Miracle-dz/UniFAR-FTUs huggingface dataset:
Assessing RNAi feasibility and susceptibility to environmental RNAi in Trichogramma dendrolimi (Hymenoptera: Trichogrammatidae)

Trichogramma, a genus of egg parasitoid wasps, are widely used as biological control agents and serve as model organisms in parasitoid research. Despite their significance, the understanding of RNA interference (RNAi) in Trichogramma remains very limited. In this study, we investigated RNAi-associated genes by bioinformatic approaches and experimentally assessed the feasibility of RNAi and the susceptibility of environmental RNAi in Trichogramma. We found that Trichogramma genomes contain a complete set of genes in the RNAi pathway and exhibit extensive gene expansion of dsRNase, which may influence RNAi efficiency by degrading dsRNA. We demonstrated successful RNAi through pupal microinjection in T. dendrolimi Matsumura, providing a technical approach for future gene functional studies. In addition, we observed no evidence of susceptibility to environmental RNAi in either T. dendrolimi adults or larvae, which might be attributed to the extensive expansion of dsRNase. This low environmental RNAi sensitivity in Trichogramma could suggest a reduced risk of RNAi-based pest management strategies affecting nontarget Trichogramma populations. Overall, this study presents a technical approach for conducting gene functional studies in Trichogramma and provides a foundation for evaluating the nontarget effects of RNAi-based pest control strategies on Trichogramma.
Medical imaging in rheumatoid arthritis: A review on deep learning approach

Abstract Arthritis is a musculoskeletal disorder. Millions of people have arthritis, making it one of the most common joint disorders. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the most common types of arthritis among the many different types available. Pain, stiffness, and inflammation are among the early signs of arthritis, which can progress to severe immobility at a later stage if left untreated. Although arthritis cannot be cured at any point in time, it can be managed if diagnosed and treated correctly. Clinical diagnostic and medical imaging methods are currently used to evaluate OA and RA, both debilitating conditions. This review is focused on deep learning approaches used by taking medical imaging (X-rays and magnetic resonance imaging) as input for the detection of RA.
Modeling Stress-Induced Responses: Plasticity in Continuous State Space and Gradual Clonal Evolution

Mathematical models of cancer and bacterial evolution have generally stemmed from a gene-centric framework, assuming clonal evolution via acquisition of resistance-conferring mutations and selection of their corresponding subpopulations. More recently, the role of phenotypic plasticity has been recognized and models accounting for phenotypic switching between discrete cell states (e.g. epithelial and mesenchymal) have been developed. However, seldom do models incorporate both plasticity and mutationally-driven resistance, particularly when the state space is continuous and resistance evolves in a continuous fashion. In this paper, we develop a framework to model plastic and mutational mechanisms of acquiring resistance in a continuous, gradual fashion. We use this framework to examine ways in which cancer and bacterial populations can respond to stress and consider implications for therapeutic strategies. Although we primarily discuss our framework in the context of cancer and bacteria, it applies broadly to any system capable of evolving via plasticity and genetic evolution.
Optimal enzyme profiles in unbranched metabolic pathways

How to optimize the allocation of enzymes in metabolic pathways has been a topic of study for many decades. Although the general problem is complex and non-linear, we have previously shown that it can be solved by convex optimization. In this paper, we focus on unbranched metabolic pathways with simplified enzymatic rate laws and derive analytic solutions to the optimization problem. We revisit existing solutions based on the limit of mass-action rate laws and present new solutions for other rate laws. Furthermore, we revisit a known relationship between flux control coefficients and enzyme abundances in optimal metabolic states. We generalize this relationship to models with density constrains on enzymes and metabolites, and present a new local relationship between optimal reaction elasticities and enzyme amounts. Finally, we apply our theory to derive simple kinetics-based formulae for protein allocation during bacterial growth.
A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer

Purpose Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. Experimental design We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. Results We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. Conclusion This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.
Unraveling the Interplay of Different Traits and Parameters Related to Nitrogen Use Efficiency in Wheat: Insights for Grain Yield Influence

