Predicting and reducing potential parasite infection between migratory livestock and resident Asiatic ibex of Pin valley, India.

Disease cross-transmission between wild and domestic ungulates can negatively impact livelihoods and wildlife conservation. In Pin valley, migratory sheep and goats share pastures seasonally with the resident Asiatic ibex (Capra sibirica), leading to potential disease cross-transmission. Focussing on gastro-intestinal nematodes (GINs) as determinants of health in ungulates, we hypothesized that infection on pastures would increase over summer from contamination by migrating livestock. Consequently, interventions in livestock that are well-timed should reduce infection pressure for ibex. Using a parasite life-cycle model, that predicts infective larval availability, we investigated GIN transmission dynamics and evaluated potential interventions. Migratory livestock were predicted to contribute most infective larvae onto shared pastures due to higher density and parasite levels, driving infections in both livestock and ibex. The model predicted a c.30-day antiparasitic intervention towards the end of the livestock's time in Pin would be most effective at reducing GINs in both hosts. Albeit with the caveats of not being able to provide evidence of interspecific parasite transmission due to the inability to identify parasite species, this case demonstrates the usefulness of our predictive model for investigating parasite transmission in landscapes where domestic and wild ungulates share pastures. Additionally, it suggests management options for further investigation.

Spoilt for choice: Do female mosquitoes experience choice overload when deciding where to lay eggs?

Animals live in complex natural environments. Based on the effects of natural selection, theory on animal information use says that it is optimal for animals to make "rational" decisions, i.e., to choose alternatives which maximize fitness gains, irrespective of the number of alternatives presented to them. Yet, animals commonly make seemingly "irrational" choices in the face of complex and variable stimuli that challenge their cognitive machinery. Here, we test the choice overload hypothesis - decision-making is negatively affected when animals experience an overload of choice. Using simultaneous-choice trials that varied in choice repertoire size, we examined oviposition site selection behaviour in Aedes aegypti towards larval predators, the nymphs of Bradinopyga geminata. Based on the underlying fitness trade-offs of oviposition decision-making, we predicted that female oviposition preference would be weaker and variation in this response would be higher in complex, multiple-choice trials than in binary-choice trials. In partial support of our hypothesis, oviposition preference was weaker in the complex, multiple-choice trials, but the variation in response depended on predator density, and did not depend on choice repertoire size. We suggest that information overload can negatively affect certain aspects of animal decision-making, resulting in choices appearing as "irrational" if the complexity of the decision-making context is not incorporated. Information overload can potentially lead to alternative strategies, such as bet-hedging or decision-making with reduced discrimination.

Prevalence and Risk of Behavioral Symptoms among Patients with Insomnia and Alzheimer's Disease: A Retrospective Database Analysis.

OBJECTIVES: This study evaluated the prevalence and patterns of behavioral symptoms, including agitation/aggression (AA), psychotic symptoms (PS), anxiety/mood disorders (MD), and delirium among patients with Alzheimer's disease (AD) and their association with diagnosed insomnia. DESIGN: A retrospective cohort analysis was conducted using the MarketScan Multi-State Medicaid Database 2016-2020. SETTING AND PARTICIPANTS: Patients aged ≥50 with newly diagnosed AD (N = 56,904) were identified during 2017-2019 and categorized into insomnia and non-insomnia groups based on billing codes recorded in medical and pharmacy claims. METHODS: The index date was defined as the earliest date of diagnosis/medication of insomnia. The new diagnosis of AD had to be established within 12 months before (baseline) or 3 months after the index date. Point prevalence of behavioral symptoms was estimated during baseline and the 12-month follow-up period. Propensity score matching was performed to match patients with and without insomnia. Multivariable conditional logistic regression was used to assess the risk of diagnosis of behavioral symptoms among insomnia and non-insomnia groups. RESULTS: The study cohort included 7808 patients with newly diagnosed AD (mean age = 79.4, SD = 9.6 years). The point prevalence of behavioral symptoms was as follows: among those with insomnia (n = 3904), in the baseline, AA = 9.0%, PS = 12.5%, and MD = 57.8%, and during the follow-up, AA = 13.9%, PS = 16.3%, and MD = 72.1%; among those without insomnia (n = 3904), in the baseline, AA = 6.2%, PS = 9.2%, and MD = 41.4%; and during the follow-up, AA = 7.4%, PS = 10.4%, and MD = 49.2%. The likelihood of being diagnosed with any behavioral symptoms in the follow-up period was significantly higher among patients with insomnia than those without [adjusted odds ratio (OR), 2.7; 95% confidence interval (CI), 2.4-3.1]. CONCLUSIONS AND IMPLICATIONS: In patients with AD, prevalence of behavioral symptoms and likelihood of being diagnosed with behavioral symptoms were significantly higher among patients with diagnosed insomnia. Further investigation is needed to understand the relationship between insomnia and behavioral symptoms in patients with AD.

