Proteomic networks of gray and white matter reveal tissue-specific changes in human tauopathy.

OBJECTIVE: To define tauopathy-associated changes in the human gray and white matter proteome. METHOD: We applied tandem mass tagged labeling and mass spectrometry, consensus, and ratio weighted gene correlation network analysis (WGCNA) to gray and white matter sampled from postmortem human dorsolateral prefrontal cortex. The sampled tissues included control as well as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal degeneration with tau pathology, and chronic traumatic encephalopathy. RESULTS: Only eight proteins were unique to gray matter while six were unique to white matter. Comparison of the gray and white matter proteome revealed an enrichment of microglial proteins in the white matter. Consensus WGCNA sorted over 6700 protein isoforms into 46 consensus modules across the gray and white matter proteomic networks. Consensus network modules demonstrated unique and shared disease-associated microglial and endothelial protein changes. Ratio WGCNA sorted over 6500 protein ratios (white:gray) into 33 modules. Modules associated with mitochondrial proteins and processes demonstrated higher white:gray ratios in diseased tissues relative to control, driven by mitochondrial protein downregulation in gray and upregulation in white. INTERPRETATION: The dataset is a valuable resource for understanding proteomic changes in human tauopathy gray and white matter. The identification of unique and shared disease-associated changes across gray and white matter emphasizes the utility of examining both tissue types. Future studies of microglial, endothelial, and mitochondrial changes in white matter may provide novel insights into tauopathy-associated changes in human brain.

The Association of Oral Processing Factors and Nutrient Intake in Community-Dwelling Older Adults: A Systematic Review and Meta-Analysis.

CONTEXT: Oral health and food oral-processing issues emerge with functional decline in the older adult population, potentially increasing the risk of malnutrition. Impairment of oral health is associated with poorer nutrition status; however, the relationship between oral factors and the intake of each nutrient remains poorly understood. OBJECTIVE: The associations between different oral factors and nutrient intakes among community-dwelling older adults were investigated. DATA SOURCES: A literature search from 5 databases (Web of Science, Scopus, Cochrane Library, Ovid [MEDLINE and Embase], and CINAHL) was completed on February 1, 2022. The search was limited to peer-reviewed articles published between the years 2012 and 2022. DATA EXTRACTION: Six cross-sectional studies were included in the meta-analysis. Two authors independently completed the data extraction and summarized the study characteristics, factors adjusted for in the statistical analysis, the outcome, and summary statistics of the results. DATA ANALYSIS: Meta-analyses showed evidence of a significant association between compromised oral factors (namely, denture status, chewing ability, and the number of teeth) with lower energy (weighted mean difference [WMD], -107 kcal d-1 (95% CI, -132 to -81), protein (WMD, -5.2 g d-1; 95% CI, -6.6 to -3.8), fat (WMD, -4.6 g d-1; 95% CI, -6.7 to -2.6), carbohydrate (WMD, -8.8 g d-1; 95% CI, -13.9 to -3.7), and vitamin C intakes (WMD, -12.9 mg d-1; 95% CI, -16.6 to -9.2) in older adults. CONCLUSION: Oral health can be an indicator of compromised daily energy, protein, fat, carbohydrate, and vitamin C intakes in older adults. However, the small sample size of the studies included in this review and the heterogeneity among macronutrient studies should be considered. Because of the lack of studies covering all aspects of food oral processing (eg, salivary flow rate, tongue pressure), the associations between oral processing and nutrient intake were not thoroughly explored. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no. CRD42022308823.

The impact of school-based cooking classes on vegetable intake, cooking skills and food literacy of children aged 4-12 years: A systematic review of the evidence 2001-2021.

BACKGROUND: Many children consume a poor quality diet with only a third of children aged 6-9 years eating vegetables daily. A high quality diet is important for good health in childhood; however, the prevalence of children living with obesity has doubled from 10% to 23% during primary school in the UK. Cooking lessons have the potential to improve diet quality and reduce obesity prevalence in childhood, both of which are associated with improved cardiometabolic outcomes in adulthood. The aim of this systematic review is to investigate the impact of school-based cooking classes on cooking skills, food literacy and vegetable intake of children aged 4-12 years. METHODS: We conducted a systematic review of OVID Medline, OVID Embase, EBSCO CINHAL and EBSCO ERIC for comparative studies that evaluated outcomes of children receiving cooking classes compared to a control group. Interventions included contained food preparation or a cooking activities and took place on school premises. Risk of bias was assessed using ROB2 and Robins-I. Outcomes were pooled in a meta-analysis using a random-effects model using standardised mean differences or reviewed using narrative synthesis. Certainty of evidence was assessed using GRADE. RESULTS: We included 21 studies, (6 randomised). Meta-analysis showed a small positive effect on cooking self-efficacy of 0.39 units (95% CI 0.05 to 0.54), and a small positive effect on vegetable intake of 0.25 units (95% CI 0.05 to 0.45). Programmes with more than 6 h of cooking showed the greatest effects. CONCLUSIONS: Children's cooking programmes result in small improvements in cooking efficacy and vegetable intake, particularly those with more than 6 h of classes. It is recommended that future interventions use consistent measurement for children's food literacy and cooking confidence.

Synthetically accessible de novo design using reaction vectors: Application to PARP1 inhibitors.

De novo design has been a hotly pursued topic for many years. Most recent developments have involved the use of deep learning methods for generative molecular design. Despite increasing levels of algorithmic sophistication, the design of molecules that are synthetically accessible remains a major challenge. Reaction-based de novo design takes a conceptually simpler approach and aims to address synthesisability directly by mimicking synthetic chemistry and driving structural transformations by known reactions that are applied in a stepwise manner. However, the use of a small number of hand-coded transformations restricts the chemical space that can be accessed and there are few examples in the literature where molecules and their synthetic routes have been designed and executed successfully. Here we describe the application of reaction-based de novo design to the design of synthetically accessible and biologically active compounds as proof-of-concept of our reaction vector-based software. Reaction vectors are derived automatically from known reactions and allow access to a wide region of synthetically accessible chemical space. The design was aimed at producing molecules that are active against PARP1 and which have improved brain penetration properties compared to existing PARP1 inhibitors. We synthesised a selection of the designed molecules according to the provided synthetic routes and tested them experimentally. The results demonstrate that reaction vectors can be applied to the design of novel molecules of biological relevance that are also synthetically accessible.

Risk of hip fracture in meat-eaters, pescatarians, and vegetarians: a prospective cohort study of 413,914 UK Biobank participants.

BACKGROUND: Meat-free diets may be associated with a higher risk of hip fracture, but prospective evidence is limited. We aimed to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UK Biobank, and to explore the role of potential mediators of any observed risk differences. METHODS: Middle-aged UK adults were classified as regular meat-eaters (n = 258,765), occasional meat-eaters (n = 137,954), pescatarians (n = 9557), or vegetarians (n = 7638) based on dietary and lifestyle information at recruitment (2006-2010). Incident hip fractures were identified by record linkage to Hospital Episode Statistics up to September 2021. Multivariable Cox regression models were used to estimate associations between each diet group and hip fracture risk, with regular meat-eaters as the reference group, over a median follow-up time of 12.5 years. RESULTS: Among 413,914 women, 3503 hip fractures were observed. After adjustment for confounders, vegetarians (HR (95% CI): 1.50 (1.18, 1.91)) but not occasional meat-eaters (0.99 (0.93, 1.07)) or pescatarians (1.08 (0.86, 1.35)) had a greater risk of hip fracture than regular meat-eaters. This is equivalent to an adjusted absolute risk difference of 3.2 (1.2, 5.8) more hip fractures per 1000 people over 10 years in vegetarians. There was limited evidence of effect modification by BMI on hip fracture risk across diet groups (pinteraction = 0.08), and no clear evidence of effect modification by age or sex (pinteraction = 0.9 and 0.3, respectively). Mediation analyses suggest that BMI explained 28% of the observed risk difference between vegetarians and regular meat-eaters (95% CI: 1.1%, 69.8%). DISCUSSION: Vegetarian men and women had a higher risk of hip fracture than regular meat-eaters, and this was partly explained by their lower BMI. Ensuring adequate nutrient intake and weight management are therefore particularly important in vegetarians in the context of hip fracture prevention. TRIAL REGISTRATION: NCT05554549, registered retrospectively.

Maternal Iodine Status and Birth Outcomes: A Systematic Literature Review and Meta-Analysis.

