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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 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.

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.

BackgroundImmunocompromised patients have an increased risk of developing severe COVID disease, as well as a tendency to suboptimal responses to vaccines. The objective of this study was to evaluate the specific cellular and humoral adaptive immune responses of a cohort of kidney transplant recipients (KTR) after 3 doses of mRNA-1273 vaccine and to determinate the main factors involved.MethodsProspective observational study in 221 KTR (149 non infected), 55 healthy volunteers (HV) and 23 dialysis patients (DP). We evaluated anti-spike (by quantitative chemiluminescence immunoassay) and anti-nucleocapsid IgG (ELISA), percentage of TCD4+ and TCD8+ lymphocytes producing IFNγ against S-protein by intracellular flow cytometry after Spike-specific 15-mer peptide stimulation and serum neutralizing activity (competitive ELISA) at baseline and after vaccination.ResultsAmong COVID-19 naïve KTR, 54.2% developed cellular and humoral response after the third dose (vs 100% in DP and 91.7% in HV), 18% only showed cell-mediated response, 22.2% exclusively antibody response and 5.6% none. A correlation of neutralizing activity with both the IgG titer (r=0.485, p1000/mm3 [4.68 (1.72-12.73, p=0.003], eGFR>30 mL/min [7.34(2.72-19.84), p

Cytotoxic CD8 T cells are crucial for the host antigen-specific immune response to viral pathogens. Here we report the identification of an essential role for the serine/arginine-rich splicing factor (SRSF) 1 in CD8 T cell homeostasis and function. Specifically, SRSF1 is necessary for the maintenance of normal CD8 T lymphocyte numbers in the lymphoid compartment, and for the proliferative capacity and cytotoxic function of CD8 T cells. Furthermore, SRSF1 is required for antigen-specific IFN-γ cytokine responses in a viral infection challenge in mice. Transcriptomics analyses of Srsf1-deficient T cells reveal that SRSF1 controls proliferation, MAP kinase signaling and IFN signaling pathways. Mechanistically, SRSF1 controls the expression and activity of the Mnk2/p38-MAPK axis at the molecular level. Our findings reveal previously unrecognized roles for SRSF1 in the physiology and function of cytotoxic CD8 T lymphocytes and a potential molecular mechanism in viral immunopathogenesis.

HLA-G is a non-classical HLA class I molecule with immunomodulatory properties. It was initially described at the maternal-fetal interface, and it was later found that this molecule was constitutively expressed on certain immuneprivileged tissues, such as cornea, endothelial and erythroid precursors, and thymus. The immunosuppressive effect of HLA-G is exerted through the interaction with its cognate receptors, expressed on immunocompetent cells, like ILT2, expressed on NK, B, T cells and APCs; ILT4, on APCs; KIR, found on the surface of NK cells; and finally, the co-receptor CD8. Because of these immunomodulatory functions, HLA-G has been involved in several processes, amongst which organ transplantation, viral infections, cancer progression, and autoimmunity. HLA-G neo-expression on tumors has been recently described in several types of malignancies. In fact, tumor progression is tightly linked to the presence of the molecule, as it exerts its tolerogenic function, inhibiting the cells of the immune system and favoring tumor escape. Several polymorphisms in the 3’UTR region condition changes in HLA-G expression (14bp and +3142C/G, among others), which have been associated with both the development and outcome of patients with different tumor types. Also, in recent years, several studies have shown that HLA-G plays an important role in the control of autoimmune diseases. The ability of HLA-G to limit the progression of these diseases has been confirmed and, in fact, levels of the molecule and several of its polymorphisms have been associated with increased susceptibility to the development of autoimmune diseases, as well as increased disease severity. Thus, modulating HLA-G expression in target tissues of oncology patients or patients with autoimmune diseases may be potential therapeutic approaches to treat these pathological conditions.

HLA-G is a non-classical class I HLA molecule that induces tolerance by acting on receptors of both innate and adaptive immune cells. When overexpressed in tumors, limits surveillance by the immune system. The HLA-G gene shows several polymorphisms involved in mRNA and protein levels. We decided to study the implication of two polymorphisms (rs371194629; 14bp INS/DEL and rs1063320; +3142 C/G) in paired tissue samples (tumoral and non-tumoral) from 107 Spanish patients with gastric adenocarcinoma and 58 healthy control individuals, to assess the possible association of the HLA-G gene with gastric adenocarcinoma susceptibility, disease progression and survival. The presence of somatic mutations involving these polymorphisms was also analyzed. The frequency of the 14bp DEL allele was increased in patients (70.0%) compared to controls (57.0%, p=0.025). In addition, the haplotype formed by the combination of the 14bp DEL/+3142 C variants is also increased in patients (54.1% vs 44.4%, p=0.034, OR=1.74 CI95% 1.05-2.89). Kaplan-Meier analysis revealed that 14bp DEL/DEL patients showed lower 5-year life-expectancy than INS/DEL or INS/INS (p=0.041). Adjusting for TNM staging (Cox regression analysis) disclosed a significant difference in death risk (p=0.03) with an expected hazard 2.6 times higher. Finally, no somatic mutations were found when comparing these polymorphisms in tumoral vs non-tumoral tissues, which indicates that this is a preexisting condition in patients and not a de novo, tumor-restricted, event. In conclusion, the variants predominant in patients were those increasing HLA-G mRNA stability and HLA-G expression, clearly involving this molecule in gastric adenocarcinoma susceptibility, disease progression and survival and making it a potential target for immunotherapeutic approaches.

