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Dismantling EPA’s research office jeopardizes environmental safety, public health, and US competitiveness

Disruption of constitutive CXCR4 oligomers impairs oncogenic properties in lymphoid neoplasms

The chemokine receptor CXCR4 is overexpressed in many cancers and contributes to pathogenesis, disease progression, and resistance to therapies. CXCR4 is known to form oligomers, but the potential functional relevance in malignancies remains elusive. Using a nanobody-based BRET method, we demonstrate that oligomerization of endogenous CXCR4 on lymphoid cancer cell lines correlates with enhanced expression levels. Specific disruption of CXCR4 oligomers reduced basal cell migration and prosurvival signaling via changes in the phosphoproteome, indicating the existence of constitutive CXCR4 oligomer-mediated signaling. Oligomer disruption also inhibited growth of primary CLL 3D spheroids and sensitized primary malignant cells to clinically used Bcl-2 inhibitor venetoclax. Given its limited efficacy in some patients and the ability to develop resistance, sensitizing malignant B cells to venetoclax is of clinical relevance. Taken together, we established a noncanonical and critical role for CXCR4 oligomers in lymphoid neoplasms and demonstrated that their selective targeting has clinical potential.

Reproductive state controls transcription in the murine liver, with implications for breast cancer liver metastasis

Liver biology is functionally linked to lactation, as liver size and metabolic output increase during lactation to support synthesis of breast milk. Upon weaning, the rodent liver returns to baseline homeostasis via hepatocyte cell death, in a process considered liver involution. To explore liver biology changes across a lactation-wean cycle, we employed transcriptomic profiling. We identified elevated hepatocyte proliferation and anabolic metabolism gene signatures during lactation, consistent with the liver being a major producer of substrates needed for milk production. Rapid loss of these capacities upon weaning correlated with catabolic metabolism, lysosomal-mediated cell death, and an enrichment of immune-suppressive cells. Furthermore, we identified that the transcriptional profiles associated with liver involution share similarities with the gene expression patterns of liver premetastatic niches. This work identifies features of reproductive control of liver biology that set a foundation for better understanding the potential role of the liver in maternal health.

A plant Lysin Motif Receptor-Like Kinase plays an ancestral function in mycorrhiza

Arbuscular mycorrhiza (AM) with soilborne Glomeromycota fungi was pivotal in the conquest of land by plants almost half a billion years ago. In flowering plants, it is hypothesized that AM is initiated by the perception of AM fungi-derived chito- and lipochito-oligosaccharides (COs/LCOs) in the host via Lysin Motif Receptor-Like Kinases (LysM-RLKs). However, it remains uncertain whether plant perception of these molecules is a prerequisite for AM establishment and for its origin. Here, we made use of the reduced LysM-RLK complement present in the liverwort Marchantia paleacea to assess the conservation of the role played by this class of receptors during AM and in CO/LCO perception. Our reverse genetic approach demonstrates the critical function of a single LysM-RLK, MpaLYKa, in AM formation, thereby supporting an ancestral function for this receptor in symbiosis. Binding studies, cytosolic calcium variation recordings and genome-wide transcriptomics indicate that another LysM-RLK of M. paleacea , MpaLYR, is also required for triggering a response to COs and tested LCOs, despite being dispensable for AM formation. Collectively, our results demonstrate that the perception of symbionts by LysM-RLK is an ancestral feature in land plants, and suggest the existence of yet-uncharacterized AM fungi signals.

Order induces toughness in anisotropic colloidal crystal composites

Spatial ordering of matter elicits exotic properties sometimes absent from a material’s constituents. A few highly mineralized natural materials achieve high toughness through delocalized damage, whereas synthetic particulate composites must trade toughness for mineral content. We test whether ordering the mineral phase in particulate composites through the formation of macroscopic colloidal crystals can trigger the same damage resistance found in natural materials. Our macroscopic silica rod-based anisotropic colloidal crystal composites are processed fully at room temperature and pressure, reach volume fractions of mineral higher than 80%, and aided by a ductile interface, unveil toughness up to two orders of magnitude higher than bulk silica through the collective movement of rods and damage delocalization over millimeter. These composites demonstrate key design rules to break free from conventionally accepted structural materials’ properties trade-off.

