Effect of the Feed Additive Fytera Start on Growth Performance and Stool Quality of Nursery Pigs Fed Nutritional and Pharmacological Copper and Zinc Diets

A total of 340 barrows (DNA 200 × 400; initially 13.4 ± 0.17 lb BW) were used in a 38-d growth study to determine the effect of Fytera Start (Selko, Indianapolis, IN) in diets with or without pharmacological levels of Zn and Cu on growth performance and stool quality of nursery pigs. Fytera Start is a blend of botanical extracts that has recently been introduced for use in nursery pig diets. Pigs were weaned at approximately 21 d of age, randomly allotted to pens based on initial BW, and then allotted to 1 of 4 dietary treatments in a completely randomized design. There were 5 pigs per pen and 17 pens per treatment across two barns. Treatment diets were formulated in three dietary phases and fed from d 0 to 10, d 10 to 21, and d 21 to 38, respectively. Treatments were arranged in a 2 × 2 factorial with main effects of Fytera Start (none or 100 ppm) and nutritional vs. pharmacological levels of Zn and Cu. The nutritional mineral concentrations were 110 ppm Zn and 16.5 ppm Cu throughout phases 1 to 3. The pharmacological mineral concentrations were 3,000, 2,000, and 110 ppm Zn in phases 1, 2, and 3, respectively, combined with 250 ppm Cu throughout phases 1 to 3. To achieve expected levels of Zn and Cu in the diet, Zn from zinc oxide and Cu from copper sulfate were added. On d 0, there was an unintentional main effect of Fytera Start (P = 0.008) on BW. As a result, d 0 BW was used as a covariate for all other growth performance responses. From d 0 to 21 and d 0 to 38, there was a Fytera Start × Zn/Cu interaction on ADG and ADFI (P \u3c 0.05) in which the addition of Fytera Start resulted in a numeric increase in ADG and ADFI in pigs not fed pharmacological levels of Zn/Cu; however, in pigs fed pharmacological levels of Zn/Cu, the inclusion of Fytera Start resulted in a numeric reduction in ADG and ADFI. There was a tendency for a main effect of Zn/Cu level on overall feed efficiency (P \u3c 0.10) where pharmacological levels of Zn/Cu improved feed efficiency. For fecal dry matter, there was a Zn/Cu × day interaction (P = 0.001) in which there was no difference in fecal DM regardless of Zn/Cu level on d 10 (P \u3e 0.10), but pigs fed pharmacological levels of Zn/Cu had lower fecal DM (P \u3c 0.001) compared to those not fed pharmacological levels of Zn/Cu on d 21. There was a main effect of day resulting in increased fecal DM (P \u3c 0.001) on d 10 compared to d 21. There was a main effect of day on fecal score (P = 0.010) resulting in a lower frequency of softer feces at d 10 compared to d 21. The lower frequency of softer feces observed on d 10 is consistent with the higher fecal DM on d 10 compared to d 21. In summary, feeding pharmacological levels of Zn and Cu resulted in increased BW, ADG, and ADFI. The inclusion of Fytera Start numerically increased BW, ADG, and ADFI in pigs fed nutritional levels of Zn/Cu and numerically decreased BW, ADG, and ADFI in pigs fed pharmacological levels of Zn/Cu. There was no impact of Fytera Start or Zn and Cu level on fecal DM on d 10. However, feeding pharmacological levels of Zn and Cu resulted in lower fecal DM at d 21. Fecal DM was higher on d 10 compared to d 21, and fecal score was numerically lower on d 10 compared to d 21

Gastrin-releasing peptide receptor-based targeting using bombesin analogues is superior to metabolism-based targeting using choline for in vivo imaging of human prostate cancer xenografts

Purpose: Prostate cancer (PC) is a major health problem. Overexpression of the gastrin-releasing peptide receptor (GRPR) in PC, but not in the hyperplastic prostate, provides a promising target for staging and monitoring of PC. Based on the assumption that cancer cells have increased metabolic activity, metabolism-based tracers are also being used for PC imaging. We compared GRPR-based targeting using the68Ga-labelled bombesin analogue AMBA with metabolism-based tar

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts

Next-gen sequencing identifies non-coding variation disrupting miRNA-binding sites in neurological disorders

Understanding the genetic factors underlying neurodevelopmental and neuropsychiatric disorders is a major challenge given their prevalence and potential severity for quality of life. While large-scale genomic screens have made major advances in this area, for many disorders the genetic underpinnings are complex and poorly understood. To date the field has focused predominantly on protein coding variation, but given the importance of tightly controlled gene expression for normal brain development and disorder, variation that affects non-coding regulatory regions of the genome is likely to play an important role in these phenotypes. Herein we show the importance of 3 prime untranslated region (3'UTR) non-coding regulatory variants across neurodevelopmental and neuropsychiatric disorders. We devised a pipeline for identifying and functionally validating putatively pathogenic variants from next generation sequencing (NGS) data. We applied this pipeline to a cohort of children with severe specific language impairment (SLI) and identified a functional, SLI-associated variant affecting gene regulation in cells and post-mortem human brain. This variant and the affected gene (ARHGEF39) represent new putative risk factors for SLI. Furthermore, we identified 3'UTR regulatory variants across autism, schizophrenia and bipolar disorder NGS cohorts demonstrating their impact on neurodevelopmental and neuropsychiatric disorders. Our findings show the importance of investigating non-coding regulatory variants when determining risk factors contributing to neurodevelopmental and neuropsychiatric disorders. In the future, integration of such regulatory variation with protein coding changes will be essential for uncovering the genetic causes of complex neurological disorders and the fundamental mechanisms underlying health and disease

A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals

A high-quality human reference panel reveals the complexity and distribution of genomic structural variants

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, the majority of studies provide neither a global view of the full spectrum of these variants nor integrate them into reference panels of genetic variation. Here, we analyse whole genome sequencing data of 769 individuals from 250 Dutch families, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels, and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion are previously under reported variants sized between 21 and 100 bp. We detect 4 megabases of novel sequence, encoding 11 new transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with SVs and demonstrate that our panel facilitates accurate imputation of SVs in unrelated individuals

Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes

Background: The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000). Methods: This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch. Results: Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal ‘sentinel’ surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (=3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has becomedominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes. Conclusions: The consortium’s aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies

Unraveling genetic predisposition to familial or early onset gastric cancer using germline whole-exome sequencing

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts