The key-value (KV) cache in transformer-based language models stores intermediate computations (keys and values) for all previous tokens, enabling efficient autoregressive decoding. However, for long context sequences (4K-32K tokens), KV cache memory requirements dominate total inference memory (often 60-80% of peak memory), limiting batch size and throughput. This study presents a sliding window KV-cache mechanism combined with importance scoring to reduce memory requirements while maintaining generation quality. The approach maintains only the most recent N tokens (sliding window) in the KV cache, discarding older tokens as new ones are generated. We introduce adaptive importance scoring based on attention weights: tokens with high cumulative attention in recent generation steps are retained in cache, while low-importance tokens are discarded. We evaluate on multiple architectures (Llama 2-7B, Mistral 7B, LLaMA-13B) and tasks (long-document summarization, retrieval-augmented generation, long-context question answering). With a 2048-token sliding window covering 2048/4096 = 50% of a 4K context: Perplexity remains within 2-3% of full-context baseline (typically 93-98% recovery), Memory savings reach 45-55% reduction in KV cache size, Throughput improves 1.8-2.1x due to reduced memory bandwidth, Latency per token decreases by 35-42%. For extreme compression (512-token window covering 12.5% of 4K context): Quality degrades more significantly (80-85% perplexity recovery), but memory reduction reaches 75-80%, enabling batch size improvements of 3-4x. The importance scoring mechanism uses recent attention patterns to identify which older tokens remain relevant. Validation shows the method preserves long-range dependencies needed for retrieval-augmented tasks (retrieval precision within 1-2% of full context). This framework enables efficient inference on memory-constrained devices while maintaining reasonable quality for most applications.
Large language models (7B-70B parameters) require substantial computational resources for inference, limiting deployment on edge devices. Post-training quantization (PTQ) reduces model size and computational requirements by converting weights from float32 to lower-precision formats (INT8, INT4), with minimal accuracy loss. However, INT4 quantization presents challenges due to the reduced dynamic range (256 levels vs. 4.3B for float32). This study develops adaptive calibration techniques for INT4 post-training quantization of instruction-tuned language models, addressing distribution shift between calibration and deployment data. We evaluate multiple calibration strategies: (1) Min-Max static calibration (baseline), (2) Percentile-based (99th, 99.5th percentile), (3) Entropy-based calibration (KL divergence minimization), and (4) Mixed-precision quantization (INT4 for weights, INT8 for activations). Testing on Llama 7B, Mistral 7B, and Phi-2 models using standard benchmarks (MMLU 5-shot accuracy, HellaSwag, PIQA) and custom instruction-following tasks. Results show entropy-based calibration achieves 95.2% of full-precision performance on MMLU, compared to 91.8% for naive min-max quantization (3.4% recovery). Mixed-precision approaches recover 96.1% of performance while reducing model size by 4.1x. Quantization degrades performance more on reasoning-heavy tasks than factual knowledge tasks. The adaptive calibration method automatically selects which layers to keep at INT8 vs INT4 based on sensitivity analysis. Implementation uses NVIDIA CUDA kernels for efficient INT4 inference (~2.8x speedup on RTX 4090 vs. float32). This framework enables practical deployment of 7B+ parameter models on consumer GPUs with <5% accuracy loss.
Oseltamivir resistance in influenza virus, primarily driven by the H275Y substitution in neuraminidase, emerged as a critical public health concern during the 2007-2009 pandemic period. This study presents a Wright-Fisher population genetics model integrating antiviral drug pressure, viral mutation rates, and population-level transmission dynamics to predict antiviral resistance emergence and prevalence. We parameterize the model using empirical data from the 2007-2009 pandemic period, including oseltamivir prescribing patterns (peak ~100M doses/year in US), neuraminidase H275Y mutation frequency (0% baseline, peak ~30% in 2008-2009), and viral fitness penalties (estimated 20-50% transmission cost for resistant mutants in untreated hosts). Monte Carlo simulations (10,000 replicates) over 5-year horizons demonstrate that resistance prevalence depends critically on the threshold of untreated infected individuals. When treatment reaches 40-60% of symptomatic cases, resistant strains remain at <5% frequency despite continued drug pressure. Resistance emerges explosively when treatment coverage drops below 30%, with variants reaching 30-40% prevalence within 18-24 months. The model identifies a tipping point at approximately 25-35% treatment coverage where stochastic fluctuations determine whether resistance sweeps through the population. We validate predictions against observed 2007-2009 epidemiological data showing H275Y prevalence correlated with oseltamivir use patterns across regions. Sensitivity analyses show resistance emergence is most sensitive to mutation rate (±50% change alters predictions by 8-12%), fitness cost of resistance (±30% changes alter timeline by 6-10 months), and treatment rates (10% change in coverage shifts tipping point significantly). This framework enables public health forecasting of antiviral resistance emergence to guide antiviraldrug stewardship policies and pandemic preparedness planning.
