As the world\'s population ages the prevalence of age-related health concerns is increasing, including neurodegeneration disorders such as mild cognitive impairment, vascular dementia and Alzheimer\'s disease. Diet is a key modifiable risk factor for the development of neurodegeneration, likely due to gut-brain axis interactions related to neuroinflammation. Analyses of dietary patterns identified dairy as being part of a cognitively healthy diet; however, its contribution to cognitive outcomes is difficult to discern. This narrative review evaluates the literature to determine whether there is sufficient evidence that the consumption of dairy products helps to maintain cognitive function in later life. A search using the terms (dairy OR milk OR cheese OR yogurt OR yogurt) AND (\"mild cognitive impairment\" OR dementia OR \"Alzheimer\'s disease\") identified 796 articles. After screening and sorting, 23 observational studies and 6 intervention studies were identified. The results of the observational studies implied that the relationship between total dairy consumption and cognitive outcomes is inverse U-shaped, with moderate consumption (1-2 servings per day) being the most beneficial. The analysis of the intake of different types of dairy products indicated that fermented products, particularly cheese, were most likely responsible for the observed benefits. The experimental studies all used dairy-derived peptides produced during fermentation as the dietary intervention, and the results indicated that these could be an effective treatment for early-stage cognitive impairment. Further experimental studies with whole dairy products, particularly fermented dairy, are needed to determine whether the regular consumption of these foods should be recommended to maximize the likelihood of healthy cognitive aging.

β-Casein, a major protein in cow\'s milk, is divided into the A1 and A2 type variants. Digestion of A1 β-casein yields the peptide β-casomorphin-7 which could cause gastrointestinal (GI) discomfort but A2 milk containing only A2 β-casein might be more beneficial than A1/A2 (regular) milk. The aim of this study was to evaluate the differences in GI discomfort after ingestion of A2 milk and A1/A2 milk. A randomized, double-blind, cross-over human trial was performed with 40 subjects who experienced GI discomfort following milk consumption. For each intervention period, either A2 milk first (A2→A1/A2) or A1/A2 milk was first consumed for 2 weeks (A1/A2→A2) following a 2-week washout period. GI symptom rating scale (GSRS) scores, questionnaire for digestive symptoms, and laboratory tests including fecal calprotectin were evaluated. For symptom analysis, generalized estimating equations gamma model was used. A2 milk increased bloating (P = 0.041) and loose stools (P = 0.026) compared to A1/A2 milk in GSRS. However, A2 milk caused less abdominal pain (P = 0.050), fecal urgency (P < 0.001) and borborygmus (P = 0.007) compared to A1/A2 milk in questionnaire for digestive symptoms. In addition, fecal calprotectin also decreased or less increased after consumption of A2 milk compared to A1/A2 milk (P = 0.030), and this change was more pronounced in males (P = 0.005) than in females. There were no significant adverse reactions during the trial. A2 milk alleviated digestive discomfort in Koreans following A2 milk consumption (ClinicalTrials.gov NCT06252636 and CRIS KCT0009301).

BACKGROUND: In the continuous endeavor to find safe and efficient treatments for Atopic Dermatitis (AD), there remains a considerable focus on dietary adjustments. Nevertheless, the limited availability of research and conflicting findings in the academic literature pose a hurdle in establishing conclusive recommendations.
METHODS: Mendelian randomization (MR) was applied to the most comprehensive genome-wide association studies (GWAS) data on tea intake (447 485), green tea intake (n = 64 949), flavored milk intake (n = 64 941), never eat eggs, dairy, wheat, sugar: Wheat products(n = 461 046), never eat eggs, dairy, wheat, sugar: Sugar or foods/drinks containing sugar (n = 461 046), never eat eggs, dairy, wheat, sugar: I eat all of the above (n = 461 046) and atopic dermatitis (n = 218 467). We used the inverse-variance weighted method (IVW) as the primary method.
RESULTS: The IVW analyses have demonstrated an increased tea intake was genetically associated with a reduced risk of AD (odds ratio [OR]: 0.646, 95% confidence interval [CI]: 0.430-0.968, p = 0.034). Furthermore, green tea intake was significantly negatively associated with AD (IVW OR: 0.986, 95% CI: 0.975-0.998; p = 0.024) in the IVW model. AD risk could be reduced by never eating wheat products (IVW OR: 8.243E-04, 95% CI: 7.223E-06-9.408E-02, p = 0.003). There was no association between never eating eggs, dairy, wheat, sugar: Sugar, or foods/drinks containing sugar, I eat all of the above and AD.
CONCLUSIONS: Our MR study suggests a causal relationship between tea intake, green tea intake, and the avoidance of eating wheat products with atopic dermatitis. Our findings recommend that preventing and managing atopic dermatitis may be achieved by never eating wheat products while increasing tea and green tea intake.

