Browse Articles
Discover research articles across all indexed journals
Immune cell profiling reveals expanded stem cell–like memory T cells in anti-GAD65-associated neurological syndromes
The immunopathogenesis of autoimmune neurological syndromes (AINS) with antibodies against the 65 kDa isoform of glutamic acid decarboxylase (anti-GAD65 AINS) remains poorly understood. To elucidate underlying disease mechanisms and identify relevant cell populations, we performed single-cell RNA and immune repertoire sequencing of cerebrospinal fluid (CSF) and peripheral blood mononuclear cells (PBMCs) of eight anti-GAD65 AINS individuals compared to eight noninflammatory controls. In addition, PBMCs from 19 anti-GAD65 AINS individuals and 20 healthy controls were analyzed by multidimensional flow cytometry, and brain tissue specimens from four anti-GAD65 AINS individuals were examined histologically. We detected higher frequencies of stem cell–like memory T cells (TSCM) within the PBMCs and a marked enrichment and clonal expansion of activated CD4 + TSCM in the CSF of anti-GAD65 AINS individuals. Expanded T cells exhibited increased expression of proinflammatory genes. Histological analyses confirmed intraparenchymal CD8 + TSCM in three of four anti-GAD65 AINS individuals and rare meningeal/intraparenchymal CD4 + TSCM in one person. Although CSF B cell receptors (BCRs) displayed little to no clonal expansion, recombinant expression of 40 CSF BCRs revealed that 25% were GAD65-reactive with increased somatic hypermutations compared to non-GAD65-reactive BCRs. These findings further support the concept of an antigen-specific intrathecal immune response. In summary, we characterize the immune landscape of anti-GAD65 AINS at single-cell resolution and identify clonally expanded TSCM with cytotoxic properties as a hallmark of this disease.
Cnpy1 is a candidate endoplasmic reticulum chaperone of vomeronasal type 2 GPCRs
Mouse vomeronasal sensory neurons are continuously generated from stem cells and differentiate to express either V1R or V2R G protein–coupled receptors (GPCRs), along with their respective Gαi2 or Gαo G-protein subunits. We previously reported that Gαo-type neurons exhibit elevated expression of endoplasmic reticulum (ER) chaperones and a distinctive hypertrophic, gyroid ER architecture, suggesting specialized proteostatic demands. Here, we identify a transcript for the mouse Canopy1 ( Cnpy1) gene that yields full-length Cnpy1 protein selectively expressed in and localized to the ER of Gαo neurons. Immunoprecipitation coupled with mass spectrometry revealed that Cnpy1 associates specifically with V2R GPCRs and multiple ER chaperones. Cnpy1 deletion resulted in mice that were deficient in Gαo neuronal activation upon exposure to vomeronasal stimuli and a marked reduction in male–male aggressive behavior. In the absence of Cnpy1, Gαo neurons develop normally till birth but undergo selective, progressive apoptosis during postnatal development. Unexpectedly, Cnpy1-null vomeronasal neurons displayed neither an obvious unfolded protein response nor defects in V2R GPCR traffic to dendritic tips, indicating that Cnpy1 is required for V2R assembly or functional maturation but dispensable for their ER export. Together, these findings identify Cnpy1 as a component of an ER chaperone complex that is essential for Gαo neuron signaling and survival.
Microstrain-engineered platinum nanoclathrins for fuel cells
Proton exchange membrane fuel cells (PEMFCs) hold great promise for clean energy conversion, yet their performance is limited by insufficient mass transport bottlenecks within the catalyst layer. Addressing this fundamental issue demands innovative catalyst nanostructuring. Inspired by the evolutionarily optimized channel systems in cellular transport mechanisms, we design clathrin-mimetic noble metal nanostructures featuring nanoporous shells and internal cavities via a selenium-induced self-assembly method. The creation of such nanoclathrin relies on the in situ formed Se, where the amorphous structure induces the disordered growth of noble metals on the surface, ultimately establishing the nanoclathrin architecture. This strategy can be extended to create diverse nanoclathrins with controlled hollow size, shell thickness, as well as composition. Furthermore, precise microstrain engineering enables performance fine-tuning of platinum nanoclathrins (Pt NCLs) for half reactions in PEMFCs. Benefiting from enhanced mass transfer and optimized microstrain, Pt NCLs can serve as both efficient cathode and anode catalysts in practical fuel cells, achieving rated power densities of 1.25 W cm −2 in H 2 /O 2 and 0.83 W cm −2 in H 2 /Air, which positions Pt NCLs among the best-performing pure-Pt catalysts and even rivals many state-of-the-art Pt-alloy catalysts. The clathrin-like structures also exhibit excellent stability, retaining 95.7% of their initial activity after 30,000 accelerated stress test cycles. This work highlights the significance of designing clathrin-like architecture with promoted mass transfer for practical devices and beyond in sustainable energy applications.
Genomic epidemiology of <i>Salmonella</i> and <i>Campylobacter</i> in poultry production: Quantifying the contribution of primary breeders
The US broiler production system processes over 9.3 billion chickens annually through a highly integrated pyramid structure where two primary breeding companies supply genetic stock to approximately 40 major integrators operating nationwide. To provide a quantitative, system-wide estimate of contamination origins, I analyzed whole-genome sequences from Salmonella and Campylobacter isolates collected from over 800 processing facilities as part of the United States Department of Agriculture’s Food Safety Inspection Service verification sampling (2019-2025). Single-linkage clustering identified isolates sharing common origins (≤2, 4, or 8 SNPs genome-wide), which were categorized by processing complex, company, and geographical distributions to infer contamination sources. Among the isolates analyzed, 78% of Campylobacter , 77% of non-Enteritidis Salmonella , and 96% of Salmonella Enteritidis belonged to clusters spanning multiple companies and geographic regions—a pattern consistent with primary breeder origin. The geographic spread of Enteritidis isolates within clusters matched a random model, and cluster populations showed temporal turnover yet spatial synchrony—patterns explicable only by contamination from the apex of the breeding pyramid. Campylobacter showed regional clustering implying sources at lower levels of the breeding pyramid. Cluster persistence exceeded multiple production cycles (median >4 y for Campylobacter , >4.5 y for 75% of Enteritidis isolates), indicating stable contamination reservoirs upstream of processing. These results demonstrate that the primary breeders are a major source of broiler contamination and suggest that upstream interventions targeting breeding stock, in particular for Enteritidis, may represent an efficient strategy for further reducing clinical cases of foodborne illness.
Tyrosine phosphoproteome profiling identifies cell-intrinsic signals limiting the efficacy of tyrosine kinase inhibitor therapies
Tyrosine kinases (TKs) are frequently mutated or overexpressed in cancer, and TK inhibitors (TKIs) are an important therapeutic modality against TK-driven cancers, but many patients show an underwhelming response to TKIs prescribed on the basis of tumor genotype. To find cell-intrinsic TK signaling patterns which might be predictive of poor response to TKI therapies, we used high-sensitivity multiplexed mass spectrometry to quantify endogenous levels of 1,222 phosphotyrosine (pY) sites across the proteomes of TK-driven human cancer cell lines with variable response to genotype-matched TKIs. In direct comparisons between TKI-tolerant and TKI-sensitive lines with a common driver TK, we found that TKI treatment was equally effective at blocking driver TK signaling, and higher basal activity of the driver TK did not always predict higher sensitivity to TKI. All tolerant lines showed a dampened proteome-wide pY response to TKI exposure compared to sensitive lines, suggesting that tumor cells with more robust TK signaling are less vulnerable to driver TK blockade. We found that each tolerant line depends on a unique set of compensatory TKs and signaling axes but are unified by hyperactivity of at least one of the SRC family kinases (SFKs) or the related ABL1/2 kinases, both at rest and under TKI treatment, despite the absence of SFK or ABL genetic mutations. In time- and dose-resolved drug combination experiments, SFK/ABL inhibitors were potently synergistic with all TKIs tested, demonstrating that elevated SFK/ABL signaling is a conserved bottleneck for maximal TKI efficacy which could be exploited therapeutically.
