Comparative effectiveness of frame-based and mask-based Gamma Knife stereotactic radiosurgery in brain metastases: A 509 patient meta-analysis.

PURPOSE: Stereotactic Radiosurgery (SRS) is the primary treatment for patients with limited numbers of small brain metastases. Head fixation is usually performed with framed-based (FB) fixation; however, mask-based (MB) fixation has emerged as a less invasive alternative. A comparative meta-analysis between both approaches has not been performed. METHODS: Databases were searched until August 28th, 2023, to identify studies comparing MB and FB SRS in the treatment of brain metastases. Our outcomes of interest included local tumor control (LTC), radiation necrosis (RN), mortality, and treatment time (TT). Mean difference (MD), risk ratio (RR), and hazard ratio (HR) were used for statistical comparisons. RESULTS: From 295 articles initially identified, six studies (1 clinical trial) involving 509 patients were included. LTC revealed comparable RR at 6-months (RR = 0.95[95%CI = 0.89-1.01], p = 0.12) and a marginal benefit in FB SRS at 1-year (RR = 0.87[95%CI = 0.78-0.96], p = 0.005). However, in oligometastases exclusively treated with single-fraction SRS, LTC was similar among groups (RR = 0.92 [95%CI = 0.89-1.0], p = 0.30). Similarly, in patients with oligometastases treated with single-fraction SRS, RN (HR = 1.69; 95%CI = 0.72-3.97, p = 0.22), TT (MD = -29.64; 95%CI = -80.38-21.10, p = 0.25), and mortality were similar among groups (RR = 0.62; 95%CI = 0.22-1.76, p = 0.37). CONCLUSION: Our findings suggest that FB and MB SRS, particularly oligometastases treated with single-fraction, are comparable in terms of LTC, RN, TT, and mortality. Further research is essential to draw definitive conclusions.

Faecal Microbiota Divergence in Allopatric Populations of Podarcis lilfordi and P. pityusensis, Two Lizard Species Endemic to the Balearic Islands.

Gut microbial communities provide essential functions to their hosts and are known to influence both their ecology and evolution. However, our knowledge of these complex associations is still very limited in reptiles. Here we report the 16S rRNA gene faecal microbiota profiles of two lizard species endemic to the Balearic archipelago (Podarcis lilfordi and P. pityusensis), encompassing their allopatric range of distribution through a noninvasive sampling, as an alternative to previous studies that implied killing specimens of these IUCN endangered and near-threatened species, respectively. Both lizard species showed a faecal microbiome composition consistent with their omnivorous trophic ecology, with a high representation of cellulolytic bacteria taxa. We also identified species-specific core microbiota signatures and retrieved lizard species, islet ascription, and seasonality as the main factors in explaining bacterial community composition. The different Balearic Podarcis populations are characterised by harbouring a high proportion of unique bacterial taxa, thus reinforcing their view as unique and divergent evolutionary entities.

Substantial Influence of ERAP2 on the HLA-B*40:02 Peptidome: Implications for HLA-B*27-Negative Ankylosing Spondylitis.

HLA-B*40:02 is one of a few major histocompatibility complex class I (MHC-I) molecules associated with ankylosing spondylitis (AS) independently of HLA-B*27. The endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme that process MHC-I ligands and preferentially trims N-terminal basic residues, is also a risk factor for this disease. Like HLA-B*27 and other AS-associated MHC-I molecules, HLA-B*40:02 binds a relatively high percentage of peptides with ERAP2-susceptible residues. In this study, the effects of ERAP2 depletion on the HLA-B*40:02 peptidome were analyzed. ERAP2 protein expression was knocked out by CRISPR in the transfectant cell line C1R-B*40:02, and the differences between the peptidomes from the wild-type and ERAP2-KO cells were determined by label-free quantitative comparisons. The qualitative changes dependent on ERAP2 affected about 5% of the peptidome, but quantitative changes in peptide amounts were much more substantial, reflecting a significant influence of this enzyme on the generation/destruction balance of HLA-B*40:02 ligands. As in HLA-B*27, a major effect was on the frequencies of N-terminal residues. In this position, basic and small residues were increased, and aliphatic/aromatic ones decreased in the ERAP2 knockout. Other peptide positions were also affected. Because most of the non-B*27 MHC-I molecules associated with AS risk bind a relatively high percentage of peptides with N-terminal basic residues, we hypothesize that the non-epistatic association of ERAP2 with AS might be related to the processing of peptides with these residues, thus affecting the peptidomes of AS-associated MHC-I molecules.

Redundancy and Complementarity between ERAP1 and ERAP2 Revealed by their Effects on the Behcet's Disease-associated HLA-B*51 Peptidome.

The endoplasmic reticulum aminopeptidases ERAP1 and ERAP2 trim peptides to be loaded onto HLA molecules, including the main risk factor for Behçet's disease HLA-B*51. ERAP1 is also a risk factor among HLA-B*51-positive individuals, whereas no association is known with ERAP2. This study addressed the mutual relationships between both enzymes in the processing of an HLA-bound peptidome, interrogating their differential association with Behçet's disease. CRISPR/Cas9 was used to generate knock outs of ERAP1, ERAP2 or both from transfectant 721.221-HLA-B*51:01 cells. The surface expression of HLA-B*51 was reduced in all cases. The effects of depleting each or both enzymes on the B*51:01 peptidome were analyzed by quantitative label-free mass spectrometry. Substantial quantitative alterations of peptide length, subpeptidome balance, N-terminal residue usage, affinity and presentation of noncanonical ligands were observed. These effects were often different in the presence or absence of the other enzyme, revealing their mutual dependence. In the absence of ERAP1, ERAP2 showed similar and significant processing of B*51:01 ligands, indicating functional redundancy. The high overlap between the peptidomes of wildtype and double KO cells indicates that a large majority of B*51:01 ligands are present in the ER even in the absence of ERAP1/ERAP2. These results indicate that both enzymes have distinct, but complementary and partially redundant effects on the B*51:01 peptidome, leading to its optimization and maximal surface expression. The distinct effects of both enzymes on the HLA-B*51 peptidome provide a basis for their differential association with Behçet's disease and suggest a pathogenetic role of the B*51:01 peptidome.

Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome.

The Endoplasmic reticulum aminopeptidase I (ERAP1) trims peptides to their optimal size for binding to Major Histocompatibility Complex class I proteins. The natural polymorphism of this enzyme is associated with ankylosing spondylitis (AS) in epistasis with the major risk factor for this disease, HLA-B*27, suggesting a direct relationship between AS and HLA-B*27-bound peptides. Three polymorphisms that affect peptide trimming protect from AS: K528R, D575N/R725Q, and Q730E. We characterized and ranked the effects of each mutation, and their various combinations, by quantitative comparisons of the HLA-B*27 peptidomes from cells expressing distinct ERAP1 variants. Five features were examined: peptide length, N-terminal flanking residues, N-terminal residues of the natural ligands, internal sequences and affinity for B*27:05. Polymorphism at residue 528 showed the largest influence, affecting all five features regardless of peptide length. D575N/R725Q showed a much smaller effect. Yet, when co-occurring with K528R, it further decreased ERAP1 activity. Polymorphism at residue 730 showed a significant influence on peptide length, because of distinct effects on trimming of nonamers compared with longer peptides. Accordingly, multiple features were affected by the Q730E mutation in a length-dependent way. The alterations induced in the B*27:05 peptidome by natural ERAP1 variants with different K528R/Q730E combinations reflected separate and additive effects of both mutations. Thus, the influence of ERAP1 on HLA-B*27 is very diverse at the population level, because of the multiplicity and complexity of ERAP1 variants, and to the distinct effects of their co-occurring polymorphisms, leading to significant modulation of disease risk among HLA-B*27-positive individuals.

Allele-specific Alterations in the Peptidome Underlie the Joint Association of HLA-A*29:02 and Endoplasmic Reticulum Aminopeptidase 2 (ERAP2) with Birdshot Chorioretinopathy.

Virtually all patients of the rare inflammatory eye disease birdshot chorioretinopathy (BSCR) carry the HLA-A*29:02 allele. BSCR is also associated with endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme involved in processing HLA class I ligands, thus implicating the A*29:02 peptidome in this disease. To investigate the relationship between both risk factors we employed label-free quantitative mass spectrometry to characterize the effects of ERAP2 on the A*29:02-bound peptidome. An ERAP2-negative cell line was transduced with lentiviral constructs containing GFP-ERAP2 or GFP alone, and the A*29:02 peptidomes from both transduced cells were compared. A similar analysis was performed with two additional A*29:02-positive, ERAP1-concordant, cell lines expressing or not ERAP2. In both comparisons the presence of ERAP2 affected the following features of the A*29:02 peptidome: 1) Length, with increased amounts of peptides >9-mers, and 2) N-terminal residues, with less ERAP2-susceptible and more hydrophobic ones. The paradoxical effects on peptide length suggest that unproductive binding to ERAP2 might protect some peptides from ERAP1 over-trimming. The influence on N-terminal residues can be explained by a direct effect of ERAP2 on trimming, without ruling out and improved processing in concert with ERAP1. The alterations in the A*29:02 peptidome suggest that the association of ERAP2 with BSCR is through its effects on peptide processing. These differ from those on the ankylosing spondylitis-associated HLA-B*27. Thus, ERAP2 alters the peptidome of distinct HLA molecules as a function of their specific binding preferences, influencing different pathological outcomes in an allele-dependent way.

Endovascular Repair of Iliac Vein Laceration Associated with Complex Pelvic Fracture.

BACKGROUND: Iliac vein injury associated with pelvic fracture due to blunt trauma is an uncommon and difficult diagnosis but a life-threatening condition which often requires an emergent management. Although open repair has been traditionally used as the treatment of choice in unstable patients, it is controversial, given the difficulty due to injured vessel exposure in patients with significant retroperitoneal hematoma as well as tamponade effect loss associated with laparotomy. We present a challenging case of iliac vein laceration successfully treated by placement of a self-expanding covered stent. METHODS: A 15-year-old male was hemodynamically unstable and was transferred to our emergency department after a severe polytrauma due to a motorcycle accident. Contrast-enhanced computed tomography showed a left external iliac vein laceration with active bleeding and retroperitoneal hematoma as well as complex pelvic and left supracondylar femoral fractures. A 13 × 100 mm self-expanding covered stent was successfully deployed through duplex ultrasound-guided percutaneous approach of both femoral veins. RESULTS: The patient's blood pressure was normalized as soon as the stent graft was placed, and then femoral fracture was reduced and fixed. At 12-month follow-up, the patient remained asymptomatic, and stent-graft patency was confirmed. CONCLUSIONS: Covered stent-graft placement can be an effective and rapid treatment for life-threatening iliac vein injury.

The Behçet's disease-associated variant of the aminopeptidase ERAP1 shapes a low-affinity HLA-B*51 peptidome by differential subpeptidome processing.

A low-activity variant of endoplasmic reticulum aminopeptidase 1 (ERAP1), Hap10, is associated with the autoinflammatory disorder Behçet's disease (BD) in epistasis with HLA-B*51, which is the main risk factor for this disorder. The role of Hap10 in BD pathogenesis is unknown. We sought to define the effects of Hap10 on the HLA-B*51 peptidome and to distinguish these effects from those due to HLA-B*51 polymorphisms unrelated to disease. The peptidome of the BD-associated HLA-B*51:08 subtype expressed in a Hap10-positive cell line was isolated, characterized by mass spectrometry, and compared with the HLA-B*51:01 peptidome from cells expressing more active ERAP1 allotypes. We additionally performed synthetic peptide digestions with recombinant ERAP1 variants and estimated peptide-binding affinity with standard algorithms. In the BD-associated ERAP1 context of B*51:08, longer peptides were generated; of the two major HLA-B*51 subpeptidomes with Pro-2 and Ala-2, the former one was significantly reduced, and the latter was increased and showed more ERAP1-susceptible N-terminal residues. These effects were readily explained by the low activity of Hap10 and the differential susceptibility of X-Pro and X-Ala bonds to ERAP1 trimming and together resulted in a significantly altered peptidome with lower affinity. The differences due to ERAP1 were clearly distinguished from those due to HLA-B*51 subtype polymorphism, which affected residue frequencies at internal positions of the peptide ligands. The alterations in the nature and affinity of HLA-B*51·peptide complexes probably affect T-cell and natural killer cell recognition, providing a sound basis for the joint association of ERAP1 and HLA-B*51 with BD.

