Exploring the Mechanism of Yiwei Decoction in the Intervention of a Premature Ovarian Insufficiency Rat Based on Network Pharmacology and the miRNA-mRNA Regulatory Network.

OBJECTIVE: our aim is to explore the mechanism of action of Yiwei decoction (YWD) in addressing premature ovarian insufficiency (POI) through a combination of transcriptomics and network pharmacology. By doing so, we hope to identify important pathways of action, key targets, and active components that contribute to the efficacy of YWD. MATERIALS AND METHODS: group A comprised of the model + traditional Chinese medicine group, while group B was the model control group and group C was the normal control group. After gavage, serum AMH and E2 levels were measured by using ELISA. HE staining was used to study the impact of YWD on ovarian follicle recovery in POI rats. Additionally, RNA-seq sequencing technology was employed to analyze the transcription levels of mRNAs and miRNAs in the ovarian tissues of each group, and the resulting data were examined using R. YWD used UPLC-Q-TOF-HRMS to analyze its active ingredients. Upon obtaining the sequencing results, the miRWalk database was utilized to forecast the targets of DEmiRNAs. Network pharmacology was then applied to predict the targets of active ingredients present in YWD, ultimately constructing a regulatory network consisting of active ingredients-mRNA-miRNA. The coexpression relationship between mRNAs and miRNAs was calculated using the Pearson correlation coefficient, and high correlation coefficients between miRNA-mRNA were confirmed through miRanda sequence combination. RESULTS: the application of YWD resulted in improved serum levels of AMH and E2, as well as an increased number of ovarian follicles in rats with POI. However, there was a minimal impact on the infiltration of ovarian lymphocytes. Through GSEA pathway enrichment analysis, we found that YWD may have a regulatory effect on PI3K-Akt, ovarian steroidogenesis, and protein digestion and absorption, which could aid in the treatment of POI. Additionally, our research discovered a total of 6 DEmiRNAs between groups A and B, including 2 new DEmiRNAs. YWD contains 111 active compounds, and our analysis of the active component-mRNA regulatory network revealed 27 active components and 73 mRNAs. Furthermore, the coexpression network included 5 miRNAs and 18 mRNAs. Our verification of MiRanda binding demonstrated that 12 of the sequence binding sites were stable. CONCLUSIONS: our research has uncovered the regulatory network mechanism of active ingredients, mRNA, and miRNA in YWD POI treatment. However, further research is needed to determine the effect of the active ingredients on key miRNAs and mRNAs.

A chimeric adenovirus-vectored vaccine based on Beta spike and Delta RBD confers a broad-spectrum neutralization against Omicron-included SARS-CoV-2 variants.

Urgent research into innovative severe acute respiratory coronavirus-2 (SARS-CoV-2) vaccines that may successfully prevent various emerging emerged variants, particularly the Omicron variant and its subvariants, is necessary. Here, we designed a chimeric adenovirus-vectored vaccine named Ad5-Beta/Delta. This vaccine was created by incorporating the receptor-binding domain from the Delta variant, which has the L452R and T478K mutations, into the complete spike protein of the Beta variant. Both intramuscular (IM) and intranasal (IN) vaccination with Ad5-Beta/Deta vaccine induced robust broad-spectrum neutralization against Omicron BA.5-included variants. IN immunization with Ad5-Beta/Delta vaccine exhibited superior mucosal immunity, manifested by higher secretory IgA antibodies and more tissue-resident memory T cells (TRM) in respiratory tract. The combination of IM and IN delivery of the Ad5-Beta/Delta vaccine was capable of synergically eliciting stronger systemic and mucosal immune responses. Furthermore, the Ad5-Beta/Delta vaccination demonstrated more effective boosting implications after two dosages of mRNA or subunit recombinant protein vaccine, indicating its capacity for utilization as a booster shot in the heterologous vaccination. These outcomes quantified Ad5-Beta/Delta vaccine as a favorable vaccine can provide protective immunity versus SARS-CoV-2 pre-Omicron variants of concern and BA.5-included Omicron subvariants.

Extracellular CIRP co-stimulated T cells through IL6R/STAT3 in pediatric IgA vasculitis.

