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Abstract Background Enhanced nutrition during the early calfhood period has been shown to lead to earlier pubertal development in heifer calves. This is of interest as earlier pubertal onset can subsequently facilitate earlier calving which can economically benefit production systems. Reproductive development in heifers is regulated by the hypothalamic-pituitary-ovarian signalling pathway. In particular the anterior pituitary gland is central to reproductive development, through the dynamics of gonadotropic pulsatility. However, despite clear knowledge of the influence of enhanced dietary intake on subsequent reproductive development, the molecular control governing this response in the pituitary gland within the hypothalamic-pituitary-ovarian signalling axis in heifer calves is not fully understood. The objective of this study was to examine the effect of an enhanced plane of nutrition during early life on the anterior pituitary gland of heifer calves through both transcriptomic and proteomic analyses. Between 3 and 21 weeks of age, heifer calves were offered either a high (HI, n = 14) or moderate (MOD, n = 14) plane of nutrition, designed to elicit target growth rates of 1.2 and 0.5 kg/d for HI and MOD groups, respectively. All calves were euthanised at 21 weeks of age and anterior pituitary tissue harvested for subsequent use in global transcriptomic and proteomic analyses. Results Average daily gain was affected by diet (P 1.5), with 277 proteins identified as differentially abundant (Padj 1.5) between contrasting dietary treatment groups. Biochemical pathway analysis of differentially affected genes and proteins revealed an enrichment for both growth hormone and GnRH signalling pathways (Padj.

BackgroundPrimary human neutrophils play a pivotal role in innate immunity, mainly through the formation of neutrophil extracellular traps (NETs) in a process known as NETosis. This cell-death pathway is crucial for combating infections but is also implicated in many inflammatory diseases, such as sepsis, systemic lupus erythematosus, and rheumatoid arthritis.MethodsThe study presented here investigates chromatin dynamics during NET formation by stimulating primary human neutrophils with phorbol 12-myristate 13-acetate (PMA). We adapt the ATAC-Seq (assay for transposase-accessible chromatin using sequencing) method to isolated neutrophils and characterize a time-dependent chromatin response.ResultsWe found that chromatin accessibility patterns are consistent across individual donors and most chromatin changes occur within 30 min, with many continuing across the 90 min assessed in this study. Regulatory regions gaining accessibility were associated with the activity of pathways that have been implicated in NOX-dependent NET formation.ConclusionsOur findings increase the understanding of the chromatin changes underlying NET formation and also identify potential early-acting targets for modulating this process in inflammatory diseases.

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.

Abstract It is known that small extracellular vesicles (sEVs) are released from cancer cells and contribute to cancer progression via crosstalk with recipient cells. We have previously reported that sEVs expressing the αVβ3 integrin, a protein upregulated in aggressive neuroendocrine prostate cancer (NEPrCa), contribute to neuroendocrine differentiation (NED) in recipient cells. Here, we examine the impact of αVβ3 expression on sEV protein content, density and function. sEVs used in this study were isolated by iodixanol density gradients and characterized by nanoparticle tracking analysis, immunoblotting and single vesicle analysis. Our proteomic profile of sEVs containing αVβ3 shows downregulation of typical effectors involved in apoptosis and necrosis and an upregulation of tumour cell survival factors compared to control sEVs. We also show that the expression of αVβ3 in sEVs causes a distinct reposition of EV markers (Alix, CD81, CD9) to a low‐density sEV subpopulation. This low‐density reposition is independent of extracellular matrix (ECM) protein interactions with sEVs. This sEV subset contains αVβ3 and an αVβ3 downstream effector, NgR2, a novel marker for NEPrCa. We show that sEVs containing αVβ3 are loaded with higher amounts of NgR2 as compared to sEVs that do not express αVβ3. Mechanistically, we demonstrate that sEVs containing NgR2 do not affect the sEV marker profile, but when injected in vivo intratumorally, they promote tumour growth and induce NED. We show that sEVs expressing NgR2 increase the activation of focal adhesion kinase (FAK), a known promoter of cancer cell proliferation, in recipient cells. We also show that NgR2 mimics the effect of sEVs containing αVβ3 since it displays increased growth of NgR2 transfectants in vivo, as compared to control cells. Overall, our results describe the changes that occur in cargo, density and functions of cancer cell‐derived sEVs containing the αVβ3 integrin and its effector, NgR2, without affecting the sEV tetraspanin profiles.

Ecological and evolutionary changes are likely to occur rapidly when outcrossing populations experience pollinator loss. However, the number and identify of plant traits that will respond to this form of selection, as well as the overall predictability of evolutionary responses, remain unclear. We experimentally evolved 20 large replicate populations of Mimulus guttatus for 10 generations under three treatments: pure outcrossing, mixed mating (10% outcrossing) and pure selfing. These populations were founded from the same genetically diverse and outcrossing natural population. After 10 generations, all measured traits evolved with flower size, phenology, and reproductive traits diverging consistently among mating system treatments. Autogamy increased dramatically in the selfing treatment, but the magnitude of adaptation only becomes clear once inbreeding depression is factored out. Selfing treatment plants evolved reduced stigma-anther separation, and also exhibited declines in flower size and per-flower reproductive capacity. Flower size also declined in selfing populations but this was driven mainly by inbreeding depression and cannot be attributed to adaptation towards the selfing syndrome. Generally, the mixed mating populations evolved trait values intermediate to the fully selfing and outcrossing populations. Overall, our experimental treatments reiterated differences that have been documented in interspecific comparisons between selfing and outcrossing species pairs. Given that such contrasts involve species separated by thousands or even millions of generations, it is noteworthy that large evolutionary responses were obtained from genetic variation segregating within a single natural population.

