Shorter effective lifespan in laboratory populations of D. melanogaster can reduce sexual selection. The role of sexual selection in mediating levels of sexual conflict has been demonstrated in many experimental evolution studies on Drosophila spp. where competition among males for mating was the target of selection. Sexual selection has also been shown to affect the evolution of life-histories. However, the influence of divergent life-histories on reproductive strategies and, therefore, sexual selection and possibly sexual conflict, has been less well studied. We examined D. melanogaster populations selected for a short development time and early age at reproduction for changes in reproductive behaviour and traits that are proxies of sexual selection. We report a large reduction in reproductive competition experienced by the males of these populations, compared to ancestral populations that are not consciously selected for rapid development or early reproduction, potentially leading to reduced sexual selection. We show that rapidly developing and early reproducing populations have very low levels of mating in their lifetime (females are more or less monandrous), low courtship levels, shorter copulation duration, and longer time from eclosion to first mating, compared to the controls. These results are discussed in the context of the previously demonstrated reduction of inter-locus sexual conflict in these populations. We show that life-history strategies might have a large and significant impact on sexual selection, with each influencing the other and contributing to the complexities of adaptation.

Significance statementSexual conflict, often manifested as an arms-race between males and females trying to enhance their own reproductive success at some cost to the other, is of great evolutionary interest because it can maintain genetic variation in populations, prevent the independent optimization of male and female traits, and also promote speciation. Sexual selection, or variation in mating success, is well known to affect levels of sexual conflict. However, it is not so clear whether, and how, the regular evolution of life-histories also affects sexual selection. Here, we show that life-history evolution in fruit fly populations selected for traits not directly related to sexual conflict might, nevertheless, mediate the possible evolution of altered sexual conflict levels through effects on sexual selection. Populations that evolved to develop to adulthood fast, and reproduce relatively early in life, are shown to potentially experience less sexual selection, which can explain the low sexual conflict levels earlier observed in them.
Host phenology can drive the evolution of intermediate virulence strategies in some parasites AO_SCPLOWBSTRACTC_SCPLOWThe traditional mechanistic trade-offs resulting in a negative correlation between transmission and virulence are the foundation of nearly all current theory on the evolution of parasite virulence. Several ecological factors have been shown to modulate the optimal virulence strategies predicted from mechanistic trade-off models, but these ecological factors have not yet been shown to be sufficient to explain the intermediate virulence strategies observed in any natural system. The timing of seasonal activity, or phenology, is a common factor that influences the types and impact of many ecological interactions but is difficult to incorporate into virulence evolution studies. We develop a mathematical model of a disease system with seasonal host activity to study the evolutionary consequences of host phenology on the virulence of obligate-killer parasite. Results from this model demonstrated that seasonal host activity is sufficient to drive the evolution of intermediate parasite virulence in some types of natural disease systems, even when a traditional mechanistic trade-off between transmission and virulence is not assumed in the modeling framework. The optimal virulence strategy in these systems can be determined by both the duration of the host activity period as well as the variation in the host emergence timing. Parasites with low virulence strategies are favored in environments with long host activity periods and in environments in which hosts emerge synchronously. The results demonstrate that host phenology can be sufficient to select for intermediate optimal virulence strategies, providing an alternative mechanism to account for virulence evolution in some natural systems.
