Showing papers by "Mark E. Cooper published in 2021"

Association of Adverse Childhood Experiences With Cardiovascular Disease Later in Life: A Review.

Abstract: Importance Adverse childhood experiences (ACEs) are potentially harmful events that occur during childhood, spanning neglect, physical or sexual abuse, parental separation, or death, among others. At least 50% of the US adult population has experienced 1 or more ACEs before the age of 18 years, but in clinical practice, ACEs remain underrecognized. Adults who have experienced ACEs are at increased risk of developing health risk behaviors and, ultimately, cardiovascular disease (CVD). This review summarizes the evidence regarding the association of ACEs with CVD and the accompanying diagnostic and therapeutic approaches in the adult population. Observations ACEs are commonly classified into 3 domains: abuse (psychological, physical, or sexual), household dysfunction (eg, substance use by household members, mental illness, parental separation), and neglect. These experiences elicit chronic activation of the stress response system, leading to autonomic, neuroendocrine, and inflammatory dysfunction. The subsequent development of traditional risk factors, such as diabetes, hypertension, smoking, and obesity, results in the onset of CVD and premature mortality. Adults with 4 or more ACEs compared with those with none have a more than 2-fold higher risk of developing CVD and an almost 2-fold higher risk of premature mortality. Conclusions and relevance Identifying methods of mitigating the health consequences of ACEs may lead to better cardiovascular outcomes. Inquiry into ACE exposure during clinical encounters and subsequent referral to psychological services when appropriate may be helpful, but strategies aimed at CVD prevention via management of ACEs in adults continue to lack adequate evidence.

Processed foods drive intestinal barrier permeability and microvascular diseases

Abstract: Intake of processed foods has increased markedly over the past decades, coinciding with increased microvascular diseases such as chronic kidney disease (CKD) and diabetes. Here, we show in rodent models that long-term consumption of a processed diet drives intestinal barrier permeability and an increased risk of CKD. Inhibition of the advanced glycation pathway, which generates Maillard reaction products within foods upon thermal processing, reversed kidney injury. Consequently, a processed diet leads to innate immune complement activation and local kidney inflammation and injury via the potent proinflammatory effector molecule complement 5a (C5a). In a mouse model of diabetes, a high resistant starch fiber diet maintained gut barrier integrity and decreased severity of kidney injury via suppression of complement. These results demonstrate mechanisms by which processed foods cause inflammation that leads to chronic disease.

Effect of Preemptive Intervention on Developmental Outcomes Among Infants Showing Early Signs of Autism: A Randomized Clinical Trial of Outcomes to Diagnosis

Abstract: Importance Intervention for individuals with autism spectrum disorder (ASD) typically commences after diagnosis. No trial of an intervention administered to infants before diagnosis has shown an effect on diagnostic outcomes to date. Objective To determine the efficacy of a preemptive intervention for ASD beginning during the prodromal period. Design, setting, and participants This 2-site, single rater-blinded randomized clinical trial of a preemptive intervention vs usual care was conducted at 2 Australian research centers (Perth, Melbourne). Community sampling was used to recruit 104 infants aged 9 to 14 months showing early behaviors associated with later ASD, as measured by the Social Attention and Communication Surveillance-Revised. Recruitment occurred from June 9, 2016, to March 30, 2018. Final follow-up data were collected on April 15, 2020. Interventions Infants were randomized on a 1:1 ratio to receive either a preemptive intervention plus usual care or usual care only over a 5-month period. The preemptive intervention group received a 10-session social communication intervention, iBASIS-Video Interaction to Promote Positive Parenting (iBASIS-VIPP). Usual care comprised services delivered by community clinicians. Main outcomes and measures Infants were assessed at baseline (approximate age, 12 months), treatment end point (approximate age, 18 months), age 2 years, and age 3 years. Primary outcome was the combined blinded measure of ASD behavior severity (the Autism Observation Scale for Infants and the Autism Diagnostic Observation Schedule, second edition) across the 4 assessment points. Secondary outcomes were an independent blinded clinical ASD diagnosis at age 3 years and measures of child development. Analyses were preregistered and comprised 1-tailed tests with an α level of .05. Results Of 171 infants assessed for eligibility, 104 were randomized; 50 infants (mean [SD] chronological age, 12.40 [1.93] months; 38 boys [76.0%]) received the iBASIS-VIPP preemptive intervention plus usual care (1 infant was excluded after randomization), and 53 infants (mean [SD] age, 12.38 [2.02] months; 32 boys [60.4%]) received usual care only. A total of 89 participants (45 in the iBASIS-VIPP group and 44 in the usual care group) were reassessed at age 3 years. The iBASIS-VIPP intervention led to a reduction in ASD symptom severity (area between curves, -5.53; 95% CI, -∞ to -0.28; P = .04). Reduced odds of ASD classification at age 3 years was found in the iBASIS-VIPP group (3 of 45 participants [6.7%]) vs the usual care group (9 of 44 participants [20.5%]; odds ratio, 0.18; 95% CI, 0-0.68; P = .02). Number needed to treat to reduce ASD classification was 7.2 participants. Improvements in caregiver responsiveness and language outcomes were also observed in the iBASIS-VIPP group. Conclusions and relevance Receipt of a preemptive intervention for ASD from age 9 months among a sample of infants showing early signs of ASD led to reduced ASD symptom severity across early childhood and reduced the odds of an ASD diagnosis at age 3 years. Trial registration http://anzctr.org.au identifier: ACTRN12616000819426.

