Borderline personality disorder (BPD) frequently co-occurs with eating disorders (EDs). Disordered eating may serve as a coping strategy to regulate emotions/manage rejection sensitivity, abandonment fears, shame, and self-disgust. Research examining disordered eating in BPD remains limited. This study explored ED pathology/related psychological constructs in adults diagnosed with BPD. Eighty participants completed questionnaires assessing BPD symptom severity, ED pathology, childhood trauma, cognitive distortions, shame, self-disgust, coping, personality traits, and emotion regulation. Mean-centered linear regression models tested whether psychological constructs influenced the association between BPD severity (BSL-95) and disordered eating (EDI-2, EDE-Q). Given the sample size, moderation analyses were considered exploratory. BSL-95 was associated with disordered eating (p < .001), consistently across EDI-2 but less robustly for EDE-Q. Two exploratory interactions emerged: person-related self-loathing strengthened the BSL-95-EDE-Q link, and agreeableness was associated with variation in the BSL-95-EDI-2 association. Findings underscore BPD-ED associations/highlight transdiagnostic vulnerabilities; however, interaction findings should be interpreted with caution due to the study's exploratory nature.

Borderline personality disorder (BPD) and attention-deficit/hyperactivity disorder (ADHD) are each associated with impulsivity, emotion dysregulation, and an increased prevalence of suicide attempts. It is unclear whether comorbid ADHD heightens suicide risk in individuals with BPD. This study examined suicide attempts among psychiatric outpatients diagnosed with either comorbid BPD and ADHD (n = 54) or BPD without ADHD (n = 330). Patients were assessed with several semistructured interviews. Contrary to our hypothesis, the BPD-only group reported significantly more lifetime suicide attempts, including both high-lethality and low-lethality attempts, than the BPD-ADHD group. Suicidal ideation at the time of the evaluation was also higher in the BPD-only group. The findings suggest that comorbid ADHD does not confer additional suicide risk in patients with BPD.

Research suggests that individuals with borderline personality disorder (BPD) display a maladaptive explanatory style, but it remains unclear whether this bias is specific to self-referential processing or reflects a broader negative tendency. We examined whether expectations about self-esteem-damaging and self-esteem-enhancing explanations, as well as associated emotions, are specific to self-referential processing in BPD, and how they relate to self-esteem and loneliness. Sixty individuals with BPD and 60 nonclinical controls evaluated the likelihood of positive, neutral, and negative explanations in self- and other-related scenarios, rated anticipated emotional responses, and completed measures of self-esteem and loneliness. Compared to controls, individuals with BPD endorsed more negative and fewer positive explanations in self-referential scenarios, with stronger negative and weaker positive emotions. Across groups, explanatory expectations related to lower self-esteem, but in BPD, reduced anticipation of positive emotions was linked to higher loneliness. These findings highlight potential intervention targets to enhance social functioning in BPD.

Memory updating promotes cognitive flexibility by enabling suppression of outdated information to optimize behavioral strategies in response to a changing environment. While some circuits involved have been identified, the synaptic mechanisms underlying this process remain uncertain. Here, using a recently developed Kv4.2 knock-in mouse model (Kv4.2TA), we identify a metaplasticity in the hippocampus that accompanies an improvement in cognitive flexibility. Mutation of a C-terminal phosphorylation site (T607) in the alpha subunit of the voltage-gated K+ channel protein Kv4.2 drives boosted depotentiation of spike timing-dependent long-term synaptic potentiation mediated by mGluR5 receptors, putative constituents of Kv4.2 macromolecular complexes. We found that mGluR5 receptors are required for the improved cognitive flexibility observed in Kv4.2TA mice. These findings reveal a synaptic correlate associated with memory updating in cognitive flexibility and spotlight the Kv4.2-mGluR5 complex as a therapeutic target for disorders characterized by impairments in cognitive flexibility.

Heme crystallization is central to malaria parasites' survival during the erythrocytic stage of the disease, yet how clinically relevant antimalarial drugs modulate this process at the molecular level remains unclear. Here we employ stage-resolved parasite assays and multiscale in vitro approaches to explore the interactions between lumefantrine (LF), one of the popular components of current combination therapies, and hematin crystallization. Pulse LF suppresses Plasmodium falciparum during both ring and trophozoite stages. Under biomimetic conditions, LF markedly reduces β-hematin crystal growth rates. High-resolution atomic force microscopy reveals that individual LF molecules bind directly to crystal steps, physically constraining step motion through a previously unreported step-capping mechanism. This localized inhibition propagates to the mesoscale, producing step broadening, reduced interstep spacing, and causing surface kinetic roughening. In contrast to its strong inhibition of crystal growth, LF enhances hematin nucleation by promoting the formation of mesoscopic hematin-rich clusters, as detected by a combination of scattering and microscopy techniques. Attachment of the nucleated crystallites to larger crystal surfaces initiates a nonclassical inhibition sequence by straining the crystal interface, which further impedes step growth.