Keratinocyte–TRPV1 sensory neuron interactions in a genetically controllable mouse model of chronic neuropathic itch

Our understanding of neural circuits that respond to skin dysfunction, triggering itch, and pathophysiological scratching remains incomplete. Here, we describe a profound chronic itch phenotype in transgenic mice expressing the tetracycline transactivator (tTA) gene within the Phox2a lineage. Phox2a; tTA mice exhibit intense, localized scratching and regional skin lesions, controllable by the tTA inhibitor, doxycycline. As gabapentin and the kappa opioid receptor agonist, nalfurafine, but not morphine, significantly reduce scratching, this phenotype has a pharmacological profile of neuropathic pruritus. Importantly, the Phox2a; tTA expression occurs in a spatially restricted population of skin keratinocytes that overlaps precisely with the skin area that is scratched. Localized G i -DREADD-mediated inactivation of these Phox2a-keratinocytes completely reverses the skin lesions, while inducible tTA activation of keratinocytes initiates the condition. Notably, ablation of TRPV1-expressing primary afferent neurons also reduces scratching and skin lesions, but this occurs slowly, over a course of two months. In contrast denervation induced loss of all cutaneous input rapidly blocks scratching. These findings identify the cellular, molecular, and topographic basis of a robust and chronic sensory neuron–dependent and gabapentin-responsive neuropathic itch that is initiated by genetic factors within keratinocytes.

Structural basis of the catalytic and allosteric mechanism of bacterial acetyltransferase PatZ

GCN5-related N -acetyltransferases (GNATs) are essential for regulating bacterial metabolism by acetylating specific target proteins. Despite their importance in bacterial physiology, the mechanisms behind their enzymatic and regulatory functions remain poorly understood. In this study, we investigated the structures of Escherichia coli protein acetyltransferase Z (PatZ), a Type I GNAT, and examined its ligand interactions, catalytic mechanism, and allosteric regulation. PatZ functions as a homotetramer, with each subunit comprising a catalytic and a regulatory domain. Our results demonstrate that the regulatory domain is vital for acetyltransferase activity, as it triggers cooperative conformational changes in the catalytic domain and directly aids in the formation of substrate-binding pockets. Additionally, a protein structure-based evolutionary analysis of bacterial GNAT types revealed a distinct regulatory domain pattern across phyla, highlighting its crucial role in responding to cellular energy levels.

Transglutaminase 2–mediated glutamine deamidation enhances p21 stability during senescence

The limited doubling capacity of human cells, known as replicative senescence or cellular senescence, is a major factor in cellular aging. This process is triggered by telomere erosion, which activates a p53-mediated DNA damage response (DDR) that halts cell proliferation. p53, a transcriptional regulator, responds to DNA damage by increasing the expression of the cyclin-dependent kinase inhibitor p21. p21 then arrests cells at specific stages of the cell cycle. Additionally, p53 upregulates serpinB2 (also known as plasminogen activator inhibitor-2, PAI-2), which stabilizes p21 in senescent cells. This study reveals that serpinB2 upregulation activates transglutaminase 2 (TGM2), which selectively deamidates multiple glutamine residues on p21, stabilizing the protein and halting cell proliferation in senescent cells. Moreover, inhibiting TGM2-mediated deamidation accelerates p21 degradation, delaying the onset of senescence. Notably, pharmacological inhibition of TGM2 improves aging phenotypes in an accelerated aging model of chronic kidney disease (CKD). These findings provide crucial insights into the role of TGM2-mediated enzymatic deamidation in senescence and its potential relevance to age-associated conditions.

