The role of B-1 cells in cancer progression and anti-tumor immunity.

In recent years, in addition to the well-established role of T cells in controlling or promoting tumor growth, a new wave of research has demonstrated the active involvement of B cells in tumor immunity. B-cell subsets with distinct phenotypes and functions play various roles in tumor progression. Plasma cells and activated B cells have been linked to improved clinical outcomes in several types of cancer, whereas regulatory B cells have been associated with disease progression. However, we are only beginning to understand the role of a particular innate subset of B cells, referred to as B-1 cells, in cancer. Here, we summarize the characteristics of B-1 cells and review their ability to infiltrate tumors. We also describe the potential mechanisms through which B-1 cells suppress anti-tumor immune responses and promote tumor progression. Additionally, we highlight recent studies on the protective anti-tumor function of B-1 cells in both mouse models and humans. Understanding the functions of B-1 cells in tumor immunity could pave the way for designing more effective cancer immunotherapies.

Optimizing cryopreservation conditions for use of fucosylated human mesenchymal stromal cells in anti-inflammatory/immunomodulatory therapeutics.

Mesenchymal stem/stromal cells (MSCs) are being increasingly used in cell-based therapies due to their broad anti-inflammatory and immunomodulatory properties. Intravascularly-administered MSCs do not efficiently migrate to sites of inflammation/immunopathology, but this shortfall has been overcome by cell surface enzymatic fucosylation to engender expression of the potent E-selectin ligand HCELL. In applications of cell-based therapies, cryopreservation enables stability in both storage and transport of the produced cells from the manufacturing facility to the point of care. However, it has been reported that cryopreservation and thawing dampens their immunomodulatory/anti-inflammatory activity even after a reactivation/reconditioning step. To address this issue, we employed a variety of methods to cryopreserve and thaw fucosylated human MSCs derived from either bone marrow or adipose tissue sources. We then evaluated their immunosuppressive properties, cell viability, morphology, proliferation kinetics, immunophenotype, senescence, and osteogenic and adipogenic differentiation. Our studies provide new insights into the immunobiology of cryopreserved and thawed MSCs and offer a readily applicable approach to optimize the use of fucosylated human allogeneic MSCs as immunomodulatory/anti-inflammatory therapeutics.

Synthesis of α3ß4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior.

Growing evidence suggests that inhibition of the α3ß4 nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), an alkaloid from Aristotelia chilensis, was identified as an α3ß4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3ß4 nAChR. These studies revealed structure-activity trends and several compounds with increased potency compared to 1 with few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit the α3ß4 nAChR noncompetitively, but do not act as channel blockers, suggesting they are negative allosteric modulators. Finally, using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal model of cocaine relapse. The results from these studies further support a role for the α3ß4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.

Structure-Activity Relationships of the Antimicrobial Peptide Natural Product Apidaecin.

With the growing crisis of antimicrobial resistance, it is critical to continue to seek out new sources of novel antibiotics. This need has led to renewed interest in natural product antimicrobials, specifically antimicrobial peptides. Nonlytic antimicrobial peptides are highly promising due to their unique mechanisms of action. One such peptide is apidaecin (Api), which inhibits translation termination through stabilization of the quaternary complex of the ribosome-apidaecin-tRNA-release factor. Synthetic derivatives of apidaecin have been developed, but structure-guided modifications have yet to be considered. In this work, we have focused on modifying key residues in the Api sequence that are responsible for the interactions that stabilize the quaternary complex. We present one of the first examples of a highly modified Api peptide that maintains its antimicrobial activity and interaction with the translation complex. These findings establish a starting point for further structure-guided optimization of Api peptides.

Examining Field Experiences of Teacher Candidates During COVID-19: Systemic Inequities Unveiled for Underserved English Learners in K-12 Grades.

The impact of coronavirus disease 2019 challenged schools and credential programs to adjust pedagogy, but rapid changes impeded equitable practices to K-12 grade English Learners (ELs). The framework stems from critical multicultural education. Data represented 81 credential candidates across three universities. Study confirmed that ELs lacked access to online learning, active engagement with peers/teachers, and differentiated instruction due to rapid changes and uncertainties to their programs.

El Impacto de COVID-19 retó a las escuelas y programas certificados a ajustar su pedagogía, pero cambios rápidos impidieron prácticas egalitarias para estudiantes de inglés (ELs siglas en inglés) en K-12. El marco de referencia se originó en la educación multicultural crítica. La información representó 81 candidatos de credencial a través de tres universidades. El estudio confirmó que ELs no tenían acceso al aprendizaje en línea, al compromiso activo de compañeros/maestros, y a la educación diferenciada debido a los cambios rápidos y la incertidumbre de sus programas.

[Benefits of early social transition in transgender minors. Family perspectives: qualitative study.] / Beneficios de la transición social temprana en menores transgénero. Perspectivas de familias: estudio cualitativo.

OBJECTIVE: The term trans brings together all transgender identities. The early social transition towards the affirmed gender has benefits in the child's development. For families, transit is a period of great uncertainty, requiring support aimed at families of trans minors. The aim of this paper was to explore the needs and experiencies of parents and close-relatives who supported the social transition of their children. METHODS: We worked with focus groups of functional families of transgender minors who had begun the transition (n=14), with a medium-high educational level and who belonged to urban areas of Tenerife. Through a semi-structured interview, they commented on their experiences in the process of supporting the social transition of their children. The data was recorded in a video recording and processed through content analysis and categorization. RESULTS: Early social transition had positive and immediate benefits on child development as well as in the reduction of anxiety. There was a general improvement in mood, self-esteem, and social and family relationships. The accompaniment of specialists and associations helped in the different social situations and favoured resilience. CONCLUSIONS: Early social transition is positive in the personal and socio-family sphere of the minor. To improve their resilience, families demand accompaniment in this process, as well as meeting other trans people who serve as transpositive references. In addition, they point out the need for specific training in health professionals.

OBJETIVO: El término trans aglutina a todas las identidades transgénero. La transición social temprana hacia el género sentido tiene beneficios en el desarrollo del menor. Para las familias, el tránsito es un periodo de grandes incertidumbres, siendo necesario el acompañamiento dirigido a las familias de menores trans. El objetivo del artículo fue explorar, desde una perspectiva paterna y familiar, las necesidades y experiencias sobre el tránsito de menores trans que sirvieran de referente a otros padres/madres que apoyan el tránsito social de sus hijos e hijas. METODOS: Se trabajó con grupos focales de familias funcionales de menores transgénero que habían iniciado la transición (n=14), de nivel educativo medio-alto y que pertenecían a zonas urbanas de Tenerife. Mediante entrevista semiestructurada, comentaron sus experiencias en el proceso de dar soporte al tránsito social de sus hijos e hijas. Los datos fueron registrados en una videograbación y se procesaron mediante análisis de contenido y categorización. RESULTADOS: La transición social temprana tuvo beneficios positivos e inmediatos en el desarrollo del menor, además de en la disminución de la ansiedad. Hubo una mejora general en el humor, la autoestima y las relaciones tanto sociales como familiares. El acompañamiento de especialistas y asociaciones ayudó en las distintas situaciones sociales y favoreció la resiliencia. CONCLUSIONES: El tránsito social temprano es positivo en la esfera personal y sociofamiliar del menor. Para mejorar su resiliencia, las familias demandan acompañamiento en este proceso, así como conocer otras personas trans que les sirvan como referentes transpositivos. Además, señalan la necesidad de formación específica en los profesionales sanitarios.