Background & aims: Iodine is important for thyroid function during pregnancy to support fetal growth, but studies of maternal iodine status and birth outcomes are conflicting. We aimed to quantify the association between iodine status and birth outcomes, including potential threshold effects using nonlinear dose−response curves. Methods: We systematically searched Medline and Embase to 10 October 2022 for relevant cohort studies. We conducted random-effects meta-analyses of urinary iodine concentration (UIC), iodine:creatinine ratio (I:Cr), and iodide intake for associations with birth weight, birth weight centile, small for gestational age (SGA), preterm delivery, and other birth outcomes. Study quality was assessed using the Newcastle-Ottawa scale. Results: Meta-analyses were conducted on 23 cohorts with 42269 participants. Birth weight was similar between UIC ≥ 150 µg/L and <150 µg/L (difference = 30 g, 95% CI −22 to 83, p = 0.3, n = 13, I2 = 89%) with no evidence of linear trend (4 g per 50 µg/L, −3 to 10, p = 0.2, n = 12, I2 = 80%). I:Cr was similar, but with nonlinear trend suggesting I:Cr up to 200 µg/g associated with increasing birthweight (p = 0.02, n = 5). Birthweight was 2.0 centiles (0.3 to 3.7, p = 0.02, n = 4, I2 = 0%) higher with UIC ≥ 150 µg/g, but not for I:Cr. UIC ≥ 150 µg/L was associated with lower risk of SGA (RR = 0.85, 0.75 to 0.96, p = 0.01, n = 13, I2 = 0%), but not with I:Cr. Conclusions: The main risk of bias was adjustment for confounding, with variation in urine sample collection and exposure definition. There were modest-sized associations between some measures of iodine status, birth weight, birth weight centile, and SGA. In pregnancy, we recommend that future studies report standardised measures of birth weight that take account of gestational age, such as birth weight centile and SGA. Whilst associations were modest-sized, we recommend maintaining iodine sufficiency in the population, especially for women of childbearing age on restricted diets low in iodide.

Nutritional strategies to optimise musculoskeletal health for fall and fracture prevention: Looking beyond calcium, vitamin D and protein.

Falls and osteoporotic fractures are a major public health problem, particularly among older adults. A third of individuals aged 65 years and over fall at least once each year, with up to 20 % of these resulting in serious injury, including fracture. In conjunction with regular exercise, the importance of diet for musculoskeletal health has largely focused upon calcium, vitamin D, and protein, particularly in the context of preventing falls and fractures. Whilst there is evidence for the benefits of these nutrients for musculoskeletal health, other aspects of the diet remain largely underexplored. For example, vegetables are rich sources of macro- and micronutrients that are essential for muscle function and bone health, which are key factors in the prevention of falls and fractures. Recent work has highlighted the importance of nutrients such as vegetable-derived nitrate and vitamin K1 in optimising muscle strength, physical function, and bone quality. In the context of dietary patterns, vegan/plant-based diets have recently gained popularity due to perceived health benefits, animal welfare, or to tackle climate change. The elimination and/or substitution of animal-based products for plant foods (without careful planning and/or expert dietary guidance) could, however, have long-term negative musculoskeletal consequences; a trend uncovered by recent evidence. Within the overarching theme of nutrition for fall and fracture prevention in older populations, the aim of this review is to (i) summarise the current evidence for calcium, vitamin D and protein; (ii) describe the importance of vegetables and selected nutrients, such as nitrate and vitamin K1, for muscle function and bone structural integrity; and (iii) highlight current evidence around different dietary patterns (e.g., plant-based, diet quality, data driven approaches) and their impact on musculoskeletal health.

Foods, nutrients and hip fracture risk: A prospective study of middle-aged women.

