Browse Articles
Discover research articles across all indexed journals
An N-terminal domain specifies developmental control by the SMAX1-LIKE family of transcriptional regulators in <i>Arabidopsis thaliana</i>
SMAX1-LIKE (SMXL) proteins in plants are cellular signaling hubs, many of which are posttranslationally regulated by karrikins from smoke, the plant hormones strigolactones (SLs), and/or cues such as light and nutrients. SMXL proteins control diverse aspects of growth, development, and environmental adaptation in plants through transcriptional corepression and interactions with transcriptional regulator proteins. In flowering plants, the SMXL family comprises four phylogenetic clades with different roles. Functions of the aSMAX1 clade include control of germination and seedling development, while the SMXL78 clade controls shoot architecture. We investigated how SMXL roles are specified in Arabidopsis thaliana. Through promoter-swapping experiments, we found that SMXL7 can partially replicate SMAX1 function, but SMAX1 cannot replace SMXL7 . This implies that the distinct roles of these genes are primarily due to differences in protein sequences rather than expression patterns. To determine which part of SMXL proteins specifies downstream control, we tested a series of protein chimeras and domain deletions of SMAX1 and SMXL7. We found an N-terminal region that is necessary and sufficient to specify control of germination, seedling growth, or axillary branching. We screened 158 transcription factors (TFs) for interactions with SMAX1 and SMXL7 in yeast two-hybrid assays. The N-terminal domain was necessary and/or sufficient for most of the 33 potential protein–protein interactions that were identified for SMAX1. This finding unlocks different ways to engineer plant growth control through cross-wiring SMXL regulatory “input” and developmental “output” domains from different clades and lays a foundation for understanding how functional differences evolved in the SMXL family.
Systemic in utero gene editing as a treatment for cystic fibrosis
In utero gene editing has the potential to modify disease-causing genes in multiple developing tissues before birth, possibly allowing for normal organ development, disease improvement, and conceivably, cure. In cystic fibrosis (CF), a disease that arises from mutations in the CF transmembrane conductance regulator ( CFTR ) gene, there are signs of multiorgan disease affecting the function of the respiratory, gastrointestinal, and reproductive systems already present at birth. Thus, treating CF patients early is crucial for preventing or delaying irreversible organ damage. Here, we demonstrate proof-of-concept of multiorgan mutation correction in CF using peptide nucleic acids encapsulated in polymeric nanoparticles and delivered systemically in utero. In utero editing was associated with sustained postnatal CFTR activity, at a level similar to that of wild-type mice, in both respiratory and gastrointestinal tissues, without detection of off-target mutations in partially homologous loci. This work suggests that systemic in utero gene editing represents a viable strategy for treating monogenic diseases before birth that impact multiple tissue types.
Electrical spinal cord stimulation promotes focal sensorimotor activation that accelerates brain–computer interface skill learning
Injuries affecting the central nervous system may disrupt neural pathways to muscles causing motor deficits. Yet the brain exhibits sensorimotor rhythms (SMRs) during movement intents, and brain–computer interfaces (BCIs) can decode SMRs to control assistive devices and promote functional recovery. However, noninvasive BCIs suffer from the instability of SMRs, requiring longitudinal training for users to learn proper SMR modulation. Here, we accelerate this skill learning process by applying cervical transcutaneous electrical spinal stimulation (TESS) to inhibit the motor cortex prior to longitudinal upper-limb BCI training. Results support a mechanistic role for cortical inhibition in significantly increasing focality and strength of SMRs leading to accelerated BCI control in healthy subjects and an individual with spinal cord injury. Improvements were observed following only two TESS sessions and were maintained for at least one week in users who could not otherwise achieve control. Our findings provide promising possibilities for advancing BCI-based motor rehabilitation.