Immunoglobulin A vasculitis (IgAV) is the most common vasculitis of childhood. Disordered immune responses play important roles in its pathogenesis, but the comprehensive immune profile of the disease and the underlying mechanisms are still largely unknown. Here we found a potential disease biomarker cold inducible RNA binding protein (CIRP) in our pediatric IgAV cohort. Serum CIRP level in these patients were elevated and positively correlated with the increased early memory (CD45RA+CD62L+CD95+) T cells revealed using multicolor flow cytometry. Immune phenotyping of the patients showed they had more activated T cells with higher IL6Ra expression. T cell culture experiment showed CIRP further activated both human CD4+ and CD8+ T cells as indicated by increased perforin secretion and phosphorylation of STAT3. Blockade of IL6Rα attenuated CIRP-induced T cell toxicity in vitro. RNA-sequencing data further supported CIRP stimulation promoted human T cell activation and migration, fueled inflammation through the JAK-STAT signaling pathway. Therefore, IL6Ra-mediated T cell activation by extracellular CIRP may contribute to pathogenesis of IgAV in children, both CIRP and IL6Ra could be new therapeutic targets for IgAV.

Nonlinear-mirror mode-locked crystal waveguide laser by intracavity fourth-harmonic loss modulation: publisher's note.

This publisher's note contains a correction to Opt. Lett.48, 6064 (2024)10.1364/OL.509275.

Gut microbiome, T cell subsets, and cytokine analysis identify differential biomarkers in tuberculosis.

Introduction: The gut microbiota, T cell subsets, and cytokines participate in tuberculosis (TB) pathogenesis. To date, the mechanisms by which these factors interactively promote TB development at different time points remain largely unclear. In the context of this study, We looked into the microorganisms in the digestive tract, T cell types, and cytokines related to tuberculosis. Methods: According to QIIME2, we analyzed 16SrDNA sequencing of the gut microbiome on the Illumina MiSeq. Enzyme-linked immunosorbent assay was used to measure the concentrations of cytokines. Results: We showed the presence of 26 identifiable differential microbiomes in the gut and 44 metabolic pathways between healthy controls and the different time points in the development of TB in patients. Five bacterial genera (Bacteroides, Bifidobacterium, Faecalibacterium, Collinsella, and Clostridium) were most closely associated with CD4/CD8, whereas three bacterial taxa (Faecalibacterium, Collinsella, and Clostridium) were most closely associated with CD4. Three bacterial taxa (Faecalibacterium, Ruminococcus, and Dorea) were most closely associated with IL-4. Ruminococcus was most closely associated with IL-2 and IL-10. Conclusion: Diverse microorganisms, subsets of T cells, and cytokines, exhibiting varying relative abundances and structural compositions, were observed in both healthy controls and patients throughout distinct phases of tuberculosis. Gaining insight into the function of the gut microbiome, T cell subsets, and cytokines may help modulate therapeutic strategies for TB.

Dual roles of dopaminergic pathways in olfactory learning and memory in the oriental fruit fly, Bactrocera dorsalis.

Dopamine (DA) is a key regulator of associative learning and memory in both vertebrates and invertebrates, and it is widely believed that DA plays a key role in aversive conditioning in invertebrates. However, the idea that DA is involved only in aversive conditioning has been challenged in recent studies on the fruit fly (Drosophila melanogaster), ants and crabs, suggesting diverse functions of DA modulation on associative plasticity. Here, we present the results of DA modulation in aversive olfactory conditioning with DEET punishment and appetitive olfactory conditioning with sucrose reward in the oriental fruit fly, Bactrocera dorsalis. Injection of DA receptor antagonist fluphenazine or chlorpromazine into these flies led to impaired aversive learning, but had no effect on the appetitive learning. DA receptor antagonists impaired both aversive and appetitive long-term memory retention. Interestingly, the impairment on appetitive memory was rescued not only by DA but also by octopamine (OA). Blocking the OA receptors also impaired the appetitive memory retention, but this impairment could only be rescued by OA, not by DA. Thus, we conclude that in B. dorsalis, OA and DA pathways mediate independently the appetitive and aversive learning, respectively. These two pathways, however, are organized in series in mediating appetitive memory retrieval with DA pathway being at upstream. Thus, OA and DA play dual roles in associative learning and memory retrieval, but their pathways are organized differently in these two cognitive processes - parallel organization for learning acquisition and serial organization for memory retrieval.

Intranasal boosting with RBD-HR protein vaccine elicits robust mucosal and systemic immune responses.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants has decreased the efficacy of SARS-CoV-2 vaccines in containing coronavirus disease 2019 (COVID-19) over time, and booster vaccination strategies are urgently necessitated to achieve sufficient protection. Intranasal immunization can improve mucosal immunity, offering protection against the infection and sustaining the spread of SARS-CoV-2. In this study, an intranasal booster of the RBD-HR vaccine after two doses of the mRNA vaccine significantly increased the levels of specific binding antibodies in serum, nasal lavage fluid, and bronchoalveolar lavage fluid compared with only two doses of mRNA vaccine. After intranasal boosting with the RBD-HR vaccine, the levels of serum neutralizing antibodies against prototype and variant strains of SARS-CoV-2 pseudoviruses were markedly higher than those in mice receiving mRNA vaccine alone, and intranasal boosting with the RBD-HR vaccine also inhibited the binding of RBD to hACE2 receptors. Furthermore, the heterologous intranasal immunization regimen promoted extensive memory T cell responses and activated CD103+ dendritic cells in the respiratory mucosa, and potently enhanced the formation of T follicular helper cells and germinal center B cells in vital immune organs, including mediastinal lymph nodes, inguinal lymph nodes, and spleen. Collectively, these data infer that heterologous intranasal boosting with the RBD-HR vaccine elicited broad protective immunity against SARS-CoV-2 both locally and systemically.

The Implication of Diabetes-Specialized Nurses in Aiming for the Better Treatment and Management of Patients with Diabetes Mellitus: A Brief Narrative Review.

Diabetes mellitus (DM) is regarded as one of the most critical public health challenges of the 21st century. It has evolved into a burgeoning epidemic since the last century, and today ranks among the major causes of mortality worldwide. Diabetes specialist nurses (DSNs) are central to good patient care and outcomes including confident self-care management. Evidence shows that DSNs are cost-effective, improve clinical outcomes, and reduce length of stay in hospital. In this brief narrative review, we aim to describe the roles of DSNs and their contribution in the treatment and management of patients with DM. This narrative review describes the importance of DSNs in healthcare practice, in the inpatient and outpatient departments, in the pediatrics department, in managing diabetic foot ulcers, in the treatment and management of gestational diabetes, in prescribing medications for DM and in diabetes self-management education on glycosylated hemoglobin, and cardiovascular risk factors. To conclude, DSNs have a crucial role in the treatment and management of patients with DM and its complications. DSNs have a great impact on diabetes therapy, and hence implementation of DSNs and nurse-led diabetic clinics might be beneficial for the health care system. Finally, having DSNs might significantly contribute to good healthcare practice and support. Even though DSNs are not available in several regions around the globe, and even though this post is still new to several health care institutions, the presence of DSNs recognized and certified by the various healthcare systems would be very useful.

Synthesis and characterization of a bio-aldehyde-based lignin adhesive with desirable water resistance.

Wood-based panels find widespread application in the furniture and construction industries. However, over 90 % of adhesives used are synthesized with formaldehyde, leading to formaldehyde emission and associated health risks. In this study, an entirely bio-based adhesive (OSL) was innovatively proposed through the condensation of multi-aldehyde derived from the oxidization of sucrose (OS) with sodium lignosulfonate (L). This approach positioned oxidized sucrose (OS) as a viable substitute for formaldehyde, ensuring safety, simplicity, and enhance water resistance upon reaction with L. The optimization of the OSL adhesive preparation process involved determining the oxidant level for high sucrose conversion to aldehyde (13 % based on sucrose), the mass ratio of OS to L (0.8), and hot-pressing temperature (200 °C). Notably, the shear strength of 3-plywood bonded with the developed adhesive (1.04 MPa) increased to 1.42 MPa after being immersed in hot water at 63 ±â€¯3 °C for 3 h. Additionally, the plywood specimens exhibited excellent performance after soaking in boiling water for 3 h, resulting in a shear strength of 1.03 MPa. Chemical analysis using Fourier-transform infrared spectroscopy (FTIR), 1H nuclear magnetic resonance (NMR), and X-ray photoelectron spectroscopy (XPS) confirmed an addition reaction between L and OS, forming a dense network structure, effectively enhanceing the water resistance of OSL adhesives. Furthermore, compared with lignin-formaldehyde resin adhesive (LF), the OSL adhesive exhibited superior wet shear strength. This study offered an innovative approach for developing lignin-based adhesives utilizing a biomass aldehyde (OS), as a promising substitute for formaldehyde in the wood industry. The findings indicated that this approach may advance lignin-based adhesives, ensuring resistance to strength deterioration under highly humid environmental conditions.

