Retinal Diseases are the main reason for vision loss and blindness worldwide. Initial identification of retinal abnormalities is essential for avoiding severe retinal-related complications and improving patient results. Traditional retinal disease diagnosis mainly depends on manual checks of retinal fundus images, which are slow and highly dependent on medical expertise. Deep learning methods are used in retinal disease classification. Existing methods are primarily based on labelled image data and often do not fully utilize complementary clinical information. The proposed hybrid multi-model framework classifies retinal diseases from the available retinal fundus images.

Non-transfusion-dependent thalassemia (NTDT) describes a group of inherited hemoglobin disorders characterized by hemolytic anemia and ineffective erythropoiesis. Although patients with NTDT do not require lifelong regular transfusions for survival, they are at a substantial risk of complications including iron overload, pulmonary hypertension, extramedullary hematopoiesis, and others. Until recently, treatment options were limited to supportive care, intermittent transfusions, occasional splenectomy, and off-label therapies. Mitapivat, an oral activator of erythrocyte pyruvate kinase, is the first disease-directed therapy for adults with NTDT to be approved by the U.S. Food and Drug Administration. Mitapivat improves red cell survival and reduces hemolysis by improving erythrocyte energy production through the glycolytic pathway. Its approval was supported by the Phase III ENERGIZE trial, which showed significant improvements in hemoglobin concentration, hemolysis markers, and fatigue among adults with α- and β-thalassemia. In this review, we summarize the rationale for pyruvate kinase activation in thalassemia, present preclinical and clinical evidence supporting the use of mitapivat in NTDT, discuss the efficacy and safety profile of mitapivat, and review practical considerations for prescribing. We also discuss knowledge gaps and the need for long-term follow-up studies to clarify the role of mitapivat within the changing therapeutic landscape for thalassemia.

Substance use disorder is a chronic relapsing condition characterized by persistent drug seeking, cognitive impairment, and neurobiological alterations in brain reward and memory circuits. Emerging evidence suggests that dysfunction of the endogenous opioid system and reduced neurotrophic signaling contribute to the pathophysiology of opioid dependence. Cell based therapeutic strategies may provide a novel approach to modulate these neural pathways. In the present experimental study, morphine dependence was induced in adult male rats using an escalating dose regimen. Animals were randomly allocated into control, morphine-dependent vehicle, and cell-treated groups. Proenkephalin-expressing differentiated mesenchymal stem cells (PENK-MSCs) were delivered via the intranasal route. Behavioral assessments were performed using conditioned place preference, novel object recognition, and the elevated plus maze to evaluate addiction related behaviors, cognitive performance, and anxiety like responses. Hippocampal brain derived neurotrophic factor (BDNF) expression was examined using immunohistochemistry. Morphine dependent rats exhibited significant behavioral alterations, including enhanced drug related preference, impaired recognition memory, and increased anxiety like behavior compared with control animals. In addition, hippocampal BDNF expression was significantly reduced following morphine exposure. Intranasal cell delivery significantly attenuated morphine-induced preference, reversed recognition memory deficits, mitigated anxiety-like behaviors, and upregulated hippocampal BDNF expression compared with the vehicle-treated morphine group. These findings demonstrate that intranasal delivery of PENK-MSCs attenuates behavioral deficits and promotes neurotrophic recovery in morphine-dependent rats. This approach may represent a promising experimental strategy for targeting neural mechanisms involved in substance use disorder, although further studies are required to confirm its long-term efficacy and translational potential.