Gene expression can be influenced by genetic variants that are closely linked to the expressed gene (cis eQTLs) and variants in other parts of the genome (trans eQTLs). We created a multiparental mapping population by sampling genotypes from a single natural population of Mimulus guttatus and scored gene expression in the leaves of 1,588 plants. We find that nearly every measured gene exhibits cis regulatory variation (91% have FDR < 0.05). cis eQTLs are usually allelic series with three or more functionally distinct alleles. The cis locus explains about two thirds of the standing genetic variance (on average) but varies among genes and tends to be greatest when there is high indel variation in the upstream regulatory region and high nucleotide diversity in the coding sequence. Despite mapping over 10,000 trans eQTL / affected gene pairs, most of the genetic variance generated by trans acting loci remains unexplained. This implies a large reservoir of trans acting genes with subtle or diffuse effects. Mapped trans eQTLs show lower allelic diversity but much higher genetic dominance than cis eQTLs. Several analyses also indicate that trans eQTLs make a substantial contribution to the genetic correlations in expression among different genes. They may thus be essential determinants of "gene expression modules," which has important implications for the evolution of gene expression and how it is studied by geneticists.

Abstract Background and aims Excess energy intake can lead to metabolic dysfunction-associated steatotic liver disease (MASLD), but the relationship between dietary carbohydrate intake and liver fat content remains unclear. This study aimed to examine the associations between types and sources of dietary carbohydrates and liver fat content. Methods UK Biobank participants with no pre-existing diabetes, liver disease or cardiovascular disease reported dietary intake of types and sources of carbohydrates (total carbohydrates, free sugars, non-free sugars, starch from whole grains, starch from refined grains, and fibre) on at least two 24-h dietary assessments. In cross-sectional analyses, (n = 22,973), odds ratios (OR) of high liver fat content (defined as a score of ≥ 36 in the hepatic steatosis index) by quintiles of carbohydrate intakes were estimated using multivariable logistic regression models. In prospective analyses, a second sample (n = 9268) had liver proton density fat fraction (PDFF) measured by magnetic resonance imaging (2014–2020). Multivariable linear regression models estimated geometric means of PDFF (%) by quintiles of carbohydrate intakes. Models were adjusted for demographic and lifestyle confounders, including total energy intake. Results In the cross-sectional analyses, 6894 cases of high liver fat content were identified. Inverse associations between intakes of fibre (OR of highest vs. lowest quintile 0.46 [95% CI: 0.41–0.52]), non-free sugars (0.63 [0.57–0.70]) and starch from whole grains (0.52 [0.47–0.57]) with liver fat were observed. There were positive associations between starch from refined grains and liver fat (1.33 [1.21–1.46]), but no association with free sugars (p=0.61). In prospective analyses, inverse associations with PDFF (%) were observed for intakes of fibre (− 0.48 geometric mean difference between highest and lowest quintile of intake [− 0.60 to − 0.35]), non-free sugars (− 0.37 [− 0.49 to − 0.25]) and starch from whole grains (− 0.31 [− 0.42 to − 0.19]). Free sugars, but not starch from refined grains, were positively associated with PDFF (0.17 [0.05 to 0.28]). Conclusion This study suggests that different carbohydrate types and sources have varying associations with liver fat, which may be important for MASLD prevention. Non-free sugars, fibre, and starch from whole grains could be protective, while associations with free sugars and starch from refined grains are less clear.

Abstract Background Limited information is available regarding the nutritive value and structural characteristics of multispecies swards when rotationally grazed. Methods Three farmlet types were investigated in terms of their nutritive value: Lolium perenne (LP); L. perenne+Trifolium repens (LP+TR); and a multispecies sward containing grasses, legumes and herbs (MSS). Farmlets were stocked with beef steers (2.5 livestock units ha−1), grazed on a 1 ha scale to 6 cm (MSS) and 4 cm (LP and LP+TR) residuals. Results A greater ash concentration was found in MSS than LP (84 vs. 75 g kg−1 DM). Both LP+TR and MSS had higher crude protein and lower neutral detergent fibre concentrations than LP. The relative ranking of water soluble carbohydrate and dry matter (DM) concentration was LP > LP+TR > MSS. Despite the leaf component of the LP farmlet contributing more to herbage DM, the organic matter digestibilities of the swards were similar. Conclusions The MSS and LP+TR farmlets achieved similar forage quality under intensive grazing to LP. However, it is worth noting that MSS had a higher concentration of acid detergent lignin, which can negatively impact digestibility. Further investigation is needed to determine optimal grazing management practices that can minimise the effects of higher lignin concentration on digestibility in multispecies swards.

BackgroundInfectious disease-related stigma is a pervasive global issue that impedes disease control efforts by increasing reluctance to seek treatment or engagement in prevention behaviors for fear of ostracism. Despite this, there is limited research on COVID-19 stigma in Africa, specifically rural South Africa, which has faced infectious disease-related stigma throughout the HIV epidemic.MethodsPopulation-based surveys were conducted among 1,662 adults living in the Agincourt Health and Socio-Demographic Surveillance System (AHDSS) area in Mpumalanga, South Africa, in August-October 2020 and August-October 2021. Surveys measured anticipated COVID-19-related stigma from low to high levels. Changes in stigma between surveys were compared using Wilcoxon ranked sign tests, and log-binomial models estimated the association between socio-demographic factors and anticipated stigma at both intervals. Qualitative interviews were conducted in 2022 among 31 adults who completed the original surveys, and the data were analyzed thematically to describe anticipated, perceived, and enacted stigma.ResultsAnticipated stigma significantly decreased from the first to the second survey (p-value:ConclusionWhile COVID-19 stigma decreased over time in rural South Africa, different forms of stigma persisted and influenced participants' willingness to reveal their COVID-19 infection status. Given South Africa's history with infectious disease-related stigma hindering public health efforts, it is crucial that government bodies prioritize strategies to mitigate stigma in rural communities.

