Miracle-dz/UniFAR-FTUs huggingface dataset:
An atlas of spider development at single-cell resolution provides new insights into arthropod embryogenesis

Spiders are a diverse order of chelicerates that diverged from other arthropods over 500 million years ago. Research on spider embryogenesis, particular studies using the common house spider Parasteatoda tepidariorum, has made important contributions to understanding the evolution of animal development, including axis formation, segmentation, and patterning. However, we lack knowledge about the cells that build spider embryos, their gene expression profiles and fate. Single-cell transcriptomic analyses have been revolutionary in describing these complex landscapes of cellular genetics in a range of animals. Therefore, we carried out single-cell RNA sequencing of P. tepidariorum embryos at stages 7, 8 and 9, which encompass the establishment and patterning of the body plan, and initial differentiation of many tissues and organs. We identified 20 cell clusters, from 18.5k cells, which were marked by many developmental toolkit genes, as well as a plethora of genes not previously investigated. There were differences in the cell cycle transcriptional signatures, suggestive of different proliferation dynamics, which related to distinctions between endodermal and some mesodermal clusters, compared with ectodermal clusters. We found many Hox genes were markers of cell clusters, and Hox gene ohnologs often were present in different clusters. This provided additional evidence of sub- and/or neo-functionalisation of these important developmental genes after the whole genome duplication in the arachnopulmonate ancestor (spiders, scorpions, and allies). We also examined the spatial expression of marker genes for each cluster to generate a comprehensive cell atlas of these embryonic stages. This revealed new insights into the cellular basis and genetic regulation of head patterning, hematopoiesis, limb development, gut development, and posterior segmentation. This atlas will serve as a platform for future analysis of spider cell specification and fate, and studying the evolution of these processes among animals at cellular resolution.
The role of diets in maternal vaccinations against typhoid toxin

Children are particularly susceptible to typhoid fever caused by the bacterial pathogen Salmonella Typhi. Typhoid fever is prevalent in developing countries where diets can be less well-balanced. Here, using a murine model, we investigated the role of the macronutrient composition of the diet in maternal vaccination efficacies of two subunit vaccines targeting typhoid toxin: ToxoidVac and PltBVac. We found that maternal vaccinations protected all offspring against a lethal-dose typhoid toxin challenge in a balanced, normal diet (ND) condition, but the declined protection in a malnourished diet (MD) condition was observed in the PltBVac group. Despite the comparable antibody titers in both MD and ND mothers, MD offspring had a significantly lower level of typhoid toxin neutralizing antibodies than their ND counterparts. We observed a lower expression of the neonatal Fc receptor on the yolk sac of MD mothers than in ND mothers, agreeing with the observed lower antibody titers in MD offspring. Protein supplementation to MD diets, but not fat supplementation, increased FcRn expression and protected all MD offspring from the toxin challenge. Similarly, providing additional typhoid toxin-neutralizing antibodies to MD offspring was sufficient to protect all MD offspring from the toxin challenge. These results emphasize the significance of balanced/normal diets for a more effective maternal vaccination transfer to their offspring. Author summary Typhoid fever is a life-threatening systemic infectious disease caused by Salmonella Typhi, which is prevalent in developing countries where diets can be less well-balanced. Here, we used mice to study the role of nutrition in maternal vaccination efficacies of two subunit vaccines targeting Salmonella’s typhoid toxin. We found maternal vaccinations protected all offspring from a lethal-dose typhoid toxin challenge in a balanced/normal diet (ND) condition, but the lack of protection in a malnourished diet (MD) condition was observed in the PltBVac group. Our data indicate that the difference in maternal vaccination outcomes between ND and MD offspring was due to the less effective maternal antibody transfer from MD mothers to their offspring. Providing additional proteins to MD mothers or additional toxin-neutralizing antibodies to MD offspring saved all malnourished offspring from a lethal-dose typhoid toxin challenge, highlighting the importance of balanced/normal diets for effective maternal vaccination outcomes.
Beyond winglets: evolutionary scaling of flight-related morphology in stick insects (Phasmatodea)

The first winged insects evolved from a wingless ancestor, but details of the transition to a fully-winged morphology remain unclear. Studying extant pterygotes with partial wings, such as the stick insects (Order Phasmatodea), may help us to understand such a transition. Here, we address how a series of flight-related morphological parameters may correlate with flight evolution by studying different phasmids representing a volancy continuum ranging from miniaturized to full-sized wings. Variation in phasmid wing shape, venation, wing mass and the mass of flight muscle can be described by specific scaling laws referenced to wing length and wing loading. Also, the mass distribution of the body-leg system is conserved in spite of a wide range of variation in body shape. With reduced wing size and increased wing loading, the longitudinal position of the wing-bearing thoracic segments is shifted closer to the insects’ center of body mass. These results demonstrate complex reconfiguration of the flight system during wing morphological transitions in phasmids, with various anatomical features potentially correlated with reduced flight performance attained with partial wings. Although these data represent phasmid-specific features of the flight apparatus and body plan, the associated scaling relationships can provide insight into functionality of intermediate conditions between wingless and fully-winged insects more generally.
Effects of Oxygen Plasma Treatment on Parylene C and Parylene N Membrane Biocompatibility for Tissue Barrier Models

Porous membranes are integral components of in vitro tissue barrier and co-culture models and their interaction with cells and tissues directly affects the performance and credibility of these models. Plasma-treated Parylene C and Parylene N are two biocompatible Parylene variants with perceived potential for use in these models but their biocompatibility and biological interactions at their interface with cells are not well understood. Here, we use a simple approach for benchtop oxygen plasma treatment and investigate the changes in cell spreading and extracellular matrix deposition as well as the changes in material surface properties. Our results support the previous findings on the persistent effects of plasma treatment on Parylene biocompatibility while showing a more pronounced improvement for Parylene C over Parylene N. It is observed that although both increased surface roughness and persistent increases in oxygen species govern the plasma-driven improvement, the changes in oxygen concentration at the interface are the dominant factor. Overall, the results of this study provide a clear picture of potential mechanisms of plasma-induced changes in synthetic polymers which have implications for their use in in vitro model systems and other BioMEMS applications.
Electrophysiological markers of memory consolidation in the human brain when memories are reactivated during sleep

Human accomplishments depend on learning, and effective learning depends on consolidation. Consolidation is the process whereby new memories are gradually stored in an enduring way in the brain so that they can be available when needed. For factual or event knowledge, consolidation is thought to progress during sleep as well as during waking states, and to be mediated by interactions between hippocampal and neocortical networks. However, consolidation is difficult to observe directly, but rather is inferred through behavioral observations. Here, we investigated overnight memory change by measuring electrical activity in and near the hippocampus. Electroencephalographic (EEG) recordings were made in five patients from electrodes implanted to determine whether a surgical treatment could relieve their seizure disorders. One night, while each patient slept in a hospital monitoring room, we recorded electrophysiological responses to 10-20 specific sounds that were presented very quietly, to avoid arousal. Half of the sounds had been associated with objects and their precise spatial locations that patients learned before sleep. After sleep, we found systematic improvements in spatial recall, replicating prior results. We assume that when the sounds were presented during sleep, they reactivated and strengthened corresponding spatial memories. Notably, the sounds also elicited oscillatory intracranial EEG activity, including increases in theta, sigma, and gamma EEG bands. Gamma responses, in particular, were consistently associated with the degree of improvement in spatial memory exhibited after sleep. We thus conclude that this electrophysiological activity in the hippocampus and adjacent medial temporal cortex reflects sleep-based enhancement of memory storage. Significance Statement Sleep contributes to memory consolidation, we presume, because memories are replayed during sleep. Understanding this aspect of consolidation can help with optimizing normal learning in many contexts, and with treating memory disorders and other diseases. Here, we systematically manipulated sleep-based processing using targeted memory reactivation; brief sounds coupled with pre-sleep learning were quietly presented again during sleep, producing (a) recall improvements for specific spatial memories associated with those sounds, and (b) physiological responses in the sleep EEG. Neural activity in the hippocampus and adjacent medial temporal cortex was thus found in association with memory consolidation during sleep. These findings advance understanding of consolidation by linking beneficial memory changes during sleep to both memory reactivation and specific patterns of brain activity.
Metamorphosis of memory circuits in Drosophila reveals a strategy for evolving a larval brain

Insects like Drosophila produce a second brain adapted to the form and behavior of a larva. Neurons for both larval and adult brains are produced by the same stem cells (neuroblasts) but the larva possesses only the earliest born neurons produced from each. To understand how a functional larval brain is made from this reduced set of neurons, we examined the origins and metamorphic fates of the neurons of the larval and adult mushroom body circuits. The adult mushroom body core is built sequentially of γ Kenyon cells, that form a medial lobe, followed by α’β’, and αβ Kenyon cells that form additional medial lobes and two vertical lobes. Extrinsic input (MBINs) and output (MBONs) neurons divide this core into computational compartments. The larval mushroom body contains only γ neurons. Its medial lobe compartments are roughly homologous to those of the adult and same MBONs are used for both. The larval vertical lobe, however, is an analogous “facsimile” that uses a larval-specific branch on the γ neurons to make up for the missing α’β’, and αβ neurons. The extrinsic cells for the facsimile are early-born neurons that trans-differentiate to serve a mushroom body function in the larva and then shift to other brain circuits in the adult. These findings are discussed in the context of the evolution of a larval brain in insects with complete metamorphosis.
Phase variation as a major mechanism of adaptation in Mycobacterium tuberculosis complex