Enhancing Nitrogen Use Efficiency (NUE) in wheat to optimize grain yield is a significant challenge. To address this challenge, a comprehensive study was conducted to investigate various morphological, biochemical, molecular parameters, and agronomic traits related to NUE. By examining various traits under both optimum-N (ON) and stressed-N (SN) conditions, the study explores the interrelationships among these traits, providing novel insights not previously reported. A set of 278 diverse wheat genotypes were assessed, encompassing eight NUE-related traits: Grain Yield, Biomass, Grain nitrogen, N at head, N at harvest, N-uptake, Nitrogen Uptake Efficiency, Nitrogen Utilization Efficiency, and NUE under both ON and SN conditions in the field. The findings demonstrated a significant positive correlation between grain yield and all NUE-related traits, highlighting their significance in comprehending the biological NUE of wheat plants. Notably, the study identified N-uptake and N-uptake related traits as key factors influencing the impact of soil nitrogen status on yield and associated parameters. These traits hold particular importance for selecting wheat genotypes with optimal yield and NUE in wheat cultivation. To complement the field data, representative genotypes were further subjected to a hydroponics experiment under absolute nitrogen control. This experiment provided insights into the effects of nitrogen stress on morphological parameters and the performance of eight essential nitrogen and carbon metabolizing enzymes. Correlation analysis highlighted the substantial influence of four key N-metabolizing enzymes, namely Nitrate Reductase, Glutamine Synthetase, Glutamate Oxo-Glutarate Amino Transferase, and Glutamate Dehydrogenase, on grain yield. Additionally, this study underscored the direct and indirect associations between seedling parameters and field traits, emphasizing the significance of shoot and root length parameters in nitrogen acquisition under nitrogen stress. In conclusion, these findings offer valuable insights into the intricate network of traits and parameters that influence wheat grain yield under varying nitrogen regimes. This knowledge can aid in the selection of wheat genotypes with enhanced NUE and grain yield, particularly in scenarios of reduced nitrogen application. Key Points A comprehensive study in field and hydroponics conditions revealed differential responses of various morphological, biochemical, molecular parameters, and agronomic traits to different nitrogen levels. N-uptake related traits in field condition and chlorophyll content and morphological parameters in hydroponics condition were found as essential factors contributing to variations under both optimum and stressed N conditions. Among the parameters observed in the seedling stage, SL and RL, along with the enzymes NR, GS, GOGAT, and GDH, demonstrated their influence on GY.
Analysis of the influence of peptidoglycan turnover and recycling on host-pathogen interaction in the Gram-positive pathogen Staphylococcus aureus (Peptidoglycan recycling and Gram-positive bacteria-host interaction)

During peptidoglycan recycling (PR) bacteria can recover extracellular fragments of peptidoglycan (PGN) liberated by peptidoglycan turnover (PT) during cell growth and division, and reuse them in cell wall biosynthesis or central carbon metabolism. In Gram-negative bacteria, PR has been well studied, and functions in the induction of resistance to certain classes of antibiotics, and in host-pathogen interaction. However, while Gram-negative cell envelope architecture allows for highly efficient PR, Gram-positive bacteria, which lack an outer cell membrane and are instead enclosed by a glycopolymer layer, can shed large quantities of PGN-derived material to the external environment during growth. Nonetheless, the occurrence of PR was recently demonstrated in several Gram-positive bacteria, including the Gram-positive bacterial pathogen Staphylococcus aureus, and its potential adaptive functions are largely unexplored. Given the known roles of PR in Gram-negative bacteria, and that Gram-positive bacteria include several important human pathogens, we asked what role PR may play during Gram-positive pathogen-host interaction. Usingthe model insect host Drosophila melanogaster, we demonstrate that S. aureus mutants impaired in extracellular PGN hydrolysis (Δatl) and PGN fragment uptake (ΔmurP) show differential virulence compared to their wild-type counterpart. This was linked to increased activation of the D. melanogaster Toll-cascade by spent supernatant from the Δatl mutant. Thus, we propose that S. aureus, and potentially other Gram-positive bacteria, may use extracellular PGN degradation during PT to simultaneously process PGN fragments for recycling and for immune evasion, while recovery and/or metabolism of peptidoglycan fragments during PR may play more subtle roles in determining virulence. Author summary PGN is a key component of the bacterial cell wall, forming a stress-bearing sacculus surrounding the cell and providing cell shape. During growth and division, the sacculus is dynamically degraded and remodelled to ensure daughter cell separation, resulting in PT. PGN fragments released during PT can be recovered and reutilised by the cell during PR. In Gram-negative pathogens, PR is linked to antibiotic resistance, virulence and modulation of host immune recognition. In Gram-positive bacteria, PR was only recently observed. Here, we explore the roles of PT and PR in host-pathogen interaction in S. aureus, a Gram-positive pathogen of significant clinical relevance. Disruption of PT in S. aureus affected host-pathogen interaction through altering host recognition of shed PGN fragments and PR through modulation of PGN fragment recovery. This improves our understanding of the biology of this important pathogen and may aid development of novel therapeutic approaches to treat S. aureus infections.
Mechanism of branching morphogenesis inspired by diatom silica formation

The silica-based cell walls of diatoms are prime examples of genetically controlled, species-specific mineral architectures. The physical principles underlying morphogenesis of their hierarchically structured silica patterns are not understood, yet such insight could indicate novel routes towards synthesizing functional inorganic materials. Recent advances in imaging nascent diatom silica allow rationalizing possible mechanisms of their pattern formation. Here, we combine theory and experiments on the model diatom Thalassiosira pseudonana to put forward a minimal model of branched rib patterns – a fundamental feature of the silica cell wall. We quantitatively recapitulate the time-course of rib pattern morphogenesis by accounting for silica biochemistry with autocatalytic formation of diffusible silica precursors followed by conversion into solid silica. We propose that silica deposition releases an inhibitor that slows down up-stream precursor conversion, thereby implementing a self-replicating reaction-diffusion system featuring a non-classical Turing mechanism. The proposed mechanism highlights the role of geometrical cues for guided self-organization, rationalizing the instructive role for the single initial pattern seed known as primary silicification site. The mechanism of branching morphogenesis that we characterize here is possibly generic and may apply also in other biological systems. Significance statement The formation of minerals by living organisms is a widespread biological phenomenon occurring throughout the evolutionary tree-of-life. The silica-based cell walls of diatom microalgae are impressive examples featuring intricate architectures and outstanding materials properties that still defy their reconstitution in vitro. Here, we developed a minimal mathematical model that explains the formation of branched patterns of silica ribs, providing unprecedented understanding of basic physico-chemical processes capable of guiding silica morphogenesis in diatoms. The generic mechanism of branching morphogenesis identified here could provide recipes for bottom-up synthesis of mineral-nanowire networks for technological applications. Moreover, similar mechanisms may apply in the biological morphogenesis of other branched structures, like corals, bacterial colonies, tracheal networks, fungal plexuses, or the vascular system.
Differentiation of hypervirulent and classical Klebsiella pneumoniae with acquired drug 1 resistance 2

: 25 Distinguishing hypervirulent (hvKp) from classical Klebsiella pneumoniae (cKp) strains is 26 important for clinical care, surveillance, and research. Some combination of iucA, iroB, peg-344, 27 rmpA, and rmpA2 are most commonly used, but it is unclear what combination of genotypic or 28 phenotypic markers (e.g. siderophore concentration, mucoviscosity) most accurately predicts 29 the hypervirulent phenotype. Further, acquisition of antimicrobial resistance may affect 30 virulence and confound identification. Therefore, 49 K. pneumoniae strains that possessed 31 some combination of iucA, iroB, peg-344, rmpA, and rmpA2 and had acquired resistance were 32 assembled and categorized as hypervirulent hvKp (hvKp) (N=16) or cKp (N=33) via a murine 33 infection model. Biomarker number, siderophore production, mucoviscosity, virulence plasmid’s 34 Mash/Jaccard distances to the canonical pLVPK, and Kleborate virulence score were measured 35 and evaluated to accurately differentiate these pathotypes. Both stepwise logistic regression 36 and a CART model were used to determine which variable was most predictive of the strain 37 cohorts. The biomarker count alone was the strongest predictor for both analyses. For logistic 38 regression the area under the curve for biomarker count was 0.955 (P = 0.004). The CART 39 model generated the classification rule that a biomarker count = 5 would classify the strain as 40 hvKP, resulting in a sensitivity for predicting hvKP of 88% (14/16), a specificity of 94% (31/33), 41 and an overall accuracy of 92% (45/49). Although a count of ≥ 4 was 100% (16/16) sensitive for 42 predicting hvKP, the specificity and accuracy decreased to 76% (25/33) and 84% (41/49) 43 respectively. These findings can be used to inform the identification of hvKp. 44 45 46 47
Globally Valid Posterior Cramér–Rao Bound for Three-Dimensional Bearings-Only Filtering

This paper addresses the problem of three-dimensional target motion analysis from bearing measurements. The established description of uncertain directional data involves azimuth and elevation angles with additive Gaussian noise. Investigation of this widely accepted representation in terms of the corresponding Fisher information matrices reveals that the underlying probability densities are only valid for small absolute elevation angles and precise measurements. Employing spherical statistics, an alternative representation is proposed that is sensible for the whole state space and arbitrarily imprecise bearing sensors. Based on this, a globally valid posterior Cramér–Rao lower bound is derived.
Post-exposure intranasal IFNα suppresses replication and neuroinvasion of Venezuelan Equine Encephalitis virus within olfactory sensory neurons