BACKGROUND AND AIMS: Hip fracture affects 1.6 million people globally each year, and increases morbidity and mortality. There is potential for risk reduction through diet modification, but prospective evidence for associations between intake of several foods and nutrients and hip fracture risk is limited. This study aimed to investigate associations between food and nutrient intakes and hip fracture risk in the UK Women's Cohort Study, and to determine the role of body mass index (BMI) as a potential effect modifier. METHODS: Dietary, lifestyle, anthropometric, and socio-economic information of UK women, ages 35-69 years, were collected in a survey at recruitment (1995-1998), and included a validated 217-item food frequency questionnaire. Hip fracture cases were identified by linking participant data at recruitment with their Hospital Episode Statistics (HES) up to March 2019. Cox regression models were used to estimate associations between standard portions of food and nutrient intakes and hip fracture risk over a median follow-up time of 22.3 years. RESULTS: Among 26,318 women linked to HES data (556,331 person-years), 822 hip fracture cases were identified. After adjustment for confounders, every additional cup of tea or coffee per day was associated with a 4% lower risk of hip fracture (HR (95% CI): 0.96 (0.92, 1.00)). A 25 g/day increment of dietary protein intake was also associated with a 14% lower risk of hip fracture (0.86 (0.73, 1.00)). In subgroup analyses, BMI modified linear associations between dietary intakes of protein, calcium, total dairy, milk, and tea and hip fracture risk (pinteraction = 0.02, 0.002, 0.003, 0.001, and 0.003, respectively); these foods and nutrients were associated with a reduced risk of hip fracture in underweight but not healthy or overweight participants. In particular, risk of hip fracture in underweight participants (28 cases, 545 participants) was 45% lower for every 25 g/day protein consumed (0.55 (0.38, 0.78)). CONCLUSIONS: This is the first prospective cohort study internationally of multiple food and nutrient intakes in relation to hip fracture risk by BMI using linkage to hospital records. Results suggest that the potential roles of some foods and nutrients in hip fracture prevention, particularly protein, tea and coffee in underweight women, merit confirmation. PROTOCOL REGISTRATION: Clinicaltrials.gov NCT05081466.

Risk of hip fracture in meat-eaters, pescatarians, and vegetarians: results from the UK Women's Cohort Study.

BACKGROUND: The risk of hip fracture in women on plant-based diets is unclear. We aimed to investigate the risk of hip fracture in occasional meat-eaters, pescatarians, and vegetarians compared to regular meat-eaters in the UK Women's Cohort Study and to determine if potential associations between each diet group and hip fracture risk are modified by body mass index (BMI). METHODS: UK women, ages 35-69 years, were classified as regular meat-eaters (≥ 5 servings/week), occasional meat-eaters (< 5 servings/week), pescatarian (ate fish but not meat), or vegetarian (ate neither meat nor fish) based on a validated 217-item food frequency questionnaire completed in 1995-1998. Incident hip fractures were identified via linkage to Hospital Episode Statistics up to March 2019. Cox regression models were used to estimate the associations between each diet group and hip fracture risk over a median follow-up time of 22.3 years. RESULTS: Amongst 26,318 women, 822 hip fracture cases were observed (556,331 person-years). After adjustment for confounders, vegetarians (HR (95% CI) 1.33 (1.03, 1.71)) but not occasional meat-eaters (1.00 (0.85, 1.18)) or pescatarians (0.97 (0.75, 1.26)) had a greater risk of hip fracture than regular meat-eaters. There was no clear evidence of effect modification by BMI in any diet group (p-interaction = 0.3). CONCLUSIONS: Vegetarian women were at a higher risk of hip fracture compared to regular meat-eaters. Further research is needed to confirm this in men and non-European populations and to identify factors responsible for the observed risk difference. Further research exploring the role of BMI and nutrients abundant in animal-sourced foods is recommended. TRIAL REGISTRATION: ClinicalTrials.gov , NCT05081466.

Glial profiling of human tauopathy brain demonstrates enrichment of astrocytic transcripts in tau-related frontotemporal degeneration.

To understand how glia may be altered in frontotemporal degeneration with tau pathology (FTD-tau), we used a NanoString glial profiling panel to measure 770 transcripts related to glial biology in human control (n = 8), Alzheimer's disease (AD) (n = 8), and FTD-tau (n = 8) dorsolateral prefrontal cortex. Compared to control, 43 genes were upregulated and 86 genes were downregulated in the FTD-tau samples. Only 3 genes were upregulated and 2 were downregulated in AD. Pathway analysis revealed many astrocyte-, microglia-, and oligodendrocyte-related pathway scores increased in FTD-tau, while neuron-related pathway scores decreased. We compared these results to a previously published proteomic dataset containing many of the same samples and found that the targeted panel approach obtained measurements for genes whose proteins were not measured in the proteomics. Our results point to the utility of multiomic approaches and marked dysregulation of glia in FTD-tau.