Significance This manuscript is a systematic evaluation of phase variation and its adaptive capacity in M. tuberculosis (Mtb) and includes large-scale computation work across a globally and genetically diverse sample of 31,428 sequenced Mtb, and experimental validation of putative adaptive phase variants. We focus on phase variation in the homopolymer tracts (HT) in Mtb in which site-specific mispairing can lead to rapid changes in both regulatory and coding regions. We estimate the in-vitro frameshift rate in a neutral HT at 100× the neutral substitution rate and find that phase variation, previously underappreciated in Mtb, plays a substantial role in the emergence of INDELs (insertions and deletions) with 12.4% of INDELs occurring in HTs despite coding for just 0.02% of the genome.
DDDT_A_275007 5375..5392

*These authors contributed equally to this work Abstract: Platinum (Pt)-based anticancer drugs such as cisplatin have been used to treat various cancers. However, they have some limitations including poor selectivity and toxicity towards normal cells and increasing chemoresistance. Therefore, there is a need for novel metallo-anticancers, which has not been met for decades. Since the initial introduction of ruthenium (Ru) polypyridyl complex, a number of attempts at structural evolution have been conducted to improve efficacy. Among them, half-sandwich Ru-arene complexes have been the most prominent as an anticancer platform. Such complexes have clearly shown superior anticancer profiles such as increased selectivity toward cancer cells and ameliorating toxicity against normal cells compared to existing Pt-based anticancers. Currently, several Ru complexes are under human clinical trials. For improvement in selectivity and toxicity associated with chemotherapy, Ru complexes as photodynamic therapy (PDT), and photoactivated chemotherapy (PACT), which can selectively activate prodrug moieties in a specific region, have also been investigated. With all these studies on these interesting entities, new metalloanticancer drugs to at least partially replace existing Pt-based anticancers are anticipated. This review covers a brief description of Ru-based anticancer complexes and perspectives.
Activation of Phenylalanine Hydroxylase Induces Positive Cooperativity Towards the Enzyme’s Natural Cofactor*

Protein misfolding with loss-of-function of the enzyme phenylalanine hydroxylase (PAH) is the molecular basis of phenylketonuria in many individuals carrying missense mutations in the PAH gene. PAH is complexly regulated by its substrate L-phenylalanine and its natural cofactor 6[R]-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4). Sapropterin dihydrochloride, the synthetic form of BH4, was recently approved as the first pharmacological chaperone to correct the loss-of-function phenotype. However, current knowledge about enzyme function and regulation in the therapeutic setting is scarce. This illustrates the need for comprehensive analyses of steady state kinetics and allostery beyond single residual enzyme activity determinations to retrace the structural impact of missense mutations on the phenylalanine hydroxylating system. Current standard PAH activity assays are either indirect (NADH) or discontinuous due to substrate and product separation prior to detection. We developed an automated fluorescence-based continuous real-time PAH activity assay that proved to be faster and more efficient but as precise and accurate as standard methods. Wild-type PAH kinetic analyses using the new assay revealed cooperativity of activated PAH towards BH4, a previously unknown finding. Analyses of structurally preactivated variants substantiated BH4-dependent cooperativity of the activated enzyme that does not rely on the presence of Lphenylalanine but is determined by activating conformational rearrangements. These findings may have implications for an individualized therapy, since they support the hypothesis that the patient’s metabolic state has a more significant effect on the interplay of the drug and the conformation and function of the target protein than currently appreciated.
HMSIW-based switchable units using super compact loaded shunt stubs and its applications on SIW/HMSIW switches

ABSTRACT Half-mode substrate integrated waveguide (HMSIW) switchable unit, built by HMSIW section with loaded single or multi-microstrip shunt stub(s), was proposed in this work. Both shorted and opened stubs were studied, investigated and compared, bandwidth enhancement method for proposed switchable units was proposed and demonstrated. Based on these switchable units, narrowband and broadband HMSIW single-pole-single-through (SPST) switches, SIW SPST switch and SIW/HMSIW-based single-pole-double-through (SPDT) switch were designed, fabricated and measured. Good performances were observed experimentally for these proposed circuits, showing the advantages of proposed concept and an excellent candidate for switchable or reconfigurable SIW/HMSIW circuits or systems.
Multi‐objective design optimization of antennas for reflection, size, and gain variability using kriging surrogates and generalized domain segmentation

