Prevent Disease Development Research Articles

Prolonged residence of an albumin-IL-4 fusion protein in secondary lymphoid organs ameliorates experimental autoimmune encephalomyelitis.

Interleukin-4 (IL-4) suppresses the development of multiple sclerosis in a murine model of experimental autoimmune encephalomyelitis (EAE). Here, we show that, in mice with EAE, the accumulation and persistence in the lymph nodes and spleen of a systemically administered serum albumin (SA)-IL-4 fusion protein leads to higher efficacy in preventing disease development than the administration of wild-type IL-4 or of the clinically approved drug fingolimod. We also show that the SA-IL-4 fusion protein prevents immune-cell infiltration in the spinal cord, decreases integrin expression in antigen-specific CD4+ T cells, increases the number of granulocyte-like myeloid-derived suppressor cells (and their expression of programmed-death-ligand-1) in spinal cord-draining lymph nodes and decreases the number of T helper 17 cells, a pathogenic cell population in EAE. In mice with chronic EAE, SA-IL-4 inhibits immune-cell infiltration into the spinal cord and completely abrogates immune responses to myelin antigen in the spleen. The SA-IL-4 fusion protein may be prophylactically and therapeutically advantageous in the treatment of multiple sclerosis.

Surgical menopause may not increase the risk of non‐alcoholic fatty liver disease

Background Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Oestrogen is theorised to have protective effects in women, preventing disease development and slowing progression. Prior studies rely on self-reporting of menopause onset, therefore are fraught with recall bias. Surgical menopause provides clear dates from which the progression of NAFLD can be studied. Methods This a retrospective study of prospectively collected data. Patients without prior diagnosis of NAFLD were prospectively enrolled in a NAFLD prevalence study from February 2015 to October 2018. They were screened for NAFLD with FibroScan (FS), MR elastography (MRE) and LiverMultiScan (LMS). Subjects exceeding pre-specified cut-off values on any imaging test were offered a liver biopsy. A retrospective chart review was performed on all female enrollees for history of surgical menopause, defined as bilateral salpingo-oophorectomy (BSO). Results Two hundred and sixty-six females met inclusion criteria with a total of 31 patients with a history of BSO. Data analysis demonstrated no statistical difference between BSO and non-BSO groups as measured by FS (4.4 ± 1.0 kPa vs 5.1 ± 2.3 kPa; P = 0.44), MRE (2.1 ± 0.3 kPa vs 2.1 ± 0.4 kPa; P = 0.80) and LMS (5.1 ± 6.5% vs 4.4 ± 5.1%; P = 0.58). Subset analysis of women with BSO before 51 years old was also conducted. Based on liver biopsy and non-invasive assessment, there was no statistical difference in NAFLD diagnosis between the BSO, non-BSO group or subset analysis group. Conclusion In this retrospective study of prospectively collected data, we found that surgical menopause is not associated with a higher prevalence of NAFLD, diagnosed by non-invasive modalities and liver biopsy.

Modifying macronutrients is superior to microbiome transplantation in treating nonalcoholic fatty liver disease

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver injury and liver transplantation in Western countries. The pathogenesis of NAFLD includes overnutrition-associated metabolic syndrome or the improper consumption of dietary macro- and micro-nutrients that either support or prevent disease development. This altered nutrient landscape has been linked to shifts within the gut microbiota which can exacerbate liver pathology and the progression of NAFLD. Treatment goals for NAFLD target lifestyle and dietary modifications that restrict calories and adjust macronutrient content. It is not well understood how different macronutrients alter the microbiota and whether the diet-educated microbiota contribute to the resolution of disease. We fed mice a diet high in fat, cholesterol and fructose for 6 weeks and then in two different arms of the study, intervened with either a diet high in saturated and polyunsaturated fats and fiber or low in fats and fiber. In a second set of experiments, we performed microbiota transplants using cecal contents from mice fed one of the intervention diets to assess whether the diet-educated microbiota could impact clinical outcomes in mice fed a NAFLD-inducing diet. Pathology, steatosis, ALT/AST levels, and liver cytokine levels were measured as primary outcomes. We found that despite different microbiota compositions, both of the intervention diets reversed the progression of NAFLD and dampened inflammation. In contrast, transplantation of cecal contents from the intervention diet-fed mice to mice receiving a NAFLD-inducing diet was unable to prevent disease progression, and, in some cases, worsened disease. These data underscore the importance of dietary modifications to treat NAFLD and caution against the use of microbiota transplantation in the absence of dietary and lifestyle modifications.

