One-Step Construction of Closed Pores Enabling High Plateau Capacity Hard Carbon Anodes for Sodium-Ion Batteries: Closed-Pore Formation and Energy Storage Mechanisms.

Closed pores play a crucial role in improving the low-voltage (<0.1 V) plateau capacity of hard carbon anodes for sodium-ion batteries (SIBs). However, the lack of simple and effective closed-pore construction strategies, as well as the unclear closed-pore formation mechanism, has severely hindered the development of high plateau capacity hard carbon anodes. Herein, we present an effective closed-pore construction strategy by one-step pyrolysis of zinc gluconate (ZG) and elucidate the corresponding mechanism of closed-pore formation. The closed-pore formation mechanism during the pyrolysis of ZG mainly involves (i) the precipitation of ZnO nanoparticles and the ZnO etching on carbon under 1100 °C to generate open pores of 0.45-4 nm and (ii) the development of graphitic domains and the shrinkage of the partial open pores at 1100-1500 °C to convert the open pores to closed pores. Benefiting from the considerable closed-pore content and suitable microstructure, the optimized hard carbon achieves an ultrahigh reversible specific capacity of 481.5 mA h g-1 and an extraordinary plateau capacity of 389 mA h g-1 for use as the anode of SIBs. Additionally, some in situ and ex situ characterizations demonstrate that the high-voltage slope capacity and the low-voltage plateau capacity stem from the adsorption of Na+ at the defect sites and Na-cluster formation in closed pores, respectively.

Dehydration-Induced Cluster Consolidation in a Metal-Organic Framework for Sieving Hexane Isomers.

Metal-organic frameworks (MOFs) that exhibit dynamic phase-transition behavior under external stimuli could have great potential in adsorptive separations. Here we report on a zinc-based microporous MOF (JNU-80) and its reversible transformation between two crystalline phases: large pore (JNU-80-LP) and narrow pore (JNU-80-NP). Specifically, JNU-80-LP can undergo a dehydration-induced cluster consolidation under heat treatment, resulting in JNU-80-NP with a reduced channel that allows exclusion of di-branched hexane isomers while high adsorption of linear and mono-branched hexane isomers. We further demonstrate the fabrication of MOF-polymer composite (JNU-80-NP-block) and its application in the purification of di-branched isomers from liquid-phase hexane mixtures (98% di-branched) at room temperature, affording the di-branched hexane isomers with 99.5% purity and close to 90% recovery rate over ten cycles. This work illustrates an interesting dehydration-induced cluster consolidation in MOF structure and the ensuing channel shrinkage for sieving di-branched hexane isomers, which may have important implications for the development of MOFs with dynamic behavior and their potential applications in non-thermal driven separation technologies.

Salmonellosis outbreak archive in China: data collection and assembly.

Infectious disease outbreaks transcend the medical and public health realms, triggering widespread panic and impeding socio-economic development. Considering that self-limiting diarrhoea of sporadic cases is usually underreported, the Salmonella outbreak (SO) study offers a unique opportunity for source tracing, spatiotemporal correlation, and outbreak prediction. To summarize the pattern of SO and estimate observational epidemiological indicators, 1,134 qualitative reports screened from 1949 to 2023 were included in the systematic review dataset, which contained a 506-study meta-analysis dataset. In addition to the dataset comprising over 50 columns with a total of 46,494 entries eligible for inclusion in systematic reviews or input into prediction models, we also provide initial literature collection datasets and datasets containing socio-economic and climate information for relevant regions. This study has a broad impact on advancing knowledge regarding epidemic trends and prevention priorities in diverse salmonellosis outbreaks and guiding rational policy-making or predictive modeling to mitigate the infringement upon the right to life imposed by significant epidemics.

Machine Learning-Assisted Discovery of Propane-Selective Metal-Organic Frameworks.

