Pediatr Infect Dis J. 2025 Jan 10. doi: 10.1097/INF.0000000000004683. Online ahead of print.

ABSTRACT

We investigated the steady-state pharmacokinetics of generic abacavir (ABC)/lamivudine (3TC) dispersible tablets (DTs) in young children living with HIV aged 3 months to <7 years, weighing 6 to <20 kg. Twenty-eight Thai children were enrolled and received ABC/3TC-DT plus pediatric dolutegravir-DT once daily. ABC/3TC was administered using WHO weight band (WB) doses: 180/90 mg, 240/120 mg and 300/150 mg for children weighing 6 to <10 kg (WB 1, n = 7), 10 to <14 kg (WB2, n = 9) and 14 to <20 kg (WB3, n = 12), respectively. ABC geometric mean (GM) AUC0-24 h (CV%) was 14.2 (50.5%), 15.6 (32.6%) and 20.7 (28.3%) mg.h/L, respectively, and 3TC GM AUC0-24 h was 14.8 (44.1%), 18.2 (28.0%) and 19.9 (26.2%) mg.h/L, respectively. ABC and 3TC exposures were within target ranges across WBs. These data supported current ABC/3TC-DT WHO-weight band dosing guidance for young children in Thailand.

PMID:39836566 | DOI:10.1097/INF.0000000000004683

Rev Mal Respir. 2025 Jan 20:S0761-8425(25)00001-4. doi: 10.1016/j.rmr.2025.01.001. Online ahead of print.

ABSTRACT

INTRODUCTION: Following two weeks of application of the triple combination therapy of Elexacaftor (E), Tezacaftor (T), and Ivacaftor (I) known as ETI, substantial pulmonary improvement in patients with cystic fibrosis is well-documented. However, few detailed data are available on the action of this treatment over the course of these first 14 days.

METHODS: In this prospective study (NCT05599230), 20 patients aged≥12 years, all of them eligible for ETI, were recruited at the initiation of treatment. Home spirometry (MIR Spirobank®) was performed during the three days preceding the start of treatment and then daily for 14 days, while a respiratory symptom score (RSS) was calculated and a log maintained concerning the events experienced by each patient.

RESULTS: Mean age (± SD) of the 20 patients was 29.4 (± 11.1) years, mean FEV1 was 84.2% (± 17.7), and the mean BMI z-score was 0.18 (± 0.82). Thirteen of them were already on modulators. When compared to the average scores recorded for the three days preceding the start of treatment, FEV1 improvement became significant from the 6th day (D6). After having significantly worsened on D1 (P<0.05), the RSS improved from D6 onwards. The quality of home FEV1 measurements was high (grade A: 81.2%).

CONCLUSIONS: Under ETI treatment, respiratory benefits were significant from D6. The side effects most commonly perceived by the patients occurred during the first four days of treatment. While daily monitoring of home spirometry could indeed be a valuable tool in follow-up of patients with cystic fibrosis, its administration requires suitable and sustained training.

PMID:39837691 | DOI:10.1016/j.rmr.2025.01.001

J Heart Lung Transplant. 2025 Jan 19:S1053-2498(25)00018-X. doi: 10.1016/j.healun.2025.01.010. Online ahead of print.

ABSTRACT

Bone health after lung transplantation has not been comprehensively reviewed in over two decades. This narrative review summarizes available literature on bone health in the context of lung transplantation, including epidemiology, presentation and post-operative management. Osteoporosis is reported in approximately 30-50% of lung transplant candidates, largely due to disease-related impact on bone and lifestyle, and corticosteroid-related effects during end-stage lung disease (interstitial lung diseases, chronic obstructive pulmonary disease, and historically cystic fibrosis). After lung transplantation, many patients experience steroid-induced bone loss, followed by stabilization or recovery to baseline levels with pharmacological management. Although evidence on fracture incidence is limited, fracture risk appears to increase in the year following transplantation, with common fracture sites including the vertebrae and the ribs. Vertebral and rib fractures restrict chest expansion and affect lung function, underscoring the importance of fracture prevention in lung transplant recipients. There is limited evidence on pharmacological management of osteoporosis after lung transplantation. Existing randomized controlled trials have focused on parenteral bisphosphonates and calcitriol, but have been underpowered to evaluate their effect on fracture outcomes. Resistance training, particularly in conjunction with antiresorptive therapy, has also been shown to improve bone health when initiated two months after transplantation. No studies to date have documented effectiveness of denosumab in lung transplant recipients; more studies on pharmacotherapy are warranted to elucidate optimal medical management. Considering high osteoporosis prevalence and high fracture risk in lung transplant populations, development of formal guidance is warranted to promote improved management after transplantation.