Implant and Peri-implant Tissue Maintenance: Protocols to Prevent Peri-implantitis

In the absence of prevention protocols, early diagnosis and predictable treatment options for peri-implant diseases, the long-term survival of dental implants may be compromised. The purpose of the present review is to outline risk factors/indicators for peri-implantitis and propose current protocols (2015–present) for their control and disease prevention. Recent evidence suggests that factors including use of proton-pump and selective serotonin-reuptake inhibitors, titanium-particle release, disruption of the implant-abutment connection, and prosthesis material/dimensions may increase peri-implantitis prevalence. Although the literature is still scarce, identifying these factors and developing appropriate maintenance protocols is imperative to prevent disease development. Peri-implantitis can be influenced by several risk factors/indicators that can be classified as patient related, clinical, and/or implant related. To facilitate the individualized patient risk profile assessment and guide clinical decisions, this review describes the impact of identified risk factors/indicators on peri-implant health and proposes preventive protocols based on the latest evidence.

Effects of IL-34 on Macrophage Immunological Profile in Response to Alzheimer's-Related Aβ42 Assemblies.

Interleukin-34 (IL-34) is a recently discovered cytokine that acts as a second ligand of the colony stimulating factor 1 receptor (CSF1R) in addition to macrophage colony-stimulating factor (M-CSF). Similar to M-CSF, IL-34 also stimulates bone marrow (BM)-derived monocyte survival and differentiation into macrophages. Growing evidence suggests that peripheral BM-derived monocyte/macrophages (BMMO) play a key role in the physiological clearance of cerebral amyloid β-protein (Aβ). Aβ42 forms are especially neurotoxic and highly associated with Alzheimer's disease (AD). As a ligand of CSF1R, IL-34 may be relevant to innate immune responses in AD. To investigate how IL-34 affects macrophage phenotype in response to structurally defined and stabilized Aβ42 oligomers and preformed fibrils, we characterized murine BMMO cultured in media containing M-CSF, IL-34, or regimens involving both cytokines. We found that the immunological profile and activation phenotype of IL-34-stimulated BMMO differed significantly from those cultured with M-CSF alone. Specifically, macrophage uptake of fibrillar or oligomeric Aβ42 was markedly reduced following exposure to IL-34 compared to M-CSF. Surface expression of type B scavenger receptor CD36, known to facilitate Aβ recognition and uptake, was modified following treatment with IL-34. Similarly, IL-34 macrophages expressed lower levels of proteins involved in both Aβ uptake (triggering receptor expressed on myeloid cells 2, TREM2) as well as Aβ-degradation (matrix metallopeptidase 9, MMP-9). Interestingly, intracellular compartmentalization of Aβ visualized by staining of early endosome antigen 1 (EEA1) was not affected by IL-34. Macrophage characteristics associated with an anti-inflammatory and pro-wound healing phenotype, including processes length and morphology, were also quantified, and macrophages stimulated with IL-34 alone displayed less process elongation in response to Aβ42 compared to those cultured with M-CSF. Further, monocytes treated with IL-34 alone yielded fewer mature macrophages than those treated with M-CSF alone or in combination with IL-34. Our data indicate that IL-34 impairs monocyte differentiation into macrophages and reduces their ability to uptake pathological forms of Aβ. Given the critical role of macrophage-mediated Aβ clearance in both murine models and patients with AD, future work should investigate the therapeutic potential of modulating IL-34 in vivo to increase macrophage-mediated Aβ clearance and prevent disease development.