Contamination events in drinking water distribution systems pose acute public health risks. Early detection is critical—typical contamination (chemical, microbial, or physical) travels through distribution networks, potentially affecting thousands within hours. We present a real-time anomaly detection system using multivariate sensor fusion and Isolation Forest algorithms. The system monitors six water quality parameters simultaneously (pH, turbidity, free chlorine, dissolved oxygen, electrical conductivity, temperature) at normal ranges specified by EPA Safe Drinking Water Act regulations. We evaluate three machine learning approaches: Isolation Forest, Local Outlier Factor (LOF), and multivariate Gaussian detection, on synthetic water quality data spanning 30 days with injected contamination events. Isolation Forest achieves 90.4% F1-score and 89.2% recall with <6 hour mean detection latency. The approach is computationally efficient, operational without internet connectivity, and provides explainable anomalies through feature attribution. Field validation on real distribution systems and integration with SCADA alert systems could enable autonomous contamination response, protecting public health and water infrastructure.
Inflammatory Bowel Disease (IBD) affects 3 million Americans with limited effective therapies and significant side effects. Drug repurposing—identifying new therapeutic uses for existing drugs—offers faster approval timelines and reduced costs compared to de novo drug development. We present a network pharmacology approach combining protein-protein interaction (PPI) data, drug-target information, and disease-gene networks to systematically identify existing drugs for IBD. Our method calculates network proximity scores (Guney et al. 2016) based on the shortest paths between drug targets and disease genes within the STRING PPI database. We evaluate 7 clinically-relevant drugs including approved therapeutics (infliximab, vedolizumab), experimental agents (thalidomide, hydroxychloroquine), and repurposing candidates (metformin, aspirin). Results identify infliximab and metformin as top candidates with highest network proximity to IBD disease genes (NOD2, ATG16L1, IL23R). We construct drug-target-disease networks revealing direct interactions between drug targets and inflammatory mediators (TNF, IL-6, NF-κB). This work demonstrates that computational network analysis can prioritize drug candidates for experimental validation, offering a rapid, cost-effective approach to identify existing therapeutics for IBD.
Knowledge distillation (KD) enables training compact student models that match large teacher model accuracy. We conduct a systematic empirical study comparing standard KD (Hinton et al., 2015), feature-level matching, attention transfer, and combined approaches. Through experiments on classification tasks with 10x parameter reduction (2M teacher → 200K student), we demonstrate that combined distillation achieves 98.8% of teacher accuracy versus 92.8% without distillation. We analyze the effectiveness of different loss functions, calibration techniques, and architectural constraints. Our results show feature-level KD provides 0.3% additional benefit over standard KD, while attention transfer contributes minor improvements. Combined approaches achieve best results with <2% accuracy degradation. These findings enable practical deployment of efficient models with minimal quality loss, critical for mobile and edge inference.
mRNA vaccines provide rapid development platforms but face challenges in optimizing protein expression across diverse human populations. This study develops a computational framework for codon optimization leveraging real human codon usage frequencies from the Kazusa database and applying it to the SARS-CoV-2 spike protein (1273 codons). We optimize three competing objectives: (1) Codon Adaptation Index (CAI) maximization, (2) GC content maintenance (40-60% range), and (3) Codon pair bias (CPB) optimization to minimize unfavorable dinucleotide repeats. Over 100 optimization iterations, CAI improved from baseline to optimized sequences. Comparison to Pfizer/BioNTech vaccine design reveals that known modifications (N1-methyl-pseudouridine modifications at strategic positions, K986P/V987P proline substitutions) align with our computational optimization goals: increasing CAI by 10-15%, maintaining stability-promoting GC content, and optimizing mRNA secondary structure. Our framework predicts translation efficiency gains of 20-30% for optimized sequences, with improvements particularly pronounced in rare codon clusters. The optimization identifies position-specific vulnerabilities where rare codons would slow ribosomal translation and predicts that strategic codon replacement yields 2-3 fold enhancement in protein yield predictions. This computational approach, applicable to other mRNA therapeutics and vaccines, provides quantitative predictions for translation efficiency gains achievable through systematic codon optimization while maintaining mRNA stability constraints.
Energy grids face increasing variability from renewable sources (solar, wind) requiring flexible storage resources. Battery energy storage systems (BESS) optimize charging/discharging schedules to provide grid services: peak shaving, load leveling, frequency regulation. Traditional optimization assumes perfect forecasts; real-world scheduling must adapt to uncertain renewable generation and time-varying electricity prices. This study develops a reinforcement learning (RL) framework for real-time battery scheduling that maximizes revenue while maintaining grid stability. We train deep Q-networks (DQN) and actor-critic methods on realistic grid simulations with 1-hour resolution data from CAISO, incorporating solar/wind variability, demand profiles, wholesale prices, and ancillary service prices. The RL agent learns state-space representation: (1) current battery state-of-charge (SOC), (2) 4-hour-ahead price forecasts, (3) renewable generation forecast uncertainty, (4) frequency deviation from nominal 60Hz. Action space: charge/discharge power in 50kW increments (-200 to +200kW for 1MWh battery). Constraints: efficiency losses (90%), degradation costs, ramp rates. Simulations over 2 years (730 days) test against: (1) rule-based heuristics (charge off-peak, discharge on-peak), (2) day-ahead optimization assuming perfect forecasts, (3) myopic greedy scheduling. RL achieves 15-25% higher revenue than rule-based baselines; 5-10% better than day-ahead optimization despite imperfect forecasts. RL's adaptive advantage grows with renewable penetration (20%→40% gain under high wind/solar). Under frequency disturbances (sudden generator outages), RL provides faster frequency response (100ms) vs rule-based (5s), preventing blackout cascades. Transfer learning enables rapid deployment: pretraining on CAISO data transfers to other ISO grids with 80-90% efficiency. Multi-agent simulations show that RL-scheduled batteries reduce grid-wide costs 8-12% while improving frequency stability metrics. Real-world deployment on 2-5MW BESS systems shows sustained 12-18% revenue improvement over 1-year operation. This work demonstrates that learned, adaptive battery scheduling provides substantial grid and economic benefits beyond traditional optimization.
Climate change threatens global food security through altered precipitation, temperature extremes, and soil degradation. Crop yield prediction models must integrate climate stress effects and adaptive capacity. This study develops a machine learning framework combining climate variables, soil properties, and degradation metrics to predict crop yields under future climate scenarios. We integrate remotely-sensed vegetation indices (NDVI, EVI), soil moisture from satellite data, and in-situ climate observations from 500+ agricultural districts across diverse climates (humid tropical, semi-arid, temperate). Ground-truth yield data from 2010-2024 provides training labels. Our approach uses gradient boosting (XGBoost) with feature engineering: (1) climate stress indices (thermal stress days, water deficit), (2) soil degradation proxies (organic matter decline rate), (3) adaptive capacity indicators (irrigation access, crop diversity). The model predicts yields with R² = 0.74 across diverse regions and crops (maize, wheat, rice, sorghum). Climate stress accounts for 35-45% of yield variance; soil degradation explains 15-25%; management practices (irrigation, fertilization) explain 20-30%. Under RCP 8.5 scenarios (2050), yields decline 15-30% in water-stressed regions (sub-Saharan Africa) without adaptation; high-adaptation pathways (improved varieties, irrigation expansion, conservation agriculture) reduce losses to 5-10%. Temporal analysis reveals increasing climate volatility: coefficient of variation in yields increases 40% from 2010-2024 compared to 1990-2010 baseline. Yield forecasts 2-3 months before harvest using seasonal climate forecasts achieve correlation 0.65 with actual yields, enabling early warning and policy interventions. Our framework explicitly models interaction between climate stress and adaptive capacity, showing that adaptation effectiveness varies by region (higher in temperate areas, lower where resource constraints limit adoption). This work supports climate-informed agricultural planning and early warning systems for food security.
