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In this work, we present and prove results underlying a method which uses functionals derived from the interaction integral to approximate the stress intensity factors along a three-dimensional crack front. We first prove that the functionals possess a pair of important properties. The functionals are well-defined and continuous for square-integrable tensor fields, such as the gradient of a finite element solution. Furthermore, the stress intensity factors are representatives of such functionals in a space of functions over the crack front. Our second result is an error estimate for the numerical stress intensity factors computed via our method. The latter property of the functionals provides a recipe for numerical stress intensity factors; we apply the functionals to the gradient of a finite element approximation for a specific set of crack front variations, and we calculate the stress intensity factors by inverting the mass matrix for those variations.

Architected materials can achieve enhanced properties compared to their plain counterparts. Specific architecting serves as a powerful design lever to achieve targeted behavior without changing the base material. Thus, the connection between architected structure and resultant properties remains an open field of great interest to many fields, from aerospace to civil to automotive applications. Here, we focus on properties related to mechanical compression, and design hierarchical honeycomb structures to meet specific values of stiffness and compressive stress. To do so, we employ a combination of techniques in a singular workflow, starting with molecular dynamics simulation of the forward design problem, augmenting with data-driven artificial intelligence models to address the inverse design problem, and verifying the behavior of de novo structures with experimentation of additively manufactured samples. We thereby demonstrate an approach for architected design that is generalizable to multiple material properties and agnostic to the identity of the base material.

To conduct a systematic review of the comparative efficacy of various psychotropic medications for the treatment of disruptive behavior (DBs) in youths. To this aim, we systematically reviewed randomized clinical trials (RCTs) of various psychotropic medications targeting symptoms of DBs and applied network meta-analysis to investigate their relative efficacy. Fifty-five RCTs meeting the inclusion criteria were selected. To predict and interpret relative treatment efficacy, we compared the efficacy of various psychotropic medications prescribed for DB symptoms based on their mechanism of action. Network meta-analysis revealed that for reducing DBs, second-generation antipsychotics, stimulants, and non-stimulant ADHD medications were more efficacious than placebo, and second-generation antipsychotics were the most efficacious. The dopaminergic modulation of top-down inhibitory process by these medications is discussed in this review. This study offers information on the relative efficacy of various psychotropic medications for the treatment of DB, and insight into a potential neurobiological underpinning for those symptoms. It also illustrates the potential utility of these neurobiological mechanisms as a target for future treatment studies.

CASE DESCRIPTION An 8-year-old spayed female Yorkshire Terrier–Poodle dog was evaluated for persistent pollakiuria and stranguria following routine cystotomy for calcium oxalate cystoliths. CLINICAL FINDINGS The dog presented for a cystotomy with intermittent hematuria. Postoperative radiographs revealed no remaining cystoliths. Urine, cystolith, and bladder mucosal aerobic cultures were negative. Pollakiuria, stranguria, and hematuria developed immediately after surgery and persisted despite antibiotics. Ultrasound revealed suspected fibrous adhesions within the urinary bladder lumen connecting the dorsal and ventral bladder wall creating a septum. This was confirmed cystoscopically 4 weeks after surgery. TREATMENT AND OUTCOME Cystoscopic-guided laser ablation was performed to incise abnormal tissue connecting the ventral and dorsal bladder wall using a holmium:yttrium-aluminum-garnet laser. Three weeks later, ultrasound revealed adhesion resolution though mild pollakiuria and stranguria persisted. Oxybutynin was prescribed and clinical signs resolved. At 27 months after ablation, hematuria occurred with recurrent cystoliths. These cystoliths were removed by percutaneous cystolithotomy, documenting a cystoscopically normal bladder wall. The patient had normal urination for 55.5 months after ablation, with normal bladder wall thickness on ultrasound repeated at 27 and 36 months after ablation. CLINICAL RELEVANCE To the authors’ knowledge, an adhesion creating a septum between the dorsal and ventral bladder wall has not been previously reported as a complication after cystotomy in any species and should be considered as a cause of persistent lower urinary signs after surgery. Ultrasound identified the lesion in this dog. Because bladder abnormalities can develop quickly after surgery, ultrasound might be considered if urine testing is not supportive of infection. Cystoscopic-guided laser ablation was a successful minimally invasive treatment in this case.

In the largest and most expansive lifespan magnetoencephalography (MEG) study to date (n = 434, 6 to 84 y), we provide critical data on the normative trajectory of resting-state spontaneous activity and its temporal dynamics. We perform cutting-edge analyses to examine age and sex effects on whole-brain, spatially-resolved relative and absolute power maps, and find significant age effects in all spectral bands in both types of maps. Specifically, lower frequencies showed a negative correlation with age, while higher frequencies positively correlated with age. These correlations were further probed with hierarchical regressions, which revealed significant nonlinear trajectories in key brain regions. Sex effects were found in absolute but not relative power maps, highlighting key differences between outcome indices that are generally used interchangeably. Our rigorous and innovative approach provides multispectral maps indicating the unique trajectory of spontaneous neural activity across the lifespan, and illuminates key methodological considerations with the widely used relative/absolute power maps of spontaneous cortical dynamics.

Alcohol and cannabis use disorder (AUD/CUD) are two of the most common addictive disorders. While studies are beginning to understand the neural changes related to acute and chronic use, few studies have examined the independent effects of AUD and CUD on neural oscillatory activity. We examined 45 adults who reported current use of both cannabis and alcohol. Participants underwent the SCID-V to determine whether they met criteria for AUD and/or CUD. Participants also completed a visual-spatial processing task while undergoing magnetoencephalography (MEG). ANCOVA with a 2 × 2 design was then used to identify the main effects of AUD and CUD on source-level oscillatory activity. Of the 45 adults, 17 met criteria for AUD, and 26 met criteria for CUD. All participants, including comparison groups, reported use of both cannabis and alcohol. Statistical analyses showed a main effect of AUD, such that participants with AUD displayed a blunted occipital alpha (8–16 Hz) response. Post-hoc testing showed this decreased alpha response was related to increased AUD symptoms, above and beyond amount of use. No effects of AUD or CUD were identified in visual theta or gamma activity. In conclusion, AUD was associated with reduced alpha responses and scaled with increasing severity, independent of CUD. These findings indicate that alpha oscillatory activity may play an integral part in networks affected by alcohol addiction.

Background: Cannabis is one of the most commonly used substances in the United States. Prior literature using task-based functional magnetic resonance imaging (fMRI) has identified that individuals with Cannabis use disorder (CUD) show impairments in emotion processing circuitry. However, whether the functional networks involving these regions are also altered in CUD remains poorly understood. Aims: Investigate changes in resting-state functional connectivity (rsFC) in regions related to emotional processing in CUD. Methods: Sixty-two participants completed resting-state fMRI, including 21 with CUD, 20 with histories of illicit substance use but no current CUD diagnosis, and 21 with no history of illicit substance use. Whole-brain seed-based connectivity analyses were performed and one-way analyses of covariance (ANCOVAs) were conducted to detect group differences in the bilateral amygdalae, hippocampi, and the anterior and posterior cingulate cortices. Results: The CUD group exhibited significant reductions in rsFC between the amygdala and the cuneus, paracentral lobule, and supplementary motor area, and between the cingulate cortices and the occipital and temporal lobes. There were no significant group differences in hippocampal functional connectivity. In addition, CUD symptom counts based on the Structured Clinical Interview for DSM-5 (SCID) and the Cannabis Use Disorders Identification Test (CUDIT) significantly correlated with multiple connectivity metrics. Conclusion: These data expand on emerging literature indicating that CUD is associated with dysfunction in the neural circuits underlying emotion processing. Dysfunction in emotion processing circuits may play a role in the behavioral impairments seen in emotion processing tasks in individuals with CUD, and the severity of CUD symptoms appears to be directly related to the degree of dysfunction in these circuits.

Many cells detect and follow gradients of chemical signals to perform their functions. Yeast cells use gradients of extracellular pheromones to locate mating partners, providing a tractable model to understand how cells decode the spatial information in gradients. To mate, yeast cells must orient polarity toward the mating partner. Polarity sites are mobile, exploring the cell cortex until they reach the proper position, where they stop moving and “commit” to the partner. A simple model to explain commitment posits that a high concentration of pheromone is only detected upon alignment of partner cells’ polarity sites, and causes polarity site movement to stop. Here we explore how yeast cells respond to partners that make different amounts of pheromone. Commitment was surprisingly robust to varying pheromone levels, ruling out the simple model. We also tested whether adaptive pathways were responsible for the robustness of commitment, but our results show that cells lacking those pathways were still able to accommodate changes in pheromone. To explain this robustness, we suggest that the steep pheromone gradients near each mating partner’s polarity site trap the polarity site in place. This mechanism has evolutionary implications because it enables sexual selection for cells making more pheromone.

Proteins evolve through the modular rearrangement of elements known as domains. Extant, multidomain proteins are hypothesized to be the result of domain accretion, but there has been limited experimental validation of this idea. Here, we introduce a technique for genetic minimization by iterative size-exclusion and recombination (MISER) for comprehensively making all possible deletions of a protein. Using MISER, we generate a deletion landscape for the CRISPR protein Cas9. We find that the catalytically-dead Streptococcus pyogenes Cas9 can tolerate large single deletions in the REC2, REC3, HNH, and RuvC domains, while still functioning in vitro and in vivo, and that these deletions can be stacked together to engineer minimal, DNA-binding effector proteins. In total, our results demonstrate that extant proteins retain significant modularity from the accretion process and, as genetic size is a major limitation for viral delivery systems, establish a general technique to improve genome editing and gene therapy-based therapeutics., Proteins evolve through the modular rearrangement of domains. Here the authors introduce MISER, a minimization by iterative size-exclusion and recombination method to make all possible deletions of a protein, uncovering functions for Cas9 domains involved in DNA binding.

People with HIV (PWH) use cannabis at a higher rate than the general population, but the influence on neural activity is not well characterized. Cannabis use among PWH may have a beneficial effect, as neuroinflammation is known to be a critical problem in PWH and cannabis use has been associated with a reduction in proinflammatory markers. Thus, it is important to understand the net impact of cannabis use on brain and cognitive function in PWH. In this study, we collected magnetoencephalographic (MEG) brain imaging data on 81 participants split across four demographically matched groups (i.e., PWH using cannabis, controls using cannabis, non‐using PWH, and non‐using controls). Participants completed a visuospatial processing task during MEG. Time–frequency resolved voxel time series were extracted to identify the dynamics of oscillatory and pre‐stimulus baseline neural activity. Our results indicated strong theta (4–8 Hz), alpha (10–16 Hz), and gamma (62–72 Hz) visual oscillations in parietal–occipital brain regions across all participants. PWH exhibited significant behavioral deficits in visuospatial processing, as well as reduced theta oscillations and elevated pre‐stimulus gamma activity in visual cortices, all of which replicate prior work. Strikingly, chronic cannabis use was associated with a significant reduction in pre‐stimulus gamma activity in the visual cortices, such that PWH no longer statistically differed from controls. These results provide initial evidence that cannabis use may normalize some neural aberrations in PWH. This study fills an important gap in understanding the impact of cannabis use on brain and cognitive function in PWH., This work used a visuospatial processing paradigm in combination with magnetoencephalographic (MEG) imaging. Voxel‐level timeseries analyses were applied to study the impact of cannabis use on behavior and neural activity in people with HIV (PWH).

Somatosensory cortical activity is altered in individuals with cerebral palsy (CP). However, previous studies have focused on the lower extremities in children with CP and have given less attention to structural changes that may contribute to these alterations. We used a multimodal neuroimaging approach to investigate the relationship between somatosensory cortical activity and cortical thickness in 17 adults with CP (age = 32.8 ± 9.3 years) and 18 healthy adult controls (age = 30.7 ± 9.8 years). Participants performed a median nerve paired-pulse stimulation paradigm while undergoing magnetoencephalography (MEG) to investigate somatosensory cortical activity and sensory gating. Participants also underwent magnetic resonance imaging to evaluate cortical thickness within the area of the somatosensory cortex that generated the MEG response. We found that the somatosensory responses were attenuated in the adults with CP (P = 0.004). The adults with CP also hypergated the second stimulation (P = 0.030) and had decreased cortical thickness in the somatosensory cortex (P = 0.015). Finally, the strength of the somatosensory response was significantly correlated with the cortical thickness (P = 0.023). These findings demonstrate that the aberrant somatosensory cortical activity in adults with CP extends to the upper extremities and appears to be related to cortical thickness.

