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Genetic selection for feed efficiency is possible in Holstein dairy cattle. However, measuring individual cow feed intake is expensive, which limits available phenotypes, resulting in lower prediction accuracy of breeding values than desired. New indicator trait phenotypes for feed efficiency could help improve breeding value accuracies if they can be measured widely across dairy herds. The objective of this study was to identify milk metabolites associated with feed intake and efficiency traits that may serve as new indicator traits. Metabolites were obtained from three sources and two distinct groups of cows. Gas chromatography mass spectrometry (GC-MS), and liquid chromatography mass spectrometry (LC-MS) assays were conducted on a subset of 39 cows identified based on their extreme residual feed intake (RFI; top and bottom 15%). Routinely collected on-farm milk testing data were evaluated on a second, larger subset of 357 cows. Statistical models were created to evaluate if metabolites: 1) provided novel feed efficiency information; 2) served as proxies for body weight traits not routinely collected on farms; and 3) were associated with breeding values for feed efficiency traits, including: predicted transmitting abilities (PTA) for feed saved (FS), RFI and body weight composite (BWC). Ontology enrichment analysis was used to identify enriched pathways from the contrast of extreme RFI cows by GC-MS and LC-MS. The false discovery rate (FDR, reported as q-values) and Hommel corrections were used as multiple testing corrections. Partial least squares discriminate analysis confirmed animals could be classified as high or low feed efficiency groups. A total of 33 GC-MS metabolites, 10 LC-MS ontology pathways (both q

BackgroundDementia with Lewy bodies (DLB) can be difficult to distinguish from Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) at different stages of its progression due to some overlaps in the clinical and neuropathological presentation of these conditions compared with DLB. Metallomic changes have already been observed in the AD and PDD brain—including widespread decreases in Cu levels and more localised alterations in Na, K, Mn, Fe, Zn, and Se. This study aimed to determine whether these metallomic changes appear in the DLB brain, and how the metallomic profile of the DLB brain appears in comparison to the AD and PDD brain.MethodsBrain tissues from ten regions of 20 DLB cases and 19 controls were obtained. The concentrations of Na, Mg, K, Ca, Zn, Fe, Mn, Cu, and Se were determined using inductively coupled plasma-mass spectrometry (ICP-MS). Case–control differences were evaluated using Mann–Whitney U tests. Results were compared with those previously obtained from AD and PDD brain tissue, and principal component analysis (PCA) plots were created to determine whether cerebral metallomic profiles could distinguish DLB from AD or PDD metallomic profiles.ResultsNa was increased and Cu decreased in four and five DLB brain regions, respectively. More localised alterations in Mn, Ca, Fe, and Se were also identified. Despite similarities in Cu changes between all three diseases, PCA plots showed that DLB cases could be readily distinguished from AD cases using data from the middle temporal gyrus, primary visual cortex, and cingulate gyrus, whereas DLB and PDD cases could be clearly separated using data from the primary visual cortex alone.ConclusionDespite shared alterations in Cu levels, the post-mortem DLB brain shows very few other similarities with the metallomic profile of the AD or PDD brain. These findings suggest that while Cu deficiencies appear common to all three conditions, metal alterations otherwise differ between DLB and PDD/AD. These findings can contribute to our understanding of the underlying pathogenesis of these three diseases; if these changes can be observed in the living human brain, they may also contribute to the differential diagnosis of DLB from AD and/or PDD.

Complete blood counts (CBCs) measure the abundance of individual immune cells, red blood cells, and related measures such as platelets in circulating blood. These measures can indicate the health status of an animal; thus, baseline circulating levels in a healthy animal may be related to the productive life, resilience, and production efficiency of cattle. The objective of this study is to determine the heritability of CBC traits and identify genomic regions that are associated with CBC measurements in lactating Holstein dairy cattle. The heritability of CBCs was estimated using a Bayes C0 model. The study population consisted of 388 cows with genotypes at roughly 75,000 markers and 16 different CBC phenotypes taken at one to three time points (n = 33, 131, and 224 for 1, 2, and 3 time points, respectively). Heritabilities ranged from 0.00 ± 0.00 (red cell distribution width) to 0.68 ± 0.06 (lymphocytes). A total of 96 different 1-Mb windows were identified that explained more than 1% of the genetic variance for at least one CBC trait, with 10 windows explaining more than 1% of the genetic variance for two or more traits. Multiple genes in the identified regions have functions related to immune response, cell differentiation, anemia, and disease. Positional candidate genes include RAD52 motif-containing protein 1 (RDM1), which is correlated with the degree of immune infiltration of immune cells, and C-X-C motif chemokine ligand 12 (CXCL12), which is critically involved in neutrophil bone marrow storage and release regulation and enhances neutrophil migration. Since animal health directly impacts feed intake, understanding the genetics of CBCs may be useful in identifying more disease-resilient and feed-efficient dairy cattle. Identification of genes responsible for variation in CBCs will also help identify the variability in how dairy cattle defend against illness and injury.