Formation and Detection of Gizzerosine in Animal Feed Matrices: Progress and Perspectives.

Gizzerosine is responsible for gizzard erosion and black vomit, owing to excessive gastric acid secretion in poultry. It is a biogenic amine that forms during feed processing. Gizzerosine, a derivative of histamine, is a serious threat to animal feed safety and poultry production because it is more potent after ingestion and more harmful to poultry than histamine. The difficulty of obtaining gizzerosine and the lack of simple, rapid, and sensitive in vitro detection techniques have hindered studies on the effects of gizzerosine on gizzard health and poultry production. In this review, we evaluated the natural formation and the chemical synthesis methods of gizzerosine and introduced seven detection methods and their principles for analyzing gizzerosine. This review summarizes the issues of gizzerosine research and suggests methods for the future development of gizzerosine detection methods.

Geography, phylogeny and host switch drive the coevolution of parasitic Gyrodactylus flatworms and their hosts.

BACKGROUND: Gyrodactylus is a lineage of monogenean flatworm ectoparasites exhibiting many features that make them a suitable model to study the host-parasite coevolutionary dynamics. Previous coevolutionary studies of this lineage mainly relied on low-power datasets (a small number of samples and a single molecular marker) and (now) outdated algorithms. METHODS: To investigate the coevolutionary relationship of gyrodactylids and their fish hosts in high resolution, we used complete mitogenomes (including two newly sequenced Gyrodactylus species), a large number of species in the single-gene dataset, and four different coevolutionary algorithms. RESULTS: The overall coevolutionary fit between the parasites and hosts was consistently significant. Multiple indicators confirmed that gyrodactylids are generally highly host-specific parasites, but several species could parasitize either multiple (more than 5) or phylogenetically distant fish hosts. The molecular dating results indicated that gyrodactylids tend to evolve towards high host specificity. Speciation by host switch was identified as a more important speciation mode than co-speciation. Assuming that the ancestral host belonged to Cypriniformes, we inferred four major host switch events to non-Cypriniformes hosts (mostly Salmoniformes), all of which occurred deep in the evolutionary history. Despite their relative rarity, these events had strong macroevolutionary consequences for gyrodactylid diversity. For example, in our dataset, 57.28% of all studied gyrodactylids parasitized only non-Cypriniformes hosts, which implies that the evolutionary history of more than half of all included lineages could be traced back to these major host switch events. The geographical co-occurrence of fishes and gyrodactylids determined the host use by these gyrodactylids, and geography accounted for most of the phylogenetic signal in host use. CONCLUSIONS: Our findings suggest that the coevolution of Gyrodactylus flatworms and their hosts is largely driven by geography, phylogeny, and host switches.

Laparoscopic orchidopexy for the treatment of cryptorchidism in adults: a description of the technique and outcomes.