Neural circuits establish a stable basal level of synaptic transmission that is maintained throughout life. When synaptic activity is perturbed, homeostatic mechanisms restore this set point, but how neurons reconcile long-term stability and rapid compensatory plasticity remains unclear. Here, we identify two competing presynaptic multimolecular complexes that control steady-state transmission and homeostatic potentiation and define the molecular switch that enables transitions between these functional states. At Drosophila neuromuscular junction, the transmembrane protein PlexinB (PlexB) and the auxiliary subunit Neto-α regulate both basal synaptic function and homeostatic plasticity. PlexB association with presynaptic KaiR1D/Neto-α receptor complexes modulates channel properties and fine-tunes neurotransmitter release, whereas PlexB signaling with Semaphorin2b (Sema2b) and Neto-α drives homeostatic potentiation. KaiR1D and Sema2b/PlexB compete for a limited pool of presynaptic Neto-α. Motor neurons switch from steady-state transmission to homeostatic potentiation by exchanging KaiR1D/Neto-α/PlexB complexes for Neto-α/PlexB/Sema2b. Critically, Neto-α must dissociate from KaiR1D-containing complexes to initiate the homeostatic response. Variants of Neto-α or KaiR1D that fail to dissociate support normal basal neurotransmission but abolish homeostatic plasticity. These findings demonstrate that dynamic reorganization of competing presynaptic protein assemblies enables neurons to preserve stable baseline transmission while mounting robust compensatory responses to perturbations. Given the widespread roles of presynaptic receptors and Semaphorin/Plexin signaling in synaptic regulation, this mechanism may represent a conserved strategy for balancing stability and plasticity in neural circuits.

Neural crest cells, a multipotent vertebrate stem cell population, undergo a tightly regulated epithelial-mesenchymal transition (EMT) to delaminate from the neural tube and initiate migration. Neural crest EMT is controlled by a transient pulse of Draxin, which acts as a molecular rheostat of canonical Wnt signaling, and is then rapidly downregulated by unknown mechanisms. To address this, here we use in vivo reporter assays and live RNA imaging to show that Draxin mRNA is rapidly degraded posttranscriptionally via its 3' untranslated region. We found that Draxin transcripts are targeted to cytoplasmic processing bodies (P-bodies), which are membrane-less sites of RNA processing and decay. Disruption of P-bodies by CRISPR/Cas9-mediated depletion of the RNA helicase DDX6 prevented posttranscriptional downregulation of Draxin and impaired neural crest EMT in vivo. These findings parallel observations in human patients carrying DDX6 mutations, who exhibit defects in P-body assembly and craniofacial abnormalities associated with neural crest dysfunction. Together, our results identify P-bodies as regulators of Draxin mRNA decay and reveal a spatially organized mechanism of RNA turnover that controls neural crest EMT during vertebrate development.

Bacteria of the human microbiota encode an abundance of natural products that likely mediate bacterial competition, local colonization patterns, and human health and disease. However, very few of these compounds have been identified and characterized to date. During our investigation of Streptococcus mitis, an important early colonizer of the oral cavity, we identified and structurally characterized a family of peptide natural products, termed miranthins herein, that contain an unusual macrocycle formed by an Asp-Cys β-carbon thioether crosslink. We determined that the most abundantly secreted miranthin is a "Trojan horse" antibiotic that enters sensitive cells via the Ami oligopeptide transporter, is hydrolyzed and activated by aminopeptidase N, and subsequently inhibits ribosomal translation to curb the growth of streptococcal competitors. The miranthins are narrow-spectrum antibiotics that could enable S. mitis to modulate community dynamics in the oral cavity, highlighting the importance of peptide natural products in interspecies competition in the microbiome.