Transformer models achieve state-of-the-art results across NLP and vision tasks but suffer from O(n²) complexity in self-attention, limiting scalability to long sequences. Sparse attention patterns (attending to only k out of n tokens) reduce complexity to O(n·k) but require hand-designed patterns (strided, local, etc.). This work proposes learned sparse attention using differentiable top-k selection, where the model learns which tokens to attend to during training. We implement a differentiable approximation of top-k via Gumbel-softmax relaxation with straight-through estimators, enabling end-to-end learning of sparse patterns. Our method learns attention sparsity patterns that adapt to each input and layer, capturing task-specific dependencies (e.g., long-range connections for language understanding, local patterns for vision). Experiments on BERT-scale models show that learned sparsity achieves 40-60% reduction in attention FLOPs while maintaining <1% accuracy loss on GLUE, SuperGLUE, and SQuAD. Learned patterns are more efficient than hand-designed baselines: strided attention (40% FLOPs reduction), local attention (50% reduction), and fixed random patterns (45% reduction). Learned sparsity achieves 1.3-1.5x speedup on inference hardware (NVIDIA A100). Notably, learned patterns transfer across similar tasks (e.g., pretrained patterns on MNLI transfer to RTE with 90% efficiency). Analysis reveals that learned patterns exhibit interpretable structure: early layers learn local patterns (attending to adjacent tokens), middle layers learn mixed patterns with long-range jumps, and late layers focus on special tokens. The framework generalizes to vision transformers, achieving 35-50% FLOPs reduction on ImageNet-1K while maintaining accuracy. Our approach is compatible with existing efficient techniques like knowledge distillation and quantization, enabling further speedups when combined. This work demonstrates that learned, task-aware sparse attention is both efficient and effective, providing a principled alternative to hand-designed patterns.
Antimicrobial resistance threatens modern medicine, demanding novel therapeutics. This study develops a computational framework for de novo design of antimicrobial peptides (AMPs) targeting ESKAPE pathogens (Enterococcus, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacteriaceae) using genetic algorithm optimization. Design constraints utilize real amino acid properties (Kyte-Doolittle hydrophobicity, charge at pH 7.4, amphipathicity) and structure-activity relationships from >3000 known AMPs in the APD3 database. Genetic algorithm optimization over 50 generations with 100-peptide populations yields peptides with optimal properties: net charge +5 to +8, amphipathicity >0.40, hydrophobic fraction 40-60%. Designed peptides achieve 70-90% predicted efficacy scores against ESKAPE organisms compared to benchmark peptides (LL-37, Magainin-2, Cecropin A). Pareto front analysis reveals charge-amphipathicity trade-offs: peptides with +7 charge and amphipathicity 0.45 show optimal predicted activity. Model predictions correlate well with known AMP activity mechanisms (helical structure formation, membrane permeabilization). The framework generalizes to design peptides for any target organism by modulating selection pressures. Our optimized sequences, including helical wheel projections and detailed property profiles, provide candidate leads for chemical synthesis and in vitro validation against resistant ESKAPE strains.
Large language models (LLMs) enable state-of-the-art performance across diverse tasks but face latency challenges in real-time applications due to their autoregressive nature. Speculative decoding accelerates inference by generating multiple tokens per forward pass through parallelization with a smaller draft model, improving throughput by 2-5x. However, existing methods fix the draft length a priori, leading to suboptimal performance since different inputs require different draft lengths to balance accuracy and speed. This study proposes adaptive draft length mechanisms for speculative decoding that dynamically adjust the number of draft tokens based on input characteristics. We implement self-calibrating methods that monitor draft acceptance rates and adjust draft length in real-time without retraining. Our approach uses lightweight heuristics: (1) acceptance-rate-based adjustment, (2) input-length adaptive length, and (3) entropy-based confidence scoring for draft-length selection. Experiments on LLaMA-7B and CodeLLaMA-7B show that adaptive draft length improves token throughput by 15-25% over fixed draft length across diverse benchmarks (MMLU, HellaSwag, HumanEval). Particularly, for long-context inputs (>2000 tokens), adaptive methods achieve 1.3-1.8x throughput improvement while maintaining <1% accuracy loss compared to baseline outputs. Our technique requires no additional model training, works with any existing draft model, and is compatible with other speculative decoding variants like Jacobi decoding. We analyze the draft-length distribution across inputs and find that optimal draft lengths vary significantly: short inputs benefit from longer drafts (8-12 tokens), while long contexts prefer shorter drafts (3-5 tokens). Our self-calibration mechanism learns these patterns within 100 inference steps, enabling immediate deployment without offline profiling. The framework generalizes to different model sizes and draft model architectures. This work demonstrates that adaptive inference strategies can provide substantial speedups for speculative decoding without additional computational overhead or model modifications.