BACKGROUND: There are few studies on cryptorchidism in adults, and its treatment is still controversial. METHODS: To summarize the surgical strategy and clinical efficacy of laparoscopic orchidopexy for the treatment of cryptorchidism in adults, 37 adult cryptorchidism patients were retrospectively analyzed between September 2017 and February 2022. All 37 patients underwent laparoscopic orchidopexy, of whom 33 underwent inguinal hernia repair without tension. The intraoperative procedures and surgical techniques were recorded in detail. Preoperative examination and regular postoperative review of color Doppler ultrasound, and reproductive hormone, alpha-fetoprotein, human chorionic gonadotropin, and lactate dehydrogenase levels were performed. RESULTS: All testes descended successfully into the scrotum, including 25 through the inguinal route and 12 through Hesselbach's triangle route. No intraoperative or postoperative complications were observed. The follow-up time was 38.6 (± 19.4) months, and no evidence of testicular malignancy was found during the follow-up period. After analyzing the reproductive hormone levels at 1 year postoperatively in 28 patients with more than 1 year of follow-up, it was found that the patients had a significant increase in testosterone levels and a decrease in follicle-stimulating hormone levels after surgery. None of the patients showed any significant improvement in semen quality after surgery. CONCLUSION: Our study suggests that laparoscopic orchidopexy is a safe and feasible surgical procedure for the treatment of cryptorchidism in adults, especially high cryptorchidism, which is difficult to treat. After comprehensive consideration, preserving the testis should be preferred for treating cryptorchidism in adults to maximize the protection of the patient's reproductive hormone secretion function.

Endogenous chemicals guard health through inhibiting ferroptotic cell death.

Ferroptosis is a new form of regulated cell death caused by iron-dependent accumulation of lethal polyunsaturated phospholipids peroxidation. It has received considerable attention owing to its putative involvement in a wide range of pathophysiological processes such as organ injury, cardiac ischemia/reperfusion, degenerative disease and its prevalence in plants, invertebrates, yeasts, bacteria, and archaea. To counter ferroptosis, living organisms have evolved a myriad of intrinsic efficient defense systems, such as cyst(e)ine-glutathione-glutathione peroxidase 4 system (cyst(e)ine-GPX4 system), guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin (BH4) system (GCH1/BH4 system), ferroptosis suppressor protein 1/coenzyme Q10 system (FSP1/CoQ10 system), and so forth. Among these, GPX4 serves as the only enzymatic protection system through the reduction of lipid hydroperoxides, while other defense systems ultimately rely on small compounds to scavenge lipid radicals and prevent ferroptotic cell death. In this article, we systematically summarize the chemical biology of lipid radical trapping process by endogenous chemicals, such as coenzyme Q10 (CoQ10), BH4, hydropersulfides, vitamin K, vitamin E, 7-dehydrocholesterol, with the aim of guiding the discovery of novel ferroptosis inhibitors.

M7G modification of FTH1 and pri-miR-26a regulates ferroptosis and chemotherapy resistance in osteosarcoma.

Doxorubicin and platinum are widely used in the frontline treatment of osteosarcoma, but resistance to chemotherapy limits its curative effect. Here, we have identified that METTL1 mediated N7-Methyladenosine (m7G) low expressed in osteosarcoma tissues, plays a critical oncogenic role, and enhances osteosarcoma chemosensitivity in osteosarcoma. Mechanistically, AlkAniline-Seq data revealed that Ferritin heavy chain (FTH1), the main component of ferritin, which is crucial for iron homeostasis and the inhibition of lipid peroxidation, is one of the top 10 genes with the most significant change in m7G methylation sites mediated by METTL1 in human osteosarcoma cells. Interestingly, METTL1 significantly increased the expression of FTH1 at the mRNA level but was remarkably suppressed at the protein level. We then identified primary (pri)-miR-26a and pri-miR-98 in the Top 20 m7G-methylated pri-miRNAs with highly conserved species. Further results confirmed that METTL1 enhances cell ferroptosis by targeting FTH1 and primary (pri)-miR-26a, promoting their maturity by enhancing RNA stability dependent on m7G methylation. The increase of mature miR-26a-5p that resulted from METTL1 overexpression could further target FTH1 mRNA and eliminate FTH1 translation efficiency. Moreover, the reduction of FTH1 translation dramatically increases cell ferroptosis and promotes the sensitivity of osteosarcoma cells to chemotherapy drugs. Collectively, our study demonstrates the METTL1/pri-miR-26a/FTH1 axis signaling in osteosarcoma and highlights the functional importance of METTL1 and m7G methylation in the progression and chemotherapy resistance of osteosarcoma, suggesting that reprogramming RNA m7G methylation as a potential and promising strategy for osteosarcoma treatment.

