Active Learning Framework for Cost-Effective TCR-Epitope Binding Affinity Prediction

T cell receptors (TCRs) are critical components of adaptive immune systems, responsible for responding to threats by recognizing epitope sequences presented on host cell surface. Computational prediction of binding affinity between TCRs and epitope sequences using machine/deep learning has attracted intense attention recently. However, its success is hindered by the lack of large collections of annotated TCR-epitope pairs. Annotating their binding affinity requires expensive and time-consuming wet-lab evaluation. To reduce annotation cost, we present ActiveTCR, a framework that incorporates active learning and TCR-epitope binding affinity prediction models. Starting with a small set of labeled training pairs, ActiveTCR iteratively searches for unlabeled TCR-epitope pairs that are ''worth'' for annotation. It aims to maximize performance gains while minimizing the cost of annotation. We compared four query strategies with a random sampling baseline and demonstrated that ActiveTCR reduces annotation costs by approximately 40%. Furthermore, we showed that providing ground truth labels of TCR-epitope pairs to query strategies can help identify and reduce more than 40% redundancy among already annotated pairs without compromising model performance, enabling users to train equally powerful prediction models with less training data. Our work is the first systematic investigation of data optimization for TCR-epitope binding affinity prediction.Comment: 10 pages, 7 figures, this paper has been accepted for publication in the proceedings of the IEEE International Conference on Bioinformatics and Biomedicine (BIBM) 202

Governance Keeping up with Sharing Economy Innovations

The sharing economy presents new regulatory issues by raising inquiries into market innovation and government intervention. This research focuses on policy areas that have not received much attention in the current debate on the sharing economy, particularly in the tourism literature. Based on the survey on local government officials in the U.S. cities and counties (n=599), the research aims at (1) exploring stakeholder groups that are perceived to be influential in acting on legislation among policymakers and (2) examining determinants that influence legislative status with a focus on sharing economy innovations. The results indicate that legislative status is influenced by stakeholder groups who actively engaged in legislation with different objectives as well as jurisdiction characteristics such as population size and geographical region. The study offers insights into how policymakers keep up with the tremendous innovations that take place in the tourism industry

WHAT\textit{WHAT}, WHEN\textit{WHEN}, and HOW\textit{HOW} to Ground: Designing User Persona-Aware Conversational Agents for Engaging Dialogue

This paper presents a method for building a personalized open-domain dialogue system to address the $\textit{WWH}$ ($\textit{WHAT}$, $\textit{WHEN}$, and $\textit{HOW}$) problem for natural response generation in a commercial setting, where personalized dialogue responses are heavily interleaved with casual response turns. The proposed approach involves weighted dataset blending, negative persona information augmentation methods, and the design of personalized conversation datasets to address the challenges of $\textit{WWH}$ in personalized, open-domain dialogue systems. Our work effectively balances dialogue fluency and tendency to ground, while also introducing a response-type label to improve the controllability and explainability of the grounded responses. The combination of these methods leads to more fluent conversations, as evidenced by subjective human evaluations as well as objective evaluations.Comment: Accepted in ACL 2023 Industry Trac

The local translation of KNa in dendritic projections of auditory neurons and the roles of KNa in the transition from hidden to overt hearing loss

Local and privileged expression of dendritic proteins allows segregation of distinct functions in a single neuron but may represent one of the underlying mechanisms for early and insidious presentation of sensory neuropathy. Tangible characteristics of early hearing loss (HL) are defined in correlation with nascent hidden hearing loss (HHL) in humans and animal models. Despite the plethora of causes of HL, only two prevailing mechanisms for HHL have been identified, and in both cases, common structural deficits are implicated in inner hair cell synapses, and demyelination of the auditory nerve (AN). We uncovered that N

Single-Cell RNA-seq Reveals Profound Alterations in Mechanosensitive Dorsal Root Ganglion Neurons with Vitamin E Deficiency.