Spatiotemporal regulation of target mRNA cleavage by 21-nt phasiRNAs in maize anthers

21-nt phasiRNAs are abundantly expressed in anthers and play crucial roles in anther development and male reproduction in grasses. In maize, the target genes that 21-nt phasiRNAs regulate remain largely unknown. Here, we show that 21-nt phasiRNAs direct the cleavage of hundreds of target mRNAs in maize. Interestingly, while 21-nt phasiRNAs in anthers (somatic anther wall cells) do not have obvious preference for a particular nucleotide at the 5′ end and target genes implicated in stress response and cellular homeostasis, 21-nt phasiRNAs in male germ cells preferentially initiate with 5′ C and target genes related to meiotic processes in a ZmAGO5c-dependent manner. Our results indicate that mRNA cleavage is a conserved mechanism used by 21-nt phasiRNAs for gene regulation in grasses. However, the sequences of 21-nt phasiRNAs and their targets show little conservation in maize and rice, suggesting that 21PHAS loci and 21-nt phasiRNA targets have undergone fast divergence in grasses.

The great phage escape: Activating and escaping lactococcal antiphage systems

In recent years, the number of newly discovered systems that bacteria use to combat bacteriophages is increasing at an impressive rate. To obtain mechanistic insights into several antiphage systems identified in previous studies, we isolated 66 phage escape mutants which had become insensitive to 13 distinct, plasmid-encoded lactococcal phage resistance systems (i.e. Rhea, Kamadhenu, Rugutis, Audmula, PARIS, type II CBASS, Septu, AbiA, AbiB, AbiD/F, AbiG, AbiJ, AbiP). Genome analysis of these phage escape mutants identified a total of 15 mutated genes. Six of the encoded proteins appear to activate specific antiphage systems. Furthermore, AbiA escape mutants were found to be insensitive to AbiJ, while distinct antiphage systems (AbiG and AbiP) were observed to be activated by a major phage tail protein, indicating mechanistic commonalities. PARIS homologues encoded by members of different bacterial genera appear to share similar sensing mechanisms, whereas our data indicate mechanistic differences between Septu homologues from different genera. Based on our escape mutant sequence analysis, previously predicted domains, and experimental data using the purified endolysin of phage c2, we propose that Audmula modifies the cell wall of the host bacterium, delaying cell lysis and release of progeny phages, protecting the host cell by a heretofore unknown mode of action. The obtained advances in our understanding of lactococcal antiphage mechanisms provide fundamental insights into phage–host interactions, which undoubtedly benefits the dairy industry but may also be useful for biotechnological or biomedical applications.

Parental mixed-gender preferences revealed by IVF twin births

In vitro fertilization (IVF) affects human fertility by 1) increasing the probability of multiple births through the transfer of multiple embryos, 2) raising the proportion of dizygotic twins, which leads to a higher occurrence of one-boy-one-girl twins, and 3) enabling gender selection through preimplantation genetic screening (PGS) when parents have specific gender preferences. While the above-mentioned increase in multiple births is well documented, the impact on the twins’ gender composition remains under-explored, partly because 2) and 3) are intertwined. This study uses millions of administrative observations from Taiwan to disentangle the effects of IVF on twin birth rates, gender composition, and parental preferences. Families are grouped by maternal age and family wealth across different periods, enabling a comparative analysis of socioeconomic and temporal factors. By examining the gender composition of first-born twins within these age-wealth-time groups, we can identify and test whether parents have gender preferences for one-boy-one-girl twins. Our empirical evidence reveals a significant increase in IVF adoption, particularly among older and wealthier mothers. The proportion of one-boy-one-girl twins among first-birth twins has risen from 20.42 to 41.86% over the past 30 y, and this proportion increases with wealth ranking, significantly exceeding expected ratios in the absence of gender preference. Parental gender preference contributed to approximately 10.95% of one-boy-one-girl twins among the wealthiest group, revealing a significant impact of parental preference on twin gender composition. These trends raise ethical and social concerns regarding reproductive technologies.