A physical model links structure and function in the plant immune system
Effector-Triggered Immunity (ETI) is an important part of the plant immune system, allowing plants to sense and respond to harmful pathogen proteins known as “effectors.” Effectors can be sensed directly or indirectly by NLR (Nucleotide-binding Leucine-rich Repeat) proteins, many of which “guard” the plant proteins targeted by effectors. Although a few effector–target–NLR interactions have been characterized, a general understanding of how these molecular interactions give rise to a functioning immune system is lacking. Here, we present a physics-based model of ETI based on protein–protein interactions. We show that the simplest physical model consistent with the biology gives rise to a robust immune sensor and explains the empirical phenomenon of effector interference as a generic consequence of molecules competing for binding partners. Using the evolutionarily conserved ZAR1 defense gene as a model, we explain how more complex interaction networks integrate multiple pathogen signals into a single response. We then examine alternatives to a guarding architecture, including direct sensing, decoys, and blended “integrated decoy” strategies, and reveal that these sensing architectures obey functional trade-offs between their sensitivity, target protection, and proteomic cost. This allows a quantitative analysis of the trade-offs between different forms of ETI. We discuss these findings in the context of the evolutionary forces shaping the plant immune system.
Equilibrium-gated pattern formation: How molecular dissociation thermodynamics drive emergent behavior in dissipative polymeric systems
Emergent patterns in biological systems arise through dissipative processes that balance reaction and transport phenomena, producing highly functional properties from self-regulating mechanisms. Synthetic fabrication, by contrast, often relies on user-controlled, multistep methods that lack the self-organizing capabilities of natural systems. Inspired by nature, we sought chemical systems that integrate strongly coupled reaction and transport phenomena, identifying frontal ring-opening metathesis polymerization (FROMP) as a method capable of creating diverse forms and functions through reactive processing. By employing discrete molecular initiators, FROMP allows precise control of key reaction steps—inhibition, initiation, and propagation. Using an integrated computational and experimental framework, we uncover how near-equilibrium inhibition dynamics, coupled with far-from-equilibrium reaction kinetics, drive pattern formation in frontally polymerized synthetic materials. We propose the concept of equilibrium-gated pattern formation, demonstrating how initiator chemistry can be tuned to achieve programmable macroscale properties. Our study reveals a surprising insight: Emergent behavior in FROMP systems arises from the inhibition-dominated regime of resin composition, expanding prior observations that such behavior is confined to a narrow compositional space near the boundary between front quenching and uniform front propagation. We identify a broader compositional window, far from the quenching regime, where emergent behavior reliably manifests. This expanded design space significantly enhances the operational flexibility of reactive systems and their capacity for self-organization. These insights provide a roadmap for designing bioinspired materials with self-organizing capabilities, unlocking possibilities in synthetic manufacturing.
Repurposing a drug to punish carbapenem-resistant <i>Acinetobacter baumannii</i>
The OXA β-lactamases in Acinetobacter baumannii represent a primary mechanism for resistance to the carbapenems, a class of antibiotics that represent a last line for treatment. In a screen of an U.S. Food and Drug Administration (FDA)-approved drug library, we identified fendiline, a calcium channel blocker, had significantly more antimicrobial activity against OXA-23 expressing cells. Genetic and proteomic studies revealed that fendiline inhibited the essential lipoprotein trafficking pathway (Lol) in both A. baumannii (LolFD) and Escherichia coli (LolCDE). We demonstrate that OXA-23 is an outer membrane lipoprotein and its overexpression resulted in increased lethality in lolFD- depleted A. baumannii . Our results indicate that overexpression of the OXA-23 β-lactamase in A. baumannii stresses normal lipoprotein trafficking, which makes these cells more susceptible to fendiline. Overall, our data reveal a link between carbapenem resistance and the Lol pathway, which can be leveraged for new drug development.
CRISPR screens and quantitative proteomics reveal remodeling of the aryl hydrocarbon receptor–driven proteome through PARP7 activity
PARP7 is an enzyme that uses donor substrate NAD + to attach a single ADP-ribose moiety onto proteins related to immunity, transcription, and cell growth and motility. Despite the importance of PARP7 in these processes, PARP7 signaling networks remain underresearched. Here, we used genome-wide CRISPR screens and multiplex quantitative proteomics in distinct lung cancer cell lines treated with a PARP7 inhibitor to better understand PARP7 molecular functions. We find that manipulating the aryl hydrocarbon receptor (AHR) transcriptional activity mediates PARP7 inhibitor sensitivity and triggers robust changes to the AHR-controlled proteome (AHR-ome). One of the striking features of such AHR-ome remodeling was the downregulation of filamins A and B concurrent with the induction of the corresponding E3 ubiquitin ligase ASB2. We also show that suppressor of cytokine signaling 3 (SOCS3) crosstalks to AHR. Inhibition of PARP7 in SOCS3 knockout cells leads to reduced viability compared to wild-type cells treated with a PARP7 inhibitor. Our results reveal signaling interplay between PARP7, AHR, and SOCS3 and establish an invaluable resource to study the role of PARP7 in the regulation of AHR signaling and innate immunity through its ADP-ribosyl transferase activity.
Measuring premature and cumulative family member bereavement: Racial disparities and later mortality risk
Though racial disparities in shortened life expectancy have been well established, racial disparities in the burden of bereavement after such premature deaths are severely understudied. This is, in part, due to a lack of measurement tools for characterizing lifetime exposure to loss. We propose three indices that simultaneously quantify premature and cumulative lifetime loss—two typically unmeasured dimensions of loss. Using a longitudinal US sample of 27,985 participants from the Health and Retirement Study (1992 to 2020) who experienced at least one lifetime loss, hierarchical linear models accounting for participants nested within households showed that Black participants and Native American participants had higher premature and cumulative burden of family member loss over the lifetime than all other racial groups across all three indices. These effects remained for Black participants after controlling for covariates such as parental education, household size, and years in the study. Second, we found that loss burden at study enrollment prospectively related to all-cause mortality. Depending on prematurity, each additional loss related to higher odds of dying during the study period after controlling for covariates such as chronic health conditions. Together, our work leverages prospective, longitudinal methodologies to identify racial disparities in exposure to earlier and repeated death and its impact on mortality among the bereaved. The proposed measurement approach has future applications for understanding how loss exposure—both “too soon” and “too much”—predicts poor health and earlier mortality.
Development of an in situ CAR-T cell protocol through optical and PSMA-targeted PET imaging
In situ T cell transfection methods overcome the complexity and high costs associated with conventional chimeric antigen receptor (CAR)-T therapy. However, the in situ CAR-T cell approach operates within the patient’s complex immune environment and bypasses preinfusion ex vivo cellular quality controls, necessitating advanced imaging techniques to track immune cell migration and function. Positron emission tomography (PET) can detect biochemical processes in patients and, when combined with a radiotracer specific for the engineered cells, can monitor CAR-T cell trafficking. Herein, we develop an approach for in situ T cell generation, tracking, and functional assessment using anti-CD5-conjugated lipid nanoparticles for codelivering CD19 CAR mRNA (mCAR19) and a prostate-specific membrane antigen mRNA (mPSMA) tag. With interleukin-7 (IL-7) preconditioning and repeated administration, this approach achieves tumor-free survival in 75% of B cell lymphoma-bearing mice (similar efficacy to ex vivo approaches), and through PET imaging of 68 Ga-PSMA-617, the generation and tumor infiltration of in situ-engineered PSMA-tagged CD19 CAR-T cells is validated.
Neuronal ALKAL2 and its ALK receptor contribute to the development of colitis-associated colorectal cancer
Tumor-infiltrating nerves play a critical role in cancer progression and treatment resistance. Our recent work identified ALKAL2, a ligand for the Anaplastic Lymphoma Kinase (ALK) receptor, as a key mediator of inflammatory pain, with its expression significantly elevated in TRPV1+ sensory neurons during inflammation. Here, we explored the regulation of neuronal ALKAL2 in a colitis-associated colorectal cancer (CAC) model. We found that neuronal ALKAL2 is upregulated at early stages of CAC, which in turn activates ALK signaling in the colonic mucosa. Notably, treating mouse colonic organoids with exogenous ALKAL2 triggered ALK activation. In vivo, mice treated with the ALK inhibitor lorlatinib at the onset of colitis exhibited a remarkable 90% reduction in tumor burden without significantly affecting overall inflammation. Moreover, activating TRPV1+ neurons using DREADD technology exacerbated tumor growth, whereas silencing these neurons significantly reduced it. These findings reveal that TRPV1+ nociceptors drive CAC progression via the ALKAL2/ALK pathway.