Antibody ligation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), CEACAM3, and CEACAM6, differentially enhance the cytokine release of human neutrophils in responses to Candida albicans Invasive candidiasis, often caused by Candida albicans, is an important healthcare-associated fungal infection that results in a high mortality rate of up to 40%. Neutrophils are the first line of defense during Candida infections. They can initiate various killing mechanisms and release cytokines to attract further immune cells to the site of infection. These responses are tightly controlled, since they can also lead to severe tissue/organ damage. We hypothesized that the regulation of C. albicans-specific neutrophil functions by the immunoregulatory C. albicans receptors CEACAM1, CEACAM3, and CEACAM6 are involved in the immune pathology of candidemia. Here, we analyzed the effects of the specific antibodies B3-17, 308/3-3, and 1H7-4B, respectively, targeting the three CEACAM receptors on C. albicans-induced neutrophil responses. We show that ligation of CEACAM6 significantly enhanced the response to C. albicans, as evidenced by the increased CXCL8/IL-8 secretion. By assessing the transcriptional responses, we found that CEACAM6 ligation and to some extent CEACAM1 ligation, but not CEACAM3 ligation, resulted in altered gene regulation of the C. albicans-stimulated neutrophils. Genes that were differentially regulated by the different CEACAM-targeting antibodies were analyzed for affected cellular processes and signaling pathways using various bioinformatics methods, including integrated network analyses and dynamic simulations of signaling cascades. Predicted changes in cellular pathways and cellular functions included CEACAM-specific alterations in apoptosis and cytokine secretion. In particular, we verified predicted changes in IL-1{beta}/IL-6 expression in response to the antibody ligation of all three targeted CEACAMs and apoptosis induction by anti-CEACAM6 antibody treatment in presence of C. albicans stimulation. Specifically, CEACAM6 ligation by 1H7-4B enhanced neutrophil apoptosis and increased immediate and long-term cytokine release in responses to C. albicans. CEACAM1 ligation by B3-17 mainly enhanced the immediate secretion of pro-inflammatory cytokines, and CEACAM3 ligation by 308/3-3 increased the long-term release of pro-inflammatory cytokines. Taken together, we demonstrated for the first time that CEACAM receptors have an important and differential impact on the regulation of C. albicans-induced immune functions in human neutrophils. TeamTree analysis: a new approach to evaluate scientific production Advances in science and technology depend on the work of research teams and the publication of results through peer-reviewed articles representing a growing socio-economic resource. Current methods to mine the scientific literature regarding a field of interest focus on content, but the workforce credited by authorship remains largely unexplored, and appropriate measures of scientific production are debated. Here, a new bibliometric approach named TeamTree analysis is introduced that visualizes the development and composition of the workforce driving a field. A new citation-independent measure that scales with the H index estimates impact based on publication record, genealogical ties and collaborative connections. This author-centered approach complements existing tools to mine the scientific literature and to evaluate research across disciplines. Development and Characterization of PAR-Trackers: New Tools for Detecting Poly(ADP-ribose) In Vitro and In Vivo AO_SCPLOWBSTRACTC_SCPLOWADP-ribosylation (ADPRylation) is a reversible post-translation modification resulting in the covalent attachment of ADP-ribose (ADPR) moieties on substrate proteins. Naturally-occurring protein motifs and domains, including WWEs, PBZs, and macrodomains, act as "readers" for protein-linked ADPR. Although recombinant, antibody-like ADPR detection reagents containing these readers have facilitated the detection of ADPR, they are limited in their ability to capture the dynamic nature of ADPRylation. Herein, we describe and characterize a set of poly(ADP-ribose) (PAR) Trackers (PAR-Ts) - optimized dimerization-dependent or split-protein reassembly PAR sensors in which a naturally occurring PAR binding domain, WWE, was fused to both halves of dimerization-dependent GFP (ddGFP) or split Nano Luciferase (NanoLuc), respectively. We demonstrate that these new tools allow the detection and quantification of PAR levels in extracts, living cells, and living tissues with greater sensitivity, as well as temporal and spatial precision. Importantly, these sensors detect changes in cellular ADPR levels in response to physiological cues (e.g., hormone-dependent induction of adipogenesis without DNA damage), as well as xenograft tumor tissues in living mice. Our results indicate that PAR Trackers have broad utility for detecting ADPR in many different experimental and biological systems. Multiplex knockout of trichome-regulating MYB duplicates in hybrid poplar using a single gRNA As the focus for CRISPR edited plants moves from proof-of-concept to real world applications, precise gene manipulation will increasingly require concurrent multiplex editing for polygenic traits. A common approach for editing across multiple sites is to design one gRNA per target; however, this complicates construct assembly and increases the possibility of off-target mutations. In this study, we utilized one gRNA to target MYB186, a known positive trichome regulator, as well as its paralogs MYB138 and MYB38 at a consensus site for mutagenesis in Populus tremula x P. alba INRA 717-1B4. Unexpected duplications of MYB186 and MYB138 resulted in a total of eight alleles for the three targeted genes in the hybrid poplar. Deep sequencing and PCR analyses confirmed editing across all eight targets in nearly all of the resultant glabrous mutants, ranging from small indels to large genomic dropouts, with no off-target activity detected at four potential sites. This highlights the effectiveness of a single gRNA targeting conserved exonic regions for multiplex editing. Additionally, cuticular wax and whole leaf analyses showed a complete absence of triterpenes in the trichomeless mutants, hinting at a previously undescribed role for the non-glandular trichomes of poplar.

