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Transrectal ultrasonography is known as the gold standard for pregnancy detection, but requires costly equipment and technical skills; therefore, access to an inexpensive and more user-friendly method with similar accuracy could benefit cattle producers. Detection of pregnancy-associated glycoproteins can accurately determine pregnancy in ruminants; however, usually requires specialized equipment for the assay. Thus, the objectives of these studies were to 1) validate the IDEXX Alertys OnFarm Pregnancy Test (lateral flow) and compare the accuracy of all three commercial PAG assays to transrectal ultrasonography and 2) to determine the postpartum interval necessary for clearance of pregnancy-associated glycoproteins from the previous pregnancy to avoid false positives. In study 1, blood samples from previously identified pregnant Bos taurus females from six different herds (nulliparous n = 1,205 and multiparous n = 1,539; samples collected between d 27 to 285 of gestation over a three-year period) were utilized. In study 2, postpartum females (primiparous n = 48 and multiparous n = 66) from one herd were utilized: (n = 1,066; samples collected weekly for up to 12 weeks postpartum). In study 1, level of agreement between different methods of pregnancy detection was determined by Pearson’s correlation and Kappa scores. In study 2, data were analyzed as a repeated measure using the MIXED procedure of SAS with main effects of parity, days postpartum (dpp), and parity by days postpartum, then data were analyzed further using the REG procedure of SAS. In study 1, transrectal ultrasonography and lateral flow were positively correlated (r = 0.77; P <0.01), with 92.4% agreement. In study 2, the abundance of absorbance of PAGs rapidly decreased from 0 to 50 days postpartum, then continued to gradually decrease ( P <0.01; r = 0.90). Prior to 42 days postpartum, PAG concentrations were sufficiently elevated resulting in false positive readings in all assays. In conclusion, there is very good agreement between transrectal ultrasonography and PAG assays, but likelihood of false positive results are highif assays are performed fewer than 42 days postpartum.

IntroductionSperm interacts with the female reproductive tract and oocyte through proteins, and these cell-to-cell interactions may play a role in sperm fertility. For consideration of a protein as a potential marker of fertility, there must be variability expressed among animals. The proteins dystroglycan (DAG1) and plasma serine protease inhibitor (SERPINA5) have been reported to play a role in cell-to-cell interactions. Thus, the objectives of this study were to characterize the localization and abundance variability of DAG1 and SERPINA5 in bovine sperm, and to investigate the relationship of DAG1 and SERPINA5 with field fertility (i.e., sire conception rate; SCR), in vitro embryo production (IVP), and sperm parameters.Material and methodsDairy bulls (n = 22) were classified as high-SCR (SCR > 1.0) or low-SCR (SCR < –4.0), and good [blastocyst (BL)-by-cleavage (CL) ratio (BL/CL) > 39%] or poor (BL/CL < 38%) BL/CL. Sperm was evaluated for DAG1 and SERPINA5 immunolocalization, and concentration in two separate ejaculates. Variance between bulls compared with within bulls was evaluated using a generalized linear model (GLM) procedure. The relationship of SCR and IVP classification on DAG1 and SERPINA5 concentrations, percentage of tail labeled for SERPINA5, SCR, sperm total and progressive motility, sperm plasma membrane integrity (PMI), CL, BL, and BL/CL were evaluated with the GLIMMIX procedure, and the correlations between these variables were evaluated.ResultsBoth proteins were localized on the sperm head; however, SERPINA5 was also localized on the sperm tail. There was greater variance in concentration among bulls than within bulls for DAG1 ( P < 0.0001; 69.4 vs . 49.1, respectively) and SERPINA5 ( P < 0.0001; 325.8 vs . 285.4, respectively). There was a positive correlation between the concentrations of DAG1 and of SERPINA5 ( P = 0.01; r = 0.54). In addition, the percentage of tail labeled for SERPINA5 was correlated with PMI ( P = 0.05; r = 0.44). There was no relationship between SCR and IVP classifications and DAG1 (P ≥ 0.55), SERPINA5 (P ≥ 0.54), or the percentage of sperm tail labeled for SERPINA5 (P ≥ 0.22).DiscussionIn conclusion, DAG1 and SERPINA5 were localized to the sperm head, and SERPINA 5 was also localized to the tail. Concentrations of DAG1 and SERPINA5 on the sperm head were correlated with each other. The percentage of tail labeled for SERPINA5 was correlated with sperm PMI; however, neither protein was associated with SCR or IVP. Thus, when evaluated by immunofluorescent microscopy, DAG1 and SERPINA5 concentrations are variable and are not good fertility markers for bull sperm.