Dairy farmers' perspectives on providing cow-calf contact in the pasture-based systems of New Zealand.

Separation of the cow and calf shortly after birth is a common practice on commercial dairy farms around the world, but there are emerging concerns about this practice among citizens and other stakeholders. Continuous improvement of on-farm management practices in collaboration with dairy sector stakeholders increases the likelihood that farming systems evolve in a way that is consistent with societal expectations. Few commercial dairy farms provide extended cow-calf contact, and there is little understanding of how dairy farmers view this practice. This study examined the views of New Zealand dairy farmers toward providing cow-calf contact, particularly the barriers to adopting such a system in a seasonal-calving pasture-based dairy system. Standard farm practice in New Zealand is to remove the calf from the cow around 24 h (but could be up to 48 h) after birth. These conventional farmers (n = 63) were randomly selected from the database of all dairy farmers in New Zealand and telephone-interviewed using a semistructured interview format. Their responses to questions about providing cow-calf contact (defined as contact beyond the standard practice of 48 h) were analyzed using thematic analysis. Three major themes of concern were identified by these farmers about providing cow-calf contact as follows: (1) poor animal welfare, especially the risk of mastitis in the dam, inadequate colostrum for the calf, increased stress from delayed separation, and lack of shelter for calves while outdoors with the cow; (2) increased labor and stress on staff; and (3) system-level changes required, including infrastructure and herd management. Many of these concerns stemmed from challenges related to the nature of large-scale seasonal-calving pasture-based dairy systems, where a large number of calves are born in a short period of time and may be exposed to inclement weather in late winter in some areas. Several small-scale farmers (n = 4) providing cow-calf contact for longer than standard practice of 48 h were also interviewed; all permitted contact for at least 4 wk. These farmers also felt that animal welfare and health were important, and that this was promoted in their cow-calf contact systems. Concerns about colostrum and mastitis, for example, were not raised by these farmers, but they did agree that additional infrastructure and shelter were important considerations for cow-calf contact systems. Some conventional farmers expressed cognitive dissonance in that they theoretically preferred cow-calf contact but could not see it being realistic or practical to implement. Farmers currently providing longer cow-calf contact may be a useful resource for better understanding of how practical and economical cow-calf contact systems could be adopted on commercial pastoral dairy farms.

RENATE: A Pseudo-retrosynthetic Tool for Synthetically Accessible de novo Design.

Reaction-based de novo design refers to the generation of synthetically accessible molecules using transformation rules extracted from known reactions in the literature. In this context, we have previously described the extraction of reaction vectors from a reactions database and their coupling with a structure generation algorithm for the generation of novel molecules from a starting material. An issue when designing molecules from a starting material is the combinatorial explosion of possible product molecules that can be generated, especially for multistep syntheses. Here, we present the development of RENATE, a reaction-based de novo design tool, which is based on a pseudo-retrosynthetic fragmentation of a reference ligand and an inside-out approach to de novo design. The reference ligand is fragmented; each fragment is used to search for similar fragments as building blocks; the building blocks are combined into products using reaction vectors; and a synthetic route is suggested for each product molecule. The RENATE methodology is presented followed by a retrospective validation to recreate a set of approved drugs. Results show that RENATE can generate very similar or even identical structures to the corresponding input drugs, hence validating the fragmentation, search, and design heuristics implemented in the tool.

Dietary risk factors for hip fracture in adults: An umbrella review of meta-analyses of prospective cohort studies.

