Genetic analysis of phenotypic indicators for heat tolerance in crossbred dairy cattle

Climate change-induced rise in global temperatures has intensified heat stress on dairy cattle and is contributing to the generally observed low milk productivity. Selective breeding aimed at enhancing animals’ ability to withstand rising temperatures while maintaining optimal performance is crucial for ensuring future access to dairy products. However, phenotypic indicators of heat tolerance are yet to be effectively factored into the objectives of most selective breeding programs. This study investigated the response of milk production to changing heat load as an indication of heat tolerance and the influence of calving season on this response in multibreed dairy cattle performing in three agroecological zones Kenya. First-parity 7-day average milk yield (65 261 milk records) of 1 739 cows were analyzed. Based on routinely recorded weather data that were accessible online, the Temperature-Humidity Index (THI) was calculated and used as a measure of heat load. THI measurements used represented averages of the same 7-day periods corresponding to each 7-day average milk record. Random regression models, including reaction norm functions, were fitted to derive two resilience indicators: slope of the reaction norm (Slope) and its absolute value (Absolute), reflecting changes in milk yield in response to the varying heat loads (THI 50 and THI 80). The genetic parameters of these indicators were estimated, and their associations with average test-day milk yield were examined. There were no substantial differences in the pattern of milk yield response to heat load between cows calving in dry and wet seasons. Animals with ≤50% Bos taurus genes were the most thermotolerant at extremely high heat load levels. Animals performing in semi-arid environments exhibited the highest heat tolerance capacity. Heritability estimates for these indicators ranged from 0.06 to 0.33 and were mostly significantly different from zero (P &lt; 0.05). Slope at THI 80 had high (0.64–0.71) negative correlations with average daily milk yield, revealing that high-producing cows are more vulnerable to heat stress and vice versa. A high (0.63–0.74) positive correlation was observed between Absolute and average milk yield at THI 80. This implied that low milk-producing cows have a more stable milk production under heat-stress conditions and vice versa. The study demonstrated that the slope of the reaction norms and its absolute value can effectively measure the resilience of crossbred dairy cattle to varying heat load conditions. The implications of these findings are valuable in improving the heat tolerance of livestock species through genetic selection.</p

Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity [version 2; peer review: 2 approved]

Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates in vivo. Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using >100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate in vivo will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity. / Registration: ClinicalTrials.gov identifier NCT02739763

Asymmetric Switching in a Homodimeric ABC Transporter: A Simulation Study

ABC transporters are a large family of membrane proteins involved in a variety of cellular processes, including multidrug and tumor resistance and ion channel regulation. Advances in the structural and functional understanding of ABC transporters have revealed that hydrolysis at the two canonical nucleotide-binding sites (NBSs) is co-operative and non-simultaneous. A conserved core architecture of bacterial and eukaryotic ABC exporters has been established, as exemplified by the crystal structure of the homodimeric multidrug exporter Sav1866. Currently, it is unclear how sequential ATP hydrolysis arises in a symmetric homodimeric transporter, since it implies at least transient asymmetry at the NBSs. We show by molecular dynamics simulation that the initially symmetric structure of Sav1866 readily undergoes asymmetric transitions at its NBSs in a pre-hydrolytic nucleotide configuration. MgATP-binding residues and a network of charged residues at the dimer interface are shown to form a sequence of putative molecular switches that allow ATP hydrolysis only at one NBS. We extend our findings to eukaryotic ABC exporters which often consist of two non-identical half-transporters, frequently with degeneracy substitutions at one of their two NBSs. Interestingly, many residues involved in asymmetric conformational switching in Sav1866 are substituted in degenerate eukaryotic NBS. This finding strengthens recent suggestions that the interplay of a consensus and a degenerate NBS in eukaroytic ABC proteins pre-determines the sequence of hydrolysis at the two NBSs

\u3ci\u3ePlasmodium falciparum\u3c/i\u3e circumsporozoite vaccine immunogenicity and efficacy trial with natural challenge quantitation in an area of endemic human malaria of Kenya

It has been hypothesized that antibody induced by Plasmodium falciparum circumsporozoite protein vaccine would be effective against endemic human malaria. In a malaria endemic region of Kenya, 76 volunteers, in 38 pairs sleeping adjacently, were immunized with subunit circumsporozoite protein Asn-Ala-Asn-Pro tetrapeptide repeatpseudomonas toxin A, or hepatitis B vaccine. After quinine and doxcycycline, volunteers were followed for illness daily, parasitemia weekly, antibody, T-lymphocyte responses, and treated if indicated. Anopheles mosquitoes resting in houses were collected, and tested for P. falciparum antigen, or dissected for sporozoites and tested for blood meal ABO type and P. falciparum antigen. Vaccine was safe, with side-eflects similar in both groups, and immunogenic, engendering IgG antibody as high as 600 µg ml-1, but did not increase the proportion of volunteers with T-lymphocyte responses. Estimation of P. falciparum challenge averaged 0.194 potentially infective Anopheles bites/volunteer/day. Mosquito blood meals showed no difference in biting intensity between vaccine and control groups. Both groups had similar malaria-free survival curves, cumulative positive blood slides, cumulative parasites mm- 3, and numbers of parasites mm- 3 on first positive blood slide, during three post-vaccination observation periods. Every volunteer had P. falciparum parastiemia at least once. Vaccinees had 82% and controls 89% incidences of symptomatic parasitemia (P=0.514, efficacy 9%, statistical power 95% probability of eficacy ~50%). Vaccine-induced anti-sporozoite antibody was not protective in this study. Within designed statistical precisions the present study is in agreement with efficacy studies in Colombia, Venezuela and Tanzania