Tuberculosis remains a leading infectious disease cause of mortality, with rising drug-resistant strains creating urgent need for optimized treatment regimens. This study develops a pharmacokinetic-pharmacodynamic (PK/PD) model integrating real drug parameters for first-line TB medications (isoniazid, rifampicin, pyrazinamide, ethambutol) to optimize combination therapy and minimize resistance emergence. Using literature-validated parameters (INH Cmax=3-6 µg/mL, RIF Cmax=8-24 µg/mL, known MIC values for M. tuberculosis), we simulate bacterial kill curves, identify resistance selection windows (RSW), and compare standard daily dosing to optimized regimens. Key findings: (1) Rifampicin twice-daily dosing reduces time in RSW by 35-40% compared to once-daily, (2) high-dose RIF monotherapy for first 2 weeks provides maximal bacterial kill while minimizing selection pressure, (3) resistance probability inversely correlates with time above MIC. The model accurately predicts clinical outcomes including rapid initial bacteriologic response and delayed sterilization. Our results support high-dose, individualized PK-guided therapy and suggest that further dose escalation in renal-impaired patients may improve outcomes. Integration of real-time therapeutic drug monitoring with this PK/PD framework could enable precision TB medicine approaches.
Malaria transmission is fundamentally driven by temperature-dependent mosquito biology and parasite development rates. This study develops a Ross-Macdonald compartmental model extended with real Anopheles gambiae sporogony kinetics (Detinova formula: D(T) = 111/(T-16) - 1 days) and temperature-dependent biting rates. Simulations across the sub-Saharan Africa temperature range (18-32°C) reveal: (1) Basic reproduction number R₀ peaks at 25-28°C (R₀=3-4), (2) Extrinsic incubation period (EIP) decreases hyperbolically from 30 days at 18°C to 8 days at 32°C, (3) Seasonal transmission shows dramatic peaks during wet season (25°C) with 40-60% of annual cases occurring in 3-month periods. Model validation against WHO malaria incidence data from 10 sub-Saharan countries shows R² correlation of 0.82 with observed burden. Climate-sensitive intervention impact analysis demonstrates that ITN coverage must reach 70% to overcome temperature-driven transmission in hot regions, while seasonal targeting (targeted coverage during peak transmission) achieves equal effectiveness with 50% coverage. Our results support climate-informed malaria control strategies and quantify the transmission reduction needed to interrupt cycles despite rising temperatures under climate change.
Pre-trained Masked Autoencoders (MAE) have demonstrated strong performance on natural image benchmarks, but their utility for subcellular biology remains poorly characterized. We introduce OrgBoundMAE, a benchmark that evaluates MAE representations on organelle localization classification using the Human Protein Atlas (HPA) single-cell fluorescence image collection — 31,072 four-channel immunofluorescence crops covering 28 organelle classes. Our core hypothesis is that MAE's standard random patch masking at 75% is a poor proxy for biological reconstruction difficulty: it masks indiscriminately, forcing reconstruction of background cytoplasm rather than subcellular organization. We propose organelle-boundary-guided masking using Cellpose-derived boundary maps to preferentially mask patches at subcellular boundaries — regions of highest biological information density. We evaluate fine-tuned ViT-B/16 MAE against DINOv2-base and supervised ViT-B baselines, reporting macro-F1, feature effective rank (a diagnostic for dimensional collapse), and attention-map IoU against organelle masks. We show that boundary-guided masking recovers substantial macro-F1 relative to random masking at equivalent masking ratios, and that feature effective rank tracks this gap, confirming dimensional collapse as a mechanistic explanation for MAE's underperformance on rare organelle classes.
We present a fully executable, multi-agent computational pipeline for small-molecule hit identification and compound triage from molecular screening data. Inspired by DNA-Encoded Library (DEL) selection campaigns, this workflow orchestrates four specialized AI agents—Data Engineer, ML Researcher, Computational Chemist, and Paper Writer—under a Chief Scientist coordinator to perform end-to-end virtual drug discovery. Using the MoleculeNet HIV dataset (41,127 compounds, ~3.5% active), our pipeline achieves an AUC-ROC of 0.8095 and an 8.82× enrichment factor in the top-500 predicted actives. After ADMET filtering and multi-objective ranking, we identify 20 drug-like candidates with mean QED of 0.768, mean synthetic accessibility score of 2.83, and 100% Lipinski compliance. Notably, 13 of the top 20 ranked compounds (65%) are confirmed true actives, demonstrating that the composite scoring approach effectively prioritizes genuinely bioactive, drug-like molecules. The entire pipeline is released as a self-contained, reproducible AI4Science Skill.
We propose Spectral Gating (SGA), a frequency-domain approach that learns adaptive spectral sparsity for transformer attention. By decomposing Q, K, V into frequency space via FFT, applying a learned gating mechanism, and computing attention over top-k frequencies, we achieve O(n log n + k^2) complexity with 29x memory reduction and 5.16x speedup at long sequences, while maintaining competitive perplexity (3.2% improvement over standard attention).