Regulation of PIN polarity in response to abiotic stress.

Plants have evolved robust adaptive mechanisms to withstand the ever-changing environment. Tightly regulated distribution of the hormone auxin throughout the plant body controls an impressive variety of developmental processes that tailor plant growth and morphology to environmental conditions. The proper flow and directionality of auxin between cells is mainly governed by asymmetrically localized efflux carriers - PINs - ensuring proper coordination of developmental processes in plants. Discerning the molecular players and cellular dynamics involved in the establishment and maintenance of PINs in specific membrane domains, as well as their ability to readjust in response to abiotic stressors is essential for understanding how plants balance adaptability and stability. While much is known about how PINs get polarized, there is still limited knowledge about how abiotic stresses alter PIN polarity by acting on these systems. In this review, we focus on the current understanding of mechanisms involved in (re)establishing and maintaining PIN polarity under abiotic stresses.

Caregivers' Perspectives of Pharmacist Intervention in Children's Antibiotic Prescriptions for Upper Respiratory Tract Infections.

Background: Community pharmacists can help fight antimicrobial resistance by intervening in children's antibiotic prescriptions for upper respiratory tract infections (URTIs). However, caregivers' attitudes and perspectives on this are unknown. Objective: To evaluate children's caregivers' acceptability of pharmacists intervening in their antibiotic prescriptions for URTIs with respect to their knowledge of and attitude toward pharmacists and knowledge, beliefs, and behaviors related to antibiotics. Methods: A 69-item survey was created and sent to a panel of caregivers. ANCOVA and path analysis were used to evaluate the relationship between caregiver characteristics and their acceptability of pharmacists intervening in children's antibiotic prescriptions for URTIs. Results: Responses from 246 caregivers who met the inclusion and exclusion criteria were analyzed. Mean caregivers' acceptability of pharmacists intervening in children's antibiotic prescriptions for URTIs was 3.25 out of 5 (±1.01). The ANCOVA model (adjusted R2 = .636) showed positive attitude toward pharmacists and being more accepting of health advice from pharmacists since the start of the COVID-19 pandemic were associated with higher caregiver acceptability of pharmacists intervening in children's antibiotic prescriptions. Caregivers with better relationships with their pharmacist also tend to have better attitudes toward pharmacists. Not wanting antibiotics for symptom relief was associated with decreased acceptability scores. Conclusion: Overall caregiver acceptability of pharmacists intervening in antibiotic prescriptions was slightly above neutral. Building a relationship with caregivers could help change their attitude and increase the acceptability of pharmacists intervening in children's antibiotic prescriptions. Caregivers seeking symptomatic relief may be more open to non-antibiotic alternatives.

Gabapentin and Opioids Utilization in Patients With Diabetic Neuropathy Enrolled in Medicare (2012-2016): A Cohort Study.