Medium-chain fatty acids in nutritional therapy: A review

Medium-Chain Fatty Acids (MCFA) are saturated fats with aliphatic rings of 6-12 carbons. It is widely accepted that the metabolism of MCFA induces ketogenesis in the liver. Ketone bodies have been suggested to produce larger amounts of energy compared to glucose. Its benefit in providing an alternative source of energy has been as one of the strategies to prevent disease development especially those diseases that are associated with glucose metabolism or mitochondrial dysfunction. The current review highlights the nutritional impacts of MCFA and its utilization in disease therapy.

SIRPα on CD11c+ cells induces Th17 cell differentiation and subsequent inflammation in the CNS in experimental autoimmune encephalomyelitis.

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c+ cells of mice (SirpaΔDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of SirpaΔDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of SirpaΔDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c+ cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c+ cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.

Breast Cancer Prevention-Is there a Future for Sulforaphane and Its Analogs?

Breast cancer is the most prevalent type of cancer among women worldwide. There are several recommended methods of breast cancer prevention, including chemoprevention. There are several approved drugs used to prevent breast cancer occurrence or recurrence and metastasizing. There are also a number of new substances undergoing clinical trials and at the stage of initial study. Studies suggest that dietary factors play a crucial role in breast cancer etiology. Epidemiological studies indicate that in particular vegetables from the Brassicaceae family are a rich source of chemopreventive substances, with sulforaphane (SFN) being one of the most widely studied and characterized. This review discusses potential applicability of SFN in breast cancer chemoprevention. A comprehensive review of the literature on the impact of SFN on molecular signalling pathways in breast cancer and breast untransformed cells is presented. The presented results of in vitro and in vivo studies show that this molecule has a potential to act as a preventive molecule either to prevent disease development or recurrence and metastasizing, and as a compound protecting normal cells against the toxic effects of cytostatics. Finally, the still scanty attempts to develop an improved analog are also presented and discussed.

Location and timing of the first osteophyte after arthroscopic knee surgeries

Purpose: Preventing disease development and/or progression of osteoarthritis of the knee (KOA) has been sought from standpoint of not only social welfare but also social economy. Due to rapid progression of aging society the requirement is growing worldwide. Unfortunately effective method is still open to be explored and researchers are straggling to establish it. One possible first step is to achieve this will be to detect initial change of KOA as early as possible. Imaging biomarkers are thought to be suitable for this purpose due to its property to assess only corresponding joint without being affected by systemic changes.

Nasal Delivery of a Commensal Pasteurellaceae Species Inhibits Nontypeable Haemophilus influenzae Colonization and Delays Onset of Otitis Media in Mice.

Nasopharyngeal colonization with nontypeable Haemophilus influenzae (NTHi) is a prerequisite for developing NTHi-associated infections, including otitis media. Therapies that block NTHi colonization may prevent disease development. We previously demonstrated that Haemophilus haemolyticus, a closely related human commensal, can inhibit NTHi colonization and infection of human respiratory epithelium in vitro We have now assessed whether Muribacter muris (a rodent commensal from the same family) can prevent NTHi colonization and disease in vivo using a murine NTHi otitis media model. Otitis media was modeled in BALB/c mice using coinfection with 1 × 104.5 PFU of influenza A virus MEM H3N2, followed by intranasal challenge with 5 × 107 CFU of NTHi R2866 Specr Mice were pretreated or not with an intranasal inoculation of 5 × 107 CFU M. muris 24 h before coinfection. NTHi and M. muris viable counts and inflammatory mediators (gamma interferon [IFN-γ], interleukin-1β [IL-1β], IL-6, keratinocyte chemoattractant [KC], and IL-10) were measured in nasal washes and middle ear tissue homogenate. M. muris pretreatment decreased the median colonization density of NTHi from 6 × 105 CFU/ml to 9 × 103 CFU/ml (P = 0.0004). Only 1/12 M. muris-pretreated mice developed otitis media on day 5 compared to 8/15 mice with no pretreatment (8% versus 53%, P = 0.0192). Inflammation, clinical score, and weight loss were also lower in M. muris-pretreated mice. We have demonstrated that a single dose of a closely related commensal can delay onset of NTHi otitis media in vivo Human challenge studies investigating prevention of NTHi colonization are warranted to reduce the global burden of otitis media and other NTHi diseases.