Machine learning is gaining momentum in the prediction and discovery of materials for specific applications. Given the abundance of metal-organic frameworks (MOFs), computational screening of the existing MOFs for propane/propylene (C3H8/C3H6) separation could be equally important for developing new MOFs. Herein, we report a machine learning-assisted strategy for screening C3H8-selective MOFs from the CoRE MOF database. Among the four algorithms applied in machine learning, the random forest (RF) algorithm displays the highest degree of accuracy. We experimentally verified the identified top-performing MOF (JNU-90) with its benchmark selectivity and separation performance of directly producing C3H6. Considering its excellent hydrolytic stability, JNU-90 shows great promise in the energy-efficient separation of C3H8/C3H6. This work may accelerate the development of MOFs for challenging separations.

Modulation of Si-O Structure in Uniformly Ultrasmall Silicon Oxycarbide for Superior Lifespan of Lithium Metal Anodes.

Utilizing nanoseeds guiding homogeneous deposition of lithium is an effective strategy to inhibit disorderly growth of lithium, where silicon oxide has been attracting attention as a transform seed. However, the research on silicon-oxide-based seeds has concentrated more on utilizing their lithiophilicity but less on their Si-O structures, which could result in different failure mechanisms. In this study, various Si-O structures of silicon oxycarbide carbon nanofibers are prepared by adjusting the content of octa(aminopropylsilsesquioxane). According to XANES and experimental observations, the C-rich SiOC has an active Si-O-C structure but generates a larger volume variation during lithiation, while in the O-rich phase, the silica-oxygen tetrahedral structure can contribute to alleviate the volume expansion but has poor electrochemical activity. SiOC, which is dominated by SiO3C, has a suitable Si-O and silica-oxygen tetrahedral-structure distribution, which balances the electrochemical activity and volume expansion. This allows the host to demonstrate an excellent lifespan over 3740 h with a tiny voltage hysteresis (22 mV) at 2 mA cm-2, and it retains a favorable capacity of 97 mA h g-1 after 630 cycles with a high Coulombic efficiency of 99.7% in full cells. This study experiences the influence of various Si-O structures on lithium metal anodes.

Genome degradation promotes Salmonella pathoadaptation by remodeling fimbriae-mediated proinflammatory response.

Understanding changes in pathogen behavior (e.g. increased virulence, a shift in transmission channel) is critical for the public health management of emerging infectious diseases. Genome degradation via gene depletion or inactivation is recognized as a pathoadaptive feature of the pathogen evolving with the host. However, little is known about the exact role of genome degradation in affecting pathogenic behavior, and the underlying molecular detail has yet to be examined. Using large-scale global avian-restricted Salmonella genomes spanning more than a century, we projected the genetic diversity of Salmonella Pullorum (bvSP) by showing increasingly antimicrobial-resistant ST92 prevalent in Chinese flocks. The phylogenomic analysis identified three lineages in bvSP, with an enhancement of virulence in the two recently emerged lineages (L2/L3), as evidenced in chicken and embryo infection assays. Notably, the ancestor L1 lineage resembles the Salmonella serovars with higher metabolic flexibilities and more robust environmental tolerance, indicating stepwise evolutionary trajectories towards avian-restricted lineages. Pan-genome analysis pinpointed fimbrial degradation from a virulent lineage. The later engineered fim-deletion mutant, and all other five fimbrial systems, revealed behavior switching that restricted horizontal fecal-oral transmission but boosted virulence in chicks. By depleting fimbrial appendages, bvSP established persistent replication with less proinflammation in chick macrophages and adopted vertical transovarial transmission, accompanied by ever-increasing intensification in the poultry industry. Together, we uncovered a previously unseen paradigm for remodeling bacterial surface appendages that supplements virulence-enhanced evolution with increased vertical transmission.

Low Dopamine D2 Receptor Expression Drives Gene Networks Related to GABA, cAMP, Growth and Neuroinflammation in Striatal Indirect Pathway Neurons.