Pharmacological Inhibition of the Nod-Like Receptor Family Pyrin Domain Containing 3 Inflammasome with MCC950.

Abstract: Activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome drives release of the proinflammatory cytokines interleukin (IL)-1β and IL-18 and induces pyroptosis (lytic cell death). These events drive chronic inflammation, and as such, NLRP3 has been implicated in a large number of human diseases. These range from autoimmune conditions, the simplest of which is NLRP3 gain-of-function mutations leading to an orphan disease, cryopyrin-associated period syndrome, to large disease burden indications, such as atherosclerosis, heart failure, stroke, neurodegeneration, asthma, ulcerative colitis, and arthritis. The potential clinical utility of NLRP3 inhibitors is substantiated by an expanding list of indications in which NLRP3 activation has been shown to play a detrimental role. Studies of pharmacological inhibition of NLRP3 in nonclinical models of disease using MCC950 in combination with human genetics, epigenetics, and analyses of the efficacy of biologic inhibitors of IL-1β, such as anakinra and canakinumab, can help to prioritize clinical trials of NLRP3-directed therapeutics. Although MCC950 shows excellent (nanomolar) potency and high target selectivity, its pharmacokinetic and toxicokinetic properties limited its therapeutic development in the clinic. Several improved, next-generation inhibitors are now in clinical trials. Hence the body of research in a plethora of conditions reviewed herein may inform analysis of the potential translational value of NLRP3 inhibition in diseases with significant unmet medical need. SIGNIFICANCE STATEMENT: The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is one of the most widely studied and best validated biological targets in innate immunity. Activation of NLRP3 can be inhibited with MCC950, resulting in efficacy in more than 100 nonclinical models of inflammatory diseases. As several next-generation NLRP3 inhibitors are entering proof-of-concept clinical trials in 2020, a review of the pharmacology of MCC950 is timely and significant.

Pro-resolving lipid mediators: regulators of inflammation, metabolism and kidney function.

Abstract: Obesity, diabetes mellitus, hypertension and cardiovascular disease are risk factors for chronic kidney disease (CKD) and kidney failure. Chronic, low-grade inflammation is recognized as a major pathogenic mechanism that underlies the association between CKD and obesity, impaired glucose tolerance, insulin resistance and diabetes, through interaction between resident and/or circulating immune cells with parenchymal cells. Thus, considerable interest exists in approaches that target inflammation as a strategy to manage CKD. The initial phase of the inflammatory response to injury or metabolic dysfunction reflects the release of pro-inflammatory mediators including peptides, lipids and cytokines, and the recruitment of leukocytes. In self-limiting inflammation, the evolving inflammatory response is coupled to distinct processes that promote the resolution of inflammation and restore homeostasis. The discovery of endogenously generated lipid mediators — specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids — which promote the resolution of inflammation and attenuate the microvascular and macrovascular complications of obesity and diabetes mellitus highlights novel opportunities for potential therapeutic intervention through the targeting of pro-resolution, rather than anti-inflammatory pathways. Inflammation is a known driver of diabetes and obesity-associated kidney disease. This Review describes the role of endogenous lipid mediators — specialized pro-resolving lipid mediators and branched fatty acid esters of hydroxy fatty acids — in the resolution of inflammation and explores how insights into their function could identify new targets for therapeutic intervention.