This retrospective cohort study describes the utilization of opioids and gabapentin among patients with diabetic neuropathy who were gabapentin and opioid naïve, and assesses predictors of concomitant use of opioids and gabapentin. Using Medicare claims data (2012-2016), 22 037 patients were identified, of whom 23.42% (N = 5161) initiated opioids without concomitant gabapentin, 4.56% (N = 1004) initiated gabapentin without concomitant opioids, and 3.87% (N = 852) had concomitant use of gabapentin and opioids 12 months following their index date (date of earliest diagnosis). Concomitant gabapentin and opioid use were more common for lower doses of both drugs and for 15 days or more cumulatively. Compared to individuals aged 65-74, those aged 75-84 (OR: .759; 95% CI: 0.653-.882) or ≥ 85 years (OR: .586, 95% CI: 0.462-.743) had lower odds of concomitant use. People residing in the Northeast had lower odds of concomitant use, compared to those residing in the South (OR: .646 95% CI: 0.535-.779). Females compared to males (OR: 1.185, 95% CI: 1.027-1.367), people with higher Charlson's Comorbidity Index (CCI) scores (OR: 1.085, 95% CI: 1.037-1.135) or those having anxiety (OR: 1.462, 95% CI: 1.131-1.889) had higher odds of concomitant use. Concomitant prescriptions of opioids and gabapentin were more common for longer durations, indicating the need for interventions aimed at minimizing this prescribing practice.

Patterns of Lipid Lowering Therapy Use Among Older Adults in a Managed Care Advantage Plan in the United States.

Background: The prevalence of cardiovascular events is increasing. There are many new lipids lowering therapies available in recent years. Increased evidence through literature and guidelines suggests that the use of lipid lowering therapy (LLT) benefits patients who are at risk for cardiovascular events.Objective: The objective of this study was to describe the current LLT use as well as patterns of treatment modification among adults ≥ 65 years.Methods: A retrospective analysis of administrative claims data between January 2016 and May 2018 was conducted. Patients with a LLT refill and continuous enrollment during 1-year prior and 1-year follow-up were identified. The treatment episodes captured were interruption of therapy, intensity changes, dose changes, treatment augmentation, switching, and discontinuation. An analysis of treatment patterns among patients ≥75 years was also performed.Results: The study included 14,360 patients with a LLT of which 99% of patients were on statins as monotherapy or combination. Overall non-statin therapy use either as monotherapy or combination was 2.1%. There were significant differences among new initiators and existing users of therapy. Among prevalent users 57.4% had no changes in the follow-up period, 13.6% interrupted therapy, and 6.6% discontinued. Among new users, 47.9% patients had interrupted therapy, 25% had no changes, and 21.9% discontinued therapy.Conclusion: Most patients were on monotherapy and statins with low non-statin use. The new users among them were more likely to discontinue and interrupt therapy, highlighting the limitations and issues that older patients face that need to increase adherence.

Barriers and facilitators for low-dose computed tomography lung cancer screening in rural populations in the United States: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to identify barriers and facilitators for low-dose computed tomography lung cancer screening uptake and adherence among rural populations in the United States. INTRODUCTION: Lung cancer is the leading cause of cancer-related death in the United States, and cancer patients from rural areas have poorer outcomes than those from metropolitan areas. Evidence exists that lung cancer screening by low-dose computed tomography significantly increases survival time but is also significantly underutilized. INCLUSION CRITERIA: Studies completed in the United States with adults who fit United States Preventive Services Task Force guidelines for lung cancer screening and who live in rural areas will be included. Studies published in English since 2013 that report on barriers and facilitators for low-dose computed tomography lung cancer screening uptake and adherence will be included in this review. Quantitative, qualitative, or mixed-methods studies will be included, along with opinion pieces published by government agencies or professional cancer-related organizations. METHODS: The search strategy will locate published primary studies, reviews, and opinion papers, including those by government and nonprofit agencies focused on cancer. The databases to be searched include MEDLINE, CINAHL Complete, Embase, Web of Science, and Cochrane Library. Gray literature databases and sources of unpublished studies will also be searched. Independent reviewers will be used throughout the search and selection process.