Beneficios de la transición social temprana en menores transgénero. Perspectivas de familias: estudio cualitativo / Benefits of early social transition in transgender minors. Family perspectives: qualitative study

FUNDAMENTOS: El término trans aglutina a todas las identidades transgénero. La transición social temprana hacia el género sentido tiene beneficios en el desarrollo del menor. Para las familias, el tránsito es un periodo de grandes incertidumbres, siendo necesario el acompañamiento dirigido a las familias de menores trans. El objetivo del artículo fue explorar, desde una perspectiva paterna y familiar, las necesidades y experiencias sobre el tránsito de menores trans que sirvieran de referente a otros padres/madres que apoyan el tránsito social de sus hijos e hijas.MÉTODOS: Se trabajó con grupos focales de familias funcionales de menores transgénero que habían iniciado la transición (n=14), de nivel educativo medio-alto y que pertenecían a zonas urbanas de Tenerife. Mediante entrevista semiestructurada, comentaron sus experiencias en el proceso de dar soporte al tránsito social de sus hijos e hijas. Los datos fueron registrados en una videograbación y se procesaron mediante análisis de contenido y categorización. RESULTADOS: La transición social temprana tuvo beneficios positivos e inmediatos en el desarrollo del menor, además de en la disminución de la ansiedad. Hubo una mejora general en el humor, la autoestima y las relaciones tanto sociales como familiares. El acompañamiento de especialistas y asociaciones ayudó en las distintas situaciones sociales y favoreció la resiliencia. CONCLUSIONES: El tránsito social temprano es positivo en la esfera personal y sociofamiliar del menor. Para mejorar su resiliencia, las familias demandan acompañamiento en este proceso, así como conocer otras personas trans que les sirvan como referentes transpositivos. Además, señalan la necesidad de formación específica en los profesionales sanitarios.(AU)

BACKGROUND: The term trans brings together all transgender identities. The early social transition towards the affirmed gender has benefits in the child’s development. For families, transit is a period of great uncertainty, requiring support aimed at families of trans minors. The aim of this paper was to explore the needs and experiencies of parents and close-relatives who supported the social transition of their children. METHODS: We worked with focus groups of functional families of transgender minors who had begun the transition (n=14), with a medium-high educational level and who belonged to urban areas of Tenerife. Through a semi-structured interview, they commented on their experiences in the process of supporting the social transition of their children. The data was recorded in a video recording and processed through content analysis and categorization. RESULTS: Early social transition had positive and immediate benefits on child development as well as in the reduction of anxiety. There was a general improvement in mood, self-esteem, and social and family relationships. The accompaniment of specialists and associations helped in the different social situations and favoured resilience.CONCLUSIONS: Early social transition is positive in the personal and socio-family sphere of the minor. To improve their resilience, families demand accompaniment in this process, as well as meeting other trans people who serve as transpositive references. In addition, they point out the need for specific training in health professionals.(AU)

Human B-1 cells are important contributors to the naturally-occurring IgM pool against the tumor-associated ganglioside Neu5GcGM3.

Only few studies have described the anti-tumor properties of natural antibodies (NAbs). In particular, natural IgM have been linked to cancer immunosurveillance due to its preferential binding to tumor-specific glycolipids and carbohydrate structures. Neu5GcGM3 ganglioside is a sialic acid-containing glycosphingolipid that has been considered an attractive target for cancer immunotherapy, since it is not naturally expressed in healthy human tissues and it is overexpressed in several tumors. Screening of immortalized mouse peritoneal-derived hybridomas showed that peritoneal B-1 cells contain anti-Neu5GcGM3 antibodies on its repertoire, establishing a link between B-1 cells, NAbs and anti-tumor immunity. Previously, we described the existence of naturally-occurring anti-Neu5GcGM3 antibodies with anti-tumor properties in healthy young humans. Interestingly, anti-Neu5GcGM3 antibodies level decreases with age and is almost absent in non-small cell lung cancer patients. Although anti-Neu5GcGM3 antibodies may be clinically relevant, the identity of the human B cells participating in this anti-tumor antibody response is unknown. In this work, we found an increased percentage of circulating human B-1 cells in healthy individuals with anti-Neu5GcGM3 IgM antibodies. Furthermore, anti-Neu5GcGM3 IgMs were generated predominantly by human B-1 cells and the antibodies secreted by these B-1 lymphocytes also recognized Neu5GcGM3-positive tumor cells. These data suggest a protective role for human B-1 cells against malignant transformation through the production of NAbs reactive to tumor-specific antigens such as Neu5GcGM3 ganglioside.

