Alzheimer's disease (AD) is a devastating neurodegenerative disorder defined by progressive memory loss and synaptic failure. For decades, therapeutic development has focused on clearing amyloid-beta plaques, yet the repeated clinical failures of this approach necessitate a fundamental paradigm shift toward the brain's immunometabolic landscape. The "Viral Mimicry" hypothesis posits that AD represents a state of sterile autoimmunity where the innate immune system mistakenly identifies self-nucleic acids as viral pathogens. This "ghost war" is ignited by the convergence of metabolic dysfunction and genomic instability: specifically, the leakage of mitochondrial DNA into the cytosol and the epigenetic derepression of ancient retrotransposons (LINE-1, HERVs). These endogenous ligands activate the cGAS-STING cytosolic sensing axis, a pathway that drives a chronic interferon response. Consequently, microglia and astrocytes are transformed into senescent, pro-inflammatory phenotypes that release a toxic Senescence-Associated Secretory Phenotype (SASP), directly fueling synaptic elimination. Crucially, major genetic risk factors, including APOE4 and TREM2 variants, exacerbate this cascade by compromising mitochondrial integrity and lipid metabolism, thereby sensitizing the brain to innate surveillance failure. By reconceptualizing AD as an acquired interferopathy driven by the "enemy within," this framework highlights novel therapeutic targets. Specifically, repurposing Nucleoside Reverse Transcriptase Inhibitors (NRTIs) to block retrotransposition and deploying senolytics to clear dysfunctional glia offer promising strategies to arrest the progression from healthy aging to cognitive decline. This review synthesizes current research on the molecular mechanisms of viral mimicry, detailing the impact of genetic risk factors and evaluating emerging therapeutic interventions targeting this innate immune axis.
The persistent global burden of tuberculosis (TB) and the context-dependent efficacy of the Bacillus Calmette–Guérin (BCG) vaccine necessitate the development of innovative prophylactic strategies. mRNA vaccine platforms have emerged as a transformative toolkit, offering unprecedented versatility in antigen design and manufacturing scalability. This inclusive innovation review synthesizes the molecular engineering and immunological mechanisms of mRNA TB vaccines, evaluating their capacity to address the unique challenges posed by the intracellular lifestyle of Mycobacterium tuberculosis (Mtb). mRNA platforms realistically offer superior endogenous antigen production for CD8⁺ T-cell activation and the flexibility to encode multi-stage fusion antigens targeting both active and latent bacilli. However, significant constraints remain; mRNA technology alone cannot resolve the spatial sequestration of Mtb within necrotic granulomas or the "recruitment lag" of systemic immunity to the lung parenchyma. Achieving sterile protection requires a transition toward mucosal delivery systems capable of inducing lung TRM cells. Furthermore, translational success must be measured beyond classical interferon-gamma (IFN-γ) readouts, prioritizing correlates of protection that reflect site-specific immunity, safety in latently infected populations, and the deployment of thermostable formulations in endemic regions. By integrating mRNA constructs into heterologous prime-boost regimens and host-directed therapies, the field moves toward a precision vaccinology framework capable of curtailing the TB epidemic.
Diabetic retinopathy (DR), a complication of type 2 diabetes (T2DM), can lead to vision loss if undetected. This review examines how social determinants of health (SDOH) influence DR prevalence and screening. Following PRISMA guidelines and PROSPERO registration (CRD42024603749), this review searched four databases through October 26, 2024, for studies on SDOH and DR. Titles, abstracts, and full texts were screened, risk of bias was assessed with the EPHPP tool, and pooled effect sizes were calculated using a random-effects model with 95
Glioblastoma (GBM) remains a lethal malignancy characterized by therapeutic resistance and recurrence. Emerging evidence suggests that senescent niches may shape tumor progression, support tumor stemness, and modulate immune engagement. We integrated transcriptomic data from the Glioma Longitudinal Analysis Consortium (GLASS; 118 primary and 113 recurrent IDH-wildtype GBM samples) with protein-level analysis from an independent cohort of 37 GBM patients (25 primary, 12 recurrent), including 6 matched primary-recurrent pairs. Senescence-, stemness-, and immune-related pathways were assessed using single-sample gene set enrichment analysis (ssGSEA), while immunohistochemistry quantified the expression of Lamin B1, Ki67, p53, SOX2, HLA-DRA, B2M, and CD56. Transcript-level validation was performed using matched-pair Wilcoxon testing in 101 GLASS pairs. Recurrent tumors demonstrated increased enrichment of senescence-associated transcriptional programs, including upregulated KAMMINGA_SENESCENCE and reduced TANG_SENESCENCE_TP53_TARGETS_DN scores. Lamin B1 and Ki67 protein levels were significantly lower in recurrent tumors (p = 0.004 and p = 0.016), while p53 expression increased overall (p = 0.001), suggestive of a senescence enrichment upon recurrence. In the matched analysis (6 pairs; 12 samples total), Lamin B1 and Ki67 generally trended lower at recurrence, although paired differences were not statistically significant. SOX2 expression remained broadly stable at the protein level but showed a modest decrease in RNA expression. Immune markers (HLA-DRA, B2M, CD56) exhibited minimal differences, although HLA-DRA increased significantly overall at recurrence (p = 0.025). Matched transcriptomic analysis in GLASS pairs supported recurrent-specific reductions in LMNB1, MKI67, and SOX2, with no consistent changes in TP53, HLA-DRA, B2M, or NCAM1. Recurrent IDH-wildtype GBM exhibits a transcriptional and protein expression shift towards a senescence-associated state with no concomitant changes in SOX2 and select immune markers.
In response to the increasing demand for high-efficiency photovoltaic materials in renewable energy technologies, this study explores a series of novel nitro-functionalized terrylenediimide (TDI) sensitizers exhibiting enhanced charge transport behavior. Nitro substituents were strategically introduced at the bay positions of the TDI molecular framework to modulate photoinduced exciton dynamics, yielding three distinct derivatives TDI-1NO2, TDI-2NO2, and TDI-3NO2, recently characterized for their optoelectronic properties ( https://doi.org/10.1021/acs.jpcc.5c02980 ). Building on these promising findings, we propose the integration of these nitrated TDI derivatives into dye-sensitized solar cells (DSSCs), investigating their favorable charge transport characteristics. A comprehensive density functional theory calculation was conducted to evaluate their structural, electronic, optical, and transport properties. The results indicate that all three derivatives adopt planar conformations, exhibit well-aligned energy levels with the TiO2 conduction band, and possess high open-circuit voltage (OCV) alongside a high injection rate (2.22 × 1015 s−1 for TDI-3NO2 derivative), attributes that collectively position them as promising candidates for DSSC technology. This investigation thus provides deep insight into the continued development and optimization of nitrated terrylenediimide-based sensitizers for advanced solar energy systems.
