Rodent and Broiler Feeding Studies with Maize Containing Genetically Modified Event DP-915635-4 Show No Adverse Effects on Health or Performance.

Several regulatory agencies continue to require animal feeding studies to approve new genetically modified crops despite such studies providing little value in the safety assessment. Feeding studies with maize grain containing event DP-915635-4 (DP915635), a new corn rootworm management trait, were conducted to fulfill that requirement. Diets fed to Crl:CD®(SD) rats for 90 days contained up to 50% ground maize grain from DP915635, non-transgenic control, or non-transgenic reference hybrids (P1197, 6158, and 6365). Ross 708 broilers received phase diets containing up to 67% maize grain from each source for 42 days. Growth performance was compared between animals fed DP915635 and control diets; rats were further evaluated for clinical and neurobehavioral measures, ophthalmology, clinical pathology, organ weights, and gross and microscopic pathology, whereas carcass parts and select organ yields were determined for broilers. Reference group inclusion assisted in determining natural variation influence on observed significant differences between DP915635 and control groups. DP915635 maize grain diet consumption did not affect any measure evaluated in either feeding study. Results demonstrated DP-915635-4 maize grain safety and nutritional equivalency when fed in nutritionally adequate diets, adding to the existing literature confirming the lack of significant effects of feeding grain from genetically modified plants.

Fructooligosaccharides act on the gut-bone axis to improve bone independent of Tregs and alter osteocytes in young adult C57BL/6 female mice.

Targeting the gut-bone axis with probiotics and prebiotics is considered as a promising strategy to reduce the risk of osteoporosis. Gut-derived short chain fatty acids (SCFA) mediate the effects of probiotics on bone via Tregs, but it is not known whether prebiotics act through a similar mechanism. We investigated how 2 different prebiotics, tart cherry (TC) and fructooligosaccharide (FOS), affect bone, and whether Tregs are required for this response. Eight-wk-old C57BL/6 female mice were fed with diets supplemented with 10% w/w TC, FOS, or a control diet (Con; AIN-93M) diet, and they received an isotype control or CD25 Ab to suppress Tregs. The FOS diet increased BMC, density, and trabecular bone volume in the vertebra (~40%) and proximal tibia (~30%) compared to the TC and control diets (Con), irrespective of CD25 treatment. Both prebiotics increased (P < .01) fecal SCFAs, but the response was greater with FOS. To determine how FOS affected bone cells, we examined genes involved in osteoblast and osteoclast differentiation and activity as well as genes expressed by osteocytes. The FOS increased the expression of regulators of osteoblast differentiation (bone morphogenetic protein 2 [Bmp2], Wnt family member 10b [Wnt10b] and Osterix [Osx]) and type 1 collagen). Osteoclasts regulators were unaltered. The FOS also increased the expression of genes associated with osteocytes, including (Phex), matrix extracellular phosphoglycoprotein (Mepe), and dentin matrix acidic phosphoprotein 1 (Dmp-1). However, Sost, the gene that encodes for sclerostin was also increased by FOS as the number and density of osteocytes increased. These findings demonstrate that FOS has a greater effect on the bone mass and structure in young adult female mice than TC and that its influence on osteoblasts and osteocytes is not dependent on Tregs.

Exerkines, Nutrition, and Systemic Metabolism.

The cornerstones of good health are exercise, proper food, and sound nutrition. Physical exercise should be a lifelong routine, supported by proper food selections to satisfy nutrient requirements based on energy needs, energy management, and variety to achieve optimal metabolism and physiology. The human body is sustained by intermediary and systemic metabolism integrating the physiologic processes for cells, tissues, organs, and systems. Recently, interest in specific metabolites, growth factors, cytokines, and hormones called exerkines has emerged to explain cooperation between nutrient supply organs and the brain during exercise. Exerkines consist of different compounds described as signaling moiety released during and after exercise. Examples of exerkines include oxylipin 12, 13 diHOME, lipid hormone adiponectin, growth factor BDNF, metabolite lactate, reactive oxygen species (ROS), including products of fatty acid oxidation, and cytokines such as interleukin-6. At this point, it is believed that exerkines are immediate, fast, and long-lasting factors resulting from exercise to support body energy needs with an emphasis on the brain. Although exerkines that are directly a product of macronutrient metabolism such as lactate, and result from catabolism is not surprising. Furthermore, other metabolites of macronutrient metabolism seem to be candidate exerkines. The exerkines originate from muscle, adipose, and liver and support brain metabolism, energy, and physiology. The purpose of this review is to integrate the actions of exerkines with respect to metabolism that occurs during exercise and propose other participating factors of exercise and brain physiology. The role of diet and macronutrients that influence metabolism and, consequently, the impact of exercise will be discussed. This review will also describe the evidence for PUFA, their metabolic and physiologic derivatives endocannabinoids, and oxylipins that validate them being exerkines. The intent is to present additional insights to better understand exerkines with respect to systemic metabolism.