Background: A salient effect of addictive drugs is to hijack the dopamine reward system, an evolutionarily conserved driver of goal-directed behavior and learning. Reduced dopamine type 2 receptor availability in the striatum is an important pathophysiological mechanism for addiction that is both consequential and causal for other molecular, cellular, and neuronal network differences etiologic for this disorder. Here, we sought to identify gene expression changes attributable to innate low expression of the Drd2 gene in the striatum and specific to striatal indirect medium spiny neurons (iMSNs). Methods: Cre-conditional, translating ribosome affinity purification (TRAP) was used to purify and analyze the translatome (ribosome-bound messenger RNA) of iMSNs from mice with low/heterozygous or wild-type Drd2 expression in iMSNs. Complementary electrophysiological recordings and gene expression analysis of postmortem brain tissue from human cocaine users were performed. Results: Innate low expression of Drd2 in iMSNs led to differential expression of genes involved in GABA (gamma-aminobutyric acid) and cAMP (cyclic adenosine monophosphate) signaling, neural growth, lipid metabolism, neural excitability, and inflammation. Creb1 was identified as a likely upstream regulator, among others. In human brain, expression of FXYD2, a modulatory subunit of the Na/K pump, was negatively correlated with DRD2 messenger RNA expression. In iMSN-TRAP-Drd2HET mice, increased Cartpt and reduced S100a10 (p11) expression recapitulated previous observations in cocaine paradigms. Electrophysiology experiments supported a higher GABA tone in iMSN-Drd2HET mice. Conclusions: This study provides strong molecular evidence that, in addiction, inhibition by the indirect pathway is constitutively enhanced through neural growth and increased GABA signaling.

An integrated nationwide genomics study reveals transmission modes of typhoid fever in China.

IMPORTANCE: Typhoid fever is a life-threatening disease caused by Salmonella enterica serovar Typhi, resulting in a significant disease burden across developing countries. Historically, China was very much close to the global epicenter of typhoid, but the role of typhoid transmission within China and among epicenter remains overlooked in previous investigations. By using newly produced genomics on a national scale, we clarify the complex local and global transmission history of such a notorious disease agent in China spanning the most recent five decades, which largely undermines the global public health network.

Fabrication of dendritic PdCu alloy supported on 3D N-doped hollow graphene for efficient ethanol electrooxidation.

Fabricating highly efficient Pd-based nanocatalysts with a well-defined structure is desired for the commercialization of direct ethanol fuel cell (DEFC). Herein, a series of hierarchical three-dimensional N-doped hollow graphene spheres (NHGS) supported dendritic PdCu alloy catalysts PdxCu(d)-NHGS (x: Cu/Pd theoretical molar ratio of 4, 2, and 1) are assembled by one-pot ascorbic acid reduction-immobilization method. Aiming to maximize the Pd utilization and realize the efficient ethanol electrooxidation, this novel electrocatalyst offers potent activity sites and promotes electron and ion kinetics simultaneously. Characterization indicates that the as-obtained Pd4Cu(d) alloy nanoparticles with average sizes of approximately 55 nm are evenly dispersed on the NHGS supporting materials obtained by using the SiO2 nanospheres template strategy. Three catalysts all exhibit enhanced electrocatalytic activity, of which the Pd4Cu(d)-NHGS shows the highest mass current activity (2683 mA mgPd-1), which is 2.59 times of the commercial Pd/C toward ethanol electrooxidation in alkaline medium. Based on the results, we believed that the Pd4Cu(d)-NHGS could exhibit extensive application prospect in alkaline DEFC.

High-Performance Branched Polymer Elastomer Based on a Topological Network Structure and Dynamic Bonding.

High performance has always been the research focus of elastomers. However, there are inherent conflicts among properties of elastomers, such as strength and toughness, strength and damping performance, strength and self-healing ability, etc. Herein, first, we synthesized a unique structure of the dangling chain containing proton donors and receptors. Then, we design and fabricate a kind of high-performance elastomer with a gradient distribution of a dangling chain and a dynamic bond structure. The dangling chains of different lengths intertwine with each other and self-assemble to form a "dense accumulation" structure driven by hydrogen bonds, and the elastomer exhibits special micro/nano scale aggregated states and microphase separation. The "dense accumulation" structure plays a vital role in the increase of mechanical properties. Meanwhile, under the joint action of a dangling chain and a dynamic bond, the damping performance and self-healing performance of the elastomer are greatly enhanced. High strength (27.5 MPa), toughness (121.9 MJ·m-3), 94.8% healing efficiency and outstanding damping performance (tan δ ≥ 0.4, high damping temperature range up to 144 °C) are simultaneously achieved beyond the current state-of-the-art. This topoarchitected polymer with a gradient distribution of dangling chains successfully solves the defects of conventional branched polymers in deteriorating their mechanical properties. This material design provides a new strategy for the development of high-performance structural and functional integrated elastomers.