Preparation and fire resistance modification on tannin-based non-isocyanate polyurethane (NIPU) rigid foams.

Non-isocyanate polyurethane (NIPU) as a new type of polyurethane material has become a hot research topic in the polyurethane industry due to its no utilization of toxic isocyanates during the synthesis process. And the developing on recyclable biomass materials has also much attention in the industrial sector, hence the preparation and application of bio-based NIPU has also become a very meaningful study work. So, in this paper, tannin as a biomass material was used to synthesize tannin based non-isocyanate polyurethanes (TNIPU) resin, and then successfully prepared a self-blowing TNIPU foam at room temperature by using formic acid as initiator and glutaraldehyde as cross-linking agent. The compressive strength of this foam as high as 0.8 MPa, which is an excellent compressive performance. Meanwhile it will return to the state before compression when removing the pressure. This indicating that the foam has good toughness. In addition, formic acid can react with the amino groups in TNIPU to form amide substances, and generated enough heat to initiate the foaming process. Glutaraldehyde, as a crosslinking agent, reacts with the amino group in TNIPU to form a network structure system. By scanning electron microscope (SEM) observation of the cell shapes, it can be seen that the foam cells were uniform in size and shape, and the cell pores showed open and closed cells. The limiting oxygen index (LOI) tested value of this TNIPU foam is 24.45 % without any flame retardant added, but compared to the LOI value of polyurethane foam (17 %-19 %), TNIPU foam reveal a better fire resistance. It has a wider application prospect.

Nonlinear-mirror mode-locked crystal waveguide laser by intracavity fourth-harmonic loss modulation.

We present a nonlinear-mirror (NLM) mode-locked crystal waveguide laser. By adding nonlinear crystals into traditional NLM devices, the fourth harmonic is generated to form loss modulation, which suppresses the Q-switching instability of mode-locked lasers and achieves the optimal equivalent transmittance. The NLM mode-locked laser delivers ∼30 W average power with a repetition rate of 32.2 MHz and a pulse width of 950 fs. It is revealed that this novel, to the best of our knowledge, design with simple, robust, and reliable structure has a great potential in the development of high-power mode-locked laser.

Influencing factors for residual kidney function in incident peritoneal dialysis patients: a systematic review and meta-analysis.

BACKGROUND: Residual kidney function (RKF) impacts patients' survival rate and quality of life when undergoing peritoneal dialysis (PD). This meta-analysis was conducted to systematically identify risk and protective factors associated with RKF decline and loss. METHODS: We searched three English and one Chinese databases from inception to January 31, 2023, for cohort and cross-sectional studies exploring factors associated with RKF decline or loss. The random effects model was employed to aggregate risk estimates and 95% confidence intervals (CIs) from multivariate analysis. Sensitivity and subgroup analyses were performed to explore the heterogeneity among the studies. RESULTS: Twenty-seven studies comprising 13549 individuals and 14 factors were included in the meta-analysis. Based on the meta-analysis results, risk factors involving male gender (hazard ratio (HR) 1.689, 95%CI 1.385-2.061), greater body mass index (BMI) (odds ratio (OR) 1.081, 95% confidence interval (CI) 1.029-1.135), higher systolic blood pressure (SBP) (HR 1.014, 95%CI 1.005-1.024), diabetes mellitus (DM) (HRRKF loss 1.873, 95%CI 1.475-2.378), DM (ORRKF decline 1.906, 95%CI 1.262-2.879), peritonitis (relative ratio (RR) 2.291, 95%CI 1.633-3.213), proteinuria (OR 1.223, 95%CI 1.117-1.338), and elevated serum phosphorus (RR 2.655, 95%CI 1.679-4.201) significantly contributed to the risk of RKF decline and loss in PD patients. Conversely, older age (HR 0.968, 95%CI 0.956-0.981), higher serum albumin (OR 0.834, 95%CI 0.720-0.966), weekly Kt/V urea (HR 0.414, 95%CI 0.248-0.690), baseline urine volume (UV) (HR 0.791, 95%CI 0.639-0.979), baseline RKF (HR 0.795, 95%CI 0.739-0.857) exhibited protective effects. However, diuretics use, automatic peritoneal dialysis (APD) modality and baseline RKF did not significantly impact RKF decline. CONCLUSIONS: Patients with male gender, greater BMI, higher SBP, DM, peritonitis, proteinuria, and elevated serum phosphorus might have a higher risk of RKF decline and loss. In contrast, older age, higher serum albumin, weekly Kt/V urea, baseline UV, and baseline RKF might protect against RKF deterioration.

