Functional redundancy revealed by the deletion of the mimivirus GMC-oxidoreductase genes.

The mimivirus 1.2 Mb genome was shown to be organized into a nucleocapsid-like genomic fiber encased in the nucleoid compartment inside the icosahedral capsid. The genomic fiber protein shell is composed of a mixture of two GMC-oxidoreductase paralogs, one of them being the main component of the glycosylated layer of fibrils at the surface of the virion. In this study, we determined the effect of the deletion of each of the corresponding genes on the genomic fiber and the layer of surface fibrils. First, we deleted the GMC-oxidoreductase, the most abundant in the genomic fiber, and determined its structure and composition in the mutant. As expected, it was composed of the second GMC-oxidoreductase and contained 5- and 6-start helices similar to the wild-type fiber. This result led us to propose a model explaining their coexistence. Then we deleted the GMC-oxidoreductase, the most abundant in the layer of fibrils, to analyze its protein composition in the mutant. Second, we showed that the fitness of single mutants and the double mutant were not decreased compared with the wild-type viruses under laboratory conditions. Third, we determined that deleting the GMC-oxidoreductase genes did not impact the glycosylation or the glycan composition of the layer of surface fibrils, despite modifying their protein composition. Because the glycosylation machinery and glycan composition of members of different clades are different, we expanded the analysis of the protein composition of the layer of fibrils to members of the B and C clades and showed that it was different among the three clades and even among isolates within the same clade. Taken together, the results obtained on two distinct central processes (genome packaging and virion coating) illustrate an unexpected functional redundancy in members of the family Mimiviridae, suggesting this may be the major evolutionary force behind their giant genomes.

Clinical course and disease burden of patients with generalized pustular psoriasis in Portugal: a multicenter retrospective cohort study.

OBJECTIVES: Generalized pustular psoriasis (GPP) is a rare, life-threatening skin inflammatory disorder. This study aimed to describe the disease course, treatment strategies, and healthcare utilization among patients with GPP in Portugal. METHODS: This multicentric, observational, retrospective study included consecutive adult patients with GPP undergoing a dermatology evaluation in different reporting institutions by experienced dermatologists between 2002 and 2023. RESULTS: A total of 59 patients were assessed. Most of the cohort had a previous history of plaque psoriasis (71%) and 83% presented at least one comorbidity. At the initial encounter, 64% of the cohort needed hospitalization. Systemic involvement was common, including fever (37%), and elevated white blood cell count and erythrocyte sedimentation rate/C-reactive protein (49%). Nearly, 73% of patients initiated systemic drugs, and 70% had to discontinue the first treatment. During the study, 98% of patients experienced at least one flare. At the last visit, 3.4% of patients had died, and 71.2% exhibited signs of active disease despite undergoing treatment. CONCLUSIONS: Our study demonstrates that GPP is a chronic, debilitating condition associated with systemic involvement, frequent flares, and hospitalizations, despite receiving multiple systemic treatments. Improved disease awareness and new treatments are needed to improve patient care and decrease the burden of the disease.

A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

Characterisation of a capsular polysaccharide from Moraxella nonliquefaciens CCUG 348T.

Moraxella nonliquefaciens is a commensal of the human upper respiratory tract (URT) but on rare occasions is recovered in cases of ocular, septic and pulmonary infections. Hence there is interest in the pathogenic determinants of M. nonliquefaciens, of which outer membrane (OM) structures such as fimbriae and two capsular polysaccharide (CPS) structures, →3)-ß-D-GalpNAc-(1→5)-ß-Kdop-(2→ and →8)-α-NeuAc-(2→, have been reported in the literature. To further characterise its surface virulence factors, we isolated a novel CPS from M. nonliquefaciens type strain CCUG 348T. This structure was elucidated using NMR data obtained from CPS samples that were subjected to various degrees of mild acid hydrolysis. Together with GLC-MS data, the structure was resolved as a linear polymer composed of two GalfNAc residues consecutively added to Kdo, →3)-ß-D-GalfNAc-(1→3)-α-D-GalfNAc-(1→5)-α-(8-OAc)Kdop-(2→. Supporting evidence for this material being CPS was drawn from the proposed CPS biosynthetic locus which encoded a potential GalfNAc transferase, a UDP-GalpNAc mutase for UDP-GalfNAc production and a putative CPS polymerase with predicted GalfNAc and Kdo transferase domains. This study describes a unique CPS composition reported in Moraxella spp. and offers genetic insights into the synthesis and expression of GalfNAc residues, which are rare in bacterial OM glycans.