Barriers and facilitators to cancer clinical trial enrollment and participation among rural populations: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to identify barriers and facilitators related to cancer clinical trial enrollment and participation among rural populations. INTRODUCTION: Advancing the effectiveness of cancer treatment and increasing early detection of cancer relies on enrollment and participation of individuals in cancer clinical trials. Lack of enrollment and participation in trials is a concern, and there is evidence that individuals living in rural areas are unlikely to participate in such trials. Information on barriers to, and facilitators of, enrollment and participation in cancer clinical trials is needed for the development of evidence-based interventions to increase the enrollment and participation of rural populations. INCLUSION CRITERIA: The review will consider studies on adults aged 18 years or older living in rural areas. Studies that report on barriers and facilitators to enrollment and participation in cancer clinical trials, including both cancer therapeutic and cancer early detection trials, will be included in the review. The review will consider quantitative, qualitative, and text and opinion papers for inclusion. METHODS: The search strategy will aim to locate published primary studies, reviews, and opinion papers, the latter including those by professional oncology organizations. The databases to be searched include MEDLINE, CINAHL, Embase, Web of Science, and Cochrane Library. Gray literature databases will also be searched. Two independent reviewers will retrieve full-text studies and extract data. The results will be presented in diagrammatic format with a narrative summary.

Dose-dependent relation between metformin and the risk of hormone receptor-positive, her2-negative breast cancer among postmenopausal women with type-2 diabetes.

PURPOSE: Metformin has demonstrated a chemoprotective effect in breast cancer but there is limited evidence on the effect of cumulative exposure to metformin and the risk of hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR + /HER2-) breast cancer. This study assessed this risk with dose and intensity of metformin in postmenopausal women with type-2 diabetes mellitus (T2DM). METHODS: This nested case-control study used the Surveillance, Epidemiology, and End Results-Medicare data (2008-2015). Cohort entry was the date of incident T2DM diagnosis. Cases were those diagnosed with HR + /HER2- breast cancer (event date) as their first/only cancer. Non-cancer T2DM controls were matched using variable-ratio-matching. Cumulative dose and average intensity of metformin were measured during the 1-year lookback period. Dose(mg) was categorized as: (1)0, (2)0-30,000, (3)30,001-136,000, (4)136,001-293,000, and (5) > 293,000, and intensity(mg/day) as: 0, 1-500, and > 500. Covariates were conceptualized using the Andersen Behavioral Model. Conditional logistic regression was used to assess the risk of HR + /HER2- breast cancer with metformin-use. RESULTS: There were 690 cases and 2747 controls. The median duration of T2DM was 1178 days in controls and 1180 days in cases. Higher cumulative dose categories: 4 (adjusted odds ratio(aOR) = 0.72, 95% CI 0.55-0.95,p = 0.02), and 5 (OR = 0.60, 95% CI 0.42-0.85,p < 0.01) had significantly lower odds of HR + /HER2- breast cancer compared to category 0. The highest intensity category of metformin had 39% lower odds of HR + /HER2- breast cancer (OR = 0.61, 95% CI 0.46-0.82,p < 0.01) compared to the 0 mg/day group. CONCLUSIONS: Higher metformin exposure was associated with reduced risk of HR + /HER2- breast cancer, adding to the evidence supporting metformin's chemoprotective effect.

A glucose-target of rapamycin signaling axis integrates environmental history of heat stress through maintenance of transcription-associated epigenetic memory in Arabidopsis.

In nature, plants cope with adversity and have established strategies that recall past episodes and enable them to better cope with stress recurrences by establishing a 'stress memory'. Emerging evidence suggests that glucose (Glc) and target of rapamycin (TOR), central regulators of plant growth, have remarkable functions in stress adaptation. However, whether TOR modulates a stress memory response is so far unknown. Global transcriptome profiling identified that Glc, through TOR, regulates the expression of numerous genes involved in thermomemory. Priming of TOR overexpressors with mild heat showed better stress endurance, whereas TOR RNAi showed reduced thermomemory. This thermomemory is linked with histone methylation at specific sites of heat stress (HS) genes. TOR promotes long-term accumulation of H3K4me3 on thermomemory-associated gene promoters, even when transcription of those genes reverts to their basal level. Our results suggest that ARABIDOPSIS TRITHORAX 1 (ATX1), an H3K4 methyltransferase already shown to regulate H3K4me3 levels at the promoters of HS recovery genes, is a direct target of TOR signaling. The TOR-activating E2Fa binds to the promoter of ATX1 and regulates its expression, which ultimately regulates thermomemory. Collectively, our findings reveal a mechanistic framework in which Glc-TOR signaling determines the integration of stress and energy signaling to regulate thermomemory.

Maternal soybean diet on prevention of obesity-related breast cancer through early-life gut microbiome and epigenetic regulation.

