Drusen and subretinal drusenoid deposits, the pathognomonic lesions for age-related macular degeneration (AMD), are rich in cholesterol. Yet, AMD is not consistently linked to plasma lipids. Here wild-type and human apolipoprotein B100-expressing (APOB100) mice were put on a Western type of diet for 13 months and then assessed for plasma lipid profile, high-density lipoprotein (HDL) heterogeneity, status of intraretinal and choroidal vasculatures, retinal structure, function, levels of cholesterol and other sterols, lipid and cholesterol distribution and expression of cholesterol-related genes. The dietary effects were more pronounced in APOB100 mice, which had human-like hyperlipidemia and different subpopulations of HDL3, than in wild-type mice. In addition, the APOB100 retina showed increased cholesterol input from the systemic circulation, higher cholesterol content, more cholesterol crystals, elevated expression of HDL-related genes, lipid accumulation in the retinal pigment epithelium and Bruch's membrane, and impaired function compared with the wild-type retina. Remarkably, in both genotypes, cholesterol crystals were detected in the choroid, piercing toward Bruch's membrane and leading to macrophage infiltration. Our data indicate how plasma lipid profile could be linked to AMD and that cholesterol crystals in the choroid should be further investigated as contributors to AMD development and progression.
Publications
2026
INTRODUCTION: Cystic fibrosis (CF) is a life-shortening genetic disorder traditionally mischaracterised as affecting only populations of European descent. This framing has contributed to under-recognition of CF in African populations, despite emerging evidence of both common and region-specific cystic fibrosis transmembrane conductance regulator mutations across the continent. Diagnostic barriers, structural inequities and lack of surveillance further exacerbate disparities in care and visibility.
METHODS AND ANALYSIS: This scoping review aims to characterise CF in African populations by synthesising evidence on clinical presentation, diagnostic practices, genotypic diversity, prevalence and structural barriers to care. We will include case reports, cohort studies, registry analyses and other primary data sources involving individuals of African descent with suspected or confirmed CF. Key outcomes include clinical phenotype, age at diagnosis, mutation profile, diagnostic testing access and mortality. Data sources include Ovid Medline, Embase, Ebsco Global Health, CAB Abstracts and Web of Science Core Collection. Multiple-reviewer screening and extraction will be conducted. We will use narrative synthesis, thematic analysis and meta-analysis for prevalence where feasible.
ETHICS AND DISSEMINATION: No ethical approval is required as the review uses published data. Results will be shared with clinicians, researchers and CF networks in Africa and globally to inform diagnostic strategies and policy.
Due to the limited size of viral genomes, most viral proteins are multifunctional; yet most direct-acting antivirals are designed as single-function inhibitors. The dengue virus (DENV) capsid protein serves as a building block for new virions while also interacting with multiple host factors to remodel the cellular environment. Using established capsid inhibitor ST148 as a targeting ligand, we develop a DENV capsid degrader, RPG-01-132, that exhibits a broadened spectrum of activity against the four DENV serotypes and an ST148-resistant mutant virus. Using multiple approaches, we show that RPG-01-132's sub-micromolar antiviral activity is due to CRL4CRBN-dependent degradation of capsid and that this mechanism disrupts capsid-related pathways required for productive infection, including infectious virus output and capsid-mediated antagonism of the interferon response. This pharmacology is well-differentiated from ST148, which interferes with assembly of new virions, but has no demonstrated effect on the capsid's nonstructural functions. These findings demonstrate that targeted protein degradation can thus enable antiviral pharmacology not observed with conventional antiviral inhibitors and that is resilient to point mutations that reduce inhibitor potency.
Neurotropic viruses invade neural tissues, resulting in severe diseases such as poliomyelitis, rabies, herpesviral encephalitis, and viral meningitis. Given this neurotropism, we investigated whether the infection of the host by these viruses is under circadian control. In this study, we found that the expression of most neurotropic virus receptors exhibits rhythmicity across cells, cerebral organoids, and animal models, with host cell susceptibility modulated by the circadian clock. We identified E2F8 as a clock-controlled gene that mediates the indirect regulation of the circadian clock on neurotropic viruses. Notably, E2F8 regulated the expression of core clock components by binding directly to the promoters of REV-ERBα and PER2, suggesting its role as a potential modulator of circadian rhythms. Additionally, we revealed a seldom-recognized viral strategy to accelerate viral replication in the host: rabies virus disrupts the host circadian clock system primarily through its glycoprotein hijacking the E3 ubiquitin ligase HUWE1 to inhibit proteasomal degradation of REV-ERBα. These findings increase our understanding of the interactions between circadian systems and neurotropic viral dynamics and highlight the potential of chronotherapy for improved antiviral treatments.
Chronic lung allograft dysfunction (CLAD) limits long-term lung graft survival, yet its specific gene expression profiles remain unclear. We performed comprehensive spatial transcriptomic analyses of human lungs from CLAD patients, non-CLAD transplant recipients, and non-transplanted controls. In CLAD, AP-1 target genes, including JUNB and FOS, were significantly upregulated in both the epithelium and endothelium, whereas anti-fibrotic genes such as A2M and surfactant proteins (SFTPA1,2) were upregulated in non-CLAD. The lymphocyte population in CLAD was predominantly composed of T cells, with elevated JAK3-IL7R signaling. TNF and IL-17 signaling pathways were commonly activated in both the epithelium and endothelium, with JUNB and FOS serving as central hubs within pro-inflammatory, pro-fibrotic gene networks. These findings suggest that coordinated AP-1 activation and shared inflammatory and fibrotic signaling across epithelial and endothelial compartments may drive CLAD. Our results highlight the transcriptionally active roles of both compartments and provide new mechanistic insights into CLAD pathogenesis.
Plant cell surface pattern recognition receptors (PRRs) perceive non- or altered-self elicitors to induce immune responses. PRRs relay information across the plasma membrane and trigger downstream signalling via receptor-like cytoplasmic kinases such as BOTRYTIS-INDUCED KINASE 1 (BIK1). BIK1 associates with several PRRs and acts as a key executor of immune responses through the phosphorylation of substrate proteins. However, a comprehensive understanding of how BIK1 targets specific substrates and a full repertoire of these substrates are lacking. Here we defined the substrate specificity of BIK1 and used these data to predict candidate substrates in Arabidopsis. Using high-throughput biochemical and genetic screening of these candidates, we confirmed many as direct BIK1 substrates in vitro and novel regulators of plant immunity. Among the BIK1 substrates identified are MULTIPLE C2 DOMAIN AND TRANSMEMBRANE REGION PROTEIN 3, which we reveal regulates flagellin 22 (flg22)-induced plasmodesmata closure and immunity, and members of the largely uncharacterized CYCLIN-DEPENDENT KINASE-LIKE family, which we uncover as novel negative regulators of immunity. In parallel, we interrogated intracellular NUCLEOTIDE-BINDING LEUCINE-RICH REPEAT (NLR) immune receptors for potential BIK1 phosphorylation motifs and identified multiple NLRs as direct BIK1 substrates. We reveal that BIK1 phosphorylation regulates NLR oligomerization, thus controlling a key activation step for these immune receptors. Together, our unbiased biochemical screens shed light on the central role of BIK1 as a key kinase shaping multiple layers of plant immune signalling.
PURPOSE OF REVIEW: We evaluate the converging evidence positioning lithium as a systemic modulator of bone and brain health through shared molecular pathways. This review examines the molecular basis, preclinical data, and clinical observations suggesting that lithium-long established as first-line therapy for bipolar disorder-may simultaneously protect against osteoporosis and neurodegeneration as two clinical conditions increasingly recognized to share biological substrates.
RECENT FINDINGS: Lithium inhibits glycogen synthase kinase-3β (GSK-3β), stabilizes β-catenin, and activates Wnt signaling in neurons and osteoblasts, while also modulating calcium-inositol homeostasis and suppressing NF-κB-mediated inflammation. Large observational studies report lower dementia incidence and reduced fracture risk in long-term lithium users, together with increases in bone mineral density. Declining brain lithium concentrations in patients with Alzheimer's disease raise the hypothesis that lithium may act as an essential micronutrient rather than solely a pharmacological agent. Bidirectional brain-bone crosstalk involving osteocalcin signaling and sclerostin transport across the blood-brain barrier provides a mechanistic basis for these pleiotropic effects. Lithium offers a unique paradigm for understanding and potentially treating age-related decline in multiple organ systems at subclinical dosage and concentration. However, observational study limitations, optimal dose uncertainties, and toxicity related to long-term usage concerns necessitate rigorous randomized controlled trials before broader clinical recommendations can be made. Future research should focus on optimizing formulation and patient selection to realize lithium's dual protective potential for bone and brain while minimizing risk.
BACKGROUND: The number of people living with HIV (PLWH) in sub-Saharan Africa who are over 50 years old is increasing rapidly, and expected to triple by 2040. Yet, how older PLWH sustain access to care and viral suppression is not well known. We examined the prevalence and correlates of viral suppression in a cohort of older PLWH in Uganda.
METHODS: We analyzed data from the Quality of Life and Aging with HIV in rural Uganda study, which follows PLWH over 50 years old who are in care at public HIV clinics in Uganda. Our outcome of interest was viral suppression, defined as HIV-1 RNA viral load less than 200 copies/mL. We estimated the prevalence of viral suppression and fitted multivariable log binomial regression models to identify correlates of viral suppression.
RESULTS: The mean cohort age was 59.7 years (standard deviation [SD] 6) and participants had been taking HIV therapy for a mean of 13.3 years (SD 3). Viral suppression was relatively high overall (87%, 240/277). In multivariable models, people aged ≥ 60 years were less likely to be virally suppressed than those aged 50-59 years (78% vs. 93%, adjusted prevalence ratio [APR] 0.85, 95% CI: 0.76, 0.93, P = 0.001). By contrast, having one or more comorbidities was positively associated with viral suppression (APR 1.10, 95% CI: 1.01, 1.18, P = 0.021).
CONCLUSION: We found a decreased prevalence of viral suppression among PLWH aged ≥ 60 years atleast in Uganda. Public health interventions that address the adherence support needs of older individuals should be evaluated and, if successful, incorporated into HIV care services, given the significant number of older people living with HIV in the region.
Newborn screening (NBS) for X-linked adrenoleukodystrophy (ALD) enables early identification of boys at risk for adrenal insufficiency (AI) and cerebral ALD (CALD). However, NBS frequently identifies ABCD1 variants of uncertain significance (VUS), which are associated with only borderline-elevated C26:0-lysophosphatidylcholine (LPC(26:0)) levels. Traditional American College of Medical Genetics and Genomics (ACMG) pathogenicity classification does not account for age-dependent penetrance or the broader phenotypic spectrum, complicating risk assessment and clinical management. Through the Grey Zone Project, we developed a risk-stratification framework using a receiver operating characteristic (ROC)-based approach prioritizing 95% sensitivity. This framework incorporates biochemical and longitudinal clinical data from 1627 control subjects and 196 confirmed ALD patients. Three pediatric risk categories were defined: "no ALD" (<110 nmol/L LPC(26:0)), "lower-risk AI/CALD" (110-177 nmol/L), and "at-risk AI/CALD" (>177 nmol/L). When applied to 108 samples carrying 51 unique ABCD1 VUSs, 26 variants were reclassified as "no ALD," 15 as "lower-risk AI/CALD," and 10 as "at-risk AI/CALD." The framework reclassifies ABCD1 variants based on biochemical risk profiles, reducing false-positive referrals, avoiding unnecessary MRI surveillance, and alleviating parental anxiety by identifying children who are unlikely to develop childhood-onset disease. Integrating biochemical thresholds with genetic and longitudinal clinical data improves the specificity of NBS without compromising its sensitivity. Providing systematic feedback on false-positive cases to screening laboratories will further refine cut-offs. This framework provides a scalable, evidence-based model for interpreting variants and enabling personalized follow-up in ALD and other disorders with a variable age of onset.