Yeast decode pheromone gradients to locate mating partners, providing a model for chemotropism. How yeast polarize toward a single partner in crowded environments is unclear. Initially, cells often polarize in unproductive directions, but then they relocate the polarity site until two partners' polarity sites align, whereupon the cells "commit" to each other by stabilizing polarity to promote fusion. Here we address the role of the early mobile polarity sites. We found that commitment by either partner failed if just one partner was defective in generating, orienting, or stabilizing its mobile polarity sites. Mobile polarity sites were enriched for pheromone receptors and G proteins, and we suggest that such sites engage in an exploratory search of the local pheromone landscape, stabilizing only when they detect elevated pheromone levels. Mobile polarity sites were also enriched for pheromone secretion factors, and simulations suggest that only focal secretion at polarity sites would produce high pheromone concentrations at the partner's polarity site, triggering commitment.

Haploid cells of the budding yeast Saccharomyces cerevisiae communicate using secreted pheromones and mate to form diploid zygotes. Mating is monogamous, resulting in the fusion of precisely one cell of each mating type. Monogamous mating in crowded conditions, where cells have access to more than one potential partner, raises the question of how multiple-mating outcomes are prevented. Here we identify mutants capable of mating with multiple partners, revealing the mechanisms that ensure monogamous mating. Before fusion, cells develop polarity foci oriented toward potential partners. Competition between these polarity foci within each cell leads to disassembly of all but one focus, thus favoring a single fusion event. Fusion promotes the formation of heterodimeric complexes between subunits that are uniquely expressed in each mating type. One complex shuts off haploid-specific gene expression, and the other shuts off the ability to respond to pheromone. Zygotes able to form either complex remain monogamous, but zygotes lacking both can re-mate.

HIV‐infection has been associated with widespread alterations in brain structure and function, although few studies have examined whether such aberrations are co‐localized and the degree to which clinical and cognitive metrics are related. We examine this question in the somatosensory system using high‐resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity. Forty‐four participants with HIV (PWH) and 55 demographically‐matched uninfected controls completed a paired‐pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. MEG data were transformed into the time‐frequency domain; significant sensor level responses were imaged using a beamformer. Virtual sensor time series were derived from the peak responses. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. The T1‐weighted sMRI data were processed using morphological methods to derive cortical thickness values across the brain. From these, the cortical thickness of the tissue coinciding with the peak response was estimated. Our findings indicated both PWH and control exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls. Follow‐up analyses indicated that the reduction in cortical thickness was significantly correlated with CD4 nadir and mediated the relationship between HIV and spontaneous cortical activity within the left postcentral gyrus. These data indicate that PWH have abnormally strong spontaneous cortical activity in the left postcentral gyrus and such elevated activity is driven by locally reduced cortical gray matter thickness., Forty‐four participants with HIV (PWH) and 55 demographically‐matched uninfected controls completed a paired‐pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. Our findings indicated both PWH and controls exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls.

Adolescence is a critical period for the development and refinement of several higher-level cognitive functions, including visual selective attention. Clinically, it has been noted that adolescents with cerebral palsy (CP) may have deficits in selectively attending to objects within their visual field. This study aimed to evaluate the neural oscillatory activity in the ventral attention network while adolescents with CP performed a visual selective attention task. Adolescents with CP (N = 14; Age = 15.7 ± 4 years; MACS I–III; GMFCS I–IV) and neurotypical (NT) adolescents (N = 21; Age = 14.3 ± 2 years) performed the Eriksen flanker task while undergoing magnetoencephalographic (MEG) brain imaging. The participants reported the direction of a target arrow that was surrounded by congruent or incongruent flanking arrows. Compared with NT adolescents, adolescents with CP had slower responses and made more errors regarding the direction of the target arrow. The MEG results revealed that adolescents with CP had stronger alpha oscillations in the left insula when the flanking arrows were incongruent. Furthermore, participants that had more errors also tended to have stronger alpha oscillatory activity in this brain region. Altogether these results indicate that the aberrant activity seen in the left insula is associated with diminished visual selective attention function in adolescents with CP.

The self-assembly of amphiphilic molecules in water has led to a wide variety of nanostructures with diverse applications. Many nanostructures are stabilized by strong interactions between monomer units, such as hydrogen bonding and π–π stacking. However, the morphological implications of these strong, anisotropic interactions can be difficult to predict. In this study, we investigate the relationships between molecular flexibility, head group repulsion, and supramolecular geometry in an aramid amphiphile nanostructure that is known to exhibit extensive hydrogen bonding and π–π stacking – features that give rise to their unusual stability. We find by electron microscopy that increasing backbone flexibility disrupts molecular packing into high aspect-ratio nanoribbons, and at the highest degree of flexibility long-range ordering is lost. Even when backbone rigidity favors tight packing, increasing head group charge through pH-modulation leads to intermolecular electrostatic repulsion that also disrupts close packing. Spectroscopic measurements suggest that these changes are accompanied by disruption of π–π stacking but not hydrogen bonding. Backbone rigidity and head group repulsion are thus important design considerations for controlling internal stability and nanostructure curvature in supramolecular assemblies stabilized by π–π stacking interactions.

A major goal of many translational neuroimaging studies is the identification of biomarkers of disease. However, a prerequisite for any such biomarker is robust reliability, which for magnetoencephalography (MEG) and many other imaging modalities has not been established. In this study, we examined the reliability of visual (Experiment 1) and somatosensory gating (Experiment 2) responses in 19 healthy adults who repeated these experiments for three visits spaced 18 months apart. Visual oscillatory and somatosensory oscillatory and evoked responses were imaged, and intraclass correlation coefficients (ICC) were computed to examine the long-term reliability of these responses. In Experiment 1, ICCs showed good reliability for visual theta and alpha responses in occipital cortices, but poor reliability for gamma responses. In Experiment 2, the time series of somatosensory gamma and evoked responses in the contralateral somatosensory cortex showed good reliability. Finally, analyses of spontaneous baseline activity indicated excellent reliability for occipital alpha, moderate reliability for occipital theta, and poor reliability for visual/somatosensory gamma activity. Overall, MEG responses to visual and somatosensory stimuli show a high degree of reliability across 3 years and therefore may be stable indicators of sensory processing long term and thereby of potential interest as biomarkers of disease.

The synthesis of protein–protein and protein–peptide conjugates is an important capability for producing vaccines, immunotherapeutics, and targeted delivery agents. Herein we show that the enzyme tyrosinase is capable of oxidizing exposed tyrosine residues into o-quinones that react rapidly with cysteine residues on target proteins. This coupling reaction occurs under mild aerobic conditions and has the rare ability to join full-size proteins in under 2 h. The utility of the approach is demonstrated for the attachment of cationic peptides to enhance the cellular delivery of CRISPR-Cas9 20-fold and for the coupling of reporter proteins to a cancer-targeting antibody fragment without loss of its cell-specific binding ability. The broad applicability of this technique provides a new building block approach for the synthesis of protein chimeras., Enzymatic oxidation of tyrosine residues followed by reaction with cysteine thiols allows the covalent coupling of proteins and peptides using only native amino acid side chains.

Directed cell growth or migration are critical for the development and function of many eukaryotic cells. These cells develop a dynamic “front” (also called “polarity site”) that can change direction. Polarity establishment involves autocatalytic accumulation of polarity regulators, including the conserved Rho-family GTPase Cdc42, but the mechanisms underlying polarity reorientation remain poorly understood. The tractable model yeast, Saccharomyces cerevisiae, relocates its polarity site when searching for mating partners. Relocation requires polymerized actin, and is thought to involve actin-mediated vesicle traffic to the polarity site. In this study, we provide a quantitative characterization of spontaneous polarity site movement as a search process and use a mechanistic computational model that combines polarity protein biochemical interactions with vesicle trafficking to probe how various processes might affect polarity site movement. Our findings identify two previously documented features of yeast vesicle traffic as being particularly relevant to such movement: tight spatial focusing of exocytosis enhances the directional persistence of movement, and association of Cdc42-directed GTPase-Activating Proteins with secretory vesicles increases the distance moved. Furthermore, we suggest that variation in the rate of exocytosis beyond simple Poisson dynamics may be needed to fully account for the characteristics of polarity site movement in vivo.