Tackling G × E × M interactions to close on-farm yield-gaps: creating novel pathways for crop improvement by predicting contributions of genetics and management to crop productivity

Abstract: Climate change and Genotype-by-Environment-by-Management interactions together challenge our strategies for crop improvement. Research to advance prediction methods for breeding and agronomy is opening new opportunities to tackle these challenges and overcome on-farm crop productivity yield-gaps through design of responsive crop improvement strategies. Genotype-by-Environment-by-Management (G × E × M) interactions underpin many aspects of crop productivity. An important question for crop improvement is “How can breeders and agronomists effectively explore the diverse opportunities within the high dimensionality of the complex G × E × M factorial to achieve sustainable improvements in crop productivity?” Whenever G × E × M interactions make important contributions to attainment of crop productivity, we should consider how to design crop improvement strategies that can explore the potential space of G × E × M possibilities, reveal the interesting Genotype–Management (G–M) technology opportunities for the Target Population of Environments (TPE), and enable the practical exploitation of the associated improved levels of crop productivity under on-farm conditions. Climate change adds additional layers of complexity and uncertainty to this challenge, by introducing directional changes in the environmental dimension of the G × E × M factorial. These directional changes have the potential to create further conditional changes in the contributions of the genetic and management dimensions to future crop productivity. Therefore, in the presence of G × E × M interactions and climate change, the challenge for both breeders and agronomists is to co-design new G–M technologies for a non-stationary TPE. Understanding these conditional changes in crop productivity through the relevant sciences for each dimension, Genotype, Environment, and Management, creates opportunities to predict novel G–M technology combinations suitable to achieve sustainable crop productivity and global food security targets for the likely climate change scenarios. Here we consider critical foundations required for any prediction framework that aims to move us from the current unprepared state of describing G × E × M outcomes to a future responsive state equipped to predict the crop productivity consequences of G–M technology combinations for the range of environmental conditions expected for a complex, non-stationary TPE under the influences of climate change.

Interleukin-1β suppression dampens inflammatory leukocyte production and uptake in atherosclerosis.

Abstract: Targeting vascular inflammation represents a novel therapeutic approach to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) using canakinumab, a monoclonal antibody, reduces the incidence of cardiovascular events in patients after myocardial infarction (MI). The biological basis for these beneficial effects remains incompletely understood. We sought to explore the mechanisms of IL-1β-targeted therapies. In mice with early atherosclerosis (ApoE-/- mice on a high-cholesterol diet for six weeks), we found that three weeks of NLRP3-inflammasome inhibition or anti-IL-1β treatment (using either MCC950, an NLRP3 inflammasome inhibitor which blocks production and release of active IL-1β; or a murine analog of canakinumab) dampened accumulation of leukocytes in atherosclerotic aortas, which consequently resulted in slower progression of atherosclerosis. Causally, we found that endothelial cells from atherosclerotic aortas lowered expression of leukocyte chemoattractants and adhesion molecules upon NLRP3-inflammasome inhibition, indicating that NLRP3-inflammasome- and IL-1β-targeted therapies reduced blood leukocyte recruitment to atherosclerotic aortas. In accord, adoptive transfer experiments revealed that anti-IL-1β treatment mitigated blood myeloid cell uptake to atherosclerotic aortas. We further report that anti-IL-1β treatment and NLRP3-inflammasome inhibition reduced inflammatory leukocyte supply by decreasing proliferation of bone marrow hematopoietic stem and progenitor cells, demonstrating that suppression of IL-1β and the NLRP3-inflammasome lowered production of disease-propagating leukocytes. Using bone marrow reconstitution experiments, we observed that hematopoietic cell-specific NLRP3-inflammasome activity contributed to both enhanced recruitment and increased supply of blood inflammatory leukocytes. Further experiments that queried whether anti-IL-1β treatment reduced vascular inflammation also in post-MI accelerated atherosclerosis documented the operation of convergent mechanisms (reduced supply and uptake of inflammatory leukocytes). In line with our pre-clinical findings, post-MI patients on canakinumab treatment showed reduced blood monocyte numbers. Our murine and human data reveal that anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened vascular inflammation and progression of atherosclerosis through reduced blood inflammatory leukocyte 1) supply and 2) uptake into atherosclerotic aortas providing additional mechanistic insights into links between hematopoiesis and atherogenesis, and into the beneficial effects of NLRP3-inflammasome- and IL-1β-targeted therapies. Therapeutic targeting of vascular inflammation represents a promising avenue to reduce complications of atherosclerosis. Neutralizing the pro-inflammatory cytokine interleukin-1β (IL-1β) reduces the incidence of cardiovascular events in patients with prior myocardial infarction. However, the mechanisms underlying these beneficial effects remain incompletely understood. This study explored how IL-1β and NLRP3-inflammasome suppression mitigated plaque progression. Our murine and human data reveal that pharmacological anti-IL-1β treatment and NLRP3-inflammasome inhibition dampened inflammatory leukocyte accumulation in atherosclerotic aortas through 1) decreased blood inflammatory leukocyte supply and 2) reduced blood inflammatory leukocyte uptake into in atherosclerotic aortas. These data provide additional mechanistic insights into links between hematopoiesis and atherogenesis, and inform future anti-inflammatory interventions in patients with atherosclerosis.