The management of heifers can have lifetime effects on their reproductive success and efficiency. Nutrition is one of the management factors that can influence steroid hormone production, oocyte development, embryo development, and uterine histotroph, thus affecting heifers’ reproductive efficiency. Therefore, the objectives of the following studies were to evaluate the impact of nutritional changes prior to and after Artificial Insemination (AI) on plasma cholesterol concentrations, and uterine mineral concentrations (Chapter 2) and the impact of nutritional change after AI on uterine mineral concentrations, steroid hormone production, and circulating metabolites (Chapter 3). In experiment 1 (Chapter 2), beef heifers (n = 79) were randomly assigned to two treatment groups of High (162% of NEm) and Low (90% of NEm) diets for 30 days prior to AI. Heifers were then randomly re-assigned at time of AI to new treatments of High (148% of NEm) and Low (81% of NEm) diets, therefore creating four Pre- by Post-AI treatments: High-High (H-H; n = 20), High-Low (H-L; n = 20), Low-Low (L-L; n = 20), and Low-High (L-H; n = 19). Post-AI diet continued for 7 or 8 days until uteri were flushed for embryo recovery. Blood samples were collected on d -3, -2, -1, 0 (day of AI), 1, 3, 5, 7, and 8 for analysis of circulating cholesterol concentrations using a colorimetric assay. Minerals (Mg, Al, P, S, K, Ca, Cu, Zn, Se, and Fe) were analyzed in uterine flushes collected on day of embryo recovery (d 7 or 8) using ICP-MS. Plasma cholesterol concentrations were analyzed using repeated measures using MIXED procedures in SAS. Uterine mineral concentrations were analyzed using MIXED procedures in SAS. Cholesterol concentrations were influenced by time (P < 0.0001) with concentrations increasing after estrus until d 5, concentrations than decreased to d 7 and 8. Pre-AI by Post-AI diet interaction tended to impact cholesterol concentrations (P = 0.10). There was an effect of embryo recovery on Mg (P < 0.04), Al (P < 0.01), S (P < 0.01), K (P < 0.01), and Ca (P < 0.01), with decreased mineral concentrations when an embryo was recovered. Pre-AI diet did not influence uterine mineral concentrations (P > 0.10); however, Post-AI diet influenced S (P < 0.02) and Ca (P = 0.03). High heifers had elevated S and Ca concentrations in comparison to Low heifers. Pre-AI diet by embryo recovery interaction impacted S concentrations. Post-AI diet by embryo interaction influenced P (P < 0.03), Zn (P = 0.02), and Se (P = 0.02). Pre-AI by Post-AI diet by embryo interaction influenced uterine Mg concentrations (P < 0.05). There was an overall tendency for a Pre-AI by Post-AI diet by embryo recovery interaction on S (P = 0.09), Cu (P = 0.07), and Fe (P = 0.09). In experiment 2 (Chapter 3), heifers (n = 50) were assigned randomly to two treatments groups of High (161.5% of NEm) or Low (77.5% of NEm) diets following AI until uteri were flushed for embryo recovery 14 days after AI. Blood samples were collected on d -3, 0 (AI), 3, 6, 9, 12, and 14. Heifer weights and uterine mineral concentrations were analyzed using MIXED procedure in SAS. Circulating concentrations of progesterone (P4), non-esterified Fatty Acids (NEFA), glucose, protein, and cholesterol were analyzed as repeated measures using the MIXED procedure of SAS. Dietary treatment impacted NEFA concentrations (P < 0.01), with Low heifers having elevated NEFA concentrations in comparison to High heifers. Diet treatment by time interaction influenced NEFA concentrations (P < 0.01) with concentrations increasing in Low heifers but remaining relatively constant in High heifers. Embryo by time interaction impacted glucose concentrations (P < 0.02): heifers with an embryo recovered had elevated glucose concentrations beginning on d 3 in comparison to heifers with no embryo recovered. Protein concentrations tended to be influenced by diet treatment by time interaction (P = 0.07). Cholesterol concentrations were affected by diet by time interaction (P < 0.01), with Low heifers having elevated cholesterol concentrations beginning on d 3 in comparison to High heifers. Diet treatment by embryo recovery by time tended to influence P4 concentrations (P < 0.06), with High heifers with no embryo having the greatest P4 concentration on d 12. Uterine Mg (P = 0.02), S (P = 0.01), and Ca (P = 0.08) concentrations decreased when an embryo was recovered. Uterine Mn (P = 0.06) concentrations increased when an embryo was recovered. Dietary treatment tended to effect Fe concentrations (P = 0.09), with High heifers having elevated Fe concentrations compared to Low heifers. In conclusion, changing the nutrient status prior to and after AI did not impact plasma cholesterol concentrations; however, nutritional changes after AI influenced circulating NEFA, cholesterol, glucose, and protein concentrations. Additionally, when an embryo was recovered uterine mineral concentrations were affected.