The hydroxylated form of docosahexaenoic acid (DHA-H) modifies the brain lipid composition in a model of Alzheimer's disease, improving behavioral motor function and survival.

We have compared the effect of the commonly used ω-3 fatty acid, docosahexaenoic acid ethyl ester (DHA-EE), and of its 2-hydroxylated DHA form (DHA-H), on brain lipid composition, behavior and lifespan in a new human transgenic Drosophila melanogaster model of Alzheimer's disease (AD). The transgenic flies expressed human Aß42 and tau, and the overexpression of these human transgenes in the CNS of these flies produced progressive defects in motor function (antigeotaxic behavior) while reducing the animal's lifespan. Here, we demonstrate that both DHA-EE and DHA-H increase the longer chain fatty acids (≥18C) species in the heads of the flies, although only DHA-H produced an unknown chromatographic peak that corresponded to a non-hydroxylated lipid. In addition, only treatment with DHA-H prevented the abnormal climbing behavior and enhanced the lifespan of these transgenic flies. These benefits of DHA-H were confirmed in the well characterized transgenic PS1/APP mouse model of familial AD (5xFAD mice), mice that develop defects in spatial learning and in memory, as well as behavioral deficits. Hence, it appears that the modulation of brain lipid composition by DHA-H could have remedial effects on AD associated neurodegeneration. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá.

Separate effects of the ankylosing spondylitis associated ERAP1 and ERAP2 aminopeptidases determine the influence of their combined phenotype on the HLA-B*27 peptidome.

Ankylosing spondylitis (AS) is an inflammatory disease strongly associated with the Major Histocompatibility Complex class I (MHC-I) allotype HLA-B*27. The endoplasmic reticulum aminopeptidases (ERAP)1 and 2, which trim peptides to their optimal length for MHC-I binding, are also susceptibility factors for this disease. Both highly active ERAP1 variants and ERAP2 expression favor AS, whereas loss-of-function ERAP1 and loss-of-expression ERAP2 variants are protective. Yet, only ERAP1 is in epistasis with HLA-B*27. We addressed two issues concerning the functional interaction of ERAP1 and ERAP2 with the HLA-B*27 peptidome in human cells: 1) distinguishing the effects of ERAP1 from those of ERAP2, and 2) determining the influence of ERAP2 in distinct ERAP1 contexts. Quantitative comparisons of the HLA-B*27:05 peptidomes from cells with various ERAP1/ERAP2 phenotypes were carried out. When cells expressing ERAP2 and either high or low activity ERAP1 variants were compared, increased amounts of nonamers, relative to longer ligands, and decreased amounts of peptides with Ala1, were observed in the more active ERAP1 context. When cells expressing ERAP2 in a low activity ERAP1 context or lacking ERAP2 but expressing a highly active ERAP1 variant were compared, the same effects on peptide length and Ala1, but also significantly lower amounts of peptides with N-terminal basic residues and lower affinity of the peptidome, were observed in the ERAP2-positive context. Thus, ERAP1 and ERAP2 have significant and distinct effects on the HLA-B*27 peptidome, suggesting that both enzymes largely act as separate entities in vivo. This may explain their different patterns of association with AS.

Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphism Relevant to Inflammatory Disease Shapes the Peptidome of the Birdshot Chorioretinopathy-Associated HLA-A*29:02 Antigen.

Birdshot chorioretinopathy is a rare ocular inflammation whose genetic association with HLA-A*29:02 is the highest between a disease and a major histocompatibility complex (MHC) molecule. It belongs to a group of MHC-I-associated inflammatory disorders, also including ankylosing spondylitis, psoriasis, and Behçet's disease, for which endoplasmic reticulum aminopeptidases (ERAP) 1 and/or 2 have been identified as genetic risk factors. Since both enzymes are involved in the processing of MHC-I ligands, it seems reasonable that common peptide-mediated mechanisms may underlie the pathogenesis of these diseases. In this study, comparative immunopeptidomics was used to characterize >5000 A*29:02 ligands and quantify the effects of ERAP1 polymorphism and expression on the A*29:02 peptidome in human cells. The peptides predominant in an active ERAP1 context showed a higher frequency of nonamers and bulkier amino acid side chains at multiple positions, compared with the peptides predominant in a less active ERAP1 background. Thus, ERAP1 polymorphism has a large influence, shaping the A*29:02 peptidome through length-dependent and length-independent effects. These changes resulted in increased affinity and hydrophobicity of A*29:02 ligands in an active ERAP1 context. The results reveal the nature of the functional interaction between A*29:02 and ERAP1 and suggest that this enzyme may affect the susceptibility to birdshot chorioretinopathy by altering the A*29:02 peptidome. The complexity of these alterations is such that not only peptide presentation but also other potentially pathogenic features could be affected.

Peptide handling by HLA-B27 subtypes influences their biological behavior, association with ankylosing spondylitis and susceptibility to endoplasmic reticulum aminopeptidase 1 (ERAP1).

HLA-B27 is strongly associated with ankylosing spondylitis (AS). We analyzed the relationship between structure, peptide specificity, folding, and stability of the seven major HLA-B27 subtypes to determine the role of their constitutive peptidomes in the pathogenicity of this molecule. Identification of large numbers of ligands allowed us to define the differences among subtype-bound peptidomes and to elucidate the peptide features associated with AS and molecular stability. The peptides identified only in AS-associated or high thermostability subtypes with identical A and B pockets were longer and had bulkier and more diverse C-terminal residues than those found only among non-AS-associated/lower-thermostability subtypes. Peptides sequenced from all AS-associated subtypes and not from non-AS-associated ones, thus strictly correlating with disease, were very rare. Residue 116 was critical in determining peptide binding, thermodynamic properties, and folding, thus emerging as a key feature that unified HLA-B27 biology. HLA-B27 ligands were better suited to TAP transport than their N-terminal precursors, and AS-associated subtype ligands were better than those from non-AS-associated subtypes, suggesting a particular capacity of AS-associated subtypes to bind epitopes directly produced in the cytosol. Peptides identified only from AS-associated/high-thermostability subtypes showed a higher frequency of ERAP1-resistant N-terminal residues than ligands found only in non-AS-associated/low-thermostability subtypes, reflecting a more pronounced effect of ERAP1 on the former group. Our results reveal the basis for the relationship between peptide specificity and other features of HLA-B27, provide a unified view of HLA-B27 biology and pathogenicity, and suggest a larger influence of ERAP1 polymorphism on AS-associated than non-AS-associated subtypes.

Negative frequency dependent selection on sympatric mtDNA haplotypes in Drosophila subobscura.

BACKGROUND: Recent experimental evidence for selection on mitochondrial DNA (mtDNA) has prompted the question as to what processes act to maintain within-population variation in mtDNA. Balancing selection though negative frequency dependent selection (NFDS) among sympatric haplotypes is a possibility, but direct empirical evidence for this is very scarce. FINDINGS: We extend the previous findings of a multi-generation replicated cage experiment in Drosophila subobscura, where mtDNA polymorphism was maintained in a laboratory setting. First, we use a set of Monte Carlo simulations to show that the haplotype frequency dynamics observed are inconsistent with genetic drift alone and most closely match those expected under NFDS. Second, we show that haplotype frequency changes over time were significantly different from those expected under either genetic drift or positive selection but were consistent with those expected under NFSD. CONCLUSIONS: Collectively, our analyses provide novel support for NFDS on mtDNA haplotypes, suggesting that mtDNA polymorphism may at least in part be maintained by balancing selection also in natural populations. We very briefly discuss the possible mechanisms that might be involved.

Combined effects of ankylosing spondylitis-associated ERAP1 polymorphisms outside the catalytic and peptide-binding sites on the processing of natural HLA-B27 ligands.

ERAP1 polymorphism involving residues 528 and 575/725 is associated with ankylosing spondylitis among HLA-B27-positive individuals. We used four recombinant variants to address the combined effects of the K528R and D575N polymorphism on the processing of HLA-B27 ligands. The hydrolysis of a fluorogenic substrate, Arg-528/Asp-575 < Lys-528/Asp-575 < Arg-528/Asn-575 < Lys-528/Asn-575, indicated that the relative activity of variants carrying Arg-528 or Lys-528 depends on residue 575. Asp-575 conferred lower activity than Asn-575, but the difference depended on residue 528. The same hierarchy was observed with synthetic precursors of HLA-B27 ligands, but the effects were peptide-dependent. Sometimes the epitope yields were variant-specific at all times. For other peptides, concomitant generation and destruction led to similar epitope amounts with all the variants at long, but not at short, digestion times. The generation/destruction balance of two related HLA-B27 ligands was analyzed in vitro and in live cells. Their relative yields at long digestion times were comparable with those from HLA-B27-positive cells, suggesting that ERAP1 was a major determinant of the abundance of these peptides in vivo. The hydrolysis of fluorogenic and peptide substrates by an HLA-B27 ligand or a shorter peptide, respectively, was increasingly inhibited as a function of ERAP1 activity, indicating that residues 528 and 575 affect substrate inhibition of ERAP1 trimming. The significant and complex effects of co-occurring ERAP1 polymorphisms on multiple HLA-B27 ligands, and their potential to alter the immunological and pathogenetic features of HLA-B27 as a function of the ERAP1 context, explain the epistatic association of both molecules in ankylosing spondylitis.

Novel HLA-B27-restricted epitopes from Chlamydia trachomatis generated upon endogenous processing of bacterial proteins suggest a role of molecular mimicry in reactive arthritis.

Reactive arthritis (ReA) is an HLA-B27-associated spondyloarthropathy that is triggered by diverse bacteria, including Chlamydia trachomatis, a frequent intracellular parasite. HLA-B27-restricted T-cell responses are elicited against this bacterium in ReA patients, but their pathogenetic significance, autoimmune potential, and relevant epitopes are unknown. High resolution and sensitivity mass spectrometry was used to identify HLA-B27 ligands endogenously processed and presented by HLA-B27 from three chlamydial proteins for which T-cell epitopes were predicted. Fusion protein constructs of ClpC, Na(+)-translocating NADH-quinone reductase subunit A, and DNA primase were expressed in HLA-B27(+) cells, and their HLA-B27-bound peptidomes were searched for endogenous bacterial ligands. A non-predicted peptide, distinct from the predicted T-cell epitope, was identified from ClpC. A peptide recognized by T-cells in vitro, NQRA(330-338), was detected from the reductase subunit. This is the second HLA-B27-restricted T-cell epitope from C. trachomatis with relevance in ReA demonstrated to be processed and presented in live cells. A novel peptide from the DNA primase, DNAP(211-223), was also found. This was a larger variant of a known epitope and was highly homologous to a self-derived natural ligand of HLA-B27. All three bacterial peptides showed high homology with human sequences containing the binding motif of HLA-B27. Molecular dynamics simulations further showed a striking conformational similarity between DNAP(211-223) and its homologous and much more flexible human-derived HLA-B27 ligand. The results suggest that molecular mimicry between HLA-B27-restricted bacterial and self-derived epitopes is frequent and may play a role in ReA.

The origin of proteasome-inhibitor resistant HLA class I peptidomes: a study with HLA-A*68:01.

Some HLA class I molecules bind a significant fraction of their constitutive peptidomes in the presence of proteasome inhibitors. In this study, A*68:01-bound peptides, and their parental proteins, were characterized through massive mass spectrometry sequencing to refine its binding motif, including the nearly exclusive preference for C-terminal basic residues. Stable isotope tagging was used to distinguish proteasome-inhibitor sensitive and resistant ligands. The latter accounted for less than 20% of the peptidome and, like in HLA-B27, arose predominantly from small and basic proteins. Under the conditions used for proteasome inhibition in vivo, epoxomicin and MG-132 incompletely inhibited the hydrolysis of fluorogenic substrates specific for the tryptic or for both the tryptic and chymotryptic subspecificities, respectively. This incomplete inhibition was also reflected in the cleavage of synthetic peptide precursors of A*68:01 ligands. For these substrates, the inhibition of the proteasome resulted in altered cleavage patterns. However these alterations did not upset the balance between cleavage at peptide bonds resulting in epitope destruction and those leading to their generation. The results indicate that inhibitor-resistant HLA class I ligands are not necessarily produced by non-proteasomal pathways. However, their generation is not simply explained by decreased epitope destruction upon incomplete proteasomal inhibition and may require additional proteolytic steps acting on incompletely processed proteasomal products.

Functional interaction of the ankylosing spondylitis-associated endoplasmic reticulum aminopeptidase 1 polymorphism and HLA-B27 in vivo.

The association of ERAP1 with ankylosing spondylitis (AS)1 among HLA-B27-positive individuals suggests that ERAP1 polymorphism may affect pathogenesis by altering peptide-dependent features of the HLA-B27 molecule. Comparisons of HLA-B*27:04-bound peptidomes from cells expressing different natural variants of ERAP1 revealed significant differences in the size, length, and amount of many ligands, as well as in HLA-B27 stability. Peptide analyses suggested that the mechanism of ERAP1/HLA-B27 interaction is a variant-dependent alteration in the balance between epitope generation and destruction determined by the susceptibility of N-terminal flanking and P1 residues to trimming. ERAP1 polymorphism associated with AS susceptibility ensured efficient peptide trimming and high HLA-B27 stability. Protective polymorphism resulted in diminished ERAP1 activity, less efficient trimming, suboptimal HLA-B27 peptidomes, and decreased molecular stability. This study demonstrates that natural ERAP1 polymorphism affects HLA-B27 antigen presentation and stability in vivo and proposes a mechanism for the interaction between these molecules in AS.

A Neurological Surgery Care Protocol for the LGBTQIA+ Community.

This research aims to propose a neurological surgery care protocol for the lesbian, gay, bisexual, transgender, queer, questioning, intersex, or asexual (LGBTQIA+) community. In recent years, people belonging to the LGBTQIA+ community have started to come out and express their identity due to growing awareness and various factors like the implementation of legal protections and rights in several countries; it is well documented in the literature that this community faces unique health needs as well as barriers and inequalities in healthcare. The lack of tailored training for medical specialists affects the level of quality and access to medical care for these individuals, and neurosurgical care is no exception. This literature review included studies in scientific journals and articles discussing problems, best practices, and gaps in the existing neurological surgical care protocols for LGBTQIA+ people. Accordingly, it highlights shared challenges such as healthcare-related difficulties, communication barriers, discrimination, and stigmatization. The primary aim is to create a safe and respectful care environment that ensures fair medical treatment to all patients regardless of their sexual orientation or gender identity. The review sheds light on the need for inclusive and sensitive neurosurgical care to improve clinical outcomes and the experience of patients belonging to the LGBTQIA+ community, thereby ensuring an environment of dignified treatment and satisfactory recovery from neurosurgical events.

ERAP1 in ankylosing spondylitis: genetics, biology and pathogenetic role.

PURPOSE OF REVIEW: Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an aminopeptidase of the endoplasmic reticulum involved in trimming of peptides to their optimal size for binding to major histocompatibility complex class I molecules. Natural ERAP1 polymorphism resulting in altered enzymatic activity is associated with ankylosing spondylitis, an inflammatory disorder very strongly linked to HLA-B27. RECENT FINDINGS: This review will summarize recent advances in the genetics of ERAP1 association with this disease, in the molecular basis of ERAP1 function and in the mechanism of functional interaction between ERAP1 and HLA-B27. SUMMARY: The findings suggest that the pathogenetic role of ERAP1 in ankylosing spondylitis is due to allotype-dependent alterations of the HLA-B27 peptidome that affect the immunologic and other features of HLA-B27.

Utility and importance of accurate Hb A2 measurements for defining a strategy for ß-thalassemia screening: experience in the Balearic Islands, Spain.

The high heterogeneity in regional profiles of ß-thalassemia (ß-thal) mutations highlights the need for population-specific carrier detection strategies. Our aim was to analyze the relationship between hematological values and ß(0) and ß(+) mutations in 154 Balearic ß-thal heterozygotes, in order to establish the most optimized mutation carrier detection strategy to be used to manage the disease in our population. The Hb A2 level was the best parameter for discriminating between both types of carriers. Taking into account the cut-off point value of 4.85% (Hb A2), obtained by a receiver-operating characteristic (ROC) curve analysis, we proposed an algorithm that would use a real-time polymerase chain reaction (RT-PCR) hybridization probe assay technique to detect one of the two most common mutations in the Balearic population, namely codon 39 (C>T) and IVS-I-110 (G>A), depending on the Hb A2 value of the patient.