PMID:39837402 | DOI:10.1016/j.healun.2025.01.010

J Leukoc Biol. 2025 Jan 22:qiaf006. doi: 10.1093/jleuko/qiaf006. Online ahead of print.

ABSTRACT

Immune cells express a variety of ion channels and transporters in the plasma membrane and intracellular organelles, responsible of the transference of charged ions across hydrophobic lipid membrane barriers. The correct regulation of ion transport ensures proper immune cell function, activation, proliferation, and cell death. Cystic fibrosis (CF) is a genetic disease in which the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel gene is defective, consequently, the CFTR protein is dysfunctional, and the chloride efflux in CF cells is markedly impaired. Cystic fibrosis is characterized by chronic inflammation in the airways, mainly triggered by neutrophilic infiltration and recurring bacterial infections, causing the decline of lung function and eventually respiratory failure. Novel modulator-based therapies have improved lung function in people with Cystic Fibrosis (pwCF) by increasing expression and function of CFTR in the plasma membrane of lung cells, however, the effects of these drugs in the lung recruited inflammatory cells, specifically neutrophils, remains unknown. Given the complex biology of neutrophils and their short lifespan, we aimed to develop a fluorometric method to evaluate CFTR-mediated chloride transport in human neutrophils by using flow cytometry and the intracellular chloride-binding MQAE dye. Our results show that CFTR-mediated chloride transport in human neutrophils or human neutrophil-like cell lines can be consistently evaluated in vitro by this methodology. Additionally, this assay measured increased chloride efflux in neutrophils collected from pwCF under modulator therapy, as compared to healthy donors, indicating this method can evaluate restoration of CFTR-mediated chloride transport in CF neutrophils.

PMID:39837350 | DOI:10.1093/jleuko/qiaf006

Cell Immunol. 2025 Jan 17;409-410:104926. doi: 10.1016/j.cellimm.2025.104926. Online ahead of print.

ABSTRACT

BACKGROUND: Lungs of people with Cystic Fibrosis (pwCF) are characterized by chronic inflammation and infection with P. aeruginosa. High levels of IL-17 A and F have been observed in sputum of pwCF and the interleukin-17(IL-17) family (A-to-F) has been suggested to play a key role in CF pulmonary disease.

METHODS: We measured mRNA levels of IL-17 receptors (IL-17R) by RT-qPCR in CF bronchial epithelial (CFBE) cultured cells upon infection with P. aeruginosa PAO1 strain or clinical exoproducts (EXO) isolated from pwCF. We measured IL-17 mRNA expression by RT-qPCR and the release of cytokines by ELISA and Bioplex from CF primary nasal epithelial (HNE) cultured cells.

RESULTS: Infection of CFBE cells with PAO1 or EXO isolated from 15 pwCF significantly increased mRNA expression of all IL-17R, except IL-17RD. Infection of HNE cells with EXO isolated from the correspondent donor significantly increased the mRNA levels of all the IL-17 cytokines and receptors, except for IL-17D and IL-17RD, and the release of the cytokines IL-17 A, IL-17B, IL-17C, IL-17E and IL-17F. HNE exposed to IL-17 A and F were induced to release pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), neutrophil chemokines (IL-8, G-CSF) and cytokines known to be involved in chloride and bicarbonate secretion, together with mucin upregulation (IL-4, IL-13).

CONCLUSION: These results highlight a wider expression of IL-17 family member in respiratory epithelial cells, which can play a role as an autocrine inflammatory amplification loop in CF airways. These in-vitro studies using patient-derived cultures underline the relevant role of IL-17 family members in CF pulmonary immune response.

PMID:39837005 | DOI:10.1016/j.cellimm.2025.104926

Ann Am Thorac Soc. 2025 Jan 21. doi: 10.1513/AnnalsATS.202411-1237LE. Online ahead of print.

NO ABSTRACT

PMID:39836962 | DOI:10.1513/AnnalsATS.202411-1237LE

Ann Am Thorac Soc. 2025 Jan 21. doi: 10.1513/AnnalsATS.202410-1070LE. Online ahead of print.

NO ABSTRACT

PMID:39836960 | DOI:10.1513/AnnalsATS.202410-1070LE

Biomedica. 2024 Dec 23;44(Sp. 2):80-93. doi: 10.7705/biomedica.7500.

ABSTRACT

INTRODUCTION: Non-cystic fibrosis bronchiectasis is a complex medical condition with multiple etiologies, characterized by chronic productive cough and radiologic evidence of airway lumen dilation and wall thickening. Associated exacerbations and declining lung function contribute to increasing disability and mortality. There are no data about the prevalence of non-cystic fibrosis bronchiectasis etiologies in the Colombian population.

OBJECTIVE: To investigate non-cystic fibrosis bronchiectasis etiology and clinical characteristics in adults evaluated in the southwest of Colombia.

MATERIALS AND METHODS: We conducted a cross-sectional, non-interventional study. Subjects diagnosed with non-cystic fibrosis bronchiectasis were referred to by their healthcare providers and then enrolled between October 2018 and April 2021. Medical records and radiological studies were evaluated. Participants underwent laboratory tests, including complete blood count, serum immunoglobulin levels, and, in some cases, additional tests.

RESULTS: We included 161 subjects. The average age was 50 years old, and 59% were females. Bronchiectasis etiology was identified in 84.6% of the cases. Postinfectious (34.6%) and immune disorders (25.3%), represented by autoimmunity (13.6%) and immunodeficiency (11.7%), were the leading causes. Gender differences were noted in autoimmune (females: 18.8% versus males: 6.1%, p = 0.021) and immunodeficiency-related bronchiectasis (males: 21.2% versus females 5.2%, p = 0.002). Immunodeficiencies-associated bronchiectases were more frequent in subjects under 50 years of age, while chronic obstructive pulmonary disease-associated bronchiectases were common in subjects over 50 years of age.

DISCUSSION: The etiologies of non-cystic fibrosis bronchiectasis in Colombia are diverse, exhibiting notable differences from other global regions. Serum immunoglobulin levels and clinical immunologist consultation should be prioritized in diagnosing patients with unclear bronchiectasis etiology, particularly those with recurrent sinopulmonary infections.

PMID:39836848 | DOI:10.7705/biomedica.7500

Biomedica. 2024 Dec 23;44(Sp. 2):131-139. doi: 10.7705/biomedica.7558.

ABSTRACT

Introducción. Los errores innatos de la inmunidad se asocian frecuentemente con bronquiectasias. Actualmente, el diagnóstico de los errores innatos de la inmunidad ha mejorado porque se conoce con certeza la asociación de estas entidades con el daño progresivo de las vías respiratorias. Esto ha permitido el reconocimiento y la intervención adecuada, lo cual reduce el deterioro de la función pulmonar y mejora la calidad de vida. Objetivo. Describir un grupo de pacientes con bronquiectasias no relacionadas con la fibrosis quística y con diagnóstico de errores innatos de la inmunidad, estudiados en un centro de referencia de inmunología en Cali, Colombia. Materiales y métodos. Se desarrolló un estudio observacional, descriptivo y retrospectivo de pacientes menores de 18 años con diagnóstico de errores innatos de la inmunidad y bronquiectasias no relacionadas con fibrosis quística, entre diciembre de 2013 y diciembre de 2023 en la Fundación Valle del Lili, en Cali (Colombia). Resultados. Se incluyeron 17 pacientes con diagnóstico de bronquiectasias no relacionadas con fibrosis quística y errores innatos de la inmunidad, cuya edad media fue de nueve años. El inferior fue el lóbulo pulmonar más frecuentemente afectado y su compromiso fue unilateral en la mayoría de los casos. La inmunodeficiencia con predominio de defectos de los anticuerpos fue la más común, seguida de las inmunodeficiencias combinadas asociadas con síndromes. Trece pacientes presentaron compromiso de la inmunidad humoral y 4 pacientes, alteraciones en la inmunidad humoral y celular. En 12 pacientes se identificaron modificaciones genéticas relacionadas con su fenotipo. Trece pacientes recibieron suplemento de inmunoglobulina intravenosa y 3 fallecieron. Conclusión. La inmunodeficiencia con predominio de defectos de los anticuerpos, seguida de las inmunodeficiencias combinadas asociadas con características sindrómicas, fueron los errores innatos de la inmunidad que con mayor frecuencia se acompañaron de bronquiectasias no relacionadas con la fibrosis quística.

PMID:39836842 | DOI:10.7705/biomedica.7558

J Endocrinol. 2025 Jan 1:JOE-24-0190. doi: 10.1530/JOE-24-0190. Online ahead of print.

ABSTRACT

Endocrine dysfunction and diabetes can develop secondary to fibrotic diseases within the pancreas including cystic fibrosis (CF). Phenotypic shift within epithelial cells has been recognised in association with pro-fibrotic signalling. We sought evidence of endocrine cell epithelial-to-mesenchymal transition in CF and non-CF pancreas. Post mortem pancreatic sections from 24 people with CF and 10 organ donors without CF or diabetes were stained for insulin/glucagon/vimentin and Sirius Red Fast Green with collagen distribution assessed semi-quantitatively (CF) and quantitatively (non-CF). Analysis of existing single-cell RNA-sequencing data sets (three adult donors without diabetes and nine with chronic pancreatitis) for α-cell vimentin expression was performed. Cells co-expressing glucagon/vimentin were detected in a proportion (32(4,61)% (median(Q1,Q3)) of islets in all CF pancreata except donors dying perinatally. CF histopathology was characterised by peri-islet fibrosis and 60(45,80)% of islets were surrounded by collagen strands. A positive correlation between islet fibrosis and vimentin-expressing α-cells was seen in non-CF donors <31 years (r=0.972, p=0.006). A possible association with donor age was seen in all donors (r=0.343, p=0.047). Single-cell RNA-sequencing analysis of isolated islets from non-diabetic donors and donors with chronic pancreatitis confirmed presence of vimentin-positive and vimentin-negative α-cells. Differentiated α-cell function-associated gene expression was maintained. Differentially upregulated processes in co-expressing cells included pathways associated with extracellular matrix organisation, cell-cell adhesion, migratory capability and self-renewal. We have identified and characterised an intermediate epithelial/mesenchymal state in a sub-population of α-cells present throughout post-natal life which may play a role in their response to extrinsic stressors including fibrosis and ageing.

PMID:39836539 | DOI:10.1530/JOE-24-0190

BMC Med. 2025 Jan 21;23(1):22. doi: 10.1186/s12916-025-03848-y.

ABSTRACT

BACKGROUND: Current research underscores the need to better understand the pathogenic mechanisms and treatment strategies for idiopathic pulmonary fibrosis (IPF). This study aimed to identify key targets involved in the progression of IPF.

METHODS: We employed Mendelian randomization (MR) with three genome-wide association studies and four quantitative trait loci datasets to identify key driver genes for IPF. Prioritized targets were evaluated for respiratory insufficiency and transplant-free survival. The therapeutic efficacy of the core gene was validated in cellular and animal models. Additionally, we conducted a comprehensive evaluation of therapeutic value, pathogenic mechanisms, and safety through phenome-wide association study (PheWAS), mediation analysis, transcriptomic analyses, shared causal variant exploration, DNA methylation MR, and protein interactions.