Longitudinal trajectories of brain development from infancy to school age and their relationship with literacy development
Reading is one of the most complex skills that we utilize daily, and it involves the early development and interaction of various lower-level subskills, including phonological processing and oral language. These subskills recruit brain structures, which begin to develop long before the skill manifests and exhibit rapid development during infancy. However, how longitudinal trajectories of early brain development in these structures support long-term acquisition of literacy subskills and subsequent reading is unclear. Children underwent structural and diffusion MRI scanning at multiple timepoints between infancy and second grade and were tested for literacy subskills in preschool and decoding and word reading in early elementary school. We developed and implemented a reproducible pipeline to generate longitudinal trajectories of early brain development. We then examined whether these trajectories were associated with literacy (sub)skills or influenced by familial risk of reading difficulty and children’s home literacy environments, two common literacy-related covariates. Results showed that individual differences in curve features (e.g., intercepts and slopes) for longitudinal trajectories of volumetric, surface-based, and white matter organization measures were linked directly to phonological processing and indirectly to early elementary school decoding and word reading skills via phonological processing. Altogether, these findings suggest that the brain bases of phonological processing, previously identified as one of the strongest behavioral predictors of decoding and word reading skills, may already begin to develop by birth but undergo further refinement between infancy and preschool. The present study underscores the importance of considering academic skill acquisition from the very beginning of life.
SlPLT6 controls ripening initiation and quality traits through modulation of histone acetylation and methylation in tomato
Improving fruit growth and quality without compromising yield is a highly sought-after goal in crop breeding. Here, we report that an EAR motif-containing transcription factor SlPLT6 controls the onset of fruit ripening and quality traits in tomato. SlPLT6 knockout caused precocious ripening initiation and enhanced fruit qualities without penalizing yield in two tomato cultivars. SlPLT6 represses genes involved in ripening initiation and major quality traits by directly binding to their promoters. Moreover, SlPLT6 connects two repressive mechanisms by recruiting Histone Deacetylase 1 via its C-terminal EAR motif and LIKE HETEROCHROMATIN PROTEIN 1b through the first AP2 domain. Furthermore, Sly-miR159 acts upstream of SlPLT6 to release its repression. Taken together, our data provide insights into the operating mode of SlPLT6 in modulating fruit ripening and quality traits and define a unique gene for targeted crop improvement aimed at upgrading fruit quality without yield penalty.
Induction of a neurotoxin in diatoms by iron limitation via cysteine synthase
The β- N -methylamino- L -alanine (BMAA) is an emerging neurotoxin associated with human neurodegenerative diseases such as Alzheimer’s disease. Here, we report the prevalence of BMAA synthesis in protein forms by marine diatoms and reconstruct its tentative biosynthesis pathway. Remarkably, the BMAA production is strongly induced by iron limitation. Transcriptomic analyses suggest that cysteine synthase (CysK) is involved in BMAA synthesis. This is verified as CRISPR/Cas9-based CysK knockout abolished BMAA production and addition of the recombinant CysK to the mutant restored BMAA synthesis. As diatoms are the most abundant primary producers in ocean, the prevalence of BMAA in diatoms has significant public health implications. The biosynthesis pathway provides biomarkers for further investigation of BMAA production in marine diatoms and insights for understanding the pathological mechanism for human neurodegenerative diseases.
Solution mapping of MHC-I:TCR interactions using a minimalistic protein system
Recognition of epitopic peptide antigens presented on class I major histocompatibility complex (MHC-I) proteins by T cell receptors (TCRs) forms the cornerstone of immune surveillance, leading to a plethora of adaptive immune responses. Characterization of TCR:peptide/MHC-I interactions is critical for understanding immune recognition, and developing immunotherapies, but the large variation in docking orientations of TCRs on their peptide/MHC-I targets challenges structural modeling. NMR spectroscopy could potentially resolve this ambiguity, but the large size of the TCR:peptide/MHC-I complex limits data quality. Here, we demonstrate that a designed MHC-I protein, SMART A*02:01, enables facile solution mapping of MHC-I:TCR interactions at scale. Our approach can be combined with computational modeling and structure-guided engineering to aid the development of TCR-based therapeutics.
