Metabolic regulation of homologous recombination repair by MRE11 lactylation.

Lactylation is a lactate-induced post-translational modification best known for its roles in epigenetic regulation. Herein, we demonstrate that MRE11, a crucial homologous recombination (HR) protein, is lactylated at K673 by the CBP acetyltransferase in response to DNA damage and dependent on ATM phosphorylation of the latter. MRE11 lactylation promotes its binding to DNA, facilitating DNA end resection and HR. Inhibition of CBP or LDH downregulated MRE11 lactylation, impaired HR, and enhanced chemosensitivity of tumor cells in patient-derived xenograft and organoid models. A cell-penetrating peptide that specifically blocks MRE11 lactylation inhibited HR and sensitized cancer cells to cisplatin and PARPi. These findings unveil lactylation as a key regulator of HR, providing fresh insights into the ways in which cellular metabolism is linked to DSB repair. They also imply that the Warburg effect can confer chemoresistance through enhancing HR and suggest a potential therapeutic strategy of targeting MRE11 lactylation to mitigate the effects.

Chromatin context-dependent regulation and epigenetic manipulation of prime editing.

We set out to exhaustively characterize the impact of the cis-chromatin environment on prime editing, a precise genome engineering tool. Using a highly sensitive method for mapping the genomic locations of randomly integrated reporters, we discover massive position effects, exemplified by editing efficiencies ranging from ∼0% to 94% for an identical target site and edit. Position effects on prime editing efficiency are well predicted by chromatin marks, e.g., positively by H3K79me2 and negatively by H3K9me3. Next, we developed a multiplex perturbational framework to assess the interaction of trans-acting factors with the cis-chromatin environment on editing outcomes. Applying this framework to DNA repair factors, we identify HLTF as a context-dependent repressor of prime editing. Finally, several lines of evidence suggest that active transcriptional elongation enhances prime editing. Consistent with this, we show we can robustly decrease or increase the efficiency of prime editing by preceding it with CRISPR-mediated silencing or activation, respectively.

A maternal-effect Padi6 variant causes nuclear and cytoplasmic abnormalities in oocytes, as well as failure of epigenetic reprogramming and zygotic genome activation in embryos.

Maternal inactivation of genes encoding components of the subcortical maternal complex (SCMC) and its associated member, PADI6, generally results in early embryo lethality. In humans, SCMC gene variants were found in the healthy mothers of children affected by multilocus imprinting disturbances (MLID). However, how the SCMC controls the DNA methylation required to regulate imprinting remains poorly defined. We generated a mouse line carrying a Padi6 missense variant that was identified in a family with Beckwith-Wiedemann syndrome and MLID. If homozygous in female mice, this variant resulted in interruption of embryo development at the two-cell stage. Single-cell multiomic analyses demonstrated defective maturation of Padi6 mutant oocytes and incomplete DNA demethylation, down-regulation of zygotic genome activation (ZGA) genes, up-regulation of maternal decay genes, and developmental delay in two-cell embryos developing from Padi6 mutant oocytes but little effect on genomic imprinting. Western blotting and immunofluorescence analyses showed reduced levels of UHRF1 in oocytes and abnormal localization of DNMT1 and UHRF1 in both oocytes and zygotes. Treatment with 5-azacytidine reverted DNA hypermethylation but did not rescue the developmental arrest of mutant embryos. Taken together, this study demonstrates that PADI6 controls both nuclear and cytoplasmic oocyte processes that are necessary for preimplantation epigenetic reprogramming and ZGA.

Discovering mechanisms of human genetic variation and controlling cell states at scale.

Population-scale sequencing efforts have catalogued substantial genetic variation in humans such that variant discovery dramatically outpaces interpretation. We discuss how single-cell sequencing is poised to reveal genetic mechanisms at a rate that may soon approach that of variant discovery. The functional genomics toolkit is sufficiently modular to systematically profile almost any type of variation within increasingly diverse contexts and with molecularly comprehensive and unbiased readouts. As a result, we can construct deep phenotypic atlases of variant effects that span the entire regulatory cascade. The same conceptual approach to interpreting genetic variation should be applied to engineering therapeutic cell states. In this way, variant mechanism discovery and cell state engineering will become reciprocating and iterative processes towards genomic medicine.

Calibration of variant effect predictors on genome-wide data masks heterogeneous performance across genes.

In silico variant effect predictions are available for nearly all missense variants but played a minimal role in clinical variant classification because they were deemed to provide only supporting evidence. Recently, the ClinGen Sequence Variant Interpretation (SVI) Working Group updated recommendations for variant effect prediction use. By analyzing control pathogenic and benign variants across all genes, they were able to compute evidence strength for predictor score intervals with some intervals generating moderate, strong, or even very strong evidence. However, this genome-wide approach could obscure heterogeneous predictor performance in different genes. We quantified the gene-by-gene performance of two top predictors, REVEL and BayesDel, by analyzing control variants in each predictor score interval in 3,668 disease-relevant genes. Approximately 10% of intervals had sufficient control variants for analysis, and ∼70% of these intervals exceeded the maximum number of incorrect predictions implied by the SVI recommendations. These trending discordant intervals arose owing to the divergence of the gene-specific distribution of predictions from the genome-wide distribution, suggesting that gene-specific calibration is needed in many cases. Approximately 22% of ClinVar missense variants of uncertain significance in genes we analyzed (REVEL = 100,629, BayesDel = 71,928) had predictions in trending discordant intervals. Thus, genome-wide calibrations could result in many variants receiving inappropriate evidence strength. To facilitate a review of the SVI's calibrations, we developed a web application enabling visualization of gene-specific predictions and trending concordant and discordant intervals.

SMAD4 mutations causing Myhre syndrome are under positive selection in the male germline.

While it is widely thought that de novo mutations (DNMs) occur randomly, we previously showed that some DNMs are enriched because they are positively selected in the testes of aging men. These "selfish" mutations cause disorders with a shared presentation of features, including exclusive paternal origin, significant increase of the father's age, and high apparent germline mutation rate. To date, all known selfish mutations cluster within the components of the RTK-RAS-MAPK signaling pathway, a critical modulator of testicular homeostasis. Here, we demonstrate the selfish nature of the SMAD4 DNMs causing Myhre syndrome (MYHRS). By analyzing 16 informative trios, we show that MYHRS-causing DNMs originated on the paternally derived allele in all cases. We document a statistically significant epidemiological paternal age effect of 6.3 years excess for fathers of MYHRS probands. We developed an ultra-sensitive assay to quantify spontaneous MYHRS-causing SMAD4 variants in sperm and show that pathogenic variants at codon 500 are found at elevated level in sperm of most men and exhibit a strong positive correlation with donor's age, indicative of a high apparent germline mutation rate. Finally, we performed in vitro assays to validate the peculiar functional behavior of the clonally selected DNMs and explored the basis of the pathophysiology of the different SMAD4 sperm-enriched variants. Taken together, these data provide compelling evidence that SMAD4, a gene operating outside the canonical RAS-MAPK signaling pathway, is associated with selfish spermatogonial selection and raises the possibility that other genes/pathways are under positive selection in the aging human testis.

The effects of mnemonic variability and spacing on memory over multiple timescales.

The memory benefit that arises from distributing learning over time rather than in consecutive sessions is one of the most robust effects in cognitive psychology. While prior work has mainly focused on repeated exposures to the same information, in the real world, mnemonic content is dynamic, with some pieces of information staying stable while others vary. Thus, open questions remain about the efficacy of the spacing effect in the face of variability in the mnemonic content. Here, in two experiments, we investigated the contributions of mnemonic variability and the timescale of spacing intervals, ranging from seconds to days, to long-term memory. For item memory, both mnemonic variability and spacing intervals were beneficial for memory; however, mnemonic variability was greater at shorter spacing intervals. In contrast, for associative memory, repetition rather than mnemonic variability was beneficial for memory, and spacing benefits only emerged in the absence of mnemonic variability. These results highlight a critical role for mnemonic variability and the timescale of spacing intervals in the spacing effect, bringing this classic memory paradigm into more ecologically valid contexts.

Harmonizing the cyano-group and Na to enhance selective photocatalytic O2 activation on carbon nitride for refractory pollutant degradation.

Manipulating exciton dissociation and charge-carrier transfer processes to selectively generate free radicals of more robust photocatalytic oxidation capacity for mineralizing refractory pollutants remains challenging. Herein, we propose a strategy by simultaneously introducing the cyano-group and Na into graphitic carbon nitride (CN) to obtain CN-Cy-Na, which makes the charge-carrier transfer pathways the dominant process and consequently achieves the selective generation of free radicals. Briefly, the cyano-group intensifies the local charge density of CN, offering a potential well to attract the hole of exciton, which accelerates the exciton dissociation. Meanwhile, the separated electron transfers efficiently under the robust built-in electric field induced by the cyano-group and Na, and eventually accumulates in the heptazine ring of CN for the following O2 reduction due to the reinforced electron sink effect caused by Na. As a result, CN-Cy-Na exhibits 4.42 mmol L-1 h-1 productivity with 97.6% selectivity for free radicals and achieves 82.1% total organic carbon removal efficiency in the tetracycline photodegradation within 6 h. Additionally, CN-Cy-Na also shows outstanding photodegradation efficiency of refractory pollutants, including antibiotics, pesticide plastic additives, and dyes. This work presents an innovative approach to manipulating the exciton effect and enhancing charge-carrier mobility within two-dimensional photocatalysts, opening an avenue for precise control of free radical generation.

Emergence of threefold symmetric helical photocurrents in epitaxial low twinned Bi2Se3.

We present evidence of a strong circular photon drag effect (PDE) in topological insulators (TIs) through the observation of helicity-dependent topological photocurrents with threefold rotational symmetry using THz spectroscopy in epitaxially-grown Bi2Se3 with reduced crystallographic twinning. We establish how twinned domains introduce competing nonlinear optical (NLO) responses inherent to the crystal structure that obscure geometry-sensitive optical processes through the introduction of a spurious mirror symmetry. Minimizing the twinning defect reveals strong NLO response currents whose magnitude and direction depend on the alignment of the excitation to the crystal axes and follow the threefold rotational symmetry of the crystal. Notably, photocurrents arising from helical light reverse direction for left/right circular polarizations and maintain a strong azimuthal dependence-a result uniquely attributable to the circular PDE, where the photon momentum acts as an applied in-plane field stationary in the laboratory frame. Our results demonstrate new levels of control over the magnitude and direction of photocurrents in TIs and that the study of single-domain films is crucial to reveal hidden phenomena that couple topological order and crystal symmetries.

Large nonlinear optical magnetoelectric response in a noncentrosymmetric magnetic Weyl semimetal.

Weyl semimetals resulting from either inversion (P) or time-reversal (T) symmetry breaking have been revealed to show the record-breaking large optical response due to intense Berry curvature of Weyl-node pairs. Different classes of Weyl semimetals with both P and T symmetry breaking potentially exhibit optical magnetoelectric (ME) responses, which are essentially distinct from the previously observed optical responses in conventional Weyl semimetals, leading to the versatile functions such as directional dependence for light propagation and gyrotropic effects. However, such optical ME phenomena of (semi)metallic systems have remained elusive so far. Here, we show the large nonlinear optical ME response in noncentrosymmetric magnetic Weyl semimetal PrAlGe, in which the polar structural asymmetry and ferromagnetic ordering break P and T symmetry. We observe the giant second harmonic generation (SHG) arising from the P symmetry breaking in the paramagnetic phase, being comparable to the largest SHG response reported in Weyl semimetal TaAs. In the ferromagnetically ordered phase, it is found that interference between this nonmagnetic SHG and the magnetically induced SHG emerging due to both P and T symmetry breaking results in the magnetic field switching of SHG intensity. Furthermore, such an interference effect critically depends on the light-propagating direction. The corresponding magnetically induced nonlinear susceptibility is significantly larger than the prototypical ME material, manifesting the existence of the strong nonlinear dynamical ME coupling. The present findings establish the unique optical functionality of P- and T-symmetry broken ME topological semimetals.

Unveiling synergy of strain and ligand effects in metallic aerogel for electrocatalytic polyethylene terephthalate upcycling.

Recently, there has been a notable surge in interest regarding reclaiming valuable chemicals from waste plastics. However, the energy-intensive conventional thermal catalysis does not align with the concept of sustainable development. Herein, we report a sustainable electrocatalytic approach allowing the selective synthesis of glycolic acid (GA) from waste polyethylene terephthalate (PET) over a Pd67Ag33 alloy catalyst under ambient conditions. Notably, Pd67Ag33 delivers a high mass activity of 9.7 A mgPd-1 for ethylene glycol oxidation reaction (EGOR) and GA Faradaic efficiency of 92.7 %, representing the most active catalyst for selective GA synthesis. In situ experiments and computational simulations uncover that ligand effect induced by Ag incorporation enhances the GA selectivity by facilitating carbonyl intermediates desorption, while the lattice mismatch-triggered tensile strain optimizes the adsorption of *OH species to boost reaction kinetics. This work unveils the synergistic of strain and ligand effect in alloy catalyst and provides guidance for the design of future catalysts for PET upcycling. We further investigate the versatility of Pd67Ag33 catalyst on CO2 reduction reaction (CO2RR) and assemble EGOR//CO2RR integrated electrolyzer, presenting a pioneering demonstration for reforming waste carbon resource (i.e., PET and CO2) into high-value chemicals.

How particle shape affects granular segregation in industrial and geophysical flows.

Industrial and environmental granular flows commonly exhibit a phenomenon known as "granular segregation," in which grains separate according to physical characteristics (size, shape, density), interfering with industrial applications (cement mixing, medicine, and food production) and fundamentally altering the behavior of geophysical flows (landslides, debris flows, pyroclastic flows, riverbeds). While size-induced segregation has been well studied, the role of grain shape has not. Here we conduct numerical experiments to investigate how grain shape affects granular segregation in dry and wet flows. To isolate the former, we compare dry, bidisperse mixtures of spheres alone with mixtures of spheres and cubes in a rotating drum. Results show that while segregation level generally increases with particle size ratio, the presence of cubes decreases segregation levels compared to cases with only spheres. Further, we find differences in the segregation level depending on which shape makes up each size class, reflecting differences in mobility when smaller grains are cubic or spherical. We find similar dynamics in simulations of a shear-driven coupled fluid-granular flow (e.g., a simulated riverbed), demonstrating that this phenomenon is not unique to rotating drums; however, in contrast to the dry system, we find that the segregation level increases in the presence of cubic grains, and fluid drag effects can qualitatively change segregation trends. Our findings demonstrate competing shape-induced segregation patterns in wet and dry flows that are independent from grain size controls, with implications for many industrial and geophysical processes.

Unraveling emergent network indeterminacy in complex ecosystems: A random matrix approach.

Indeterminacy of ecological networks-the unpredictability of ecosystem responses to persistent perturbations-is an emergent property of indirect effects a species has on another through interaction chains. Thus, numerous indirect pathways in large, complex ecological communities could make forecasting the long-term outcomes of environmental changes challenging. However, a comprehensive understanding of ecological structures causing indeterminacy has not yet been reached. Here, using random matrix theory (RMT), we provide mathematical criteria determining whether network indeterminacy emerges across various ecological communities. Our analytical and simulation results show that indeterminacy intricately depends on the characteristics of species interaction. Specifically, contrary to conventional wisdom, network indeterminacy is unlikely to emerge in large competitive and mutualistic communities, while it is a common feature in top-down regulated food webs. Furthermore, we found that predictable and unpredictable perturbations can coexist in the same community and that indeterminate responses to environmental changes arise more frequently in networks where predator-prey relationships predominate than competitive and mutualistic ones. These findings highlight the importance of elucidating direct species relationships and analyzing them with an RMT perspective on two fronts: It aids in 1) determining whether the network's responses to environmental changes are ultimately indeterminate and 2) identifying the types of perturbations causing less predictable outcomes in a complex ecosystem. In addition, our framework should apply to the inverse problem of network identification, i.e., determining whether observed responses to sustained perturbations can reconstruct their proximate causalities, potentially impacting other fields such as microbial and medical sciences.

The spillover effect of mandatory renewable portfolio standards.

Renewable Portfolio Standards (RPSs) are one of the most prevalent and impactful clean energy policies implemented by states in the United States. This paper investigates the regional spillover effect of RPS policies using a directed dyad panel dataset of renewable electricity generation in US states from 1991 to 2021. Regional spillover effect is measured in two ways: by considering the influence of an RPS enacted in neighboring states and in states in the same regional transmission organization or independent system operator region. We use dyadic fixed effects estimation and conclude that the neighboring state's RPS stringency score is a strong determinant of a state's total renewable electricity generation. For states without an RPS, the positive influence of an RPS in a neighboring state is larger when the non-RPS state has more abundant renewable energy resources than the neighboring RPS state. Our findings suggest that past RPS policy evaluation research using a confined within-state focus may have underestimated the holistic impact of an RPS, as the impacts of an RPS policy can extend beyond the enacting state's borders. Overall, this study contributes to an improved understanding of the holistic impact of state RPS policies.

Metamagnetic multiband Hall effect in Ising antiferromagnet ErGa2.

Frustrated rare-earth-based intermetallics provide a promising platform for emergent magnetotransport properties through exchange coupling between conduction electrons and localized rare-earth magnetic moments. Metamagnetism, the abrupt change of magnetization under an external magnetic field, is a signature of first-order magnetic phase transitions; recently, metamagnetic transitions in frustrated rare earth intermetallics have attracted interest for their accompanying nontrivial spin structures (e.g., skyrmions) and associated nonlinear and topological Hall effects (THE). Here, we present metamagnetism-induced Hall anomalies in single-crystalline ErGa2, which recalls features arising from the THE but wherein the strong Ising-type anisotropy of Er moments prohibits noncoplanar spin structures. We show that the observed anomalies are neither due to anomalous Hall effect nor THE; instead, can be accounted for via 4f-5d interactions which produce a band-dependent mobility modulation. This leads to a pronounced multiband Hall response across the magnetization process-a metamagnetic multiband Hall effect that resembles a topological-Hall-like response but without nontrivial origins. The present findings may be of general relevance in itinerant metamagnetic systems regardless of coplanar/noncoplanar nature of spins and are important for the accurate identification of Hall signals due to emergent magnetic fields.

Top-down modulation in canonical cortical circuits with short-term plasticity.

Cortical dynamics and computations are strongly influenced by diverse GABAergic interneurons, including those expressing parvalbumin (PV), somatostatin (SST), and vasoactive intestinal peptide (VIP). Together with excitatory (E) neurons, they form a canonical microcircuit and exhibit counterintuitive nonlinear phenomena. One instance of such phenomena is response reversal, whereby SST neurons show opposite responses to top-down modulation via VIP depending on the presence of bottom-up sensory input, indicating that the network may function in different regimes under different stimulation conditions. Combining analytical and computational approaches, we demonstrate that model networks with multiple interneuron subtypes and experimentally identified short-term plasticity mechanisms can implement response reversal. Surprisingly, despite not directly affecting SST and VIP activity, PV-to-E short-term depression has a decisive impact on SST response reversal. We show how response reversal relates to inhibition stabilization and the paradoxical effect in the presence of several short-term plasticity mechanisms demonstrating that response reversal coincides with a change in the indispensability of SST for network stabilization. In summary, our work suggests a role of short-term plasticity mechanisms in generating nonlinear phenomena in networks with multiple interneuron subtypes and makes several experimentally testable predictions.

Variation in the relationship between odd isotopes of tin in mass-independent fractionation induced by the magnetic isotope effect.

Experimental results are presented showing the variation in the relationship between odd isotopes of tin (Sn) in mass-independent fractionation caused by the magnetic isotope effect (MIE), which has previously only been observed for mercury. These results are consistent with the trend predicted from the difference between the magnitudes of nuclear magnetic moments of odd isotopes with a nuclear spin. However, the correlation between odd isotopes in fractionation induced by the MIE for the reaction system used in this study (solvent extraction using a crown ether) was different from that reported for the photochemical reaction of methyltin. This difference between the two reaction systems is consistent with a theoretical prediction that the correlation between odd isotopes in fractionation induced by the MIE is controlled by the relationship between the spin conversion time and radical lifetime. The characteristic changes in the correlation between odd isotopes in fractionation induced by the MIE observed for Sn in this study provide a guideline for quantitatively determining fractionation patterns caused by the MIE for elements that have multiple isotopes with a nuclear spin. These results improve our understanding of the potential impact of the MIE on mass-independent fractionation observed in natural samples, such as meteorites, and analytical artifacts of high-precision isotope analysis for heavy elements.

Photomolecular effect: Visible light interaction with air-water interface.

Although water is almost transparent to visible light, we demonstrate that the air-water interface interacts strongly with visible light via what we hypothesize as the photomolecular effect. In this effect, transverse-magnetic polarized photons cleave off water clusters from the air-water interface. We use 14 different experiments to demonstrate the existence of this effect and its dependence on the wavelength, incident angle, and polarization of visible light. We further demonstrate that visible light heats up thin fogs, suggesting that this process can impact weather, climate, and the earth's water cycle and that it provides a mechanism to resolve the long-standing puzzle of larger measured clouds absorption to solar radiation than theory could predict based on bulk water optical constants. Our study suggests that the photomolecular effect should happen widely in nature, from clouds to fogs, ocean to soil surfaces, and plant transpiration and can also lead to applications in energy and clean water.

Giant elastocaloric effect at low temperatures in TmVO4 and implications for cryogenic cooling.

Adiabatic decompression of paraquadrupolar materials has significant potential as a cryogenic cooling technology. We focus on TmVO[Formula: see text], an archetypal material that undergoes a continuous phase transition to a ferroquadrupole-ordered state at 2.15 K. Above the phase transition, each Tm ion contributes an entropy of [Formula: see text] due to the degeneracy of the crystal electric field groundstate. Owing to the large magnetoelastic coupling, which is a prerequisite for a material to undergo a phase transition via the cooperative Jahn-Teller effect, this level splitting, and hence the entropy, can be readily tuned by externally induced strain. Using a dynamic technique in which the strain is rapidly oscillated, we measure the adiabatic elastocaloric response of single-crystal TmVO[Formula: see text], and thus experimentally obtain the entropy landscape as a function of strain and temperature. The measurement confirms the suitability of this class of materials for cryogenic cooling applications and provides insight into the dynamic quadrupole strain susceptibility.

Bridging the gap between models based on ordinary, delayed, and fractional differentials equations through integral kernels.

Evolution equations with convolution-type integral operators have a history of study, yet a gap exists in the literature regarding the link between certain convolution kernels and new models, including delayed and fractional differential equations. We demonstrate, starting from the logistic model structure, that classical, delayed, and fractional models are special cases of a framework using a gamma Mittag-Leffler memory kernel. We discuss and classify different types of this general kernel, analyze the asymptotic behavior of the general model, and provide numerical simulations. A detailed classification of the memory kernels is presented through parameter analysis. The fractional models we constructed possess distinctive features as they maintain dimensional balance and explicitly relate fractional orders to past data points. Additionally, we illustrate how our models can reproduce the dynamics of COVID-19 infections in Australia, Brazil, and Peru. Our research expands mathematical modeling by presenting a unified framework that facilitates the incorporation of historical data through the utilization of integro-differential equations, fractional or delayed differential equations, as well as classical systems of ordinary differential equations.