Venezuelan Equine Encephalitis virus (VEEV) may enter the central nervous system (CNS) within olfactory sensory neurons (OSN) that originate in the nasal cavity after intranasal exposure. While it is known that VEEV has evolved several mechanisms to inhibit type I interferon (IFN) signaling within infected cells, whether this inhibits virologic control during neuroinvasion along OSN has not been studied. Here, we utilized an established murine model of intranasal infection with VEEV to assess the cellular targets and IFN signaling responses after VEEV exposure. We found that immature OSN, which express higher levels of the VEEV receptor LDLRAD3 than mature OSN, are the first cells infected by VEEV. Despite rapid VEEV neuroinvasion after intranasal exposure, olfactory neuroepithelium (ONE) and olfactory bulb (OB) IFN responses, as assessed by evaluation of expression of interferon signaling genes (ISG), are delayed for up to 48 hours during VEEV neuroinvasion, representing a potential therapeutic window. Indeed, a single intranasal dose of recombinant IFNα triggers early ISG expression in both the nasal cavity and OB. When administered at the time of or early after infection, IFNα treatment delayed onset of sequelae associated with encephalitis and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the ONE, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human encephalitic alphavirus exposures. AUTHOR SUMMARY Venezuelan Equine Encephalitis virus (VEEV) may enter the brain through the nasal cavity upon intranasal exposure. The nasal cavity normally displays brisk antiviral immune responses, thus it is unclear why this type of exposure leads to fatal VEEV infection. Using an established murine model of intranasal infection with VEEV we identified the initial targets of infection within the nasal cavity and found that antiviral immune responses to virus at this site and during brain infection are delayed for up to 48 hours. Thus, administration of a single intranasal dose of recombinant IFNα at the time of or early after infection improved early antiviral immune responses and suppressed viral replication, which delayed onset of brain infection and extended survival by several days. VEEV replication after IFN treatment was also transiently suppressed in the nasal cavity, which inhibited subsequent invasion into the CNS. Our results demonstrate a critical and promising first evaluation of intranasal IFNα for the treatment of human VEEV exposures.
A RabGAP-Rab GTPase pair regulates plant autophagy and immunity

Plants rely on autophagy and membrane trafficking to tolerate stress, combat infections, and maintain cellular homeostasis. However, the molecular interplay between autophagy and membrane trafficking is poorly understood. Using an AI-assisted approach, we identified Rab3GAP-like (Rab3GAPL) as an important membrane trafficking node that controls plant autophagy negatively. Rab3GAPL suppresses autophagy by binding to ATG8, the core autophagy adaptor, and deactivating Rab8a, a small GTPase essential for autophagosome formation and defense-related secretion. Rab3GAPL from Nicotiana benthamiana, but not its mutated form deficient in ATG8 binding, reduced autophagic flux in N. benthamiana and Arabidopsis. Furthermore, Rab3GAPL-knockout mutants of the liverwort Marchantia polymorpha exhibited enhanced autophagic flux under both normal and heat stress conditions, suggesting that Rab3GAPL’s negative regulatory role in autophagy is conserved in land plants. Beyond autophagy regulation, Rab3GAPL modulates focal immunity against the oomycete pathogen Phytophthora infestans by preventing defense-related secretion. Altogether, our results suggest that Rab3GAPL acts as a molecular rheostat to coordinate autophagic flux and defense-related secretion by restraining Rab8a-mediated trafficking. This unprecedented interplay between a RabGAP-Rab pair and ATG8 sheds new light on the intricate membrane transport mechanisms underlying plant autophagy and immunity.
Investigation of swine caecal microbiomes in the northern region of Thailand

Introduction The northern region of Thailand serves as a crucial area for swine production, contributing to the global food supply. Previous studies have highlighted the presence of foodborne pathogens originating from swine farms in this region, posing a threat to both human and animal health. Gap statement Multiple swine pathogens have been studied at a species level, but the distribution and co-occurrence of pathogens in agricultural swine has not been well established. Aim Our study employed the intestinal scraping technique to directly examine the microorganisms interacting with the swine host. Methodology We used shotgun metagenomic sequencing to analyse the caecal microbiomes of swine from five commercial farms in northern Thailand. Results Swine caecal microbiomes contained commensal bacteria such as Bifidobacterium, Lactobacillus, and Faecalibacterium, which are associated with healthy physiology and feed utilisation. We also identified multiple pathogenic and opportunistic bacteria present in all samples, including Escherichia coli, Clostridium botulinum, Staphylococcus aureus, and the Corynebacterium genus. From a One Health perspective, these species are important foodborne and opportunistic pathogens in both humans and agricultural animals. Antimicrobial resistance genes were also detected in all samples, specifically conferring resistance to tetracycline and aminoglycosides which have historically been used extensively in swine farming. Conclusion The findings further support the need for improved sanitation standards in swine farms, and additional monitoring of agricultural animals and farm workers to reduce contamination and improved produce safety for human consumption.