IntroductionVascular dementia (VaD) is one of the most common causes of dementia among the elderly. Despite this, the molecular basis of VaD remains poorly characterized when compared to other age-related dementias. Pervasive cerebral elevations of urea have recently been reported in several dementias; however, a similar analysis was not yet available for VaD.MethodsHere, we utilized ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to measure urea levels from seven brain regions in post-mortem tissue from cases of VaD (n = 10) and controls (n = 8/9). Brain-urea measurements from our previous investigations of several dementias were also used to generate comparisons with VaD.ResultsElevated urea levels ranging from 2.2- to 2.4-fold-change in VaD cases were identified in six out of the seven regions analysed, which are similar in magnitude to those observed in uremic encephalopathy. Fold-elevation of urea was highest in the basal ganglia and hippocampus (2.4-fold-change), consistent with the observation that these regions are severely affected in VaD.DiscussionTaken together, these data not only describe a multiregional elevation of brain-urea levels in VaD but also imply the existence of a common urea-mediated disease mechanism that is now known to be present in at least four of the main age-related dementias.

The Great Artesian Basin of Australia represents one of the largest and deepest basins of freshwater on Earth. Thousands of springs fed by the Basin are scattered across Australia’s arid zone, often representing the sole sources of freshwater for thousands of kilometers. As “islands” in the desert, the springs support endemic fauna and flora that have undergone millions of years of evolution in almost total isolation. Here, we review the current body of knowledge surrounding Great Artesian Basin springs and their significance from ecological, evolutionary, and cultural perspectives using South Australian spring wetlands as a case study. We begin by identifying the status of these springs as critical sources of groundwater, the unique biodiversity they support, and their cultural significance to the Arabana people as Traditional Custodians of the land. We then summarize known threats to the springs and their biota, both exogenous and endogenous, and the potential impacts of such processes. Finally, considering the status of these at-risk habitats as time capsules of biodiversity, we discuss lessons that can be learnt from current conservation and management practices in South Australia. We propose key recommendations for improved biodiversity assessment and monitoring of Great Artesian Basin springs nationwide, including 1) enhanced legal protections for spring biota; 2) increased taxonomic funding and capacity; 3) improved biodiversity monitoring methods, and 4) opportunities for reciprocal knowledge-sharing with Aboriginal peoples when conducting biodiversity research.

Animal health and feed intake are closely interrelated, with the latter being an important indicator of an animal’s health status. Automated sensors for dairy cattle have been developed to detect changes in indicators of health, such as decreased rumination or activity. Previous studies have identified associations between sensor measurements and feed intake. Thus, the objective of this study was to determine if health disorders impact the associations identified between sensors and dry matter intake (DMI), and to measure the impact of health disorders on DMI. A total of 934 cows with health disorders (lameness, mastitis, and other), of which 57, 94, and 333 cows had observations for a rumen bolus and one of two ear tags, were analyzed to determine how health disorders impact the association of sensors with DMI. Eleven sensor measurements were collected across the three sensors, including total and point-in-time activity, rumination time, inner-ear temperature, rumen pH and rumen temperature. Associations of health disorders and sensor measures with DMI were evaluated when accounting for systematic effects (i.e., contemporary group, parity, and days in milk) and energy sinks accounted for in determination of feed efficiency (e.g., milk production, body weight and composition). In order to determine if inclusion of health disorders or sensor measures improved model fit, model AICs were assessed. Health disorders were significantly associated with all sensor measurements (P< 0.0001), with the direction of association dependent on sensor measure and health disorder. Moreover, DMI decreased with all health disorders, with larger impacts observed in animals in third and higher lactations. Numerous sensor measurements were associated with DMI, including when DMI was adjusted for energy sink variables and health. Inclusion of rumen bolus temperature, rumination or activity with health data reduced model AIC when evaluating DMI as the dependent variable. Some sensor measures, including measurements of activity, temperature and rumination, accounted for additional variation in feed intake when adjusted for health disorders. Results from the study indicate that feed intake and sensor measures are impacted by health disorders. These findings may have implications for use of sensors in genetic evaluations and precision feeding of dairy cattle.

