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CATH-ddG: Towards Robust Mutation Effect Prediction on Protein-Protein Interactions Out of Cath Homologous Superfamily
No full textMotivation: Protein-protein interactions (PPIs) are fundamental aspects in understanding biological processes. Accurately predicting the effects of mutations on PPIs remains a critical requirement for drug design and disease mechanistic studies. Recently, deep learning models using protein 3D structures have become predominant for predicting mutation effects. However, significant challenges remain in practical applications, in part due to the considerable disparity in generalization capabilities between easy and hard mutations. Specifically, a hard mutation is defined as one with its maximum TM-score \u3c 0.6 when compared to the training set. Additionally, compared to physics-based approaches, deep learning models may overestimate performance due to potential data leakage.
Results: We propose new training/test splits that mitigate data leakage according to the CATH homologous superfamily. Under the constraints of physical energy, protein 3D structures, and CATH domain objectives, we employ a hybrid noise strategy as data augmentation and present a geometric encoder scenario, named CATH-ddG, to represent the mutational microenvironment differences between wild-type and mutated protein complexes. Additionally, we fine-tune ESM2 representations by incorporating a lightweight nonlinear module to achieve the transferability of sequence co-evolutionary information. Finally, our study demonstrates that CATH-ddG framework provides enhanced generalization by outperforming other baselines on non-superfamily leakage splits, which plays a crucial role in exploring robust mutation effect regression prediction. Independent case studies demonstrate successful enhancement of binding affinity on 419 antibody variants to human epidermal growth factor receptor 2 (HER2) and 285 variants in the receptor-binding domain (RBD) of SARS-CoV-2 to angiotensin-converting enzyme 2 (ACE2) receptor.
Availability and implementation: CATH-ddG is available at https://github.com/ak422/CATH-ddG
HIV Protein TAT Dysregulates Multiple Pathways in Human iPSCs- Derived Microglia
No full textIn the era of combined antiretroviral therapy, around 50% of chronic HIV (+) individuals show varying degrees of memory and cognitive deficiency (NeuroHIV), a phenomenon of accelerated brain aging. HIV protein transactivator of transcription (TAT) has been well-accepted as a risk factor contributing to NeuroHIV through dysregulating microglia (Mg) functions. Previous studies have demonstrated that HIV-TAT can affect lipid metabolism, immune responses, autophagy, and senescence in rodent Mg. However, due to the significant species differences between rodent and human Mg (hMg), it is essential to take caution when interpreting the results obtained from rodent models into human conditions. For the unanswered questions, we generated hMg from human inducible pluripotent stem cells (iPSCs) and exposed them to HIV-TAT. The results obtained from Flow analysis and immunostaining experiments reveal that TAT can induce LD accumulation and increase perilipin-2 (Plin2) levels in hMg. Meanwhile, HIV-TAT can upregulate autophagosome formation and p53 levels. Through human immune array assay, we showed that TAT can increase the expression of multiple pro-inflammatory mediators, cytokines, and chemokines in hMg. Extensive bioinformatic analysis shows that HIV-TAT can affect multiple neuroimmune signaling pathways and indicates that microRNAs (miRNAs) are coherently involved in such dysregulation. Overall, our findings provide direct evidence showing that HIV-TAT can affect lipid metabolism, autophagy, senescence signaling, and multiple neuroimmune-related pathways in hMg and indicate the roles of novel miRNAs on NeuroHIV pathogenesis, which deserves further investigations
Threats to Democracy: A Danger to Social Justice for All
No full textThis essay argues that threats to democracy—both global and domestic—pose an existential risk to the advancement of social justice. It explores how democratic backsliding undermines efforts to achieve social justice for all, examining anti-democratic practices such as misinformation, voter suppression, institutional dismantling, and the politicization of public service. Highlighting the interdependence between democratic institutions and social equity in public governance, the authors propose a multilevel response framework to foster democratic resilience through civic engagement, institutional accountability, and collective action. In this essay, members of the Board of the Section on Democracy and Social Justice (DSJ) of the American Society for Public Administration (ASPA) introduce a call to action for public servants, scholars, and civil society to reaffirm their commitment to democracy as essential for meaningful and enduring social justice
Ocular Distribution of Tacrolimus After Topical Administration as EyeSol Formulations in Rabbits and Dogs
No full textPurpose : Tacrolimus is a highly potent calcineurin inhibitor, mainly used as systemic immunosuppressant. One application of tacrolimus, albeit off-label, is orally in non-infectious uveitis. The water-free drug delivery platform EyeSol® has the potential to deliver tacrolimus to the uvea after topical administration. The use of eye drops could lead to a safe and convenient alternative to the use of high dose steroids or orally applied calcineurin inhibitors.To investigate the ocular distribution after topical ocular administration, pharmacokinetics of different tacrolimus formulations was studied in rabbits and dogs.