Enforced mesenchymal stem cell tissue colonization counteracts immunopathology.

Mesenchymal stem/stromal cells (MSCs) are distributed within all tissues of the body. Though best known for generating connective tissue and bone, these cells also display immunoregulatory properties. A greater understanding of MSC cell biology is urgently needed because culture-expanded MSCs are increasingly being used in treatment of inflammatory conditions, especially life-threatening immune diseases. While studies in vitro provide abundant evidence of their immunomodulatory capacity, it is unknown whether tissue colonization of MSCs is critical to their ability to dampen/counteract evolving immunopathology in vivo. To address this question, we employed a murine model of fulminant immune-mediated inflammation, acute graft-versus-host disease (aGvHD), provoked by donor splenocyte-enriched full MHC-mismatched hematopoietic stem cell transplant. aGvHD induced the expression of E-selectin within lesional endothelial beds, and tissue-specific recruitment of systemically administered host-derived MSCs was achieved by enforced expression of HCELL, a CD44 glycoform that is a potent E-selectin ligand. Compared to mice receiving HCELL- MSCs, recipients of HCELL+ MSCs had increased MSC intercalation within aGvHD-affected site(s), decreased leukocyte infiltrates, lower systemic inflammatory cytokine levels, superior tissue preservation, and markedly improved survival. Mechanistic studies reveal that ligation of HCELL/CD44 on the MSC surface markedly potentiates MSC immunomodulatory activity by inducing MSC secretion of a variety of potent immunoregulatory molecules, including IL-10. These findings indicate that MSCs counteract immunopathology in situ, and highlight a role for CD44 engagement in unleashing MSC immunobiologic properties that maintain/establish tissue immunohomeostasis.

Altered transcriptional responses in the lungs of aged mice after influenza infection.

BACKGROUND: Influenza causes a serious infection in older individuals who are at the highest risk for mortality from this virus. Changes in the immune system with age are well known. This study used transcriptomic analysis to evaluate how aging specifically affects the functional host response to influenza in the lung. Adult (12-16 weeks) and aged (72-76 weeks) mice were infected with influenza and lungs were processed for RNA analysis. RESULTS: Older mice demonstrated a delayed anti-viral response on the level of transcription compared to adults, similar to the immunologic responses measured in prior work. The transcriptional differences, however, were evident days before observable differences in the protein responses described previously. The transcriptome response to influenza in aged mice was dominated by immunoglobulin genes and B cell markers compared to adult animals, suggesting immune dysregulation. Despite these differences, both groups of mice had highly similar transcriptional responses involving non-immune genes one day after inoculation and T cell genes during resolution. CONCLUSIONS: These results define a delayed and dysregulated immune response in the lungs of aged mice infected with influenza. The findings implicate B cells and immunoglobulins as markers or mechanisms of immune aging. In addition to discovering new therapeutic targets, the findings underscore the value of transcription studies and network analysis to characterize complex biological processes, and serve as a model to analyze the susceptibility of the elderly to infectious agents.

Breakthrough Infections Following mRNA SARS-CoV-2 Vaccination in Kidney Transplant Recipients.

BACKGROUND: The clinical effectiveness of coronavirus disease 2019 (COVID-19) vaccination in kidney transplant (KT) recipients is lower than in the general population. METHODS: From April to October 2021, 481 KT recipients with COVID-19, included in the Spanish Society of Nephrology COVID-19 Registry, were analyzed. Data regarding vaccination status and vaccine type were collected, and outcomes of unvaccinated or partially vaccinated patients (n = 130) were compared with fully vaccinated patients (n = 351). RESULTS: Clinical picture was similar and survival analysis showed no differences between groups: 21.7% of fully vaccinated patients and 20.8% of unvaccinated or partially vaccinated died (P = 0.776). In multivariable analysis, age and pneumonia were independent risk factors for death, whereas vaccination status was not related to mortality. These results remained similar when we excluded patients with partial vaccination, as well as when we analyzed exclusively hospitalized patients. Patients vaccinated with mRNA-1273 (n = 213) showed a significantly lower mortality than those who received the BNT162b2 vaccine (n = 121) (hazard ratio: 0.52; 95% confidence interval, 0.31-0.85; P = 0.010). CONCLUSIONS: COVID-19 severity in KT patients has remained high and has not improved despite receiving 2 doses of the mRNA vaccine. The mRNA-1273 vaccine shows higher clinical effectiveness than BNT162b2 in KT recipients with breakthrough infections. Confirmation of these data will require further research taking into account the new variants and the administration of successive vaccine doses.