AIM: To summarise the totality of evidence regarding dietary risk factors for hip fracture in adults, evaluating the quality of evidence, to provide recommendations for practice and further research. DESIGN: Systematic review of meta-analyses of prospective cohort studies. ELIGIBILITY CRITERIA: Systematic reviews with meta-analyses reporting summary risk estimates for associations between hip fracture incidence and dietary exposures including oral intake of a food, food group, beverage, or nutrient, or adherence to dietary patterns. INFORMATION SOURCES: Medline, Embase, Web of Science, and the Cochrane Library from inception until November 2020. DATA SYNTHESIS: The methodological quality of systematic reviews and meta-analyses was assessed using AMSTAR-2, and the quality of evidence for each association was assessed using GRADE. Results were synthesised descriptively. RESULTS: Sixteen systematic reviews were identified, covering thirty-four exposures, including dietary patterns (n = 2 meta-analyses), foods, food groups, or beverages (n = 16), macronutrients (n = 3), and micronutrients (n = 13). Identified meta-analyses included 6,282 to 3,730,424 participants with between 322 and 26,168 hip fractures. The methodological quality (AMSTAR-2) of all systematic reviews was low or critically low. The quality of evidence (GRADE) was low for an inverse association between hip fracture incidence and intake of fruits and vegetables combined (adjusted summary relative risk for higher vs lower intakes: 0.92 [95% confidence interval: 0.87 to 0.98]), and very low for the remaining thirty-three exposures. CONCLUSION: Dietary factors may play a role in the primary prevention of hip fracture, but the methodological quality of systematic reviews and meta-analyses was below international standards, and there was a lack of high-quality evidence. More long-term cohort studies reporting absolute risks and robust, well-conducted meta-analyses with dose-response information are needed before policy guidelines can be formed. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020226190.

Voluntary Oral Ingestion of a Sedative Prior to Euthanasia with CO2: Behavioural Responses of Mice.

Laboratory mice are commonly euthanised with carbon dioxide (CO2); however, there is ample evidence that this gas is aversive. Previous work suggests that sedation achieved via injection with benzodiazepines prior to CO2 administration could reduce aversive behaviours during euthanasia. We explored the potential of using a voluntarily ingested sedative (tiletamine-zolazepam, Zoletil®) prior to euthanasia. Male and female C57BL/6 mice were allocated into one of the five experimental groups, which differed in the dose of Zoletil: 0, 10, 20, 40, 80 or 100 mg/kg. A dose of 20 mg/kg was found to achieve mild sedation prior to euthanasia; mice which received this dose numerically reared and walked on the cage lid less, and showed ataxia, immobility and recumbency for longer than mice that received a lower dose. During euthanasia, mice that received 20 mg/kg showed fewer aversive responses to CO2. Doses of 40 to 100 mg/kg were associated with signs of moderate to severe sedation, but resulted in an incomplete intake of the sedative, which made the interpretation of the aversiveness to CO2 difficult. Voluntary oral administration of a sedative is an effective, affordable, and easy way to minimize the stress of mice to euthanasia with CO2.

Do Walking Distance and Time Away from the Paddock Influence Daily Behaviour Patterns and Milk Yield of Grazing Dairy Cows?

In pasture-based systems, cows may spend several hours away from the paddock and may also walk several kilometres to meet daily milking requirements; this could lead cows to experience time constraints for grazing, ruminating and lying time in the paddock. This study investigated how walking distance and time spent away from the paddock affected daily behavioural patterns (i.e., grazing, ruminating and lying time) and milk yield. Dairy cows were managed in three rotationally grazed groups (n = 29 cows each) on the same farm and milked twice daily. A triaxial ear tag accelerometer on each cow recorded daily duration of grazing and ruminating, and a leg-based accelerometer recorded the daily lying time, for 13 days. GPS collars on four cows per group recorded the daily walking distance and total time away from the paddock for the group. A mixed repeated measures model tested how time off-paddock and walking distance affected the daily behavioural patterns; age, breed, milk yield and maximum ambient temperature were used as covariates with group as the observational unit. A second similar model tested how these factors affected milk yield. Walking distance and time spent away from the paddock were not correlated. When daily walking distance increased (to a maximum of 4 km/d), cows spent more time grazing and less time ruminating, but lying time was not affected. This result may, in part, be related to the greater energy expenditure demands for walking longer distances and milk production. When time away from the paddock increased (to a maximum of 4 h/d), cows spent less time lying, but grazing and ruminating times were not affected. Milk yield was not affected by walking distance, but one of the groups experienced a lower milk yield when time away from the paddock was increased. This result suggests that, for some cows, lying times may be shorter when experiencing a longer time away from the paddock, which may also affect milk yield. Overall, this study indicates that paddock behaviours are associated with walking distance to the milking parlour and time spent away from the paddock. Efforts to reduce walking distance and time spent away from the paddock are likely to provide cows with greater opportunity to engage in daily behaviours in the paddock that meet their needs and maintain their milk yield.

Heart Rate and Heart Rate Variability Change with Sleep Stage in Dairy Cows.

