Browse Articles

Symmetries and synchronization from whole-neural activity in the <i>Caenorhabditis elegans</i> connectome: Integration of functional and structural networks

Understanding the dynamical behavior of complex systems from their underlying network architectures is a long-standing question in complexity theory. Therefore, many metrics have been devised to extract network features like motifs, centrality, and modularity measures. It has previously been proposed that network symmetries are of particular importance since they are expected to underlie the synchronization of a system’s units, which is ubiquitously observed in nervous system activity patterns. However, perfectly symmetrical structures are difficult to assess in noisy measurements of biological systems, like neuronal connectomes. Here, we devise a principled method to infer network symmetries from combined connectome and neuronal activity data. Using nervous system-wide population activity recordings of the Caenorhabditis elegans backward locomotor system, we infer structures in the connectome called fibration symmetries, which can explain which group of neurons synchronize their activity. Our analysis suggests functional building blocks in the animal’s motor periphery, providing testable hypotheses on how descending interneuron circuits communicate with the motor periphery to control behavior. Our approach opens a door to exploring the structure–function relations in other complex systems, like the nervous systems of larger animals.

Acyclic Quaternary Stereocenters via Catalytic Asymmetric Cross‐Couplings with Unactivated Alkyl <i>N</i> ‐Hydroxyphthalimide Esters

Abstract While significant advancements have been made in creating quaternary stereocenters (all‐carbon substituents) within cyclic frameworks, generating acyclic quaternary stereocenters poses a more formidable task due to increased conformational flexibility. Herein, we report an enantioselective synthesis of compounds containing acyclic quaternary stereocenters through an iron‐catalyzed alkylation reaction between an acyclic tertiary alkyl source and an unactivated primary alkyl source. This method not only facilitates the rapid construction of sterically hindered motifs but also effectively enhances the saturation level of the molecule. Key to this method is an outer‐sphere C─C bond formation mechanism, where enantioselectivity is governed by a cooperative triple catalysis system that combines photoredox, chiral Lewis acid, and iron catalysis. A series of compounds featuring acyclic quaternary stereocenters is produced under mild reaction conditions, and various transformations are presented to illustrate the potential applications of this approach. A comprehensive mechanistic study supports the crucial S H 2 (bimolecular homolytic substitution) mechanism.

Diagnostic accuracy of dual energy computed tomography for suspected pyogenic spondylodiscitis

Abstract While magnetic resonance imaging (MRI) is the diagnostic method of choice, we here analyze the diagnostic potential of dual-energy computed tomography (DECT) in differentiating abnormal discs from normal-appearing discs and in differentiating between infectious and degenerative conditions. Twenty-eight patients with suspected spondylodiscitis who underwent DECT and MRI of the spine were retrospectively included. Eighteen patients were diagnosed with spondylodiscitis and ten patients with degenerative disc disease. A combined clinical reference standard for the diagnosis was used. One abnormal disc and one normal-appearing disc per patient were included. Three blinded readers analyzed CT, DECT cMaps and MRI images. Quantitative analysis was performed in standardized regions of interest placed in each of the two discs included. Mixed-model analysis was used to identify correlations between CT density alterations and spondylodiscitis or degenerative disc disease. Diagnostic accuracy for differentiating abnormal discs and normal-appearing discs: 69.7% (95% CI, 56.0 to 81.2) for CT, 76.8% (95% CI, 63.6 to 87.0) for CT + DECT, 58.9% (95% CI, 45.0 to 71.9) for MRI; for differentiating spondylodiscitis and degenerative disc disease: 64.3% (95% CI, 44.1 to 81.4) for CT, 60.7% (95% CI, 40.6 to 78.5) for CT + DECT, 53.6% (95% CI, 33.9 to 72.5) for MRI. Mixed-model analysis revealed that normal-appearing discs had higher average density than abnormal discs in DECT (mean difference = 47.0 HU (95% CI, 32.8 to 61.3), p = &lt; 0.001). In summary, both qualitative and quantitative DECT can distinguish normal-appearing discs from abnormal discs. Spondylodiscitis and degenerative disc disease were not distinguished accurately by DECT in this study.

