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Background: MHC-E restricted T-cell responses have been observed in SIV-vaccine strategies using CMV-based vectors but their contribution to virus control is unclear. HLA-E was originally identified as a ligand of some NKG2 family receptors expressed by NK cells. Two highly frequent, functional, HLA-E alleles (*01:01 and *01:03) have been defined and T-cell responses to bacterial and viral pathogens restricted by these molecules have been described. Methods: In order to evaluate the interaction of HLA-E-presented viral epitopes with NK- and T-cell receptors, we modeled the structural interaction of HLA-E presenting canonical (VL9) and non-canonical (HIV-derived RL9 and PM9) epitopes with NKG2A/2C or TCR. We determined the ability of 14 peptides (including VL9, 1 CMV-, 1 EBV-and 11 HIV-derived) to stabilize HLA-E *01:01 and *01:03 and how this modified NK degranulation and cytotoxic activity. In vitro inhibition of viral replication by NK cells was assessed in autologous HIV infected CD4+ T-cells from HIV-seronegative individuals (N = 12). HLA-E expression on these target cells was assessed by RT-PCR and flow cytometry. The relationship of HLA-E expression with in-vivo HIV control was tested by measuring HLA-E expression in HIV-controllers (N = 31) and non-controllers (N = 16) by RT-PCR. Results: Our structural models evidenced that TCR have less affinity for HLA-E than NKG2 receptors. Interestingly, HIV peptides RL9 or PM9 presented by HLA-E*01:01 or HLA-E*01:03 showed a predicted increase in affinity to NKG2A and NKG2C, respectively. In vitro experiments indicated that HLA-E*01:01 was generally less stable on the cell surface, but none of HIV-derived peptides stabilized HLA-E. HIV KG9-HLA-E*01*03 and RL9/TP9/VI9/YG9-HLA-E*01*01 decreased NK cytokine secretion. RL9/MD9-HLA-E*01:01 resulted in increased lysis of peptide pulsed target cells. NK-mediated inhibition of viral replication correlated positively with HLA-E expression. Conversely, in HIV-infected individuals, HLA-E expression on total PBMC was significantly higher in non-controller individuals. Conclusions: The elevated expression of HLA-E in uncontrolled HIV infection and its potential differential interaction with NKG2 molecules depending on peptide binding indicates a pivotal role in NK during HIV infection. As such, HLA-E presenting HIV-derived epitopes may sensitize target cells for NK lysis in early infection whereas prolonged, elevated expression of HLA-E may lead to NK reduced viral control., OA05.01 L. Romero-Martin (1); C. Duran-Castells (1); M. Olivella (2); M. Rosas-Umbert (1); M. Ruiz-Riol (1); A. Olvera (1) and C. Brander (1) (1) Institut de Recerca de la Sida [...]

In this work, two vegetable wastes (i.e. grape stalks and cork bark) have been investigated as potential sorbents for the removal of the dye basic violet 14 or commonly named basic fuchsin from aqueous solution. The physical and chemical properties of grape stalks and cork bark defined by elemental analysis, polarity index, acidic functional groups, FTIR analysis, surface area and porosity were investigated to explain the different sorption behaviour of these two sorbents towards basic fuchsin removal. Effect of solution pH on basic fuchsin sorption onto both vegetable wastes has been investigated and sorption kinetics and isotherms determined. Results have been compared to those obtained using a commercial activated carbon. Langmuir maximum sorption capacity of grape stalks (106.8 mg g−1 ) estimated by the orthogonal distance regression method was of similar magnitude to that obtained by activated carbon (158.5 mg g−1 ) but cork bark (29.9 mg g−1) resulted to be about five times less effective than activated carbon. The textural results indicate that grape stalks and cork bark present a remarkable macropore surface area with a minor contribution of mesopores. The large pore size exhibited by both sorbents surface seems to be unable to efficiently uptake such small basic fuchsin molecules. The lower sorption capacity shown by cork bark compared to that of grape stalks may be explained by surface chemistry effects. Basic fuchsin sorption is not favoured by the presence of acidic functional groups on the sorbent surface. Acidic groups such as hydroxyl groups may promote the formation of hydration clusters that effectively reduce and/or hinder electrostatic and π interactions between basic fuchsin and the sorbents surface. FTIR analysis revealed that lignin moieties on the sorbents surface play a significant role on the dye sorption. As a final remark, the knowledge of some physical and chemical properties of the sorbents can be helpful for predicting their sorption affinity for organic pollutants. [ABSTRACT FROM AUTHOR]

