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Milk is a lipid-in-water emulsion with a primary role in the nutrition of newborns. Milk fat globules (MFGs) are a mixture of proteins and lipids with nutraceutical properties related to the milk fat globule membrane (MFGM), which protects them, thus preventing their coalescence. Human and bovine MFGM proteomes have been extensively characterized in terms of their formation, maturation, and composition. Here, we review the most recent comparative proteomic analyses of MFGM proteome, above all from humans and bovines, but also from other species. The major MFGM proteins are found in all the MFGM proteomes of the different species, although there are variations in protein expression levels and molecular functions across species and lactation stages. Given the similarities between the human and bovine MFGM and the bioactive properties of MFGM components, several attempts have been made to supplement infant formulas (IFs), mainly with polar lipid fractions of bovine MFGM and to a lesser extent with protein fractions. The aim is thus to narrow the gap between human breast milk and cow-based IFs. Despite the few attempts made to date, supplementation with MFGM proteins seems promising as MFGM lipid supplementation. A deeper understanding of MFGM proteomes should lead to better results.

Abstract Objectives While aberrations in the VHL gene and chromosome 3p resulting in clear cell renal cell carcinoma (CCRCC) are well established, we know that additional mutations in chromatin remodeling genes PBRM1, SETD2, and BRCA1-associated protein 1 (BAP1) contribute to pathogenesis in some cases. Given the known aggressive clinical behavior of BAP1-mutated CCRCC, we sought to define the pathologic phenotype of BAP1-mutated CCRCC. Methods We identified 14 cases of molecularly proven BAP1-mutated CCRCC and investigated their clinicopathologic features. Results BAP1-mutated CCRCC frequently showed papillary, tubulopapillary, or expanded nested architecture; demonstrated granular to diffusely eosinophilic cytoplasm with prominent eosinophilic globules; and contained high-grade nuclei. This morphology demonstrates significant overlap with Xp11 translocation renal cell carcinoma (RCC). Immunohistochemistry notably demonstrates loss of BAP1 expression in almost all tumors, in addition to strong p504S expression. A conventional CCRCC component was frequently present adjacent to the characteristic BAP1 areas and showed retained BAP1 expression and only patchy p504S. Approximately two-thirds of BAP1-mutated CCRCCs were stage pT3, renal vein invasion was common, and 50% developed metastases. Conclusions Herein, we describe the histologic and immunohistochemical findings in BAP1-mutated CCRCC, which has important implications for utilization of molecular testing, prognosis, future therapeutics, and distinction from other RCC subtypes such as Xp11 translocation RCC.

As the methodologies available for the detection of positive selection from genomic data vary in terms of assumptions and execution, weak correlations are expected among them. However, if there is any given signal that is consistently supported across different methodologies, it is strong evidence that the locus has been under past selection. In this paper, a straightforward frequentist approach based on the Stouffer Method to combine P -values across different tests for evidence of recent positive selection in common variations, as well as strategies for extracting biological information from the detected signals, were described and applied to high density single nucleotide polymorphism (SNP) data generated from dairy and beef cattle (taurine and indicine). The ancestral Bovinae allele state of over 440,000 SNP is also reported. Using this combination of methods, highly significant (P <3.17×10 −7) population-specific sweeps pointing out to candidate genes and pathways that may be involved in beef and dairy production were identified. The most significant signal was found in the Cornichon homolog 3 gene (CNIH3) in Brown Swiss (P = 3.82×10 −12), and may be involved in the regulation of pre-ovulatory luteinizing hormone surge. Other putative pathways under selection are the glucolysis/gluconeogenesis, transcription machinery and chemokine/cytokine activity in Angus; calpain-calpastatin system and ribosome biogenesis in Brown Swiss; and gangliosides deposition in milk fat globules in Gyr. The composite method, combined with the strategies applied to retrieve functional information, may be a useful tool for surveying genome-wide selective sweeps and providing insights in to the source of selection.

Recently, camel milk (CM) has been considered as a health-promoting icon due to its medicinal and nutritional benefits. CM fat globule membrane has numerous health-promoting properties, such as anti-adhesion and anti-bacterial properties, which are suitable for people who are allergic to cow’s milk. CM contains milk fat globules with a small size, which accounts for their rapid digestion. Moreover, it also comprises lower amounts of cholesterol and saturated fatty acids concurrent with higher levels of essential fatty acids than cow milk, with an improved lipid profile manifested by reducing cholesterol levels in the blood. In addition, it is rich in phospholipids, especially plasmalogens and sphingomyelin, suggesting that CM fat may meet the daily nutritional requirements of adults and infants. Thus, CM and its dairy products have become more attractive for consumers. In view of this, we performed a comprehensive review of CM fat’s composition and nutritional properties. The overall goal is to increase knowledge related to CM fat characteristics and modify its unfavorable perception. Future studies are expected to be directed toward a better understanding of CM fat, which appears to be promising in the design and formulation of new products with significant health-promoting benefits.

Background Standard procedures for milk sample collection for transcriptome analysis use ice as preservation method, which can affect the RNA stability and requires immediate sample processing. These problems would be eased if the milk samples could be snap-frozen in liquid nitrogen. This study describes the applicability of a new method for milk sample collection and subsequent RNA extraction from milk fat globules, determining whether the quality, integrity and quantity of the RNA extracts met the minimum requirements for downstream RNA-seq. Results The quality of the extracts measured by A 260/280 ratio and the Integrity and Quality (IQ) values obtained fulfilled the reference values of 1.9 - 2.1 ( P1  < 0.05 and P2  < 0.05) and ≥ 9 ( P  < 0.05), respectively. However, the RNA Integrity Number (RIN), based on rRNA 18S and 28S analysis, was 3.59 ( P  > 0.05) and failed to meet the RIN ≥ 7 benchmark for RNA-seq ( P  > 0.05). Milk fat globules contain low molecular-weight RNA fragments and minimal 18S and 28S rRNA, suggesting low RIN values were inherent to sample type. Likewise, the RNA concentration from milk fat globules were generally low (120.43 ± 22.27 ng/µL, 102.87 ± 15.64 ng/µL and 109.43 ± 22.69 ng/µL, measured by Nanodrop, Qubit HS and QuanTI Ribogreen, respectively). Nevertheless, RNA-seq yielded 52.7 million paired-end reads per sample. The raw reads passed all quality control parameters having the same sequence-read lengths (151 bp), 100% base-coverage, 49% GC base content, and base quality scores of 36, enabling successful transcriptome profiling. Moreover, milk proteins were identified as the most abundant transcripts in MFG in the analysis of the most expressed genes, indicating that the sequenced reads would accurately reflect the transcriptome of this milk fraction. Conclusions Milk preservation in liquid nitrogen is a suitable sample collection method that overcomes the limitations of immediate sample processing required if ice is used. Thus, this procedure, together with the subsequent RNA isolation from milk fat globules and its sequencing by RNA-seq, would provide a practical and a non-invasive method for measuring the mammary epithelial cell transcriptome, improving the feasibility of conducting studies related to mammary gland and lactation physiology.

How do proteins fold, and why do they fold in that way? This Perspective integrates earlier and more recent advances over the 50-y history of the protein folding problem, emphasizing unambiguously clear structural information. Experimental results show that, contrary to prior belief, proteins are multistate rather than two-state objects. They are composed of separately cooperative foldon building blocks that can be seen to repeatedly unfold and refold as units even under native conditions. Similarly, foldons are lost as units when proteins are destabilized to produce partially unfolded equilibrium molten globules. In kinetic folding, the inherently cooperative nature of foldons predisposes the thermally driven amino acid-level search to form an initial foldon and subsequent foldons in later assisted searches. The small size of foldon units, ∼20 residues, resolves the Levinthal time-scale search problem. These microscopic-level search processes can be identified with the disordered multitrack search envisioned in the “new view” model for protein folding. Emergent macroscopic foldon–foldon interactions then collectively provide the structural guidance and free energy bias for the ordered addition of foldons in a stepwise pathway that sequentially builds the native protein. These conclusions reconcile the seemingly opposed new view and defined pathway models; the two models account for different stages of the protein folding process. Additionally, these observations answer the “how” and the “why” questions. The protein folding pathway depends on the same foldon units and foldon–foldon interactions that construct the native structure.

[Display omitted] •The diameter of fat globules in infant formulas was not similar to human milk.•The fatty acid profile of infant formulas was not similar to human milk.•Starter Infant Formula presented a diameter of fat globules closer to human milk. The lipid fraction, fatty acid profile, and diameter of fat globules of infant formulas show great differences from human milk. These characteristics influence fat digestion and, consequently, the development and health of infants. The aim of this study was to evaluate the diameter of fat globules in infant formulas and compare them with those in human milk. The diameter of fat globules of 10 infant formulas and human milk samples was determined using scanning electron microscopy. The starter infant formula was the only one that showed a mean diameter value (3.52 ± 2.17 µm) similar to that obtained for human milk (3.44 ± 1.68 µm). The starter infant formula showed the highest values of volume-surface D3,2 (6.13 µm) and volume-weighted D4,3, (7.05 µm) mean diameters among the infant formulas analyzed, and close to those obtained for the human milk sample (5.16 and 5.98 µm, respectively). The infant formulas whey protein partially hydrolyzed, soy protein isolate-based, whey protein extensively hydrolyzed, and thickened with pregelatinized starch had the lowest mean diameters of fat globules 0.64 ± 0.22, 0.70 ± 0.19, 1.06 ± 0.34, and 1.22 ± 0.48 µm, respectively. The analysis of principal components showed that none of the analyzed infant formulas had similarity with the diameter of fat globules and the fatty acid profile of human milk.

The most commonly occurring intrinsically disordered proteins (IDPs) are polyampholytes, which are defined by the duality of low net charge per residue and high fractions of charged residues. Recent experiments have uncovered nuances regarding sequence–ensemble relationships of model polyampholytic IDPs. These include differences in conformational preferences for sequences with lysine vs. arginine and the suggestion that well-mixed sequences form a range of conformations, including globules, conformations with ensemble averages that are reminiscent of ideal chains, or self-avoiding walks. Here, we explain these observations by analyzing results from atomistic simulations. We find that polyampholytic IDPs generally sample two distinct stable states, namely, globules and self-avoiding walks. Globules are favored by electrostatic attractions between oppositely charged residues, whereas self-avoiding walks are favored by favorable free energies of hydration of charged residues. We find sequence-specific temperatures of bistability at which globules and self-avoiding walks can coexist. At these temperatures, ensemble averages over coexisting states give rise to statistics that resemble ideal chains without there being an actual counterbalancing of intrachain and chain-solvent interactions. At equivalent temperatures, arginine-rich sequences tilt the preference toward globular conformations whereas lysine-rich sequences tilt the preference toward self-avoiding walks. We also identify differences between aspartate- and glutamate-containing sequences, whereby the shorter aspartate side chain engenders preferences for metastable, necklace-like conformations. Finally, although segregation of oppositely charged residues within the linear sequence maintains the overall two-state behavior, compact states are highly favored by such systems.

The formation of volatile-rich phases in magmatic sulfide systems has been interpreted at least in six different ways. The most popular model attributes their origin to secondary processes, mostly due to the presence of serpentine, chlorite, phlogopite, amphibole, and calcite. While chlorite and serpentine are likely to form as alteration products, the other volatile-rich minerals have the potential to originate in a range of ways, including by primary magmatic processes. Based on mineralogical and petrological studies, it was recently suggested that volatile- and incompatible element-rich halos around sulfide globules may form due to the interaction between three immiscible liquids: silicate, carbonate, and sulfide. This hypothesis was confirmed by experimental data revealing the systematic envelopment of sulfide globules by carbonate melt, indicating their mutual affinity. In this study, we present data on isotopic signatures and trace element distributions of three minerals commonly found in spatial association with sulfides—calcite, apatite, and zircon—to address the question of the source and nature of volatiles and other incompatible elements involved in the formation of the halos. Here we compare our new hypothesis with all the previously proposed explanations to show if they can be consistent with obtained results. Our findings indicate that both mantle and crustal sources play a role in the formation of volatile- and incompatible element-rich halos, strongly correlating with sulfur isotope data previously reported for the sulfide globules in the same intrusions. This correlation confirms the shared origin of sulfides, carbonate and fluids during ore-forming processes, ruling out the secondary origin of volatile-rich phases. The isotope and trace element signatures support the newly proposed hypothesis that volatile- and incompatible element-rich halos could have been formed due to the interaction of immiscible sulfide, carbonate, and silicate melts. The volatile-rich carbonate melt could be sourced from the mantle or it could be added from the crust. Regardless of the origin, carbonate melt and sulfide liquid both immiscible with mafic magma tend to stick to each other resulting in the formation of volatile- and incompatible element-rich halos commonly documented in magmatic sulfide deposits.

The Devonian Rudniy intrusion is a composite magmatic body comprising two gabbroid units. Located in the Tsagaan-Shuvuut ridge in NW Mongolia, it is the only one known to contain disseminated sulfide Ni-Cu-PGE minerals out of numerous gabbroid intrusions surrounding the Tuva depression. The ore occurs as disseminated sulfide globules made of pyrrhotite, pentlandite, chalcopyrite, and cubanite, confined to a narrow troctolitic layer at the margins of a melanogabbro, at the contact with a previously emplaced leucogabbro. Globules generally display mantle-dominated sulfur isotopic signatures but show variable metallogenic and mineralogical characteristics, as well as notably different sizes and morphologies reflecting variable cooling and crystallization regimes in different parts of the intrusion. Sulfides from the chilled margin of the melanogabbro are surrounded and intergrown with volatile-rich (i.e., CO2-, H2O-, F-, and Cl) phases such as calcite, chlorite, mica, amphibole, and apatite. Based on the mineralogical and textural relationships of volatile-rich phases with sulfides, we argue that this assemblage represents the product of the crystallization of volatile-rich carbonate melt immiscible with both silicate and sulfide liquids. We put forward the hypothesis that volatile-rich carbonate melt envelops sulfide droplets facilitating their transport in magmatic conduits and that this process may be more widespread than commonly thought. The smaller sulfide globules, which are interpreted to derive from the breakup of larger globules during transport and emplacement, do not display an association with volatile-rich phases, suggesting that the original carbonate melt could have been detached from them during the evolution of the magmatic system. Variable rates of crystallization may have been responsible for the observed disparities in the mineralogical and metallogenic characteristics of different sulfide globules entrained in the Rudniy intrusion.