RESULTS: Multiple MR results revealed that BRSK2 has a significant pathogenic impact on IPF at both transcriptional and translational levels, with a lung tissue-specific association (OR = 1.596; CI, 1.300-1.961; Pval = 8.290 × 10 - 6). BRSK2 was associated with IPF progression driven by high-risk factors, with mediation effects ranging from 34.452 to 69.665%. Elevated BRSK2 expression in peripheral blood mononuclear cells correlated with reduced pulmonary function, while increased circulating BRSK2 levels suggested respiratory failure and shorter transplant-free survival in IPF patients. BRSK2 silencing attenuated lung fibrosis progression in cellular and animal models. Transcriptomic integration identified PSMB1, CTSD, and CTSH as significant downstream effectors of BRSK2, with PSMB1 showing robust shared causal variant support (PPH4 = 0.800). Colocalization analysis and phenotype scan deepened the pathogenic association of BRSK2 with IPF, while methylation MR analysis highlighted the critical role of epigenetic regulation in BRSK2-driven IPF pathogenesis. PheWAS revealed no significant drug-related toxicities for BRSK2, and its therapeutic potential was further underscored by protein interaction analyses.

CONCLUSIONS: BRSK2 is identified as a critical pathogenic factor in IPF, with strong potential as a therapeutic target. Future studies should focus on its translational implications and the development of targeted therapies to improve patient outcomes.

PMID:39838395 | DOI:10.1186/s12916-025-03848-y

Sci Total Environ. 2025 Jan 20;964:178409. doi: 10.1016/j.scitotenv.2025.178409. Online ahead of print.

ABSTRACT

Air pollution has been associated with a higher incidence of idiopathic pulmonary fibrosis (IPF), yet this metabolic mechanism remains unclear. 185,865 participants were included in the UK Biobank. We estimated air pollution exposure using the bilinear interpolation approach, including fine particle matter with diameter < 2.5 μm (PM2.5), particle matter with diameter < 10 μm (PM10), nitrogen dioxide (NO2), and nitrogen oxides (NOx). We identified metabolites and established the metabolic signature with air pollutants using an elastic net regularized regression. Cox proportional hazards models combined with generalized propensity score (GPS) were conducted to evaluate the relationships between metabolic signatures and incident IPF, and mediation analysis was performed to evaluate potential mediators. During a median follow-up of 12.3 years, 1239 IPF cases were ascertained. We identified multi-metabolite profiles comprising 87 metabolites for PM2.5, 65 metabolites for PM10, 71 metabolites for NO2, and 76 metabolites for NOx. Metabolic signatures were associated with incident IPF, with HRs of 1.20 (95 % CI: 1.13, 1.27), 1.09 (95 % CI: 1.03, 1.15), 1.23 (95 % CI: 1.16, 1.31), and 1.24 (95 % CI: 1.17, 1.31) per standard deviation (SD) increase in metabolic profiles associated with PM2.5, PM10, NO2, and NOx, respectively. Furthermore, metabolic signatures of PM2.5, PM10, NO2 and NOx significantly mediated 5.71 %, 3.98 %, 4.21 %, and 4.58 % of air pollution on IPF. Long-term air pollution was associated with a higher risk of IPF, with metabolites potentially playing a mediating role. The findings emphasize the significance of improving metabolic status for the prevention of IPF.

PMID:39837121 | DOI:10.1016/j.scitotenv.2025.178409

BMC Vet Res. 2025 Jan 21;21(1):31. doi: 10.1186/s12917-024-04465-2.

ABSTRACT

BACKGROUND: Small extracellular vesicles (sEVs) derived from mesenchymal stem cells (MSCs) are recognized for their therapeutic potential in immune modulation and tissue repair, especially in veterinary medicine. This study introduces an innovative sequential stimulation (IVES) technique, involving low-oxygen gas mixture preconditioning using in vitro fertilization gas (IVFG) and direct current electrical stimulation (ES20), to enhance the anti-inflammatory properties of sEVs from canine adipose-derived MSCs (cAD-MSCs). Initial steps involved isolation and comprehensive characterization of cAD-MSCs, including morphology, gene expression, and differentiation potentials, alongside validation of the electrical stimulation protocol. IVFG, ES20, and IVES were applied simultaneously with a control condition. Stimulated cAD-MSCs were evaluated for morphological changes, cell viability, and gene expressions. Conditioned media were collected and purified for sEV isolation on Day1, Day2, and Day3. To validate the efficacy of IVES for sEV production, various analyses were conducted, including microscopic examination, surface marker assessment, zeta-potential measurement, protein quantification, nanoparticle tracking analysis, and determination of anti-inflammatory activity.

RESULTS: We found that IVES demonstrated non-cytotoxicity and induced crucial genotypic changes associated with sEV production in cAD-MSCs. Interestingly, IVFG influenced cellular adaptation, while ES20 induced hypoxia activation. By merging these stimulations, IVES enhanced sEV stability and quality profiles. The cAD-MSC-derived sEVs exhibited anti-inflammatory activity in lipopolysaccharide-induced RAW264.7 macrophages, emphasizing their improved effectiveness without cytotoxicity or immunogenicity. These effects were consistent across day 3 collection, indicating the establishment of an effective protocol for sEV production.

CONCLUSIONS: This research established an innovative sequential stimulation method with positive impact on sEV characteristics including stability, quality, and anti-inflammatory activity. This study not only contributes to the enhancement of sEV production but also sheds light on their functional aspects for therapeutic interventions.

PMID:39838398 | DOI:10.1186/s12917-024-04465-2

Commun Biol. 2025 Jan 21;8(1):105. doi: 10.1038/s42003-025-07457-6.

ABSTRACT

Metabolic and neurological disorders commonly display dysfunctional branched-chain amino acid (BCAA) metabolism, though it is poorly understood how this leads to neurological damage. We investigated this by generating Drosophila mutants lacking BCAA-catabolic activity, resulting in elevated BCAA levels and neurological dysfunction, mimicking disease-relevant symptoms. Our findings reveal a reduction in neuronal AMP-activated protein kinase (AMPK) activity, which disrupts autophagy in mutant brain tissues, linking BCAA imbalance to brain dysfunction. Mechanistically, we show that excess BCAA-induced mitochondrial reactive oxygen species (ROS) triggered the binding of protein phosphatase 2 A catalytic subunit (PP2Ac) to AMPK, suppressing AMPK activity. This initiated a dysregulated feedback loop of AMPK-mitochondrial interactions, exacerbating mitochondrial dysfunction and oxidative neuronal damage. Our study identifies BCAA imbalance as a critical driver of neuronal damage through AMPK suppression and autophagy dysfunction, offering insights into metabolic-neuronal interactions in neurological diseases and potential therapeutic targets for BCAA-related neurological conditions.

PMID:39838082 | DOI:10.1038/s42003-025-07457-6

Cell Res. 2025 Jan 21. doi: 10.1038/s41422-025-01076-w. Online ahead of print.

NO ABSTRACT

PMID:39837997 | DOI:10.1038/s41422-025-01076-w

Sci Rep. 2025 Jan 21;15(1):2711. doi: 10.1038/s41598-025-85927-x.

ABSTRACT

Drug development is known to be a costly and time-consuming process, which is prone to high failure rates. Drug repurposing allows drug discovery by reusing already approved compounds. The outcomes of past clinical trials can be used to predict novel drug-disease associations by leveraging drug- and disease-related similarities. To tackle this classification problem, collaborative filtering with implicit feedback (and potentially additional data on drugs and diseases) has become popular. It can handle large imbalances between negative and positive known associations and known and unknown associations. However, properly evaluating the improvement over the state of the art is challenging, as there is no consensus approach to compare models. We propose a reproducible methodology for comparing collaborative filtering-based drug repurposing. We illustrate this method by comparing 11 models from the literature on eight diverse drug repurposing datasets. Based on this benchmark, we derive guidelines to ensure a fair and comprehensive evaluation of the performance of those models. In particular, an uncontrolled bias on unknown associations might lead to severe data leakage and a misestimation of the model's true performance. Moreover, in drug repurposing, the ability of a model to extrapolate beyond its training distribution is crucial and should also be assessed. Finally, we identified a subcategory of collaborative filtering that seems efficient and robust to distribution shifts. Benchmarks constitute an essential step towards increased reproducibility and more accessible development of competitive drug repurposing methods.