ONE SENTENCE SUMMARYTargeting conserved sequences with a single gRNA allowed efficient mutagenesis of a multigene family and the recovery of trichomeless and triterpene-free poplar mutants. Individual variations in Brain age relate to early life factors more than to longitudinal brain change Brain age is a widely used index for quantifying individuals brain health as deviation from a normative brain aging trajectory. Higher than expected brain age is thought partially to reflect above-average rate of brain aging. We explicitly tested this assumption in two large datasets and found no association between cross-sectional brain age and steeper brain decline measured longitudinally. Rather, brain age in adulthood was associated with early-life influences indexed by birth weight and polygenic scores. The results call for nuanced interpretations of cross-sectional indices of the aging brain and question their validity as markers of ongoing within-person changes of the aging brain. Longitudinal imaging data should be preferred whenever the goal is to understand individual change trajectories of brain and cognition in aging. Diverse stem-chondrichthyan oral structures and evidence for an independently acquired acanthodid dentition The teeth of sharks famously form a series of transversely-organised files with conveyor-belt replacement that are borne directly on the jaw cartilages, in contrast to the dermal plate-borne dentition of bony fishes that undergoes site-specific replacement. A major obstacle in understanding how this system evolved is the poorly understood relationships of the earliest chondrichthyans and the profusion of morphologically and terminologically diverse bones, cartilages, splints and whorls that they possess. Here we use tomographic methods to investigate mandibular structures in several early branching  acanthodian-grade stem-chondrichthyans. We show that the dentigerous jaw bones of disparate genera of ischnacanthids are united by a common construction, being growing bones with non-shedding dentition. Mandibular splints, which support the ventro-lateral edge of the Meckels cartilage in some taxa, are formed from dermal bone and may be an acanthodid synapomorphy. We demonstrate that the teeth of Acanthodopsis are borne directly on the mandibular cartilage and that this taxon is deeply nested within an edentulous radiation, representing an unexpected independent origin of teeth. Many or even all of the range of unusual oral structures may be apomorphic, but they should nonetheless be considered when building hypotheses of tooth and jaw evolution, both in chondrichthyans and more broadly. ChAdOx1 nCoV-19 (AZD1222) protects hamsters against SARS-CoV-2 B.1.351 and B.1.1.7 1 disease We investigated ChAdOx1 nCoV-19 (AZD1222) vaccine efficacy against SARS-CoV-2 variants of concern (VOCs) B.1.1.7 and B.1.351 in Syrian hamsters. We previously showed protection against SARS-CoV-2 disease and pneumonia in hamsters vaccinated with a single dose of ChAdOx1 nCoV-19. Here, we observed a 9.5-fold reduction of virus neutralizing antibody titer in vaccinated hamster sera against B.1.351 compared to B.1.1.7. Vaccinated hamsters challenged with B.1.1.7 or B.1.351 did not lose weight compared to control animals. In contrast to control animals, the lungs of vaccinated animals did not show any gross lesions. Minimal to no viral subgenomic RNA (sgRNA) and no infectious virus was detected in lungs of vaccinated animals. Histopathological evaluation showed extensive pulmonary pathology caused by B.1.1.7 or B.1.351 replication in the control animals, but none in the vaccinated animals. These data demonstrate the effectiveness of the ChAdOx1 nCoV-19 vaccine against clinical disease caused by B.1.1.7 or B.1.351 VOCs. Genome-wide association study suggests an independent genetic basis of zinc and cadmium concentrations in fresh sweet corn kernels Despite being one of the most consumed vegetables in the United States, the elemental profile of sweet corn (Zea mays L.) is limited in its dietary contributions. To address this through genetic improvement, a genome-wide association study was conducted for the concentrations of 15 elements in fresh kernels of a sweet corn association panel. In concordance with mapping results from mature maize kernels, we detected a probable pleiotropic association of zinc and iron concentrations with nicotianamine synthase5 (nas5), which purportedly encodes an enzyme involved in synthesis of the metal chelator nicotianamine. Additionally, a pervasive association signal was identified for cadmium concentration within a recombination suppressed region on chromosome 2. The likely causal gene underlying this signal was heavy metal ATPase3 (hma3), whose counterpart in rice, OsHMA3, mediates vacuolar sequestration of cadmium and zinc in