Complex neurodevelopmental disorders such as autism spectrum disorders (ASD) and schizophrenia are characterized by impaired social interactions, cognitive deficits, and repetitive behaviors. Genome-wide association studies (GWAS) have identified the α5 nicotinic acetylcholine receptor (α5-nAChR) subunit as a significant risk factor for these neuropsychiatric conditions. The α5 subunit is a critical modulator of neural circuit dynamics, specifically through its functional involvement within vasoactive intestinal peptide (VIP)-positive interneurons; however, its role in the sex-dependent maturation of behavioral phenotypes remains poorly understood. We characterized α5-nAChR knockout (ACNA5) mice to investigate the neurodevelopmental consequences of α5 subunit loss. ACNA5 mice displayed sexually dimorphic and age-dependent core symptoms relevant to ASD and schizophrenia. Regarding anxiety-like behavior, there was an opposite sex pattern between genotypes, evident only in adulthood. Cognitive assessment using the novel object location task revealed early-onset spatial memory deficits in ACNA5 females, whereas males exhibited a progressive decline from adolescence to adulthood. In the social domain, adult ACNA5 mice failed to exhibit social novelty preference; females displayed complete social indifference, while males displayed a pronounced familiarity bias. In addition, ACNA5 mice of both sexes displayed amplified repetitive behavior, emerging earlier in males, and poor nest-building scores across developmental stages. Together, these findings identify the α5-nAChR subunit as a crucial modulator of the maturation of neural circuits underlying social motivation, cognition, and emotional regulation. Our results implicate α5-containing nicotinic receptors in the pathogenesis of neurodevelopmental disorders and establish the ACNA5 mouse as a valuable model for investigating sex-specific developmental trajectories and therapeutic windows.

Alexander disease (AxD) is a rare neurodegenerative disorder characterized by the pathological accumulation of Rosenthal fibers (RFs) and astrocytic inflammation. Despite advances in elucidating its genetic basis, effective therapeutic strategies remain limited. Recent studies indicate that astrocytes in AxD exhibit excessive mitochondrial fragmentation, which may cause mitochondrial dysfunction and inflammatory response. Photobiomodulation (PBM) has been shown to improve mitochondrial function and exert anti-inflammatory effects, suggesting it may be a promising candidate for the treatment of AxD. Here, we report that exposure to 1070-nm infrared light exerts therapeutic efficacy in AxD. Specifically, using the astrocytes derived from AxD patients and a mouse model of AxD, we demonstrate that PBM regulates AMPK/mTOR signaling and promotes mitophagy, thereby attenuating reactive oxygen species production from fragmented mitochondria and subsequent inflammatory status. This study suggests PBM may serve as a novel, non-invasive therapeutic approach for the treatment of AxD.

Cells maintain homeostasis by dynamically reorganizing their organelles to tune metabolism in response to stress. Fluorescence microscopy maps organelle structures with subcellular resolution but provides limited chemical information. Infrared (IR) imaging offers a label-free alternative for probing intrinsic molecular vibrations that report on lipids, carbohydrates, and nucleic acids. Here, we combine submicron optical photothermal IR imaging with machine learning to classify subcellular structures in fixed U-2 OS cells in a cell state dependent manner. Using fluorescent-labeled organelles as ground truth, we trained and evaluated random forest (RF) classifiers and U-Net convolutional neural networks to identify organelles from IR spectra in healthy cells. The classifiers accurately identified multiple organelles, including the endoplasmic reticulum, Golgi apparatus, mitochondria, nucleus, nucleolus, and stress granules. Classifiers trained in U-2 OS cells transferred without retraining to HEK 293 cells, consistent with conserved organelle biochemical composition across cell types. Conversely, the classifiers failed under cellular stress which indicates sensitivity to stress-induced changes in organelle state. Together, these results establish a scalable, label-free strategy for high-resolution mapping of organelle biochemical composition and provide a foundation for subcellular biomarker discovery and disease-state diagnostics.

We aimed to comprehensively evaluate the associations of a broad panel of systemic inflammation-related biomarkers with overall survival (OS) in metastatic nasopharyngeal carcinoma (mNPC) and to assess whether these signatures mediate the adverse impact of high EBV DNA burden on long-term outcomes. This study included 1847 patients with mNPC treated at Sun Yat-sen University Cancer Center between 2016 and 2022. Multivariable Cox proportional hazards models, restricted cubic spline (RCS) models, and time-dependent receiver operating characteristic (ROC) curve analyses were used to evaluate associations of inflammation-related indices with OS. Exploratory mediation analyses quantified the extent to which biomarkers partially mediated the association between plasma EBV DNA burden and mortality risk. Mean follow-up was 45.4 months; 713 (38.6%) deaths occurred. Plasma EBV DNA showed stable discrimination (AUCs of 0.63, 0.62, and 0.61 for 1-, 3-, and 5-year OS). After full adjustment, CALLY and LCR were protective, whereas CAR, NAR, SIRI, IBI, MLR, NC, PC, GPS, mGPS, and LCS were adverse. CAR, CALLY, LCR, IBI, and NC showed the highest discrimination (1-year AUCs, 0.65-0.66). Mediation analyses indicated that MLR, SIRI, CALLY, and NC accounted for 7.6%-9.6% of the EBV DNA load-mortality association. Elevated pretreatment EBV DNA was associated with a coordinated systemic inflammatory profile and worse OS in mNPC. Selected inflammatory markers statistically accounted for a modest proportion of the observed association between EBV DNA burden and mortality. Integrating EBV DNA with inflammatory profiles may improve risk stratification and guide intensified surveillance, earlier assessment, and risk-adapted therapy.

Adverse childhood experiences (ACEs) are a significant determinant of health across the life course and exhibit a dose-dependent relationship with the risk of mental and physical disorders in adulthood. One common yet under-recognized ACE is growing up in a family with an alcohol problem. The objective of this study was to review current data on the neurobiological mechanisms and clinical consequences of early exposure to parental alcohol use disorder, considered an ACE, along with implications for medical practice. A review was conducted of the literature on ACEs, with a particular focus on exposure to parental alcohol use disorder, the co-occurrence of other developmental adversities, and health outcomes in adulthood. Data on ACE screening and the trauma-informed care approach were also included. Parental alcohol use disorder often co-occurs with violence, neglect, and mental health disorders among caregivers, increasing overall stress exposure. Chronic developmental stress is associated with hypothalamic-pituitary-adrenal axis dysregulation and persistent inflammation, as well as an increased risk of depression, anxiety disorders, posttraumatic stress disorder, and substance use disorders. Somatic consequences are also described, including a higher risk of type 2 diabetes and cardiovascular disease, as well as a poorer response to treatment in individuals with ACE exposure. The term adult children of alcoholics is descriptive in nature and does not constitute a diagnostic entity. Early exposure to a parent's alcohol use disorder as an ACE is associated with multidimensional health consequences in adulthood. Further research is needed on the efficacy and safety of ACE screening and the implementation of trauma-informed care.

Hepatic sinusoidal obstruction syndrome (HSOS) is a life-threatening liver microvascular disorder characterized by hepatic sinusoidal endothelial cells (HSECs) injury, for which safe and effective pharmacological treatments are currently lacking. Tangeretin (TAN), a natural polymethoxylated flavone, exhibits anti-inflammatory, antioxidant, and hepatoprotective properties. However, its therapeutic potential and mechanisms in HSOS remain unclear. This study investigated the protective role and molecular mechanisms of TAN against monocrotaline (MCT)-induced HSOS. In the murine HSOS model, TAN intervention alleviated hepatic sinusoidal congestion, lobular injury and elevated serum transaminase levels in a dose-dependent manner. Mechanistic studies revealed that TAN blocks the binding of Keap1 and Nrf2, inhibits Keap1-mediated ubiquitination and degradation of Nrf2, and facilitates its nuclear translocation. Activated Nrf2 enhances mitophagy and restores mitochondrial homeostasis, thereby suppressing NLRP3 inflammasome activation and M1 macrophage polarization to alleviate hepatic sinusoidal endothelial cell injury. Furthermore, genetic ablation of NLRP3, or pharmacological blockade of Nrf2 (ML385) and mitophagy (Mdivi-1), markedly attenuated the protective effects of TAN in restraining M1 macrophage polarization and ameliorating HSOS pathological lesions. In conclusion, TAN activates the Keap1-Nrf2 pathway and promotes mitophagy, which further inhibits NLRP3 inflammasome activation and M1 macrophage polarization, ultimately alleviating MCT-induced hepatic sinusoidal obstruction syndrome. These findings suggest that TAN may serve as a potential candidate drug for the treatment of HSOS.