PMID:39837888 | DOI:10.1038/s41598-025-85927-x

J Neurosci. 2025 Jan 21:e1337242025. doi: 10.1523/JNEUROSCI.1337-24.2025. Online ahead of print.

ABSTRACT

Microglia respond to cytotoxic protein aggregates associated with the progression of neurodegenerative disease. Pathological protein aggregates activate the microglial NLRP3 inflammasome resulting in proinflammatory signaling, secretion, and potentially pyroptotic cell death. We characterized mixed sex primary mouse microglia exposed to microbial stressors and alpha synuclein preformed fibrils (αsyn PFFs) to identify cellular mechanisms related to Parkinson's disease. Microglia package and release the endosome fate regulator Coronin1A (Coro1A) in EVs in an Nlrp3-dependent manner in widely used experimental activation conditions. We were surprised to find that Coro1A packaging and release was not Nlrp3-dependent in αsyn PFF exposure conditions. Coro1A-/- microglia exposed to αsyn PFFs trafficked more αsyn to lysosomal compartment increasing lysosomal membrane permeabilization. This corresponds to a decrease in αsyn released in EVs suggesting that Coro1A functions to shunt pathological proteins to a secretory pathway to attenuate lysosomal stress. αsyn PFF driven lysosomal stress resulting from Coro1a loss was associated with enhanced cytotoxicity. Intrinsic apoptosis signaling was unaffected, but we observed elevated cytosolic cathepsin B and the presence of a cathepsin associated 55kD PARP cleavage product. Post-mortem analysis of the PD mesencephalon supported a role for Coro1a in microglia, revealing elevated levels of Coro1A protein in human PD brains compared to those of healthy donors. Findings are relevant to the distribution of pathological αsyn and indicate that Coro1a protects microglia from lysosomal overload, inflammasome activation, and pyroptotic demise.Significance Statement Microglia are responsible for clearing toxic protein aggregates such as alpha synuclein (αsyn) in Parkinson's Disease (PD). PD is slowly progressive, implying that microglia are under proteinaceous stress for an extended time, maintaining some level of homeostasis while attempting to clear pathologically aggregated proteins. Pathological proteins can overload the lysosomes resulting in rupture, decreasing the ability of microglia to clear protein aggregates, and contributing to a hyperreactive inflammatory state. We determined that the protein Coronin1A functions in microglia to attenuate αsyn-induced lysosomal stress, preventing Nlrp3-inflammasome activation, and cell death. These findings identify a protective cellular mechanism operating in microglia that may contribute to the distribution of pathological proteins into the microenvironment.

PMID:39837661 | DOI:10.1523/JNEUROSCI.1337-24.2025

Proc Biol Sci. 2025 Jan;292(2039):20241559. doi: 10.1098/rspb.2024.1559. Epub 2025 Jan 22.

ABSTRACT

The two main extensions of rain forest in South America are the Amazon (Amazônia) and the Atlantic rain forest (Mata Atlântica), which are separated by a wide 'dry diagonal' of seasonal vegetation. We used the species-rich tree genus Inga to test if Amazônia-Mata Atlântica dispersals have been clustered during specific time periods corresponding to past, humid climates. We performed hybrid capture DNA sequencing of 810 nuclear loci for 453 accessions representing 164 species that included 62% of Mata Atlântica species and estimated a dated phylogeny for all accessions using maximum likelihood, and a species-level tree using coalescent methods. There have been 16-20 dispersal events to the Mata Atlântica from Amazônia with only one or two dispersals in the reverse direction. These events have occurred over the evolutionary history of Inga, with no evidence for temporal clustering, and model comparisons of alternative biogeographic histories and null simulations showing the timing of dispersal events matches a random expectation. Time-specific biogeographic corridors are not required to explain dispersal between Amazônia and the Mata Atlântica for rain forest trees such as Inga, which are likely to have used a dendritic net of gallery forests to cross the dry diagonal.