In-plane ferroelectricity with high Curie temperatures in nonequilibrium SnSe _1-x S _x van der Waals semiconductors

While symmetry breaking in 2D ferroelectrics is obviously linked to the single-layer structure, layered (van der Waals) ferroelectrics can have a multitude of underlying mechanisms, making their identification nontrivial and often controversial. This complexity is exemplified by tin chalcogenides whose equilibrium structure, the orthorhombic α-phase with space group Pnma , includes an inversion center and which therefore should not be ferroelectric. Yet, recent work demonstrated polarization switching and ferroelectric domains in few-layer SnS and SnSe. Here, we use in situ electron microscopy and diffraction to determine the mechanism and characteristics of ferroelectricity across the SnSe 1-x S x system. We identify two distinct phases of synthetic SnSe 1-x S x : nonpolar (centrosymmetric) equilibrium (α-phase) crystals and metastable crystals adopting a distorted monoclinic structure, which are in-plane ferroelectrics with Curie temperatures of 320 to 420 °C. A surprising structural plasticity of the ferroelectric crystals during heating/cooling indicates a shallow energy landscape. This in turn suggests absence of a pronounced driving force for conversion to the α-phase that can explain the formation of the nonequilibrium crystals and their stability even after transfer to other supports. Our results highlight opportunities for the discovery of novel ferroelectrics among nonequilibrium van der Waals crystals.

Author Correction: Wound healing approach based on excretory-secretory product and lysate of liver flukes

Structure and organization of full-length epidermal growth factor receptor in extracellular vesicles by cryo-electron tomography

We report here transport of full-length epidermal growth factor receptor (EGFR), Insulin Receptor, 7-pass transmembrane receptor Smoothened, and 13-pass Sodium-iodide symporter to extracellular vesicles (EVs) for structural and functional studies. Mass spectrometry confirmed the transported proteins are the most abundant in EV membranes, and the presence of many receptor-interacting proteins in EVs demonstrates their utility for characterizing membrane protein interactomes. Cryo-electron tomography of EGFR-containing EVs reveals that EGFR forms clusters in both the presence and absence of EGF with a ~3 nm gap between the inner membrane and cytoplasmic density. EGFR extracellular region (ECR) dimers do not form regular arrays in these clusters. Subtomogram averaging of the 150 kDa EGF-bound EGFR ECR dimer yielded a 15 Å map into which the crystal structure of the ligand-bound EGFR ECR dimer fits well. These findings refine our understanding of EGFR activation, clustering, and signaling and establish EVs as a versatile platform for structural and functional characterization of human membrane proteins in cell-derived membranes.

The cell-permeable iron chelator M606 inhibits MYCN-driven neuroblastoma via an E2F3-mediated response

Despite Myc oncoproteins being major causal factors in human cancer, they remain “undruggable.” The MYCN oncogene is one of the most powerful prognostic markers for the childhood cancer neuroblastoma and represents an important target for developing novel therapeutics. Here, we report the finding and characterization of M606, a selective small molecule inhibitor of MYCN, which was identified by screening a diverse chemical library. M606 reduced MYCN protein levels in neuroblastoma cell lines and upregulated hypoxia-inducible factor 1 alpha (HIF1A). Using siRNA-mediated knockdown of MYCN , c-Myc , or HIF1A in HepG2 and BE(2)-C cells followed by M606 treatment, we demonstrated that Myc downregulation and HIF1A upregulation were two independent effects of M606 treatment. M606 selectively targeted neuroblastoma cell lines expressing higher levels of MYCN protein and delayed neuroblastoma development in the TH-MYCN transgenic mouse model. Metabolomic analysis showed that M606 modulated glucose metabolism, consistent with a hypoxic response and iron deprivation. Biochemical characterization of M606 not only confirmed its iron-chelating properties but also revealed its ability to downregulate MYCN promoter activity, which could be rescued by the addition of iron. Luciferase assays identified the minimal MYCN promoter region required for the M606 response, which contained overlapping E2F transcription factor binding sites. Further evaluation defined a key role for E2F3 in the M606-mediated response. The finding of a potent cell-permeable iron chelator that can chelate iron to directly downregulate MYCN transcription via an E2F3-mediated response represents a potentially valuable therapeutic approach in the treatment of cancers overexpressing Myc oncoproteins.

