Evolutionary process of Bos taurus cattle in favourable versus unfavourable environments and its implications for genetic selection

The evolutionary processes that have enabled Bos taurus cattle to establish around the globe are at the core to the future success of livestock production. Our study focuses on the history of cattle domestication including the last 60 years of B. taurus breeding programmes in both favourable and unfavourable environments and its consequences on evolution and fitness of cattle. We discuss the emergence of ‘production diseases’ in temperate production systems and consider the evolutionary genetics of tropical adaptation in cattle and conclude that the Senepol, N'Dama, Adaptaur and Criollo breeds, among others with similar evolutionary trajectories, would possess genes capable of improving the productivity of cattle in challenging environments. Using our own experimental evidence from northern Australia, we review the evolution of the Adaptaur cattle breed which has become resistant to cattle tick. We emphasize that the knowledge of interactions between genotype, environment and management in the livestock systems will be required to generate genotypes for efficient livestock production that are both economically and environmentally sustainable. Livestock producers in the 21st century will have less reliance on infrastructure and veterinary products to alleviate environmental stress and more on the animal's ability to achieve fitness in a given production environment

Mucosal associated invariant T cells are altered in patients with Hidradenitis Suppurativa and contribute to the inflammatory milieu

Mucosal Associated Invariant T cells are a population of “innate” T cells, which express the invariant T cell receptor (TCR) a chain Va7.2-Ja33 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-g and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin. On-going research has highlighted their involvement in numerous inflammatory diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is currently unknown. In this study we show for the first time, that MAIT cells are altered in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17 cytokine bias. We show that CCL20 expression is elevated in lesions of patients with H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT cells can accumulate in the lesionsfrom patients with H.S. when compared to adjacent skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation of dermal fibroblasts, promoting the expression of chemotactic signals including CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively our data detailsIL-17 producing MAIT cells as a novel player in the pathogenesis of H.S and highlights the potential of RORyt inhibition as a novel therapeutic strategy

Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome

MicroRNA (miRNA)-mediated RNA interference regulates many immune processes, but how miRNA circuits orchestrate aberrant intestinal inflammation during inflammatory bowel disease (IBD) is poorly defined. Here, we report that miR-223 limits intestinal inflammation by constraining the nlrp3 inflammasome. miR-223 was increased in intestinal biopsies from patients with active IBD and in preclinical models of intestinal inflammation. miR-223-/y mice presented with exacerbated myeloid-driven experimental colitis with heightened clinical, histopathological, and cytokine readouts. Mechanistically, enhanced NLRP3 inflammasome expression with elevated IL-1β was a predominant feature during the initiation of colitis with miR-223 deficiency. Depletion of CCR2+ inflammatory monocytes and pharmacologic blockade of IL-1β or NLRP3 abrogated this phenotype. Generation of a novel mouse line, with deletion of the miR-223 binding site in the NLRP3 3′ untranslated region, phenocopied the characteristics of miR-223-/y mice. Finally, nanoparticle-mediated overexpression of miR-223 attenuated experimental colitis, NLRP3 levels, and IL-1β release. Collectively, our data reveal a previously unappreciated role for miR-223 in regulating the innate immune response during intestinal inflammation

Reconciling autonomy and beneficence in treatment decision-making for animal patients

This article explores how the concept of consent to medical treatment applies in the veterinary context, and aims to evaluate normative justifications for owner consent to treatment of animal patients. We trace the evolution of the test for valid consent in human health decision-making, against a backdrop of increased recognition of the importance of patient rights and a gradual judicial espousal of a doctrine of informed consent grounded in a particular understanding of autonomy. We argue that, notwithstanding the adoption of a similar discourse of informed consent in professional veterinary codes, notions of autonomy and informed consent are not easily transferrable to the veterinary medicine context, given inter alia the tripartite relationship between veterinary professional, owner and animal patient. We suggest that a more appropriate, albeit inexact, analogy may be drawn with paediatric practice which is premised on a similarly tripartite relationship and where decisions must be reached in the best interests of the child. However, acknowledging the legal status of animals as property and how consent to veterinary treatment is predicated on the animal owner’s willingness and ability to pay, we propose that the appropriate response is for veterinary professionals generally to accept the client’s choice, provided this is informed. Yet such client autonomy must be limited where animal welfare concerns exist, so that beneficence continues to play an important role in the veterinary context. We suggest that this ‘middle road’ should be reflected in professional veterinary guidance

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

Targeting hallmarks of cancer to enhance radiosensitivity in gastrointestinal cancers

Radiotherapy is used in the treatment of approximately 50% of all malignancies including gastrointestinal cancers. Radiation can be given prior to surgery (neoadjuvant radiotherapy) to shrink the tumour or after surgery to kill any remaining cancer cells. Radiotherapy aims to maximize damage to cancer cells, while minimizing damage to healthy cells. However, only 10–30% of patients with rectal cancer or oesophageal cancer have a pathological complete response to neoadjuvant chemoradiation therapy, with the rest suffering the negative consequences of toxicities and delays to surgery with no clinical benefit. Furthermore, in pancreatic cancer, neoadjuvant chemoradiation therapy results in a pathological complete response in only 4% of patients and a partial pathological response in only 31%. Resistance to radiation therapy is polymodal and associated with a number of biological alterations both within the tumour itself and in the surrounding microenvironment including the following: altered cell cycle" repopulation by cancer stem cells" hypoxia" altered management of oxidative stress" evasion of apoptosis" altered DNA damage response and enhanced DNA repair" inflammation" and altered mitochondrial function and cellular energetics. Radiosensitizers are needed to improve treatment response to radiation, which will directly influence patient outcomes in gastrointestinal cancers. This article reviews the literature to identify strategies — including DNA-targeting agents, antimetabolic agents, antiangiogenics and novel immunotherapies — being used to enhance radiosensitivity in gastrointestinal cancers according to the hallmarks of cancer. Evidence from radiosensitizers from in vitro and in vivo models is documented and the action of radiosensitizers through clinical trial data is assessed

Can the Efficacy of [¹⁸F]FDG-PET/CT in Clinical Oncology Be Enhanced by Screening Biomolecular Profiles?

Positron Emission Tomography (PET) is a functional imaging modality widely used in clinical oncology. Over the years the sensitivity and specificity of PET has improved with the advent of specific radiotracers, increased technical accuracy of PET scanners and incremental experience of Radiologists. However, significant limitations exist—most notably false positives and false negatives. Additionally, the accuracy of PET varies between cancer types and in some cancers, is no longer considered a standard imaging modality. This review considers the relative influence of macroscopic tumour features such as size and morphology on 2-Deoxy-2-[18F]fluoroglucose ([18F]FDG) uptake by tumours which, though well described in the literature, lacks a comprehensive assessment of biomolecular features which may influence [18F]FDG uptake. The review aims to discuss the potential influence of individual molecular markers of glucose transport, glycolysis, hypoxia and angiogenesis in addition to the relationships between these key cellular processes and their influence on [18F]FDG uptake. Finally, the potential role for biomolecular profiling of individual tumours to predict positivity on PET imaging is discussed to enhance accuracy and clinical utility