Wall teichoic acid substitution with glucose governs phage susceptibility of Staphylococcus epidermidis.

The species- and clone-specific susceptibility of Staphylococcus cells for bacteriophages is governed by the structures and glycosylation patterns of wall teichoic acid (WTA) glycopolymers. The glycosylation-dependent phage-WTA interactions in the opportunistic pathogen Staphylococcus epidermidis and in other coagulase-negative staphylococci (CoNS) have remained unknown. We report a new S. epidermidis WTA glycosyltransferase TagE whose deletion confers resistance to siphoviruses such as ΦE72 but enables binding of otherwise unbound podoviruses. S. epidermidis glycerolphosphate WTA was found to be modified with glucose in a tagE-dependent manner. TagE is encoded together with the enzymes PgcA and GtaB providing uridine diphosphate-activated glucose. ΦE72 transduced several other CoNS species encoding TagE homologs, suggesting that WTA glycosylation via TagE is a frequent trait among CoNS that permits interspecies horizontal gene transfer. Our study unravels a crucial mechanism of phage-Staphylococcus interaction and horizontal gene transfer, and it will help in the design of anti-staphylococcal phage therapies.IMPORTANCEPhages are highly specific for certain bacterial hosts, and some can transduce DNA even across species boundaries. How phages recognize cognate host cells remains incompletely understood. Phages infecting members of the genus Staphylococcus bind to wall teichoic acid (WTA) glycopolymers with highly variable structures and glycosylation patterns. How WTA is glycosylated in the opportunistic pathogen Staphylococcus epidermidis and in other coagulase-negative staphylococci (CoNS) species has remained unknown. We describe that S. epidermidis glycosylates its WTA backbone with glucose, and we identify a cluster of three genes responsible for glucose activation and transfer to WTA. Their inactivation strongly alters phage susceptibility patterns, yielding resistance to siphoviruses but susceptibility to podoviruses. Many different CoNS species with related glycosylation genes can exchange DNA via siphovirus ΦE72, suggesting that glucose-modified WTA is crucial for interspecies horizontal gene transfer. Our finding will help to develop antibacterial phage therapies and unravel routes of genetic exchange.

Identification of a capsular polysaccharide from Enterococcus faecium U0317 using a targeted approach to discover immunogenic carbohydrates for vaccine development.

Enterococcus faecium, a gram-positive opportunistic pathogen, has become a major concern for nosocomial infections due to its resistance to several antibiotics, including vancomycin. Finding novel alternatives for treatment prevention, such as vaccines, is therefore crucial. In this study, we used various techniques to discover a novel capsular polysaccharide. Firstly, we identified an encapsulated E. faecium strain by evaluating the opsonophagocytic activity of fifteen strains with antibodies targeting the well-known lipoteichoic acid antigen. This activity was attributed to an unknown polysaccharide. We then prepared a crude cell wall glycopolymer and fractionated it, guided by immunodot-blot analysis. The most immunoreactive fractions were used for opsonophagocytic inhibition assays. The fraction containing the inhibitory polysaccharide underwent structural characterization using NMR and chemical analyses. The elucidated structure presents a branched repeating unit, with the linear part being: →)-ß-d-Gal-(1 â†’ 4)-ß-d-Glc-(1 â†’ 4)-ß-d-Gal-(1 â†’ 4)-ß-d-GlcNAc-(1→, further decorated with a terminal α-d-Glc and a d-phosphoglycerol moiety, attached to O-2 and O-3 of the 4-linked Gal unit, respectively. This polysaccharide was conjugated to BSA and the synthetic glycoprotein used to immunize mice. The resulting sera exhibited good opsonic activity, suggesting its potential as a vaccine antigen. In conclusion, our effector-function-based approach successfully identified an immunogenic capsular polysaccharide with promising applications in immunotherapy.

Moraxella ovis and Moraxella bovoculi lipooligosaccharide biosynthesis genes, and structural characterisation of oligosaccharide from M. ovis 354T.

Moraxella ovis is a Gram-negative bacterium isolated from sheep conjunctivitis cases and is a rare isolate of infectious bovine keratoconjunctivitis (IBK). This species is closely related to M. bovoculi, another species which can also be isolated from IBK, or cattle upper respiratory tract (URT). Prior to molecular identification techniques, M. bovoculi was frequently misclassified as M. ovis. We previously described the structure of two oligosaccharides (lipooligosaccharide-derived, minor and major glycoforms) from M. bovoculi 237T (type strain, also ATCC BAA-1259T). Here, we have identified the genetic loci for lipooligosaccharide synthesis in M. ovis 354T (NCTC11227) and compared it with M. bovoculi 237T. We identified genes encoding the known glycosyltransferases Lgt6 and Lgt3 in M.ovis. These genes are conserved in Moraxella spp., including M bovoculi. We identified three further putative OS biosynthesis genes that are restricted to M. ovis and M. bovoculi. These encode enzymes predicted to function as GDP-mannose synthases, namely a mannosyltransferase and a glycosyltransferase. Adding insight into the genetic relatedness of M.ovis and M. bovoculi, the M. ovis genes have higher similarity to those in M. bovoculi genotype 2 (nasopharyngeal isolates from asymptomatic cattle), than to M. bovoculi genotype 1 (isolates from eyes of IBK-affected cattle). Sequence analysis confirmed that the predicted mannosyltransferase in M. bovoculi 237T is interrupted by a C>T polymorphism. This mutation is not present in other M. bovoculi strains sequenced to date. We isolated and characterised LOS-derived oligosaccharide from M. ovis 354T. GLC-MS and NMR spectroscopy data revealed a heptasaccharide structure with three ß-D-Glcp residues attached as branches to the central 3,4,6-α-D-Glcp, with subsequent attachment to Kdo. This inner core arrangement is consistent with the action of Lgt6 and Lgt3 glycosyltransferases. Two α-D-Manp residues are linearly attached to the 4-linked ß-D-Glcp, consistent with the presence of the two identified glycosyltransferases. This oligosaccharide structure is consistent with the previously reported minor glycoform isolated from M. bovoculi 237T.

Use of Picosecond Laser for Melasma Treatment: A Narrative Review.

Background: Melasma results from the imbalance of the mechanisms that regulate skin pigmentation, causing the appearance of hyperpigmented patches. Treatment includes topical and oral agents, chemical peelings, microneedling, and laser therapy. The picosecond laser was developed to minimize pain and skin discoloration, which can sometimes be associated with laser treatments. It emits short pulses of energy that last from 300 to 500 picoseconds, leading to a more significant fragmentation of melanin, with miniminal risk of scarring and thermal lesions in the surrounding skin. Objective: The authors aimed to review the use of picosecond laser in the treatment of melasma and further provide an overview of the other current available options. Conclusions: While the use of picosecond laser for the treatment of melasma has yielded good results, further studies with longer follow-up periods and a higher number of patients are needed.

Comparative Analysis of the Physicochemical and Biological Characteristics of Freeze-Dried PEGylated Cationic Solid Lipid Nanoparticles.

Cationic solid-lipid nanoparticles (cSLNs) have become a promising tool for gene and RNA therapies. PEGylation (PEG) is crucial in enhancing particle stability and protection. We evaluated the impact of PEG on the physicochemical and biological characteristics of cholesteryl-oleate cSLNs (CO-cSLNs). Several parameters were analyzed, including the particle size, polydispersity index, zeta potential, shape, stability, cytotoxicity, and loading efficiency. Five different formulations with specific PEGs were developed and compared in both suspended and freeze-dried states. Small, homogeneous, and cationic suspended nanoparticles were obtained, with the Gelucire 50/13 (PEG-32 hydrogenated palm glycerides; Gelucire) and DSPE-mPEG2000 (1,2-distearoyl-phosphatidylethanolamine-methyl-polyethyleneglycol conjungate-2000; DSPE) formulations exhibiting the smallest particle size (~170 nm). Monodisperse populations of freeze-dried nanoparticles were also achieved, with particle sizes ranging from 200 to 300 nm and Z potential values of 30-35 mV. Notably, Gelucire again produced the smallest particle size (211.1 ± 22.4), while the DSPE and Myrj S100 (polyoxyethylene (100) stearate; PEG-100 Stearate) formulations had similar particle sizes to CO-cSLNs (~235 nm). The obtained PEGylated nanoparticles showed suitable properties: they were nontoxic, had acceptable morphology, were capable of forming SLNplexes, and were stable in both suspended and lyophilized states. These PEG-cSLNs are a potential resource for in vivo assays and have the advantage of employing cost-effective PEGs. Optimizing the lyophilization process and standardizing parameters are also recommended to maintain nanoparticle integrity.

Mucoadhesive capsules based on bacterial nanocellulose and chitosan as delivery system of turmeric extract.

Current efforts in stomach-related drug design focus on improving drug bioavailability within the gastric region. Bacterial nanocellulose (BNC) has been established as a suitable material for drug delivery systems; however, it lacks adhesion to the gastric environment. This limitation can be addressed by leveraging the mucoadhesive properties of low molecular weight chitosan (LMWC). Therefore, we aimed to develop mucoadhesive capsules constructed from BNC coated with crosslinked LMWC, intended for targeted drug delivery in the gastric region. The capsules were characterized using scanning electron microscopy, infrared spectroscopy, thermogravimetric analysis, and mucoadhesion assessments. Under acidic conditions, crosslinked chitosan exhibited enhanced swelling relative to neutral conditions. The coating of chitosan onto the BNC fibrillar network of the capsules resulted in the superimposition of vibration bands and enhanced thermal stability. Furthermore, the capsules exhibited significant mucoadhesive properties in the gastric environment, with an attachment force measuring 89.151 ± 6.226 mN. To validate the efficacy of the system, we utilized antioxidant turmeric extract (TE) as a bioactive compound with chemopreventive potential against stomach cancer. TE was adsorbed onto BNC in a reversible multilayer system, enabling controlled adsorption and desorption. These findings highlight the significance of developing mucoadhesive capsules as a tailored drug delivery system for gastric conditions, particularly in the context of treating stomach diseases as cancer.

Mapping sentinel lymph nodes in early-stage ovarian cancer (MELISA) trial - a further step towards lymphadenectomy replacement.

OBJECTIVE: Sistematic pelvic and para-aortic lymphadenectomy is part of the staging surgery for early-stage epithelial ovarian cancer, with no therapeutic value. The Mapping Sentinel Lymph Nodes In Early-Stage Ovarian Cancer (MELISA) trial prospectively assessed the SLN detection rate and the diagnostic accuracy of the SLN mapping technique in patients with early-stage epithelial ovarian cancer. METHODS: This prospective, single-arm study included patients diagnosed with early-stage epithelial ovarian cancer (FIGO stages I and II), via either primary surgery or re-staging surgery. SLN mapping was performed by injecting 0.2 mL of 37-mBq 99mTc-nanocoloid albumin and 2 mL of 2.5 mg/mL indocyanine green into the infundibulopelvic and utero-ovarian ligaments. After removal of SLNs, a complete systematic pelvic and para-aortic lymphadenectomy was performed. SLN Ultrastaging analysis was applied. The primary outcome was the overall SLN detection rate, either with one or both tracers. Secondary outcomes were the diagnostic accuracy of detecting lymph node metastases and factors that may influence SLN detection. RESULTS: Thirty patients were included. SLNs were identified in 27 patients (90%). Detection rates in primary and re-staging surgery were 89% and 92%, respectively. Para-aortic drainage was the predominant lymphatic spread, observed in 26 of 27 patients. Ultrastaging pathologic reports listed 1 SLN with macrometastasis, 1 with micrometastasis, and 5 with isolated tumor cells; the sensitivity of SLN mapping was 100%, with a false-negative rate of 0%. Univariate analysis showed a nonsignificant higher proportion of patients with uterine fibroids, adenomyosis, and endometriosis (100%, 67%, 67%, respectively) in patients in whom SLNs were not detected. CONCLUSION: SLN mapping has a high detection rate (90%) and is an accurate technique for detecting lymph node involvement in early-stage epithelial ovarian cancer. SLN mapping is a potential alternative to systematic lymphadenectomy to reduce associated morbidity, but further research is needed to evaluate the impact of SLN mapping on oncologic outcomes and its cost-effectiveness.

N-glycosylation in Archaea: Unusual sugars and unique modifications.

Archaea are microorganisms that comprise a distinct branch of the universal tree of life and which are best known as extremophiles, residing in a variety of environments characterized by harsh physical conditions. One seemingly universal trait of Archaea is the ability to perform N-glycosylation. At the same time, archaeal N-linked glycans present variety in terms of both composition and architecture not seen in the parallel eukaryal or bacterial processes. In this mini-review, many of the unique and unusual sugars found in archaeal N-linked glycans as identified by nuclear magnetic resonance spectroscopy are described.

The Evolution and Future Trends of Unsaturated Polyester Biocomposites: A Bibliometric Analysis.

Unsaturated polyester resin (UPR) is one of the first commercialized polymer matrices for composites reinforced with glass fibers, but has remained popular to this day. To reduce their environmental impact, natural fibers have been used as reinforcements. Researchers all over the world are still interested in these composites, and numerous papers have been published in the last four decades. Using bibliometric analysis, this work provides compiled, structured, and relevant information about the evolution and current state of these materials. This first study on UPR biocomposites based on bibliometric analysis examined 531 published papers identified in the Scopus database from 1982 to July 2022. An analysis of the most active states, leading institutions, and leading authors is followed by the identification of key areas such as the most common natural fibers used as reinforcements, fiber treatments, and composite design parameters such as processing techniques; recently, composite testing; and technological applications. The findings emphasize the importance of staying active in this global field and provide information on novel promising topics for future research.

Hybrid-APC treatment for gastric vascular ectasia of atypical location after failed radiofrequency ablation.

A 76-year-old woman was being followed up for chronic anemia secondary to bleeding from vascular ectasias at the gastric antrum and the cardial and subcardial region. On several occasions the patient required fulguration of these lesions with conventional APC, which resulted in no clear improvement. Radiofrequency ablation of these lesions was then attempted using a 90-degree probe, which was successful on antral angiodysplasias but failed to remove lesions in the cardial and subcardial region since anatomy there prevented proper apposition of the probe onto the target mucosa. Given the absence of any improvement, it was decided to use fulguration for angiectasias at the cardial and subcardial level by means of Hybrid-APC, which consists of lifting the mucosa with an injection through the APC probe and then fulgurating in the pulsedAPC® mode, thus achieving a broader ablation area in a shorter time. During the subsequent review a clear reduction of vascular ectasias was observed.

LncRNA ARGI Contributes to Virus-Induced Pancreatic ß Cell Inflammation Through Transcriptional Activation of IFN-Stimulated Genes.