Precision health through prediction modelling: factors to consider before implementing a prediction model in clinical practice.

INTRODUCTION Precision medical practice emphasises early detection, improved surveillance and prevention through targeted intervention. Prediction models can help identify high-risk individuals to be targeted for healthy behavioural changes or medical treatment to prevent disease development and assist both health professionals and patients to make informed decisions. Concerns exist regarding the adequacy, accuracy, validity and reliability of prediction models. AIM The purpose of this study is to introduce readers to the basic concept of prediction modelling in precision health and recommend factors to consider before implementing a prediction model in clinical practice. METHODS Prediction models developed maintaining proper process and with quality prediction and validation can be used in clinical practice to improve patient care. RESULTS Aspects of prediction models that should be considered before implementation include: appropriateness of the model for the intended purpose; adequacy of the model; validation, face validity and clinical impact studies of the model; a parsimonious model with data easily measured in clinical settings; and easily accessible models with decision support for successful implementation. DISCUSSION Choosing clinical prediction models requires cautious consideration and several practical factors before implementing a model in clinical practice.

Diet in Parkinson's Disease: Critical Role for the Microbiome.

Background: Parkinson's disease (PD) is the most common movement disorder affecting up to 1% of the population above the age of 60 and 4–5% of those above the age of 85. Little progress has been made on efforts to prevent disease development or halt disease progression. Diet has emerged as a potential factor that may prevent the development or slow the progression of PD. In this review, we discuss evidence for a role for the intestinal microbiome in PD and how diet-associated changes in the microbiome may be a viable approach to prevent or modify disease progression.Methods: We reviewed studies demonstrating that dietary components/foods were related to risk for PD. We reviewed evidence for the dysregulated intestinal microbiome in PD patients including abnormal shifts in the intestinal microbiota composition (i.e., dysbiosis) characterized by a loss of short chain fatty acid (SCFA) bacteria and increased lipopolysaccharide (LPS) bacteria. We also examined several candidate mechanisms by which the microbiota can influence PD including the NLRP3 inflammasome, insulin resistance, mitochondrial function, vagal nerve signaling.Results: The PD-associated microbiome is associated with decreased production of SCFA and increased LPS and it is believed that these changes may contribute to the development or exacerbation of PD. Diet robustly impacts the intestinal microbiome and the Western diet is associated with increased risk for PD whereas the Mediterranean diet (including high intake of dietary fiber) decreases PD risk. Mechanistically this may be the consequence of changes in the relative abundance of SCFA-producing or LPS-containing bacteria in the intestinal microbiome with effects on intestinal barrier function, endotoxemia (i.e., systemic LPS), NLRP3 inflammasome activation, insulin resistance, and mitochondrial dysfunction, and the production of factors such as glucagon like peptide 1 (GLP-1) and brain derived neurotrophic factor (BDNF) as well as intestinal gluconeogenesis.Conclusions: This review summarizes a model of microbiota-gut-brain-axis regulation of neuroinflammation in PD including several new mechanisms. We conclude with the need for clinical trials in PD patients to test this model for beneficial effects of Mediterranean based high fiber diets.

Food Components and Dietary Habits: Keys for a Healthy Gut Microbiota Composition.