Ultrasound-responsive liposomes: A mechanistic framework to decode the effects of acoustic parameters
Ultrasound offers a noninvasive, clinically relevant means to achieve precise spatiotemporal control of cargo release from ultrasound-responsive drug delivery systems within deep tissues. This approach enables targeted delivery of therapeutic agents, enhancing efficacy while minimizing systemic toxicity. While previous studies show that release from ultrasound-responsive liposomes depends on acoustic parameters, the underlying mechanisms remain unclear. A deeper mechanistic understanding is essential to achieve precision over release and maximize therapeutic outcomes. To address this, we propose a sonoporation-based framework to describe release dynamics across varying frequencies, pressures, duty cycles, and pulse repetition frequencies for ultrasound-responsive poly(ethylene glycol)-functionalized liposomes. Using computational simulations validated by empirical results, our framework identifies a critical pressure threshold for release onset and demonstrates how the time spent above this threshold, modulated by acoustic parameters, governs release efficiency. To elucidate these effects, custom-built ultrasound transducers with different resonance frequencies were fabricated and characterized to ensure precise sample alignment, minimize acoustic distortion, and maintain a controlled focal-volume-to-sample-volume ratio across different frequencies. COMSOL simulations indicated that oscillatory acoustic pressure plays a more dominant role than acoustic radiation force, while coarse-grained molecular dynamics simulations captured pressure-dependent pore formation dynamics within the lipid bilayer. Together, our experiments and simulations highlight mechanical effects—particularly oscillatory acoustic pressure—as the primary driver of sonoporation-facilitated release. Finally, we discuss how optimizing acoustic parameters through this mechanistic framework could facilitate safe and effective clinical translation by considering tissue safety and ultrasound transducer design.
Global stability of ecological and evolutionary dynamics via equivalence
The replicator and the Generalized Lotka–Volterra equations are closely related, foundational models in evolutionary game theory and community ecology, respectively. The concept of evolutionary stability and its relationship with dynamic stability has received significant attention: In the replicator equation, an evolutionarily stable strategy is also dynamically globally stable—i.e., will be reached by any trajectory originating from positive conditions. Intriguingly, the converse is not true: There are replicator equations yielding dynamically stable strategies that are not evolutionarily stable. Here, we consider two classes of equivalence (i.e., transformations that do not alter the qualitative dynamics) for the replicator equation, to determine whether a globally stable, but not evolutionarily stable strategy maps into an equivalent state that is evolutionarily stable—and show that this is the case for the examples that have been put forward so far. We derive the same two classes of equivalence for the Generalized Lotka–Volterra model, obtaining the same conditions for stability as for the replicator equation, and show that in this way we can characterize stability when other methods fail. By unifying the approach to proving stability for the replicator equation and Lotka–Volterra models, we bring these foundational equations even closer together.
PHGDH phosphorylation mediated by WNK1 serves as a dual marker of metabolic vulnerability and responsiveness to oxaliplatin treatment
Metabolic reprogramming is a fundamental hallmark of cancer progression. However, the oncogenic mechanisms underlying serine metabolism and its impact on chemotherapeutic sensitivity in gastric cancer (GC) remain poorly defined. Here, through integrated metabolomics and 13 C-labeled metabolic flux analysis, we identify marked dysregulation of serine metabolism in GC, primarily driven by increased expression of phosphoglycerate dehydrogenase (PHGDH). Mechanistically, we show that with no lysine kinase 1 (WNK1) phosphorylates PHGDH at Ser349 and Ser371, enhancing its enzymatic activity and protein stability by preventing ubiquitin-mediated degradation. In vivo, WNK1 knockout mice exhibit significantly reduced gastric tumor burden, accompanied by decreased serine levels and disrupted redox balance, supporting the protumorigenic role of the WNK1–PHGDH axis. Clinically, enhanced PHGDH activity, elevated serine levels, and increased glutathione abundance are strongly associated with poor oxaliplatin response in GC patient cohorts, suggesting PHGDH as a potential predictive biomarker for chemotherapy resistance. Together, these findings delineate a WNK1–PHGDH–driven serine metabolic reprogramming axis that promotes redox adaptation and chemoresistance in GC, highlighting its dual value as a mechanistic driver and a therapeutic vulnerability in cancer treatment.