Increased understanding of whether individuals who have recovered from COVID-19 are protected from future SARS-CoV-2 infection is an urgent requirement. We aimed to investigate whether antibodies against SARS-CoV-2 were associated with a decreased risk of symptomatic and asymptomatic reinfection. A large, multicentre, prospective cohort study was done, with participants recruited from publicly funded hospitals in all regions of England. All health-care workers, support staff, and administrative staff working at hospitals who could remain engaged in follow-up for 12 months were eligible to join The SARS-CoV-2 Immunity and Reinfection Evaluation study. Participants were excluded if they had no PCR tests after enrolment, enrolled after Dec 31, 2020, or had insufficient PCR and antibody data for cohort assignment. Participants attended regular SARS-CoV-2 PCR and antibody testing (every 2–4 weeks) and completed questionnaires every 2 weeks on symptoms and exposures. At enrolment, participants were assigned to either the positive cohort (antibody positive, or previous positive PCR or antibody test) or negative cohort (antibody negative, no previous positive PCR or antibody test). The primary outcome was a reinfection in the positive cohort or a primary infection in the negative cohort, determined by PCR tests. Potential reinfections were clinically reviewed and classified according to case definitions (confirmed, probable, or possible) and symptom-status, depending on the hierarchy of evidence. Primary infections in the negative cohort were defined as a first positive PCR test and seroconversions were excluded when not associated with a positive PCR test. A proportional hazards frailty model using a Poisson distribution was used to estimate incidence rate ratios (IRR) to compare infection rates in the two cohorts. From June 18, 2020, to Dec 31, 2020, 30 625 participants were enrolled into the study. 51 participants withdrew from the study, 4913 were excluded, and 25 661 participants (with linked data on antibody and PCR testing) were included in the analysis. Data were extracted from all sources on Feb 5, 2021, and include data up to and including Jan 11, 2021. 155 infections were detected in the baseline positive cohort of 8278 participants, collectively contributing 2 047 113 person-days of follow-up. This compares with 1704 new PCR positive infections in the negative cohort of 17 383 participants, contributing 2 971 436 person-days of follow-up. The incidence density was 7·6 reinfections per 100 000 person-days in the positive cohort, compared with 57·3 primary infections per 100 000 person-days in the negative cohort, between June, 2020, and January, 2021. The adjusted IRR was 0·159 for all reinfections (95% CI 0·13–0·19) compared with PCR-confirmed primary infections. The median interval between primary infection and reinfection was more than 200 days. A previous history of SARS-CoV-2 infection was associated with an 84% lower risk of infection, with median protective effect observed 7 months following primary infection. This time period is the minimum probable effect because seroconversions were not included. This study shows that previous infection with SARS-CoV-2 induces effective immunity to future infections in most individuals. Department of Health and Social Care of the UK Government, Public Health England, The National Institute for Health Research, with contributions from the Scottish, Welsh and Northern Irish governments.

Cholangiocarcinoma (CCA) is a tumor with increasing prevalence around the world. The prevalence of CCA is highest in East Asia and most significantly in the countries through which the Mekong River flows, owing to the presence of liver flukes, which are consumed in raw fish dishes. Outside Asia, the causes of bile duct cancers for the most part are unknown. In this review, we assess the current state of knowledge in both fluke-associated and sporadic CCA, from etiological, diagnostic, and treatment perspectives.