Reduced estrogen signaling contributes to bone loss and cardiac dysfunction in interleukin-10 knockout mice.

Characterization of the interleukin (IL)-10 knockout (KO) mouse with chronic gut inflammation, cardiovascular dysfunction, and bone loss suggests a critical role for this cytokine in interorgan communication within the gut, bone, and cardiovascular axis. We sought to understand the role of IL-10 in the cross-talk between these systems. Six-week-old IL-10 KO mice and their wild type (WT) counterparts were maintained on a standard rodent diet for 3 or 6 months. Gene expression of proinflammatory markers and Fgf23, serum 17ß-estradiol (E2), and cardiac protein expression were assessed. Ileal Il17a and Tnf mRNA increased while Il6 mRNA increased in the bone and heart by at least 2-fold in IL-10 KO mice. Bone Dmp1 and Phex mRNA were repressed at 6 months in IL-10 KO mice, resulting in increased Fgf23 mRNA (~4-fold) that contributed to increased fibrosis. In the IL-10 KO mice, gut bacterial ß-glucuronidase activity and ovarian Cyp19a1 mRNA were lower (p < 0.05), consistent with reduced serum E2 and reduced cardiac pNOS3 (Ser1119 ) in these mice. Treatment of ileal lymphocytes with E2 reduced gut inflammation in WT but not IL-10 KO mice. In conclusion, our data suggest that diminished estrogen and defective bone mineralization increased FGF23 which contributed to cardiac fibrosis in the IL-10 KO mouse.

Extract of Artemisia dracunculus L. Modulates Osteoblast Proliferation and Mineralization.

Thiazolidinediones (TZD) significantly improve insulin sensitivity via action on adipocytes. Unfortunately, TZDs also degrade bone by inhibiting osteoblasts. An extract of Artemisia dracunculus L., termed PMI5011, improves blood glucose and insulin sensitivity via skeletal muscle, rather than fat, and may therefore spare bone. Here, we examine the effects of PMI5011 and an identified active compound within PMI5011 (2',4'-dihydroxy-4-methoxydihydrochalcone, DMC-2) on pre-osteoblasts. We hypothesized that PMI5011 and DMC-2 will not inhibit osteogenesis. To test our hypothesis, MC3T3-E1 cells were induced in osteogenic media with and without PMI5011 or DMC-2. Cell lysates were probed for osteogenic gene expression and protein content and were stained for osteogenic endpoints. Neither compound had an effect on early stain outcomes for alkaline phosphatase or collagen. Contrary to our hypothesis, PMI5011 at 30 µg/mL significantly increases osteogenic gene expression as early as day 1. Further, osteogenic proteins and cell culture mineralization trend higher for PMI5011-treated wells. Treatment with DMC-2 at 1 µg/mL similarly increased osteogenic gene expression and significantly increased mineralization, although protein content did not trend higher. Our data suggest that PMI5011 and DMC-2 have the potential to promote bone health via improved osteoblast maturation and activity.

Supplemental wheat germ modulates phosphorylation of STAT3 in the gut and NF-κBp65 in the adipose tissue of mice fed a Western diet.

Background: Commensal gut bacteria, including Lactobacillus, can produce metabolites that stimulate the release of gut antimicrobial peptides (AMPs) via the signal transducer and activator of transcription (STAT)3 pathway and prevent obesity-associated leaky gut and chronic inflammation. We have previously reported that wheat germ (WG) selectively increased cecal Lactobacillus in obese mice. Objectives: This study investigated the effects of WG on gut STAT3 activation and AMPs (Reg3γ and Reg3ß) as well as the potential of WG to inhibit nuclear Nf-κB-activation and immune cell infiltration in the visceral adipose tissue (VAT) of mice fed a Western diet (i.e., high-fat and sucrose diet [HFS]). Methods: Six-wk-old male C57BL/6 mice were randomly assigned to 4 groups (n = 12/group): control (C, 10% fat and sucrose kcal) or HFS (45% fat and 26% sucrose kcal) diet with or without 10% WG (wt/wt) for 12 wk. Assessments include serum metabolic parameters jejunal AMPs genes, inflammatory markers, and phosphorylation of STAT3 as well as VAT NF-κBp65. Independent and interaction effects of HFS and WG were analyzed with a 2-factor ANOVA. Results: WG significantly improved markers of insulin resistance and upregulated jejunal Il10 and Il22 genes. The HFS + WG group had a 15-fold increase in jejunal pSTAT3 compared with the HFS group. Consequently, WG significantly upregulated jejunal mRNA expression of Reg3γ and Reg3ß. The HFS group had a significantly higher VAT NF-κBp65 phosphorylation than the C group, while the HFS + WG group suppressed this to the level of C. Moreover, VAT Il6 and Lbp genes were downregulated in the HFS + WG group compared with HFS. Genes related to macrophage infiltration in the VAT were repressed in the WG-fed mice. Conclusion: These findings show the potential of WG to influence vital regulatory pathways in the gut and adipose tissue which may reduce the chronic inflammatory burden on these tissues that are important targets in obesity and insulin resistance.

Wheat Germ Supplementation Reduces Inflammation and Gut Epithelial Barrier Dysfunction in Female Interleukin-10 Knockout Mice Fed a Pro-Atherogenic Diet.

BACKGROUND: Mice lacking IL-10 are prone to gut inflammation. Additionally, decreased production of short-chain fatty acids (SCFAs) plays a significant role in the high-fat (HF) diet-induced loss of gut epithelial integrity. We have previously shown that wheat germ (WG) supplementation increased ileal expression of IL-22, an important cytokine in maintaining gut epithelial homeostasis. OBJECTIVES: This study investigated the effects of WG supplementation on gut inflammation and epithelial integrity in IL-10 knockout mice fed a pro-atherogenic diet. METHODS: Eight-week-old female C57BL/6 wild type mice were fed a control diet (10% fat kcal), and age-matched knockout mice were randomly assigned to 1 of 3 diets (n = 10/group): control, high-fat high-cholesterol (HFHC) [(43.4% fat kcal (∼49% saturated fat, 1% cholesterol)], or HFHC + 10% WG (HFWG) for 12 wk. Fecal SCFAs and total indole, ileal, and serum proinflammatory cytokines, gene or protein expression of tight junctions, and immunomodulatory transcription factors were assessed. Data were analyzed by 1-way ANOVA, and P < 0.05 was considered statistically significant. RESULTS: Fecal acetate, total SCFAs, and indole increased (P < 0.05) by at least 20% in HFWG compared with the other groups. WG increased (P < 0.0001, 2-fold) ileal Il22 (interleukin 22) to Il22ra2 (interleukin 22 receptor, alpha 2) mRNA ratio and prevented the HFHC diet-mediated increase in ileal protein expression of indoleamine 2,3 dioxygenase and pSTAT3 (phosphorylated signal transducer and activator of transcription 3). WG also prevented the HFHC diet-mediated reduction (P < 0.05) in ileal protein expression of the aryl hydrocarbon receptor and the tight junction protein, zonula occludens-1. Serum and ileal concentrations of the proinflammatory cytokine, IL-17, were lower (P < 0.05) by at least 30% in the HFWG group than in the HFHC group. CONCLUSIONS: Our findings demonstrate that the anti-inflammatory potential of WG in IL-10 KO mice consuming an atherogenic diet is partly attributable to its effects on the IL-22 signaling and pSTAT3-mediated production of T helper 17 proinflammatory cytokines.

In vivo biodistribution and pharmacokinetics of sotrovimab, a SARS-CoV-2 monoclonal antibody, in healthy cynomolgus monkeys.