Crystalline Silagermenides as Powerful Synthons: Unraveling π‐Bonding and Lone Pair Effects in the Multiple Bonds of Heavier Main Group Analogs of the Vinyl Anion

Abstract Compared to common vinyl anions, their heavier heteronuclear analog, silagermenides [R 2 Si═GeR]ˉ, remain exceedingly rare. Herein, we present a systematic investigation of silagermenides, synthesized via a straightforward desilylation route. We delve into the bonding characteristics, revealing a weak, polarized Si─Ge π bond with a significant nonbonded lone pair character at the β‐Si position. This β‐Si exhibits predominantly nucleophilic behavior, while the α‐Ge position demonstrates subtly electrophilic tendencies, despite the presence of a vinylic, formally anionic Ge atom. This leads to the formation of silagermenide complexes in an unprecedented η 2 coordination mode, as well as various silagermenes and germylenes with unconventional substituents. We also document the facile cleavage of the ambiphilic Si═Ge double bond, resulting in the transfer of a formal doubly reduced silylene and a formal germyliumylidene. Our findings expand the understanding of heavier main group analogs of the vinyl anion, with important implications for their synthesis and reactivity.

Concerted transport and phosphorylation of diacylglycerol at ER–PM contact sites regulate phospholipid dynamics during stress

A universal response of plants to environmental stresses is the activation of plasma membrane (PM) phospholipase C, which hydrolyzes phosphoinositides to produce soluble inositol phosphate and diacylglycerol (DAG). Because of their conical shape, DAG amounts have to be tightly regulated or they can destabilize membranes. We previously showed that upon stress, Synaptotagmin1 (SYT1) transports DAG from the PM to the endoplasmic reticulum (ER) at ER–PM Contact Sites (CS). Here, we addressed the fate of the incoming DAG in the ER. We show that diacylglycerol kinases (DGKs) DGK1 and DGK2 form a module with SYT1 functionally coupling DAG transport and phosphorylation at ER–PM CS. Although SYT1 and DGK1/DGK2 do not show exclusive ER–PM CS localization, their interaction occurs specifically at ER–PM CS and the removal of ER–PM CS abolishes the interaction. Lipidomic analysis of a dgk1dgk2 double mutant supports that DGK1 and DGK2 phosphorylate DAG at the ER and transcriptomic and phenotypic analyses indicate that SYT1 and DGK1/DGK2 are functionally related. Taken together, our results highlight a mechanism at ER–PM CS that coordinates the transfer of DAG from the PM to the ER by SYT1 upon stress and the concomitant phosphorylation of DAG by DGK1 and DGK2 at the ER. These findings underscore the critical role of spatial coordination in lipid metabolism during stress-induced membrane remodeling.

Declining coral calcification to enhance twenty-first-century ocean carbon uptake by gigatonnes

The sensitivity of coral reefs to climate change is well established. As the oceans warm and acidify, the calcification of coral reefs declines with net calcium carbonate dissolution projected under even moderate emissions trajectories. The impact of this on the global carbon cycle is however yet to be accounted for. Here, we use a synthesis of the sensitivity of coral reef calcification to climate change, alongside reef distribution products to estimate alkalinity and dissolved inorganic carbon fluxes resulting from reductions in reef calcification. Using a global ocean biogeochemical model, we simulate the impact on ocean carbon uptake under different emissions scenarios, accounting for uncertainty in present-day calcification rates. Reductions in net coral reef carbonate production can enhance the ocean carbon sink by up to 1.25 GtCO 2 y −1 by midcentury (0.48 GtCO 2 y −1 median estimate) with cumulative ocean carbon uptake up to 13% greater by 2300 (7% median estimate). Our findings indicate that accounting for the coral reef feedback in projections will increase estimates of the remaining carbon budget associated with global warming thresholds, as well as the likelihood that net zero emissions can be achieved without negative emissions.

Pathophysiologically relevant bisphenol S exposure accelerates aging by disrupting brown adipose tissue–regulated energy metabolism

Bisphenol A (BPA) substitutes are widely used as food contact materials and consumer products, while the effects of pathophysiologically relevant concentrations of BPA substitutes on aging remain unclear. In this study, we used Caenorhabditis elegans ( C. elegans ) to investigate the effects of five BPA substitutes [bisphenol S (BPS), bisphenol B, bisphenol F (BPF), tetramethyl BPF, and 4,4′-(Perfluoropropane-2,2-diyl)diphenol] at pathophysiologically relevant exposure levels during aging and examined the underlying mechanisms using a mouse model. Our results indicated that, among the five BPA substitutes, exposure to pathophysiologically relevant concentrations of BPS (300, 450, and 600 nM) accelerated aging in C. elegans . In mice, exposure to a pathophysiologically relevant concentration of BPS (125 μg/kg/day, from 4 to 20 mo of age) similarly reduces the life and health span and accelerates aging phenotypes in multiple tissues. Further investigations demonstrated that long-term BPS exposure resulted in a significantly higher accumulation of BPS in brown adipose tissue (BAT) than in other organs. RNA sequencing analysis of BAT revealed that BPS accelerates BAT aging through multiple pathways. Importantly, transplantation of BAT from BPS-exposed mice into BPS-naive mice accelerated aging in recipients. Conversely, transplantation of BAT from unexposed mice into BPS-exposed mice significantly improved their metabolic status and delayed aging. These findings elucidate the impact of pathophysiologically relevant concentrations of BPS on the aging process and suggest that these effects are likely mediated through the disruption of BAT function.

Mechanistic Insights into the CO ₂ ‐Assisted NO Electrochemical Deoxygenation and Hydrogenation

Abstract Electrocatalytic NO reduction to NH 3 holds significant potential for pollutant treatment and resource recovery. Herein, we report that the introduction of CO 2 on octahedral oxide‐derived copper (o‐OD‐Cu) significantly enhances the electrochemical reduction of NO to NH 3 . With 10% NO in a CO 2 environment, the Faradaic efficiency for NH 3 production in a flow cell remains around 80% over a wide current density range from 20 to 250 mA cm −2 . At a current density of 250 mA cm −2 , the yield can reach up to 1403.9 µmol cm −2  h −1 , which is 3.71 times higher than without CO 2 and surpasses the performance reported in similar literature. Moreover, even at a low concentration of 1% NO, the Faradaic efficiency can reach a maximum of 70.11% at a current density of 20 mA cm −2 . In situ investigations and theoretical calculations revealed that, in the coexistence of NO and CO 2 , the NO reduction pathway involves a unique route wherein *CO and *COOH, produced from CO 2 reduction, can respectively promote the deoxygenation of *NO and hydrogenation of *N by acquiring O atoms from *NO and providing H atoms for the sustained hydrogenation of *N, thereby accelerating the conversion process of NO to NH 3 .

Structure–function coupling in the first month of life: Associations with age and attention

How brain structure relates to function is a critical and open question in neuroscience. Here, we characterize regional variation in structure–function coupling, capturing the degree to which a cortical region’s structural connections relate to patterns of coordinated neural activity in healthy, term-born neonates ( n = 239). Regional structure–function coupling is heterogeneously patterned across the cortex, with higher coupling in the auditory, lateral prefrontal, and inferior parietal cortices. Average structure–function coupling is negatively associated with age during the first month of life, with age-associated decreases seen in primary sensory systems, specifically in auditory and somatomotor regions. Age-associated “decoupling” of structure and function reflects increasingly segregated patterns of functional connectivity and increasingly integrated patterns of white matter connectivity with age. Notably, higher structure–function coupling after accounting for age in the dorsal attention, cingulo-opercular, and visual systems at birth is associated with faster visuospatial attention to faces at one year of age. These results yield valuable insight into the development of structural and functional connectivity across the cortex, including how interregional variation in structure–function coupling during the first month of life might shape later attention.

Dimensionality Reduction of Metal–Organic Frameworks to Monolayers for Enhanced Electrocatalysis

Abstract Metal–organic frameworks (MOFs) are potential candidates for electrocatalysis due to their well‐defined, tunable structures, and ability to incorporate diverse active sites. However, their inherent insulating nature restricts electron transfer from electrode to remote active sites, leading to diminished catalytic performance. In this work, we present a novel strategy to overcome this limitation by reducing 3D MOFs (3D_MOFs) into monolayered MOFs (monoMOFs) with a thickness of ∼1.8 nm, maximizing the exposure of catalytic sites to the electrode and enhancing electrocatalytic performance. We designed and synthesized a monoMOF incorporating cobalt(II)–porphyrin sites in the linker (monoMOF‐Co) for CO 2 electroreduction. After being grafted onto graphene oxide, the monoMOF‐Co exhibited a peak faradaic efficiency for CO production (FE CO  = 93%), surpassing the performance of a 3D_MOF incorporating the same porphyrin–Co‐based linker (3D_MOF‐Co, FE CO  = 51%). Additionally, monoMOF‐Co achieved a turnover frequency of 10 600 h −1 at −0.8 V versus the reversible hydrogen electrode (RHE) and maintained stability over 47 h in a near‐neutral aqueous solution. In situ spectroscopic studies further confirmed the distinct electric field environment in the Stern layer between monoMOF‐Co and 3D_MOF‐Co. Furthermore, similar enhancement effects of monoMOFs over 3D_MOFs were observed in the nitrate and oxygen electroreduction reactions, highlighting the broader applicability of monoMOFs in electrocatalysis.