Tyramine and its Amtyr1 receptor modulate attention in honey bees (Apis mellifera).

Animals must learn to ignore stimuli that are irrelevant to survival and attend to ones that enhance survival. When a stimulus regularly fails to be associated with an important consequence, subsequent excitatory learning about that stimulus can be delayed, which is a form of nonassociative conditioning called 'latent inhibition'. Honey bees show latent inhibition toward an odor they have experienced without association with food reinforcement. Moreover, individual honey bees from the same colony differ in the degree to which they show latent inhibition, and these individual differences have a genetic basis. To investigate the mechanisms that underly individual differences in latent inhibition, we selected two honey bee lines for high and low latent inhibition, respectively. We crossed those lines and mapped a Quantitative Trait Locus for latent inhibition to a region of the genome that contains the tyramine receptor gene Amtyr1 [We use Amtyr1 to denote the gene and AmTYR1 the receptor throughout the text.]. We then show that disruption of Amtyr1 signaling either pharmacologically or through RNAi qualitatively changes the expression of latent inhibition but has little or slight effects on appetitive conditioning, and these results suggest that AmTYR1 modulates inhibitory processing in the CNS. Electrophysiological recordings from the brain during pharmacological blockade are consistent with a model that AmTYR1 indirectly regulates at inhibitory synapses in the CNS. Our results therefore identify a distinct Amtyr1-based modulatory pathway for this type of nonassociative learning, and we propose a model for how Amtyr1 acts as a gain control to modulate hebbian plasticity at defined synapses in the CNS. We have shown elsewhere how this modulation also underlies potentially adaptive intracolonial learning differences among individuals that benefit colony survival. Finally, our neural model suggests a mechanism for the broad pleiotropy this gene has on several different behaviors.

To efficiently navigate their environment, animals must pay attention to cues associated with events important for survival while also dismissing meaningless signals. The difference between relevant and irrelevant stimuli is learned through a range of complex mechanisms that includes latent inhibition. This process allows animals to ignore irrelevant stimuli, which makes it more difficult for them to associate a cue and a reward if that cue has been unrewarded before. For example, bees will take longer to 'learn' that a certain floral odor signals a feeding opportunity if they first repeatedly encountered the smell when food was absent. Such a mechanism allows organisms to devote more attention to other stimuli which have the potential to be important for survival. The strength of latent inhibition ­ as revealed by how quickly and easily an individual can learn to associate a reward with a previously unrewarded stimulus ­ can differ between individuals. For instance, this is the case in honey bee colonies, where workers have the same mother but may come from different fathers. Such genetic variation can be beneficial for the hive, with high latent inhibition workers being better suited for paying attention to and harvesting known resources, and their low latent inhibition peers for discovering new ones. However, the underlying genetic and neural mechanisms underpinning latent inhibition variability between individuals remained unclear. To investigate this question, Latshaw et al. cross-bred bees from high and low latent inhibition genetic lines. The resulting progeny underwent behavioral tests, and the genome of low and high latent inhibition individuals was screened. These analyses revealed a candidate gene, Amtyr1, which was associated with individual variations in the learning mechanism. Further experiments showed that blocking or disrupting the production the AMTYR1 protein led to altered latent inhibition behavior as well as dampened attention-related processing in recordings from the central nervous system. Based on these findings, a model was proposed detailing how varying degrees of Amtyr1 activation can tune Hebbian plasticity, the brain mechanism that allows organisms to regulate associations between cues and events. Importantly, because of the way AMTYR1 acts in the nervous system, this modulatory role could go beyond latent inhibition, with the associated gene controlling the activity of a range of foraging-related behaviors. Genetic work in model organisms such as fruit flies would allow a more in-depth understanding of such network modulation.