The gut microbiota is a changing ecosystem, containing trillions of bacteria, continuously shaped by many factors, such as dietary habits, seasonality, lifestyle, stress, antibiotics use, or diseases. A healthy host–microorganisms balance must be respected in order to optimally maintain the intestinal barrier and immune system functions and, consequently, prevent disease development. In the past several decades, the adoption of modern dietary habits has become a growing health concern, as it is strongly associated with obesity and related metabolic diseases, promoting inflammation and both structural and behavioral changes in gut microbiota. In this context, novel dietary strategies are emerging to prevent diseases and maintain health. However, the consequences of these different diets on gut microbiota modulation are still largely unknown, and could potentially lead to alterations of gut microbiota, intestinal barrier, and the immune system. The present review aimed to focus on the impact of single food components (macronutrients and micronutrients), salt, food additives, and different dietary habits (i.e., vegan and vegetarian, gluten-free, ketogenic, high sugar, low FODMAP, Western-type, and Mediterranean diets) on gut microbiota composition in order to define the optimal diet for a healthy modulation of gut microbiota.

Influence of snow mold on winter rye productivity in the Kirov region

In the conditions of the Kirov region, the major factor reducing the productivity of winter crops is infestation with snow mold (Microdochium nivale (Fr.) Samuels et. Hallet. - synonym Fusarium nivale (Fr.) Ces.), which annually grows by 80-100%. Therefore, the main direction of breeding is receiving winter rye varieties having maximum resistance to this disease. During the period of 2003-2017 there was carried out the assessment of zoned and perspective cultivars of domestic breeding of various ecological-and-geographical origin for snow mold infestation in natural provocative conditions. Weather conditions differed greatly in all periods of rye development. It has been established that plant resistance to M. nivale pathogen is influenced greatly by the condition of plants before wintering regulated by the sowing time. Well-developed plants of Falenskaya 4 variety formed the optimum density of an agro-phytocenosis, accumulated bigger amount of sugars (more than 7%), regenerated during spring re-growth by more than 90%, and produced stable high yield (more than 4.9 t/ha). In order to realize the biological potential of the variety, there was a need to shift the previously established sowing time to 5-10 days later period. The productivity was influenced greatly by April conditions, namely, by the period of total clearing of sowings from snow, which took only several days (3-6). Warm and dry weather favored an active re-growth of rye and prevented disease development. Cold and damp weather provoked fungus development, which affected quickly the plants weakened after rewintering. It was revealed that winter rye varieties of different ecological-and-geographical groups responded to this disease differently. The variability in productivity of each cultivar by years was high (CV = 25.8…65.4%). The greatest stability was characteristic for varieties bred in FARC North-East. The main methods of breeding for the resistance to snow mold are crossing and selection in the conditions of a provocative background. The efficiency of a selection method is confirmed with creation from Falenskaya 4 a highly winter-hardy variety Flora with active regeneration after snow mold infestation (100%) and stable productivity by years – 4.62 t/ha (addition yield to an initial cultivar was 0.27 t/ha). The distinctive feature of Flora variety is active formation of powerful green mass in spring that is important for the early use for green forage for cattle and poultry. Since 2012 the variety is included in the State Register of breeding achievements in Volga-Vyatka and North-West regions of the Russian Federation.

Preharvest multiple sprays with sodium nitroprusside promote wound healing of harvested muskmelons by activation of phenylpropanoid metabolism