Oscillatory redox behavior in oxides: Cyclic surface reconstruction and reactivity modulation via the Mars–van Krevelen mechanism

The breaking of translational symmetry at oxide surfaces gives rise to coordinatively unsaturated cations/anions and surface restructuring—key factors that govern surface reactivity. Using direct in situ environmental transmission electron microscopy (TEM) observations along with atomistic modeling, we report oscillatory redox behavior in CuO under H 2 , where cyclic surface reconstruction and reactivity modulation occur via the Mars–van Krevelen (MvK) mechanism. We observe self-switching between oxygen-rich and oxygen-deficient surface reconstructions, alternately activating and deactivating the surface for H 2 O formation. During periods of chemical inactivity, the oxygen-deficient surface undergoes slow reoxidation via lattice oxygen diffusing from subsurface and bulk reservoirs, restoring the active oxygen-rich surface termination. The inherent disparity in chemical activity among undercoordinated surface ions, along with sluggish subsurface-to-surface oxygen replenishment, drives this oscillatory redox cycle, modulating H 2 -induced loss of lattice oxygen at the surface and its delayed replenishment from the subsurface. This creates spatiotemporally separated redox steps at the oxide surface. The phenomena and atomistic insights presented here have significant implications for manipulating the surface reactivity of oxides by tuning the separation of these redox steps.

Metallicity and anomalous Hall effect in epitaxially strained, atomically thin RuO ₂ films

The anomalous Hall effect (AHE), a hallmark of time-reversal symmetry breaking, has been reported in rutile RuO 2 , a debated metallic altermagnetic candidate. Previously, AHE in RuO 2 was observed only in strain-relaxed thick films under extremely high magnetic fields (~50 T). Yet, in ultrathin strained films with distinctive anisotropic electronic structures, there are no reports, likely due to disorder and defects suppressing metallicity thus hindering its detection. Here, we demonstrate that ultrathin, fully strained 2 nm TiO 2 / t nm RuO 2 /TiO 2 (110) heterostructures, grown by hybrid molecular beam epitaxy, retain metallicity and exhibit a sizeable AHE at a significantly lower magnetic field (< 9 T). Density functional theory calculations reveal that epitaxial strain stabilizes a noncompensated magnetic ground state and reconfigures magnetic ordering in RuO 2 (110) thin films. These findings establish ultrathin RuO 2 as a platform for strain-engineered magnetism and underscore the transformative potential of epitaxial design in advancing spintronic technologies.

Ligand-specific regulation of a binary enhancer code dictating cellular senescence

Cellular senescence, a major contributor to aging and age-related pathologies, is characterized by irreversible proliferative arrest and a disease-linked, proinflammatory profile known as the Senescence Associated Secretory Phenotype (SASP). A critical unanswered question is whether these properties are regulated by specific enhancer subsets, potentially licensing strategies that selectively block deleterious SASP components. Here, we identify two functionally distinct and independently regulated enhancer programs underlying senescence that are controlled by different TGF-β family ligands. Whereas Activin A stimulates recruitment of nuclear factor IA/C (NFIA/C) and SMAD2/3 transcription factors to an enhancer network that induces proliferation arrest, TGF-β2 promotes SMAD2/3-mediated suppression of a p65-dependent enhancer cohort driving the SASP. We have also uncovered reciprocal SMAD2/3-super-enhancer-regulated feedback loops that govern expression of the TGF-β2 ( TGFB2) and Activin A ( INHBA ) transcription units, both of which are significantly up-regulated in replicative senescence. The characteristic enhancer usage and transcriptional landscape of high-passage senescent cells are sensitive to rapamycin treatment, discontinuation of which results in robust but selective senescent enhancer activation and exacerbation of the SASP. Collectively, this study uncovers separable enhancer programs and their key constituent transcription factors that contribute to the canonical features of cellular senescence, potentially informing the development of SASP-targeted therapies.

Bias-aware training and evaluation of link prediction algorithms in network biology

For biomedical applications, new link prediction algorithms are continuously being developed. These algorithms are typically evaluated computationally, using test sets generated by sampling the edges uniformly at random. However, as we demonstrate, this evaluation approach introduces a bias toward “rich nodes,” i.e., those with higher degrees in the network. More concerningly, this bias persists even when different network snapshots are used for evaluation, as recommended in the machine learning community. This creates a cycle in research where newly developed algorithms generate more knowledge on well-studied biological entities while understudied entities are commonly overlooked. To overcome this issue, we propose a weighted validation setting specifically focusing on low-degree nodes and present AWARE strategies to facilitate bias-aware training and evaluation of link prediction algorithms. These strategies can help researchers gain better insights from computational evaluations and promote the development of new algorithms focusing on novel findings and understudied proteins.

N6-methyladenosine modification of HCMV IE1 transcript promotes the repressive state of viral genome to achieve latent infection

Human cytomegalovirus (HCMV) is a prevalent pathogen that chronically infects the majority of human population. Among the many features that allow such widespread HCMV infection, one is its ability to maintain a transcriptionally dormant immune-evasive state called latency by suppressing its own major immediate early promoter (MIEP) via epigenetic alterations. In this study, we show a mechanism of MIEP regulation in which the major immediate early (MIE) gene product, immediate early 1 (IE1) transcript, downregulates its own promoter activity in an m 6 A modification-dependent manner. We found that the loss of the m 6 A writer, METTL3, in host cells impedes latency establishment in these cells. Through transcriptome-wide m 6 A profiling of latently infected monocytes, we identified that the major immediate early gene product IE1 transcript is m 6 A-modified during latent infection. Using IE1-specific m 6 A-abolished mutants, we found that m 6 A modification of the IE1 transcript was necessary for the efficient repression of MIEP, and these mutant viruses exhibited a significant defect in establishing latency and progressed toward lytic-like infection in the human monocytic cell line (THP-1) and primary CD14+ monocytes. Our findings demonstrate that HCMV exploits the host m 6 A machinery to suppress its own lytic program to establish latency and uncover an unexpected role of immediate early gene messenger RNA (mRNA) in regulating its own expression.

Feedback regulation between histone lactylation and ALKBH3-mediated glycolysis regulates age-related macular degeneration pathology

Age-related macular degeneration (AMD) is a leading cause of blindness among the elderly. It is characterized by degeneration of the retinal pigment epithelium (RPE), which can develop into choroidal neovascularization (CNV) to cause severe and rapid vision loss. Preventing this progression might help save vision, but the exact mechanisms remain unclear. In this study, using clinical AMD samples and the gene knockout mice, we reported that the m 1 A eraser ALKBH3 reshaped retinal metabolism to promote this progression. In RPE, the dm 1 ACRISPR system demonstrated that ALKBH3 demethylated the rate-limiting glycolytic enzyme HK2 to activate glycolysis, resulting in excess lactate production. This lactate promoted histone lactylation at H3K18, which in turn bound to ALKBH3 to amplify its transcription, establishing a positive feedback loop. The ALKBH3 inhibitor HUHS015 disrupted this loop, effectively mitigating RPE degeneration. Furthermore, ALKBH3 directly targeted the proangiogenic factor VEGFA to modulate the metabolic cross-talk between RPE and choroidal capillaries, thus promoting CNV. HUHS015 inhibited CNV synergistically with the anti-VEGF drug Aflibercept. Overall, our study provides critical insights into the molecular mechanisms and metabolic events that facilitates the progression from RPE degeneration to CNV in AMD, laying the groundwork for new treatments of age-related retinal disorders.

