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PubMed1979

Arylsulphatases A and B in human diploid fibroblasts: differential assay with 4-methylumbelliferylsulphate and AgNO3.

A new technique is introduced for the differential assay of arylsulphatases A and B in centrifuged homogenates of cultured human skin fibroblasts, using 4-methylumbelliferyl-sulphate as a substrate and AgNO3 as a selective inhibitor of arylsulphatase A. The method can be applied in the diagnosis of metachromatic leucodystrophy, mucopolysaccharidosis type VI and mucosulphatidosis. Normal arylsulphatase activities were found in fibroblasts derived from patients with mucopolysaccharidoses types II, III-A and IV, known to be caused by deficiencies of various other sulphatases.

Cerebroside-Sulfatase↗
PubMed2026

Whole-genome sequencing links a Salmonella Newport ST164 outbreak on Fernando de Noronha to prior circulation in the Brazilian poultry supply chain.

Foodborne outbreaks at geographically isolated tourist destinations pose distinctive One Health challenges, combining limited local surveillance capacity, complex intercontinental supply chains, and high visitor turnover. In May 2021, a diarrheal outbreak linked to a gastronomic festival in Fernando de Noronha, that is a remote UNESCO World Heritage island off northeastern Brazil, was attributed to Salmonella enterica serovar Newport ST164. We applied an integrated genomic approach and epidemiological investigation to propose a transmission chain contextualizing and refining case definition of the S. Newport epidemic clone within national and international diversity. Whole-genome sequencing (WGS), SNP-based phylogenomic, pangenome analysis, Salmonella pathogenicity island (SPI) profiling, and resistome characterization was performed on 17 epidemiologically attributed outbreak isolates and 68 contextual genomes from Brazil, France, the United Kingdom, and the United States. The SNP analysis identified a 13 genome clonal core with less than 20 different SNPs demonstrating the possible connection between 9 patient isolates, 2 food isolates, and 2 food handler isolates, consistent with the involvement of colonised kitchen staff in cross-contamination of the ready-to-eat mussel dish. Three poultry isolates in 2020 from a mainland producer, ∼2180 km from Fernando de Noronha, differed only 13 to 17 Core-SNPs from the outbreak core, suggesting prior lineage circulation in the supply chain. Pangenome analysis also supports this evidence revealing near-complete genomic overlap of 4544 shared genes within the 5745 gene clusters (99.9%) between outbreak and non-outbreak backgrounds that mostly differentiate by a defense/prophage-associated accessory module. The resistome comprised intrinsic efflux determinants without acquired resistance and showed 35.3% of intermediate ciprofloxacin susceptibility. This One Health based study provides a WGS genomic reconstruction of a S. Newport ST164 outbreak at a remote tourist island, supporting the possibility of circulation from poultry-associated mainland reservoirs and findings consistent with cross-contamination at a gastronomic seafood festival.

Brazil↗
PubMed2026

Lysyl oxidase inhibition disrupts mitochondrial homeostasis to create vulnerability to ferroptosis in TNBC.

High metabolic heterogeneity and plasticity of triple-negative breast cancer (TNBC) contribute to therapy resistance, necessitating identification of therapeutic vulnerabilities. Here, we identify non-canonical functions of the extracellular matrix (ECM) remodeler, lysyl oxidase (LOX), in regulating glucose metabolism and mitochondrial homeostasis and show that inhibiting LOX generates targetable vulnerability to ferroptosis. Mechanistically, LOX interacts with PARKIN and its upstream kinase PINK1, which we identified as a substrate of LOX. LOX-mediated PINK1 oxidation suppresses PARKIN phosphorylation, stabilizing hypoxia-inducible factor 1-alpha (HIF-1α) and increasing glycolysis. Concomitantly, LOX inhibits PARKIN-mediated mitophagy and maintains mitochondria-ER contacts through VDAC1 stabilization, while the LOX-HSP90 complex promotes mitochondrial Ca2+ transport and ATP production. Inhibiting LOX suppresses glycolysis, disrupts mitochondrial dynamics, reduces OXPHOS and GPX4/FSP1, and induces compensatory DHODH activity. Our "one-two punch" approach combining LOX inhibition with clinical DHODH inhibitor suppresses tumor growth in vivo in chemo-free setting. Notably, LOX protein correlates with HIF-1α/GLUT1/GPX4 in TNBC patient tumors, supporting its clinical relevance.

Ferroptosis↗
PubMed2024

X-chromosome-wide association study for Alzheimer's disease.

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

Humans↗
PubMed2026

APOE-stratified genome-wide association analyses provide insights into the genetic etiology of Alzheimers's disease.

Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.

Journal Article↗
PubMed2026

Evolutionary persistence of a highly prevalent multicopy mitochondrial-derived nuclear insertion (Mega-NUMT) in Neotropical Drosophila flies.

Although strict maternal transmission of mitochondria is a general feature of animals for ensuring homogeneity in mitochondrial DNA (mtDNA) across generations, exceptions were reported in the recent past. For example, some extremely rare but spectacular cases of heteroplasmy and paternal transmission in humans have questioned the universal evolutionary principle. Hence, as an alternative, the Mega-NUMT concept was coined to explain this discovery and was thereafter partly proven to exist. This concept expands on the quite common transfer of mtDNA fragments to the nucleus (NUMTs) by considering the existence of multicopy mitochondrial nuclear insertions. Mega-NUMT reports are currently restricted to a few cases in animals, including humans. However, their detailed genomic organization, natural prevalence, and potential biological functions remain unclear. Here, we discovered that up to 60 full-sized mitochondrial genomes are integrated into the nuclear genome of the neotropical Drosophila paulistorum using long-read sequencing and in situ hybridization. The copies are organized in one cluster on chromosome 3, which we designated the "Dpau Mega-NUMT". Contrary to the rarity in humans, this Mega-NUMT is found at high prevalence (40%) in both laboratory lines and natural D. paulistorum populations of different semispecies. Additionally, the Mega-NUMT copies are phylogenetically separated from the current mitotypes of D. paulistorum. Together, these observations suggest long-term maintenance of the Mega-NUMT in nature. Hence, we propose that the Dpau Mega-NUMT may have been transferred to the nuclear genome before the D. paulistorum semispecies radiation and speculate based on these findings that it possibly is maintained at relatively high prevalence in nature by balancing selection or due to a yet undetermined function.

Animals↗
PubMed2025

Logan: Planetary-Scale Genome Assembly Surveys Life's Diversity.

The breadth of life's diversity is unfathomable, but public nucleic acid sequencing data offers a window into the dispersion and evolution of genetic diversity across Earth. However the rapid growth and accumulation of sequence data have outpaced efficient analysis capabilities. The largest collection of freely available sequencing data is the Sequence Read Archive (SRA), comprising 27.3 million datasets or 5 × 1016 basepairs. To realize the potential of the SRA, we constructed Logan, a massive sequence assembly transforming short reads into long contigs and compressing the data over 100-fold, enabling highly efficient petabase-scale analysis. We created Logan-Search, a k-mer index of Logan for free planetary-scale sequence search, returning matches in minutes. We used Logan contigs to identify >200 million plastic-degrading enzyme homologs, and validate novel enzymes with catalytic activities exceeding current reference standards. Further, we vastly expand the known diversity of proteins (30-fold over UniRef50), plasmids (22-fold over PLSDB), P4 satellites (4.5-fold), and the recently described Obelisk RNA elements (3.7-fold). Logan also enables ecological and biomedical data mining, such as global tracking of antimicrobial resistance genes and the characterization of viral reactivation across millions of human BioSamples. By transforming the SRA, Logan democratizes access to the world's public genetic data and opens frontiers in biotechnology, molecular ecology, and global health.

Journal Article↗
PubMed1979

Effect of fluoride on ion exchange, remineralization and acid resistance of surface enamel.

In a system of constant ion activities the rates of F- exchange in enamel, under conditions of exchange alone and remineralization, depended on the concentration of F- in solutions. Acid resistance of surface minerals resulted from exchange of F- for OH- in the enamel at pH 7.0 and 4.5. The level of 0.5 mM NaF, compared to 0.05 and 6.0 mM, caused maximum rates of isotopic exchange of 45Ca and maximum acid resistance of enamel. Similarly low levels of F- may be feasible for use in caries prevention in the absence and presence of remineralization.

Animals↗
PubMed2026

Detection and characterization of antiviral-resistant viruses during the influenza season of 2024-25.

UNLABELLED: During the high severity season of 2024-25, CDC with public health partners sequenced and analyzed genomes of >10,000 influenza viruses for antiviral resistance markers. Available sequence-flagged and representative viruses were tested with antivirals using in vitro assays. In the US, three oseltamivir-resistant A(H3N2) viruses had treatment-emergent neuraminidase (NA) mutations, either E119V or R292K. Oseltamivir-resistant A(H1N1)pdm09 viruses with NA-H275Y were detected in 15 states, albeit at a low frequency (0.53%). They belonged to several phylogenetic groups, with hemagglutinin (HA) subclade D.3.1 combined with either NA subclade D.1 or D.2 being most common. Based on shared sequence data, nearly all H275Y viruses from Australia, Canada, and Chile also belonged to these HA and NA subclades. Conversely, most H275Y viruses (68/81) from China belonged to HA subclade C.1.9 and NA subclade D and shared the permissive mutation R257K. Influenza polymerase acidic (PA) mutations conferring 4- to 92-fold decreased baloxavir susceptibility were detected in nine influenza A viruses. Viruses with PA-I38T showed mild attenuation of replicative fitness in three cell lines. Based on available data, NA-H275Y and PA-I38T viruses were collected from patients with no exposure to antivirals. Baseline susceptibility to all US-approved influenza antivirals remained largely unchanged compared to previous seasons. All swine-origin viruses detected in the US had adamantane resistance-conferring marker, M2-S31N, but remained susceptible to other approved antivirals. Monitoring antiviral susceptibility has substantially improved with increased sequencing capacities and bioinformatic support at public health laboratories. Information gained through influenza surveillance has been used to guide recommendations on antiviral use. IMPORTANCE: Circulation of influenza viruses with reduced susceptibility to antivirals can diminish the usefulness of medications prescribed for influenza. This study informs on the prevalence of drug-resistant influenza viruses in the US during the high severity season of 2024-25. It provides information on susceptibility profile to all approved antiviral medications and on replicative fitness of representative drug-resistant viruses. Most drug-resistant viruses were collected from patients who were not exposed to antivirals indicating their ability to transmit from human to human. Whole-genome sequence (WGS)-based analysis is the cornerstone for surveillance, and numerous laboratories have been utilizing this approach. However, CDC laboratory is the only laboratory in the US conducting phenotypic testing of circulating viruses needed to confirm the outcomes of sequence-based analysis and to identify new molecular markers of resistance. Data gathered through virologic surveillance give much-needed information on drug susceptibility of influenza viruses which are used to guide recommendations on antiviral use.

Antiviral Agents↗
PubMed2026

Human IL-34 Deficiency Primes Microglia Toward Alzheimer's Disease-Associated States.

BACKGROUND: Genome-wide association studies (GWAS), with independent replication in large European consortia, have identified a common nonsense variant in IL-34 (Y213X) as a genetic risk factor for late-onset Alzheimer's disease (AD). However, the biological consequences of this IL-34 mutation in humans, its prevalence in the population, and the mechanisms by which IL-34-Y213X alters microglial homeostasis, cerebrospinal fluid (CSF) proteomic networks, and amyloid pathology remain poorly understood. METHODS: We combined human genetics, cerebrospinal fluid (CSF) and serum proteomics, transcriptomics, large-scale phenome-wide association analyses, and preclinical experimental models to define the impact of human IL-34 deficiency. IL-34 concentrations were first quantified in CSF and serum from deeply phenotyped AD cohorts stratified by the common IL-34-Y213X nonsense variant. IL-34 levels and IL-34-Y213X status were then integrated with unbiased CSF proteomic networks and AD biomarkers. Transcriptomic profiling of purified microglia from IL-34 knockout mice was performed to assess disease-associated microglial programs. Using APP/PS1 mice lacking IL-34, we examined the effects of IL-34 deficiency on microglial survival, tiling, and plaque encapsulation. Finally, we performed postmortem analyses of temporal cortex from AD patients carrying IL-34-Y213X to assess microglial density, spatial organization, and plaque-associated responses. FINDINGS: IL-34-Y213X was a strong, dose-dependent loss-of-function (LOF) allele that reduced IL-34 levels by up to 2.5 standard deviations in CSF and serum and was common in multiple populations. IL-34 deficiency reshaped CSF proteomic networks, downregulating axon guidance and microglial support modules while upregulating inflammatory and extracellular matrix signatures, and showed pleiotropic associations with neurological, inflammatory, and metabolic traits. Transcriptomic analysis of sorted microglia from healthy 9-month-old IL-34KO compare to wild-type mice revealed a profound pro-inflammatory and disease-associated microglial transcriptional program enriched for disease-associated microglia (DAM) signatures, inflammatory pathways, and AD risk genes including APOE, CLU, and CASS4. In APP/PS1 mice, genetic IL-34 deletion selectively depleted homeostatic gray-matter microglia, disrupted microglial tiling, and impaired plaque encapsulation, resulting in altered amyloid structure and enhancing neuritic injury. Concordantly, AD patients homozygous for IL-34-Y213X displayed markedly reduced cortical microglial density and increased microglial spatial dispersion, indicating a breakdown of the microglial network organization in the human brain. INTERPRETATION: A common human IL-34 LOF variant creates a naturally occurring model of IL-34 deficiency that links microglial survival, CSF network signatures, and amyloid pathology in both mice and humans. Importantly, IL-34 deficiency alone is sufficient to induce inflammatory, AD-associated microglial states beyond simply reducing microglial number. These findings identify IL-34/CSF1R signaling as a critical determinant of microglial resilience and a potential upstream pathway linking human genetic variation to AD susceptibility, highlighting IL-34-dependent pathways as promising targets for disease modification. FUNDING: This work was supported by grants from the Spanish Ministerio de Ciencia, Innovación y Universidades/FEDER/UE (PID2024-157400OB-I00) and FORTALECE program (FORT23/00008; Instituto de Salud Carlos III, Spain) to RRL and JLV, ISCIII of Spain co-financed by FEDER funds (European Union) through grants PI24/00308 (JV) and CIBERNED collaborative grant 2022/01 to JV, PID2023-147125OB-I00 and CEX2023-001386-S (Severo Ochoa Programme) to SMTBC. A.R. is supported by STAR Award. University of Texas System. Tx, United States, The South Texas ADRC. National Institute of Aging. National Institutes of Health. USA. (P30AG066546), the Keith M. Orme and Pat Vigeon Orme Endowed Chair in Alzheimer's and Neurodegenerative Diseases (2024-2025) and Patricia Ruth Frederick Distinguished Chair for Precision Therapeutics in Alzheimer's and Neurodegenerative Diseases (2025-2028). AR is also supported by the Agency for Innovation and Entrepreneurship (VLAIO) grant N° PR067/21 for the HARPONE project and the ADAPTED project the EU/EFPIA Innovative Medicines Initiative Joint Undertaking Grant N° 115975 and CIBERNED (ISCIII).

Journal Article↗