Understanding Oxidative Instability of Protein Pharmaceuticals

Mechanism of oxidation of methionine residues in protein pharmaceuticals by hydrogen peroxide was investigated via ab initio calculations. Specifically, two reactions, hydrogen transfer of hydrogen peroxide to form water oxide and the oxidation of dimethyl sulfide (DMS) by hydrogen peroxide to form dimethyl sulfoxide, were studied as models of these processes in general. Solvent effects are included both via including explicitly water molecules and via the polarizable continuum model. Specific interactions including hydrogen bonding with 2-3 water molecules can provide enough stabilization for the charge separation at the activation complex. The major reaction coordinates of the reaction are the breaking of the O-O bond of H₂O₂ and the formation of the S-O bond, the transfer of hydrogen to the distal oxygen of hydrogen peroxide occurring after the system has passed the transition state. Reaction barriers of the hydrogen transfer of H₂O₂ are in average of 10 kcal/mol or higher than the oxidation of DMS. Therefore, a two step oxidation mechanism in which the transfer of hydrogen atom occurs first to form water oxide and the transfer of oxygen to substrate occurs as the second step, is unlikely to be correct. Our proposed oxidation mechanism does not suggest pH dependence of oxidation rate within a moderate range around neutral pH (i.e. under conditions in which hydronium and hydroxide ions do not participate directly in the reaction), and it agrees with experimental observations over moderate pH values.Singapore-MIT Alliance (SMA

On the Oxidation of Methionine Residues during the Storage of Protein Pharmaceuticals in an Aqueous Formulation

This study addresses the fundamentals of an important degradation pathway of storing protein pharmaceuticals in an aqueous formulation, oxidation of methionine residues by peroxides. First, a mechanism by which methionine residues are oxidized is identified via ab initio calculations. The major difference of this new mechanism to previous ones is the role of solvent molecules in the oxidation process. Previously proposed mechanisms suggested that solvent molecules facilitate the transfer of hydrogen associated with the oxidation reaction, but the estimated activation energies and pH dependence of oxidation rates derived from this mechanism rates do not agree with experimental observations. In our proposed mechanism, however, water molecules stabilize the charge separation in the transition-state complex through specific interaction such as hydrogen bonding. This mechanism satisfies all experimental studies on the oxidation of organic sulfides by peroxides. A correct picture of instability mechanism is essential in developing stabilization strategies to design a robust formulation. Based on this mechanism, a structure/instability relationship is built to explain the oxidation rates of methionine residues in a protein molecule. Specifically, a structural property, two-shell water coordination number, is found to correlate semi-quantitatively to the rates of oxidation of methionine residues in G-CSF (granulocyte colony-stimulating factor) and hPTH (human parathoid hormone). We also show that a traditionally used structural property, solvent accessible area, can not provide such accurate correlation and that the dynamic motion of protein molecules and an explicit treatment of solvent molecules are essential to describe the rates of oxidation of methionine residues. Furthermore, the insight provided by the molecule-level understanding in developing a stabilizing formulation is discussed.Singapore-MIT Alliance (SMA

Long range and duration underwater localization using molecular messaging

In this paper, we tackle the problem of how to locate a single entity with an unknown location in a vast underwater search space. In under-water channels, traditional wave-based signals suffer from rapid distance- and time-dependent energy attenuation, leading to expensive and lengthy search missions. In view of this, we investigate two molecular messaging methods for location discovery: a Rosenbrock gradient ascent algorithm, and a chemical encoding messaging method. In absence of explicit diffusion channel knowledge and in presence of diffusion noise, the Rosenbrock method is adapted to account for the blind search process and allow the robot to recover in areas of zero gradient. The two chemical methods are found to offer attractive performance trade-offs in complexity and robustness. Compared to conventional acoustic signals, the chemical methods proposed offers significantly longer propagation distance (1000km) and longer signal persistence duration (months)

FOCUS: Fairness via Agent-Awareness for Federated Learning on Heterogeneous Data

Federated learning (FL) allows agents to jointly train a global model without sharing their local data. However, due to the heterogeneous nature of local data, it is challenging to optimize or even define fairness of the trained global model for the agents. For instance, existing work usually considers accuracy equity as fairness for different agents in FL, which is limited, especially under the heterogeneous setting, since it is intuitively "unfair" to enforce agents with high-quality data to achieve similar accuracy to those who contribute low-quality data, which may discourage the agents from participating in FL. In this work, we propose a formal FL fairness definition, fairness via agent-awareness (FAA), which takes different contributions of heterogeneous agents into account. Under FAA, the performance of agents with high-quality data will not be sacrificed just due to the existence of large amounts of agents with low-quality data. In addition, we propose a fair FL training algorithm based on agent clustering (FOCUS) to achieve fairness in FL measured by FAA. Theoretically, we prove the convergence and optimality of FOCUS under mild conditions for linear and general convex loss functions with bounded smoothness. We also prove that FOCUS always achieves higher fairness in terms of FAA compared with standard FedAvg under both linear and general convex loss functions. Empirically, we show that on four FL datasets, including synthetic data, images, and texts, FOCUS achieves significantly higher fairness in terms of FAA while maintaining competitive prediction accuracy compared with FedAvg and state-of-the-art fair FL algorithms

Sarcoma of the Larynx: Treatment Results and Literature Review

BackgroundSarcomas of the larynx are rare neoplasms that constitute less than 1% of laryngeal malignancies. A Medline search found no large series focusing on laryngeal sarcomas. We reviewed the cases of laryngeal sarcomas treated in our cancer center and compared our experiences and treatment results with those from other centers.MethodsA retrospective review of 10 patients with laryngeal sarcoma treated in our institute between 1980 and 2000 was done to identify tumor characteristics, therapeutic modalities, and treatment outcomes.ResultsThe patients showed a male predominance (9/10) and presented 8 types of pathology. Nine patients underwent surgery, including 2 total laryngectomy, 4 partial laryngectomy, and 3 endoscopic laser cordectomy. During a median follow-up of 92 months, the 5-year overall survival and disease-specific survival were 76% and 90%, respectively. Two patients developed recurrence, including 1 local recurrence and 1 distant metastasis.ConclusionSurgical intervention was the first choice in the treatment of laryngeal sarcomas. The prognosis is relatively good when compared with sarcoma originating from other anatomic sites