Type 1 diabetes (T1D) is a complex autoimmune disease that develops in genetically susceptible individuals. Most T1D-associated single nucleotide polymorphisms (SNPs) are located in non-coding regions of the human genome. Interestingly, SNPs in long non-coding RNAs (lncRNAs) may result in the disruption of their secondary structure, affecting their function, and in turn, the expression of potentially pathogenic pathways. In the present work, the function of a virus-induced T1D-associated lncRNA named ARGI (Antiviral Response Gene Inducer) is characterized. Upon a viral insult, ARGI is upregulated in the nuclei of pancreatic ß cells and binds to CTCF to interact with the promoter and enhancer regions of IFNß and interferon-stimulated genes, promoting their transcriptional activation in an allele-specific manner. The presence of the T1D risk allele in ARGI induces a change in its secondary structure. Interestingly, the T1D risk genotype induces hyperactivation of type I IFN response in pancreatic ß cells, an expression signature that is present in the pancreas of T1D patients. These data shed light on the molecular mechanisms by which T1D-related SNPs in lncRNAs influence pathogenesis at the pancreatic ß cell level and opens the door for the development of therapeutic strategies based on lncRNA modulation to delay or avoid pancreatic ß cell inflammation in T1D.

Reengagement strategies for hepatitis C patients lost to follow-up: A randomized clinical trial.

BACKGROUND AND AIMS: To achieve the World Health Organization's goal of eliminating HCV by 2030, reengagement of lost to follow-up cases is mandatory. However, there is lack of evidence concerning the best strategy. Our study evaluated the effectiveness, efficiency, predictive factors, and costs of 2 different strategies. METHODS: We identified patients positive for HCV antibodies without RNA requests from 2005 to 2018. Patients fulfilling trial criteria (NCT04153708) were randomized to (1) phone call or (2) letter of invitation to schedule an appointment, followed by switching strategy. RESULTS: Three hundred forty-five patients among 1167 lost to follow-up were identified. An analysis of the first 270 randomized patients (72% male, 51±13 y) showed a higher contact rate in the mail than in the phone call strategy (84.5% vs. 50.3%). In the intention-to-treat analysis, no differences were found related to appointment attendance (26.5% vs. 28.5%). Regarding efficiency, 3.1 letters and 8 phone calls were needed to successfully link 1 patient (p<0.001) but dropped down to 2.3 phone calls if we only considered the first call attempt (p=0.008). Prior specialist's evaluation and HCV testing in the predirect-acting antiviral era were the only factors associated with no showing up for the appointment. The cost per patient was €621.3 (2.5 quality-adjusted life-years) in the phone call strategy and €611.8 (2.4 quality-adjusted life-years) in the mail letter strategy. CONCLUSIONS: Reengagement of patients with HCV is feasible, and equally effective with similar costs in both strategies. The mail letter was more efficient, except when only 1 phone call was considered. Prior specialist's evaluation and testing in the predirect-acting antiviral era were factors associated with nonattendance to the appointment.

Bacterial Nanocellulose from Komagataeibacter Medellinensis in Fique Juice for Activated Carbons Production and Its Application for Supercapacitor Electrodes.

This paper presents the results obtained from the chemical activation of bacterial nanocellulose (BCN) using fique juice as a culture medium. BNC activation (BNCA) was carried out with H3PO4 and KOH at activation temperatures between 500 °C to 800 °C. The materials obtained were characterized morphologically, physicochemically, superficially, and electrochemically, using scanning electron microscopy, X-ray photoelectron spectroscopy (XPS), the physisorption of gases N2 and CO2 at 77 K and 273 K, respectively, cyclic voltammetry, chronopotentiometry, and electrochemical impedance spectroscopy (EIS). The samples activated with H3PO4 presented specific surface areas (SBET) around 780 m2 g-1, while those activated with KOH values presented specific surface areas between 680 and 893 m2 g-1. The XPS analysis showed that the PXPS percentage on the surface after H3PO4 activation was 11 wt%. The energy storage capacitance values ranged between 97.5 F g-1 and 220 F g-1 by EIS in 1 M H2SO4. The samples with the best electrochemical performance were activated with KOH at 700 °C and 800 °C, mainly due to the high SBET available and the accessibility of the microporosity. The capacitance of BNCAs was mainly improved by electrostatic effects due to the SBET rather than that of pseudocapacitive ones due to the presence of phosphorus heteroatoms.

GLP-1R agonists demonstrate potential to treat Wolfram syndrome in human preclinical models.

AIMS/HYPOTHESIS: Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. METHODS: The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. RESULTS: Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. CONCLUSIONS/INTERPRETATION: Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome.