Safety profile and signal detection of phosphodiesterase type 5 inhibitors for erectile dysfunction: a Food and Drug Administration Adverse Event Reporting System analysis.

Background: Phosphodiesterase type 5 inhibitors (PDE5Is) are generally well tolerated but have been associated with uncommon and significant adverse events (AEs). Aim: This study aims to investigate and compare the characteristics of AEs associated with PDE5Is used for erectile dysfunction and identify any safety signals in a postmarketing surveillance database between 2010 and 2021. Methods: A descriptive analysis was conducted for all AEs reported to the Food and Drug Administration Adverse Event Reporting System for 4 PDE5Is-avanafil, sildenafil, tadalafil, and vardenafil-indicated for erectile dysfunction between January 2010 and December 2021. The frequency of the most reported AEs and outcomes were identified. A disproportionality analysis based on proportional reporting ratio (PRR) and reporting odds ratio (ROR) was conducted for the most common and clinically important AEs to identify signals to gain insights into potential differences in safety profiles. Outcomes: The outcome measures of the study are frequency of reported AEs and outcomes following AE. Results: A total of 29 236 AEs were reported for PDE5Is during the study period. The most reported AE was "drug ineffective" with 7115 reports (24.3%). Eight safety signals were detected across the 4 drugs. Key signals were sexual disorders (PRR, 3.13 [95% CI, 2.69-3.65]; ROR, 3.24 [95% CI, 2.77-3.79]) and death (PRR, 3.17 [2.5-4.01]; ROR, 3.211 [2.52-4.06]) for sildenafil, priapism (PRR, 3.63 [2.11-6.24]; ROR, 3.64 [2.12-6.26]) for tadalafil, and drug administration error (PRR, 2.54 [1.84-3.52]; ROR, 2.6 [1.86-3.63]) for vardenafil. The most reported outcomes were other serious events with 6685 events (67.2%) and hospitalization with 1939 events (19.5%). Clinical Implications: The commonly reported AEs and detected signals may guide clinicians in treatment decision making for men with erectile dysfunction. Strengths and Limitations: This is the first comprehensive report and disproportionality analysis on all types of AEs associated with PDE5Is used for erectile dysfunction in the United States. The findings should be interpreted cautiously due to limitations in the Adverse Event Reporting System, which includes self-reports, duplicate and incomplete reports, and biases in reporting and selection. Therefore, establishing a causal relationship between the reported AEs and the use of PDE5Is is uncertain, and the data may be confounded by other medications and indications. Conclusion: PDE5Is demonstrate significantly increased risks of reporting certain clinically important AEs. While these events are not common, it is imperative to continually monitor PDE5I use at the levels of primary care to national surveillance to ensure safe utilization.

Multi-Layered Triboelectric Nanogenerators with Controllable Multiple Spikes for Low-Power Artificial Synaptic Devices.

In the domains of wearable electronics, robotics, and the Internet of Things, there is a demand for devices with low power consumption and the capability of multiplex sensing, memory, and learning. Triboelectric nanogenerators (TENGs) offer remarkable versatility in this regard, particularly when integrated with synaptic transistors that mimic biological synapses. However, conventional TENGs, generating only two spikes per cycle, have limitations when used in synaptic devices requiring repetitive high-frequency gating signals to perform various synaptic plasticity functions. Herein, a multi-layered micropatterned TENG (M-TENG) consisting of a polydimethylsiloxane (PDMS) film and a composite film that includes 1H,1H,2H,2H-perfluorooctyltrichlorosilane/BaTiO3 /PDMS are proposed. The M-TENG generates multiple spikes from a single touch by utilizing separate triboelectric charges at the multiple friction layers, along with a contact/separation delay achieved by distinct spacers between layers. This configuration allows the maximum triboelectric output charge of M-TENG to reach up to 7.52 nC, compared to 3.69 nC for a single-layered TENG. Furthermore, by integrating M-TENGs with an organic electrochemical transistor, the spike number multiplication property of M-TENGs is leveraged to demonstrate an artificial synaptic device with low energy consumption. As a proof-of-concept application, a robotic hand is operated through continuous memory training under repeated stimulations, successfully emulating long-term plasticity.