Tear 1H Nuclear Magnetic Resonance-Based Metabolomics Application to the Molecular Diagnosis of Aqueous Tear Deficiency and Meibomian Gland Dysfunction.

PURPOSE: Meibomian gland dysfunction (MGD) is a major cause of signs and symptoms related to dry eyes (DE) and eyelid inflammation. We investigated the composition of human tears by metabolomic approaches in patients with aqueous tear deficiency and MGD. METHODS: Participants in this prospective, case-control pilot study were split into patients with aqueous tear deficiency and MGD (DE-MGD [n = 15]) and healthy controls (CG; n = 20). Personal interviews, ocular surface disease index (OSDI), and ophthalmic examinations were performed. Reflex tears collected by capillarity were processed to 1H nuclear magnetic resonance (NMR) spectroscopy and quantitative data analysis to identify molecules by spectra comparison to library entries of purified standards and/or unknown entities. Statistical analyses were made by the SPSS 22.0 program. RESULTS: Chemometric analysis and 1H NMR spectra comparison revealed the presence of 60 metabolites in tears. Differentiating features were evident in the NMR spectra of the 2 clinical groups, characterized by significant upregulation of phenylalanine, glycerol, and isoleucine, and downregulation of glycoproteins, leucine, and -CH3 lipids, as compared to the CG. The 1H NMR metabolomic analyses of human tears confirmed the applicability of this platform with high predictive accuracy/reliability. CONCLUSIONS: Our key distinctive findings support that DE-MGD induces tear metabolomics profile changes. Metabolites contributing to a higher separation from the CG can presumably be used, in the foreseeable future, as DE-MGD biomarkers for better managing the diagnosis and therapy of this disease.

Exofucosylation of Adipose Mesenchymal Stromal Cells Alters Their Secretome Profile.

Mesenchymal stromal cells (MSCs) constitute the cell type more frequently used in many regenerative medicine approaches due to their exclusive immunomodulatory properties, and they have been reported to mediate profound immunomodulatory effects in vivo. Nevertheless, MSCs do not express essential adhesion molecules actively involved in cell migration, a phenotypic feature that hampers their ability to home inflamed tissues following intravenous administration. In this study, we investigated whether modification by fucosylation of murine AdMSCs (mAdMSCs) creates Hematopoietic Cell E-/L-selectin Ligand, the E-selectin-binding CD44 glycoform. This cell surface glycan modification of CD44 has previously shown in preclinical studies to favor trafficking of mAdMSCs to inflamed or injured peripheral tissues. We analyzed the impact that exofucosylation could have in other innate phenotypic and functional properties of MSCs. Compared to unmodified counterparts, fucosylated mAdMSCs demonstrated higher in vitro migration, an altered secretome pattern, including increased expression and secretion of anti-inflammatory molecules, and a higher capacity to inhibit mitogen-stimulated splenocyte proliferation under standard culture conditions. Together, these findings indicate that exofucosylation could represent a suitable cell engineering strategy, not only to facilitate the in vivo MSC colonization of damaged tissues after systemic administration, but also to convert MSCs in a more potent immunomodulatory/anti-inflammatory cell therapy-based product for the treatment of a variety of autoimmune, inflammatory, and degenerative diseases.

Bone Marrow-Derived Mononuclear Cell Transplants Decrease Retinal Gliosis in Two Animal Models of Inherited Photoreceptor Degeneration.