Modelling selection response in plant-breeding programs using crop models as mechanistic gene-to-phenotype (CGM-G2P) multi-trait link functions

Abstract: Plant breeding programs are designed and operated over multiple cycles to systematically change the genetic makeup of plants to achieve improved trait performance for a Target Population of Environments (TPE). Within each cycle, selection applied to the standing genetic variation within a structured reference population of genotypes (RPG) is the primary mechanism by which breeding programs make the desired genetic changes. Selection operates to change the frequencies of the alleles of the genes controlling trait variation within the RPG. The structure of the RPG and the TPE has important implications for the design of optimal breeding strategies. The breeder’s equation, together with the quantitative genetic theory behind the equation, informs many of the principles for design of breeding programs. The breeder’s equation can take many forms depending on the details of the breeding strategy. Through the genetic changes achieved by selection, the cultivated varieties of crops (cultivars) are improved for use in agriculture. From a breeding perspective, selection for specific trait combinations requires a quantitative link between the effects of the alleles of the genes impacted by selection and the trait phenotypes of plants and their breeding value. This gene-to-phenotype link function provides the G2P map for one to many traits. For complex traits controlled by many genes, the infinitesimal model for trait genetic variation is the dominant G2P model of quantitative genetics. Here we consider motivations and potential benefits of using the hierarchical structure of crop models as CGM-G2P trait link functions in combination with the infinitesimal model for the design and optimisation of selection in breeding programs.

In pursuit of a better world: crop improvement and the CGIAR

Abstract: The CGIAR crop improvement (CI) programs, unlike commercial CI programs, which are mainly geared to profit though meeting farmers' needs, are charged with meeting multiple objectives with target populations that include both farmers and the community at large. We compiled the opinions from >30 experts in the private and public sector on key strategies, methodologies, and activities that could the help CGIAR meet the challenges of providing farmers with improved varieties while simultaneously meeting the goals of: (i) nutrition, health, and food security; (ii) poverty reduction, livelihoods, and jobs; (iii) gender equality, youth, and inclusion; (iv) climate adaptation and mitigation; and (v) environmental health and biodiversity. We review the crop improvement processes starting with crop choice, moving through to breeding objectives, production of potential new varieties, selection, and finally adoption by farmers. The importance of multidisciplinary teams working towards common objectives is stressed as a key factor to success. The role of the distinct disciplines, actors, and their interactions throughout the process from crop choice through to adoption by farmers is discussed and illustrated.

Reproductive resilience but not root architecture underpins yield improvement under drought in maize.

Abstract: Because plants capture water and nutrients through roots, it was proposed that changes in root systems architecture (RSA) might underpin the 3-fold increase in maize (Zea mays L.) grain yield over the last century. Here we show that both RSA and yield have changed with decades of maize breeding, but not the crop water uptake. Results from X-ray phenotyping in controlled environments showed that single cross (SX) hybrids have smaller root systems than double cross (DX) hybrids for root diameters between 2465 µm and 181µm (P<0.05). Soil water extraction measured under field conditions ranged between 2.6 mm d-1 and 2.9 mm d-1 but were not significantly different between SX and DX hybrids. Yield and yield components were higher for SX than DX hybrids across densities and irrigation (P<0.001). Taken together, the results suggest that changes in RSA were not the cause of increased water uptake but an adaptation to high-density stands used in modern agriculture. This adaptation may have contributed to shift in resource allocation to the ear and indirectly improved reproductive resilience. Advances in root physiology and phenotyping can create opportunities to maintain long-term genetic gain in maize, but a shift from ideotype to crop and production system thinking will be required.