Spending, Utilization, and Price Trends for Immune Checkpoint Inhibitors in US Medicaid Programs: An Empirical Analysis from 2011 to 2021.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs) have become a cornerstone in cancer treatment. With high treatment costs and an increasing number of young and low-income patients with cancer, there is a need to determine the current spending and utilization of ICIs in a real-world population. The objective of this study was to outline the drug spending, utilization, and price trends of ICIs for US Medicaid programs from 2011 to 2021. METHODS: A retrospective descriptive analysis was conducted using the Medicaid State Drug Utilization pharmacy summary files managed by the Centers for Medicare and Medicaid Services. Six ICIs for this study include ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, and cemiplimab. Yearly reimbursement and prescription numbers were calculated for six ICIs billed through Medicaid between 2011 and 2021. The average spending per prescription was calculated as a proxy for drug prices. RESULTS: Overall spending and utilization on ICIs have risen exponentially over the past decade. Between 2011 and 2021, expenditures increased from $2.8 million to $4.1 billion. Utilization increased from 94 prescriptions to 462,049 prescriptions in 2021 with six ICIs. The average spending per prescription, or average drug price, decreased 70%, from $29,795.88 in 2011 to $8914.69 in 2021. CONCLUSIONS: Spending on and utilization of ICIs have increased dramatically over the past decade. These findings shed new light on the impact of ICIs on state Medicaid programs and may provide insight into potential cost drivers that need to be addressed through policy.

Pharmacists' facilitators and barriers to implementing and billing for patient care services: Interviews from the Ohio Medicaid Project.

BACKGROUND: In the past several decades, a growing body of literature is recognizing the benefits of pharmacist-led health care services in improving clinical and economic outcomes. Despite this evidence, pharmacists are not recognized on a federal level as health care providers in the United States. Ohio Medicaid managed care plans began partnering with local pharmacies in 2020 to launch initial programs for implementing pharmacist-provided clinical services. OBJECTIVES: This study aimed to identify barriers and facilitators to implementing and billing for pharmacist-provided services in Ohio Medicaid managed care plan programs. METHODS: This qualitative study interviewed pharmacists involved in the initial programs using a semistructured interview based on the Consolidated Framework for Implementation Research (CFIR). Interview transcripts were coded for thematic analysis. Identified themes were mapped to the CFIR domains. RESULTS: Four Medicaid payors partnered with 12 pharmacy organizations, representing 16 unique sites of care. Interviews were conducted with 11 participants. The thematic analysis found data fit within the 5 domains with 32 total themes. Pharmacists described the implementation process of their services. The primary themes for improvement of implementation process were system integration, payor rule clarity, and patient eligibility and access. The 3 themes that emerged as key facilitators were communication between payors and pharmacists, communication between pharmacist and care teams, and the perceived value of the service. CONCLUSIONS: Payors and pharmacists can work collaboratively to improve patient care opportunities by increasing access with sustainable reimbursement, clear guidelines, and open communication. Continued improvement is needed in system integration, payor rule clarity, and patient eligibility and access.

Photosensitive ion channels in layered MXene membranes modified with plasmonic gold nanostars and cellulose nanofibers.

Ion channels transduce external stimuli into ion-transport-mediated signaling, which has received considerable attention in diverse fields such as sensors, energy harvesting devices, and desalination membrane. In this work, we present a photosensitive ion channel based on plasmonic gold nanostars (AuNSs) and cellulose nanofibers (CNFs) embedded in layered MXene nanosheets. The MXene/AuNS/CNF (MAC) membrane provides subnanometer-sized ionic pathways for light-sensitive cationic flow. When the MAC nanochannel is exposed to NIR light, a photothermal gradient is formed, which induces directional photothermo-osmotic flow of nanoconfined electrolyte against the thermal gradient and produces a net ionic current. MAC membrane exhibits enhanced photothermal current compared with pristine MXene, which is attributed to the combined photothermal effects of plasmonic AuNSs and MXene and the widened interspacing of the MAC composite via the hydrophilic nanofibrils. The MAC composite membranes are envisioned to be applied in flexible ionic channels with ionogels and light-controlled ionic circuits.

Adaptive IR- and Water-Gating Textiles Based on Shape Memory Fibers.

