Effect of substituting glutamine with lysine on structural and biological properties of antimicrobial peptide Polybia-MP1.

The natural antimicrobial peptide Polybia-MP1 is a promising candidate for developing new treatment therapy for infection and cancer. It showed broad-spectrum antimicrobial and anticancer activity with high safety on healthy cells. However, previous sequence modification usually resulted in at least one of two consequences: a notable increase in hemolytic activity or a considerable decrease in activity against Gram-negative bacteria and cancer cells. Herein, a new approach was applied by replacing the amino acid Glutamine at position 12 with Lysine and generating the MP1-Q12K analog. Our preliminary data suggested an enhancement in antibacterial and antifungal activity, whereas the anticancer and hemolytic activity of the two peptides were comparable. Moreover, MP1-Q12K was found to be less self-assembly than Polybia-MP1, which further supports the enhancement of antimicrobial properties. Hence, this study provides new information regarding the structure-activity relationships of Polybia-MP1 and support for the development of potent, selective antimicrobial peptides.

Neuroprotective effects of total alkaloids fraction of Huperzia serrata on scopolamine-induced neurodegenerative animals.

Huperzia serrata contains Huperzine A (HupA)-an alkaloid used to treat cognitive dysfunction. In this study, we used the total alkaloids (HsAE) to investigate their potential in managing cognitive impairment in comparison with HupA. The antioxidant activity was measured by DPPH assay. In the cellular study, the cell viability and level of ACh of SH-SY5Y cells were evaluated after pretreated with HsAE and scopolamine. For in vivo assay, mice were pre-treated with HsAE, and HupA and undergone scopolamine injection for cognitive impairment. The behavioral tests including the Y-maze and Morris water maze test and the AChE activity, the SOD, CAT, MDA level in the hippocampus and cortex were evaluated. HsAE showed significant scavenging properties on DPPH radicals. HsAE was not toxic to SH-SY5Y cells, and can rescue these cells upon scopolamine treatment. Intriguingly, HsAE showed the neuroprotection against scopolamine-induced amnesia in mice. Moreover, HsAE decreased AChE activity, MDA level, increased antioxidative enzyme activity in the hippocampus as well as cortex of mice, which was relatively better than that of HupA. These findings suggested that HsAE may significantly protect the neurons of mice with scopolamine-induced memory impairment connected to AChE depletion and oxidative stress.

Anti-neuroinflammatory effects of alkaloid-enriched extract from Huperzia serrata on lipopolysaccharide-stimulated BV-2 microglial cells.

CONTEXT: Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. OBJECTIVE: This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. MATERIALS AND METHODS: BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. RESULTS: HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1ß compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. DISCUSSION AND CONCLUSIONS: HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.

Tin oxide artificial synapses for low power temporal information processing.

Lateral memristors configured with inert Pt contacts and mixed phase tin oxide layers have exhibited immediate, forming-free, low-power bidirectional resistance switching. Activity dependent conductance and relaxation in the low resistance state resembled short term potentiation in biological synapses. After scanning probe microscopy, x-ray photoelectron spectroscopy and electrical measurements, the device characteristics were attributed to Joule heating induced decomposition of the minority SnO phase and formation of a SnO2 conducting filament with higher effective n-type doping. Finally, the devices recognized input voltage pulse sequences and spectral data by returning unique conductance states, suggesting suitability for bio-inspired pattern recognition systems.

Tet controls axon guidance in early brain development through glutamatergic signaling.

Mutations in ten-eleven translocation (TET) proteins are associated with human neurodevelopmental disorders. We find a function of Tet in regulating Drosophila early brain development. The Tet DNA-binding domain (TetAXXC) is required for axon guidance in the mushroom body (MB). Glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is significantly down-regulated in the TetAXXC brains. Loss of Gs2 recapitulates the TetAXXC phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in IPCs rescues the defects of TetAXXC. Feeding TetAXXC with metabotropic glutamate receptor antagonist MPEP rescues the phenotype while glutamate enhances it. Mutants in Tet and Drosophila Fmr1, the homolog of human FMR1, have similar defects, and overexpression of Gs2 in IPCs also rescues the Fmr1 phenotype. We provide the first evidence that Tet controls the guidance of developing brain axons by modulating glutamatergic signaling.

