Milk recording data indicates the importance of fertility, including age at first calving, on the progression of first lactation cows to second lactation.

Dairy farmers do not recoup the rearing costs incurred from birth to first calving until second lactation but varying proportions of first lactation cows are removed from the herd before second calving. Herein, we used milk recording data to examine the outcomes and performance of first lactation cows to gain insight into farmer decisions to keep or remove them from the herd. An InterHerd+ dataset derived from 500 milk recording dairy herds in UK was used to examine first lactation cows which calved in 2020. Of 29,128 first lactation cows that calved in 2020, 82.6% remained within the herd and re-calved, 4.9% conceived but exited the herd before re-calving, 6.0% were served but exited the herd after failing to conceive and 6.6% exited the herd without being served. The fertility data on these cows support the logical conclusion that farmers retain cows that are served and conceive sooner, possibly in order to keep within a broadly seasonal calving pattern. Cows which were served but not conceived had a median AFC 16-20 days greater than the median AFC for those that conceived. Farmers may also be retaining cows with relatively high milk yields and lower somatic cell counts, or these parameters may be an indicator of a range of attributes affecting the farmer's decision. The data also suggest that farmers are rearing more replacements than required, because over one third of the cows removed in first lactation are never served, and 70% of these are sold within 120 days post-partum. These cows had a significantly older median age at first calving of 818 days, but their early removal without serving suggests there is an oversupply of replacements forcing farmers to dispose of these cows early in lactation. In order to develop a deeper understanding of herd turnover and replacement, future work could examine cow removals in lactation 2 onwards.

Changes in the Johne's disease situation in GB dairy herds over 10 years, as revealed by regular milk ELISA data.

Effective management of cattle infected with Johne's Disease (JD) is crucial to minimizing transmission and within-herd prevalence. Within Great Britain (GB), the voluntary National Johne's Management Plan (NJMP) requires farmers and a certified vet to conduct a risk assessment to determine the herd risk, examine the herd JD status and formulate a management plan. Individual milk ELISA tests for JD antibodies are widely used to monitor infection. The JD Tracker application, available within the dairy data management software InterHerd+ and other web-based environments, is being used by farmers and veterinarians to facilitate the practical use of milk ELISA data to aid JD-related management decisions. The JD Tracker application uses a herd's milk ELISA data to calculate a collection of 'JD parameters' that are indicative of the current JD status of the herd alongside contemporary and retrospective drivers linked to transmission and maintenance of infection. Herein, we use milk ELISA data from 154 regularly testing herds to review the temporal trends in JD parameters from 2013 to 2022. Since 2015, JD Tracker parameters have improved in these herds, most notably average test value (ATV) and within-herd prevalence (%Pos30). Trends in driver parameters suggest that farmers are progressively less likely to serve repeat test-positive (J5) cows and are more readily removing them. The data also reveal that the burden of JD is disproportionately greater in herds with higher ATV. In 2022, the 25 % of herds with the highest ATVs accounted for 42 % of positive tests and 42 % of repeat ELISA positive (J5) cows. Retrospectively, it is not possible to identify with certainty factors that directly contributed to the trends in JD parameters, but it is notable that the introduction of the NJMP was coincided with the improving JD situation. In 2019, participation in the NJMP or an equivalent scheme became mandatory for dairy farms to be compliant with the food and farms standards assurance scheme Red Tractor, with the result that JD management plans are now completed by 95 % of UK dairy farms. As far as we know, the UK is unique in its development of a tool (the JD Tracker) which adds utility to milk ELISA data using specifically designed JD parameters. Anticipated further work includes the development of a national database of JD testing herds and application of the JD Tracker at national scale to enable more comprehensive industry-level monitoring of JD within GB dairy farms.

Challenges for the management of Johne's disease in the UK: Expectation management, space, 'free riding', and vet-farmer communication.