Impact of large-scale solar on property values in the United States: Diverse effects and causal mechanisms
As the renewable energy transition continues into less receptive communities, local opposition is expected to intensify, potentially slowing the process. Since the local impacts are neither well quantified nor widely recognized, we lack policies and common practices to mitigate the potential associated welfare loss in affected communities. Based on a nationwide dataset combining property transactions and large-scale solar photovoltaic (LSSPV) sites, we analyze the heterogeneous effects of LSSPV on property prices and the associated causal pathways. Difference-in-differences estimates show that LSSPV significantly increases agricultural or vacant land value by about 19.4% within a 2-mile radius, while simultaneously reducing residential property values within 3 miles by about 4.8%. The estimated average negative impact on home values is primarily driven by site proximity and diminishes with both distance and time. Effect estimates are more robust to alternative specifications when proximity pairs with visibility rather than invisibility, but no evidence suggests visibility significantly amplifies the proximity effect. Heterogeneous effect estimates indicate that high solar lease potential, being in heavily Democratic-leaning counties, and brownfield redevelopment largely mitigate the negative residential value impact. The analysis reveals no significant heterogeneity across a few factors, including varying site visibility, directional orientation of properties relative to the LSSPV site, and different tracking systems. Evidence indicates that the negative impact on residential values might mainly stem from negative perceptions, but channels through physical conditions cannot be entirely dismissed. Our assessment provides benchmark information for local externality mitigation plans, potentially reducing community opposition and expediting the renewable energy transition.
Organellar genome divergence and environmental stress induce transcriptional cytonuclear responses in wheat alloplasmic hybrids
The union of two or more different nuclear genomes with maternally inherited organellar genomes may lead to cytonuclear incompatibilities in plant allopolyploids. These incompatibilities may be reconciled by coevolutionary responses at the genomic and transcriptional levels. To date, the relationship between extent of divergence among parental organellar genomes and cytonuclear coevolutionary responses remains largely unexplored. Here, we studied transcriptional cytonuclear expression in synthetic alloplasmic allohexaploid wheat lines having the same nuclear subgenomic composition (the nuclear genome of Chinese Spring) but with varying cytoplasmic organelles (plasmon donors from B- and D- lineage Triticum/Aegilops species). A positive association between the extent of plastid organellar divergence from naturally occurring organelles in euplasmic Chinese Spring and transcriptional cytonuclear responses was observed. This response was enhanced under stress (highlight) treatment and was determined to be related to differential subgenomic methylation levels. These data comprise a transcriptional dimension of cytonuclear responses to polyploidy and point to a potentially responsible epigenomic regulatory mechanism.
The CARD14 <i>sh</i> –BCL10–MALT1 complex regulates MAVS-mediated antiviral response in keratinocytes
The Mitochondrial Antiviral Signaling Protein (MAVS) is a key adaptor in antiviral immunity, mediating type I interferon responses downstream of RIG1 and TLR3. While MAVS regulation is essential for antiviral defense, its modulation in keratinocytes is poorly understood. Here, we examine the role of the CARD14–BCL10–MALT1 (CBM) complex, a skin-specific signaling module, in controlling MAVS-dependent antiviral responses. We identify CARD14 short as a dual regulator that activates NF-κB while inhibiting IRF3 signaling. Psoriasis-associated CARD14 mutations are less efficient in restricting IRF3 activation and cytokine production upon Poly (I:C) stimulation, highlighting a potential mechanism in psoriasis pathogenesis. BCL10 is essential for MAVS-induced IRF3 activation, while MALT1 limits IRF3 signaling by promoting MAVS cleavage, K48-linked ubiquitination, and proteasomal degradation. Genetic and chemical inhibition of MALT1 enhances IRF3 activation and type I IFN expression. These findings reveal a MAVS-CBM regulatory network linking innate immunity to epithelial homeostasis.
Homology-arm length of donor DNA affects the impact of Msh2 loss on homologous recombination–mediated gene targeting
Efficient targeted integration (TI) of homologous donor DNA is crucial for precise genome editing. Although mismatch repair (MMR) is known to suppress TI as well as homologous recombination (HR) when sequence divergence is present, it remains controversial as to whether MMR affects TI of isogenic donor DNA. In this study, we investigated whether and how the MMR protein Msh2 affects TI of isogenic donor DNA. We found that HR-dependent TI is suppressed by Msh2 only when a homology arm of donor DNA is as short as 1.7 kb. In contrast, single-strand annealing–mediated TI, which is cell cycle–independent and becomes prominent when HR or non-homologous end joining is inactivated, is weakly but constantly affected by Msh2 irrespective of the size of homology arms. Our results reveal a previously unrecognized type of HR suppression by Msh2 and provide implications for precise genome editing using short-arm donor DNA vectors.