We have applied two PCR techniques, differential PCR (diffPCR) and qPCR for the identification of HER2 gene amplifications in genomic DNA of tumor and distal gastric samples from patients with gastric cancer. The diffPCR technique consists of the simultaneous amplification of the HER2 gene and a housekeeping gene by conventional PCR and the densitometric analysis of the bands obtained. We established a cut-off point based on the mean and standard deviation analyzing the DNA of 30 gastric tissues from patients undergoing non-cancer gastrectomy. diffPCR and qPCR yielded consistent results. HER2-overexpression was detected in 25% of patients and was further confirmed by immunohistochemistry and immunofluorescence. The approaches herein described may serve as complementary and reliable methods to assess HER2 amplification.

Marine invertebrate-associated symbiotic bacteria produce a plethora of novel secondary metabolites which may be structurally unique with interesting pharmacological properties. Selection of strains usually relies on literature searching, genetic screening and bioactivity results, often without considering the chemical novelty and abundance of secondary metabolites being produced by the microorganism until the time-consuming bioassay-guided isolation stages. To fast track the selection process, metabolomic tools were used to aid strain selection by investigating differences in the chemical profiles of 77 bacterial extracts isolated from cold water marine invertebrates from Orkney, Scotland using liquid chromatography-high resolution mass spectrometry (LC-HRMS) and nuclear magnetic resonance (NMR) spectroscopy. Following mass spectrometric analysis and dereplication using an Excel macro developed in-house, principal component analysis (PCA) was employed to differentiate the bacterial strains based on their chemical profiles. NMR 1H and correlation spectroscopy (COSY) were also employed to obtain a chemical fingerprint of each bacterial strain and to confirm the presence of functional groups and spin systems. These results were then combined with taxonomic identification and bioassay screening data to identify three bacterial strains, namely Bacillus sp. 4117, Rhodococcus sp. ZS402 and Vibrio splendidus strain LGP32, to prioritize for scale-up based on their chemically interesting secondary metabolomes, established through dereplication and interesting bioactivities, determined from bioassay screening.

Resumen: La presencia de un trombo en el cayado aórtico sin anomalías es inusual, sin embargo, supone un reto para el clínico. Por un lado, su diagnóstico suele ser incidental o secundario a una embolia sistémica y, por otro, no existe consenso para su tratamiento debido a la falta de estudios aleatorizados.Presentamos el caso de un varón de 54 años que ingresó en la unidad de reanimación tras ictus isquémico de la arteria cerebral media izquierda no revascularizable. Una angiografía por tomografía computarizada con contraste evidenció un trombo pediculado de 7 cm en la aorta torácica con origen en la aorta ascendente medio-distal, aparentemente sin otras anomalías. Se realizó extracción completa del trombo y de la membrana en la base de implantación ante la sospecha de un posible síndrome aórtico agudo. El examen histológico confirmó la presencia de fibrina, sin embargo, los estudios de laboratorio no establecieron una causa principal que justificara la formación del trombo. Abstract: Flotant thrombus in the aortic arch without abnormalities is unusual. Arterial embolic disease continues to challenge clinicians. The diagnosis is usually incidental or secondary to a systemic embolism, although there are no randomized controlled trials for consensus as to its treatment.A 54-year-old man was admitted to the critical care resuscitation unit after a nonrevascularizable left middle cerebral ischaemic stroke. CTA with contrast showed a 7-cm pedunculated thrombus in the thoracic aorta originating from the mid ascending aorta and arch, without other abnormalities. Complete removal of the thrombus and complete resection of the basement membrane were performed due to the suspicion of a possible acute aortic syndrome. Histological examination confirmed the presence of fibrin, however, laboratory studies did not establish a main cause that justified the formation of the thrombus.