Chromium (VI) removal and its reduction to chromium (III) from aqueous solution by untreated and heat-treated Quercus cerris and heat-treated Quercus suber black agglomerate cork granules was investigated. Initial screening studies revealed that among the sorbents tested, untreated Q. cerris and Q. suber black agglomerate are the most efficient in the removal of Cr(VI) ions and were selected for adsorption essays. Heat treatment adversely affected chromium adsorption and chromium (VI) reduction in Q. cerris cork. The highest metal uptake was found at pH 3.0 for Q. cerris and pH 2.0 for black agglomerate. The experimental data fitted the Langmuir model and the calculated qmax was 22.98 mg/g in black agglomerate and 21.69 mg/g in untreated Q. cerris cork. The FTIR results indicated that while in black agglomerate, lignin is the sole component responsible for Cr(VI) sorption, and in untreated Q. cerris cork, suberin and polysaccharides also play a significant role on the sorption. The SEM-EDX results imply that chromium has a homogenous distribution within both cork granules. Also, phloemic residues in Q. cerris granules showed higher chromium concentration. The results obtained in this study show that untreated Q. cerris and black agglomerate cork granules can be an effective and economical alternative to more costly materials for the treatment of liquid wastes containing chromium. [ABSTRACT FROM AUTHOR]

Two vegetable wastes, cork bark and grape stalks, were investigated for the removal of methylene blue from aqueous solution. The effects of contact time, dye concentration, pH, and temperature on sorption were studied relative to adsorption on a commercially-activated carbon. The highest adsorption yield was obtained within the pH range 5 to 10 for grape stalks and 7 to 10 for cork bark. The sorption kinetics of dye onto activated carbon and grape stalks was very fast. Kinetics data were fitted to the pseudo-first and second order kinetic equations, and the values of the pseudo-second-order initial rate constants were found to be 1.69 mg g-1 min-1 for activated carbon, 2.24 mg g-1 min-1 for grape stalks, and 0.90 mg g-1 min-1 for cork bark. Langmuir maximum sorption capacities for activated carbon, grape stalks, and cork bark for methylene blue estimated by the Orthogonal Distance Regression method (ODR) were 157.5 mg g-1, 105.6 mg g-1, and 30.52 mg g-1, respectively. FTIR spectra indicated that carboxylic groups and lignin play a significant role in the sorption of methylene blue. Electrostatic forces, n-π interactions, cation-π, and π- π stacking interactions contribute to methylene blue sorption onto grape stalks and cork bark. Grape stalks can be considered an efficient biosorbent and as a viable alternative to activated carbon and ion-exchange resins for the removal of methylene blue. [ABSTRACT FROM AUTHOR]

In previous studies we found significant differences in the suberin content with respect to the bark layer of Quercus suber samples. In this study the monomer composition of suberin from the two bark layers (i.e., back and cork) of three provenances (Extremadura, Castile-la Mancha, and Portugal) was investigated using pyrolysis in the presence of tetramethylammonium hydroxide (TMAH) with gas chromatography-mass spectrometry (GC/MS). The major compounds released were octadec-9-enedioic acid, docosanedioic acid, and 9,10-epoxyocta-decanedioic acid with mean values of 17%, 14.5%, and 11%, respectively. The former is more abundant in back than in cork, and the latter in cork than in back with mean differences, in terms of percentages, between the back and cork of 4.3 ± 0.81 and 2.2 ± 0.52, respectively. [ABSTRACT FROM AUTHOR]

Sirtuin 7 (SIRT7) is a member of the mammalian family of nicotinamide adenine dinucleotide (NAD + )-dependent histone/protein deacetylases, known as sirtuins. It acts as a potent oncogene in numerous malignancies, but the molecular mechanisms employed by SIRT7 to sustain lung cancer progression remain largely uncharacterized. We demonstrate that SIRT7 exerts oncogenic functions in lung cancer cells by destabilizing the tumor suppressor alternative reading frame (ARF). SIRT7 directly interacts with ARF and prevents binding of ARF to nucleophosmin, thereby promoting proteasomal-dependent degradation of ARF. We show that SIRT7-mediated degradation of ARF increases expression of protumorigenic genes and stimulates proliferation of non-small-cell lung cancer (NSCLC) cells both in vitro and in vivo in a mouse xenograft model. Bioinformatics analysis of transcriptome data from human lung adenocarcinomas revealed a correlation between SIRT7 expression and increased activity of genes normally repressed by ARF. We propose that disruption of SIRT7-ARF signaling stabilizes ARF and thus attenuates cancer cell proliferation, offering a strategy to mitigate NSCLC progression., Competing Interests: Competing interests statement:The authors declare no competing interest.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The study of inborn errors of neurotransmission has been mostly focused on monoamine disorders, GABAergic and glycinergic defects. The study of the glutamatergic synapse using the same approach than classic neurotransmitter disorders is challenging due to the lack of biomarkers in the CSF. A metabolomic approach can provide both insight into their molecular basis and outline novel therapeutic alternatives. We have performed a semi-targeted metabolomic analysis on CSF samples from 25 patients with neurogenetic disorders with an important expression in the glutamatergic synapse and 5 controls. Samples from patients diagnosed with MCP2, CDKL5-, GRINpathies and STXBP1-related encephalopathies were included. We have performed univariate (UVA) and multivariate statistical analysis (MVA), using Wilcoxon rank-sum test, principal component analysis (PCA), and OPLS-DA. By using the results of both analyses, we have identified the metabolites that were significantly altered and that were important in clustering the respective groups. On these, we performed pathway- and network-based analyses to define which metabolic pathways were possibly altered in each pathology. We have observed alterations in the tryptophan and branched-chain amino acid metabolism pathways, which interestingly converge on LAT1 transporter-dependency to cross the blood-brain barrier (BBB). Analysis of the expression of LAT1 transporter in brain samples from a mouse model of Rett syndrome (MECP2) revealed a decrease in the transporter expression, that was already noticeable at pre-symptomatic stages. The study of the glutamatergic synapse from this perspective advances the understanding of their pathophysiology, shining light on an understudied feature as is their metabolic signature., (© 2023 SSIEM.)

The objective of the study is to evaluate the evolving phenotype and genetic spectrum of patients with succinic semialdehyde dehydrogenase deficiency (SSADHD) in long-term follow-up. Longitudinal clinical and biochemical data of 22 pediatric and 9 adult individuals with SSADHD from the patient registry of the International Working Group on Neurotransmitter related Disorders (iNTD) were studied with in silico analyses, pathogenicity scores and molecular modeling of ALDH5A1 variants. Leading initial symptoms, with onset in infancy, were developmental delay and hypotonia. Year of birth and specific initial symptoms influenced the diagnostic delay. Clinical phenotype of 26 individuals (median 12 years, range 1.8-33.4 years) showed a diversifying course in follow-up: 77% behavioral problems, 76% coordination problems, 73% speech disorders, 58% epileptic seizures and 40% movement disorders. After ataxia, dystonia (19%), chorea (11%) and hypokinesia (15%) were the most frequent movement disorders. Involvement of the dentate nucleus in brain imaging was observed together with movement disorders or coordination problems. Short attention span (78.6%) and distractibility (71.4%) were the most frequently behavior traits mentioned by parents while impulsiveness, problems communicating wishes or needs and compulsive behavior were addressed as strongly interfering with family life. Treatment was mainly aimed to control epileptic seizures and psychiatric symptoms. Four new pathogenic variants were identified. In silico scoring system, protein activity and pathogenicity score revealed a high correlation. A genotype/phenotype correlation was not observed, even in siblings. This study presents the diversifying characteristics of disease phenotype during the disease course, highlighting movement disorders, widens the knowledge on the genotypic spectrum of SSADHD and emphasizes a reliable application of in silico approaches., (© 2024 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Background: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability., Methods: A clinical and histopathological characterisation of 25 Roma individuals with LGMD R18 caused by the homozygous TRAPPC11 c.1287+5G>A variant is reported. Functional effects of the variant on mitochondrial function were investigated., Results: The c.1287+5G>A variant leads to a phenotype characterised by early onset muscle weakness, movement disorder, intellectual disability and elevated serum creatine kinase, which is similar to other series. As novel clinical findings, we found that microcephaly is almost universal and that infections in the first years of life seem to act as triggers for a psychomotor regression and onset of seizures in several individuals with TRAPPC11 variants, who showed pseudometabolic crises triggered by infections. Our functional studies expanded the role of TRAPPC11 deficiency in mitochondrial function, as a decreased mitochondrial ATP production capacity and alterations in the mitochondrial network architecture were detected., Conclusion: We provide a comprehensive phenotypic characterisation of the pathogenic variant TRAPPC11 c.1287+5G>A, which is founder in the Roma population. Our observations indicate that some typical features of golgipathies, such as microcephaly and clinical decompensation associated with infections, are prevalent in individuals with LGMD R18., Competing Interests: Competing interests: Authors report no disclosures. ÀG-C has received honoraria for lectures from PTC Therapeutics International GT, Immedica, Biomarin and Recordati Rare Diseases Foundation; she has also received a research grant from PTC Therapeutics and is a co-founder of the Sant Joan de Déu start up ‘Neuroprotect Life Sciences’., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)