for binary structures in sensorimotor synchronization, observed in the tapping of duplets by non-musicians, which can be extended to other subdivisions after extensive musical training.


title: HLA binding of self-peptides is biased towards proteins with specific molecular functions

abstract: Human leukocyte antigen (HLA) is highly polymorphic and plays a key role in guiding adaptive immune responses by presenting foreign and self peptides to T cells. Each HLA variant selects a minor fraction of peptides that match a certain motif required for optimal interaction with the peptide-binding groove. These restriction rules define the landscape of peptides presented to T cells. Given these limitations, one might suggest that the choice of peptides presented by HLA is non-random and there is preferential presentation of an array of peptides that is optimal for distinguishing self and foreign proteins. In this study we explore these preferences with a comparative analysis of self peptides enriched and depleted in HLA ligands. We show that HLAs exhibit preferences towards presenting peptides from certain proteins while disfavoring others with specific functions, and highlight differences between various HLA genes and alleles in those preferences. We link those differences to HLA anchor residue propensities and amino acid composition of preferentially presented proteins. The set of proteins that peptides presented by a given HLA are most likely to be derived from can be used to distinguish between class I and class II HLAs and HLA alleles. Our observations can be extrapolated to explain the protective effect of certain HLA alleles in infectious diseases, and we hypothesize that they can also explain susceptibility to certain autoimmune diseases and cancers. We demonstrate that these differences lead to differential presentation of HIV, influenza virus, SARS-CoV-1 and SARS-CoV-2 proteins by various HLA alleles. Finally, we show that the reported self peptidome preferences of distinct HLA variants can be compensated by combinations of HLA-A/HLA-B and HLA-A/HLA-C alleles in frequent haplotypes.

category: bioinformatics