Reperfusion therapy is critical for saving heart muscle after myocardial infarction, but the process of restoring blood flow can itself exacerbate injury to the myocardium. This phenomenon is known as myocardial ischemia-reperfusion injury (MIRI), which includes oxidative stress, inflammation, and further cell death. microRNA-146a (miR-146a) is known to play a significant role in regulating the immune response and inflammation, and has been studied for its potential impact on the improvement of heart function after myocardial injury. However, the delivery of miR-146a to the heart in a specific and efficient manner remains a challenge as extracellular RNAs are unstable and rapidly degraded. Milk exosomes (MEs) have been proposed as ideal delivery platform for miRNA-based therapy as they can protect miRNAs from RNase degradation. In this study, the effects of miR-146a containing MEs (MEs-miR-146a) on improvement of cardiac function were examined in a rat model of MIRI. To enhance the targeting delivery of MEs-miR-146a to the site of myocardial injury, the ischemic myocardium-targeted peptide IMTP was modified onto the surfaces, and whether the modified MEs-miR-146a could exert a better therapeutic role was examined by echocardiography, myocardial injury indicators and the levels of inflammatory factors. Furthermore, the expressions of miR-146a mediated NF-κB signaling pathway-related proteins were detected by western blotting and qRT-PCR to further elucidate its mechanisms. MiR-146 mimics were successfully loaded into the MEs by electroporation at a square wave 1000 V voltage and 0.1 ms pulse duration. MEs-miR-146a can be up-taken by cardiomyocytes and protected the cells from oxygen glucose deprivation/reperfusion induced damage in vitro. Oral administration of MEs-miR-146a decreased myocardial tissue apoptosis and the expression of inflammatory factors and improved cardiac function after MIRI. The miR-146a level in myocardium tissues was significantly increased after the administration IMTP modified MEs-miR-146a, which was higher than that of the MEs-miR-146a group. In addition, intravenous injection of IMTP modified MEs-miR-146a enhanced the targeting to heart, improved cardiac function, reduced myocardial tissue apoptosis and suppressed inflammation after MIRI, which was more effective than the MEs-miR-146a treatment. Moreover, IMTP modified MEs-miR-146a reduced the protein levels of IRAK1, TRAF6 and p-p65. Therefore, IMTP modified MEs-miR-146a exerted their anti-inflammatory effect by inhibiting the IRAK1/TRAF6/NF-κB signaling pathway. Taken together, our findings suggested miR-146a containing MEs may be a promising strategy for the treatment of MIRI with better outcome after modification with ischemic myocardium-targeted peptide, which was expected to be applied in clinical practice in future.