PURPOSE: Sotrovimab (VIR-7831), a human IgG1κ monoclonal antibody (mAb), binds to a conserved epitope on the SARS-CoV-2 spike protein receptor binding domain (RBD). The Fc region of VIR-7831 contains an LS modification to promote neonatal Fc receptor (FcRn)-mediated recycling and extend its serum half-life. Here, we aimed to evaluate the impact of the LS modification on tissue biodistribution, by comparing VIR-7831 to its non-LS-modified equivalent, VIR-7831-WT, in cynomolgus monkeys. METHODS: 89Zr-based PET/CT imaging of VIR-7831 and VIR-7831-WT was performed up to 14 days post injection. All major organs were analyzed for absolute concentration as well as tissue:blood ratios, with the focus on the respiratory tract, and a physiologically based pharmacokinetics (PBPK) model was used to evaluate the tissue biodistribution kinetics. Radiomics features were also extracted from the PET images and SUV values. RESULTS: SUVmean uptake in the pulmonary bronchi for 89Zr-VIR-7831 was statistically higher than for 89Zr-VIR-7831-WT at days 6 (3.43 ± 0.55 and 2.59 ± 0.38, respectively) and 10 (2.66 ± 0.32 and 2.15 ± 0.18, respectively), while the reverse was observed in the liver at days 6 (5.14 ± 0.80 and 8.63 ± 0.89, respectively), 10 (4.52 ± 0.59 and 7.73 ± 0.66, respectively), and 14 (4.95 ± 0.65 and 7.94 ± 0.54, respectively). Though the calculated terminal half-life was 21.3 ± 3.0 days for VIR-7831 and 16.5 ± 1.1 days for VIR-7831-WT, no consistent differences were observed in the tissue:blood ratios between the antibodies except in the liver. While the lung:blood SUVmean uptake ratio for both mAbs was 0.25 on day 3, the PBPK model predicted the total lung tissue and the interstitial space to serum ratio to be 0.31 and 0.55, respectively. Radiomics analysis showed VIR-7831 had mean-centralized PET SUV distribution in the lung and liver, indicating more uniform uptake than VIR-7831-WT. CONCLUSION: The half-life extended VIR-7831 remained in circulation longer than VIR-7831-WT, consistent with enhanced FcRn binding, while the tissue:blood concentration ratios in most tissues for both drugs remained statistically indistinguishable throughout the course of the experiment. In the bronchiolar region, a higher concentration of 89Zr-VIR-7831 was detected. The data also allow unparalleled insight into tissue distribution and elimination kinetics of mAbs that can guide future biologic drug discovery efforts, while the residualizing nature of the 89Zr label sheds light on the sites of antibody catabolism.

A Pilot Study of Associations Between the Occurrence of Palpitations and Cytokine Gene Variations in Women Prior to Breast Cancer Surgery.

OBJECTIVES: Palpitations are common and have a negative impact on women's quality of life. While evidence suggests that inflammatory mechanisms may play a role in the development of palpitations, no studies have evaluated for this association in patients with breast cancer who report palpitations prior to surgery. The purpose of this pilot study was to evaluate for associations between the occurrence of palpitations and single nucleotide polymorphisms (SNPs) in genes for pro- and anti-inflammatory cytokines, their receptors, and transcriptional regulators. METHODS: Patients were recruited prior to surgery and completed a self-report questionnaire on the occurrence of palpitations. Genotyping of SNPs in cytokine genes was performed using a custom array. Multiple logistic regression analyses were done to identify associations between the occurrence of palpitations and SNPs in fifteen candidate genes. RESULTS: Of the 82 SNPs evaluated in the bivariate analyses, eleven SNPs in 6 genes were associated with the occurrence of palpitations. After controlling for functional status, the occurrence of back pain, and self-reported and genomic estimates of race/ethnicity, 3 SNPs in 3 different genes (i.e., interleukin (IL) 1-beta (IL1B) rs1143643, IL10 rs3024505, IL13 rs1295686) were associated with the occurrence of palpitations prior to surgery (all p ≤ .038). CONCLUSIONS: While these preliminary findings warrant replication, they suggest that inflammatory mechanisms may contribute to the subjective sensation of palpitations in women prior to breast cancer surgery.

Mathematical modeling of the effects of Wnt-10b on bone metabolism.

Bone health is determined by factors including bone metabolism or remodeling. Wnt-10b alters osteoblastogenesis through pre-osteoblast proliferation and differentiation and osteoblast apoptosis rate, which collectively lead to the increase of bone density. To model this, we adapted a previously published model of bone remodeling. The resulting model for the bone compartment includes differential equations for active osteoclasts, pre-osteoblasts, osteoblasts, osteocytes, and the amount of bone present at the remodeling site. Our alterations to the original model consist of extending it past a single remodeling cycle and implementing a direct relationship to Wnt-10b. Four new parameters were estimated and validated using normalized data from mice. The model connects Wnt-10b to bone metabolism and predicts the change in trabecular bone volume caused by a change in Wnt-10b input. We find that this model predicts the expected increase in pre-osteoblasts and osteoblasts while also pointing to a decrease in osteoclasts when Wnt-10b is increased.