roots, whereby regulating zinc homeostasis and cadmium accumulation in grains. In our association panel, hma3 associated with cadmium but not zinc accumulation in fresh kernels. This finding implies that selection for low cadmium will not affect zinc levels in fresh kernels. Although less resolved association signals were detected for boron, nickel, and calcium, all 15 elements were shown to have moderate predictive abilities via whole-genome prediction. Collectively, these results help enhance our genomics-assisted breeding efforts centered on improving the elemental profile of fresh sweet corn kernels. Co-option of immune effectors by the hormonal signalling system triggering metamorphosis in Drosophila melanogaster Insect metamorphosis is regulated by the production, secretion and degradation of two peripheral hormones: 20-hydroxyecdysone (ecdysone) and juvenile hormone (JH). In addition to their roles in developmental regulation, increasing evidence suggests that these hormones are involved in innate immunity processes, such as phagocytosis and the induction of antimicrobial peptide (AMP) production. AMP regulation includes systemic responses as well as local responses at surface epithelia that contact with the external environment. At pupariation, Drosophila melanogaster increases dramatically the expression of three AMP genes, drosomycin (drs), drosomycin-like 2 (drsl2) and drosomycin-like 5 (drsl5). We show that the systemic action of drs at pupariation is dependent on ecdysone signalling in the fat body and operates via the ecdysone downstream target, Broad-Z4. In parallel, ecdysone also regulates local responses, specifically through the activation of drsl2 expression in the gut. Finally, we confirm the relevance of this ecdysone dependent AMP expression for the control of bacterial persistence by showing that flies lacking drs expression in the fat body have higher bacterial persistence over metamorphosis. Together, our data emphasize the importance of the association between ecdysone signalling and immunity using in vivo studies and establish a new role for ecdysone at pupariation, which impacts developmental success by regulating the immune system in a stage-dependent manner. We speculate that this co-option of immune effectors by the hormonal system may constitute a pre-emptive mechanism to control bacterial numbers in the pupa at the core of metamorphosis evolution. G protein-coupled estrogen receptor activation by Bisphenol-A disrupts protection from apoptosis conferred by estrogen receptors ERα and ERβ in pancreatic beta cells 17{beta}-estradiol protects pancreatic {beta}-cells from apoptosis via the estrogen receptors ER, ER{beta} and GPER. Conversely, the endocrine disruptor Bisphenol-A (BPA), which exerts multiple effects in this cell type via the same estrogen receptors, increased basal apoptosis. The molecular initiated events that trigger these opposite actions have yet to be identified. We demonstrated that combined genetic downregulation and pharmacological blockade of each estrogen receptor increased apoptosis to a different extent. The increase in apoptosis induced by BPA was diminished by the pharmacological blockade or the genetic silencing of GPER, and it was partially reproduced by the GPER agonist G1. BPA and G1-induced apoptosis were abolished upon pharmacological inhibition, silencing of ER and ER{beta}, or in dispersed islet cells from ER{beta} knockout (BERKO) mice. Yet, the ER and ER{beta} agonists, PPT and DPN, respectively, had no effect on beta cell viability. To exert their biological actions, ER and ER{beta} form homodimers and heterodimers. Molecular dynamic simulations together with proximity ligand assay and coimmunoprecipitation experiments indicated that the interaction of BPA with ER and ER{beta} as well as the GPER activation by G1 decreased ER{beta} heterodimers. We propose that ER{beta} heterodimers play an antiapoptotic role in beta cells and that BPA- and G1-induced decrease in ER{beta} heterodimers leads to beta cell apoptosis. Unveiling how different estrogenic chemicals affect the crosstalk among estrogen receptors should help to identify diabetogenic endocrine disruptors.

HighlightsO_LIPharmacological blockade and gene silencing of estrogen receptors ER, ER{beta} and GPER indicate that they are antiapoptotic in basal conditions.
C_LIO_LIGPER activation by G1 and BPA triggered apoptosis via a crosstalk with ER and ER{beta}.
C_LIO_LIBPA interaction with ER and ER{beta} as well as GPER activation decreased ER{beta} heterodimers, which was associated to increased apoptosis.
C_LIO_LIThis pathway represents a novel molecular initiating event underlying the pro-apoptotic effect of BPA
C_LIO_LIThe EndoC-{beta}H1 cell line may be a valid model of human {beta}-cells for identifying diabetogenic pollutants.
