Impact of bovine somatotropin on ranking for genetic value of dairy sires for milk yield traits and somatic cell score

Records of Holstein cows were used to examine how different models account for the effect of bovine somatotropin (bST) treatment on genetic evaluation of dairy sires for yield traits and somatic cell score. Data set 1 included 65,720 first-lactation records. Set 2 included 50,644 second-lactation records. Set 3 included 45,505 records for lactations three, four and five. Estimated breeding values (EBV) of sires were with three different animal models. With Model 1, bST administration was ignored. With Model 2, bST administration was used as a fixed effect. With Model 3, administration of bST was used to define the contemporary group (herd-year-month of calving-bST). Correlations for EBV of 1,366 sires with treated daughters between pairs of the three models were calculated for milk, fat and protein yields and somatic cell score for the three data sets. Correlations for EBV of sires between pairs of models for all traits ranged from 0.971 to 0.999. Fractions of sires with bST-treated progeny selected in common (top 10 to 15%) were 0.94 and usually greater for all pairs of models for all traits and parities. For this study, the method of statistical adjustment for bST treatment resulted in a negligible effect on genetic evaluations of sires when some daughters were treated with bST and suggests that selection of sires to produce the next generation of sires and cows might not be significantly affected by how the effect of bST is modeled for prediction of breeding values for milk, fat and protein yields and somatic cell score.     

Characterization of the SARS-CoV-2 ExoN (nsp14ExoN–nsp10) complex: implications for its role in viral genome stability and inhibitor identification

The SARS-CoV-2 coronavirus is the causal agent of the current global pandemic. SARS-CoV-2 belongs to an order, Nidovirales, with very large RNA genomes. It is proposed that the fidelity of coronavirus (CoV) genome replication is aided by an RNA nuclease complex, comprising the non-structural proteins 14 and 10 (nsp14–nsp10), an attractive target for antiviral inhibition. Our results validate reports that the SARS-CoV-2 nsp14–nsp10 complex has RNase activity. Detailed functional characterization reveals nsp14–nsp10 is a versatile nuclease capable of digesting a wide variety of RNA structures, including those with a blocked 3′-terminus. Consistent with a role in maintaining viral genome integrity during replication, we find that nsp14–nsp10 activity is enhanced by the viral RNA-dependent RNA polymerase complex (RdRp) consisting of nsp12–nsp7–nsp8 (nsp12–7–8) and demonstrate that this stimulation is mediated by nsp8. We propose that the role of nsp14–nsp10 in maintaining replication fidelity goes beyond classical proofreading by purging the nascent replicating RNA strand of a range of potentially replication-terminating aberrations. Using our developed assays, we identify drug and drug-like molecules that inhibit nsp14–nsp10, including the known SARS-CoV-2 major protease (M^pro) inhibitor ebselen and the HIV integrase inhibitor raltegravir, revealing the potential for multifunctional inhibitors in COVID-19 treatment.     

Cubic-spline interpolation to estimate effects of inbreeding on milk yield in first lactation Holstein cows

Milk yield records (305d, 2X, actual milk yield) of 123,639 registered first lactation Holstein cows were used to compare linear regression (y = β(0) + β(1)X + e), quadratic regression, (y = β(0) + β(1)X + β(2)X(2) + e) cubic regression (y = β(0) + β(1)X + β(2)X(2) + β(3)X(3) +e) and fixed factor models, with cubic-spline interpolation models, for estimating the effects of inbreeding on milk yield. Ten animal models, all with herd-year-season of calving as fixed effect, were compared using the Akaike corrected-Information Criterion (AICc). The cubic-spline interpolation model with seven knots had the lowest AICc, whereas for all those labeled as "traditional", AICc was higher than the best model. Results from fitting inbreeding using a cubic-spline with seven knots were compared to results from fitting inbreeding as a linear covariate or as a fixed factor with seven levels. Estimates of inbreeding effects were not significantly different between the cubic-spline model and the fixed factor model, but were significantly different from the linear regression model. Milk yield decreased significantly at inbreeding levels greater than 9%. Variance component estimates were similar for the three models. Ranking of the top 100 sires with daughter records remained unaffected by the model used.     

The SARS-CoV-2 RNA polymerase is a viral RNA capping enzyme

SARS-CoV-2 is a positive-sense RNA virus responsible for the Coronavirus Disease 2019 (COVID-19) pandemic, which continues to cause significant morbidity, mortality and economic strain. SARS-CoV-2 can cause severe respiratory disease and death in humans, highlighting the need for effective antiviral therapies. The RNA synthesis machinery of SARS-CoV-2 is an ideal drug target and consists of non-structural protein 12 (nsp12), which is directly responsible for RNA synthesis, and numerous co-factors involved in RNA proofreading and 5′ capping of viral RNAs. The formation of the 5′ 7-methylguanosine (m⁷G) cap structure is known to require a guanylyltransferase (GTase) as well as a 5′ triphosphatase and methyltransferases; however, the mechanism of SARS-CoV-2 RNA capping remains poorly understood. Here we find that SARS-CoV-2 nsp12 is involved in viral RNA capping as a GTase, carrying out the addition of a GTP nucleotide to the 5′ end of viral RNA via a 5′ to 5′ triphosphate linkage. We further show that the nsp12 NiRAN (nidovirus RdRp-associated nucleotidyltransferase) domain performs this reaction, and can be inhibited by remdesivir triphosphate, the active form of the antiviral drug remdesivir. These findings improve understanding of coronavirus RNA synthesis and highlight a new target for novel or repurposed antiviral drugs against SARS-CoV-2.     