Overnutrition-induced obesity and metabolic dysregulation are considered major risk factors contributing to breast cancer. The origin of both obesity and breast cancer can retrospect to early development in human lifespan. Genistein (GE), a natural isoflavone enriched in soybean products, has been proposed to associate with a lower risk of breast cancer and various metabolic disorders. Our study aimed to determine the effects of maternal exposure to soybean dietary GE on prevention of overnutrition-induced breast cancer later in life and explore potential mechanisms in different mouse models. Our results showed that maternal dietary GE treatment improved offspring metabolic functions by significantly attenuating high-fat diet-induced body fat accumulation, lipid panel abnormalities and glucose intolerance in mice offspring. Importantly, maternal dietary GE exposure effectively delayed high-fat diet-simulated mammary tumor development in female offspring. Mechanistically, we found that maternal dietary GE may exert its chemopreventive effects through affecting essential regulatory gene expression in control of metabolism, inflammation and tumor development via, at least in part, regulation of offspring gut microbiome, bacterial metabolites and epigenetic profiles. Altogether, our findings indicate that maternal GE consumption is an effective intervention approach leading to early-life prevention of obesity-related metabolic disorders and breast cancer later in life through dynamically influencing the interplay between early-life gut microbiota, key microbial metabolite profiles and offspring epigenome.

Combinatorial epigenetic mechanisms of sulforaphane, genistein and sodium butyrate in breast cancer inhibition.

Dietary phytochemicals are currently being studied with great interest due to their ability to regulate the epigenome resulting in prevention of cancer. Some natural botanicals have been reported to have enhanced and synergistic impact on cancer suppression when administered at optimum concentrations and in-conjunction. Sulforaphane (SFN) is an isothiocyanate found in cruciferous vegetables and sodium butyrate (NaB) is a short-chain fatty acid produced by gut microbiota. They have been intensively explored due to numerous anti-cancerous properties and ability to modulate epigenetic machinery by inhibition of histone deacetylase (HDAC). Genistein (GE), present in soy, is a known DNA methyltransferase (DNMT) inhibitor. While combined chemoprotective epigenetic effects induced by SFN and GE have been investigated, the key impact of combinatorial SFN-NaB, GE-NaB, and SFN-GE-NaB bioactive components in regulation of various mechanisms are poorly defined. In the present study, we found that combinations of dietary compounds had synergistic effects in decreasing cellular viability at lower dosages than their single dosages in breast cancer cell lines. The respective combinations limited growth and increased apoptosis and necrosis in cancerous cells among which the tri-combination displayed the most significant impact. Additionally, the respective combinations of compounds arrested MDA-MB-231 and MCF-7 breast cancer cells at G2/M phase. Our further mechanistic evaluation revealed that respective di-combinations and tri-combination had higher impact in down-regulation of DNMTs (DNMT3A and DNMT3B), HDACs (HDAC1, HDAC6 and HDAC11), histone methyltransferases (EZH2 and SUV39H1) and histone acetyltransferases (GCN5, PCAF, P300 and CBP) levels as compared to singly administered compounds. We also found that these combinations exhibited global epigenetic changes by inhibition of DNMT and HDAC activity, histone H3 at lysine 27 methylation (H3K27me) and histone H3 at lysine 9 methylation (H3K9me) levels, and by induction of histone acetyltransferases activity. Collectively, our investigation indicates that combined SFN, GE and NaB is highly effective in inhibiting breast cancer genesis by, at least in part, regulating epigenetic modifications, which may have implications in breast cancer therapy.

A negative feedback loop of TOR signaling balances growth and stress-response trade-offs in plants.

TOR kinase is a central coordinator of nutrient-dependent growth in eukaryotes. Maintaining optimal TOR signaling is critical for the normal development of organisms. In this study, we describe a negative feedback loop of TOR signaling helping in the adaptability of plants in changing environmental conditions. Using an interdisciplinary approach, we show that the plant-specific zinc finger protein FLZ8 acts as a regulator of TOR signaling in Arabidopsis. In sugar sufficiency, TOR-dependent and -independent histone modifications upregulate the expression of FLZ8. FLZ8 negatively regulates TOR signaling by promoting antagonistic SnRK1α1 signaling and bridging the interaction of SnRK1α1 with RAPTOR1B, a crucial accessory protein of TOR. This negative feedback loop moderates the TOR-growth signaling axis in the favorable condition and helps in the activation of stress signaling in unfavorable conditions, establishing its importance in the adaptability of plants.