Individuals exhibiting an intermediate alcohol drinking pattern in conjunction with signs of metabolic risk present clinical features of both alcohol‐associated and metabolic‐associated fatty liver diseases. However, such combination remains an unexplored area of great interest, given the increasing number of patients affected. In the present study, we aimed to develop a preclinical DUAL (alcohol‐associated liver disease plus metabolic‐associated fatty liver disease) model in mice. C57BL/6 mice received 10% vol/vol alcohol in sweetened drinking water in combination with a Western diet for 10, 23, and 52 weeks (DUAL model). Animals fed with DUAL diet elicited a significant increase in body mass index accompanied by a pronounced hypertrophy of adipocytes, hypercholesterolemia, and hyperglycemia. Significant liver damage was characterized by elevated plasma alanine aminotransferase and lactate dehydrogenase levels, extensive hepatomegaly, hepatocyte enlargement, ballooning, steatosis, hepatic cell death, and compensatory proliferation. Notably, DUAL animals developed lobular inflammation and advanced hepatic fibrosis. Sequentially, bridging cirrhotic changes were frequently observed after 12 months. Bulk RNA‐sequencing analysis indicated that dysregulated molecular pathways in DUAL mice were similar to those of patients with steatohepatitis. Conclusion: Our DUAL model is characterized by obesity, glucose intolerance, liver damage, prominent steatohepatitis and fibrosis, as well as inflammation and fibrosis in white adipose tissue. Altogether, the DUAL model mimics all histological, metabolic, and transcriptomic gene signatures of human advanced steatohepatitis, and therefore serves as a preclinical tool for the development of therapeutic targets.

Background. Reduced TCRζ chain surface has been reported in T cells from patients with different inflammatory conditions and cancer. However, the causes of this diminished expression in cancer remain elusive. Methods. T cell-enriched populations of blood or tissue (tumoral and nontumoral) origin from 44 patients with gastric adenocarcinoma and 33 healthy subjects were obtained. Samples were subjected to cytofluorimetry, Western blot analysis, TCRζ cDNA sequencing experiments, measurement of TCRζ mRNA levels, and caspase-3 activity assays. Results. Cytofluorimetry revealed a decreased TCRζ expression in T cells of patients, assessed either as percentage of cells expressing this chain (blood: control subjects 99.8±0.1%, patients 98.8±1.1%P

This article describes the way in which six nontraditional legs collaborate to provide locomotion to a walking machine when it moves along a path. Such legs are based on the one-degree-of-freedom Peaucellier–Lipkin mechanism, which was modified by the addition of four degrees of freedom. Such five-degree-of-freedom legs have the ability to adapt their postures according to the center of rotation around of which the machine walks. The attributes and abilities of the hexapod are expressed by means of a mathematical framework, which grants the spatial description and required joint variables, according to a specific task, resulting in the configuration of its legs for a particular path planning. Additionally, the article presents an illustrative example describing a detailed procedure concerning the configurations and collaboration of their legs according to an imposed center of rotation around of which the six-legged robot walks.

This article presents the principles upon which a new nonanthropomorphic biped exoskeleton was designed, whose legs are based on an eight-bar mechanism. The main function of the exoskeleton is to assist people who have difficulty walking. Every leg is based on the planar Peaucellier–Lipkin mechanism, which is a one degree of freedom linkage. To be used as a robotic leg, the Peaucellier–Lipkin mechanism was modified by including two more degrees of freedom, as well as by the addition of a mechanical system based on toothed pulleys and timing belts that provides balance and stability to the user. The use of the Peaucellier–Lipkin mechanism, its transformation from one to three degrees of freedom, and the incorporation of the stability system are the main innovations and contributions of this novel nonanthropomorphic exoskeleton. Its mobility and performance are also presented herein, through forward and inverse kinematics, together with its application in carrying out the translation movement of the robotic foot along paths with the imposition of motion laws based on polynomial functions of time.

This article shows the characteristics of a sprawling robotic leg inspired by the limb postures of certain reptilian animals known as sprawling-legged creatures. The main part of the robotic limb is based on the eight-bar Peaucellier–Lipkin linkage, and its main attribute is the ability to trace a true straight line, due to the rotational motion of the input link. However, when the eight-bar linkage is modified, it is capable of tracing true circular concave or convex arcs, when two of its constitutive links have distinct and precise lengths. This gives rise to the concepts of concavity and convexity, related to a robotic leg based on the Peaucellier–Lipkin mechanism, such as the one described herein. Our bioinspired robotic leg can trace concave or convex curves, as well as straight lines, making it a reptile-like robotic limb that is very similar to the natural one. We also introduce the concept of rotation center tuning, which refers to the ability of the leg to adapt its posture to the center of rotation of the entire walking machine, resulting in an easy and suitable gait process. The theoretical information is illustrated through the simulation of an example that provides a path-planning procedure, focusing on the rotation center tuning process and a walking gait. The example also includes the design of an elliptical path projected onto the cylindrical workspace and followed by the reptilian foot.

This article deals with the kinematics and dynamics of a novel leg based on the Peaucellier–Lipkin mechanism, which is better known as the straight path tracer. The basic Peaucellier–Lipkin linkage with 1 degree of freedom was transformed into a more skillful mechanism, through the addition of 4 more degrees of freedom. The resulting 5-degree-of-freedom leg enables the walking machine to move along paths that are straight lines and/or concave or convex curves. Three degrees of freedom transform the leg in relation to a reachable center of rotation that the machine walks around. Once the leg is transformed, the remaining 2 degrees of freedom position the foot at a desirable Cartesian point during the transfer or support phase. We analyzed the direct and inverse kinematics developed for the leg when the foot describes a straight line and found some interesting relationships among the motion parameters. The dynamic model equations of motion for the leg were derived from the Lagrangian dynamic formulation to calculate the required torques during a particular transfer phase.

Objective: Superior venous system stenosis (superior vena cava (SVC) - right subclavian vein - innominate vein - left subclavian vein) is a clinical situation that frequently appears in patients with long-term implanted cardiac stimulation devices, due to venous system thrombosis and in those with congenital heart disease who need corrective surgery, due to chronic complications inherent to surgical techniques. In clinical practice, venous system stenosis may manifest as a SVC syndrome. In many cases, we are not able to correct stenosis or obstructions, since it is impossible to cross them. In this article, we describe the surgical technique that we have implemented in our hospital to solve this challenge, especially in those patients with pacing/defibrillation devices who present with this pathology. Our objective was to perform an extraction of the pacemaker and defibrillation electrodes, to allow the passage of a support wire to achieve the implantation of the endovascular stent(s) to correct the SVC syndrome. Methods: We present a retrospective series of six consecutive patients with SVC syndrome studied in a single center from 2012 to 2021.Three of them presented with thrombosis related to pacing or defibrillation electrodes and the other three presented with complications derived from Mustard or Senning techniques in patients with pacemakers and D-transposition of the great arteries. Results: In all cases, a complete re-vascularization of the SVC system was achieved using a stent, and new leads could have been implanted through it. Combined treatment of lead extraction and endovascular stent implantation corrected the syndrome in all cases. Conclusions: Angioplasty and stenting of the central venous system is a standardized technique with validated results, in acute, for the recanalization of chronic occlusions secondary to transvenous devices.

Objective: Superior venous system stenosis (superior vena cava (SVC) - right subclavian vein - innominate vein - left subclavian vein) is a clinical situation that frequently appears in patients with long-term implanted cardiac stimulation devices, due to venous system thrombosis and in those with congenital heart disease who need corrective surgery, due to chronic complications inherent to surgical techniques. In clinical practice, venous system stenosis may manifest as a SVC syndrome. In many cases, we are not able to correct stenosis or obstructions, since it is impossible to cross them. In this article, we describe the surgical technique that we have implemented in our hospital to solve this challenge, especially in those patients with pacing/defibrillation devices who present with this pathology. Our objective was to perform an extraction of the pacemaker and defibrillation electrodes, to allow the passage of a support wire to achieve the implantation of the endovascular stent(s) to correct the SVC syndrome. Methods: We present a retrospective series of six consecutive patients with SVC syndrome studied in a single center from 2012 to 2021.Three of them presented with thrombosis related to pacing or defibrillation electrodes and the other three presented with complications derived from Mustard or Senning techniques in patients with pacemakers and D-transposition of the great arteries. Results: In all cases, a complete re-vascularization of the SVC system was achieved using a stent, and new leads could have been implanted through it. Combined treatment of lead extraction and endovascular stent implantation corrected the syndrome in all cases. Conclusions: Angioplasty and stenting of the central venous system is a standardized technique with validated results, in acute, for the recanalization of chronic occlusions secondary to transvenous devices.

Recent years have witnessed an upsurge in the usage of ballistocardiography (BCG) and seismocardiography (SCG) to record myocardial function both in normal and pathological populations. Kinocardiography (KCG) combines these techniques by measuring 12 degrees-of-freedom of body motion produced by myocardial contraction and blood flow through the cardiac chambers and major vessels. The integral of kinetic energy (iK) obtained from the linear and rotational SCG/BCG signals, and automatically computed over the cardiac cycle, is used as a marker of cardiac mechanical function. The present work systematically evaluated the test–retest (TRT) reliability of KCG iK derived from BCG/SCG signals in the short term (SCG and BCG recordings. Exceptions to this finding were limited to metrics computed in left lateral decubitus position where the TRT reliability was moderate-to-high. Second, we found low-to-moderate long-term TRT reliability for KCG metrics as expected and confirmed by blood pressure measurements. In summary, KCG parameters derived from BCG/SCG signals show high repeatability and should be further investigated to confirm their use for cardiac condition longitudinal monitoring.