The prevalence of cholangiocarcinoma (CCA) in Southeast Asia is much higher than other areas of the world. Eating raw, fermented, or undercooked cyprinid fish, infected with the liver fluke, sensu lato (sl), results in chronic biliary inflammation, periductal fibrosis, and increased cancer risk. There may be associated glomerulonephritis. The process of infection is difficult to disrupt because eating practices have proven extremely difficult to change, and the life cycle of the fluke cannot be broken due to high prevalence in canine and feline reservoir hosts. Fecal analysis and enzyme-linked immunosorbent assay tests can be used to diagnose opisthorchiasis. Diagnosis of CCA is complex, partly due to the lack of definitive imaging characteristics but also due to the difficulty of obtaining samples for cytology or histology. This cancer has proven to be resistant to common chemotherapy treatments and so the two avenues of treatment available are surgical resection and liver transplantation, both requiring early detection of the tumor for the best chances of success. Late presentation of symptoms reduces the chances of successful surgical intervention. While liver fluke infections can be treated with praziquantel, individuals will often become reinfected, and multiple reinfections can be more harmful than a singular, long-term infection. A key research on the detection and characterization of novel biomarkers in all parts of the carcinogenic pathway for early diagnosis is needed.

A meta-analysis of previous genome-wide association studies of Crohn’s disease and ulcerative colitis, the two most common forms of inflammatory bowel disease, with a combined total of more than 75,000 cases and controls, finds that most loci contribute to both phenotypes and other immune-mediated disorders. Pathogenesis of inflammatory bowel disease Genetic studies have implicated unsuspected mechanisms in the pathogenesis of Crohn's disease and ulcerative colitis, two of the most common forms of inflammatory bowel disease. This paper presents a meta-analysis of published genome-wide association studies, together with validation in more than 75,000 cases and controls. In addition to several new associations, the authors find that most loci contribute to both phenotypes, but also to other immune-mediated disorders. The data reveal an overlap between susceptibility loci for inflammatory bowel disease and mycobacterial infection, and between the pathways that govern host responses to mycobacteria and those predisposing to inflammatory bowel disease. Crohn’s disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations 1 . Genome-wide association studies and subsequent meta-analyses of these two diseases 2 , 3 as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy 4 , in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases 5 . Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn’s disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.

In July 2015, the New Horizons spacecraft flew through the Pluto system at high speed, humanity's first close look at this enigmatic system on the outskirts of our solar system. In a series of papers, the New Horizons team present their analysis of the encounter data downloaded so far: Moore et al. present the complex surface features and geology of Pluto and its large moon Charon, including evidence of tectonics, glacial flow, and possible cryovolcanoes. Grundy et al. analyzed the colors and chemical compositions of their surfaces, with ices of H 2 O, CH 4 , CO, N 2 , and NH 3 and a reddish material which may be tholins. Gladstone et al. investigated the atmosphere of Pluto, which is colder and more compact than expected and hosts numerous extensive layers of haze. Weaver et al. examined the small moons Styx, Nix, Kerberos, and Hydra, which are irregularly shaped, fast-rotating, and have bright surfaces. Bagenal et al. report how Pluto modifies its space environment, including interactions with the solar wind and a lack of dust in the system. Together, these findings massively increase our understanding of the bodies in the outer solar system. They will underpin the analysis of New Horizons data, which will continue for years to come. Science , this issue pp. 1284 , 10.1126/science.aad9189 , 10.1126/science.aad8866 , 10.1126/science.aae0030 , & 10.1126/science.aad9045 Pluto’s atmosphere is cold, rarefied, and made mostly of nitrogen and methane, with layers of haze. Observations made during the New Horizons flyby provide a detailed snapshot of the current state of Pluto’s atmosphere. Whereas the lower atmosphere (at altitudes of less than 200 kilometers) is consistent with ground-based stellar occultations, the upper atmosphere is much colder and more compact than indicated by pre-encounter models. Molecular nitrogen (N 2 ) dominates the atmosphere (at altitudes of less than 1800 kilometers or so), whereas methane (CH 4 ), acetylene (C 2 H 2 ), ethylene (C 2 H 4 ), and ethane (C 2 H 6 ) are abundant minor species and likely feed the production of an extensive haze that encompasses Pluto. The cold upper atmosphere shuts off the anticipated enhanced-Jeans, hydrodynamic-like escape of Pluto’s atmosphere to space. It is unclear whether the current state of Pluto’s atmosphere is representative of its average state—over seasonal or geologic time scales.