Tau catalyzes amyloid-β aggregation and toxicity in a polymorph-dependent manner
Interactions between amyloidogenic proteins are emerging as critical drivers of neurodegenerative diseases. Among others, in Alzheimer’s disease (AD) and severe forms of chronic traumatic encephalopathy (CTE), codeposition of tau and amyloid-β (Aβ) leads to worsening of clinical outcomes and disease progression. Despite the importance of such heterotypic interactions, the underlying molecular mechanisms have proven challenging to be established. Here, we investigated the direct interaction between Aβ and tau, combining in vitro reconstruction, and in vivo models. We find that characteristic AD paired helical filament (PHF) and CTE folds catalyze the primary nucleation of Aβ42 in a fold-specific manner with enzyme-like kinetics. In particular, CTE fibrils exhibit the highest catalytic activity and constrain Aβ42 polymorphism, suggesting templating effects. Moreover, PHF and CTE tau fibrils increase Aβ42 toxicity in SH-SY5Y neuroblastoma cells and transgenic Caenorhabditis elegans, preserving fold-dependent reactivities. Our findings shed light on the molecular mechanisms of heterotypic interaction between amyloidogenic proteins in disease-relevant conditions, highlighting the role of amyloid structure and recognition mechanisms as key determinants. These results offer insights into the pathological mechanisms of multiple proteinopathies. The mechanisms described here might be used as a blueprint for structure-based design of new therapeutic agents targeting specific amyloidogenic interactions.
Polypharmacology of S-1117, an Fc-fused IgG-selective degrading enzyme, for chronic treatment of autoantibody-mediated diseases
Antigen-specific immunoglobulin-G (IgG) antibodies cause or contribute to the pathogenesis of a wide spectrum of human diseases and conditions. Multiple therapeutic approaches have been developed, yet they are limited by variable safety and efficacy, patient inconvenience, and cost. IdeS, a cysteine protease derived from S. pyogenes , specifically cleaves IgG antibodies, representing a unique opportunity for the treatment of IgG-mediated diseases. However, clinical utilization of IdeS is limited by the immunogenic nature of bacterial proteases and short half-life. Using Seismic’s IMPACT platform, we engineered S-1117, an IgG cleaving enzyme fused to a human effectorless IgG1 Fc domain for an extended half-life. S-1117 is being developed to address the limitations of existing therapies in IgG-mediated diseases. In vitro and in vivo pharmacology studies demonstrate that S-1117 exhibits reduced B and T cell immunogenicity, a superior pharmacokinetic profile, and manufacturability and developability properties resembling those of monoclonal antibodies. S-1117 cleavage of IgG reduces circulating levels of IgG, including pathogenic IgG autoantibodies and IgG immune-complexes, and reduces IgG antibody effector functions, such as complement fixation, antibody-dependent cellular cytotoxicity, and antibody-dependent cell phagocytosis. The polypharmacology of S-1117 further extends to cleaving the antigen receptor on IgG-positive memory B cells, thereby modulating activation of memory B cells.
Neural signatures of human psychological resilience driven by acute stress
Neurophysiological mechanisms underlying psychological resilience—the ability to overcome adversity—have been extensively studied in animals. However, compared to that in animals, human resilience is unique in that it is underpinned by higher-order cognitive functions, such as self-confidence, tenacity, and a positive attitude to challenges. Given these discrepancies, the neurophysiological mechanisms underlying human-specific resilience remain unclear. To address this issue, we aimed to record multimodal responses after acute stress exposure over 1.5 h using functional brain imaging and peripheral physiological measurements. We showed that the degree of individual resilience is indexed by multiple changes in neural dynamics 1 h after acute stress. Functional magnetic resonance imaging and electroencephalography show that activity in the cortical salience network and power in high-beta and gamma oscillations increase in less resilient individuals. Contrastingly, activity in the cortical default mode network and spontaneous activity in the posterior hippocampus increase in more resilient individuals. Machine learning analysis confirmed that, 1 h after stress exposure, the functional connectivity in the salience network was the most influential, followed by that in the default mode network, gamma power, high-beta power, and hippocampal activity. The neurophysiological dynamics for resilience do not occur as previously thought, but rather in a time-lagged manner against stress exposure. Our findings shed light on an approach to recovery from stress-induced deficits such as delayed neuromodulation after a stressful event.
A conserved ethylene-triggered cell death mechanism may underlie hollow stem formation across plant species
Hollow stems have independently evolved multiple times across the plant kingdom and play crucial roles in plant development and various environmental adaptations. However, the mechanisms underlying stem hollowness remain poorly understood. Water spinach ( Ipomoea aquatica ) is one of the few hollow-stemmed plants in the Convolvulaceae family (eudicot: asterid), and its hollow stems are essential for thriving in aquatic environments. Using histochemical staining and transcriptome analysis, we found that programmed cell death (PCD) is involved in cavity formation at water spinach shoot tips. Single-cell and spatial transcriptome analyses further revealed that ethylene and reactive oxygen species (ROS) likely drive and regulate this process by activating transcription factors IaNAC074 , IaNAC087 , IaNAC029 , IaNTL9 , and IaTGA9 , which likely initiate PCD, senescence, and autophagy, collectively leading to pith cell death. These findings were validated through treatments with ethylene and ROS reagents in water spinach, as well as transient expression assays in tobacco. Additionally, transcriptomic data suggest that these mechanisms may also play a role in hollow stem formation in horsetail (fern), moso bamboo (monocot), and broad bean (eudicot: rosid), highlighting the conservation of PCD regulatory mechanisms in hollow stem formation. This study not only fills a major knowledge gap in the adaptive mechanisms of hollow stem formation but also opens broad avenues for agricultural and ecological applications, offering strategies to enhance crop tolerance to flooding and accelerate crop growth.
A modular platform for Sterically Masked Activated Cytokines (SMACks)
Cytokines are critical signaling molecules, but their therapeutic potential remains unrealized due to pleiotropic effects across cell types. Current strategies to develop conditionally active cytokines involve complex engineering and production, limiting their application to a select few cytokines and receptors. Here, we describe a simple, highly modular format called Sterically Masked Activated Cytokine (SMACk) via facile assembly of a targeting Fab/VHH, cytokine, and Fc. We first develop an interleukin-22 (IL-22) SMACk selective for intestinal epithelial cells, wherein the Fab/VHH serves a dual masking and targeting role. Detailed analysis revealed a cis signaling mechanism via a reduced on-rate and identified tunable format parameters. In mice, the IL-22-SMACk showed selective activity in the colon and efficacy in a colitis model. Finally, we highlight the versatility of SMACks by selectively directing interferon-α, IL-2, IL-4, or IL-7 to CD8 + T cells, underscoring the potential of this platform to advance cytokine research and therapies.
Data-driven Mori–Zwanzig modeling of Lagrangian particle dynamics in turbulent flows
The dynamics of Lagrangian particles in turbulence play a crucial role in mixing, transport, and dispersion in complex flows. Their trajectories exhibit highly nontrivial statistical behavior, motivating the development of surrogate models that can reproduce these trajectories without incurring the high computational cost of direct numerical simulations of the full Eulerian field. This task is particularly challenging because reduced-order models typically lack access to the full set of interactions with the underlying turbulent field. Novel data-driven machine learning techniques can be powerful in capturing and reproducing complex statistics of the reduced-order/surrogate dynamics. In this work, we show how one can learn a surrogate dynamical system that is able to evolve a turbulent Lagrangian trajectory in a way that is point-wise accurate for short-time predictions (with respect to Kolmogorov time) and stable and statistically accurate at long times. This approach is based on the Mori–Zwanzig formalism, which prescribes a mathematical decomposition of the full dynamical system into resolved dynamics that depend on the current state and the past history of a reduced set of observables, and the unresolved orthogonal dynamics due to unresolved degrees of freedom of the initial state. We show how by training this reduced order model on a point-wise error metric on short time-prediction, we are able to correctly learn the dynamics of Lagrangian turbulence, such that also the long-time statistical behavior is stably recovered at test time. This opens up a range of applications, for example, for the control of active Lagrangian agents in turbulence.
DIRAS2 modulates MAPK pathway–mediated ferroptosis to regulate excitation/inhibition balance and seizure susceptibility
Epilepsy is a common neurological disorder that is widely believed to be associated with an imbalance between neuronal excitation and inhibition (E/I). DIRAS2, a Ras-related GTPase, has not been well understood regarding its role and function within the nervous system. In this study, we found that DIRAS2 is downregulated in the hippocampus during the epileptogenesis phase in a kainic acid-induced epilepsy model, while it is upregulated during the chronic phase in this epilepsy model and in patients with temporal lobe epilepsy. Overexpression of DIRAS2 alleviates epileptic seizure susceptibility and activity, whereas knockdown of DIRAS2 has an opposite effect. Whole-cell patch-clamp recordings reveal that DIRAS2 reduces the neuronal E/I ratio and alleviates neuronal hyperexcitability. Mechanistically, quantitative proteomic analysis reveals that ferroptosis is involved in mediating the effects of DIRAS2. Knockdown of DIRAS2 can exacerbate ferroptosis, while overexpression protects against ferroptosis in both in vivo and in vitro studies. Ferrostatin-1, a ferroptosis inhibitor, can rescue the E/I imbalance and epileptic behavioral changes induced by DIRAS2 knockdown. Finally, we found that DIRAS2 regulates ferroptosis by inhibiting the extracellular signal-regulated kinase/p38 mitogen-activated protein kinase pathway in epileptic mice. In summary, our study demonstrates the role of DIRAS2 in epilepsy and provides a potential target for epilepsy treatment.
DNA methylation site loss for plasticity-led novel trait genetic fixation
Phenotypic plasticity allows organisms to adapt traits in response to environmental changes, yet the molecular basis by which such plastic traits become genetically fixed remains unclear. Here, we investigated gut-length plasticity in medaka fish ( Oryzias latipes ) through genome-wide methylation profiling, CRISPR/Cas9-mediated deletion, and population genomic analyses. We found that seasonal methylation of CpG sites upstream of the Plxnb3 is correlated with gut-length plasticity, and deletion of this region abolishes plasticity. Additionally, standing variation in Ppp3r1 is associated with genetically fixed longer gut length in populations lacking plasticity. These results suggest that loss of epigenetic regulation via CpG site reduction triggers the genetic fixation of novel traits. Our findings provide molecular evidence linking epigenetic plasticity and genetic assimilation, advancing understanding of plasticity-led evolution in natural populations.
Dendro-plexing of Single Input Spikes via Multiple Synaptic Contacts Can Enhance Cortical Neuron Computation and Reduce Axonal Wiring
A cortical neuron typically makes multiple synaptic contacts on the dendrites of its postsynaptic target neuron. The functional implications of this apparent redundancy are unclear. Due to dendritic cable filtering, proximal dendritic synapses generate brief somatic postsynaptic potentials (PSPs) whereas distal synapses give rise to broader PSPs. Consequently, with multiple synaptic contacts, a single presynaptic spike results in a somatic PSP composed of multiple temporal profiles. We developed a "Filter-and-Fire" (F&F) neuron model that incorporates multiple contacts and cable filtering; it demonstrates threefold increase in memory capacity as compared to a leaky Integrate-and-Fire (I&F) neuron, when trained to emit precisely timed spikes for specific input patterns. Furthermore, the F&F neuron can learn to recognize spatio-temporal input patterns, e.g., MNIST digits, where the I&F model completely fails. We conclude that “dendro-plexing” single input spikes by multiple synaptic contacts enriches the computational capabilities of cortical neurons and can dramatically reduce axonal wiring. Significance Statement Cortical neurons often connect to their postsynaptic targets by making multiple synaptic contacts over the dendrites of the receiving cell. This multi-synapse connectivity pattern, discovered some 30 years ago and rediscovered many times since (including recently via EM studies), is puzzling as it appears to be redundant and wasteful. To date, no convincing explanation for this phenomenon has been provided. Here we propose a novel potential solution to this puzzle by incorporating temporal filtering properties of dendrites. We propose a conceptually and mathematically simple filter and fire (F&F) neuron model that incorporates both multiple contacts and dendritic filtering and reach surprising consequences from both the computational perspective as well as the "hardware savings" perspective.
Structural insight of a photosystem I-CpcL-phycobilisome supercomplex from a cyanobacterium <i>Anabaena</i> sp. PCC 7120
Phycobilisomes (PBSs) are supramolecular pigment–protein complexes composed of phycobiliproteins and linker proteins, serving as the major light-harvesting complexes that capture and transfer light energy to photosystem II (PSII) and photosystem I (PSI) in cyanobacteria and eukaryotic red algae. In cyanobacteria, a rod-type PBS that does not have a core is specifically connected to PSI by a linker protein CpcL to form a PSI-CpcL-PBS supercomplex. However, the mechanism of CpcL-PBS association to PSI remains unclear. Here, we report the cryoelectron microscopic structures of PSI-CpcL-PBS at 2.98 Å and CpcL-PBS at 2.93 Å resolution from a cyanobacterium Anabaena sp. PCC 7120, respectively. CpcL-PBS is located on the stromal side of a PSI tetramer and exhibits a structure of three-layered PBS consisting of four linkers (CpcL, CpcC1, CpcC2, PecC) and 18 pairs of phycocyanin αβ monomers. The C-terminal transmembrane helix of CpcL inserts to the membrane and interacts with PsaA, PsaB, and PsaM of PSI at an interface I between two PSI monomers, enabling the formation of the PSI-CpcL-PBS supercomplex. The exact structure of protein subunits and arrangement of bilin and chlorophyll pigments are revealed, which provide a structural basis for the assembly of PSI-CpcL-PBS and possible excitation energy transfer pathways from antennas to PSI within this supercomplex, shedding light on the organization and attachment of CpcL-PBS in cyanobacterial thylakoids.
Cell-intrinsic regulation of epilepsy-associated pathology by mTORC1 and mTORC2
Mechanistic target of rapamycin (mTOR) signaling is mediated through mTORC1 and mTORC2. mTORC1 signaling requires the regulatory protein Raptor, while mTORC2 signaling requires Rictor. mTOR signaling is increased during epileptogenesis, and manipulations to inhibit mTOR have been shown to reduce seizure incidence in some epilepsy models. Inhibiting mTOR signaling is hypothesized to prevent epileptogenic changes. To test this hypothesis, and to assess how mTORC1 and mTORC2 might modulate epileptogenesis, we deleted Raptor or Rictor from a subset of hippocampal dentate granule cells in male and female mice to cell-autonomously inhibit mTORC1 or mTORC2, respectively. Gene deletion effects were examined in healthy mice and following status epilepticus, which leads to the development of epilepsy. Raptor and Rictor knockout cells had fewer dendritic spines than neighboring wildtype cells, and Raptor knockout cells had reduced presynaptic terminal volume and contributed less to mossy fiber axon sprouting. Raptor deletion decreased somatic contact with parvalbumin inhibitory neuron puncta and reduced soma area, while Rictor knockout cells were more likely to be c-Fos immunoreactive. Findings demonstrate that Raptor and Rictor deletion exert mixed effects on morphological changes associated with epilepsy, implying that mTORC1 and mTORC2 have both overlapping and distinct neuroanatomical targets. In addition, the magnitude of gene deletion effects was similar in saline and SE-exposed animals. The observation implies that rather than specifically blocking epileptogenic circuit rewiring in acquired epilepsy, mTOR inhibition acts similarly on granule cells in healthy and epileptic mice to produce mixed changes on structures underlying excitatory and inhibitory synaptic transmission. Significance Statement The mTOR signaling pathway is a critical regulator of cell growth and metabolism, and is implicated in the development of numerous diseases, including cancer, autism and epilepsy. mTOR signaling is mediated through two arms, mTORC1 and mTORC2. Here, we manipulated signaling through the two arms to assess the impact on neuronal structure in control and epileptic brains. Manipulating mTORC1 and mTORC2 signaling produced both overlapping and distinct effects on neuronal structure – in some cases offsetting changes associated with epilepsy, but in most cases producing similar effects in healthy and epileptic animals. Findings provide new insights into the role of mTOR signaling in epilepsy, and guidance for predicting off target effects of mTOR antagonism.
The power of leadership in changing social norms in heterogeneous societies
Abandoning detrimental social norms is complex due to the strong pressure to conform. We examine how leaders can guide norm change in heterogeneous societies where individual preferences evolve at different rates. Inspired by the model and experimental design of [J. Andreoni, N. Nikiforakis, and S. Siegenthaler, Proc. Natl. Acad. Sci. U.S.A. 118 , e2014893118 (2021)], we conduct a large-scale laboratory experiment in which we manipulate the speed at which preferences change within a society and introduce leaders with different, evolving preferences. Without leaders, a minority of citizens with rapidly changing preferences cannot overturn an existing norm in a society where most individuals have slow-changing preferences. When fast-changing citizens form the majority, norm change occurs in most groups, but at high welfare costs. In contrast, exogenously selected leaders are highly effective at coordinating expectations and shifting heterogeneous societies toward a more efficient norm—at lower welfare costs and regardless of the underlying distribution of preference evolution across individuals. However, the timing of norm change depends on whether leaders prioritize their preferences (autocratic leadership) or those of the majority (democratic leadership). A follow-up experiment shows that peer-to-peer communication encourages leaders to adopt a more democratic leadership style. These results highlight the pivotal role of leadership in driving norm change and the importance of public voice in shaping leaders’ behavior.