Knowledge of how pathogens, in the context of a changing environment, shape the structure of ecological communities remains limited, and little information exists on the ability of small-scale field experiments to predict the consequences of large-scale environmental impacts. We addressed these issues using the emergence of a widespread epidemic (sea star wasting disease, SSWD) on rocky intertidal shorelines. Prior experiments demonstrated strong reductions in sessile species diversity in response to the local experimental removal of the sea star Pisaster ochraceus [R. T. Paine, Am. Nat. 100, 65-75 (1966); R. T. Paine, Oceologia 15, 93-120 (1974)] at our site. In surveys of sea star populations over 8 y spanning the onset of the SSWD epidemic, P. ochraceus populations declined by 90%, then subsequently recovered to about one third of pre-epidemic size under an endemic disease phase. Using four different types of temporal data, we documented large increases in populations of the competitively dominant mussel Mytilus californianus following P. ochraceus decline, which were of similar magnitude to those observed in prior field experiments. As in the field experiments, sessile species richness and diversity declined strongly following the onset of the SSWD epidemic as mussels were released from predator control. Our results reveal a strong effect of a pathogen in regulating ecological community structure by disrupting the role of a keystone species, a result anticipated by prior small-scale field experiments.

The origin and early radiation of winged insects (Pterygota) represent one of the most transformative events in terrestrial evolution, yet phylogenetic relationships among their basalmost lineages (Ephemeroptera, Odonata and Neoptera) continue to be a central debate within insect systematics. Here, we present the most taxonomically comprehensive phylogenomic analysis to date, leveraging genomic and transcriptomic data from 101 species, including 16 sequenced ephemeropteran genomes. Employing 1,367 universal single-copy orthologs across two supermatrices, we used concatenation- and coalescent-based frameworks under homogeneous and heterogeneous, and multispecies coalescent models. Our analyses support Palaeoptera monophyly. Although coalescent-based methods initially suggested a Chiastomyaria (Ephemeroptera + Neoptera) topology, subsequent signal dissection and topology tests confirm that the preponderance of genomic signal favors a monophyletic Palaeoptera. Furthermore, we identify incomplete lineage sorting and gene tree estimation error as the primary drivers of previous topological conflicts. Our molecular dating results point to an Early Devonian origin of crown-Pterygota, whereas crown-Palaeoptera first emerged in the Late Devonian. By reconciling molecular evidence with morphological synapomorphies, such as wing-base sclerite homologies, this study provides a coherent framework for the early evolution of winged insects, supports a single origin of wings, and identifies the neopteran wing-folding mechanism as a singular evolutionary innovation.

In mammals, a small population of spermatogonial stem cells (SSCs) is established shortly after birth. These cells self-renew and produce sperm for the male's reproductive lifespan, passing the genome on to the next generation. Establishment of a population of SSCs with high genomic integrity is essential. SSCs are derived from a much larger precursor population of male germ cells (MGCs) that differentiate during fetal life. During the last third of gestation, MGCs undergo a prolonged period of G0 cell cycle arrest during which they sustain high levels of transcription and acquire epigenetic programming for SSC fate. Although these differentiation steps can cause cellular and genomic damage, it has been unclear whether selection for germ cell quality occurs during G0 arrest since no classic markers of cell death have been detected. In this study, we used a mouse model to characterize a population of MGCs that begin to accumulate markers of cell death, such as AnnexinV (AnV) and propidium iodide (PI), at E16.5. The AnV- and PI-positive MGC population is characterized by low expression of the RNA-binding protein, Dead End 1, and exhibits dsDNA breaks and mitochondrial dysfunction. Interestingly, we do not see evidence of an active cell death cascade until the time of birth, when phosphorylation of MLKL, a hallmark of necroptotic cell death, occurs. Based on these findings, we propose that variable cellular health is an important basis for selection of SSC precursors.

Metabotropic glutamate receptor 5 (mGlu5) is essential for synaptic plasticity and memory, making it a potential therapeutic target in Alzheimer's disease (AD). While hemispheric asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show a physiological left-right asymmetry in hippocampal mGlu5 expression in wild-type mice, with higher levels in the left hemisphere, consistent with previous reports. This physiological asymmetry is lost in two distinct mouse models of AD, the J20 and 5xFAD mice, revealing a hemisphere-specific disruption of hippocampal mGlu5 regulation. Using the light-controllable negative allosteric modulator Alloswitch-1, we show that selective inhibition of left, but not right, hippocampal mGlu5 restores working and short-term memory in AD mice. This finding indicates that altered mGlu5 expression does not simply reflect receptor loss, but rather a dysregulated signaling state that remains functionally relevant and pharmacologically targetable. Left-specific modulation also normalizes pathological downstream signaling, including aberrant Pyk2 and GSK-3β activation and tau hyperphosphorylation, across both hemispheres, indicating a widespread impact of hemisphere-selective intervention. These findings establish a functional lateralization of hippocampal mGlu5 signaling and identify the left hippocampus as a critical site for mGlu5-dependent memory dysfunction in AD. They also highlight the therapeutic potential of region-specific photopharmacology for precise intervention in early AD pathology, providing a strategy for spatially targeted modulation of pathological synaptic signaling in neurodegenerative disease.