In the formation of species, adaptation by natural selection generates distinct combinations of traits that function well together. The maintenance of adaptive trait combinations in the face of gene flow depends on the strength and nature of selection acting on the underlying genetic loci. Floral pollination syndromes exemplify the evolution of trait combinations adaptive for particular pollinators. The North American wildflower genus Penstemon displays remarkable floral syndrome convergence, with at least 20 separate lineages that have evolved from ancestral bee pollination syndrome (wide blue-purple flowers that present a landing platform for bees and small amounts of nectar) to hummingbird pollination syndrome (bright red narrowly tubular flowers offering copious nectar). Related taxa that differ in floral syndrome offer an attractive opportunity to examine the genomic basis of complex trait divergence. In this study, we characterized genomic divergence among 229 individuals from a Penstemon species complex that includes both bee and hummingbird floral syndromes. Field plants are easily classified into species based on phenotypic differences and hybrids displaying intermediate floral syndromes are rare. Despite unambiguous phenotypic differences, genome-wide differentiation between species is minimal. Hummingbird-adapted populations are more genetically similar to nearby bee-adapted populations than to geographically distant hummingbird-adapted populations, in terms of genome-wide dXY. However, a small number of genetic loci are strongly differentiated between species. These approximately 20 "species-diagnostic loci," which appear to have nearly fixed differences between pollination syndromes, are sprinkled throughout the genome in high recombination regions. Several map closely to previously established floral trait quantitative trait loci (QTLs). The striking difference between the diagnostic loci and the genome as whole suggests strong selection to maintain distinct combinations of traits, but with sufficient gene flow to homogenize the genomic background. A surprisingly small number of alleles confer phenotypic differences that form the basis of species identity in this species complex.

Abstract Background Recent studies have reported that the associations between dietary carbohydrates and cardiovascular disease (CVD) may depend on the quality, rather than the quantity, of carbohydrates consumed. This study aimed to assess the associations between types and sources of dietary carbohydrates and CVD incidence. A secondary aim was to examine the associations of carbohydrate intakes with triglycerides within lipoprotein subclasses. Methods A total of 110,497 UK Biobank participants with ≥ two (maximum five) 24-h dietary assessments who were free from CVD and diabetes at baseline were included. Multivariable-adjusted Cox regressions were used to estimate risks of incident total CVD (4188 cases), ischaemic heart disease (IHD; 3138) and stroke (1124) by carbohydrate intakes over a median follow-up time of 9.4 years, and the effect of modelled dietary substitutions. The associations of carbohydrate intakes with plasma triglycerides within lipoprotein subclasses as measured by nuclear magnetic resonance (NMR) spectroscopy were examined in 26,095 participants with baseline NMR spectroscopy measurements. Results Total carbohydrate intake was not associated with CVD outcomes. Free sugar intake was positively associated with total CVD (HR; 95% CI per 5% of energy, 1.07;1.03–1.10), IHD (1.06;1.02–1.10), and stroke (1.10;1.04–1.17). Fibre intake was inversely associated with total CVD (HR; 95% CI per 5 g/d, 0.96;0.93–0.99). Modelled isoenergetic substitution of 5% of energy from refined grain starch with wholegrain starch was inversely associated with total CVD (0.94;0.91–0.98) and IHD (0.94;0.90–0.98), and substitution of free sugars with non-free sugars was inversely associated with total CVD (0.95;0.92–0.98) and stroke (0.91;0.86–0.97). Free sugar intake was positively associated with triglycerides within all lipoproteins. Conclusions Higher free sugar intake was associated with higher CVD incidence and higher triglyceride concentrations within all lipoproteins. Higher fibre intake and replacement of refined grain starch and free sugars with wholegrain starch and non-free sugars, respectively, may be protective for incident CVD.

Abstract Background The endogenous tissue inhibitor of metalloproteinase-2 (TIMP-2), through its homeostatic action on certain metalloproteinases, plays a vital role in remodelling extracellular matrix (ECM) to facilitate cancer progression. This study investigated the role of TIMP-2 in an ovarian cancer cell line in which the expression of TIMP-2 was reduced by either siRNA or CRISPR/Cas9. Methods OVCAR5 cells were transiently and stably transfected with either single or pooled TIMP-2 siRNAs (T2-KD cells) or by CRISPR/Cas9 under the influence of two distinct guide RNAs (gRNA1 and gRNA2 cell lines). The expression of different genes was analysed at the mRNA level by quantitative real time PCR (qRT-PCR) and at the protein level by immunofluorescence (IF) and western blot. Proliferation of cells was investigated by 5-Ethynyl-2′-deoxyuridine (EdU) assay or staining with Ki67. Cell migration/invasion was determined by xCELLigence. Cell growth in vitro was determined by 3D spheroid cultures and in vivo by a mouse xenograft model. Results Approximately 70–90% knock down of TIMP-2 expression were confirmed in T2-KD, gRNA1 and gRNA2 OVCAR5 ovarian cancer cells at the protein level. T2-KD, gRNA1 and gRNA2 cells exhibited a significant downregulation of MMP-2 expression, but concurrently a significant upregulation in the expression of membrane bound MMP-14 compared to control and parental cells. Enhanced proliferation and invasion were exhibited in all TIMP-2 knocked down cells but differences in sensitivity to paclitaxel (PTX) treatment were observed, with T2-KD cells and gRNA2 cell line being sensitive, while the gRNA1 cell line was resistant to PTX treatment. In addition, significant differences in the growth of gRNA1 and gRNA2 cell lines were observed in in vitro 3D cultures as well as in an in vivo mouse xenograft model. Conclusions Our results suggest that the inhibition of TIMP-2 by siRNA and CRISPR/Cas-9 modulate the expression of MMP-2 and MMP-14 and reprogram ovarian cancer cells to facilitate proliferation and invasion. Distinct disparities in in vitro chemosensitivity and growth in 3D culture, and differences in tumour burden and invasion to proximal organs in a mouse model imply that selective suppression of TIMP-2 expression by siRNA or CRISPR/Cas-9 alters important aspects of metastasis and chemosensitivity in ovarian cancer.

Abstract This study characterizes evolution at ≈1.86 million Single Nucleotide Polymorphisms (SNPs) within a natural population of yellow monkeyflower (Mimulus guttatus). Most SNPs exhibit minimal change over a span of 23 generations (less than 1% per year), consistent with neutral evolution in a large population. However, several thousand SNPs display strong fluctuations in frequency. Multiple lines of evidence indicate that these ‘Fluctuating SNPs’ are driven by temporally varying selection. Unlinked loci exhibit synchronous changes with the same allele increasing consistently in certain time intervals but declining in others. This synchrony is sufficiently pronounced that we can roughly classify intervals into two categories, “green” and “yellow,” corresponding to conflicting selection regimes. Alleles increasing in green intervals are associated with early life investment in vegetative tissue and delayed flowering. The alternative alleles that increase in yellow intervals are associated with rapid progression to flowering. Selection on the Fluctuating SNPs produces a strong ripple effect on variation across the genome. Accounting for estimation error, we estimate the distribution of allele frequency change per generation in this population. While change is minimal for most SNPs, diffuse hitchhiking effects generated by selected loci may be driving neutral SNPs to a much greater extent than classic genetic drift.

Abstract Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, to which it associates; we also show that it promotes NED and anchorage-independent growth, as well as a motile phenotype of PrCa cells. Given our observations that high levels of αVβ3 and, as shown here, of NgR2 are detected in human and mouse NEPrCa, our findings appear to be highly relevant to this aggressive and metastatic subtype of PrCa. This study is novel because NgR2 role has only minimally been investigated in cancer and has instead predominantly been analyzed in neurons. These data thus pave new avenues toward a comprehensive mechanistic understanding of integrin-directed signaling during PrCa progression toward a NE phenotype.

Esthesioneuroblastoma (ENB) is a rare neuroendocrine malignancy of the olfactory epithelium that infrequently presents with syndrome of inappropriate antidiuretic hormone (SIADH). We discuss the case of a 37-year-old woman with history of primary hypothyroidism and systemic lupus erythematosus (SLE) presenting with SIADH prior to the diagnosis of a left nasal cavity ENB (Kadish stage B, Hyams grade 1). Her SIADH diagnosis was obfuscated by concomitant discovery of a pituitary microadenoma, primary hypothyroidism, and adrenal insufficiency due to longstanding corticosteroid use for SLE. The ENB was discovered in the setting of recurrent epistaxis. The patient experienced resolution of her hyponatremia immediately following endonasal endoscopic tumor resection with negative margins. Workup for SIADH of unknown origin should include attention to sinus disease with MRI brain for the rare possibility of ENB. In patients with ENB with associated SIADH, repeat sodium levels may provide additional surveillance for recurrence.

Abstract Selection that acts in a sex‐specific manner causes the evolution of sexual dimorphism. Sex‐specific phenotypic selection has been demonstrated in many taxa and can be in the same direction in the two sexes (differing only in magnitude), limited to one sex, or in opposing directions (antagonistic). Attempts to detect the signal of sex‐specific selection from genomic data have confronted numerous difficulties. These challenges highlight the utility of “direct approaches,” in which fitness is predicted from individual genotype within each sex. Here, we directly measured selection on Single Nucleotide Polymorphisms (SNPs) in a natural population of the sexually dimorphic, dioecious plant, Silene latifolia. We measured flowering phenotypes, estimated fitness over one reproductive season, as well as survival to the next year, and genotyped all adults and a subset of their offspring for SNPs across the genome. We found that while phenotypic selection was congruent (fitness covaried similarly with flowering traits in both sexes), SNPs showed clear evidence for sex‐specific selection. SNP‐level selection was particularly strong in males and may involve an important gametic component (e.g., pollen competition). While the most significant SNPs under selection in males differed from those under selection in females, paternity selection showed a highly polygenic tradeoff with female survival. Alleles that increased male mating success tended to reduce female survival, indicating sexual antagonism at the genomic level. Perhaps most importantly, this experiment demonstrates that selection within natural populations can be strong enough to measure sex‐specific fitness effects of individual loci.

Progress in the management of rare diseases, including rare cancers, is dependent upon clinical trials; however, as many as 32% of rare-disease trials go uncompleted or unpublished due to insufficient accrual. Monitoring practices may differ between institutions. We sought to survey the regulatory standards for various trial types among major U.S. cancer centers. A 10-question survey was designed using Qualtrics assessment software. The survey was sent via email to an internal server of member institutions of the Association of American Cancer Institutes (AACI). Of 103 AACI centers, 31% completed the survey (n = 32). Respondents differed in their definitions of a rare disease, minimum expectations for rare tumor studies, and frequency of accrual monitoring by their institutional Protocol Review and Monitoring Committee. Seventy-three percent of respondents did not close trials based on low accrual. Strategies to optimize accrual included investigator incentives for high accrual and penalties for low accrual in 37% and 13% of respondents, respectively.

Abstract Background Cell free DNA, in the form of nucleosomes, is released into circulation during apoptosis and necrosis in a variety of diseases. They are small fragments of chromosomes that are composed of DNA wrapped around a histone core made of four duplicate histone proteins forming an octamer. The nucleosome compartment is a relatively uninvestigated area of circulating tumor biomarkers in dogs. The objectives of this study were to quantify and better characterize nucleosome concentrations in 528 dogs with various common malignancies and compare them to 134 healthy dogs. Results The sensitivity of increased circulating nucleosome concentrations for the detection of cancer in all dogs was 49.8% with a specificity of 97% with an area under the curve of 68.74%. The top 4 malignancies detected by the test included lymphoma, hemangiosarcoma, histiocytic sarcoma and malignant melanoma. The malignancies least likely to be detected were soft tissue sarcomas, osteosarcoma and mast cell tumors. Conclusions A variety of tumor types may cause increased nucleosome concentrations in dogs. Tumors of hematopoietic origin are most likely to cause elevations and local tumors such as soft tissue sarcomas are least likely to cause elevations in plasma nucleosome concentrations.

IntroductionPrior studies have demonstrated that an intake of foods rich in dietary fiber is associated with a favorable impact on health status and body weight. However, the association between fiber intake and weight loss has not been well-studied in employer settings. This research aimed to assess the relationship between dietary fiber and weight loss among individuals participating in the Full Plate Living (FPL) program.MethodsThe 16-week plant-predominant fiber-rich eating program was delivered to 72 employers, primarily in the Southwest U.S., over 3 years (2017–2019). Participants received weekly video lessons, FPL materials, and additional online resources. A retrospective analysis of repeated measures was conducted using participant data obtained from 4,477 participants, of which 2,792 (62.5%) reduced body weight. Analysis of variance with post hoc analysis was used to assess the statistical significance of the changes between baseline and follow-up measures of dietary fiber intake in each of the food categories, specifically the relationship between changes in individual and combined (composite) daily servings of fruits, vegetables, whole grains, beans, and nuts on body weight measures among three groups at follow-up: those who lost, maintained, or gained weight. Multilevel modeling was used to test the hypothesis that increased intake of fiber was associated with greater weight loss.ResultsThe mean weight loss for the weight loss group was 3.28 kg. As compared to the two other groups, the intake of whole fiber-rich foods at follow-up was significantly higher among the weight loss group with fruits (2.45 servings), vegetables (2.99 servings), beans (1.03 servings), and total fiber composites (9.07 servings; P < 0.001). A significant increase in servings of grains was also noted (P < 0.05). Multilevel modeling demonstrated that a higher total fiber composite (Model 1), as well as higher intakes of either vegetables or fruits (Model 2), resulted in greater weight loss.DiscussionOur findings indicate that the FPL program can be a part of a lifestyle medicine approach to healthy eating and weight loss. Delivering the program in clinical, community, and workplace settings can increase its reach as an effective and low-cost offering.

Introduction: Heavy metal pollutants can have long lasting negative impacts on ecosystem health and can shape the evolution of species. The persistent and ubiquitous nature of heavy metal pollution provides an opportunity to characterize the genetic mechanisms that contribute to metal resistance in natural populations.Methods: We examined variation in resistance to copper, a common heavy metal contaminant, using wild collections of the model organism Drosophila melanogaster. Flies were collected from multiple sites that varied in copper contamination risk. We characterized phenotypic variation in copper resistance within and among populations using bulked segregant analysis to identify regions of the genome that contribute to copper resistance.Results and Discussion: Copper resistance varied among wild populations with a clear correspondence between resistance level and historical exposure to copper. We identified 288 SNPs distributed across the genome associated with copper resistance. Many SNPs had population-specific effects, but some had consistent effects on copper resistance in all populations. Significant SNPs map to several novel candidate genes involved in refolding disrupted proteins, energy production, and mitochondrial function. We also identified one SNP with consistent effects on copper resistance in all populations near CG11825, a gene involved in copper homeostasis and copper resistance. We compared the genetic signatures of copper resistance in the wild-derived populations to genetic control of copper resistance in the Drosophila Synthetic Population Resource (DSPR) and the Drosophila Genetic Reference Panel (DGRP), two copper-naïve laboratory populations. In addition to CG11825, which was identified as a candidate gene in the wild-derived populations and previously in the DSPR, there was modest overlap of copper-associated SNPs between the wild-derived populations and laboratory populations. Thirty-one SNPs associated with copper resistance in wild-derived populations fell within regions of the genome that were associated with copper resistance in the DSPR in a prior study. Collectively, our results demonstrate that the genetic control of copper resistance is highly polygenic, and that several loci can be clearly linked to genes involved in heavy metal toxicity response. The mixture of parallel and population-specific SNPs points to a complex interplay between genetic background and the selection regime that modifies the effects of genetic variation on copper resistance.

Abstract Background Following a vegetarian diet has become increasingly popular and some evidence suggests that being vegetarian may be associated with a lower risk of cancer overall. However, for specific cancer sites, the evidence is limited. Our aim was to assess the associations of vegetarian and non-vegetarian diets with risks of all cancer, colorectal cancer, postmenopausal breast cancer, and prostate cancer and to explore the role of potential mediators between these associations. Methods We conducted a prospective analysis of 472,377 UK Biobank participants who were free from cancer at recruitment. Participants were categorised into regular meat-eaters (n = 247,571), low meat-eaters (n = 205,385), fish-eaters (n = 10,696), and vegetarians (n = 8685) based on dietary questions completed at recruitment. Multivariable-adjusted Cox regressions were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for all cancer incidence and separate cancer sites across diet groups. Results After an average follow-up of 11.4 years, 54,961 incident cancers were identified, including 5882 colorectal, 7537 postmenopausal breast, and 9501 prostate cancers. Compared with regular meat-eaters, being a low meat-eater, fish-eater, or vegetarian were all associated with a lower risk of all cancer (HR: 0.98, 95% CI: 0.96–1.00; 0.90, 0.84–0.96; 0.86, 0.80–0.93, respectively). Being a low meat-eater was associated with a lower risk of colorectal cancer in comparison to regular meat-eaters (0.91, 0.86–0.96); however, there was heterogeneity in this association by sex (p = 0.007), with an inverse association across diet groups in men, but not in women. Vegetarian postmenopausal women had a lower risk of breast cancer (0.82, 0.68–0.99), which was attenuated and non-significant after adjusting for body mass index (BMI; 0.87, 0.72–1.05); in mediation analyses, BMI was found to possibly mediate the observed association. In men, being a fish-eater or a vegetarian was associated with a lower risk of prostate cancer (0.80, 0.65–0.99 and 0.69, 0.54–0.89, respectively). Conclusion The lower risk of colorectal cancer in low meat-eaters is consistent with previous evidence suggesting an adverse impact of meat intake. The lower risk of postmenopausal breast cancer in vegetarian women may be explained by their lower BMI. It is not clear whether the other differences observed for all cancers and for prostate cancer reflect any causal relationships or are due to other factors such as residual confounding or differences in cancer detection.

BackgroundHematopoietic malignancies are extremely common in pet dogs and represent nearly 30% of the malignancies diagnosed in this population each year. Clinicians commonly use existing tools such as physical exam findings, radiographs, ultrasound and baseline blood work to monitor these patients for treatment response and remission. Circulating biomarkers, such as prostate specific antigen or carcinoembryonic antigen, can be useful tools for monitoring treatment response and remission status in human cancer patients. To date, there has a been a lack of useful circulating biomarkers available to veterinary oncology patients.MethodsCirculating plasma nucleosome concentrations were evaluated at diagnosis, throughout treatment and during remission monitoring for 40 dogs with lymphoma, acute myelogenous leukemia and multiple myeloma. Additionally, C-reactive protein and thymidine kinase-1 levels were recorded.ResultsPlasma nucleosome concentrations were significantly higher at diagnosis and progressive disease than they were when dogs were in remission. All but two dogs had plasma nucleosome concentrations that returned to the low range during treatment. These two dogs had the shortest progression free and overall survival times. Dogs with the highest plasma nucleosome concentrations had a significantly shorter first progression free survival than dogs with lower plasma nucleosome concentrations at diagnosis. Plasma nucleosome concentrations correlated better with disease response and progression than either thymidine kinase or C reactive protein.ConclusionsPlasma nucleosome concentrations can be a useful tool for treatment monitoring and disease progression in dogs with hematopoietic malignancies.

Ruminant livestock play a key role in global society through the conversion of lignocellulolytic plant matter into high-quality sources of protein for human consumption. However, as a consequence of the digestive physiology of ruminant species, methane (CH4), which originates as a byproduct of enteric fermentation, is accountable for 40% of global agriculture's carbon footprint and ~6% of global greenhouse gas (GHG) emissions. Therefore, meeting the increasing demand for animal protein associated with a growing global population while reducing the GHG intensity of ruminant production will be a challenge for both the livestock industry and the research community. In recent decades, numerous strategies have been identified as having the potential to reduce the methanogenic output of livestock. Dietary supplementation with antimethanogenic compounds, targeting members of the rumen methanogen community and/or suppressing the availability of methanogenesis substrates (mainly H2 and CO2), may have the potential to reduce the methanogenic output of housed livestock. However, reducing the environmental impact of pasture-based beef cattle may be a challenge, but it can be achieved by enhancing the nutritional quality of grazed forage in an effort to improve animal growth rates and ultimately reduce lifetime emissions. In addition, the genetic selection of low-CH4-emitting and/or faster-growing animals will likely benefit all beef cattle production systems by reducing the methanogenic potential of future generations of livestock. Similarly, the development of other mitigation technologies requiring minimal intervention and labor for their application, such as anti-methanogen vaccines, would likely appeal to livestock producers, with high uptake among farmers if proven effective. Therefore, the objective of this review is to give a detailed overview of the CH4 mitigation solutions, both currently available and under development, for temperate pasture-based beef cattle production systems. A description of ruminal methanogenesis and the technologies used to estimate enteric emissions at pastures are also presented.

Abstract The aim was to examine the effect of rapid body weight gain during early calfhood consistent with earlier sexual development on the transcriptional profile of the hypothalamus. Angus X Holstein–Friesian heifer calves (19 ± 5 days of age) were offered a high (HI, n = 14) or moderate (MOD, n = 15) plane of nutrition from 3 to 21 weeks of age to achieve a growth rate of 1.2 kg/d and 0.5 kg/d, respectively. Following euthanasia at 21 weeks, the arcuate nucleus (ARC) region was separated from the remainder of the hypothalamus and both were subjected to RNA-Seq. HI calves exhibited altered expression of 80 and 39 transcripts in the ARC and the remaining hypothalamus, respectively (P

Abstract Adipose tissue represents not only an important energy storage tissue but also a major endocrine organ within the body, influencing many biochemical systems including metabolic status, immune function and energy homeostasis. The objective of this study was to evaluate the effect of an enhanced dietary intake during the early calfhood period on the transcriptome of visceral adipose tissue. Artificially reared Angus × Holstein–Friesian heifer calves were offered either a high (HI, n = 15) or moderate (MOD, n = 15) plane of nutrition from 3 to 21 weeks of life. At 21 weeks of age all calves were euthanized, visceral adipose harvested and samples subsequently subjected to mRNA sequencing. Plane of nutrition resulted in the differential expression of 1214 genes within visceral adipose tissue (adj. p 1.5). Differentially expressed genes were involved in processes related to metabolism and energy production. Biochemical pathways including Sirtuin signalling (adj. p

The study objective was to determine intake and performance of beef cattle individually offered perennial ryegrass-dominant grass silage ad libitum supplemented with 4 kg dry matter daily of, rolled barley or maize meal-based concentrate rations containing supplements of flaked field beans, flaked peas, maize dried distillers grains (MDD) or maize gluten feed (MGF) for 110 days (Experiment 1), rolled barley or rolled oats with or without supplements of flaked field beans or flaked peas for 146 days (Experiment 2), and to quantify the nitrogen balance of diets similar to those offered in Experiment 2 (Experiment 3). The protein supplements were formulated to have similar crude protein concentrations. Cereal type or protein source did not affect intake, growth, feed efficiency and carcass traits in Experiment 1 or 2. Inclusion of a legume protein supplement with barley or oats had no effect on intake or growth performance (Experiment 2), whereas their exclusion decreased nitrogen intake, plasma urea concentrations and urinary and total nitrogen excretion (Experiment 3). The feeding value of barley was similar to oats and maize meal, and flaked beans and peas were similar to MGF and MDD, as supplements to grass silage. Excluding protein ingredients from a cereal-based concentrate did not affect animal performance and reduced nitrogen excretion.

Problem Management Plus (PM+) is a low-intensity psychological intervention developed by the World Health Organization that can be delivered by nonspecialists to address common mental health conditions in people affected by adversity. Emerging evidence demonstrates the efficacy of PM+ across a range of settings. However, the published literature rarely documents the adaptation processes for psychological interventions to context or culture, including curriculum or implementation adaptations. Practical guidance for adapting PM+ to context while maintaining fidelity to core psychological elements is essential for mental health implementers to enable replication and scale. This paper describes the process of contextually adapting PM+ for implementation in Rwanda, Peru, Mexico and Malawi undertaken by the international nongovernmental organisation Partners In Health. To our knowledge, this initiative is among the first to adapt PM+ for routine delivery across multiple public sector primary care and community settings in partnership with Ministries of Health. Lessons learned contribute to a broader understanding of effective processes for adapting low-intensity psychological interventions to real-world contexts. Key implications for practice PM+ can be contextualised based on cultural and implementation considerations while maintaining core psychological elements across different settings. The adaptation of PM+ for local health systems and articulation of practical guidance on implementation for routine care is essential. Partnerships across implementing sites are fundamental for iterative PM+ adaptation and provide opportunities for sharing lessons learned.

Abstract Genome‐wide genotyping and Bayesian inference method (BORICE) were employed to estimate outcrossing rates and paternity in two small plant populations of Tolpis succulenta (Asteraceae) on Graciosa island in the Azores. These two known extant populations of T. succulenta on Graciosa have recently evolved self‐compatibility. Despite the expectation that selfing would occur at an appreciable rate (self‐incompatible populations of the same species show low but nonzero selfing), high outcrossing was found in progeny arrays from maternal plants in both populations. This is inconsistent with an immediate transition to high selfing following the breakdown of a genetic incompatibility system. This finding is surprising given the small population sizes and the recent colonization of an island from self‐incompatible colonists of T. succulenta from another island in the Azores, and a potential paucity of pollinators, all factors selecting for selfing through reproductive assurance. The self‐compatible lineage(s) likely have high inbreeding depression (ID) that effectively halts the evolution of increased selfing, but this remains to be determined. Like their progeny, all maternal plants in both populations are fully outbred, which is consistent with but not proof of high ID. High multiple paternity was found in both populations, which may be due in part to the abundant pollinators observed during the flowering season.

With the advent of high throughput technology, it is now feasible to study the complex relationship of the rumen microbiota with methanogenesis in large populations of ruminant livestock divergently ranked for enteric emissions. Recently, the residual methane emissions (RME) concept has been identified as the optimal phenotype for assessing the methanogenic potential of ruminant livestock due to the trait’s independence from animal productivity but strong correlation with daily methane emissions. However, there is currently a dearth of data available on the bacterial and archaeal microbial communities residing in the rumens of animals divergently ranked for RME. Therefore, the objective of this study was to investigate the relationship between the rumen microbiota and RME in a population of finishing beef cattle. Methane emissions were estimated from individual animals using the GreenFeed Emissions Monitoring system for 21 days over a mean feed intake measurement period of 91 days. Residual methane emissions were calculated for 282 crossbred finishing beef cattle, following which a ∼30% difference in all expressions of methane emissions was observed between high and low RME ranked animals. Rumen fluid samples were successfully obtained from 268 animals during the final week of the methane measurement period using a trans-oesophageal sampling device. Rumen microbial DNA was extracted and subjected to 16S rRNA amplicon sequencing. Animals ranked as low RME had the highest relative abundances (P < 0.05) of lactic-acid-producing bacteria (Intestinibaculum, Sharpea, and Olsenella) and Selenomonas, and the lowest (P < 0.05) proportions of Pseudobutyrivibrio, Butyrivibrio, and Mogibacterium. Within the rumen methanogen community, an increased abundance (P < 0.05) of the genus Methanosphaera and Methanobrevibacter RO clade was observed in low RME animals. The relative abundances of both Intestinibaculum and Olsenella were negatively correlated (P < 0.05) with RME and positively correlated with ruminal propionate. A similar relationship was observed for the abundance of Methanosphaera and the Methanobrevibacter RO clade. Findings from this study highlight the ruminal abundance of bacterial genera associated with the synthesis of propionate via the acrylate pathway, as well as the methanogens Methanosphaera and members of the Methanobrevibacter RO clade as potential microbial biomarkers of the methanogenic potential of beef cattle.

Abstract Background Juvenile idiopathic arthritis (JIA)-associated uveitis is a chronic paediatric ocular inflammatory condition that can result in visual impairment. Adalimumab, a tumour necrosis factor (TNF)-alpha inhibitor, effectively controls joint and eye inflammation; however, its long-term use may increase the risk of adverse health outcomes and place an undue financial burden on the patient and healthcare system given its high cost. There is great interest for patients to stop adalimumab following remission due to these reasons but there is a lack of information on the ability to maintain control after discontinuing adalimumab. Methods The Adalimumab in Juvenile Idiopathic Arthritis-associated Uveitis Trial (ADJUST) is a multicentred, international trial that will randomise 118 participants aged 2 years and older with controlled JIA-associated uveitis to either continue adalimumab or discontinue adalimumab and receive a placebo. The trial will compare the time to uveitis recurrence between the two groups over 12 months. All participants will receive the standard weight-based dose of adalimumab or placebo: 20 mg biweekly (if

Abstract Background Pre‐clinical studies suggest that metformin and statins may delay prostate cancer (PCa) metastases; however, data in humans are limited. To the best of our knowledge, this is the first human study aimed to quantify the individual and joint effects of statin and metformin use among patients with high‐risk PCa. Methods This population‐based retrospective cohort study identified patients from the Surveillance, Epidemiology, and End Results (SEER)‐Medicare linked database. Exposure to metformin and statins was ascertained from Medicare Prescription Drug Event files. The association with all‐cause and PCa mortality were evaluated using Cox proportional hazard model with competing causes of death, where propensity scores were used to adjusted imbalances in covariates across groups. Results Based on 12 700 patients with high‐risk PCa, statin alone or in combination with metformin was significantly associated with reduced all‐cause mortality (Hazard Ratio [HR]: 0.89; 95% Confidence Interval [CI]: 0.83, 0.96; and HR: 0.75; 95% CI, 0.67‐0.83, respectively) and PCa mortality (HR, 0.80; 95% CI: 0.69, 0.92) and 0.64; 95% CI, d 0.51‐0.81, respectively. The effects were more pronounced in post‐diagnostic users: combination use of metformin/statins was associated with a 32% reduction in all‐cause mortality (95% CI, 0.57‐0.80), and 54% reduction in PCa mortality (95% CI, 0.30‐0.69). No significant association of metformin alone was observed with either all‐cause mortality or PCa mortality. Conclusions Statin use alone or in combination with metformin was associated with lower all‐cause and PCa mortality among high‐risk patients, particularly in post‐diagnostic settings; further studies are warranted.

Abstract Introduction Angelman syndrome (AS) is a rare neurodevelopmental disorder caused by mutation or loss of UBE3A and marked by intellectual disability, ataxia, autism‐like symptoms, and other atypical behaviors. One route to treatment may lie in the role that environment plays early in postnatal life. Environmental enrichment (EE) is one manipulation that has shown therapeutic potential in preclinical models of many brain disorders, including neurodevelopmental disorders. Here, we examined whether postweaning EE can rescue behavioral phenotypes in Ube3a maternal deletion mice (AS mice), and whether any improvements are sex‐dependent. Methods Male and female mice (C57BL/6J Ube3atm1Alb mice and wild‐type (WT) littermates; ≥10 mice/group) were randomly assigned to standard housing (SH) or EE at weaning. EE had a larger footprint, a running wheel, and a variety of toys that promoted foraging, burrowing, and climbing. Following 6 weeks of EE, animals were submitted to a battery of tests that reliably elicit behavioral deficits in AS mice, including rotarod, open field, marble burying, and forced swim; weights were also monitored. Results In male AS‐EE mice, we found complete restoration of motor coordination, marble burying, and forced swim behavior to the level of WT‐SH mice. We also observed a complete normalization of exploratory distance traveled in the open field, but we found no rescue of vertical behavior or center time. AS‐EE mice also had weights comparable to WT‐SH mice. Intriguingly, in the female AS‐EE mice, we found a failure of EE to rescue the same behavioral deficits relative to female WT‐SH mice. Conclusions Environmental enrichment is an effective route to correcting the most penetrant phenotypes in male AS mice but not female AS mice. This finding has important implications for the translatability of early behavioral intervention for AS patients, most importantly the potential dependency of treatment response on sex.

Evaluating wildlife population trends is necessary for the development of effective management strategies, which are particularly relevant for highly threatened species. Hawksbill marine turtles (Eretmochelys imbricata) are considered endangered globally and are rare in Hawai‘i. Remnant hawksbill nesting beaches were identified in Hawai‘i in the late 1980s and the primary sites have been monitored since that time. In this study we summarize all available hawksbill nesting activity around the Hawaiian Islands between 1988 and 2018, highlighting relevant demographic and geographic data for the species. Because monitoring effort varied substantially across space and time, we implemented a predictive modeling approach that accounted for varying effort to explore potential trends in annual number of nesting females and nests over time. Field monitoring efforts documented an annual average of 14 ± 4.3 (range: 5–26) nesting females and 48 ± 19.0 (range: 12–93) nests, with a cumulative total of 178 individual nesting females and 1,280 nests recorded across all years. Nesting has been documented on four Hawaiian Islands, with the overwhelming majority of nesting females (78.4%) and nests (86.5%) recorded at four beaches along the southern coast of Hawai‘i Island. Recent monitoring (2018) at a beach on Moloka‘i Island revealed numbers similar to the most important beaches on Hawai‘i Island. Despite difficulty discerning obvious trends when looking solely at the raw tabulated numbers from field monitoring, our analysis suggests both the number of nesting females and nests have been positively trending since 2006, and this is supported by a higher percentage (57.1% of annual cohorts) of neophyte (vs. remigrant) nesters over the second half of the monitoring timeframe. The masking of obvious trends in the tabulated numbers is likely due to decreased overall monitoring effort as a result of reduced funding in recent years, coupled with a shift in focal monitoring effort from the historical primary nesting site of Kamehame, to the more recently established nesting site of Pōhue. Although the positive trend is encouraging, our findings highlight the precarious state of hawksbills in Hawai‘i and the need to enhance monitoring across all sites to support more robust population assessments and management decision making.

Specific characteristics of the male Achroia grisella acoustic mating signal determine a male’s attractiveness toward females. These features are genetically variable in populations, and mapping experiments have been used to identify loci contributing to song variation, and understand the evolutionary forces acting on this important sexual trait. Here we built on this foundation and carried out QTL (Quantitative Trait Locus) mapping using >1,000 recombinant individuals, genotyping this large cohort at thousands of sequence-based markers covering the entire collection of 30 A. grisella chromosomes. This dense marker set, coupled with our development of an annotated, draft genome of A. grisella, allowed us to link >3,000 genome scaffolds, >10,000 predicted genes, and close to 275Mb of genome sequence to chromosomes. Our QTL mapping confirmed a fraction of the QTL identified in a previous study, and additionally revealed novel loci. Collectively, QTL explained only small fractions of the phenotypic variance, suggesting many more causative factors remain below the detection threshold of our study. A surprising, and ultimately challenging feature of our study was the low level of intrachromosomal recombination present in our mapping population. This led to difficulty ordering markers along linkage groups, necessitating a chromosome-by-chromosome mapping approach, rather than true interval mapping, and precluded confident ordering/orienting of scaffolds along each chromosome. Nonetheless, our study increased the genomic resources available for the A. grisella system. Enabled by ever more powerful technologies, future investigators will be able to leverage our data to provide more detailed genetic dissection of male song variation in A. grisella.

Evolution by natural selection occurs when the frequencies of genetic variants change because individuals differ in Darwinian fitness components such as survival or reproductive success. Differential fitness has been demonstrated in field studies of many organisms, but it remains unclear how well we can quantitatively predict allele frequency changes from fitness measurements. Here, we characterize natural selection on millions of Single Nucleotide Polymorphisms (SNPs) across the genome of the annual plant Mimulus guttatus. We use fitness estimates to calibrate population genetic models that effectively predict allele frequency changes into the next generation. Hundreds of SNPs experienced "male selection" in 2013 with one allele at each SNP elevated in frequency among successful male gametes relative to the entire population of adults. In the following generation, allele frequencies at these SNPs consistently shifted in the predicted direction. A second year of study revealed that SNPs had effects on both viability and reproductive success with pervasive trade-offs between fitness components. SNPs favored by male selection were, on average, detrimental to survival. These trade-offs (antagonistic pleiotropy and temporal fluctuations in fitness) may be essential to the long-term maintenance of alleles. Despite the challenges of measuring selection in the wild, the strong correlation between predicted and observed allele frequency changes suggests that population genetic models have a much greater role to play in forward-time prediction of evolutionary change.

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer.