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An antibody–drug conjugate active against antibiotic-resistant <i> <i>Neisseria</i> gonorrhoeae </i>

Neisseria gonorrhoeae is the causative agent of gonorrhea, a sexually transmitted infection which is rising in incidence, with increasing drug-resistant strains posing a significant public health threat. To address the urgent need for novel therapies, we developed an antibody–drug conjugate (ADC) that targets this important human pathogen. We utilized Tridecaptin A 1, a potent antimicrobial peptide (AMP) against Gram-negative bacteria that exhibits significant toxicity against human cells, limiting its development for clinical use. By conjugating the Tridecaptin A 1 analogue, Oct-TriA 1 to a monoclonal antibody (mAb) that specifically targets gonococcal MtrE, the outer membrane component of a drug efflux pump that is upregulated in resistant strains, we aim to selectively deliver the AMP to the gonococcus. However, Oct-TriA 1 was not bactericidal when directly conjugated to mAb. To circumvent this, we exploited an immune evasion mechanism employed by the gonococcus by introducing a linker between Oct-TriA 1 and the mAb which is specifically cleaved by the IgA protease (IgAP) secreted by the gonococcus; the IgAP inactivates human IgA. This ADC has no detectable toxicity for relevant human cells, kills the gonococcus in an MtrE- and IgAP-dependent manner, and is active against a strain which is resistant to first line agents. This modular ADC platform could be extended to other bacterial pathogens which employ proteases to evade immune killing, offering a strategy in the fight against antimicrobial resistance.

Trimeric autotransporter adhesins driving chain-like adhesion diversify surface colonization strategies in Shiga toxin-producing Escherichia coli

Abstract Bacteria frequently colonize host and environmental surfaces under fluid flow. Chain-like adherence pattern (CLAP) is an EibG-mediated surface colonization phenotype of certain Shiga toxin-producing Escherichia coli (STEC) that lack the locus of enterocyte effacement (LEE). EibG, an immunoglobulin-binding trimeric autotransporter adhesin, drives CLAP, but the temporal dynamics and genetic diversity underlying chain formation remain unclear. Here, we use live-cell time-lapse imaging to show that chains arise from single cells that elongate and divide without separation. Under flow, chains resist detachment and undergo shear-dependent fragmentation at cell-cell junctions, releasing viable clonal units that disperse downstream. Comparative genomics reveals diversity among EibG-related adhesins and identifies distinct lineages, including chain-like adhesins (Cla) that mediate CLAP while lacking IgG binding. Screening of 1,354 genomes from England shows that claB is present in 95.6% of strains from major LEE-negative STEC serotypes, highlighting its epidemiological prevalence. Targeted mutagenesis demonstrates that chain formation and IgG binding are mediated by distinct structural domains, revealing the modular functional architecture of these adhesins. Furthermore, we show that EibG, ClaA, and ClaB confer robust resistance to complement-mediated killing. Collectively, these findings establish CLAP as a dynamic, surface-associated strategy of LEE-negative STEC and reveal diversification among adhesins that drive this behavior.

Balanced polymorphism in a floral transcription factor underlies the ancient rhythm of daily sex alternation in avocado

In avocado and certain wild relatives in Lauraceae, a highly synchronized daily rhythm of floral sex timing promotes cross-pollination between two hermaphroditic flowering types. A-type plants present female-phase flowers in the morning and male-phase flowers in the afternoon, while B-types show the complementary pattern—a form of heterodichogamy. We mapped this dimorphism to a pair of dominant and recessive haplotypes at SDMYB , which belongs to a subgroup of R2R3 MYB transcription factors established as key regulators of floral maturation with links to circadian hormone signaling. Rhythmic diel SDMYB expression is associated with biphasic floral anthesis, and the dominant allele, which contains nonsynonymous changes in conserved functional domains, exhibits a cis -regulated phase delay, corresponding to the delayed second anthesis of A-type flowers. The SDMYB haplotypes form an ancient trans-species polymorphism, maintained by negative frequency-dependent balancing selection over 42 My, and they segregate in at least 26 nonavocado species, including in a genus where this mating system has not been reported. Although exceptionally old, the polymorphism is absent in other magnoliids with highly similar mating systems, suggesting daily forms of heterodichogamy can convergently evolve when rhythmic floral movements are coupled with the temporal separation of sexes.

The recent enhancement of the surface melt over the Antarctic Peninsula dictated by thermodynamics

Structures of the sodium-coupled phosphate importer SLC34A2 reveal a distinct architecture and gating mechanism

Dysregulation of inorganic phosphate (Pi) homeostasis contributes to metabolic disease, cancer, pathological calcification, and kidney disease. Systemic phosphate balance is regulated by SLC34 transporters that mediate renal Pi retention (SLC34A1/A3) and intestinal dietary Pi absorption (SLC34A2). SLC34s couple Pi uptake to the symport of sodium (Na + ) down its electrochemical gradient. Mutations or altered expression of SLC34 proteins are linked to disorders such as chronic kidney disease, where hyperphosphatemia is a major complication, and the lung disease pulmonary alveolar microlithiasis, caused by inactivating SLC34A2 mutations. SLC34A2 is also overexpressed in most ovarian and uterine tumors, making it an attractive target for antibody–drug conjugates. We present cryoelectron microscopy structures of SLC34A2 when the transporter is empty, bound to Na + ions only, fully loaded with Na + ions and Pi, and bound to an inhibitor phosphonoformic acid, revealing its distinct architecture, substrate and ion binding sites, the role of Na + , and multiple transporter states. Pi binds at a highly symmetric, membrane-embedded pocket positioned approximately mid-membrane and is coordinated by its signature four residue QSSS repeat motifs. Na + shapes the Pi-binding pocket and drives the transition from the outward-open to occluded state. Integrated with functional analyses, these structures reveal that SLC34 transporters operate through an atypical alternating access cycle defined by coordinated elevator movements of an auxiliary gate domain. This work lays a foundational framework for understanding Pi regulation and opens avenues for therapeutic strategies targeting disorders linked to phosphate imbalance.

A second yearly booster dose of the VLA15 Lyme borreliosis vaccine candidate in healthy individuals

Parenthood decisions in uncertain times: Experimental evidence from four countries

Fertility rates are declining across much of the globe, yet the forces driving this decline have become increasingly complex, and classic theories have become less adequate to explain recent trends. While economic and gender-related explanations have long dominated fertility research, emerging global uncertainties, such as climate change, democratic backsliding, economic crises, and regional conflicts, may also shape how individuals evaluate childbearing. In addition to the more classical factors, this cross-national study examines how macrolevel uncertainties influence perceptions of fertility intentions in Italy, Argentina, the United States, and Germany. These countries offer distinct fertility trajectories and face unique combinations of sociopolitical and environmental challenges. Using a conjoint experiment, we examine how individuals evaluate, across hypothetical scenarios, their intention of having a child under varying household, policy, and macrolevel conditions. Across all four countries, material security remains central: household income is the strongest predictor of fertility intentions, with homeownership and childcare playing smaller roles. At the same time, perceptions of macrolevel stability, including expectations about climate conditions, economic prospects, democratic functioning, and peace, exert substantial and meaningful effects, comparable to homeownership and childcare provision but more pronounced than those associated with gender-role arrangements. Cross-country differences show that macroeconomic stability and climate change are most consequential in Argentina, while in the United States respondents are less responsive to geopolitical conflict. These findings show that individuals evaluate childbearing not only through their immediate circumstances, but also through expectations about broader societal futures, highlighting the importance of incorporating macrolevel uncertainty when explaining contemporary fertility decline.

Publisher Correction: CFTR mediates Cl- transport in osteocytes to sustain cell viability and skeletal homeostasis

Treating language contact as normal: Coalescent-theoretic modeling of the prehistory of the Bantu language family

The Bantu language family of sub-Saharan Africa is among the largest in the world by the number of languages, by geographical extent, and by the number of speakers. The expansion of the Bantu languages is an important example of large-scale language-family expansions in the history of humankind. To learn the early prehistory of the Bantu language family, one needs to disentangle the signal of the original splits and diversification from that of the subsequent language contact, known to be strong in the Bantu languages. We introduce a coalescent-theoretic model to computationally study the prehistory of the Bantu family. Our model treats language contact as a norm rather than a rare exception, in contrast to earlier computational work. Applying Approximate Bayesian Computation, we show the rates of both language change and language contact to have been so high within the Bantu family that the signal of the original diversification has been largely erased in the currently available Bantu lexical data.

Interfacial chemistry governs nanoparticle self-sorting during biomimetic crystallization

Abstract Biominerals comprise composite crystals in which organic constituents are spatially organized within mineral matrices with exquisite precision, giving rise to hierarchically ordered architectures. Despite extensive efforts, achieving precise control over organic–inorganic interactions to construct biomimetic composite materials with programmable composition and spatial organization remains a major challenge. Here we show that diblock copolymer nanoparticles with distinct compositions and dimensions—resembling pseudo-proteins—undergo spontaneous self-sorting during occlusion within growing calcite crystals, yielding artificial biominerals in which two nanoparticle populations are selectively localized in distinct crystalline domains. Using in situ monitoring techniques and atomic force microscopy, we demonstrate that this self-sorting process arises from nanoparticle surface chemistry, which leads to differing polymer–mineral interfacial interactions. Moreover, the resulting composite crystals exhibit spatiotemporal release of the occluded species, highlighting the potential for advanced delivery systems. More broadly, self-sorting occlusion establishes a conceptual framework for understanding the spatial organization of organic components in biominerals and provides a versatile strategy for the rational design of next-generation biomimetic materials.

Adaptive molecular convergence is pervasive across deep time and largely decoupled from phenotypic convergence

Reuse of homologous genes during the evolution of similar traits or ecological transitions is often taken as evidence that evolution is repeatable at the molecular level. To study gene reuse, biologists frequently select specific convergent phenotypes and search for signatures of natural selection in genomes associated with those phenotypes. However, the causes and frequency of genome-scale molecular convergence remain unresolved, especially over deep timescales. We use phylotranscriptomics and analyses of sequence evolution to show that adaptive molecular convergence—defined as excess convergence of nonsynonymous substitutions between homologs, consistent with positive selection—is widespread across Medusozoa. Molecular convergence declines slightly over time but persists among lineages separated by over 600 My, consistently exceeding null expectations based on random overlap. Moreover, lineages sharing repeatedly evolved phenotypes (eyes, medusa loss, and upright colonies) do not exhibit elevated molecular convergence relative to other comparisons. Instead, convergence occurs idiosyncratically among species pairs and is broadly concentrated in genes associated with environment-facing functions, including metabolism, immunity, and xenobiotic processing. Our results suggest that selection often drives similar protein substitutions in disparate lineages, but that the selective causes of molecular convergence reflect multifaceted, lineage-specific interactions between organisms and their environments.

Promoter identity shapes splicing outcomes and fidelity

Pair living emerged early in placental mammals

It is widely assumed that the first placental mammals were solitary. Here, we tested this assumption and which ecological and life history factors are related to mammalian social organization. We compiled a comprehensive database by reviewing over 14,000 primary peer-reviewed publications on the social organization of the 5,390 extant placental mammal species. We found empirical data for 726 species across 1,473 populations: 353 populations were primarily solitary, 250 populations pair living, and 870 populations group living. Notably, 367 species (51%) and 583 populations (40%) exhibited intraspecific variation in social organization. Using a Bayesian phylogenetic framework that incorporates intraspecific variation, we show that the ancestral placental mammal was mainly but not exclusively solitary, displaying intraspecific variation. Pair living was estimated to account for approximately 26% of ancestral social organization. Phylogeny explained most of the variation between species, while life history and ecology were less important. Our analysis found that the ecology and life history of extant solitary and pair-living mammals is very similar and different from those of group-living mammals. Our results revise prevailing theories of mammalian social evolution, revealing that pair living emerged early, shifting the focus of studying mammalian social evolution from the origins of pair living to the origins of group living.

Single-cell profiling decodes patagium development in gliding mammal

Science for America’s next 250 years

All-fiber random Kerr optical frequency combs

Proteolytic activation of c-MYC facilitated by DOT1L

c-MYC is a key regulator of growth and metabolism. Functional and molecular cooperation between the H3K79 methyltransferase DOT1L and c-MYC has been reported in several human cancer types, but the nature of their interaction remains undefined. We demonstrate that DOT1L and MYC [Myc and Mondo-like (MML-1) in Caenorhabditis elegans ] coregulate genes in the nematode model and mammalian cancer cells. Moreover, both c-MYC and MML-1 exhibit cleavage products facilitated by DOT1L function. Surprisingly, we found a similarity between a conserved sequence in DOT1 proteins and the DDI-family protease catalytic motif. We characterize a c-MYC sequence preceding the DNA-binding domain as a site of nuclear proteolytic cleavage, demonstrate its importance for transcription activation by c-MYC, and propose that c-MYC is activated by a protease, as previously reported for Nuclear factor erythroid 2-related factor (NRF) and SREBP transcription factors. Our results suggest that DOT1L may activate c-MYC and other transcription factors in the nucleus by acting as a protease.

Enhancing the longevity of lithium-manganese-rich layered oxides by promoting oxygen redox reversibility

Psychological inoculation against climate doom

Individuals encounter “climate doom,” extreme portrayals of climate change, on social media. While climate doom may be intended to motivate action, it may also be perceived as manipulative or elicit hopelessness. Yet, no research has examined whether psychological inoculation helps to improve recognition of climate doom or influences engagement with it on social media. In this preregistered study ( n = 521), we tested whether inoculation improves discernment of climate doom and influences engagement with it by collecting behavioral data using a social media simulator. We find that inoculation substantially improves discernment of climate doom and that this is due to increased perceived manipulation of doom messaging specifically ( d = 0.68). There was no interaction between the inoculation condition and political leaning and while higher perceived manipulation of doom content predicted lower behavioral intentions, inoculation did not moderate this relationship. Inoculation increased engagement, particularly disliking and flagging of doom content, and decreased sharing. Overall, our results should lead climate communicators to reconsider doom messaging as a mobilization strategy and demonstrate that inoculation is an effective tool for increasing recognition of, and critical engagement with, climate doom across the political spectrum.

A Lactate–H4K12la–HDAC1 epigenetic axis governs microglial state transitions during experimental autoimmune encephalomyelitis in female mice