Muskmelons are susceptible to mechanical damage at harvest and subsequent postharvest handling before storage. The wounds provide an easy pathway for fungi to infect, leading to postharvest decay of fruit during storage. Wound healing is considered as a positive defense process, which can restrict the invasion of pathogens. In this study, muskmelon fruit (Cucumis melo cv. Manao) during growth were repeatedly sprayed with 0.5 mM sodium nitroprusside (SNP, a exogenous donor of nitric oxide (NO)) or 0.1 mM 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO, a scavenger of NO), to test the effect of these preharvest treatments on wound healing of harvested muskmelon fruit. The results showed that SNP sprays reduced decay incidence and disease severity of harvested muskmelons inoculated with Trichothecium roseum. SNP also promoted the accumulation of suberin and lignin at wound sites through increasing phenylalanine ammonia lyase (PAL) activity and stimulating the accumulation in total phenolics, flavonoids and lignin. On the contrary, c-PTIO sprays enhanced decay incidence and disease severity of wounded inoculated fruit, while decreasing PAL activity, the content of total phenolics, flavonoids and lignin and reduced the accumulation of suberin and lignin at wound sites. The present results suggest that NO released by SNP sprays promote the wound healing and prevent disease development in harvested muskmelons by inducing increase in PAL activity, the contents of phenolics, flavonoids, suberin and lignin accumulation at wound sites.

Berberine attenuates cancer cell growth via modulating the cell cycle dynamics but not apoptosis in human colorectal HCT-116 3D spheroid model

Colorectal carcinoma is a cosmopolitan type of cancer with a poor prognosis, motivating seeking novel strategies to prevent disease development and progression. The poor prognosis is attributed to the severe toxic side effects of the current therapeutic regimes. Hence, novel less toxic treatment strategies are urgently warranted. Berberine is a natural compound with several biological and pharmacological properties, including anti-fungal, anti-diabetic, cardioprotective effects. Some reports showed that berberine inhibits cell growth by inducing cell cycle arrest and promotion of apoptosis in cancer cells. Importantly, the anticancer potential of berberine in colorectal cancer has not been previously investigated. Hence, this work aims to investigate whether berberine possesses anticancer properties against colorectal HCT116 cancer cells. The potential effect of berberine on cell cycle regulation and apoptosis will also be deeply investigated. This work was conducted using the more physiological 3D spheroid culture model that mimics better the impact of the tumor microenvironment as well as the cell-cell interaction in the cellular response to therapy. When compared to the previous studies, this work will explain the mode of action of berberine in more physiological conditions that better mimics the in vivo situation. To achieve the goal of this work, spheroid growth assay, as well as proliferation assay, were performed. Spheroid cell suspensions were further investigated using flow cytometry to assess the cell cycle distribution of cells upon berberine application. BrdU immunostaining was performed to elucidate the S-phase fraction of cells. The proliferation potential and the level of apoptosis were also investigated by Ki67 and Annexin V labeling, respectively. The results showed that berberine attenuated tumor spheroid growth and limits the proliferative capacity of HCT116 cells. This could be attributed to the berberine-mediated G1-phase cell cycle delay. The S-phase fraction of cells was significantly decreased upon berberine application. Unexpectedly, berberine did not induce a significant difference in the % of apoptotic cell fraction of cells as compared to the controls. Collectively, these results suggest that berberine possesses an anti-tumor efficacy in 3D culture preparations via modulating the cell cycle progression. Specifically, berberine induces G1-phase cell cycle delay and decreases the S-phase fraction of cells. Thus, it limits the proliferative capacity of cells. Also, berberine did not induce programmed cell death in the HCT116 spheroids.

The Potential of Flavonoids for the Treatment of Neurodegenerative Diseases.

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS), currently affect more than 6 million people in the United States. Unfortunately, there are no treatments that slow or prevent disease development and progression. Regardless of the underlying cause of the disorder, age is the strongest risk factor for developing these maladies, suggesting that changes that occur in the aging brain put it at increased risk for neurodegenerative disease development. Moreover, since there are a number of different changes that occur in the aging brain, it is unlikely that targeting a single change is going to be effective for disease treatment. Thus, compounds that have multiple biological activities that can impact the various age-associated changes in the brain that contribute to neurodegenerative disease development and progression are needed. The plant-derived flavonoids have a wide range of activities that could make them particularly effective for blocking the age-associated toxicity pathways associated with neurodegenerative diseases. In this review, the evidence for beneficial effects of multiple flavonoids in models of AD, PD, HD, and ALS is presented and common mechanisms of action are identified. Overall, the preclinical data strongly support further investigation of specific flavonoids for the treatment of neurodegenerative diseases.