BACKGROUND: Poor infant and child feeding practices, in combination with increased rates of infectious diseases, are the main immediate causes of malnutrition during the first two years of life. Non-breastfed children require milk and other dairy products, as they are rich sources of calcium and other nutrients. As far as our search is concerned, there is no evidence on the pooled magnitude and determinants of minimum milk feeding frequency among non-breastfed children in sub-Saharan Africa conducted using the most recent indicators for assessing infant and young child feeding practices published in 2021. Therefore, this study is intended to determine the magnitude and associated factors of minimum milk feeding frequency among non-breastfed children aged 6-23 months in sub-Saharan Africa using the most recent guideline and demographic and health survey dataset.
METHODS: Data from the most recent health and demographic surveys, which were carried out between 2015 and 2022 in 20 sub-Saharan African countries, were used. The study comprised a weighted sample consisting of 13,315 non-breastfed children between the ages of 6 and 23 months. STATA/SE version 14.0 statistical software was used to clean, recode, and analyze data that had been taken from DHS data sets. Utilizing multilevel mixed-effects logistic regression, the factors associated with the outcome variable were identified. Model comparison and fitness were assessed using deviance (-2LLR), likelihood ratio test, median odds ratio, and intra-class correlation coefficient. Finally, variables with a p-value < 0.05 and an adjusted odds ratio with a 95% confidence interval were declared statistically significant.
RESULTS: The pooled magnitude of minimum milk feeding frequency among non-breastfed children aged 6-23 months in sub-Saharan African countries was 12.39% (95% CI: 11.85%, 12.97%). Factors like maternal educational level [AOR = 1.61; 95% CI (1.35, 1.91)], marital status of the mother [AOR = 0.77; 95% CI (0.67, 0.89)], maternal working status [AOR = 0.80; 95% CI (0.71, 0.91)], media exposure [AOR = 1.50; 95% CI (1.27, 1.77)], wealth index [AOR = 1.21; 95% CI (1.03, 1.42)], place of delivery [AOR = 1.45; 95% CI (1.22, 1.72)], ANC visit attended during pregnancy [AOR = 0.49; 95% CI (0.39, 0.62)], PNC checkup [AOR = 1.57; 95% CI (1.40, 1.76)], child\'s age [AOR = 0.70; 95% CI (0.53, 0.93)], and residence [AOR = 2.15; 95% CI (1.87, 2.46)] were significantly associated with minimum milk feeding frequency.
CONCLUSIONS: In sub-Saharan Africa, the proportion of minimum milk feeding frequency among non-breastfed children aged between 6 and 23 months was low. The likelihood of minimum milk feeding frequency increases with high levels of education, unemployment, media exposure, rich wealth status, being unmarried, having a child born in a health facility, getting PNC checks, being between 6 and 8 months old, and living in an urban area. Hence, promoting women\'s education, increasing the economic status of the household, disseminating nutrition information through media, strengthening maternal health service utilization like health facility delivery and PNC services, and giving prior attention to mothers with older children and from rural areas are strongly recommended.

Isolation of extracellular vesicles (EV) has been developing rapidly in parallel with the interest in EVs. However, commonly utilized protocols may not suit more challenging sample matrixes and could potentially yield suboptimal results. Knowing and assessing the pitfalls of isolation procedure to be used, should be involved to some extent for EV analytics. EVs in cow milk are of great interest due to their abundancy and large-scale availability as well as their cross-species bioavailability and possible use as drug carriers. However, the characteristics of milk EVs overlap with those of other milk components. This makes it difficult to isolate and study EVs individually. There exists also a lack of consensus for isolation methods. In this study, we demonstrated the differences between various differential centrifugation-based approaches for isolation of large quantities of EVs from cow milk. Samples were further purified with gradient centrifugation and size exclusion chromatography (SEC) and differences were analyzed. Quality measurements were conducted on multiple independent platforms. Particle analysis, electron microscopy and RNA analysis were used, to comprehensively characterize the isolated samples and to identify the limitations and possible sources of contamination in the EV isolation protocols. Vesicle concentration to protein ratio and RNA to protein ratios were observed to increase as samples were purified, suggesting co-isolation with major milk proteins in direct differential centrifugation protocols. We demonstrated a novel size assessment of vesicles using a particle mobility analyzer that matched the sizing using electron microscopy in contrast to commonly utilized nanoparticle tracking analysis. Based on the standards of the International Society for Extracellular Vesicles and the quick checklist of EV-Track.org for EV isolation, we emphasize the need for complete characterization and validation of the isolation protocol with all EV-related work to ensure the accuracy of results and allow further analytics and experiments.

Breast milk is essential for facilitating the growth and development of infants and for providing immune protection against viral infections in the infant\'s airways. Yet, regulation of inflammation by milk components may be needed to reduce immune pathology. While milk-derived extracellular vesicles (EVs) are bestowed with immunomodulatory capacities, their role in bronchial epithelial barrier function and inflammation has not yet been examined. We hypothesised that during feeding, milk is not only ingested, but aerosols containing milk EVs are inhaled and locally delivered to the infant\'s airways to suppress aberrant inflammation. A bronchial epithelial model of viral infection was used to explore the direct effect of milk EVs on cellular barrier function and cytokine release during stimulation with a viral dsRNA analogue (Poly I:C). We demonstrate that milk EVs improved the dsRNA-mediated decrease in ionic barrier integrity, limited tight junction reorganisation and reduced inflammatory cytokine production (IL-6, IL-8 and TNF-α). This protective response was EV-mediated, could be successfully titrated and exhibited a time-dependent response. The results indicate that if EV-containing milk aerosols are inhaled during feeding, this may lead to protection of the airway integrity from adverse inflammatory effects.

Milk is a good source of nutrition but is also a source of allergenic proteins such as α-lactalbumin, β-lactoglobulin (BLG), casein, and immunoglobulins. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas technology has the potential to edit any gene, including milk allergens. Previously, CRISPR/Cas has been successfully employed in dairy cows and goats, but buffaloes remain unexplored for any milk trait. In this study, we utilized the CRISPR/Cas9 system to edit the major milk allergen BLG gene in buffaloes. First, the editing efficiency of designed sgRNAs was tested in fibroblast cells using the T7E assay and Sanger sequencing. The most effective sgRNA was selected to generate clonal lines of BLG-edited cells. Analysis of 15 single-cell clones, through TA cloning and Sanger sequencing, revealed that 7 clones exhibited bi-allelic (-/-) heterozygous, bi-allelic (-/-) homozygous, and mono-allelic (-/+) disruptions in BLG. Bioinformatics prediction analysis confirmed that non-multiple-of-3 edited nucleotide cell clones have frame shifts and early truncation of BLG protein, while multiple-of-3 edited nucleotides resulted in slightly disoriented protein structures. Somatic cell nuclear transfer (SCNT) method was used to produce blastocyst-stage embryos that have similar developmental rates and quality with wild-type embryos. This study demonstrated the successful bi-allelic editing (-/-) of BLG in buffalo cells through CRISPR/Cas, followed by the production of BLG-edited blastocyst stage embryos using SCNT. With CRISPR and SCNT methods described herein, our long-term goal is to generate gene-edited buffaloes with BLG-free milk.

Gut microbiomes of mammals carry a complex symbiotic assemblage of microorganisms. Feeding newborn infants milk from the mammary gland allows vertical transmission of the parental milk microbiome to the offspring\'s gut microbiome. This has benefits, but also has hazards for the host population. Using mathematical models, we demonstrate that biparental vertical transmission enables deleterious microbial elements to invade host populations. In contrast, uniparental vertical transmission acts as a sieve, preventing these invasions. Moreover, we show that deleterious symbionts generate selection on host modifier genes that keep uniparental transmission in place. Since microbial transmission occurs during birth in placental mammals, subsequent transmission of the milk microbiome needs to be maternal to avoid the spread of deleterious elements. This paper therefore argues that viviparity and the hazards from biparental transmission of the milk microbiome, together generate selection against male lactation in placental mammals.

Dairy production in the UK has undergone substantial restructuring over the last few decades. Farming intensification has led to a reduction in the total numbers of farms and animals, while the average herd size per holding has increased. These ever-changing circumstances have important implications for the health and welfare of dairy cows, as well as the overall business performance of farms. For decision-making in dairy farming, it is essential to understand the underlying causes of the inefficiencies and their relative impact. The investigation of yield gaps regarding dairy cattle has been focused on specific causes. However, in addition to the risk of overestimating the impact of a specific ailment, this approach does not allow understanding of the relative contribution to the total, nor does it allow understanding of how well-described that gap is in terms of underlying causes. Using the English and Welsh dairy sectors as an example, this work estimates the Loss Gap-composed of yield losses and health expenditure - using a benchmarking approach and scenario analysis. The Loss Gap was estimated by comparing the current performance of dairy herds as a baseline with that of scenarios where assumptions were made about the milk production of cows, production costs, market prices, mortality, and expenditure related to health events. A deterministic model was developed, consisting of an enterprise budget, in which the cow was the unit, with milking herd and young stock treated separately. When constraining milk production, the model estimated an annual Loss Gap of £148 to £227 million for the whole sector. The reduction in costs of veterinary services and medicines, alongside herd replacement costs, were important contributors to the estimate with some variation between the scenarios. Milk price had a substantial impact in the estimate, with revenue from milk yield representing more than 30% of the Loss Gap, when milk price was benchmarked against that of the top performing farms. This framework provides the boundaries for understanding the relative burden from specific causes in English and Welsh dairy cattle, ensuring that the sum of the estimated losses due to particular problem does not exceed the losses from all-causes, health or non-health related.