Thermoregulation is an essential function of the human body for adapting to the surrounding temperature. Stimuli-responsive smart textiles can provide effective protection of the human skin temperature from a continuously changing environment. Herein, we develop a smart textile based on shape memory polymer (SMP) fibers for adaptive regulation of IR and water transmission on human skin. An SMP textile is fabricated with hierarchical micro/nanoporous structures to enhance thermal insulation performance, and silver nanowires are coated on one side to provide asymmetric IR reflectivity and hydrophilicity. The porous SMP textile shows great tunability of thermal insulation and asymmetric wettability by deformation and recovery of the shape and structure in response to stimuli. The degree of thermal insulation is controlled by 65.7% of the original value, and the surface temperature of the SMP textile on a hot plate is successfully controlled in the IR images due to adaptive IR reflectivity. Additionally, the directional transportation of water droplets can be switched on/off according to the shape of the SMP textiles, which can be employed for sweat removal from the human skin. This IR- and water-gating smart textile can provide a feasible strategy for protecting the human skin from external environmental changes.

Cost-Utility Analysis Comparing Direct Oral Anticoagulant and Low Molecular Weight Heparin Therapies for Secondary Prevention of Cancer-Associated Thrombosis.

BACKGROUND AND OBJECTIVE: Cancer patients are at elevated risk of cancer-associated thrombosis (CAT). Randomized controlled trials have found that direct oral anticoagulants (DOACs) are associated with fewer recurrent venous thromboembolism (VTE) events and an increased risk of bleeding than low molecular weight heparins (LMWHs) in CAT. With new clinical data available, this study aims to assess the comparative cost-effectiveness of DOACs and LMWHs over 6- and 60-month treatment durations from the US healthcare system and societal perspectives. METHODS: A Markov model for cancer patients eligible to receive rivaroxaban, edoxaban, apixaban, enoxaparin, or dalteparin was used to conduct a cost-utility analysis. Clinical scenarios were analyzed based on 6- and 60-month time horizons from the US healthcare system and societal perspectives. The main outcome was the incremental cost-effectiveness ratio (ICER), expressed as cost in US dollars per quality-adjusted life year (QALY). One-way and probabilistic sensitivity analyses were performed to evaluate the robustness of the results. RESULTS: DOACs were cost-saving and clinically superior to LMWHs and were associated with a cost change ranging from - $9134.66 to - $15,281.92 and incremental effectiveness of 0.43-1.25 QALYs among four clinical scenarios. The most influential model inputs for ICER were the utility associated with LMWH use and probabilities of non-VTE and non-bleeding related death. Probabilistic sensitivity analyses were consistent with the results. CONCLUSIONS: DOACs were found to dominate LMWHs, suggesting that DOACs may be a cost-effective alternative to LMWHs for CAT. This study can help inform decision-makers on the cost-effectiveness of anticoagulation strategies and help in the development of future practice recommendations for cancer patients.

Ultrasensitive Multimodal Tactile Sensors with Skin-Inspired Microstructures through Localized Ferroelectric Polarization.

Multifunctional electronic skins have attracted considerable attention for soft electronics including humanoid robots, wearable devices, and health monitoring systems. Simultaneous detection of multiple stimuli in a single self-powered device is desired to simplify artificial somatosensory systems. Here, inspired by the structure and function of human skin, an ultrasensitive self-powered multimodal sensor is demonstrated based on an interlocked ferroelectric copolymer microstructure. The triboelectric and pyroelectric effects of ferroelectric microstructures enable the simultaneous detection of mechanical and thermal stimuli in a spacer-free single device, overcoming the drawbacks of conventional devices, including complex fabrication, structural complexity, and high-power consumption. Furthermore, the interlocked microstructure induces electric field localization during ferroelectric polarization, leading to enhanced output performance. The multimodal tactile sensor provides ultrasensitive pressure and temperature detection capability (2.2 V kPa-1 , 0.27 nA °C-1 ) over a broad range (0.1-98 kPa, -20 °C < ΔT < 30 °C). Furthermore, multiple simultaneous stimuli can be distinguished based on different response times of triboelectric and pyroelectric effects. The remarkable performance of this sensor enables real-time monitoring of pulse pressure, acoustic wave detection, surface texture analysis, and profiling of multiple stimuli.

Flexible Pyroresistive Graphene Composites for Artificial Thermosensation Differentiating Materials and Solvent Types.

When we touch an object, thermosensation allows us to perceive not only the temperature but also wetness and types of materials with different thermophysical properties (i.e., thermal conductivity and heat capacity) of objects. Emulation of such sensory abilities is important in robots, wearables, and haptic interfaces, but it is challenging because they are not directly perceptible sensations but rather learned abilities via sensory experiences. Emulating the thermosensation of human skin, we introduce an artificial thermosensation based on an intelligent thermo-/calorimeter (TCM) that can objectively differentiate types of contact materials and solvents with different thermophysical properties. We demonstrate a TCM based on pyroresistive composites with ultrahigh sensitivity (11.2% °C-1) and high accuracy (<0.1 °C) by precisely controlling the melt-induced volume expansion of a semicrystalline polymer, as well as the negative temperature coefficient of reduced graphene oxide. In addition, the ultrathin TCM with coplanar electrode design shows deformation-insensitive temperature sensing, facilitating wearable skin temperature monitoring with accuracy higher than a commercial thermometer. Moreover, the TCM with a high pyroresistivity can objectively differentiate types of contact materials and solvents with different thermophysical properties. In a proof-of-principle application, our intelligent TCM, coupled with a machine-learning algorithm, enables objective evaluation of the thermal attributes (coolness and wetness) of skincare products.

Electronic Textiles Based on Highly Conducting Poly(vinyl alcohol)/Carbon Nanotube/Silver Nanobelt Hybrid Fibers.

Highly stable conducting fibers have attracted significant attention in electronic textile (e-textile) applications. Here, we fabricate highly conducting poly(vinyl alcohol) (PVA) nanocomposite fibers with high thermal and chemical stability based on silver nanobelt (AgNB)/multiwalled carbon nanotube (MWCNT) hybrid materials as conducting fillers. At 20 vol % AgNB/MWCNT, the electrical conductivity of the fiber dramatically increased (∼533 times) from 3 up to 1600 S/cm after thermal treatment at 300 °C for 5 min. Moreover, PVA/AgNB/MWCNT fiber resists the harsh conditions of good solvents for PVA as well as high temperatures over the melting point of PVA, whereas pure PVA fiber is unstable in these environments. The significantly enhanced electrical conductivity and chemical stability can be realized through the post-thermal curing process, which is attributed to the coalescence between adjacent AgNBs and additional intensive cross-linking of PVA. These remarkable characteristics make our conducting fibers suitable for applications in e-textiles such as water leakage detectors and wearable heaters. In particular, heating behavior of e-textiles by Joule heating can accelerate the desorption of physically trapped moisture from the fiber surface, resulting in the fully reversible operation of water leakage monitoring. This smart e-textile sensor based on highly stable and conductive composite fibers will pave the way for diverse e-textile applications.

High-Performance Triboelectric Devices via Dielectric Polarization: A Review.

Energy harvesting devices based on the triboelectric effect have attracted great attention because of their higher output performance compared to other nanogenerators, which have been utilized in various wearable applications. Based on the working mechanism, the triboelectric performance is mainly proportional to the surface charge density of the triboelectric materials. Various approaches, such as modification of the surface functional group and dielectric composition of the triboelectric materials, have been employed to enhance the surface charge density, leading to improvements in triboelectric performances. Notably, tuning the dielectric properties of triboelectric materials can significantly increase the surface charge density because the surface charge is proportional to the relative permittivity of the triboelectric material. The relative dielectric constant is modified by dielectric polarization, such as electronic, vibrational (or atomic), orientation (or dipolar), ionic, and interfacial polarization. Therefore, such polarization represents a critical factor toward improving the dielectric constant and consequent triboelectric performance. In this review, we summarize the recent insights on the improvement of triboelectric performance via enhanced dielectric polarization.

Tailored Poly(vinylidene fluoride-co-trifluoroethylene) Crystal Orientation for a Triboelectric Nanogenerator through Epitaxial Growth on a Chitin Nanofiber Film.

Tailoring the crystal orientation of poly(vinylidene fluoride-co-trifluoroethylene) (PVDF-TrFE) has attracted widespread interest because of its effects on the ferroelectric properties required for various electronic devices. In this study, we investigated the epitaxial growth of PVDF-TrFE on a chitin film for developing triboelectric nanogenerators (TENGs). The crystallographic match between the chitin and PVDF-TrFE enables the development of the intended crystal orientation, with the PVDF-TrFE polarization axis aligned perpendicular to the substrate. In addition, the epitaxially grown PVDF-TrFE on chitin not only enhances the performance of the TENG but also increases the stability of the hygroscopic chitin film against water. The corresponding TENG exhibits a significantly higher output current compared to that of a nonepitaxial PVDF-TrFE/chitin film. Furthermore, the triboelectric sensors based on epitaxial PVDF-TrFE/chitin films allow the monitoring of subtle pressures, suggesting that tailoring the crystal orientation of PVDF-TrFE is a promising approach for developing high-performance TENGs.

Ferroelectric Multilayer Nanocomposites with Polarization and Stress Concentration Structures for Enhanced Triboelectric Performances.

Although ferroelectric composites have been reported to enhance the performance of triboelectric (TE) devices, their performances are still limited owing to randomly dispersed particles. Herein, we introduce high-performance TE sensors (TESs) based on ferroelectric multilayer nanocomposites with alternating poly(vinylidenefluoride-co-trifluoroethylene) (PVDF-TrFE) and BaTiO3 (BTO) nanoparticle (NP) layers. The multilayers comprising alternating soft/hard layers can induce stress concentration and increase the effective stress-induced polarization and interfacial polarization between organic and inorganic materials, leading to a dielectric constant (17.06) that is higher than those of pure PVDF-TrFE films (13.9) and single PVDF-TrFE/BTO nanocomposites (15.9) at 10 kHz. As a result, the multilayered TESs with alternating BTO NP layers exhibit TE currents increased by 2.3 and 1.5 times compared to pure PVDF-TrFE without BTO NPs and PVDF-TrFE/BTO nanocomposites without multilayer structures, respectively. The multilayered TESs exhibit a high pressure sensitivity of 0.94 V/kPa (48.7 nA/kPa) and output power density of 29.4 µWcm-2, enabling their application in the fabrication of highly sensitive healthcare monitoring devices and high-performance acoustic sensors. The suggested architecture of ferroelectric multilayer nanocomposites provides a robust platform for TE devices and self-powered wearable electronics.

Effect of Interfacial Interaction on the Conformational Variation of Poly(vinylidene fluoride) (PVDF) Chains in PVDF/Graphene Oxide (GO) Nanocomposite Fibers and Corresponding Mechanical Properties.

Poly(vinylidene fluoride) (PVDF)/graphene oxide (GO) nanocomposite fibers were dry-jet wet spun at the GO concentrations of 0, 1, and 2 wt % with respect to the polymer. The as-spun fibers were drawn in the draw ratio (DR) range of 2-6.5, and the correlation between the PVDF chain conformation and the mechanical properties of the fibers upon drawing has been studied by two-dimensional correlation spectroscopy of Fourier-transformed infrared, wide-angle X-ray diffraction, differential scanning calorimetry, and tensile testing. The PVDF/GO nanocomposite fibers exhibited that the mobile PVDF crystals due to the conformational defects and kinks were nucleated because of the polar interaction between PVDF chains and functional groups of GO, whereas the control PVDF fiber showed the conventional conversion of crystal polymorphs (α and γ phases to ß phase). As a result, the nanocomposite fiber showed dramatically improved toughness (enhanced by 1123% at a DR of 2 and 120% at a DR of 6.5) as compared to that of the control fiber. Furthermore, the tensile strength and modulus of the PVDF/GO (2 wt %) fiber were 394 MPa and 4.6 GPa, respectively, whereas those of the control PVDF fiber were 295 MPa and 3.9 GPa, respectively.

Flexible Ferroelectric Sensors with Ultrahigh Pressure Sensitivity and Linear Response over Exceptionally Broad Pressure Range.

Flexible pressure sensors with a high sensitivity over a broad linear range can simplify wearable sensing systems without additional signal processing for the linear output, enabling device miniaturization and low power consumption. Here, we demonstrate a flexible ferroelectric sensor with ultrahigh pressure sensitivity and linear response over an exceptionally broad pressure range based on the material and structural design of ferroelectric composites with a multilayer interlocked microdome geometry. Due to the stress concentration between interlocked microdome arrays and increased contact area in the multilayer design, the flexible ferroelectric sensors could perceive static/dynamic pressure with high sensitivity (47.7 kPa-1, 1.3 Pa minimum detection). In addition, efficient stress distribution between stacked multilayers enables linear sensing over exceptionally broad pressure range (0.0013-353 kPa) with fast response time (20 ms) and high reliability over 5000 repetitive cycles even at an extremely high pressure of 272 kPa. Our sensor can be used to monitor diverse stimuli from a low to a high pressure range including weak gas flow, acoustic sound, wrist pulse pressure, respiration, and foot pressure with a single device.