Efficacy of Bacillus subtilis strain QST 713 (Rhapsody) against four major diseases of greenhouse cucumbers

Diseases of cucumber (Cucumis sativus L.) are a major limiting factor during commercial greenhouse production of the crop. The biological control agent Bacillus subtilis strain QST 713 (Rhapsody, containing 1 × 109 colony-forming units per g) was evaluated for efficacy against four major diseases affecting greenhouse cucumbers grown in British Columbia, Canada. These diseases included powdery mildew, Fusarium root and stem rot, Pythium crown and root rot, and gummy stem blight. Rhapsody was applied as a root drench or spray to leaves or flowers at a rate of 1.0 L product/100 L water, or in some experiments at 1.5 L product/100 L water. Applications were made 1 and 4 days prior to, as well as after, pathogen inoculation. Weekly foliar applications of Rhapsody significantly (P ≤ 0.05) reduced powdery mildew colony development and showed eradicative effects on established leaf infections. Leaf area infected on untreated plants was 80–100% compared to 15–20% on Rhapsody-treated plants. Two drenches of Rhapsody made 1 and 4 days prior to Fusarium inoculation significantly (P ≤ 0.05) improved plant growth (height and dry weight) after five weeks, but growth was lower compared to the noninoculated control plants. Treatments made 1 and 4 days post-inoculation were much less effective in preventing disease development. Application of Rhapsody to Pythium-inoculated plants, prior to or after inoculation, did not significantly increase plant height or dry weight compared to the pathogen-only treatment. Developing cucumber fruit inoculated with a mycelial suspension of the gummy stem blight pathogen caused 24–30% post-harvest decay after fruit were incubated at 20–22 °C for 7–10 days. Fruit infection was reduced by almost 55% when Rhapsody was applied 24 h prior to pathogen inoculation while an application made 24 h after pathogen inoculation had no effect. Preventative applications of Rhapsody were effective in reducing development of powdery mildew, Fusarium root and stem rot, and gummy stem blight on cucumber, while eradicative applications were effective against powdery mildew only. There was no effect observed against Pythium root rot.

Prenatal immune activation induces age-related alterations in rat offspring: Effects upon NMDA receptors and behaviors

Prenatal exposure to polyriboinosinic–polyribocytidylic acid (poly I:C) results in psychotic-like behavior in mature rat offspring as well as enduring modifications of glutamatergic excitatory synaptic transmission. However, little is known about the dynamic behavioral and glutamate N-methyl-D-aspartate (NMDA) receptor changes in rat offspring following poly I:C treatment of pregnant dams. In this study, poly I:C was administered to rats intravenously at a dose of 10 mg/kg on gestational day 9 in order to assess changes in behavior and NMDA receptors in offspring over time. Results demonstrate progressive worsening behaviors in adolescents and adults that manifest as increased anxiety, cognitive impairment, and pre-pulse inhibition deficits. Age-related alteration of NMDA receptors in the prefrontal cortex and hippocampus, either total number or distribution, were observed from weaning to adulthood. These results suggest that abnormalities of NMDA receptors occur prior to obvious schizophrenia-like behavioral manifestations. Hence, NMDA receptors may be potential therapeutic targets to prevent disease development during asymptomatic periods of schizophrenia, and may serve as targets for preventive and/or therapeutic strategies for schizophrenia. Further, PSD95, a scaffolding protein that is a component of the NMDA receptor signaling complex, is increased in the hippocampus of adult offspring, when serious behavioral abnormalities emerge. This result suggests that PSD95 may be involved in behavioral abnormalities of schizophrenia.

Phospholipid membranes drive abdominal aortic aneurysm development through stimulating coagulation factor activity

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE-/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE-/- deletion, and many were absent in Alox-/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.