Common Dietary Modifications in Preclinical Models to Study Skeletal Health.

Bone is a highly dynamic tissue that undergoes continuous remodeling by bone resorbing osteoclasts and bone forming osteoblasts, a process regulated in large part by osteocytes. Dysregulation of these coupled catabolic and anabolic processes as in the case of menopause, type 2 diabetes mellitus, anorexia nervosa, and chronic kidney disease is known to increase fracture risk. Recent advances in the field of bone cell metabolism and bioenergetics have revealed that maintenance of the skeleton places a high energy demand on these cells involved in bone remodeling. These new insights highlight the reason that bone tissue is the beneficiary of a substantial proportion of cardiac output and post-prandial chylomicron remnants and requires a rich supply of nutrients. Studies designed for the specific purpose of investigating the impact of dietary modifications on bone homeostasis or that alter diet composition and food intake to produce the model can be found throughout the literature; however, confounding dietary factors are often overlooked in some of the preclinical models. This review will examine some of the common pre-clinical models used to study skeletal biology and its pathologies and the subsequent impact of various dietary factors on these model systems. Furthermore, the review will include how inadvertent effects of some of these dietary components can influence bone cell function and study outcomes.

Dried Plum's Polyphenolic Compounds and Carbohydrates Contribute to Its Osteoprotective Effects and Exhibit Prebiotic Activity in Estrogen Deficient C57BL/6 Mice.

Evidence of dried plum's benefits on bone continues to emerge. This study investigated the contribution of the fruit's polyphenol (PP) and carbohydrate (CHO) components on a bone model of postmenopausal osteoporosis to explore their prebiotic activity. Osteopenic ovariectomized mice were fed diets supplemented with dried plum, a crude extract of dried plum's polyphenolic compounds, or the PP or CHO fraction of the crude extract. The effects of treatments on the bone phenotype were assessed at 5 and 10 weeks as well as the prebiotic activity of the different components of dried plum. Both the CHO and PP fractions of the extract contributed to the effects on bone with the CHO suppressing bone formation and resorption, and the PP temporally down-regulating formation. The PP and CHO components also altered the gut microbiota and cecal short chain fatty acids. These findings demonstrate that the CHO as well as the PP components of dried plum have potential prebiotic activity, but they have differential roles in mediating the alterations in bone formation and resorption that protect bone in estrogen deficiency.

Montmorencytart cherry supplementation improved markers of glucose homeostasis but has modest effects on indicators of gut health in mice fed a Western diet.

The gut microbiota plays an important role in the pathophysiology of obesity and type 2 diabetes. Emerging evidence suggests that anthocyanin-rich foods such as US Montmorency tart cherry (TC) can promote health by influencing the gut microbiota and maintaining gut integrity. This study investigated the effects of TC supplementation on the gut microbiota, markers of gut health, and metabolic parameters in mice fed a western diet (WD). Seventy-two C57BL/6 male mice were assigned to dietary treatments in a 2 × 3 factorial design with diet (control, WD) and TC (0, 5, 10% wt/wt) as factors. After 12 weeks of dietary treatment, tissues were collected to evaluate metabolic parameters and markers of gut health including cecal content microbiota and fecal short chain fatty acids (SCFAs). TC supplementation significantly increased the bacterial phylum, Actinobacteria, cecal weight, and fecal SCFAs and reduced the Proteobacteria and Deferribacteres phyla. However, gut histological parameters and expression of genes related to gut integrity were unaffected by TC. Body weight, serum cholesterol, triglyceride, leptin, plasminogen activator inhibitor-1 and resistin were increased with WD and TC had no effect on these parameters. Fasting blood glucose and the surrogate marker of insulin resistance, homeostatic model assessment of insulin resistance (HOMA-IR), was significantly increased by WD which was improved by TC particularly the 5% dose. In conclusion, TC supplementation, particularly the 5% dose, improved markers of glucose homeostasis but has modest effects on gut microbial population and SCFAs production. The mechanism by which TC improved markers of glucose homeostasis needs to be further investigated.

Principles for Management of Extractables and Leachables in Ophthalmic Drug Products.

Ophthalmic solutions and suspensions have long been classified into a high-risk category with respect to concerns over extractables and leachables (E&L), though specific guidance on the management of leachables in these products is generally absent from regulatory authorities or the scientific literature. As a result, ophthalmic drug products (ODPs) were originally included in the scope of the Product Quality Research Institute Leachables and Extractables Working Group for Parenteral and Ophthalmic Drug Products (PQRI-PODP). Relative to other high concern dosage forms such as metered-dose inhalers or injectables, ODPs possess unique challenges with respect to the nature of impactful E&L as well as the safety assessment of leachables. For example, extensive use of semipermeable low-density polyethylene primary packaging for ODPs necessitates a strong focus on E&L from secondary packaging sources. For safety assessment, a key challenge is the lack of a sufficient database developed on all relevant ophthalmic toxicity endpoints. As result, the working group is unable to recommend a safety concern threshold (SCT) for ODPs at this time. Nevertheless, the ophthalmic industry has developed a number of time-tested practices to manage E&L for ODPs. This article describes those science-based practices and key considerations in the analysis, management, and safety assessment of E&L in ODPs.

Reduction in Health Care Facility-Onset Clostridioides difficile Infection: A Quality Improvement Initiative.

OBJECTIVE: To reduce health care facility-onset (HCFO) Clostridioides difficile infection (CDI) incidence by improving diagnostic stewardship and reducing the inappropriate testing of C difficile assays. PATIENTS AND METHODS: A multidisciplinary team conducted a quality improvement initiative from January 1, 2020, through March 31, 2021. Clostridioides difficile infection and inappropriate testing were identified via electronic health records using predefined criteria related to stool quantity/caliber, confounding medications, and laboratory data. An intervention bundle was designed including (1) provider education, (2) implementation of an appropriate testing algorithm, (3) expert review of C difficile orders, and (4) batch testing of assays to facilitate review and cancellation if inappropriate. RESULTS: Compared with a baseline period from January to September 2020, implementation of our intervention bundle from December 2020 to March 2021 resulted in an 83.6% reduction in inappropriate orders tested and a 41.7% reduction in HCFO CDI incidence. CONCLUSION: A novel prevention bundle improved C difficile diagnostic stewardship and HCFO CDI incidence by reducing testing of inappropriate orders. Such initiatives targeting HCFO CDI may positively affect patient safety and hospital reimbursement.

Long-Term Efficacy and Safety of RNAi-Mediated Virus Resistance in 'HoneySweet' Plum.

Interfering RNA technology has been established as an effective strategy to protect plants against viral infection. Despite this success, interfering RNA (RNAi) has rarely been applied due to the regulatory barriers that confront genetically engineered plants and concerns over possible environmental and health risks posed by non-endogenous small RNAs. 'HoneySweet' was developed as a virus-resistant plum variety that is protected by an RNAi-mediated process against Sharka disease caused by the plum pox virus. 'HoneySweet' has been approved for cultivation in the United States but not in countries where the plum pox virus is endemic. In this study, we evaluated the long-term efficacy of virus resistance in 'HoneySweet,' the nature and stability of its sRNA profile, and the potential health risks of consuming 'HoneySweet' plums. Graft-challenged 'HoneySweet' trees carrying large non-transgenic infected limbs remained virus-free after more than 10 years in the field, and the viral sequences from the non-transgenic infected limbs showed no evidence of adaptation to the RNAi-based resistance. Small RNA profiling revealed that transgene-derived sRNA levels were stable across different environments and, on average, were more than 10 times lower than those present in symptom-less fruits from virus-infected trees. Comprehensive 90-day mouse feeding studies showed no adverse health impacts in mice, and there was no evidence for potential siRNA off-target pathologies predicted by comparisons of the most abundant transgene-derived sRNAs to the mouse genome. Collectively, the data confirmed that RNAi provides a highly effective, stable, and safe strategy to combat virus diseases in crop plants.

Optimizing mechanically sensed atrial tracking in patients with atrioventricular-synchronous leadless pacemakers: A single-center experience.