Reliability of international normalised ratios from two point of care test systems: comparison with conventional methods

Objective To find out how accurately two point of care test systems—CoaguChek Mini and TAS PT-NC (RapidPointCoag)—display international normalised ratios (INRs).Design Comparison of the INRs from the two systems with a “true” INR on a conventional manual test from the same sample of blood.Setting 10 European Concerted Action on Anticoagulation centres.Participants 600 patients on long term dosage of warfarin.Main outcome measures Comparable results between the different methods.Results The mean displayed INR differed by 21.3% between the two point of care test monitoring systems. The INR on one system was 15.2% higher, on average, than the true INR, but on the other system the INR was 7.1% lower. The percentage difference between the mean displayed INR and the true INR at individual centres varied considerably with both systems.Conclusions Improved international sensitivity index calibration of point of care test monitors by their manufacturers is needed, and better methods of quality control of individual instruments by their users are also needed.     

Modeling Nociception in Zebrafish: A Way Forward for Unbiased Analgesic Discovery

Acute and chronic pain conditions are often debilitating, inflicting severe physiological, emotional and economic costs and affect a large percentage of the global population. However, the development of therapeutic analgesic agents based primarily on targeted drug development has been largely ineffective. An alternative approach to analgesic development would be to develop low cost, high throughput, untargeted animal based behavioral screens that model complex nociceptive behaviors in which to screen for analgesic compounds. Here we describe the development of a behavioral based assay in zebrafish larvae that is effective in identifying small molecule compounds with analgesic properties. In a place aversion assay, which likely utilizes supraspinal neuronal circuitry, individually arrayed zebrafish larvae show temperature-dependent aversion to increasing and decreasing temperatures deviating from rearing temperature. Modeling thermal hyperalgesia, the addition of the noxious inflammatory compound and TRPA1 agonist allyl isothiocyanate sensitized heat aversion and reversed cool aversion leading larvae to avoid rearing temperature in favor of otherwise acutely aversive cooler temperatures. We show that small molecules with known analgesic properties are able to inhibit acute and/or sensitized temperature aversion.     

Scientists' judgements of the prospects for biological nitrogen fixation research

Summary More than 100 scientists responded to a mail survey concerning prospects for 33 technological developments related to biological nigrogen fixation. Respondents anticipated that most of the hypothesized developments in the legume/Rhizobium and rice/Azolla areas would occur in the next 10 years, while generally developments in nitrogen-fixing cereals and other research would occur later. An additional 28 technological advances were suggested by respondents. Scientists responded that the increasing cost of chemical fertilizer was the major driving force, lack of trained extension workers the major constraint, and research funding the most important issue concerning the development and adoption of the technology.

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Resumen Más de 100 científicos han contestado a una encuesta por correo sobre las perspectivas de 33 avances tecnológicos relacionados con la fijación biológica de nitrógeno. Los encuestados anticiparon que la mayor parte de los hipotéticos avances en los temas: leguminosas/Rhizobium y arroz/Azolla ocurrirían en los próximos 10 años, mientras que descubrimientos en cereales fijadores de nitrógeno y otros temas afines ocurrirían más tarde. Los encuestados sugirieron además otros 28 posibles avances tecnológicos. Los científicos identificaron la carestía de los fertilizantes como el motivo más importante que impulsa la investigación en estas areas, señalaron la falta de extensionistas cualificados como el mayor problema y la financiación de la investigación como la cuestión más importante para el desarrollo e implementación de neuvas tecnologías.

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Résumé Plus de 100 scientifiques ont répondu à une enquête menée par courrier et concernant la perspective de 33 développements technologiques relatifs à la fixation biologique de l'azote. Ces scientifiques anticipent que la plupart des développements prévus par hypothèse dans domaines des interractions légumes-Rhizobium et riz/Azolla vont se réaliser dans les 10 prochaines années, tandis que d'une manière plus générale, les développements dans les céréales fixatrices d'azote et d'autres domaines de recherche, vont se réaliser plus tard. Ces scientifiques suggèrent en outre 28 développements technologiques supplémentaires. Ils ont fait savoir que le coût accru de fertilisants chimiques était la force motrice principale, que le manque d'ouvriers qualifiés d'entretien était la contrainte principale et que la subsidation de la recherche était l'objectif le plus important pour le développement et la popularisation de cette technologie.

     

Involvement of the central adrenomedullin peptides in the baroreflex

The peptides derived from post-translational processing of preproadrenomedullin are produced in and act on areas of the autonomic nervous system important for blood pressure regulation. We examined the role of endogenous, brain-derived adrenomedullin (AM) and proadrenomedullin N-terminal 20 peptide (PAMP) in the central nervous system arm of the baroreflex by using passive immunoneutralization to block the actions of the endogenous peptides. Our results indicate that the preproadrenomedullin-derived peptides do not play a role in sensing changes in blood pressure (baroreflex sensitivity), but the adrenomedullin peptides do regulate the speed with which an animal returns to a normal, stable blood pressure. These findings suggest that endogenous, brain-derived AM and PAMP participate in the regulation of autonomic activity in response to baroreceptor activation and inactivation.     

Cyclosporin A: a powerful immunosuppressant.

Cyclosporin A (CyA) is a powerful immunosuppressive agent whose lack of myelotoxicity makes it unique among nonsteroidal drugs currently given for immunosuppression. It has been used with initial success in recipients of kidney, liver, bone marrow and pancreas transplants, and it may also have clinical application in the treatment of autoimmune disorders. In regard to its use in transplant recipients, there are many remaining questions about its mechanism of action, the optimum dose, whether it should be used alone or with other immunosuppressants, whether it can suppress chronic rejection and what its long-term side effects may be. These questions can only be answered by further careful laboratory investigation and controlled clinical trials. Until then, CyA should only be administered in centres experienced in its use.