Methods : NZW rabbits and Beagle dogs received multiple topical ocular doses of tacrolimus (as 0.03% solution or 0.03%, 0.1%, 0.3% suspension) TID for 3 days and a single dose on Day 4. Animals were then sacrificed at specific timepoints after the last dose (rabbit: 0.5h, 1h, 2h, 4h, 8h, 24h; dog: 1h, 4h). Ocular tissues were collected, and levels of tacrolimus were evaluated in aqueous humor, cornea, vitreous, bulbar and palpebral conjunctivae, iris/ciliary body, retina, RPE/choroid, sclera and blood using LC-MS/MS.
Results : In both species, the highest mean concentrations of tacrolimus were observed between 0.5 and 2 hours post dose in the anterior segment of the eye, as expected for a topical treatment. Significant concentrations reached the uvea with levels well above the recommended systemic exposure for transplant rejection (10 ng/g). For the highest dose levels tested (0.03% solution and 0.3% suspension) also pharmacologically relevant retina exposure was detected in rabbit. Systemic concentrations were negligible, and all formulations were well tolerated in both studies. The comparison of different formulations showed a dose response for all three suspensions, and the 0.03% solution was comparable to the highest suspension. The tissue concentrations in rabbits were approx. 3 times higher compared to dogs, which is an expected finding considering the differences in size and anatomy of the eyes. The distribution pattern of all test articles was overall comparable.
Conclusions : Repeated topical ocular dosing of tacrolimus in EyeSol® resulted in pharmacologically active levels of tacrolimus in the uvea target tissues, in both rabbit and dog. These results and published findings from in-vivo models indicate potential for tacrolimus as a topical treatment option for uveitis
Application of Fuzzy Logic for Evaluation of Student Performance
No full textThe evaluation of student performance is a multifaceted process that traditionally relies on rigid grading systems, often failing to capture the complexity of student abilities and learning dynamics. This paper explores the application of fuzzy logic to enhance the accuracy and adaptability of student performance evaluation. By leveraging fuzzy logic principles, such as membership functions and linguistic variables, we model and assess the various factors influencing student performance—ranging from academic grades to engagement, participation, and personal learning styles. The approach allows for the representation of imprecise, uncertain, and subjective data, offering a more holistic view of a student’s progress. We propose a fuzzy inference system that combines multiple assessment criteria to generate more flexible and context-sensitive evaluations. The results demonstrate that this method provides more meaningful insights, offering educators a powerful tool for personalized learning, identification of at-risk students, and tailored interventions. The findings suggest that fuzzy logic-based models hold significant potential for transforming the traditional student evaluation process into a more dynamic, inclusive, and accurate system, adaptable to diverse educational contexts
High-Fidelity SOH Prediction in Lithium-Ion Batteries Using Hybrid ML Networks
No full textAccurate and efficient prediction of lithium-ion battery state of health (SOH) is critical for ensuring reliability in electric vehicles, grid storage, and aerospace systems. Traditional SOH estimation methods often struggle with nonlinear degradation behaviors and lack sensitivity to subtle electrochemical signals, limiting their real-world deployment. To address these challenges, this study examines hybrid deep learning models that integrate differential capacity (dQ/dV) analysis to enhance predictive accuracy. Four hybrid architectures - hybrid CNN-LSTM multihead, CNN extractor for LSTM, DNN-LSTM, and DNN Bi-LSTM - were developed and evaluated using the NASA randomized battery usage dataset, offering a realistic benchmark under diverse operational profiles. Among these, the hybrid DNN-LSTM model achieved the best performance, with high predictive accuracy (R² = 0.9968, MAE = 0.63%) and computational efficiency, making it well-suited for real-time battery management applications. Its lightweight design allows rapid adaptation to different chemistries and usage conditions, with potential for remaining useful life (RUL) estimation and diagnostics. This study highlights the advantages of combining dQ/dV analysis with hybrid deep learning architectures, providing a scalable and practical solution for modern battery health management
A Unique Case of Jena Valve TAVR Post-Transcatheter Mitral Valve in Valve Replacement