C_LI Cryptic fertility costs of viral infection in a model social insect Declining insect populations emphasize the importance of understanding the drivers underlying reductions in insect fitness. Here, we investigated viruses as a threat to social insect reproduction, using honey bees as a model species. We report that in a sample of N = 93 honey bee (Apis mellifera) queens from nine beekeeping operations across a wide geographic range, high levels of natural viral infection are associated with decreased ovary mass. We confirmed this finding in an independent sample of N = 54 queens. Failed (poor quality) queens displayed higher levels of viral infection, reduced sperm viability, smaller ovaries, and altered ovary protein composition compared to healthy queens. We experimentally infected queens with Israeli acute paralysis virus (IAPV) and found that the ovary masses of IAPV-injected queens were significantly smaller than control queens, demonstrating a causal relationship between viral infection and ovary size. Queens injected with IAPV also had significantly lower expression of vitellogenin, the main source of nutrition deposited into developing oocytes, and higher levels of heat-shock proteins (HSPs), which are part of the honey bees antiviral response. This work together shows that viral infections occurring naturally in the field are compromising queen reproductive success. An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay The nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. Previous studies indicate that the extension of a conserved regulatory loop in the UPF1LL helicase core confers a decreased propensity to dissociate from RNA upon ATP hydrolysis relative to the major UPF1 isoform, designated UPF1 SL. Using biochemical and transcriptome-wide approaches, we find that UPF1LL overcomes the protective RNA binding proteins PTBP1 and hnRNP L to preferentially bind and down-regulate long 3UTRs normally shielded from NMD. Unexpectedly, UPF1LL supports induction of NMD on new populations of substrate mRNAs in response to activation of the integrated stress response and impaired translation efficiency. Thus, while canonical NMD is abolished by moderate translational repression, UPF1LL activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress. The compound of baicalein, wogonin, and oroxylin-A inhibiting EMT in A549 cell line via PI3K/AKT-TWIST1-glycolysis pathway Non-small cell lung cancer (NSCLC) is a worldwide disease with high morbidity and mortality, which is most derived from its metastasis. Some researches show that the epithelial-mesenchymal transition (EMT) process promotes lung cancer cells migration and invasion, leading to NSCLC metastasis. Total Flavonoid Aglycones Extract (TFAE) isolated from Scutellaria baicalensis was reported to inhibit tumor growth and induce apoptosis. In this study, we found that baicalein, wogonin, and oroxylin-A were the active compounds of TFAE. After reconstructing with these three compounds (baicalein (65.8%), wogonin (21.2%), and oroxylin-A (13.0%)), the reconstructed TFAE (reTFAE) present inhibitory effect on the EMT process of A549 cells. Then, bioinformatic technology was employed to elucidate the potential pharmacodynamic mechanism network of reTFAE. We identified the relationship between reTFAE and PI3K/Akt signaling pathways, with TWIST1 as the key protein. LY294002, the inhibitor of PI3K/Akt signaling pathway, and knock-down TWIST1 could significantly enhance the efficacy of reTFAE, with increasing expression of epithelial markers and decreasing expression of mesenchymal markers in A549 cells at the same time. Furthermore, stable isotope dimethyl-labeled proteomics technology was conducted to complement the follow-up mechanism that the EMT-inhibition process may be realized through glycolysis pathway. In conclusion, we claim that TWIST1-targeted flavonoids could provide a new strategy to inhibit EMT progress for the treatment of NSCLC. Environment dependent benefits of inter-individual variation in honey bee recruitment Inter-individual differences in behaviour within the members of a social group can affect the groups productivity. In eusocial insects, individual differences amongst workers in a colony play a central role division of labour and task allocation. Extensive empirical and theoretical work has highlighted variation in response thresholds as a proximate mechanism underlying individual behavioural differences and hence division of labour. However, other response parameters, like response probability and intensity, can affect these differences. In this study, we first extended a previously published agent-based model on honey bee foraging to understand the relative importance of response (dance) probability and response (dance) intensity in the task of recruitment. Comparing variation obtained from the simulations with previously published empirical data, we found that response intensity plays a more important role than probability in producing consistent inter-individual differences in recruitment behaviour. We then explored the benefits provided by this individual variation in recruitment behaviour to the colonys collective foraging effort under different environmental conditions. Our results revealed that individual variation leads to a greater energetic yield per forager, but only when food is abundant. Our study highlights the need to consider all response parameters while studying division of labour and adds to the growing body of evidence linking individual variation in behavioural responses to the success of social groups. Gradient-mixing LEGO robots for purifying DNA origami nanostructures of multiple components by rate-zonal centrifugation DNA origami purification is critical in emerging applications of functionalized DNA nanostructures from basic fundamental biophysics, nanorobots to therapeutics. Advances in DNA origami purification have led to the establishment of rate-zonal centrifugation (RZC) as a scalable, high-yield, and contamination-free approach to purifying DNA origami nanostructures. In RZC purification, a linear density gradient is created using viscous agents, such as glycerol and sucrose, to separate molecules based on their mass and shape during high-rpm centrifugation. However, current methods for creating density gradients are typically time-consuming because of their reliance on slow passive diffusion. Here, we built a LEGO gradient mixer to rapidly create a quasi-continuous density gradient with minimal layering of concentrations using simple rotational motion. We found that rotating two layers of different concentrations at an angle can reduce the diffusion time from a few hours to mere minutes. The instrument needed to perform the movement can be constructed from low-cost components, such as Arduino and LEGO Mindstorms pieces, and has comparable efficacy to commercial gradient mixers currently available. Our results demonstrate that the creation of a linear density gradient can be achieved with minimal labor, time, and cost with this machine. With the recent advances in DNA origami production, we anticipate our findings to further improve the viability of scaling up DNA origami purification in grams quantities. Our simple process enables automated large-scale purification of functionalized DNA origami more feasible in resource-constrained settings. Where there's smoke, there's fuel: dynamic vegetation data improve predictions of wildfire hazard in the Great Basin Wildfires are a growing management concern in western US rangelands, where invasive annual grasses have altered fire regimes and contributed to an increased incidence of catastrophic large wildfires. Fire activity in arid, non-forested ecosystems is thought to be largely controlled by interannual variation in fuel amount, which in turn is controlled by antecedent weather. Thus, long-range forecasting of fire activity in rangelands should be feasible given annual estimates of fuel quantity. Using a 32 yr time series of spatial data, we employed machine learning algorithms to predict the relative probability of large (>405 ha) wildfire in the Great Basin based on fine-scale annual and 16-day estimates of cover and production of vegetation functional groups, weather, and multitemporal scale drought indices. We evaluated the predictive utility of these models with a leave-one-year-out cross-validation, building spatial hindcasts of fire probability for each year that we compared against actual footprints of large wildfires. Herbaceous aboveground biomass production, bare ground cover, and long-term drought indices were the most important predictors of burning. Across 32 fire seasons, 88% of the area burned in large wildfires coincided with the upper 3 deciles of predicted fire probabilities. At the scale of the Great Basin, several metrics of fire activity were moderately to strongly correlated with average fire probability, including total area burned in large wildfires, number of large wildfires, and maximum fire size. Our findings show that recent years of exceptional fire activity in the Great Basin were predictable based on antecedent weather-driven growth of fine fuels and reveal a significant increasing trend in fire probability over the last three decades driven by widespread changes in fine fuel characteristics. Identifying Cross-Cancer Similar Patients via a Semi-Supervised Deep Clustering Approach The treatment decisions for a cancer patient are typically based on the patients diagnosed cancer type. With the characterization of cancer tumors at the molecular level, there have been reports of patients being similar despite being diagnosed with different cancer types. Motivated from these observations, we aim at discovering cross-cancer patients, which we define as patients whose tumors are more similar to patient tumors diagnosed with another cancer type. We develop DeepCrossCancer to identify cross-cancer patients that always co-cluster with the other patient from another cancer type. The input to DeepCrossCancer is the transcriptomic profiles of the patient tumors, the age, and sex of the patient. To solve the clustering problem, we use a semi-supervised deep learning-based clustering method in which the clustering task is supervised by cancer type labels and the survival times of the patients. Applying the method to patient data from nine different cancers, we discover 20 cross-cancer patients that consistently co-cluster. By analyzing the predictive genes of the cross-cancer patients and other genomic information available for the patient such as somatic mutations and copy number variations, we identify striking genomic similarities across these patients providing support. The detection of cross-cancer patients opens up possibilities for transferring clinical decisions across patients at a single patient level. The source code is available at github.com/tastanlab/DeepCrossCancer Effects of substrate on shrimp growth, water quality and bacterial community in the biofloc system nursing Penaeus vannamei postlarvae This study aimed to investigate the effects of substrate on water quality, shrimp growth and bacterial community in the biofloc system with a salinity of 5{per thousand}. Two treatments, biofloc system with (sB) or without (nB) addition of elastic solid packing filler (nylon) as substrate, were set up. Penaeus vannamei postlarvae (PL, [~] stage 15) were stocked at a density of 4000 PL m-3 in each treatment with triplicates for a 28-days culture experiment, taking glucose as carbon source (C:N 15:1). Results showed that the survival rate (96.3{+/-}3.6%), FCR (0.76{+/-}0.06) and productivity (1.54{+/-}0.12 kg m-3) in sB treatment were significantly better than those in nB treatment (81.0{+/-}7.1%, 0.98{+/-}0.08 and 1.14{+/-}0.09 kg m-3, P<0.05). All water parameters were in the recommended ranges. Substrate showed significant effect on TAN, TSS, turbidity, biofloc volume, pH and carbonate alkalinity (P < 0.05). Actinobacteria (4.0-22.7%), Bacteroidetes (10.4-33.5%), Firmicutes (0.2-11.2%), Planctomycetes (4.0-14.9%) and Proteobacteria (29.4-59.0%) were the most dominant phyla for both treatments. However, the bacterial community in sB treatment showed to be significantly different from that in nB treatment (Jaccard distance 0.94{+/-}0.01, P=0.001). Substrate showed significant effects on Shannon, Heip, Pielou and Simpson index, as well as relative abundances of Actinobacteria, Bacteroidetes and Planctomycetes (P < 0.05). The results suggested that addition of substrate affected the shrimp growth, water quality and bacterial community in the biofloc system nursing P. vannamei PL with a 5{per thousand} salinity. Innovative GenExpA software for selecting suitable reference genes for reliable normalization of gene expression in melanoma The algorithms commonly used to select the best stable reference gene in RT-qPCR data analysis have their limitations. We showed that simple selection of the reference gene or pair of genes with the lowest stability value from the pool of potential reference genes - a commonly used approach - is not sufficient to accurately and reliably normalize the target gene transcript and can lead to biologically incorrect conclusions. For reliable assessment of changes in a target gene expression level, we propose our innovative GenExpA software, which works in a manner independent of the experimental model and the normalizer used. GenExpA software selects the best reference by combining the NormFinder algorithm with progressive removal of the least stable gene from the candidate genes in a given experimental model and in the set of daughter models assigned to it. The reliability of references is validated based on the consistency of the statistical analyses of normalized target gene expression levels through all models, described by the coherence score (CS). The use of the CS value imparts a new quality to qPCR analysis because it clarifies how low the stability value of reference must be in order for biologically correct conclusions to be drawn. We tested our method on qPCR data for the B4GALT genes family in melanoma, which is characterized by a high mutation rate, and in melanocytes. GenExpA is available at https://github.com/DorotaHojaLukowicz/GenExpA or https://www.sciencemarket.pl/baza-programow-open-source#oferty.

HighlightsGenExpA - next-generation software for normalizer selection and validation

The GenExpA tool defines how low the stability value of the reference should be

The GenExpA tool determines the level of gene expression analysis robustness

The GenExpA tool increases the speed of analysis and reduces cost Rho Kinase regulates neutrophil NET formation that is involved in UVB-induced skin inflammation ObjectiveUltraviolet B (UVB) is an important trigger of skin inflammation and lupus with leukocyte recruitment to inflamed skin. We recently reported the involvement of neutrophil NETosis in UVB-induced skin inflammation, and that NETotic nuclear envelope rupture is driven by PKC-mediated nuclear lamin B disassembly. To address the role of Actin cytoskeleton in NETosis, we investigated the effects of Rho kinase (ROCK) and its downstream actomyosin cytoskeletal networks on PKC nuclear translocation and NET formation, as well as their involvement in UVB-induced skin inflammation.

MethodsWe studied the dynamic changes of ROCK and actomyosin cytoskeletal networks during NETosis induction and their involvement in PKC nuclear translocation. Using mice with hematopoietic-specific ROCK1 deficiency, we investigated the effects of ROCK1 deficiency on NETosis, and its involvement in UVB-induced skin inflammation.

ResultsOur time course studies demonstrated the dynamic changes of actin polymerization and ROCK activation, support the role of actin cytoskeleton in nuclear translocation of cytosolic PKC in early stage of NETosis induction. Inhibition of actin polymerization or key molecules of the ROCK/MLCK/myosin pathway decreased PKC nuclear translocation and NET formation. Genetic deficiency of ROCK1, inhibited NETosis ex vivo and in vivo, decreased extracellular display of NET-associated IL-17A, TNF, IFN{gamma}, and IFN in inflamed skin, which were correlated with the ameliorated skin inflammation in UVB-irradiated mice with hematopoietic-specific ROCK1 deficiency.

ConclusionsROCK regulated NETosis through modulation of PKC nuclear translocation via actomyosin cytoskeletal networks in neutrophils. ROCK1 deficiency ameliorated UVB- induced skin inflammation by attenuation of NETosis and NET-associated cytokines. Embedded 3D printing in self-healing annealable composites for precise patterning of functionally mature human neural constructs Human in vitro models of neural tissue with controllable cellular identity, tunable microenvironment, and defined spatial arrangement are needed to facilitate studies of brain development and disease. Towards this end, embedded printing in jammed microgel supports (i.e., granular gels) holds great promise as it allows precise and programmable patterning of extremely soft and compliant tissue constructs. However, in contrast to the vast material landscape available for bulk hydrogels, granular printing support formulations are restricted to a handful of materials without the ability for facile adjustment of biofunctional properties of the cellular microenvironment. Therefore, there has been a need for novel materials that take advantage of versatile biomimicry of bulk hydrogels while providing high-fidelity support for embedded printing akin to granular gels. To address this need, we present a modular platform for bioengineering of neuronal networks via direct embedded 3D printing of human stem cells inside Self-Healing Annealable Particle-Extracellular matrix (SHAPE) composites. SHAPE composites consist of soft microgels immersed in viscous extracellular-matrix solution to enable precise freeform patterning of human stem cells and consequent generation and long-term maintenance of mature subtype-specific neurons that extend projections within the volume of the annealed support. The developed approach further allows multi-ink deposition, live spatial and temporal monitoring of oxygen levels, as well as creation of vascular channels. Due to its modularity, SHAPE biomanufacturing toolbox not only offers a solution for functional modeling of mechanically sensitive neural constructs, but also has potential to be applied to a wide range of biomaterials with different crosslinking mechanisms to model tissues and diseases where recapitulation of complex architectural features and topological cues is essential. Measuring cystic fibrosis drug responses in organoids derived from 2D differentiated nasal epithelia Cystic Fibrosis (CF) is caused by genetic defects that impair the cystic fibrosis transmembrane conductance regulator (CFTR) channel in airway epithelial cells. These defects may be overcome by specific CFTR modulating drugs, for which the efficacy can be predicted in a personalized manner using 3D nasal-brushing-derived airway organoids in a forskolin-induced swelling assay. Despite of this, previously described application of 3D airway organoids in CFTR function assays have not been fully optimal. In this report we therefore describe an alternative method of culturing nasal brushing-derived airway organoids, which are created from an equally differentiated airway epithelial monolayer of a 2D air-liquid interface culture. In addition, we have defined organoid culture conditions, with the growth factor/cytokine combination neuregulin-1{beta} and interleukine-1{beta}, which enabled consistent detection of CFTR modulator responses in nasal airway organoids cultures from subjects with CF. Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term Divergence followed by Convergence, or DiCo. We found that DiCo was most prevalent among tissue-specific genes and associated with loss of tissue identity, which is confirmed using data from independent mouse and human datasets. Further, using publicly available single-cell transcriptome data, we showed that DiCo could be driven both by alterations in tissue cell type composition and also by cell-autonomous expression changes within particular cell types. Understanding the Spin Crossover Dynamical Effects of the Dioxygen Binding and Activation on HOD Enzyme For the cofactor-free 1-H-3-hydroxy-4-oxoquinaldine-2,4-dioxygenase (HOD), the dioxygen (O2) dependent steps are rate-limiting along with a spin state crossover to the singlet spin state. Here, the primary triplet O2 molecule activation on the 2-methyl-3-hydroxy-4(1H)-quinolone (MHQ) is investigated, and the catalytic role of the intersystem crossing effects is highlighted by directly comparing results from the Born-Oppenheimer dynamics and non-adiabatic surface hopping dynamics. This work confirms non-adiabatic dynamical effects are essential to modulate the O2 activation on the substrate MHQ. The time scale of the equilibration and conversion from triplet to singlet state should be in the range of a few hundreds of femtoseconds. We hope this work provides us a fresh look at the underlying physics of dioxygen activation reactions involving more than one spin state.