Chimeric antigen receptor (CAR) T-cell therapy has emerged recently as a standard of care treatment for patients with relapsed or refractory acute lymphoblastic leukemia (ALL) and several subtypes of B-cell non-Hodgkin lymphoma (NHL). However, its use remains limited to highly specialized centers, given the complexity of its administration and its associated toxicities. We previously reported our experience in using a novel Sleeping Beauty (SB) CD19-specific CAR T-cell therapy in the peri-transplant setting, where it exhibited an excellent safety profile with encouraging survival outcomes. We have since modified the SB CD19 CAR construct to improve its efficacy and shorten its manufacturing time. We report here the phase 1 clinical trial safety results. Fourteen heavily treated patients with relapsed/refractory ALL and NHL were infused. Overall, no serious adverse events were directly attributed to the study treatment. Three patients developed grades 1-2 cytokine release syndrome and none of the study patients experienced neurotoxicity. All dose levels were well tolerated and no dose-limiting toxicities were reported. For efficacy, 3 of 8 (38%) patients with ALL achieved CR/CRi (complete remission with incomplete count recovery) and 1 (13%) patient had sustained molecular disease positivity. Of the 4 patients with DLBCL, 2 (50%) achieved CR. The SB-based CAR constructs allow manufacturing of targeted CAR T-cell therapies that are safe, cost-effective and with encouraging antitumor activity.

Vascular dementia (VaD) is the second most common cause of cognitive impairment amongst the elderly. However, there are no known disease-modifying therapies for VaD, probably due to incomplete understanding of the molecular basis of the disease. Despite the complex etiology of neurodegenerative conditions, a growing body of research now suggests the potential involvement of metal dyshomeostasis in the pathogenesis of several of the age-related dementias. However, by comparison, there remains little research investigating brain metal levels in VaD. In order to shed light on the possible involvement of metal dyshomeostasis in VaD, we employed inductively coupled plasma-mass spectrometry to quantify the levels of essential metals in post-mortem VaD brain tissue (n = 10) and age-/sex-matched controls (n = 10) from seven brain regions. We found novel evidence for elevated wet-weight cerebral sodium levels in VaD brain tissue in six out of the seven regions analyzed. Decreased cerebral-potassium levels as well as increased Na/K ratios (consistent with high tissue sodium and low potassium levels) were also observed in several brain regions. These data suggest that reduced Na+/K+-exchanging ATPase (EC 7.2.2.13) activity could contribute to the contrasting changes in sodium and potassium measured here.

Sporadic Alzheimer’s disease (sAD) is the commonest cause of age-related neurodegeneration and dementia globally, and a leading cause of premature disability and death. To date, the quest for a disease-modifying therapy for sAD has failed, probably reflecting our incomplete understanding of aetiology and pathogenesis. Drugs that target aggregated Aβ/tau are ineffective, and metabolic defects are now considered to play substantive roles in sAD pathobiology. We tested the hypothesis that the recently identified, pervasive cerebral deficiency of pantothenate (vitamin B5) in sAD, might undermine brain energy metabolism by impairing levels of tricarboxylic acid (TCA)-cycle enzymes and enzyme complexes, some of which require the pantothenate-derived cofactor, coenzyme A (CoA) for their normal functioning. We applied proteomics to measure levels of the multi-subunit TCA-cycle enzymes and their cytoplasmic homologues. We analysed six functionally distinct brain regions from nine sAD cases and nine controls, measuring 33 cerebral proteins that comprise the nine enzymes of the mitochondrial-TCA cycle. Remarkably, we found widespread perturbations affecting only two multi-subunit enzymes and two enzyme complexes, whose function is modulated, directly or indirectly by CoA: pyruvate dehydrogenase complex, isocitrate dehydrogenase, 2-oxoglutarate dehydrogenase complex, and succinyl-CoA synthetase. The sAD cases we studied here displayed widespread deficiency of pantothenate, the obligatory precursor of CoA. Therefore, deficient cerebral pantothenate can damage brain-energy metabolism in sAD, at least in part through impairing levels of these four mitochondrial-TCA-cycle enzymes.