Utilizing Ultra-homogeneous SiOx and Defects to Achieve Interlayer Protection for Lithium Metal Anodes.

The uncontrollable growth and uneven nucleation of lithium metal can be addressed by utilizing spatial confinement structures in conjunction with lithiophilic sites. However, their complex fabrication technique and the inhomogeneous dispersion of lithiophilic sites make the application ineffective. In this work, ultra-uniformly dispersed SiOx seeds and defects are produced in situ to achieve the spatially restricted protection within the reduced graphene oxide (rGO) layer. The in situ formed SiOx and defects during annealing double constrain lithium nucleation and growth behaviors thanks to the superlithiophilic characteristic, while both provide the fast Li+ transport channel to utilize the interlayer protection of rGO in limiting lithium dendrite growth. Furthermore, XANES and XPS analyze the SiOx seeds that are dominated by various valence states, and theoretical calculations further verify the control on the nucleation of lithium atoms. Benefiting from the optimum average valence of three for the "control site", the host realizes steady circulation. In asymmetric cells, the host demonstrates excellent coulombic efficiency of 99.1% and stable lifespans over 1250 h at 1 mA cm-2 . When assembled in LiFePO4 full cells, it retains a favorable capacity of 116.2 mA h g-1 after 170 cycles.

Influence of lattice water molecules on the magnetization dynamics of binuclear dysprosium(III) compounds: insights from magnetic and ab initio calculations.

Lattice water effects on the structures and magnetic properties of single-molecule magnets (SMMs) have attracted considerable attention. Herein, we have successfully synthesized two centrosymmetric binuclear compounds [Dy2(2,3'-ppcad)2(C2H3O2)4(H2O)2] (1) and [Dy2(2,3'-ppcad)2(C2H3O2)4(H2O)2]·6H2O (2) (2,3'-Hppcad = N3-(2-pyrazinyl)-3-pyridinecarboxamidrazone) by elaborately varying the amount of the base (LiOH·H2O). Through isothermal titration calorimetry (ITC), the interactions between DyIII ions and 2,3'-Hppcad with different amounts of LiOH·H2O were monitored in real time. Magnetic studies reveal that two compounds exhibit the typical zero-field single-molecule magnet behavior with different energy barrier (Ueff) values of 103.43 K for 1 and 386.48 K for 2, wherein the SMM performance for 2 stands out among the reported nine-coordinated Dy2-SMMs systems with spherical capped square antiprism (C4v) geometries. To rationalize the observed difference in the magnetic properties of 1 and 2, ab initio calculations have been performed. The introduction of lattice water molecules leads to differences in the J values observed for 1 and 2. The stronger antiferromagnetic DyIII-DyIII couplings in 2 were presented and the fast quantum tunneling of magnetization was further suppressed, thereby achieving a higher Ueff value. This work provides an effective strategy to enhance the SMM performance, and combines with ab initio calculations to explain how lattice water molecules can affect the magnetic interactions of Dy2-SMMs.

Identification and Evaluation of Novel Antigen Candidates against Salmonella Pullorum Infection Using Reverse Vaccinology.

Pullorum disease, caused by the Salmonella enterica serovar Gallinarum biovar Pullorum, is a highly contagious disease in the poultry industry, leading to significant economic losses in many developing countries. Due to the emergence of multidrug-resistant (MDR) strains, immediate attention is required to prevent their endemics and global spreading. To mitigate the prevalence of MDR Salmonella Pullorum infections in poultry farms, it is urgent to develop effective vaccines. Reverse vaccinology (RV) is a promising approach using expressed genomic sequences to find new vaccine targets. The present study used the RV approach to identify new antigen candidates against Pullorum disease. Initial epidemiological investigation and virulent assays were conducted to select strain R51 for presentative and general importance. An additional complete genome sequence (4.7 Mb) for R51 was resolved using the Pacbio RS II platform. The proteome of Salmonella Pullorum was analyzed to predict outer membrane and extracellular proteins, and was further selected for evaluating transmembrane domains, protein prevalence, antigenicity, and solubility. Twenty-two high-scored proteins were identified among 4713 proteins, with 18 recombinant proteins successfully expressed and purified. The chick embryo model was used to assess protection efficacy, in which vaccine candidates were injected into 18-day-old chick embryos for in vivo immunogenicity and protective effects. The results showed that the PstS, SinH, LpfB, and SthB vaccine candidates were able to elicit a significant immune response. Particularly, PstS confers a significant protective effect, with a 75% survival rate compared to 31.25% for the PBS control group, confirming that identified antigens can be promising targets against Salmonella Pullorum infection. Thus, we offer RV to discover novel effective antigens in an important veterinary infectious agent with high priority.

Production of Diethyl Maleate via Oxidative Depolymerization of Organosolv Lignin from Wheat Stalk over the Cooperative Acidic Ionic Liquid Pair.

Lignin, the second largest component of biomass, is considered as an important alternative source of fossil reserves for the production of fuels and chemicals. Here, we developed a novel method to oxidatively degrade organosolv lignin into value-added four-carbon esters, particularly diethyl maleate (DEM), with the cooperative catalyst consisting of 1-(3-sulfobutyl) triethylammonium hydrogen sulfate ([BSTEA]HSO4) and 1-butyl-3-methylimidazolium ferric chloride ([BMIM]Fe2Cl7). Under optimized conditions (1.00 MPa initial O2 pressure, 160 °C, 5 h), the lignin aromatic ring was effectively cleaved by oxidation to form DEM with a yield of 15.85% and a selectivity of 44.25% in the presence of the synergistic catalyst of [BMIM]Fe2Cl7-[BSMIM]HSO4 (1/3, mol/mol). The structure and composition analysis of lignin residues and liquid products confirmed that the aromatic units in lignin were effectively and selectively oxidized. Furthermore, the catalytic oxidation of lignin model compounds was explored for obtaining a possible reaction pathway of oxidative cleavage of lignin aromatic units to DEM. This study provides a promising alternative method for the production of traditional petroleum-based chemicals.

Characterization of two-component system CitB family in Salmonella enterica serovar Gallinarum biovar Gallinarum.

Salmonella enterica serovar Gallinarum biovar Gallinarum is an avian-adapted pathogen causing fowl typhoid and leading to enormous economic loss in the global poultry industry. Two-component systems (TCSs) are crucial for bacteria survival, virulence, sensing and responding to the environment. 23 pairs of TCSs classified into five families were found in S. Gallinarum strain 287/91, of which the CitB family contains three pairs of TCSs, namely CitA/CitB, DcuS/DcuR and DpiB/DpiA, whose functions remained unaddressed. Thus, four mutants of S. Gallinarum strain U20, ΔcitAB (Δcit), ΔdcuSR (Δdcu), ΔdpiBA (Δdpi) and ΔcitABΔdcuSRΔdpiBA (Δ3), were constructed. The results suggested that the CitB family did not affect the growth or the metabolic capacities tested, while different TCSs exerted various effects on biofilm formation and antimicrobial resistance against multiple drug classes. Furthermore, the CitB family negatively impacted the tolerance of environmental stress, contributing to compromised virulence in chicken embryos and in vivo survival of S. Gallinarum. Collectively, this research provided new knowledge of how the CitB family is involved in the pathogenicity of S. Gallinarum.

Producing Lignin and Ethyl Levulinate from Wheat Stalk Using 1-(3-Sulfobutyl) Triethylammonium Hydrogen Sulfate and USY Zeolite.

The facile, green, and efficient strategy for the separation of lignin from straw and subsequent production of value-added chemicals is crucial to the current utilization of straw. Herein, up to 23.72% of lignin was isolated from wheat stalk over cheap and green 1-(3-sulfobutyl) triethylammonium hydrogen sulfate ([BSTEA]HSO4) in aqueous ethanol (Vethanol: Vwater = 4:1). The acquired lignin was verified as a p-hydroxyphenyl-guaiacyl-syringyl type, which had a narrower molecular weight distribution, better thermal stability, and higher purity compared with those of the lignin obtained using 1-methyl-3-(4-sulfobutyl)-imidazolium hydrogen sulfate and 1-(3-sulfobutyl) pyridinium hydrogen sulfate. Moreover, a carbohydrate-rich liquid containing [BSTEA]HSO4 was obtained by water removal from the waste liquid after lignin separation and further converted to ethyl levulinate (EL) by a one-pot process in the presence of inexpensive and stable USY zeolite. The yield of EL reached 30.23% at 200 °C for 60 min over the presence of 40% [BSTEA]HSO4 and 60% USY zeolite. Under optimal conditions, the yields of lignin and EL can respectively reach 83.89 and 72.28% of those catalyzed by a fresh catalyst after five cycles. In short, the above-mentioned methods present a green, economic, and efficient route for the extraction of lignin and further treatment of the liquid waste generated during the extraction process.

Simple Construction of Multistage Stable Silicon-Graphite Hybrid Granules for Lithium-Ion Batteries.

Because of its high specific capacity, the silicon-graphite composite (SGC) is regarded as a promising anode for new-generation lithium-ion batteries. However, the frequently employed two-section preparation process, including the modification of silicon seed and followed mixture with graphite, cannot ensure the uniform dispersion of silicon in the graphite matrix, resulting in a stress concentration of aggregated silicon domains and cracks in composite electrodes during cycling. Herein, inspired by powder engineering, the two independent sections are integrated to construct multistage stable silicon-graphite hybrid granules (SGHGs) through wet granulation and carbonization. This method assembles silicon nanoparticles (Si NPs) and graphite and improves compatibility between them, addressing the issue of severe stress concentration caused by uncombined residue of Si NPs. The optimal SGHG prepared with 20% pitch content exhibits a highly reversible specific capacity of 560.0 mAh g-1 at a current density of 200 mA g-1 and a considerable stability retention of 86.1% after 1000 cycles at 1 A g-1 . Moreover, as a practical application, the full cell delivers an outstanding capacity retention of 85.7% after 400 cycles at 2 C. The multistage stable structure constructed by simple wet granulation and carbonization provides theoretical guidance for the preparation of commercial SGC anodes.

Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer's disease.

HYPOTHESIS: We hypothesized that Lomecel-B, an allogeneic medicinal signaling cell (MSC) therapeutic candidate for Alzheimer's disease (AD), is safe and potentially disease-modifying via pleiotropic mechanisms of action. KEY PREDICTIONS: We prospectively tested the predictions that Lomecel-B administration to mild AD patients is safe (primary endpoint) and would provide multiple exploratory indications of potential efficacy in clinical and biomarker domains (prespecified secondary/exploratory endpoints). STRATEGY AND KEY RESULTS: Mild AD patient received a single infusion of low- or high-dose Lomecel-B, or placebo, in a double-blind, randomized, phase I trial. The primary safety endpoint was met. Fluid-based and imaging biomarkers indicated significant improvement in the Lomecel-B arms versus placebo. The low-dose Lomecel-B arm showed significant improvements versus placebo on neurocognitive and other assessments. INTERPRETATION: Our results support the safety of Lomecel-B for AD, suggest clinical potential, and provide mechanistic insights. This early-stage study provides important exploratory information for larger efficacy-powered clinical trials.

An ato-topology metal-organic framework with large C2H2 adsorption and C2H2/CO2 separation capacity.

The efficient separation of C2H2/CO2 is challenging and energy intensive due to their similar molecular shapes and kinetic diameters. Here we report an ato-topology metal-organic framework (JNU-7a) with a specific surface area of 2046 cm2 g-1 and open-metal-site density of 2.05 mmol cm-3, resulting in a large C2H2 adsorption capacity of (176 cm3 g-1) and high C2H2/CO2 adsorption selectivity (6.2).

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.