An ice-templated, pH-tunable self-assembly route to hierarchically porous graphene nanoscroll networks.

Porous graphene nanostructures are of great interest for applications in catalysis and energy storage. However, the fabrication of three-dimensional (3D) macroporous graphene nanostructures with controlled morphology, porosity and surface area still presents significant challenges. Here we introduce an ice-templated self-assembly approach for the integration of two-dimensional graphene nanosheets into hierarchically porous graphene nanoscroll networks, where the morphology of porous structures can be easily controlled by varying the pH conditions during the ice-templated self-assembly process. We show that freeze-casting of reduced graphene oxide (rGO) solution results in the formation of 3D porous graphene microfoam below pH 8 and hierarchically porous graphene nanoscroll networks at pH 10. In addition, we demonstrate that graphene nanoscroll networks show promising electrocatalytic activity for the oxygen reduction reaction (ORR).

Computational design of binding proteins to EGFR domain II.

We developed a process to produce novel interactions between two previously unrelated proteins. This process selects protein scaffolds and designs protein interfaces that bind to a surface patch of interest on a target protein. Scaffolds with shapes complementary to the target surface patch were screened using an exhaustive computational search of the human proteome and optimized by directed evolution using phage display. This method was applied to successfully design scaffolds that bind to epidermal growth factor receptor (EGFR) domain II, the interface of EGFR dimerization, with high reactivity toward the target surface patch of EGFR domain II. One potential application of these tailor-made protein interactions is the development of therapeutic agents against specific protein targets.

Spatial and functional organization of mitochondrial protein network.

Characterizing the spatial organization of the human mitochondrial proteome will enhance our understanding of mitochondrial functions at the molecular level and provide key insight into protein-disease associations. However, the sub-organellar location and possible association with mitochondrial diseases are not annotated for most mitochondrial proteins. Here, we characterized the functional and spatial organization of mitochondrial proteins by assessing their position in the Mitochondrial Protein Functional (MPF) network. Network position was assigned to the MPF network and facilitated the determination of sub-organellar location and functional organization of mitochondrial proteins. Moreover, network position successfully identified candidate disease genes of several mitochondrial disorders. Thus, our data support the use of network position as a novel method to explore the molecular function and pathogenesis of mitochondrial proteins.

Evolutionary history of human disease genes reveals phenotypic connections and comorbidity among genetic diseases.

The extent to which evolutionary changes have impacted the phenotypic relationships among human diseases remains unclear. In this work, we report that phenotypically similar diseases are connected by the evolutionary constraints on human disease genes. Human disease groups can be classified into slowly or rapidly evolving classes, where the diseases in the slowly evolving class are enriched with morphological phenotypes and those in the rapidly evolving class are enriched with physiological phenotypes. Our findings establish a clear evolutionary connection between disease classes and disease phenotypes for the first time. Furthermore, the high comorbidity found between diseases connected by similar evolutionary constraints enables us to improve the predictability of the relative risk of human diseases. We find the evolutionary constraints on disease genes are a new layer of molecular connection in the network-based exploration of human diseases.

Rewiring of PDZ domain-ligand interaction network contributed to eukaryotic evolution.

PDZ domain-mediated interactions have greatly expanded during metazoan evolution, becoming important for controlling signal flow via the assembly of multiple signaling components. The evolutionary history of PDZ domain-mediated interactions has never been explored at the molecular level. It is of great interest to understand how PDZ domain-ligand interactions emerged and how they become rewired during evolution. Here, we constructed the first human PDZ domain-ligand interaction network (PDZNet) together with binding motif sequences and interaction strengths of ligands. PDZNet includes 1,213 interactions between 97 human PDZ proteins and 591 ligands that connect most PDZ protein-mediated interactions (98%) in a large single network via shared ligands. We examined the rewiring of PDZ domain-ligand interactions throughout eukaryotic evolution by tracing changes in the C-terminal binding motif sequences of the PDZ ligands. We found that interaction rewiring by sequence mutation frequently occurred throughout evolution, largely contributing to the growth of PDZNet. The rewiring of PDZ domain-ligand interactions provided an effective means of functional innovations in nervous system development. Our findings provide empirical evidence for a network evolution model that highlights the rewiring of interactions as a mechanism for the development of new protein functions. PDZNet will be a valuable resource to further characterize the organization of the PDZ domain-mediated signaling proteome.