Evolutionarily conserved BON1 regulates the basal cytosolic Ca ²⁺ level by calmodulin-independent activation of Ca ²⁺ pumps in <i>Arabidopsis</i>

Plasma membrane-localized autoinhibited Ca 2+ pumps are essential for maintaining basal cytosolic Ca 2+ levels for regulating growth processes and environmental responses. These pumps are known to be activated by calmodulins to maintain Ca 2+ homeostasis in plants and animals. Here, we demonstrate that the evolutionarily conserved copine protein BON1 is critical for maintaining low cytosolic Ca 2+ concentrations by directly regulating two plasma membrane-localized Ca 2+ pumps ACA8 and ACA10 in Arabidopsis . BON1 interacts with a region within the N-terminal domain of ACA8 and ACA10, preceding the calmodulin binding sites, and stimulates ACA8 activity. This activation can occur without calmodulin binding, indicating that BON1 and calmodulin independently regulate the Ca 2+ pump. Loss of BON1 function results in elevated basal cytosolic Ca 2+ concentrations, which can be partially rescued by overexpressing hyperactive ACA8 or ACA10. Furthermore, we show that BON1 has one high-affinity Ca 2+ binding site in the VWA domain that is critical for activation of ACA8 as well as for BON1 function, suggesting a feedback mechanism for Ca 2+ homeostasis at resting concentrations. Our findings suggest that this Ca 2+ responsive regulatory mechanism extends beyond Arabidopsis , as we show interactions between ACA and BON proteins from algae to flowering plants, pointing to an ancient regulatory mechanism for maintaining low basal cytosolic Ca 2+ . Notably, a human plasma membrane-localized autoinhibited Ca 2+ pump can also be activated by a human BON protein in a yeast functional assay system, suggesting evolutionary conservation in Ca 2+ regulation across species.

Synthesis of Chiral δ‐Aminoboronic Esters by Enantioselective Hydrogenation of 1,2‐Azaborines

Abstract We describe herein an iridium‐catalyzed highly diastereo‐ and enantioselective hydrogenation of 1,2‐azaborines to access δ‐aminoboronic esters of potential biological importance. This method represents the first enantioselective hydrogenation of a boron‐containing heteroarene and features diverse substitution patterns and wide scope. The synthetic utility of our method was demonstrated by the synthesis of (−)‐phenibut and the formal synthesis of (+)‐3‐PPP and fluvirucinine A 1 .

Circuit complexity and functionality: A statistical thermodynamics perspective

Circuit complexity, defined as the minimum circuit size required for implementing a particular Boolean computation, is a foundational concept in computer science. Determining circuit complexity is believed to be a hard computational problem. Recently, in the context of black holes, circuit complexity has been promoted to a physical property, wherein the growth of complexity is reflected in the time evolution of the Einstein-Rosen bridge (“wormhole”) connecting the two sides of an anti-de Sitter “eternal” black hole. Here, we are motivated by an independent set of considerations and explore links between complexity and thermodynamics for functionally equivalent circuits, making the physics-inspired approach relevant to real computational problems, for which functionality is the key element of interest. In particular, our thermodynamic framework provides an alternative perspective on the obfuscation of programs of arbitrary length—an important problem in cryptography—as thermalization through recursive mixing of neighboring sections of a circuit, which can be viewed as the mixing of two containers with “gases of gates.” This recursive process equilibrates the average complexity and leads to the saturation of the circuit entropy, while preserving functionality of the overall circuit. The thermodynamic arguments hinge on ergodicity in the space of circuits which we conjecture is limited to disconnected ergodic sectors due to fragmentation. The notion of fragmentation has important implications for the problem of circuit obfuscation as it implies that there are circuits of same size and functionality that cannot be connected via a polynomial number of local moves. Furthermore, we argue that fragmentation is unavoidable unless the complexity classes NP and coNP coincide, a statement that implies the collapse of the polynomial hierarchy of computational complexity theory to its first level.