Inherited photoreceptor degenerations are not treatable diseases and a frequent cause of blindness in working ages. In this study we investigate the safety, integration and possible rescue effects of intravitreal and subretinal transplantation of adult human bone-marrow-derived mononuclear stem cells (hBM-MSCs) in two animal models of inherited photoreceptor degeneration, the P23H-1 and the Royal College of Surgeons (RCS) rat. Immunosuppression was started one day before the injection and continued through the study. The hBM-MSCs were injected in the left eyes and the animals were processed 7, 15, 30 or 60 days later. The retinas were cross-sectioned, and L- and S- cones, microglia, astrocytes and Müller cells were immunodetected. Transplantations had no local adverse effects and the CD45+ cells remained for up to 15 days forming clusters in the vitreous and/or a 2-3-cells-thick layer in the subretinal space after intravitreal or subretinal injections, respectively. We did not observe increased photoreceptor survival nor decreased microglial cell numbers in the injected left eyes. However, the injected eyes showed decreased GFAP immunoreactivity. We conclude that intravitreal or subretinal injection of hBM-MSCs in dystrophic P23H-1 and RCS rats causes a decrease in retinal gliosis but does not have photoreceptor neuroprotective effects, at least in the short term. However, this treatment may have a potential therapeutic effect that merits further investigation.

Silibinin Differentially Decreases the Aggressive Cancer Phenotype in an In Vitro Model of Obesity and Prostate Cancer.

Aim: Obesity increases the risk for aggressive and fatal prostate cancer (PCa). The bioactive compound silibinin has been researched for its chemopreventative properties and may benefit obese or overweight individuals with PCa.Methods: This study used an in vitro model of obesity exposing prostate cancer cells to sera from obese, overweight, or normal weight males with or without the addition of silibinin. Molecular activity was assayed as well as the phenotype of PCa cells with various treatments.Results: Obesity increased the expression of proliferative signaling including COX-2, IL-6, AKT, ERK, and AR, which was attenuated with silibinin. Cell growth, and invasive capacity of prostate cancer cells was increased with obese and overweight sera, and silibinin was able to mitigate this affect. However, there are limitations to this study in that an in vivo model was not used to validate these in vitro results nor a co-culture model, which may better recapitulate the tumor microenvironment.Conclusions: Silibinin may be a safe intervention for those with or at risk for prostate cancer, and it may be the most beneficial for obese or overweight males.

Human B-1 Cells and B-1 Cell Antibodies Change With Advancing Age.

Age-related deficits in the immune system have been associated with an increased incidence of infections, autoimmune diseases, and cancer. Human B cell populations change quantitatively and qualitatively in the elderly. However, the function of human B-1 cells, which play critical anti-microbial and housekeeping roles, have not been studied in the older age population. In the present work, we analyzed how the frequency, function and repertoire of human peripheral blood B-1 cells (CD19+CD20+CD27+CD38low/intCD43+) change with age. Our results show that not only the percentage of B-1 cells but also their ability to spontaneously secrete IgM decreased with age. Further, expression levels of the transcription factors XBP-1 and Blimp-1 were significantly lower, while PAX-5, characteristic of non-secreting B cells, was significantly higher, in healthy donors over 65 years (old) as compared to healthy donors between 20 and 45 years (young). To further characterize the B-1 cell population in older individuals, we performed single cell sequencing analysis of IgM heavy chains from healthy young and old donors. We found reduced repertoire diversity of IgM antibodies in B-1 cells from older donors as well as differences in usage of certain VH and DH specific genes, as compared to younger. Overall, our results show impairment of the human B-1 cell population with advancing age, which might impact the quality of life and onset of disease within the elderly population.

Cryopreserved amniotic membrane in the treatment of diabetic foot ulcers: a case series.