CO2 transporters enable bacterial CO2-concentrating mechanisms by catalyzing directional hydration of CO2, yet the basis of this vectorial carbonic anhydrase (CA) activity remains an open question. We used cryoelectron microscopy to determine the structure of the DAB1 complex from Thermocrinis albus to 2.29 Å, revealing a heterotrimer in which a deeply buried β-CA active site in DabA is structurally coupled to the proton-translocating subunit DabB. Two conformational states define distinct solvent channels for substrate entry and product exit. A suppressor screen identifies mutations that disrupt coupling while retaining CA activity, underlying the importance of conserved residues that link proton translocation to active-site remodeling. These results support a model in which proton-driven conformational changes regulate substrate access to the active site, enabling vectorial CO2 hydration.

Tau assembles into fibrillar aggregates that are pathological hallmarks of a group of neurodegenerative diseases collectively called tauopathies. Templated aggregation of naïve tau to seeding-competent fibrils that proceed from cell to cell is a key driver of prion-like progression of tauopathies. This study tests the hypothesis that tau, an intrinsically disordered protein, achieves in-register stacking to form seed-competent fibrils by a pinning action of tau to each other and/or the seed surface via a single dominant hotspot to avoid mismatch in tau stacking to fibrils. Structured solvation water has been proposed to be a signature of such hot spots at both the tau fibril-end surface and soluble tau monomers. Although jR2R3-P301L tau exhibits a heterogeneous hydration landscape in its intrinsically disordered state, with enhanced water structuring near the P301L mutation site, it is unclear whether a localized hotspot exists at the fibril end surface and surface water facilitates the initial contacts in templated aggregation. Using rapid 1H-15N SOFAST-HMQC NMR to track seed-induced aggregation of jR2R3-P301L in real time, complemented by molecular dynamics simulation of fibril surface hydration, we identify a residue-specific pinning hotspot that is prone to dewetting followed by sequential folding and incorporation of the remaining segment in a two-step dock-and-lock process. Site-specific spin labeling further demonstrates that blocking this pinning hotspot disrupts templated aggregation, leading to shorter fibrils. The identification of a dominant pinning site will facilitate the rational design of binders to effectively disrupt fibril extension or serve as diagnostic or therapeutic strategies.

Fragment crystallizable (Fc)-fusion proteins are formed by the fusion of functional peptides or receptor extracellular domains (ECDs) with Fc. They are normally very heterogeneous with multiple N- and O-glycosylation sites and a high level of sialylation. Characterization of O-glycosylation in Fc-fusion proteins is important for understanding their biological significance and for monitoring process consistency during drug development. However, due to the heterogeneity, close localization, and especially low ionization efficiency of O-glycans, it is challenging to achieve the overall O-glycosylation profile at the protein level. In this study, a supercharging reagent, m-nitrobenzyl alcohol (m-NBA), was applied to mobile phases for hydrophilic interaction liquid chromatography-mass spectrometry (HILIC-MS) analysis of two Fc-fusion proteins at the domain level. The addition of m-NBA mitigated MS signal suppression caused by TFA in mobile phases and enabled the characterization of the overall O-glycosylation profiles of ECDs. While de-N-glycosylation of Fc resulted in only a slight increase in MS signal intensity, the average MS signal intensity of the top three ECD-derived O-glycoforms increased by approximately 11.4- to 13.0-fold and 6.9- to 10.8-fold for these Fc-fusion proteins with and without terminal sialic acid, respectively. This observation indicates that m-NBA facilitates increased MS signal intensity for glycosylated proteins, with a pronounced effect on sialylated species. In addition, the enhanced MS signal intensity of major released N-glycans achieved through supercharging enabled their identification without the need for sample separation, derivatization, and enrichment. Overall, this HILIC-MS method combined with supercharging provides a promising approach for domain-level characterization of O-glycans and simultaneous analysis of released N-glycan without derivatization.