PMID:39837505 | DOI:10.1098/rspb.2024.1559

Prog Neuropsychopharmacol Biol Psychiatry. 2025 Jan 19:111258. doi: 10.1016/j.pnpbp.2025.111258. Online ahead of print.

ABSTRACT

BACKGROUND: Type 2 diabetes (T2D) is a chronic metabolic disorder that has high comorbidity with mental disorders. The genetic relationships between T2D and depression are far from being well understood.

METHODS: We performed genetic correlation, polygenic overlap, Mendelian randomization (MR) analyses, cross-trait meta-analysis, and Bayesian colocalization analysis to assess genetic relationships between T2D and depression, in the forms of major depressive disorder (MDD) and depressed affect (DAF). Then, the summary data-based MR (SMR) analysis was performed to prioritize genes contributing to MDD and to T2D from functional perspective. MDD-driven signaling pathways were constructed to understand the influence of MDD on T2D at the molecular level.

RESULTS: T2D has positive genetic correlations both with MDD (rg = 0.14) and with DAF (rg = 0.19). The polygenic overlap analysis showed that about 60 % of causal variants for T2D are shared with MDD and DAF. The MR analysis indicated that genetic liabilities to both MDD (OR: 1.24, 95 % CI: 1.11-1.38) and DAF (OR: 1.48, 95 % CI: 1.23-1.78) are associated with an increased risk for T2D, while genetic liability to T2D is not associated with the risk for MDD (OR: 1.00, 95 % CI: 0.99-1.01) or DAF (OR: 1.01, 95 % CI: 1.00-1.02). The cross-trait meta-analysis identified 271 genomic loci, of which 29 were novel. Genetic predisposition to MDD and T2D shares six overlapping loci, involving some well-characterized genes, such as TCF4 and NEGR1. Colocalization analysis revealed three shared chromosome regions between MDD and T2D, which covers mediator genes including SCYL1, DENND1A, and MAD1L1. Molecular pathway analysis suggests mechanisms that promote the development of T2D through inflammatory pathways overactive in patients with MDD. The SMR analysis and the meta-analysis highlighted seven genes with functional implications for both MDD and T2D, including TNKS2, CCDC92, FADS1, ERI1, THUMPD3, NUCKS1, and PM20D1.

CONCLUSIONS: Our study points out that depression, in the forms of MDD and DAF, may increase the risk of T2D. Analysis of underlying genetic variation and the molecular pathways, connecting depression and T2D, indicate that the pathophysiological foundations of these two conditions have a notable overlap.

PMID:39837361 | DOI:10.1016/j.pnpbp.2025.111258

Neuron. 2025 Jan 16:S0896-6273(24)00926-7. doi: 10.1016/j.neuron.2024.12.026. Online ahead of print.

ABSTRACT

Gliomas are aggressive neoplasms that diffusely infiltrate the brain and cause neurological symptoms, including cognitive deficits and seizures. Increased mTOR signaling has been implicated in glioma-induced neuronal hyperexcitability, but the molecular and functional consequences have not been identified. Here, we show three types of changes in tumor-associated neurons: (1) downregulation of transcripts encoding excitatory and inhibitory postsynaptic proteins and dendritic spine development and upregulation of cytoskeletal transcripts via neuron-specific profiling of ribosome-bound mRNA, (2) marked decreases in dendritic spine density via light and electron microscopy, and (3) progressive functional alterations leading to neuronal hyperexcitability via in vivo calcium imaging. A single acute dose of AZD8055, a combined mTORC1/2 inhibitor, reversed these tumor-induced changes. These findings reveal mTOR-driven pathological plasticity in neurons at the infiltrative margin of glioma and suggest new strategies for treating glioma-associated neurological symptoms.

PMID:39837324 | DOI:10.1016/j.neuron.2024.12.026