A synthetic jasmonate receptor agonist uncouples the growth–defense trade-off in rice

Herbivore attack elicits jasmonate (JA) signaling which in turn elicits both anti-herbivore plant defenses and growth inhibitions. The resulting growth–defense trade-offs constrain the utility of JA-based plant defense inducers to enhance endogenous pest resistance. Here, we designed and screened selective JA receptor agonists by synthesizing 6-substituted 1-oxoindanoyl isoleucine (In-Ile) conjugates and their free-acid forms, structural mimics of the bioactive hormone (+)-7-iso-jasmonoyl-L-Ile. These compounds differentially activate JA responses through selective binding of specific COI-JAZ coreceptor complexes. Notably, In-Ile treatments enhanced rice resistance to brown planthopper attack, a destructive rice pest, under both laboratory and field conditions, without compromising rice’s growth or yield. Mechanistically, this agonist activates the OsMYB55-mediated lignin biosynthesis defense receptor module [OsCOI1a/2-OsJAZs (3,4,6,7,12)] without activating the growth-suppression receptor module (OsCOI1b-OsJAZs). These findings demonstrate that synthetic JA agonists can provide nuanced manipulations of endogenous plant defenses without yield penalties—a promising biorational strategy for pest control in rice.

Abundant piRNA production mediated by the <i>Drosophila</i> GTSF1 homolog Tpp ensures Aubergine localization and germ plasm assembly

Germ cells transmit genetic information to offspring and maintain the genome of the species. In many animals including Drosophila , germ cell formation relies on maternal determinants in the germ plasm. Several proteins present in the germ plasm of oocytes also localize to the perinuclear nuage in nurse cells, where they contribute to the production of PIWI-interacting RNAs (piRNAs). These piRNAs guide the silencing of transposons, thereby protecting the germline genome from invading mobile elements. Aubergine (Aub) is a germ plasm/nuage protein and a piRNA-directed endonuclease that inactivates transposons. Aub is also essential for germ plasm assembly. The Aub-bound piRNAs in the germ plasm are inherited by the progeny germline and serve as templates for piRNA biogenesis in the next generation. Thus, piRNA production in the nurse cell nuage is thought to be coordinated with germ plasm assembly in the oocyte. However, the underlying mechanism remains unclear. Here, we report that a maternal factor, named tiny pole plasm ( tpp ), mediates this coordination. Tpp is a GTSF1 family PIWI cofactor. In tpp − ovaries, the production of piRNAs, particularly Aub-bound piRNAs, is defective, resulting in reduced Aub localization to the germ plasm and impaired germ cell formation. Notably, the levels of piRNA production required for proper Aub localization are much higher than those required for transposon silencing. We propose that producing abundant piRNAs beyond what is required for transposon silencing in the ovary promotes germ plasm assembly, thereby enabling the progeny germline to properly silence transposons for species survival.

Observation-based estimate of Earth’s effective radiative forcing

Human emissions continue to influence Earth’s climate. Effective radiative forcing quantifies the effect of such anthropogenic emissions together with natural factors on Earth’s energy balance. Evaluating the exact rate of effective radiative forcing is challenging, because it can not be directly observed. Therefore, estimating the effective forcing usually relies on climate models. Here, we present an estimate of effective radiative forcing that makes optimal use of observations. We use machine learning to learn the relationship between surface temperature and radiation caused by internal variability in a multimodel ensemble. Combining this with observations of surface temperature and the Earth’s net radiative imbalance, we predict an effective forcing trend of 0.71 ± 0.21 Wm − 2 per decade for 2001–2024. This is an independent assessment of the observed effective radiative forcing since 1985, that can be updated simultaneously with available observations and aligns with our physical understanding of radiative feedbacks. We make advances to close the Earth’s energy budget on annual timescales, by separating the influence of forcing versus the radiative response to surface temperature variations. Effective radiative forcing has substantially increased since 2021 and has not been countered by a strongly negative radiative response until 2024, consistent with exceptional warmth in 2023 and 2024.