Enhanced Luminance of Pentaazaphenalene‐Based Delayed Fluorescence Emitters by Breaking Forbidden Transition

Abstract 1,3,4,6,9 b ‐pentaazaphenalene (5AP) derivatives are of growing interest because of their potential for exhibiting thermally activated delayed fluorescence and inverted singlet–triplet excited state properties. However, a major challenge has been the nonemissive nature of 5AP. This study reports a donor‐5AP‐acceptor‐type molecular design for converting nonemissive 5AP into highly emissive molecules. The newly designed molecules, 2,5‐di(1‐pyrrolidino)‐7,9‐bis(4‐(trifluoromethyl)phenyl)‐1,3,4,6,9 b ‐pentaazaphenalene ( Pyr‐5AP‐CF 3 ) and 2,5‐di(1‐pyrrolidino)‐7,9‐bis(4‐benzonitrile)‐1,3,4,6,9 b ‐pentaazaphenalene ( Pyr‐5AP‐CN ), exhibited delayed fluorescence and achieved high photoluminescence quantum yields of 83.5% and 90.6%, respectively, in solid films. These values dramatically exceed those of previously reported 5AP derivatives with only 8% or less. Furthermore, Pyr‐5AP‐CF 3 and Pyr‐5AP‐CN exhibited the fastest radiative decays and the narrowest emission spectra among all the 5AP based materials reported to date. This study provides a promising solution to the nonemissive nature of 5AP, leading to the development of a class of highly luminescent materials for future organic light‐emitting diodes.

A mouse model of Jansen’s metaphyseal chondrodysplasia for investigating disease mechanisms and candidate therapeutics

Jansen’s metaphyseal chondrodysplasia (JMC) is a rare disorder caused by activating mutations in the parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor (PTH1R). Patients exhibit short stature, dysmorphic bones, and severe growth plate abnormalities, as well as hypercalcemia, hypercalciuria, hypophosphatemia, and reduced plasma PTH levels. Humanized PTH1R (hPTH1R) mice expressing the H223R-hPTH1R JMC mutation die early without breeding. We therefore generated and characterized a stable mouse line expressing the T410R-hPTH1R allele, which confers a milder disease phenotype in patients. Mutant mice show near-normal longevity and reproductive capacity yet exhibit a profound skeletal phenotype characteristic of the disease. The long bones of T410R mice are markedly misshapen and have expanded metaphyses with disarrayed chondrocyte zones in growth plates and reduced primary spongiosa. PET/CT scanning revealed diminished uptake of [ 18 F]-sodium fluoride in the growth plate area, consistent with reduced mineralization and vascularization. Genetic ablation of Hdac4 rescued the growth plate abnormalities in T410R mice, thereby establishing the PTH1R-Gαs-cAMP-PKA-SIK3-HDAC4/5 pathway as the main mediator of growth plate abnormalities in JMC. Serum calcium was elevated and endogenous PTH was suppressed in T410R mice, and both parameters could be normalized by acute injection of an optimized PTH inverse agonist peptide. The T410R mouse thus represents a stable animal model of JMC that recapitulates the abnormalities in skeletal development and mineral ion homeostasis which characterize this disease. The mice should help efforts to further define the cellular and molecular mechanisms underlying the JMC phenotype and to develop a potential mode of therapy.

High‐Throughput DFT‐Assisted Design of Electrode for Efficient High‐Temperature Electrochemical Dehydrogenation

Abstract Protonic ceramic electrolysis cell (PCEC) is a promising technique to enable efficient dehydrogenation reactions for producing valuable chemicals, but is still limited by the lack of stable electrocatalysts to achieve efficient O─H/C─H dissociation. In this work, upon high‐throughput first‐principles calculations, Ba(Zr,Co,Fe,M)O 3 ‐based (M represents dopants) perovskite is formulated, and oxygen vacancy formation energy () and hydration energy (Δ E hydr ) are taken as two key performance indicators to screen potential PCEC electrode materials derived from this category. Trivalent doping elements, particularly Y, Yb, Er, and Tm, achieve a good balance between and Δ E hydr . Experiments further validate that the BaZr 0.125 Co 0.375 Fe 0.375 Tm 0.125 O 3−δ showed impressive dehydrogenation reaction activity, with faradaic efficiency as high as 98.90% in water electrolysis, and outstanding ethane conversion rate (67.60%) and ethylene yield (62.62%) for ethane dehydrogenation reaction at 700 °C. The computational approach can be applied to the rational design of novel electrode materials for other electrochemical reactions in energy and environment devices.