Feed efficiency is an important trait to dairy production because of its impact on sustainability and profitability. Measuring individual cow feed intake on commercial farms would be unfeasibly costly at present. Thus, developing cheap and portable indicators of feed intake would be highly beneficial for genetic selection and precision feeding management tools. Given the growing use of automated sensors on dairy farms, the objective of this study was to determine the relationship between measurements recorded from multiple wearable sensors and feed intake. A total of three different wearable sensors were evaluated for their association with dry mater intake (DMI). The sensors measured activity (sensors = 3), rumination (sensors = 1), ear temperature (sensors = 1), rumen pH (sensors = 1) and rumen temperature (sensors = 1). A range of 56–340 cows with assorted sensors from 24 to 313 days in milk (DIM) were modeled to evaluate associations with DIM, parity, and contemporary group (CG; comprised of pen and study cohort). Models extending upon these variables included known energy sinks (i.e., milk production, milk fat/protein and metabolic body weight), to characterize the association of sensors measures and DMI. Statistically significant (i.e., P < 0.05) regression coefficients for individual sensor measures with DMI ranged from 9.01E-07 to −3.45 kg DMI/day. When integrating all measures from a single sensor in a model, estimated regression coefficients ranged 8.83E-07 to −3.48 kg DMI/day. Significant associations were also identified for milk production traits, parity, DIM and CG. Associations tended to be highest for timepoints around the time of feeding and when multiple measurements within a sensor were integrated in a single model. The findings of this study indicate sensor measures are associated with feed intake and other energy sink traits and variables impacting feed efficiency. This information would be helpful to improve feed and feeding efficiency on commercial farms as proxy measurements for feed intake.

ObjectivePrevalence of type 2 diabetes (T2D) is disproportionately higher in younger outwardly lean Asian Chinese compared to matched Caucasians. Susceptibility to T2D is hypothesised due to dysfunctional adipose tissue expansion resulting in adverse abdominal visceral and organ fat accumulation. Impact on early risk, particularly in individuals characterised by the thin-on-the-outside-fat-on-the-inside (TOFI) phenotype, is undetermined.MethodsSixty-eight women [34 Chinese, 34 Caucasian; 18–70 years; body mass index (BMI), 20–45 kg/m2] from the TOFI_Asia study underwent magnetic resonance imaging and spectroscopy to quantify visceral, pancreas, and liver fat. Total body fat was (TBF) assessed by dual-energy x-ray absorptiometry, and fasting blood biomarkers were measured. Ethnic comparisons, conducted using two-sample tests and multivariate regressions adjusted for age, % TBF and ethnicity, identified relationships between abdominal ectopic fat depots with fasting plasma glucose (FPG), insulin resistance (HOMA2-IR), and related metabolic clinical risk markers in all, and within ethnic groups.ResultsDespite being younger and of lower bodyweight, Chinese women in the cohort had similar BMI and % TBF compared to their Caucasian counterparts. Protective high-density lipoprotein cholesterol, total- and high-molecular weight adiponectin were significantly lower, while glucoregulatory glucagon-like peptide-1 and glucagon significantly higher, in Chinese. There were no ethnic differences between % pancreas fat and % liver fat. However, at low BMI, % pancreas and % liver fat were ∼1 and ∼2% higher in Chinese compared to Caucasian women. In all women, % pancreas and visceral adipose tissue had the strongest correlation with FPG, independent of age and % TBF. Percentage (%) pancreas fat and age positively contributed to variance in FPG, whereas % TBF, amylin and C-peptide contributed to IR which was 0.3 units higher in Chinese.ConclusionPancreas fat accumulation may be an early adverse event, in TOFI individuals, with peptides highlighting pancreatic dysfunction as drivers of T2D susceptibility. Follow-up is warranted to explore causality.

