Search Results (3,472)

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder caused by mutations in the TYMP gene, typically characterized by severe and progressive gastrointestinal and neurological manifestations. Recent reports have identified a subset of patients presenting with generalized lipodystrophy and metabolic abnormalities, suggesting that adipose tissue involvement may be an underrecognized feature of the disease. Herein, we report the case of a 16-year-old female carrying a previously described homozygous TYMP variant (c.1178_1201dup; p.Arg393_Val400dup), who presented during adolescence with generalized lipodystrophy, insulin resistance, hypertriglyceridemia, hepatic steatosis, and other metabolic complications. At diagnosis, she exhibited no overt neurological or gastrointestinal symptoms; however, electroneurography revealed subclinical peripheral neuropathy. This case broadens the phenotypic spectrum of TYMP-related disease by documenting a lipodystrophic and metabolic presentation associated with the p.Arg393_Val400dup variant. While TYMP mutations have been linked to lipodystrophy in rare cases, this specific variant had previously been reported only in the context of classical MNGIE, with no documented evidence of adipose tissue or metabolic derangement. Our findings highlight the importance of considering TYMP involvement in the differential diagnosis of atypical lipodystrophy syndromes, particularly when features suggest underlying mitochondrial dysfunction. Full article

Recovery from disasters is the complex process requiring coordinated measures to restore infrastructure, services and quality of life. While remote sensing is a well-established means for damage assessment, so far very few studies have shown how satellite imagery can be used by technical officers of affected countries to provide crucial, up-to-date information to monitor the reconstruction progress and natural restoration. To address this gap, the present study proposes a multi-temporal observatory method relying on GIS, change detection techniques and open and free multi-sensor satellite imagery to generate thematic maps documenting, over time, the impact and recovery from hydrological disasters such as hurricanes, tropical storms and induced flooding. The demonstration is carried out with regard to Hurricane Matthew, which struck Haiti in October 2016 and triggered a humanitarian crisis in the Sud and Grand’Anse regions. Synthetic Aperture Radar (SAR) amplitude change detection techniques were applied to pre-, cross- and post-disaster Sentinel-1 image pairs from August 2016 to September 2020, while optical Sentinel-2 images were used for verification and land cover classification. With regard to inundated areas, the analysis allowed us to determine the needed time for water recession and rural plain areas to be reclaimed for agricultural exploitation. With regard to buildings, the cities of Jérémie and Les Cayes were not only the most impacted areas, but also were those where most reconstruction efforts were made. However, some instances of new settlements located in at-risk zones, and thus being susceptible to future hurricanes, were found. This result suggests that the thematic maps can support policy-makers and regulators in reducing risk and making the reconstruction more resilient. Finally, to evaluate the replicability of the proposed method, an example at a country-scale is discussed with regard to the June 2023 flooding event. Full article

N-glycanase 1 (NGLY1) is a cytoplasmic glycoenzyme that removes N-linked glycans from misfolded glycoproteins. It plays an important role in the endoplasmic reticulum-associated degradation (ERAD) pathway in mammalian cells. NGLY1 dysfunction in humans causes NGLY1 deficiency as a rare autosomal recessive disorder that is characterized by neurodevelopmental delay, hypotonia, movement disorders, seizures, and multi-system involvement. In this review, we summarize recent advances in understanding the neural functions of NGLY1 and the neuropathological phenotypes associated with its deficiency. We discuss the molecular basis of NGLY1 deficiency in the central nervous system (CNS) and pathophysiological insights from animal and human induced pluripotent stem cell (iPSC)-based models. We also highlight emerging gene therapy approaches aimed at restoring NGLY1 activity and alleviating neurological symptoms. Full article

Background/Objectives: Gaucher disease type 1 is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the GBA1 gene. Although enzyme replacement therapy has improved patient outcomes, there is limited long-term real-world data on taliglucerase alfa. This study aimed to evaluate the long-term efficacy and safety of taliglucerase alfa in both treatment-naïve and previously treated patients with Gaucher disease type 1 over a 10-year period. Methods: This prospective, single-centre cohort study involved 29 patients (13 treatment-naïve and 16 previously treated with imiglucerase) who received taliglucerase alfa from 2015 to 2024. Clinical, hematological, visceral, skeletal, and biochemical parameters were assessed at baseline and at 12, 60, and 120 months. Biomarkers included chitotriosidase and glucosylsphingosine. Safety was evaluated through adverse event reporting and anti-drug antibody testing. Results: Hemoglobin and platelet counts improved or remained stable in all patients. By 60 months, liver volume had normalised in treatment-naïve patients (mean reduction: 23.1%), while spleen volume had decreased by up to 47.3%. Lyso-Gb1 levels decreased by 86.1% in patients who had not previously received treatment and by 59.5% overall, with a strong correlation to adherence. Bone mineral density improved in most cases. 137 adverse events were reported, 24% of which were mild infusion-related reactions. Anti-drug antibody developed in two patients, including one with a reduced therapeutic response. Conclusions: Taliglucerase alfa offers sustained long-term clinical, hematological and biochemical benefits in both treatment-naïve and previously treated Gaucher disease type 1 patients, with a favorable safety profile. Glucosylsphingosine proved to be a highly sensitive biomarker for monitoring therapeutic efficacy and detecting treatment response. Full article

Office is one of the core sectors within the buildings sector, attracting tens of billions of dollars in global real estate investment flows. Most of these are achieved through non-listed investments, where office real estate represents one of the major sectoral investment exposures for many global institutional real estate investors and investment managers. The rising interest rates in recent years have been a significant concern, impacting the global real estate markets significantly. Based on these premises and by using quarterly total returns of non-listed office real estate across the US, UK, Germany, Canada, and Australia from June 2008 to June 2024, this research assesses the risk-adjusted performance and portfolio diversification benefits of non-listed office real estate across the five markets over both interest rate cut and interest rate hike cycles. The results empirically validate the added-value role of non-listed office real estate in institutional multi-asset portfolios across the UK, Germany, Canada, and Australia during the interest rate hike cycle preceding the COVID recession. In the 10% capped real estate allocation, the average allocation was 0.7% in the UK, 0.4% in Germany, 0.7% in Canada, and 9.1% in Australia. Over the interest rate hike cycle after the COVID recession, Australian non-listed office real estate offered enhanced benefits as part of the multi-asset portfolio, constituting an average of 0.8% in the capped real estate allocation. In the global non-listed office real estate portfolio, the US dominated the portfolio across varying interest rate cycles, with an average allocation of approximately 65%. The average allocation to Australia was 24.2% over the interest rate hike cycles, while the average allocation to Germany was 32.0% over the interest rate cut cycles. These findings offer institutional real estate investors and investment managers critical and practical insights into how the investment performance and portfolio construction strategy of office assets—an essential component of the buildings sector and a major non-listed real estate investment exposure for global institutional real estate investors—respond to macro-financial and interest rate cycles. The investment implications of the findings are also discussed. Full article

Epidermolysis bullosa (EB) is a group of debilitating, genetic skin disorders characterized by excessive skin fragility, blistering, and ulcerations that cause a cyclical wound healing process. EB presents itself in various subtypes, such as EB simplex (EBS), junctional EB (JEB), dystrophic (DEB), and Kindler Syndrome (KS), which all differ in their genetic cause, severity, and harbor different causes of mortality. Of these variants, JEB and DEB are the most severe, with EBS being the mildest form of the disease and KS presenting in extremely rare cases. The JEB variant tends to cause mortality early on in children less than two years of age due to failure to thrive, sepsis from wound infections, and airway obstruction. In the recessive form of DEB (RDEB), cutaneous squamous cell carcinoma (cSCC) is the major cause of death in patients, with one study reporting a mere 4-year survival after the first EB-cSCC diagnosis. Cutaneous SCCs in the setting of RDEB are particularly concerning because they are often more aggressive and show greater metastatic potential, as compared to ultraviolet-induced SCCs. This review aims to explore the pathophysiology of these EB variants as well as their implications for developing cSCCs. It will also discuss elements of the clinical presentation of such lesions in EB patients and the challenges associated with making a definitive diagnosis. Additionally, we will illuminate various diagnostic techniques, current and future management and treatment strategies for both cSCC and EB, and the importance of early screening and education for patients with EB to maximize patient lifespan and quality of life. Full article