Ninety percent of Americans consume less than the estimated average requirements of dietary vitamin E (vitE). Severe vitE deficiency due to genetic mutations in the tocopherol transfer protein (TTPA) in humans results in ataxia with vitE deficiency (AVED), with proprioceptive deficits and somatosensory degeneration arising from dorsal root ganglia neurons (DRGNs). Single-cell RNA-sequencing of DRGNs was performed in Ttpa-/- mice, an established model of AVED. In stark contrast to expected changes in proprioceptive neurons, Ttpa-/- DRGNs showed marked upregulation of voltage-gated Ca2+ and K+ channels in mechanosensitive, tyrosine-hydroxylase positive (TH+) DRGNs. The ensuing significant conductance changes resulted in reduced excitability in mechanosensitive Ttpa-/- DRGNs. A highly supplemented vitE diet (600 mg dl-α-tocopheryl acetate/kg diet) prevented the cellular and molecular alterations and improved mechanosensation. VitE deficiency profoundly alters the molecular signature and functional properties of mechanosensitive TH+ DRGN, representing an intriguing shift of the prevailing paradigm from proprioception to mechanical sensation

Sodium-activated potassium channels shape peripheral auditory function and activity of the primary auditory neurons in mice

Potassium (K+) channels shape the response properties of neurons. Although enormous progress has been made to characterize K+ channels in the primary auditory neurons, the molecular identities of many of these channels and their contributions to hearing in vivo remain unknown. Using a combination of RNA sequencing and single molecule fluorescent in situ hybridization, we localized expression of transcripts encoding the sodium-activated potassium channels K(Na)1.1(SLO2.2/Slack) and K(Na)1.2 (SLO2.1/Slick) to the primary auditory neurons (spiral ganglion neurons, SGNs). To examine the contribution of these channels to function of the SGNs in vivo, we measured auditory brainstem responses in K(Na)1.1/1.2 double knockout (DKO) mice. Although auditory brainstem response (wave I) thresholds were not altered, the amplitudes of suprathreshold responses were reduced in DKO mice. This reduction in amplitude occurred despite normal numbers and molecular architecture of the SGNs and their synapses with the inner hair cells. Patch clamp electrophysiology of SGNs isolated from DKO mice displayed altered membrane properties, including reduced action potential thresholds and amplitudes. These findings show that K(Na)1 channel activity is essential for normal cochlear function and suggest that early forms of hearing loss may result from physiological changes in the activity of the primary auditory neurons

Cooperativity of Kv7.4 channels confers ultrafast electromechanical sensitivity and emergent properties in cochlear outer hair cells.

The mammalian cochlea relies on active electromotility of outer hair cells (OHCs) to resolve sound frequencies. OHCs use ionic channels and somatic electromotility to achieve the process. It is unclear, though, how the kinetics of voltage-gated ionic channels operate to overcome extrinsic viscous drag on OHCs at high frequency. Here, we report ultrafast electromechanical gating of clustered Kv7.4 in OHCs. Increases in kinetics and sensitivity resulting from cooperativity among clustered-Kv7.4 were revealed, using optogenetics strategies. Upon clustering, the half-activation voltage shifted negative, and the speed of activation increased relative to solitary channels. Clustering also rendered Kv7.4 channels mechanically sensitive, confirmed in consolidated Kv7.4 channels at the base of OHCs. Kv7.4 clusters provide OHCs with ultrafast electromechanical channel gating, varying in magnitude and speed along the cochlea axis. Ultrafast Kv7.4 gating provides OHCs with a feedback mechanism that enables the cochlea to overcome viscous drag and resolve sounds at auditory frequencies

Innovation in US metroploitan areas: the role of global connectivity

Managing and leveraging innovation and knowledge generation are key components of value creation by firms in a globally connected world. In this project we analyze innovative activity in the over a 35-year period (1975-2010) to understand the nature and extent of international connectedness of U.S. knowledge networks. Our analysis parses a comprehensive dataset comprising the population of USPTO patents to extract information on inventor co-location. We use this to generate a knowledge map of inventor networks for each of the top 35 Core-Based Statistical Areas (CBSAs), tracking innovative activity and connectedness across geography and over time. We find that in the 1975-90 period, inventor numbers and growth rates tracked overall population numbers, so that the large population centers (New York, Chicago, Los Angeles and Philadelphia) accounted for the largest shares. However, in the decades between 1990 and 2010, inventor numbers rose most rapidly in West and South, so that by the end of the period the dominant innovative centers of the country were the Silicon Valley CBSAs of San Francisco and San Jose, Austin, Seattle, Portland and San Diego