Johne's disease in cattle is a significant global animal health challenge. Johne's disease is chronic, affecting the gastrointestinal tract of cattle and other ruminants and is caused by the bacteria Mycobacterium avium ssp. Paratuberculosis. Many countries have introduced schemes and programmes to try and control the spread of Johne's disease, including the UK. Despite efforts to control it, however, Johne's disease remains consistently ranked by UK producers as the top ranked disease negatively affecting productivity, indicating that schemes are not perceived to have solved the problem fully. Building on a global systematic review of the literature on barriers and solutions for Johne's disease control on-farm, we conducted an empirical study with over 400 farmers and 150 veterinary professionals across the UK. The study used workshops and semi-structured interviews to understand better the challenges dairy farmers and veterinarians face in implementing on-farm Johne's disease management schemes with the aim of identifying solutions. The study found that four main challenges are faced in the on-farm control of Johne's - (1) Management of farmer expectations around Johne's disease, with eradication near impossible, (2) Issues regarding space for segregation and the related economics of control (3) A 'free-riding' problem which can be influenced by the voluntary nature of control plans and (4) Challenges in vet-farmer communication, including levels of knowledge. Our findings have relevance for the control of Johne's disease in the UK and other countries, including for regions with voluntary and compulsory control programmes.

Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice.

Serotonin 5-HT(2A) and metabotropic glutamate 2 (mGlu2) are G protein-coupled receptors suspected in the pathophysiology of psychiatric disorders, such as schizophrenia, depression, and suicide. Previous findings demonstrate that mGlu2 mRNA expression is down-regulated in brain cortical regions of 5-HT2A knockout (KO) mice. However, the molecular mechanism responsible for this alteration remains unknown. We show here repressive epigenetic changes at the promoter region of the mGlu2 gene in frontal cortex of 5-HT(2A)-KO mice. Disruption of 5-HT(2A) receptor-dependent signaling in mice was associated with decreased acetylation of histone H3 (H3ac) and H4 (H4ac) and increased tri-methylation of histone H3 at lysine 27 (H3K27me3) at the mGlu2 promoter, epigenetic changes that correlate with transcriptional repression. Neither methylation of histone H3 at lysine 4 (H3K4me1/2/3) nor tri-methylation of histone H3 at lysine 9 (H3K9me3) was affected. We found that Egr1, a transcription factor in which promoter activity was positively regulated by the 5-HT(2A) receptor agonist 4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide, binds less to the mGlu2 promoter in frontal cortex of 5-HT(2A)-KO, compared with wild-type mice. Furthermore, expression of mGlu2 was increased by viral-mediated gene transfer of FLAG-tagged Egr1 in mouse frontal cortex. Together, these observations suggest that 5-HT(2A) receptor-dependent signaling epigenetically affects mGlu2 transcription in mouse frontal cortex.

East Coast fever immunisation field trial in crossbred dairy cattle in Hanang and Handeni districts in northern Tanzania.

East Coast fever (ECF) causes considerable mortality and production losses in the Tanzania smallholder dairy sector and limits the introduction of improved dairy breeds in areas where the disease is present. The infection and treatment method (ITM) was adopted by smallholder dairy farms for ECF immunisation in Hanang and Handeni districts of Tanzania. This study recorded incidence rates for ECF and other tick-borne diseases (TBDs) for ECF-immunised and non-immunised cattle between 1997 and 2000. Approximately 80% of smallholder households from both sites (n = 167) participated in this longitudinal study, with immunisations carried out at the request of the livestock owners. Efficacy of ITM for preventing ECF cases in these crossbred dairy cattle was estimated at 97.6%, while that for preventing ECF deaths was 97.9%. One percent of the cattle developed clinical ECF as a result of immunisation. Since ECF immunisation permits a reduction in acaricide use, an increase in other TBDs is a potential concern. Sixty-three percent of farmers continued to use the same acaricide after immunisation, with 80% of these reducing the frequency of applications. Overall, 78% of farmers increased the acaricide application interval after immunisation beyond that recommended by the manufacturer, resulting in annual savings in the region of USD 4.77 per animal. No statistical difference was observed between the immunised and non-immunised animals in the incidence of non-ECF TBDs. However, immunised animals that succumbed to these diseases showed fewer case fatalities. ITM would therefore appear to be a suitable method for ECF control in Tanzania's smallholder dairy sector.

Non-phosphorylatable mutants of Ser184 lead to incomplete activation of Bax.

The S184 residue of Bax is the target of several protein kinases regulating cell fate, including AKT. It is well-established that, in cellulo, the substitution of S184 by a non-phosphorylatable residue stimulates both the mitochondrial localization of Bax, cytochrome c release, and apoptosis. However, in in vitro experiments, substituted mutants did not exhibit any increase in their binding capacity to isolated mitochondria or liposomes. Despite exhibiting a significant increase of the 6A7 epitope exposure, substituted mutants remain limited in their ability to form large oligomers, suggesting that they high capacity to promote apoptosis in cells was more related to a high content than to an increased ability to form large pores in the outer mitochondrial membranes.

THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders.

There is a strong association between cannabis use and schizophrenia but the underlying cellular links are poorly understood. Neurons derived from human-induced pluripotent stem cells (hiPSCs) offer a platform for investigating both baseline and dynamic changes in human neural cells. Here, we exposed neurons derived from hiPSCs to Δ9-tetrahydrocannabinol (THC), and identified diagnosis-specific differences not detectable in vehicle-controls. RNA transcriptomic analyses revealed that THC administration, either by acute or chronic exposure, dampened the neuronal transcriptional response following potassium chloride (KCl)-induced neuronal depolarization. THC-treated neurons displayed significant synaptic, mitochondrial, and glutamate signaling alterations that may underlie their failure to activate appropriately; this blunted response resembles effects previously observed in schizophrenia hiPSC- derived neurons. Furthermore, we show a significant alteration in THC-related genes associated with autism and intellectual disability, suggesting shared molecular pathways perturbed in neuropsychiatric disorders that are exacerbated by THC.

Animal models of serotonergic psychedelics.

The serotonin 5-HT(2A) receptor is the major target of psychedelic drugs such as lysergic acid diethylamide (LSD), mescaline, and psilocybin. Serotonergic psychedelics induce profound effects on cognition, emotion, and sensory processing that often seem uniquely human. This raises questions about the validity of animal models of psychedelic drug action. Nonetheless, recent findings suggest behavioral abnormalities elicited by psychedelics in rodents that predict such effects in humans. Here we review the behavioral effects induced by psychedelic drugs in rodent models, discuss the translational potential of these findings, and define areas where further research is needed to better understand the molecular mechanisms and neuronal circuits underlying their neuropsychological effects.

Clozapine-induced locomotor suppression is mediated by 5-HT2A receptors in the forebrain.

The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT(2A)), serotonin 2C (5-HT(2C)), and dopamine 2 receptors (D2) in mediating adverse effects associated with canonical first- and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT(2A) knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT(2A) KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine's locomotor-suppressing effects. Restoration of 5-HT(2A) expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D2. We also demonstrate that clozapine decreases locomotor activity in a 5-HT(2A)-dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT(2A) that mediate the locomotor-suppressing effects of clozapine.

HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity.

Histone deacetylases (HDACs) compact chromatin structure and repress gene transcription. In schizophrenia, clinical studies demonstrate that HDAC inhibitors are efficacious when given in combination with atypical antipsychotics. However, the molecular mechanism that integrates a better response to antipsychotics with changes in chromatin structure remains unknown. Here we found that chronic atypical antipsychotics downregulated the transcription of metabotropic glutamate 2 receptor (mGlu2, also known as Grm2), an effect that was associated with decreased histone acetylation at its promoter in mouse and human frontal cortex. This epigenetic change occurred in concert with a serotonin 5-HT(2A) receptor-dependent upregulation and increased binding of HDAC2 to the mGlu2 promoter. Virally mediated overexpression of HDAC2 in frontal cortex decreased mGlu2 transcription and its electrophysiological properties, thereby increasing psychosis-like behavior. Conversely, HDAC inhibitors prevented the repressive histone modifications induced at the mGlu2 promoter by atypical antipsychotics, and augmented their therapeutic-like effects. These observations support the view of HDAC2 as a promising new target for schizophrenia treatment.