BACKGROUND: Atrioventricular (AV)-synchronous single-chamber leadless pacing using a mechanical atrial sensing algorithm produced high AV synchrony in clinical trials, but clinical practice experience with these devices has not yet been described. OBJECTIVE: To describe pacing outcomes and programming changes with AV-synchronous leadless pacemakers in clinical practice. METHODS: Consecutive patients without persistent atrial fibrillation who received an AV-synchronous leadless pacemaker and completed follow-up between February 2020 and April 2021 were included. We evaluated tracking index (atrial mechanical sense followed by ventricular pace [AM-VP] divided by total VP), total AV synchrony (sum of AM-ventricular sense [AM-VS], AM-VP, and AV conduction mode switch), use of programming optimization, and improvement in AV synchrony after optimization. RESULTS: Fifty patients met the inclusion criteria. Mean age was 69 ± 16.8 years, 24 (48%) were women, 24 (48%) had complete heart block, and 17 (34%) required ≥50% pacing. Mean tracking index was 41% ± 34%. Thirty-five patients (70%) received ≥1 programming change. In 36 patients with 2 follow-up visits, tracking improved by +9% ± 28% (P value for improvement = .09) and +18% ± 19% (P = .02) among 15 patients with complete heart block. Average total AV synchrony increased from 89% [67%, 99%] to 93% [78%, 100%] in all patients (P = .22), from 86% [52%, 98%] to 97% [82%, 99%] in those with complete heart block (P = .04), and from 73% [52%, 80%] to 78% [70%, 85%] in those with ≥50% pacing (P = .09). CONCLUSION: In patients with AV-synchronous leadless pacemakers, programming changes are frequent and are associated with increased atrial tracking and increased AV synchrony in patients with complete heart block.

Evaluation of the safety and nutritional equivalency of maize grain with genetically modified event DP-Ø23211-2.

Feeding studies were conducted with rats and broiler chickens to assess the safety and nutrition of maize grain containing event DP-Ø23211-2 (DP23211), a newly developed trait-pyramid product for corn rootworm management. Diets containing 50% ground maize grain from DP23211, non-transgenic control, or non-transgenic reference hybrids (P0928, P0993, and P1105) were fed to Crl:CD®(SD) rats for 90 days. Ross 708 broilers were fed phase diets containing up to 67% maize grain from each source for 42 days. Body weight, gain, and feed conversion were determined for comparisons between animals fed DP23211 and control diets in each study. Additional measures included clinical and neurobehavioral evaluations, ophthalmology, clinical pathology, organ weights, and gross and microscopic pathology for rats, and carcass parts and select organ yields for broilers. Reference groups were included to determine if any observed significant differences between DP23211 and control groups were likely due to natural variation. No diet-related effects on mortality or evaluation measures were observed between animal fed diets produced with DP23211 maize grain and animal fed diets produced with control maize grain. These studies show that maize grain containing event DP-Ø23211-2 is as safe and nutritious as non-transgenic maize grains when fed in nutritionally adequate diets. The results are consistent with previously published studies, providing further demonstration of the absence of hazards from edible-fraction consumption of genetically modified plants.

A role for zinc transporter gene SLC39A12 in the nervous system and beyond.

The SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.

U.S. Montmorency Tart Cherry Juice Decreases Bone Resorption in Women Aged 65-80 Years.

Pre-clinical studies have demonstrated that tart cherries, rich in hydroxycinnamic acids and anthocyanins, protect against age-related and inflammation-induced bone loss. This study examined how daily consumption of Montmorency tart cherry juice (TC) alters biomarkers of bone metabolism in older women. Healthy women, aged 65-80 years (n = 27), were randomly assigned to consume ~240 mL (8 fl. oz.) of juice once (TC1X) or twice (TC2X) per day for 90 d. Dual-energy x-ray absorptiometry (DXA) scans were performed to determine bone density at baseline, and pre- and post-treatment serum biomarkers of bone formation and resorption, vitamin D, inflammation, and oxidative stress were assessed. Irrespective of osteoporosis risk, the bone resorption marker, tartrate resistant acid phosphatase type 5b, was significantly reduced with the TC2X dose compared to baseline, but not with the TC1X dose. In terms of indicators of bone formation and turnover, neither serum bone-specific alkaline phosphatase nor osteocalcin were altered. No changes in thiobarbituric acid reactive substances or high sensitivity C-reactive protein were observed in response to either TC1X or TC2X. We conclude that short-term supplementation with the higher dose of tart cherry juice decreased bone resorption from baseline without altering bone formation and turnover biomarkers in this cohort.