Prescribing trends of proton pump inhibitors, antipsychotics and benzodiazepines of medicare part d providers.

BACKGROUND: Proton pump inhibitors, benzodiazepines, and antipsychotics are considered potentially inappropriate medications in older adults according to the American Geriatric Society Beers Criteria, and deprescribing algorithms have been developed to guide use of these drug classes. The objective of this study was to describe the number of beneficiaries prescribed these medications, provider specialty and regional trends in prescribing, and the aggregate costs for these claims in Medicare Part D. METHODS: This was a retrospective cross-sectional study using publicly available Medicare Provider Utilization and Payment Data: Part D Prescriber data for years 2013-2019. Descriptive statistics and the Cochrane-Armitage test were used to summarize the trends. RESULTS: Overall, 30.1%, 25.6%, 4.6% of Medicare Part D beneficiaries had a proton pump inhibitor, benzodiazepine, and antipsychotic claim in 2013, respectively. These rates decreased to 27.5%, 17.5%, 4.1% in 2019 (p-value < 0.0001). However, the number of standardized 30-day claims increased from 63 million in 2013 to 84 million in 2019 for proton pump inhibitors, remained steady for benzodiazepines and slightly increased (10 million to 13 million) for antipsychotics. Total aggregate costs decreased by almost $1.5 billion for proton pump inhibitor, $100 million for benzodiazepine, and $700 million for antipsychotic from 2013 to 2019 (p-value < 0.0001). Almost 93% of gastroenterologists prescribed a proton pump inhibitor, and 60% of psychiatrists prescribed benzodiazepines and antipsychotics all seven years. The Other region had the highest percentage of providers prescribing all three classes and the highest number of standardized 30-day benzodiazepine claims. CONCLUSIONS: The overall rate of use of proton pump inhibitors, benzodiazepines, and antipsychotics decreased from 2013-2019 among Medicare Part D beneficiaries. Despite the increase in raw number of standardized 30-day claims, the costs decreased which is likely due to generics made available. These prescribing trends may aid in identifying and targeting potential deprescribing interventions.

An integrated analysis of the effects of maternal broccoli sprouts exposure on transcriptome and methylome in prevention of offspring mammary cancer.

Broccoli sprouts (BSp), a cruciferous vegetable, has shown promising effects on prevention of many types of cancer including breast cancer (BC). BC has a developmental foundation, and maternal nutrition status may influence an offspring's risk to BC later in life. What is less understood, however, is the influence of maternal nutrition intervention on reversing epigenomic abnormalities that are essential in BC programming during early development. Our research focused on how maternal exposure to BSp diet prevents offspring BC and investigation of possible epigenetic mechanisms during these processes. Our results showed that maternal feeding of BSp can prevent mammary tumor development in the offspring of a transgenic mouse model. Through comprehensive integrated multi-omics studies on transcriptomic and methylomic analysis, we identified numerous target genes exhibiting significantly differential gene expression and DNA methylation patterns in the offspring mammary tumor. We discovered that maternal exposure to BSp diet can induce both gene and methylation changes in several key genes such as Avpr2, Cyp4a12b, Dpp6, Gria2, Pcdh9 and Tspan11 that are correlated with pivotal biological functions during carcinogenesis. In addition, we found an impact of maternal BSp treatment on DNA methyltransferase and histone deacetylases activity. Our study provides knowledgeable information regarding how maternal BSp diet influences key tumor-related gene expression and the epigenetic changes using a genome-wide perspective. Additionally, these findings provide mechanistic insights into the effectiveness of maternal BSp administration on the prevention of BC in the offspring later in life, which may lead to an early-life BC chemopreventive strategy that benefits the progenies' long-term health.

Jasmonic acid coordinates with light, glucose and auxin signalling in regulating branching angle of Arabidopsis lateral roots.