Human enamel is an incredibly resilient biological material, withstanding repeated daily stresses for decades. The mechanisms behind this resilience remain an open question, with recent studies demonstrating a crack-deflection mechanism contributing to enamel toughness and other studies detailing the roles of the organic matrix and remineralization. Here, we focus on the mineral and hypothesize that self-healing of cracks in enamel nanocrystals may be an additional mechanism acting to prevent catastrophic failure. To test this hypothesis, we used a molecular dynamics (MD) approach to compare the fracture behavior of hydroxyapatite (HAP) and calcite, the main minerals in human enamel and sea urchin teeth, respectively. We find that cracks heal under pressures typical of mastication by fusion of crystals in HAP but not in calcite, which is consistent with the resilience of HAP enamel that calcite teeth lack. Scanning transmission electron microscopy (STEM) images of structurally intact ("sound") human enamel show dashed-line nanocracks that resemble and therefore might be the cracks healed by fusion of crystals produced

Science, technology, engineering, and mathematics (STEM) career barriers persist for individuals from marginalized communities due to financial and educational inequality, unconscious bias, and other disadvantaging factors. To evaluate differences in plans and interests between historically underrepresented (UR) and well-represented (WR) groups, we surveyed more than 3000 undergraduates enrolled in chemistry courses. Survey responses showed all groups arrived on campus with similar interests in learning more about science research. Over the 4 years of college, WR students maintained their interest levels, but UR students did not, creating a widening gap between the groups. Without intervention, UR students participated in lab research at lower rates than their WR peers. A case study pilot program, Biosciences Collaborative for Research Engagement (BioCoRE), encouraged STEM research exploration by undergraduates from marginalized communities. BioCoRE provided mentoring and programming that increased community cohesion and cultivated students' intrinsic scientific mindsets. Our data showed that there was no statistical significant difference between BioCoRE WR and UR students when surveyed about plans for a medical profession, graduate school, and laboratory scientific research. In addition, BioCoRE participants reported higher levels of confidence in conducting research than non-BioCoRE Scholars. We now have the highest annual number of UR students moving into PhD programs in our institution's history.

DNA nanostructures are a promising tool to deliver molecular payloads to cells. DNA origami structures, where long single-stranded DNA is folded into a compact nanostructure, present an attractive approach to package genes; however, effective delivery of genetic material into cell nuclei has remained a critical challenge. Here, we describe the use of DNA nanostructures encoding an intact human gene and a fluorescent protein encoding gene as compact templates for gene integration by CRISPR-mediated homology-directed repair (HDR). Our design includes CRISPR–Cas9 ribonucleoprotein binding sites on DNA nanostructures to increase shuttling into the nucleus. We demonstrate efficient shuttling and genomic integration of DNA nanostructures using transfection and electroporation. These nanostructured templates display lower toxicity and higher insertion efficiency compared to unstructured double-stranded DNA templates in human primary cells. Furthermore, our study validates virus-like particles as an efficient method of DNA nanostructure delivery, opening the possibility of delivering nanostructures in vivo to specific cell types. Together, these results provide new approaches to gene delivery with DNA nanostructures and establish their use as HDR templates, exploiting both their design features and their ability to encode genetic information. This work also opens a door to translate other DNA nanodevice functions, such as biosensing, into cell nuclei.

We present Multi-miR, a microRNA-embedded shRNA system modeled after endogenous microRNA clusters that enables simultaneous expression of up to three or four short hairpin RNAs (shRNAs) from a single promoter without loss of activity, enabling robust combinatorial RNA interference (RNAi). We further developed complementary all-in-one vectors that are over one log-scale more sensitive to doxycycline-mediated activation invitro than previous methods and resistant to shRNA inactivation invivo. We demonstrate the utility of this system for intracranial expression of shRNAs in a glioblastoma model. Additionally, we leverage this platform to target the redundant RAF signaling node in a mouse model of KRAS-mutant cancer and show that robust combinatorial synthetic lethality efficiently abolishes tumor growth.