The Impact of Frailty on the Effectiveness and Safety of Intensive Glucose Control and Blood Pressure-Lowering Therapy for People With Type 2 Diabetes: Results From the ADVANCE Trial.

Abstract: OBJECTIVE: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90-1.19) in the frail versus 0.84 (95% CI 0.74-0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15-10.63) vs. 4.80 (3.84-5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.

Small-molecule screen reveals synergy of cell cycle checkpoint kinase inhibitors with DNA-damaging chemotherapies in medulloblastoma

Abstract: Medulloblastoma (MB) consists of four core molecular subgroups with distinct clinical features and prognoses. Treatment consists of surgery, followed by radiotherapy and cytotoxic chemotherapy. Despite this intensive approach, outcome remains dismal for patients with certain subtypes of MB, namely, MYC-amplified Group 3 and TP53-mutated SHH. Using high-throughput assays, six human MB cell lines were screened against a library of 3208 unique compounds. We identified 45 effective compounds from the screen and found that cell cycle checkpoint kinase (CHK1/2) inhibition synergistically enhanced the cytotoxic activity of clinically used chemotherapeutics cyclophosphamide, cisplatin, and gemcitabine. To identify the best-in-class inhibitor, multiple CHK1/2 inhibitors were assessed in mice bearing intracranial MB. When combined with DNA-damaging chemotherapeutics, CHK1/2 inhibition reduced tumor burden and increased survival of animals with high-risk MB, across multiple different models. In total, we tested 14 different models, representing distinct MB subgroups, and data were validated in three independent laboratories. Pharmacodynamics studies confirmed central nervous system penetration. In mice, combination treatment significantly increased DNA damage and apoptosis compared to chemotherapy alone, and studies with cultured cells showed that CHK inhibition disrupted chemotherapy-induced cell cycle arrest. Our findings indicated CHK1/2 inhibition, specifically with LY2606368 (prexasertib), has strong chemosensitizing activity in MB that warrants further clinical investigation. Moreover, these data demonstrated that we developed a robust and collaborative preclinical assessment platform that can be used to identify potentially effective new therapies for clinical evaluation for pediatric MB.

The palliative care needs and experiences of people with advanced head and neck cancer: A scoping review

Abstract: Background:The palliative care needs of people with advanced head and neck cancer pose unique complexities due to the impact the illness has on eating, speaking, appearance and breathing. Examining...

Big Data Approach to Characterize Restricted and Repetitive Behaviors in Autism.

Abstract: Objective Despite being a core diagnostic feature of autism spectrum disorder (ASD), demographic, developmental and clinical correlates of restricted and repetitive behaviors and interests (RRB) remain poorly characterized. This study aimed to utilize the largest available RRB data set to date to provide a comprehensive characterization of how distinct RRB domains vary according to a range of individual characteristics. Method Data were obtained from 17,581 children and adolescents with ASD (meanage= 8.24 years, SDage= 4.06) from the Simons Foundation Powering Autism Research for Knowledge cohort. Caregivers completed the Repetitive Behavior Scale−Revised questionnaire as a measure of repetitive motor behaviors, self-injurious behaviors, compulsions, insistence on sameness, and circumscribed interests RRB domains. Caregivers also provided information on children’s cognitive functioning, language ability, and social and communication impairments. Results Male sex was associated with higher severity of repetitive motor behaviors and restricted interests and with lower severity of compulsions and self-injurious behaviors; no sex differences were found for the insistence on sameness domain. Although repetitive motor behaviors showed a mostly linear (negative) association with age, other RRB domains showed more complex and nonlinear pattern of associations. Higher severity of social and communication impairments provided significant independent contribution in predicting higher severity of all RRB domains at the p Conclusion Findings reported here provide further evidence that RRB subdomains show a somewhat distinct pattern of associations with demographic, developmental, and clinical variables, with a key implication that separate consideration of these domains can help to facilitate efforts to understand diverse ASD etiology and to inform the design of effective interventions.

Human β-defensin-2 suppresses key features of asthma in murine models of allergic airways disease

Abstract: Background: Asthma is an airway inflammatory disease and a major health problem worldwide. Anti-inflammatory steroids and bronchodilators are the gold-standard therapy for asthma. However, they do not prevent the development of the disease, and critically, a subset of asthmatics are resistant to steroid therapy. Objective: To elucidate the therapeutic potential of human β-defensins (hBD), such as hBD2 mild to moderate and severe asthma. Methods: We investigated the role of hBD2 in a steroid-sensitive, house dust mite-induced allergic airways disease (AAD) model and a steroid-insensitive model combining ovalbumin-induced AAD with C muridarum (Cmu) respiratory infection. Results: In both models, we demonstrated that therapeutic intranasal application of hBD2 significantly reduced the influx of inflammatory cells into the bronchoalveolar lavage fluid. Furthermore, key type 2 asthma-related cytokines IL-9 and IL-13, as well as additional immunomodulating cytokines, were significantly decreased after administration of hBD2 in the steroid-sensitive model. The suppression of inflammation was associated with improvements in airway physiology and treatment also suppressed airway hyper-responsiveness (AHR) in terms of airway resistance and compliance to methacholine challenge. Conclusions and Clinical relevance: These data indicate that hBD2 reduces the hallmark features and has potential as a new therapeutic agent in allergic and especially steroid-resistant asthma.

Relationship between type 2 cytokine and inflammasome responses in obesity-associated asthma.

Abstract: Background Obesity is a risk factor for asthma, and obese asthmatic individuals are more likely to have severe, steroid-insensitive disease. How obesity affects the pathogenesis and severity of asthma is poorly understood. Roles for increased inflammasome-mediated neutrophilic responses, type 2 immunity, and eosinophilic inflammation have been described. Objective We investigated how obesity affects the pathogenesis and severity of asthma and identified effective therapies for obesity-associated disease. Methods We assessed associations between body mass index and inflammasome responses with type 2 (T2) immune responses in the sputum of 25 subjects with asthma. Functional roles for NLR family, pyrin domain–containing (NLRP) 3 inflammasome and T2 cytokine responses in driving key features of disease were examined in experimental high-fat diet–induced obesity and asthma. Results Body mass index and inflammasome responses positively correlated with increased IL-5 and IL-13 expression as well as C-C chemokine receptor type 3 expression in the sputum of subjects with asthma. High-fat diet–induced obesity resulted in steroid-insensitive airway hyperresponsiveness in both the presence and absence of experimental asthma. High-fat diet–induced obesity was also associated with increased NLRP3 inflammasome responses and eosinophilic inflammation in airway tissue, but not lumen, in experimental asthma. Inhibition of NLRP3 inflammasome responses reduced steroid-insensitive airway hyperresponsiveness but had no effect on IL-5 or IL-13 responses in experimental asthma. Depletion of IL-5 and IL-13 reduced obesity-induced NLRP3 inflammasome responses and steroid-insensitive airway hyperresponsiveness in experimental asthma. Conclusion We found a relationship between T2 cytokine and NLRP3 inflammasome responses in obesity-associated asthma, highlighting the potential utility of T2 cytokine–targeted biologics and inflammasome inhibitors.

Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy

Abstract: To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN). Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD). Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters. Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.

Risk Factors for Gut Dysbiosis in Early Life.

Abstract: Dysbiosis refers to a reduction in microbial diversity, combined with a loss of beneficial taxa, and an increase in pathogenic microorganisms. Dysbiosis of the intestinal microbiota can have a substantial effect on the nervous and immune systems, contributing to the onset of several inflammatory diseases. Epidemiological studies provided insight in how changes in the living environment have contributed to an overall loss of diversity and key taxa in the gut microbiome, coinciding with increased reports of atopy and allergic diseases. The gut microbiome begins development at birth, with major transition periods occurring around the commencement of breastfeeding, and the introduction of solid foods. As such, the development of the gut microbiome remains highly plastic and easily influenced by environmental factors until around three years of age. Developing a diverse and rich gut microbiome during this sensitive period is crucial to setting up a stable gut microbiome into adulthood and to prevent gut dysbiosis. Currently, the delivery route, antibiotic exposure, and diet are the best studied drivers of gut microbiome development, as well as risk factors of gut dysbiosis during infancy. This review focuses on recent evidence regarding key environmental factors that contribute to promoting gut dysbiosis.

Can We Harness "Enviromics" to Accelerate Crop Improvement by Integrating Breeding and Agronomy?

Abstract: The diverse consequences of genotype-by-environment (GxE) interactions determine trait phenotypes across levels of biological organization for crops, challenging our ambition to predict trait phenotypes from genomic information alone. GxE interactions have many implications for optimizing both genetic gain through plant breeding and crop productivity through on-farm agronomic management. Advances in genomics technologies have provided many suitable predictors for the genotype dimension of GxE interactions. Emerging advances in high-throughput proximal and remote sensor technologies have stimulated the development of "enviromics" as a community of practice, which has the potential to provide suitable predictors for the environment dimension of GxE interactions. Recently, several bespoke examples have emerged demonstrating the nascent potential for enhancing the prediction of yield and other complex trait phenotypes of crop plants through including effects of GxE interactions within prediction models. These encouraging results motivate the development of new prediction methods to accelerate crop improvement. If we can automate methods to identify and harness suitable sets of coordinated genotypic and environmental predictors, this will open new opportunities to upscale and operationalize prediction of the consequences of GxE interactions. This would provide a foundation for accelerating crop improvement through integrating the contributions of both breeding and agronomy. Here we draw on our experience from improvement of maize productivity for the range of water-driven environments across the US corn-belt. We provide perspectives from the maize case study to prioritize promising opportunities to further develop and automate "enviromics" methodologies to accelerate crop improvement through integrated breeding and agronomic approaches for a wider range of crops and environmental targets.

Asymmetric Synthesis and Biological Screening of Quinoxaline-Containing Synthetic Lipoxin A 4 Mimetics (QNX-sLXms)

Abstract: Failure to resolve inflammation underlies many prevalent pathologies. Recent insights have identified lipid mediators, typified by lipoxins (LXs), as drivers of inflammation resolution, suggesting potential therapeutic benefit. We report the asymmetric preparation of novel quinoxaline-containing synthetic-LXA4-mimetics (QNX-sLXms). Eight novel compounds were screened for their impact on inflammatory responses. Structure-activity relationship (SAR) studies showed that (R)-6 (also referred to as AT-02-CT) was the most efficacious and potent anti-inflammatory compound of those tested. (R)-6 significantly attenuated lipopolysaccharide (LPS)- and tumor-necrosis-factor-α (TNF-α)-induced NF-κB activity in monocytes and vascular smooth muscle cells. The molecular target of (R)-6 was investigated. (R)-6 activated the endogenous LX receptor formyl peptide receptor 2 (ALX/FPR2). The anti-inflammatory properties of (R)-6 were further investigated in vivo in murine models of acute inflammation. Consistent with in vitro observations, (R)-6 attenuated inflammatory responses. These results support the therapeutic potential of the lead QNX-sLXm (R)-6 in the context of novel inflammatory regulators.

Predicting phenotypes from genetic, environment, management, and historical data using CNNs.

Abstract: Convolutional Neural Networks (CNNs) can perform similarly or better than standard genomic prediction methods when sufficient genetic, environmental, and management data are provided. Predicting phenotypes from genetic (G), environmental (E), and management (M) conditions is a long-standing challenge with implications to agriculture, medicine, and conservation. Most methods reduce the factors in a dataset (feature engineering) in a subjective and potentially oversimplified manner. Deep neural networks such as Multilayer Perceptrons (MPL) and Convolutional Neural Networks (CNN) can overcome this by allowing the data itself to determine which factors are most important. CNN models were developed for predicting agronomic yield from a combination of replicated trials and historical yield survey data. The results were more accurate than standard methods when tested on held-out G, E, and M data (r = 0.50 vs. r = 0.43), and performed slightly worse than standard methods when only G was held out (r = 0.74 vs. r = 0.80). Pre-training on historical data increased accuracy compared to trial data alone. Saliency map analysis indicated the CNN has "learned" to prioritize many factors of known agricultural importance.

Mesoporous Silica Nanoparticles Improve Oral Delivery of Antitubercular Bicyclic Nitroimidazoles.

Abstract: Pretomanid and MCC7433, a novel nitroimidazopyrazinone analog, are promising antitubercular agents that belong to the bicyclic nitroimidazole family. Despite possessing high cell permeability, they suffer from poor aqueous solubility and require specialized formulations in order to be orally bioavailable. To address this limitation, we investigated the use of mesoporous silica nanoparticles (MCM-41) as drug carriers. MCM-41 nanoparticles were synthesized using a sol-gel method, and their surface was further modified with amine and phosphonate groups. A simple rotary evaporation method was used to incorporate the compounds of interest into the nanoparticles, leading to a high encapsulation efficiency of ≥86% with ∼10% loading (w/w). An overall significant improvement of solubility was also observed, and the pharmacological activity of pretomanid and MCC7433 was fully retained when tested in vitro against Mycobacterium tuberculosis using these nanocarriers. Amino-functionalized MCM-41 nanoparticles were found to enhance the systemic exposure of MCC7433 in mice (1.3-fold higher Cmax) compared to MCC7433 alone. The current work highlights the potential of using nanoparticles such as mesoporous silica as a carrier for oral delivery of poorly soluble antibacterial agents against tuberculosis.

Strategies and considerations for implementing genomic selection to improve traits with additive and non-additive genetic architectures in sugarcane breeding

Abstract: Simulations highlight the potential of genomic selection to substantially increase genetic gain for complex traits in sugarcane. The success rate depends on the trait genetic architecture and the implementation strategy. Genomic selection (GS) has the potential to increase the rate of genetic gain in sugarcane beyond the levels achieved by conventional phenotypic selection (PS). To assess different implementation strategies, we simulated two different GS-based breeding strategies and compared genetic gain and genetic variance over five breeding cycles to standard PS. GS scheme 1 followed similar routines like conventional PS but included three rapid recurrent genomic selection (RRGS) steps. GS scheme 2 also included three RRGS steps but did not include a progeny assessment stage and therefore differed more fundamentally from PS. Under an additive trait model, both simulated GS schemes achieved annual genetic gains of 2.6-2.7% which were 1.9 times higher compared to standard phenotypic selection (1.4%). For a complex non-additive trait model, the expected annual rates of genetic gain were lower for all breeding schemes; however, the rates for the GS schemes (1.5-1.6%) were still greater than PS (1.1%). Investigating cost-benefit ratios with regard to numbers of genotyped clones showed that substantial benefits could be achieved when only 1500 clones were genotyped per 10-year breeding cycle for the additive genetic model. Our results show that under a complex non-additive genetic model, the success rate of GS depends on the implementation strategy, the number of genotyped clones and the stage of the breeding program, likely reflecting how changes in QTL allele frequencies change additive genetic variance and therefore the efficiency of selection. These results are encouraging and motivate further work to facilitate the adoption of GS in sugarcane breeding.

The course and prognostic capability of motor difficulties in infants showing early signs of autism.

Abstract: Delays within the motor domain are often overlooked as an early surveillance marker for autism. The present study evaluated motor difficulties and its potential as an early predictive marker for later autism likelihood in a cohort of infants (N = 96) showing early behavioral signs of autism aged 9–14 months. The motor domain was evaluated using the motor subscales of the Mullen Scales of Early Learning at baseline, and at a 6-month follow-up. The Autism Diagnostic Observation Schedule – Toddler Module (ADOS-T) was completed at follow-up as a measure of autism likelihood. Motor difficulties were common at baseline, with 63/96 (65.6%) infants scoring very low or below average in the gross motor domain and 29/96 (30.2%) in the fine motor domain. At follow-up, gross motor difficulties had resolved for many, with 23/63 (36.5%) infants maintaining these difficulties. Fine motor difficulties resolved in fewer infants, with 20/29 (69.0%) continuing to present with fine motor delays at follow-up. Adjusted linear regression models suggested that fine motor scores at baseline (β = −0.12, SE = 0.04) and follow-up (β = −0.17, SE = 0.05) were associated with higher ADOS-T scores; with difficulties across both timepoints (β = 5.60, SE = 1.35) the strongest (largest in magnitude) association with ADOS-T scores of the predictors examined. Motor difficulties are prominent in children displaying emerging signs of autism, with persistent fine motor difficulties predictive of the developing autism phenotype. The findings indicate the potential clinical value of including evaluation of motor skills within early autism surveillance measures. Lay Summary: This prospective study evaluated motor development over a 6-month period in infants showing early behavioral signs of autism. Atypical motor development was a common feature of infants showing early signs of autism and persistent fine motor difficulties were predictive of the emerging autism phenotype.

Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-β-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicol.

Abstract: Carbapenem-resistant Klebsiella pneumoniae has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC) The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing K pneumoniae However, the mechanism(s) underpinning their synergistic killing are not well studied We employed an in vitro pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing K pneumoniae using a metabolomic approach Metabolomic analysis was integrated with an isolate-specific genome-scale metabolic network (GSMN) Our results show that metabolic responses to polymyxin B and/or chloramphenicol against NDM-producing K pneumoniae involved the inhibition of cell envelope biogenesis, metabolism of arginine and nucleotides, glycolysis, and pentose phosphate pathways Our metabolomic and GSMN modeling results highlight the novel mechanisms of a synergistic antibiotic combination at the network level and may have a significant potential in developing precision antimicrobial chemotherapy in patients