Cost‐efficient multi‐objective design optimization of antennas is presented. The framework exploits auxiliary data‐driven surrogates, a multi‐objective evolutionary algorithm for initial Pareto front identification, response correction techniques for design refinement, as well as generalized domain segmentation. The purpose of this last mechanism is to reduce the volume of the design space region that needs to be sampled in order to construct the surrogate model, and, consequently, limit the number of training data points required. The recently introduced segmentation concept is generalized here to allow for handling an arbitrary number of design objectives. Its operation is illustrated using an ultra‐wideband monopole optimized for best in‐band reflection, minimum gain variability, and minimum size. When compared with conventional surrogate‐based approach, segmentation leads to reduction of the initial Pareto identification cost by over 20%. Numerical results are supported by experimental validation of the selected Pareto‐optimal antenna designs.
Morrow, Gael B. and Nicholas, Robert A. and Kennedy, Charles (2014) UTP is not a biased agonist at human P2Y11 receptors. Purinergic

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Novel cancer therapy targeting microbiome

: In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, in ﬂ ammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.
Large Strain Viscoelastic Material Model for Deformation, Stress and Strain Analysis of O-rings

Primary aim of this paper is to investigate the mechanical behavior of an O-ring seal made of NBR rubber material using finite element method. Further aim is to identify the O-ring’s critical locations where it can fail under normal operating conditions. For these a large-strain viscoelastic material model was set up. The recommended strain range where the material model should be sufficient is 0-100 % for normal conditions, but when the effect of overload or the temperature is the question, the strain range should be 0-150 %. From designer point of view, a large-strain viscoelastic material model with a 5 parameter Mooney-Rivlin term is appropriate. To make sure the material model′s accurate response, uniaxial tension, pure shear and equibiaxial measurements are needed, completed with dynamic measurements with a DMTA machine. The results show two critical locations where the failure of the O-ring is expected. One is on the edge of the O-ring near the gap, when friction is present, the other one is under the edge near the gap.
Tolerance to Lipopolysaccharide Involves Mobilization of Nuclear Factor KB with Predominance of p 50 Homodimers *

Stimulation of the human monocytic cell line Mono Mac 6 with lipopolysaccharide (LPS) leads to rapid and transient expression of cytokines like tumor necrosis factor (TNF). When such cells are precultured for 2 days with a low dose of LPS (20 ng/ml) followed by stimulation with a high dose of LPS (1 pg/ml), expression of the TNF gene is minimal, Le. the cells are tolerant. In nuclear run-on analysis, such tolerant cells show only a low degree of transcription, indicating that tolerance operates at or upstream of the transcription level. The CD14 LPS receptor is, however, up-regulated (not down-regulated) in tolerant cells, and LPS can, in fact, still lead to activation of tolerant cells as evidenced by mobilization of the transcription factor nuclear factor KB (NF-KB). Resolution of the NF-KB complex in gel shift analysis shows that the binding protein, mobilized in naive Mono Mac 6 cells, consists mainly of p50-p65 heterodimers, while in tolerant cells, the p50 homodimer is predominant. This increase in p50 homodimers coincides with an increase in p105 mRNA, suggestive of a transcriptional up-regulation of p50. Reporter gene analysis reveals that the NF-KB complex mobilized in tolerant cells is functionally inactive in that NF-&-dependent luciferase constructs containing the human immunodeficiency virus long terminal repeat or the TNF 5'-region show only minimal transactivation after LPS stimulation. Similar to Mono Mac 6 cells, primary blood monocytes, when precultured with a low dose of LPS, also become tolerant and produce little TNF after LPS stimulation. The tolerant blood monocytes also up-regulate CD14, and they mobilize NF-KB with a predominance of p50 homodimers. Taken together, these results demonstrate that tolerance to LPS is determined by post-receptor mechanisms
Query-Based (cid:96) -Diversity

—We propose a new privacy notion called query-based (cid:96) -diversity . A database instance T is (cid:96) -diverse with respect to given authorized queries if an attacker cannot narrow down the number of possible values of the sensitive information to less than (cid:96) by inference using the result of the authorized queries on the instance T and the meaning of the queries. We provide two approaches to deciding the query-based (cid:96) -diversity. In the ﬁrst approach, a decision algorithm is given by using relational operations, which can be directly implemented by a relational database management system, e.g., Structured Query Language (SQL). The second approach transforms a given input to a logical formula and decides the problem by model counting using a #SAT solver. We discuss the effectiveness and scalability of the two approaches based on the experimental results.