Vascular dementia (VaD) is thought to be the second most common cause of age-related dementia amongst the elderly. However, at present, there are no available disease-modifying therapies for VaD, probably due to insufficient understanding about the molecular basis of the disease. While the notion of metal dyshomeostasis in various age-related dementias has gained considerable attention in recent years, there remains little comparable investigation in VaD. To address this evident gap, we employed inductively coupled-plasma mass spectrometry to measure the concentrations of nine essential metals in both dry- and wet-weight hippocampal post-mortem tissue from cases with VaD (n = 10) and age-/sex-matched controls (n = 10). We also applied principal component analysis to compare the metallomic pattern of VaD in the hippocampus with our previous hippocampal metal datasets for Alzheimer’s disease, Huntington’s disease, Parkinson’s disease, and type-2 diabetes, which had been measured using the same methodology. We found substantive novel evidence for elevated hippocampal Na levels and Na/K ratios in both wet- and dry-weight analyses, whereas decreased K levels were present only in wet tissue. Multivariate analysis revealed no distinguishable hippocampal differences in metal-evoked patterns between these dementia-causing diseases in this study. Contrasting levels of Na and K in hippocampal VaD tissue may suggest dysfunction of the Na+/K+-exchanging ATPase (EC 7.2.2.13), possibly stemming from deficient metabolic energy (ATP) generation. These findings therefore highlight the potential diagnostic importance of cerebral sodium measurement in VaD patients.

Polyphenolic compounds are thought to show considerable promise for the treatment of various metabolic disorders, including type 2 diabetes mellitus (T2DM). This review addresses evidence from in vitro, in vivo, and clinical studies for the antidiabetic effects of certain polyphenolic compounds. We focus on the role of cytotoxic human amylin (hA) aggregates in the pathogenesis of T2DM, and how polyphenols can ameliorate this process by suppressing or modifying their formation. Small, soluble amylin oligomers elicit cytotoxicity in pancreatic islet β-cells and may thus cause β-cell disruption in T2DM. Amylin oligomers may also contribute to oxidative stress and inflammation that lead to the triggering of β-cell apoptosis. Polyphenols may exert antidiabetic effects via their ability to inhibit hA aggregation, and to modulate oxidative stress, inflammation, and other pathways that are β-cell-protective or insulin-sensitizing. There is evidence that their ability to inhibit and destabilize self-assembly by hA requires aromatic molecular structures that bind to misfolding monomers or oligomers, coupled with adjacent hydroxyl groups present on single phenyl rings. Thus, these multifunctional compounds have the potential to be effective against the pleiotropic mechanisms of T2DM. However, substantial further research will be required before it can be determined whether a polyphenol-based molecular entity can be used as a therapeutic for type 2 diabetes.

Alzheimer’s disease (AD) is a neurodegenerative disorder, accounting for at least two-thirds of dementia cases. A combination of genetic, epigenetic and environmental triggers is widely accepted to be responsible for the onset and development of AD. Accumulating evidence shows that oxidative stress and dysregulation of energy metabolism play an important role in AD pathogenesis, leading to neuronal dysfunction and death. Redox-induced protein modifications have been reported in the brain of AD patients, indicating excessive oxidative damage. Coenzyme A (CoA) is essential for diverse metabolic pathways, regulation of gene expression and biosynthesis of neurotransmitters. Dysregulation of CoA biosynthesis in animal models and inborn mutations in human genes involved in the CoA biosynthetic pathway have been associated with neurodegeneration. Recent studies have uncovered the antioxidant function of CoA, involving covalent protein modification by this cofactor (CoAlation) in cellular response to oxidative or metabolic stress. Protein CoAlation has been shown to both modulate the activity of modified proteins and protect cysteine residues from irreversible overoxidation. In this study, immunohistochemistry analysis with highly specific anti-CoA monoclonal antibody was used to reveal protein CoAlation across numerous neurodegenerative diseases, which appeared particularly frequent in AD. Furthermore, protein CoAlation consistently co-localized with tau-positive neurofibrillary tangles, underpinning one of the key pathological hallmarks of AD. Double immunihistochemical staining with tau and CoA antibodies in AD brain tissue revealed co-localization of the two immunoreactive signals. Further, recombinant 2N3R and 2N4R tau isoforms were found to be CoAlated in vitro and the site of CoAlation mapped by mass spectrometry to conserved cysteine 322, located in the microtubule binding region. We also report the reversible H2O2-induced dimerization of recombinant 2N3R, which is inhibited by CoAlation. Moreover, CoAlation of transiently expressed 2N4R tau was observed in diamide-treated HEK293/Pank1β cells. Taken together, this study demonstrates for the first time extensive anti-CoA immunoreactivity in AD brain samples, which occurs in structures resembling neurofibrillary tangles and neuropil threads. Covalent modification of recombinant tau at cysteine 322 suggests that CoAlation may play an important role in protecting redox-sensitive tau cysteine from irreversible overoxidation and may modulate its acetyltransferase activity and functional interactions.

Widespread elevations in brain urea have, in recent years, been reported in certain types of age-related dementia, notably Alzheimer’s disease (AD) and Huntington’s disease (HD). Urea increases in these diseases are substantive, and approximate in magnitude to levels present in uraemic encephalopathy. In AD and HD, elevated urea levels are widespread, and not only in regions heavily affected by neurodegeneration. However, measurements of brain urea have not hitherto been reported in Parkinson’s disease dementia (PDD), a condition which shares neuropathological and symptomatic overlap with both AD and HD. Here we report measurements of tissue urea from nine neuropathologically confirmed regions of the brain in PDD and post-mortem delay (PMD)-matched controls, in regions including the cerebellum, motor cortex (MCX), sensory cortex, hippocampus (HP), substantia nigra (SN), middle temporal gyrus (MTG), medulla oblongata (MED), cingulate gyrus, and pons, by applying ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Urea concentrations were found to be substantively elevated in all nine regions, with average increases of 3–4-fold. Urea concentrations were remarkably consistent across regions in both cases and controls, with no clear distinction between regions heavily affected or less severely affected by neuronal loss in PDD. These urea elevations mirror those found in uraemic encephalopathy, where equivalent levels are generally considered to be pathogenic, and those previously reported in AD and HD. Increased urea is a widespread metabolic perturbation in brain metabolism common to PDD, AD, and HD, at levels equal to those seen in uremic encephalopathy. This presents a novel pathogenic mechanism in PDD, which is shared with two other neurodegenerative diseases.

Several studies of Parkinson's disease (PD) have reported dysregulation of cerebral metals, particularly decreases in copper and increases in iron in substantia nigra (SN). However, few studies have investigated regions outside the SN, fewer have measured levels of multiple metals across different regions within the same brains, and there are no currently-available reports of metal levels in Parkinson's disease dementia (PDD). This study aimed to compare concentrations of nine essential metals across nine different brain regions in cases of PDD and controls. Investigated were: primary motor cortex (MCX); cingulate gyrus (CG); primary visual cortex (PVC); hippocampus (HP); cerebellar cortex (CB); SN; locus coeruleus (LC); medulla oblongata (MED); and middle temporal gyrus (MTG), thus covering regions with severe, moderate, or low levels of neuronal loss in PDD. Levels of eight essential metals and selenium were determined using an analytical methodology involving the use of inductively-coupled plasma mass spectrometry (ICP-MS), and compared between cases and controls, to better understand the extent and severity of metal perturbations. Findings were also compared with those from our previous study of sporadic Alzheimer's disease dementia (ADD), which employed equivalent methods, to identify differences and similarities between these conditions. Widespread copper decreases occurred in PDD in seven of nine regions (exceptions being LC and CB). Four PDD-affected regions showed similar decreases in ADD: CG, HP, MTG, and MCX. Decreases in potassium and manganese were present in HP, MTG and MCX; decreased manganese was also found in SN and MED. Decreased selenium and magnesium were present in MCX, and decreased zinc in HP. There was no evidence for increased iron in SN or any other region. These results identify alterations in levels of several metals across multiple regions of PDD brain, the commonest being widespread decreases in copper that closely resemble those in ADD, pointing to similar disease mechanisms in both dementias.