Background/Objectives: Wilson’s disease (WD) is an autosomal recessive disorder characterized by pathological copper accumulation, primarily in the liver and brain. Severe hepatic involvement can be effectively treated with liver transplantation (LT). Geographic variation in ATP7B mutations suggests the presence of regional patterns that may impact disease presentation and management. This study aims to investigate the genetic basis of WD in patients from a major LT center in Iran. Methods: A retrospective analysis was conducted on clinical, biochemical, and pathological data from patients suspected of WD who underwent evaluation for LT between May 2020 and June 2025 at Shiraz University of Medical Sciences. Genetic testing was carried out on 20 patients at the Shiraz Transplant Research Center (STRC). Direct mutation analysis of ATP7B was performed for all patients, and the results correlated with clinical and demographic information. Results: In total, 20 WD patients who underwent liver transplantation (15 males, 5 females) carried 25 pathogenic or likely pathogenic ATP7B variants, 21 of which were previously unreported. Fifteen patients were homozygous, and five were compound-heterozygous; all heterozygous combinations occurred in the offspring of second-degree consanguineous unions. Recurrent changes included p.L549V, p.V872E, and p.P992S/L, while two nonsense variants (p.E1293X, p.R1319X) predicted truncated proteins. Variants were distributed across copper-binding, transmembrane, phosphorylation, and ATP-binding domains, and in silico AlphaMissense scores indicate damaging effects for most novel substitutions. Post-LT follow-up showed biochemical normalization in the majority of recipients, with five deaths recorded during the study period. Conclusions: This single-center Iranian study reveals a highly heterogeneous ATP7B mutational landscape with a large proportion of novel population-specific variants and underscores the benefit of comprehensive gene sequencing for timely WD diagnosis and family counseling, particularly in regions with prevalent consanguinity. Full article

Introduction: Genes in the endolysosome and autophagy pathways are major contributors to hereditary spastic paraplegia (HSP). A pathogenetic link between HSP and Alzheimer disease (AD) involving macroautophagy is well established. Sortilin-related receptor 1 (SORL1), an endosomal trafficking protein, plays a key role in glutamatergic neuron homeostasis and white matter tract integrity. Until now, SORL1 has only been associated with dominant AD and cerebral amyloid angiopathy. Methods: A case of HSP with cerebroretinal vasculopathy (CRV) negative on exome sequencing was further investigated using whole-genome sequencing. RNA-seq, Western blot, and immunofluorescence imaging were performed to explore a potential loss-of-function mechanism. Results: Sequencing revealed a biallelic SORL1 splice donor variant (c.1211 + 1G > A). Transcriptomics confirmed nonsense-mediated decay and aberrant splicing, predicting a disrupted reading frame. Reduced SORLA protein levels and significant enlargement of endolysosomes in patient-derived fibroblasts further cemented the pathogenicity of the variant. Conclusions: The probability that SORL1 acts as a recessive disease-causing gene gathers support from the following data: SORL1 genomic constraint score pRec = 1, high meiotic recombination rates on the locus, phenotype of Sorl1^−/− mice reminiscent of HSP with CRV, and endolysosomal enlargement in SORL1^−/− glutamatergic neurons in vitro. Taken together, SORL1 is probably a new candidate for a recessive form of complicated HSP. Full article

Background: The aim of this bibliometric study was to evaluate publication trends in the most frequently cited clinical trials on the treatment of gingival recession, taking into account the augmentation materials used. Methods: A Web of Science search was performed among articles published by 30 September 2024. Two independent reviewers evaluated year of publication, journal, authorship country of authors, collaborative relationship, keywords, and the main domains. Results: The top one hundred most-cited clinical trials were published in the span of 26 years from 1993 to 2019, and the total citation counts varied from 44 to 284 (83.69 citations per paper). There was correlation between the time of publication and the number of citations. The articles were authored by 333 researchers representing twenty-two countries. Italy contributed the highest number of articles (n = 36), followed by the USA (n = 28) and Brazil (n = 17). International collaborations were predominantly observed between Italy, the USA, and Switzerland. The type of graft was the most cited field of research (34), followed by guided tissue regeneration (17) and enamel matrix derivative (13). Conclusions: The country that produced the highest number publications among the 100 most-cited clinical trials on gingival recession treatment was Italy. The use of connective tissue graft (CTG) and coronally advanced flap (CAF) was the most prominent trend. Future work should combine bibliometric mapping with critical quality appraisal and explore whether citation trends align with best available evidence. Full article

Background/Objectives: Lactate (LA) is a key metabolite in exercise metabolism, transported across cell membranes by monocarboxylate transporters (MCTs). Although genetic variation in MCT genes has been linked to LA kinetics, evidence in athletic populations remains limited. This study investigated nine MCT1 polymorphisms (rs4301628, rs12028967, rs10857983, rs3789592, rs10776763, rs1049434, rs6537765, rs7556664, rs7169) in relation to LA metabolism. Methods: 337 Polish and Czech males (elite athletes, sub-elite competitors, physically active controls) performed two maximal Wingate tests. Buccal swabs were collected for DNA extraction and single nucleotide polymorphism (SNP) genotyping. LA was assessed before and after the tests. Results: Five variants (rs3789592, rs7556664, rs7169, rs1049434, rs6537765) remained significantly associated with LA measured 30 min after the second Wingate (LA30′) and delta clearance capacity (DCC) in elites (codominant and recessive models: p = 0.01–0.03; false discovery rate (FDR)-adjusted p = 0.02–0.04). Rs10776763 showed the broadest associations, surviving FDR for LA30′ in all models (p = 0.003–0.03; FDR-adjusted p = 0.01–0.03) and for LA accumulation capacity (ACC) in the recessive model (p = 0.01; FDR-adjusted p = 0.03). Rs12028967 also supported a clearance role, with LA30′ significant in elites (p = 0.004; FDR-adjusted p = 0.01) and DCC in the overall cohort (p = 0.02; FDR-adjusted p = 0.03). In contrast, rs4301628 and rs10857983 demonstrated isolated LA30′ effects in elites (p = 0.004–0.01; FDR-adjusted p = 0.01), and no production-phase endpoint other than rs10776763 survived FDR; ACC remained significant in the recessive model (p = 0.01; FDR-adjusted p = 0.03). Conclusions: The results suggest that MCT1 polymorphisms contribute to differences in LA metabolism and warrant replication in larger, more diverse cohorts. Full article

Seed dormancy and germination is regulated by internal hormones and exogenous environment cues. Ethylene is one of the hormones that break seed dormancy and induce seed germination. Our previous study showed that N-degron pathway gene, proteolysis6 (PRT6) was involved in dormancy release by ethylene, the defection of which exhibiting ethylene-insensitivity in Arabidopsis thaliana. In the present study, through screening an ethyl methyl sulfonate-mutagenized (EMS) population of prt6−1, we isolated a recessive mutant that acted as a suppressor of prt6 that rescued its insensitivity to ethylene as well as a phenotype of shorter silique length. Further bulk segregant analysis on F2 population identified a premature termination located in the third exon of LONGIFOLIA1 (LNG1), previously reported in the regulation of longitudinal cell elongation. Mutation of LNG1 in prt6−1 background by CRISPR-Cas9 confirmed that LNG1 was epistatic to PRT6 in seed responsiveness to ethylene. Our finding proposed the pleiotropic effect of LNG1 in seed dormancy breakage by ethylene via PRT6, providing novel functional component at the downstream of the coordinated PRT6 and ethylene signaling pathway. Full article

The COVID-19 pandemic has renewed the global focus on the role of public health spending, particularly in developing regions where fiscal space is mostly limited. Many African countries have started reassessing the health sector as a core economic resilience component. This study examines how government health expenditure responds to macroeconomic fluctuations in African countries. Attention was given to asymmetries between positive and negative periods of GDP growth and the impact of COVID-19 on these dynamics. The analysis uses annual data from 45 African economies from 2000 to 2022 and applies a panel NARDL framework to capture nonlinear and dynamic relationships. The sample is further disaggregated into low-income and middle-income groups. The results from the full sample indicate a procyclical pattern of health spending, where expenditure rises during economic expansions, but it discloses an acyclical relationship during recessions. Further analysis reveals that health spending in low-income countries follows a similar procyclical trend, while middle-income countries exhibit a countercyclical response to positive and negative growth shocks. Inflation consistently reduces health spending across the sample. The COVID-19 period has altered the cyclical pattern of health expenditure, at least in the short-run, especially for low-income countries. These findings highlight the need for more resilient and countercyclical fiscal strategies in the health sector, specifically during economic downturns, to ensure sustained investment. Full article

Despite significant advances in understanding the genetics of Parkinson’s disease (PD) and Parkinsonism, the diagnostic yield remains low. Pathogenic variants of GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase and causes recessive Gaucher dis-ease, are recognized as the most important genetic risk factor for PD in heterozygous carriers. This study focuses on the functional genomics of rare genetic variations in other lysosomal hydrolytic enzymes genes in patient-derived fibroblasts. We examined 49 early-onset PD patients using whole exome sequencing and in silico panel analysis based on a curated PD gene list. Two patients were found to carry the p.Asp313Tyr variant in the X-linked GLA gene (encoding GALA, typically associated with Fabry disease), and one patient carried the p.Arg419Gln variant in GLB1 (encoding β-Gal, linked to the recessive GM1 gangliosidosis and mucopolysaccharidosis type IVB). The in silico study of both variants supports a potentially damaging impact on the encoded protein function and structural destabilization. Additional candidate variants were found related to lysosomes, Golgi apparatus and neurodegeneration, suggesting a multifactorial contribution to the disease. However, none of these variants met diagnostic standards. Functional assays showed a significant decrease in GALA expression and partial retention of the enzyme in the trans-Golgi network in fibroblasts with GLA:p.Asp313Tyr, while altered Golgi morphology was observed in fibroblasts with GLB1:p.Arg419Gln. Moreover, all patients exhibited abnormalities in lysosomal morphology, altered lysosomal pH, and impaired autophagic flux. Our findings suggest that rare, heterozygous variants in lysosomal-related genes, even when individually insufficient for monogenic disease, can converge to impair lysosomal homeostasis and autophagic flux in EOPD. The underlying genetic and cellular heterogeneity among patients emphasizes the importance of combining genetic and functional approaches to better understand the mechanisms behind the EOPD, which could enhance both diagnosis and future treatments. Full article

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of fatty acid oxidation that can have life-threatening consequences if not promptly treated. Early diagnosis by means of newborn screening (NBS) has the potential to reduce morbidity and mortality. This study investigates the incidence and molecular characteristics of MCADD in Italy over a five-year period within the framework of the expanded NBS program. Between January 2019 and December 2023, a total of 1,976,473 newborns were screened. Ninety unrelated neonates were diagnosed with MCADD, providing an estimated incidence of 1/21,960 live births (95% CI: 1:17,780–1:27,200), comparable to rates reported in other Mediterranean populations. Molecular analysis identified c.985A>G (p.Lys329Glu) as the most frequent pathogenic ACADM gene variant, observed in 56 patients (63%), including eighteen patients (20%) who were homozygous and thirty-eight (43%) who were compound heterozygotes for this variant. To our knowledge, this study represents the first comprehensive investigation to document the high prevalence of MCADD among the Italian population. Full article

Baseflow is the part of the groundwater aquifer that replenishes surface streamflow and is one of the main components of studying the interaction between groundwater and surface water. It is a key factor in maintaining the healthy development of basin ecosystems and is of great significance for promoting the sustainable utilization and scientific management of water resources. However, the understanding of runoff and baseflow in the MYRB is still unclear, and the relationship between streamflow and baseflow has not been fully grasped. At the same time, there is currently no water balance function applicable to the MYRB. In order to solve the above problems, this article uses digital filtering methods to segment the baseflow and the MRC method to construct the main recession curve. The baseflow rate of MYRB was calculated, and the water balance function applicable to MYRB was found. The results obtained are as follows: the average annual baseflow index values for different basins were 0.81, 0.76, 0.81, 0.82, 0.79, and 0.79, respectively. The fitting of the Boussinesq function, the Maillet function, and the Brutsaert and Nieber function was significantly better than the other two functions. Full article