No full textSevere aortic regurgitation presents unique technical challenges for transcatheter aortic valve replacement (TAVR) due to the absence of annular calcification and device malanchoring risks. These challenges are inherently heightened with previous valve replacements and cardiac procedures, especially in patients with prior mitral valve-in-valve (TMViV) procedures. This case report describes a high-risk patient with symptomatic severe aortic regurgitation following TMViV procedure for mitral regurgitation, managed with a transapical valve-in-valve implantation of the JenaValve for compassionate use. The JenaValve, a device specifically engineered for AR, demonstrated successful anchoring, elimination of significant regurgitation, and low paravalvular leak after the procedure. Post-procedural imaging revealed optimal valve function and preserved mitral bioprosthesis integrity. The patient was alive and in good clinical condition at 30 days of follow-up. This case report supports the feasibility and safety of transcatheter leaflet-capturing valve systems for the treatment of severe aortic regurgitation in complex multivalve settings, where surgery carries prohibitive risk. The case report highlights the need for further research to define long-term outcomes in this population
Staged Cervical Laminoplasty and Pulmonary Endarterectomy in a Patient with Concomitant Cervical Stenosis and Severe Pulmonary Hypertension
No full textSix-Year Survival Following Liver Transplant in Val30Met Hereditary Transthyretin Amyloidosis
No full textBackground: Hereditary transthyretin amyloidosis (ATTRv) is a progressive, multisystem disorder caused by pathogenic TTR mutations affecting the heart and peripheral nerves. While disease-modifying agents such as tafamidis are available, liver transplantation (LTx) remains an option in selected genotypes, with over 50% of Val30Met carriers surviving up to 20 years post-transplant.
Case: A 53-year-old male with a permanent pacemaker for complete atrioventricular block presented with NYHA class II dyspnea, syncope, and lower extremity paresthesias. ECG showed atrial fibrillation. Transthoracic echocardiography revealed preserved ejection fraction, biventricular wall thickening with granular appearance, moderate left atrial dilation, and moderate mitral regurgitation. Speckle-tracking echocardiography demonstrated relative apical sparing of longitudinal strain. Cardiac MRI showed diffuse subendocardial late gadolinium enhancement. Serum and urine electrophoresis and free light chain assays excluded monoclonal gammopathy. Technetium-99m pyrophosphate scan showed grade 3 myocardial uptake. Genetic testing identified a heterozygous Val30Met (p.Val50Met) pathogenic variant in the TTR gene, confirming ATTRv.
The patient was started on tafamidis and continued anticoagulation. Within six months, dyspnea progressed from NYHA II to III despite medical management. After multidisciplinary discussion considering rapid progression, multisystem involvement, and a favorable genotype, LTx was successfully performed. At six years of follow-up, the patient remains alive with preserved graft function, stable neurologic status, and NYHA III symptoms.
Conclusion: This case illustrates that LTx remains a valid disease-modifying option in selected Val30Met ATTRv patients, particularly those with rapid clinical deterioration despite pharmacologic therapy. Early genetic diagnosis and timely referral to transplant centers are essential to maximizing survival and functional stability
Association Between Cardiovascular Risk and Kidney Function in a Real-World Peruvian Cohort
No full textBackground: Cardiovascular risk and kidney function are interrelated, with variations by sex and age. Middle-aged women often have slightly lower kidney function than men, increasing susceptibility to early renal effects of elevated cardiovascular risk, but data from Latin America remain limited.
Methods: Cross-sectional study of adults aged 40-79 years evaluated at a tertiary hospital in Peru between January and June 2024. We excluded individuals with established cardiovascular disease, statin use, LDL \u3e190 mg/dL, or incomplete ASCVD risk data. Ten-year ASCVD risk was estimated using the 2013 Pooled Cohort Equations with race set as “Other” and classified as low, borderline, intermediate, or high. eGFR was calculated with the 2021CKD-EPI equation, compared across ASCVD categories with Kruskal–Wallis test, and examined for trends using Spearman correlation. Multivariable linear models adjusted for age, sex, BMI, and systolic BP, with subgroup analyses by sex and age (\u3c 60 vs ≥60 years).
Results: We included 207 participants (mean age 62.9 years, 54.6% women). Mean eGFR declined progressively across ASCVD categories (H = 40.79, p \u3c 0.001) and inversely correlated with ASCVD risk (rho = –0.436, p \u3c 0.001). Higher ASCVD risk remained independently associated with lower eGFR in adjusted models. The strongest effect was in women \u3c 60 years, with each 1% ASCVD risk increase associated with –2.8 mL/min/1.73 m² lower eGFR (95% CI –5.37 to –0.23; p = 0.033).
Conclusion: In this Peruvian cohort, kidney function decreased with increasing cardiovascular risk, with a particularly pronounced effect in younger women, underscoring the need for early prevention in this group