Changes to the amount and patterns of sleep stages could be a useful tool to assess the effects of stress or changes to the environment in animal welfare research. However, the gold standard method, polysomnography PSG, is difficult to use with large animals such as dairy cows. Heart rate (HR) and heart rate variability (HRV) can be used to predict sleep stages in humans and could be useful as an easier method to identify sleep stages in cows. We compared the mean HR and HRV and lying posture of dairy cows at pasture and when housed, with sleep stages identified through PSG. HR and HRV were higher when cows were moving their heads or when lying flat on their side. Overall, mean HR decreased with depth of sleep. There was more variability in time between successive heart beats during REM sleep, and more variability in time between heart beats when cows were awake and in REM sleep. These shifts in HR measures between sleep stages followed similar patterns despite differences in mean HR between the groups. Our results show that HR and HRV measures could be a promising alternative method to PSG for assessing sleep in dairy cows.

A proteomic network approach resolves stage-specific molecular phenotypes in chronic traumatic encephalopathy.

BACKGROUND: There is an association between repetitive head injury (RHI) and a pathologic diagnosis of chronic traumatic encephalopathy (CTE) characterized by the aggregation of proteins including tau. The underlying molecular events that cause these abnormal protein accumulations remain unclear. Here, we hypothesized that identifying the human brain proteome from serial CTE stages (CTE I-IV) would provide critical new insights into CTE pathogenesis. Brain samples from frontotemporal lobar degeneration due to microtubule associated protein tau (FTLD-MAPT) mutations were also included as a distinct tauopathy phenotype for comparison. METHODS: Isobaric tandem mass tagged labeling and mass spectrometry (TMT-MS) followed by integrated differential and co-expression analysis (i.e., weighted gene co-expression network analysis (WGCNA)) was used to define modules of highly correlated proteins associated with clinical and pathological phenotypes in control (n = 23), CTE (n = 43), and FTLD-MAPT (n = 12) post-mortem cortical tissues. We also compared these findings to network analysis of AD brain. RESULTS: We identified over 6000 unique proteins across all four CTE stages which sorted into 28 WGCNA modules. Consistent with Alzheimer's disease, specific modules demonstrated reduced neuronal protein levels, suggesting a neurodegeneration phenotype, while other modules were increased, including proteins associated with inflammation and glial cell proliferation. Notably, unique CTE-specific modules demonstrated prominent enrichment of immunoglobulins, including IGHM and IGLL5, and extracellular matrix (ECM) proteins as well as progressive protein changes with increasing CTE pathologic stage. Finally, aggregate cell subtype (i.e., neurons, microglia, astrocytes) protein abundance levels in CTE cases were similar in expression to AD, but at intermediate levels between controls and the more exaggerated phenotype of FTLD-MAPT, especially in astrocytes. CONCLUSIONS: Overall, we identified thousands of protein changes in CTE postmortem brain and demonstrated that CTE has a pattern of neurodegeneration in neuronal-synaptic and inflammation modules similar to AD. We also identified unique CTE progressive changes, including the enrichment of immunoglobulins and ECM proteins even in early CTE stages. Early and sustained changes in astrocyte modules were also observed. Overall, the prominent overlap with FTLD-MAPT cases confirmed that CTE is on the tauopathy continuum and identified CTE stage specific molecular phenotypes that provide novel insights into disease pathogenesis.

Machine learning prediction of sleep stages in dairy cows from heart rate and muscle activity measures.

Sleep is important for cow health and shows promise as a tool for assessing welfare, but methods to accurately distinguish between important sleep stages are difficult and impractical to use with cattle in typical farm environments. The objective of this study was to determine if data from more easily applied non-invasive devices assessing neck muscle activity and heart rate (HR) alone could be used to differentiate between sleep stages. We developed, trained, and compared two machine learning models using neural networks and random forest algorithms to predict sleep stages from 15 variables (features) of the muscle activity and HR data collected from 12 cows in two environments. Using k-fold cross validation we compared the success of the models to the gold standard, Polysomnography (PSG). Overall, both models learned from the data and were able to accurately predict sleep stages from HR and muscle activity alone with classification accuracy in the range of similar human models. Further research is required to validate the models with a larger sample size, but the proposed methodology appears to give an accurate representation of sleep stages in cattle and could consequentially enable future sleep research into conditions affecting cow sleep and welfare.