OBJECTIVE: The amniotic membrane (AM) is a tissue with low immunogenity and high therapeutic potential due to its anti-inflammatory, anti-fibrotic and antimicrobial effects. This paper describes the use of cryopreserved amniotic membrane allografts to treat diabetic foot ulcers (DFUs) in patients with diabetes. METHOD: In this case series, AM was processed to obtain a final medicinal product: cryopreserved amniotic membrane. cryopreserved AM was applied every 7-10 days until total epithelialisation of the DFUs. RESULTS: A total of 14 patients with DFUs (median size: 12.30cm, (range: 0.52-42.5cm2) were treated and followed up until complete closure (median time: 20 weeks, range: 7-56 weeks). Patients received 4-40 AM applications. All patients in this study achieved complete epithelialisation of the wound. No adverse events were observed. CONCLUSION: AM is a feasible and safe treatment in complex DFUs. Furthermore, the treatment is successful in achieving epithelialisation of long-evolution, unhealed wounds resistant to conventional therapies.

A procedure to assess the spatial variability in the importance of abiotic factors affecting distributions: the case of world freshwater fishes.

Understanding the factors shaping species' distributions is a key longstanding topic in ecology with unresolved issues. The aims were to test whether the relative contribution of abiotic factors that set the geographical range of freshwater fish species may vary spatially and/or may depend on the geographical extent that is being considered. The relative contribution of factors, to discriminate between the conditions prevailing in the area where the species is present and those existing in the considered extent, was estimated with the instability index included in the R package SPEDInstabR. We used 3 different extent sizes: 1) each river basin where the species is present (local); 2) all river basins where the species is present (regional); and 3) the whole Earth (global). We used a data set of 16,543 freshwater fish species with a total of 845,764 geographical records, together with bioclimatic and topographic variables. Factors associated with temperature and altitude show the highest relative contribution to explain the distribution of freshwater fishes at the smaller considered extent. Altitude and a mix of factors associated with temperature and precipitation were more important when using the regional extent. Factors associated with precipitation show the highest contribution when using the global extent. There was also spatial variability in the importance of factors, both between species and within species and from region to region. Factors associated with precipitation show a clear latitudinal trend of decreasing in importance toward the equator.

GM3(Neu5Gc) ganglioside: an evolution fixed neoantigen for cancer immunotherapy.

Numerous molecules have been considered as targets for cancer immunotherapy because of their levels of expression on tumor cells, their putative importance for tumor biology, and relative immunogenicity. In this review we focus on the ganglioside GM3(Neu5Gc), a glycosphingolipid present on the outer side of the plasma membrane of vertebrate cells. The reasons for selecting GM3(Neu5Gc) as a tumor-specific antigen and its use as a target for cancer immunotherapy are discussed, together with the development of antitumor therapies focused on this target by the Center of Molecular Immunology (CIM, Cuba).

A Dual Interaction Between the 5'- and 3'-Ends of the Melon Necrotic Spot Virus (MNSV) RNA Genome Is Required for Efficient Cap-Independent Translation.

In eukaryotes, the formation of a 5'-cap and 3'-poly(A) dependent protein-protein bridge is required for translation of its mRNAs. In contrast, several plant virus RNA genomes lack both of these mRNA features, but instead have a 3'-CITE (for cap-independent translation enhancer), a RNA element present in their 3'-untranslated region that recruits translation initiation factors and is able to control its cap-independent translation. For several 3'-CITEs, direct RNA-RNA long-distance interactions based on sequence complementarity between the 5'- and 3'-ends are required for efficient translation, as they bring the translation initiation factors bound to the 3'-CITE to the 5'-end. For the carmovirus melon necrotic spot virus (MNSV), a 3'-CITE has been identified, and the presence of its 5'-end in cis has been shown to be required for its activity. Here, we analyze the secondary structure of the 5'-end of the MNSV RNA genome and identify two highly conserved nucleotide sequence stretches that are complementary to the apical loop of its 3'-CITE. In in vivo cap-independent translation assays with mutant constructs, by disrupting and restoring sequence complementarity, we show that the interaction between the 3'-CITE and at least one complementary sequence in the 5'-end is essential for virus RNA translation, although efficient virus translation and multiplication requires both connections. The complementary sequence stretches are invariant in all MNSV isolates, suggesting that the dual 5'-3' RNA:RNA interactions are required for optimal MNSV cap-independent translation and multiplication.