The role of jasmonates (JAs) in primary root growth and development and in plant response to external stimuli is already known. However, its role in lateral root (LR) development remains to be explored. Our work identified methyl jasmonate (MeJA) as a key phytohormone in determining the branching angle of Arabidopsis LRs. MeJA inclines the LRs to a more vertical orientation, which was dependent on the canonical JAR1-COI1-MYC2,3,4 signalling. Our work also highlights the dual roles of light in governing LR angle. Light signalling enhances JA biosynthesis, leading to erect root architecture; whereas, glucose (Glc) induces wider branching angles. Combining physiological and molecular assays, we revealed that Glc antagonises the MeJA response via TARGET OF RAPAMYCIN (TOR) signalling. Moreover, physiological assays using auxin mutants, MYC2-mediated transcriptional activation of LAZY2, LAZY4 and auxin biosynthetic gene CYP79B2, and asymmetric distribution of DR5::GFP and PIN2::GFP pinpointed the role of an intact auxin machinery required by MeJA for vertical growth of LRs. We also demonstrated that light perception and signalling are indispensable for inducing vertical angles by MeJA. Thus, our investigation highlights antagonism between light and Glc signalling and how they interact with JA-auxin signals to optimise the branching angle of LRs.

Maternal soybean genistein on prevention of later-life breast cancer through inherited epigenetic regulations.

Breast cancer has strong developmental origins and maternal nutrition composition may influence later-life breast cancer risk in the offspring. Our study focused on a bioactive dietary component, genistein (GE) enriched in soybean products, to investigate specific timing of maternal GE exposure that may influence preventive efficacy of GE on offspring breast cancer later in life, and to explore the potential epigenetic mechanisms. Our results indicate a time-dependent effect of maternal GE exposure on early-life breast cancer development in offspring mice. Through integrated transcriptome and methylome analyses, we identified several candidate genes showing significantly differential gene expression and DNA methylation changes. We further found maternal long-term GE treatment can induce inherited epigenetic landmark changes in a candidate tumor suppressor gene, Trp63, resulting in transcriptional activation of Trp63 and induction of the downstream target genes. Our results suggest that maternal long-term exposure to soybean GE may influence early-life epigenetic reprogramming processes, which may contribute to its temporal preventive effects on breast cancer in the offspring. This study provides important mechanistic insights into an appropriate maternal administration of soybean products on prevention of breast cancer later in offspring life.

Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms.

Consumption of dietary natural components such as genistein (GE) found in soy-rich sources is strongly associated with a lower risk of breast cancer. However, bioactive dietary component-based therapeutic strategies are largely understudied in breast cancer treatment. Our investigation sought to elucidate the potential mechanisms linking bioactive dietary GE to its breast cancer chemotherapeutic potential in a special subtype of aggressive breast cancer-triple-negative breast cancer (TNBC)-by utilizing two preclinical patient-derived xenograft (PDX) orthotopic mouse models: BCM-3204 and TM00091. Our study revealed that administration of GE resulted in a delay of tumor growth in both PDX models. With transcriptomics analyses in TNBC tumors isolated from BCM-3204 PDXs, we found that dietary soybean GE significantly influenced multiple tumor-regulated gene expressions. Further validation assessment of six candidate differentially expressed genes (DEGs)-Cd74, Lpl, Ifi44, Fzd9, Sat1 and Wwc1-demonstrated a similar trend at gene transcriptional and protein levels as observed in RNA-sequencing results. Mechanistically, GE treatment-induced Cd74 downregulation regulated the NF-κB/Bcl-xL/TAp63 signal pathway, which may contribute to soybean GE-mediated therapeutic effects on TNBC tumors. Additionally, our findings revealed that GE can modify expression levels of key epigenetic-associated genes such as DNA methyltransferases (Dnmt3b), ten-eleven translocation (Tet3) methylcytosine dioxygenases and histone deacetyltransferase (Hdac2), and their enzymatic activities as well as genomic DNA methylation and histone methylation (H3K9) levels. Collectively, our investigation shows high significance for potential development of a novel therapeutic approach by using bioactive soybean GE for TNBC patients who have few treatment options.