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Abstract HLA and disease studies by using single allele statistics have been fruitless during the last 40 years for explaining association pathogenesis of the associated diseases.Other approaches are necessary to untangle this puzzle. We aim to revisit complement alleleism in humans and primates for both studying MHC and disease association to complotypes and extended MHC haplotypes in order to also explain the positive directional selection of maintaining immune response genes (complement, MHC adaptive and MHC non-specific genes) that keeps these three type of genes together in a short chromosome stretch (MHC) for million years. These genes may be linked to conjointly avoid microbes attack and autoimmunity. In the present paper, it is obtained a new Bf chimpanzee allele, provisionaly named Patr-Bf*A:01,that differs from other Bf alleles by having CTG at eleventh codon of exon 2 in order to start the newly suggested methodology and explain functional and evolutionary MHC obscure aspects. Exons 1 to 6 of Ba fragment of Bf gene were obtained from chimpanzee. This new chimpanzee Factor B allele (Patr-Bf*A:01) is to be identical to a infrequent human Bf allele (SNP rs641153); it stresses the strong evolutive pressure upon certain alleles that are trans specific. It also may apply to MHC extended haplotipes which may conjointly act to start an adequate immune response. It is the first time that a complement MHC class III allele is described to undergo trans species evolution,in contrast to class I and class II alleles which had already been reported . Allelism of complement factors are again proposed for studying MHC complement genes, complotypes, and extended MHC haplotypes which may be more informative that single MHC marker studies.

The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual’s life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA’s real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as “microgenobiota”.

Abstract The contribution of migrated people from once green Sahara (about 10,000–6000 years bc) towards Mediterranean area had probably a double effect: both genetic and cultural connections have been described between Western Europe and North Africa. Sudanese populations from different ethnicities have been studied for HLA-A, -B, -DRB1 and -DQB1 antigens by a standard microlymphotoxicity method. Results found show that Nubians are genetically related with African Sub-Saharan populations and distant from other Sudanese tribes, who are closer to Mediterranean populations than to Sub-Saharan ones. This is concordant with other authors and meta-analysis data. Our present work is, to our knowledge, the first and only one HLA research that studies Sudanese people according to different Sudan ethnic groups: samples were collected before Sudan partition between North and South. A prehistoric genetic and peoples exchange between Africa and the Mediterranean basin may be observed and is supported with the results obtained in this Sudanese HLA study. However, demic diffusion model of agriculture and other anthropological traits from Middle East to West Europe/Maghreb do not exist: a more detailed Sahel and North African countries ancient and recent admixture studies are also being carried out which may clearer explain pastoralists/agriculture innovations origins in Eurafrican Mediterranean and Atlantic façade.

The Human Leukocyte Antigen (HLA) system contains a set of genes involved at many levels in the innate and adaptive immune response. Among the non-classical HLA class I genes, HLA-G stands out for the numerous studies about its pivotal role in regulating/modulating immune responses. Also, its involvement in extravillous cytotrophoblast function, viral infections, autoimmunity, and cancer has been extensively documented. The present study explores for the first time the relationship between natural alleles of HLA-G, rather than STSs, SNPs, or partial gene polymorphisms, and the development of gastric adenocarcinoma, by analyzing the genetic profile of a cohort of 40 Spanish patients with this type of tumor using DNA extracted from paired biopsies of tumoral and adjacent non-tumoral gastric tissue. Our results reveal a significant statistical relationship between the presence of the HLA-G*01:01:01 allele and the development of gastric cancer, while other common alleles such as -G*01:04 or -G*01:05N did not demonstrate a significant correlation. Studying the involvement of HLA genes in the development of many diseases is relevant to understanding their pathophysiology. However, the absence of specific mechanisms underlying these associations suggests that investigating complete HLA natural alleles' extended haplotypes or complotypes may offer a more precise and valuable approach to elucidating the association of HLA with the pathogenesis of disease. [ABSTRACT FROM AUTHOR]

ABSTRACT: Metabolic, circadian, sleep, and reproductive systems are integrated and reciprocally regulated, but the understanding of the mechanism is limited. To study this integrated regulation, the circadian timing system was disrupted by exposing late pregnant nonlactating (dry) cows to chronic shifts in the light-dark phase, and rhythms of body temperature and circulating cortisol (CORT), progesterone (P4), serotonin (5HT), melatonin (MEL), and growth hormone (GH) concentrations were measured. Specifically, across 2 identical studies (1 and 2), at 35 d before expected calving (BEC) multiparous cows were assigned to control (CON; n = 24) and exposed to 16 h light and 8 h dark or phase shift (PS; n = 24) treatments and exposed to 6-h light-dark phase shifts every 3 d until parturition. All cows were exposed to control lighting after calving. Blood samples were collected in the first study at 0600 h on d 35 BEC, d 21 BEC, and 2 d before calving, and d 0, 2, 9, 15, and 22 postpartum (PP). A subset of cows (n = 6/group) in study 1 was blood sampled every 4 h over 48 h beginning on d 23 BEC, 9 BEC, and 5 PP. Body temperature was measured every 30 min (n = 8–16/treatment) for 48 h at 23 BEC and 9 BEC in both studies; and at 14 PP and 60 PP only in study 2. Treatment did not affect levels of CORT, GH, or P4 at 0600 h, but overall level of 5HT was lower and MEL higher in PS cows across days sampled. A 2-component versus single-component cosinor model better described [>coefficient of determination (R2);

Background: Major Human Histocompatibility complex (MHC or HLA in humans) has been associated to autoimmune diseases. However, only statistical phenomenological and no pathogenetic description has been reached after decades. This shows that MHC single locus association studies are probably useless for HLA/diseases association. Extended HLA (class I and class II genes) haplotypes should also be studied conjointly with class III or complement alleles (complotypes). Complotypes in humans are defined as alleles belonging to C2, C4 and Bf (Factor B) genes/proteins (class III). Also, the placing of MHC class I and class II genes close together with complement genes from at least birds to humans shows existence of a strong selection to gather conjointly these loci that fight microbes, help self-maintenance and avoid autoimmunity. In this paper we aim to study Bf alleles in primates in order to rise again interest to study the role of Bf alleles together with other MHC genes in their physiopathology and evolution. Methods: Orangutan (Pongo pygmaeus, Popy) cell lines RNA from 6 different individuals were retrotranscribed, PCR amplified, cloned and DNA sequenced in order to study Bf alleles. Results: A Bf allele identical to that found in chimpanzee (Patr-Bf*A01) and human (rs641153) was found in two of the six studied orangutans: Popy-Bf*A01 and Popy-Bf*A02. This polymorphism is placed in Factor B codon 32 that defines BF*S and Bf*F proteins in man and produce Leu instead of Arg (Bf*S) or Gln (Bf*F). In addition, each new orangutan allele present synonymous differences with each other at codon 25: Popy-Bf*A01 shows ACG while Popy-Bf*A02 bears ACA, both codifying for Thr. Conclusions: The selection for about 15 million years (time gap of evolutionary appearance between orangutan and hominids) shows the importance of this particular allele conservation in immune and self defense in primates. The complotypes (Bf,C2 and C4 loci) alleles together with other MHC class I and Cass II loci alleles are often transmitted in block to the germinal line: this indicates that all specific alleles from the MHC different loci may work together to accomplish MHC functions. All MHC loci alleles should be studied together to unveil their physiopathology and also maintenance of specific alleles (like the one described in this paper) for so long time in evolution should be further studied in Bf and the other neighbouring complement loci (C2 and C4). [ABSTRACT FROM AUTHOR]

The relationship between microbiota and the immune system is complex and characterized by the ways in which microbiota directs immune function interactions, both innate and acquired and also keeps activating the immune system throughout an individual's life. In this respect, the human Major Histocompatibility Complex (MHC, referred to as HLA in humans) plays a crucial role and is also established in self-defense against microbes by presenting microbial-derived peptides to the immune cells. However, this assumption has some unclear aspects that should be investigated. For example, how is the microbiota shaped by microbe species diversity, quantity and functions of the immune system, as well as the role and molecular mechanisms of the HLA complex during this process. There are autoimmune diseases related to both HLA and specific microbiota changes or alterations, many of which are mentioned in the present review. In addition, the HLA peptide presenting function should be put in a framework together with its linkage to diseases and also with HLA compatibility necessary for transplants to be successful. These are still quite an enigmatically statistical and phenomenological approach, but no firm pathogenic mechanisms have been described; thus, HLA's real functioning is still to be fully unveiled. After many years of HLA single-genes studies, firm pathogenesis mechanisms underlying disease linkage have been discovered. Finally, microbiota has been defined as conformed by bacteria, protozoa, archaea, fungi, and viruses; notwithstanding, endogenous viral sequences integrated into the human genome and other viral particles (obelisks) recently found in the digestive mucosa should be taken into account because they may influence both the microbiome and the immune system and their interactions. In this context, we propose to integrate these microbial-genetic particle components into the microbiome concept and designate it as "microgenobiota". [ABSTRACT FROM AUTHOR]

Milk fats are vital to neonate survival and development, but vary highly by diet, maternal metabolic state and stage of lactation. To gain a better understanding of changes in lipid composition of sow milk across lactation, milk was collected from nine multiparous sows on days 0, 3, 7, and 14, relative to birth and lipids were profiled using multiple reaction monitoring (MRM) profiling. Percent fat was determined by creamatocrit, and found to be different (P

The role the mammary epithelial circadian clock plays in gland development and lactation is unknown. We hypothesized that mammary epithelial clocks function to regulate mammogenesis and lactogenesis, and propose the core clock transcription factor BMAL1:CLOCK regulates genes that control mammary epithelial development and milk synthesis. Our objective was to identify transcriptional targets of BMAL1 in undifferentiated (UNDIFF) and lactogen differentiated (DIFF) mammary epithelial cells (HC11) using ChIP-seq. Ensembl gene IDs with the nearest transcriptional start site to ChIP-seq peaks were explored as potential targets, and represented 846 protein coding genes common to UNDIFF and DIFF cells and 2773 unique to DIFF samples. Genes with overlapping peaks between samples (1343) enriched cell-cell adhesion, membrane transporters and lipid metabolism categories. To functionally verify targets, an HC11 line with Bmal1 gene knocked out (BMAL1-KO) using CRISPR-CAS was created. BMAL1-KO cultures had lower cell densities over an eight-day growth curve, which was associated with increased (p

Irregular rest-activity patterns can disrupt metabolic and hormonal physiology and potentially lead to disease. Little is known regarding rest-activity patterns during gestation and their association with hormonal rhythms and health in pregnant women. We conducted a pilot study to determine if 24 h rest-activity was related to saliva cortisol rhythms and maternal-fetal health in an economically disadvantaged population. Primiparous women wore a wrist actigraphy device for a week to record activity during gestational weeks 22 (G22; n = 50) and 32 (G32; n = 46) and postpartum week one (PPW1; n = 39). Participants collected saliva samples every 4 hr over a 24 hr period during G22 (n = 22), G32 (n = 20) and 24-48 hr postnatal (n = 20), and cortisol concentrations were measured with ELISA. Circadian rhythmicity was assessed using autocorrelation coefficient (r24) and cosinor analysis. Blood glucose levels, body mass index (BMI), gestational disease data, and gestational age of infant at birth were abstracted from medical charts. Time of cortisol peak (acrophase) during G22 was related with acrophase of activity (r = 0.66; p = 0.001) and blood glucose levels (r = 0.58; p = 0.006). During G22, minutes of wake after sleep onset was positively related to cortisol mesor and AUC (p

Perinatal nutrition affects future milk production. The number of mammary epithelial cells affect milk production capacity. Therefore, it was hypothesized that the level of colostrum intake affects the proliferation rate and the total number of mammary epithelial cells in the gland. The ratio of newly synthesized protein to newly synthesized DNA reflects the relative amount of cellular differentiation to cell division. The study objective was to determine the relationship between the level of colostrum intake and 24 h-level of circulating amino acid, glucose and insulin with mammary parenchyma histological features, cell division and protein synthesis over the first week postnatal. One of two standardized doses of a homogenate colostrum sample, 10% (n = 8) and 20% (n = 8) of birth bodyweight, was fed to gilts over the first 24 h postnatal. Gilts were administered deuterium oxide immediately after birth and daily to label newly synthesized DNA and proteins. Gilts were euthanized on postnatal day seven, and DNA and protein were isolated from mammary parenchyma. DNA and protein fractional synthesis (f) and fractional synthetic rate (FSR) were calculated using mass isotopomer distribution analysis. The ratio of protein f and FSR to DNA f and FSR were calculated and used to indicate the relative amounts of differentiation to cell division. Mammary morphological development was also analyzed by measuring the parenchymal epithelial area and the stromal and epithelial proliferation index on postnatal day seven. Colostrum dose was not related to any of the variables used to evaluate mammary development. However, plasma lysine levels at 24 h postnatal were positively related to average daily gain (ADG; r = 0.54, p = 0.05), DNA f (r = 0.57; p = 0.03) and DNA FSR (r = 0.57; p = 0.03) in mammary parenchyma. Plasma lysine was inversely related to the ratio of protein to DNA f and FSR (r = −0.56; p = 0.04). ADG was related to the parenchymal epithelial area and DNA and protein f and FSR (p < 0.05). These relationships support the idea that the nutritional environment affects early mammary development and that higher lysine levels in the perinatal period favored a greater degree of cell division versus differentiation in mammary of neonatal pigs and thus, warrant further investigations.

Due to insufficient dry matter intake and heightened nutrient requirements in early lactation, periparturient dairy cows mobilize adipose and muscle tissues to bridge energy and amino acid gaps, respectively. Our objective was to evaluate the relationship between the relative muscle thickness of late pregnant cows and their early lactation performance. At 35 d before expected calving (BEC), longissimus dorsi muscle thickness (LDT) was measured in forty-one multiparous Holstein cows via ultrasound. Tissue mobilization was evaluated via ultrasound images of LDT and backfat thickness (BFT) at 21 and 7 d BEC as well as at 0, 10, 30, and 60 DIM. Plasma concentrations of 3-methylhistidine (3-MH), creatinine (CRE), non-esterified fatty acids (NEFA), and β-hydroxybutyrate (BHB) were evaluated weekly. Milk yield and milk component data were collected through 60 DIM. Cattle were assigned post hoc to high-muscle (HM; n = 20; LDT > 4.49 cm) or low-muscle (LM; n = 21; ≤4.37 cm) groups, with mean LDT at 35 d BEC greater in HM (5.05 ± 0.49) than in LM (3.52 ± 0.65) animals. Between 35 and 21 d BEC, LM cows gained LDT, whereas HM cows gained BFT. HM cows mobilized more muscle from 21 d BEC to 30 DIM, as reflected by a greater loss of LDT, greater 3-MH concentrations (532 vs. 438 ± 30 ng/mL), and a greater 3-MH:CRE ratio (0.164 vs. 0.131 ± 0.008) in the first three weeks postpartum. The LDT and BFT at 21 d BEC were related to the amount of respective tissue mobilized through 30 DIM (R2 = 0.37 and 0.88, respectively). Although calves born to HM cattle were larger (45.2 vs. 41.8 ± 0.7 kg), HM cows produced less milk (38.8 vs. 41.6 ± 0.8 kg/d) with a tendency towards higher fat content (4.33 vs. 4.05 ± 0.12%), likely related to the mobilization of more backfat from 0 to 60 DIM (1.78 vs. 0.68 ± 0.34 mm), compared to LM cattle. These findings suggest that a cow’s metabolic status, as measured by LDT and BFT prepartum, may influence the metabolic strategy the animal uses to meet energy and amino acid requirements in late gestation and early lactation.

Maternal diet supplementation with pro- and prebiotics is associated with decreased incidence of diarrhea and greater piglet performance. This study investigated the impact adding whole ground oat as a prebiotic, alone or in combination with a probiotic, yeast culture (YC) (Saccharomyces cerevisiae), to sow gestation and lactation rations had on milk protein composition, piglet growth, and incidence of post-weaning diarrhea (PWD). Diets: control (CON), CON + yeast culture (YC) [5 g/kg], CON + oat (15% inclusion rate) (Oat) or CON+ YC [5 g/kg] + Oat (15%) were fed the last 30 days of gestation and throughout lactation (18–21 days). Shotgun proteome analysis of day 4 and 7 postpartum milk found 36 differentially abundant proteins (P-adj < 0.1) in both Oat and YC supplemented sows relative to CON. Notable was the increased expression of antimicrobial proteins, lactoferrin and chitinase in milk of Oat and YC sows compared to CON. The levels of IgA, IgM (within colostrum and milk) and IgG (within milk) were similar across treatments. However, colostral IgG levels in Oat-supplemented sows were significantly lower (p < 0.05) than that of the control sows, IgG from Oat-supplemented sows displayed greater reactivity to E. coli-antigens compared with CON and YC. Piglets from sows that consumed Oat alone or in combination weighed significantly more (p < 0.05) at birth compared to CON and YC. However, piglets in the Oat + YC group weighed less at weaning and had the lowest weight gain (p < 0.05) postweaning, compared with CON. Taken together with the observation that piglets of either YC- or Oat-fed sows had less PWD compared to CON and YC+ Oat suggests that Oat or YC supplementation positively impacts piglets through expression of certain milk-associated immune and antimicrobial proteins.