Rehabilitation Surgery for Peripheral Facial Nerve Injury after Facial Trauma.

Introduction Facial trauma can cause damage to the facial nerve, which can have negative effects on function, aesthetics, and quality of life if left untreated. Objective To evaluate the effectiveness of peripheral facial nerve direct end-to-end anastomosis and/or nerve grafting surgery for patients with facial nerve injury after facial trauma. Methods Fifty-nine patients with peripheral facial nerve paralysis after facial injuries underwent facial nerve rehabilitation surgery from November 2017 to December 2021 at Ho Chi Minh City National Hospital of Odontology. Results All 59 cases of facial trauma with damage to the peripheral facial nerve underwent facial nerve reconstruction surgery within 8 weeks of the injury. Of these cases, 25/59 (42.3%) had end-to-end anastomosis, 22/59 (37.3%) had nerve grafting, and 12/59 (20.4%) had a combination of nerve grafting and end-to-end anastomosis. After surgery, the rates of moderate and good recovery were 78.4% and 11.8%, respectively. All facial paralysis measurements showed statistically significant improvement after surgery, including the Facial Nerve Grading Scale 2.0 (FNGS 2.0) score, the Facial Clinimetric Evaluation (FaCE) scale, and electroneurography. The rate of synkinesis after surgery was 34%. Patient follow-up postoperatively ranged from 6 to > 36 months; 51 out of 59 patients (86.4%) were followed-up for at least 12 months or longer. Conclusion Nerve rehabilitation surgery including direct end-to-end anastomosis and nerve grafting is effective in cases of peripheral facial nerve injury following facial trauma. The surgery helps restore nerve conduction and improve facial paralysis.

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.

Skin-inspired, sensory robots for electronic implants.

Drawing inspiration from cohesive integration of skeletal muscles and sensory skins in vertebrate animals, we present a design strategy of soft robots, primarily consisting of an electronic skin (e-skin) and an artificial muscle. These robots integrate multifunctional sensing and on-demand actuation into a biocompatible platform using an in-situ solution-based method. They feature biomimetic designs that enable adaptive motions and stress-free contact with tissues, supported by a battery-free wireless module for untethered operation. Demonstrations range from a robotic cuff for detecting blood pressure, to a robotic gripper for tracking bladder volume, an ingestible robot for pH sensing and on-site drug delivery, and a robotic patch for quantifying cardiac function and delivering electrotherapy, highlighting the application versatilities and potentials of the bio-inspired soft robots. Our designs establish a universal strategy with a broad range of sensing and responsive materials, to form integrated soft robots for medical technology and beyond.

Tet Controls Axon Guidance in Early Brain Development through Glutamatergic Signaling.

Mutations in human TET proteins have been found in individuals with neurodevelopmental disorders. Here we report a new function of Tet in regulating Drosophila early brain development. We found that mutation in the Tet DNA-binding domain ( Tet AXXC ) resulted in axon guidance defects in the mushroom body (MB). Tet is required in early brain development during the outgrowth of MB ß axons. Transcriptomic study shows that glutamine synthetase 2 (Gs2), a key enzyme in glutamatergic signaling, is significantly downregulated in the Tet AXXC mutant brains. CRISPR/Cas9 mutagenesis or RNAi knockdown of Gs2 recapitulates the Tet AXXC mutant phenotype. Surprisingly, Tet and Gs2 act in the insulin-producing cells (IPCs) to control MB axon guidance, and overexpression of Gs2 in these cells rescues the axon guidance defects of Tet AXXC . Treating Tet AXXC with the metabotropic glutamate receptor antagonist MPEP can rescue while treating with glutamate enhances the phenotype confirming Tet function in regulating glutamatergic signaling. Tet AXXC and the Drosophila homolog of Fragile X Messenger Ribonucleoprotein protein mutant ( Fmr1 3 ) have similar axon guidance defects and reduction in Gs2 mRNA levels. Interestingly, overexpression of Gs2 in the IPCs also rescues the Fmr1 3 phenotype, suggesting functional overlapping of the two genes. Our studies provide the first evidence that Tet can control the guidance of axons in the developing brain by modulating glutamatergic signaling and the function is mediated by its DNA-binding domain.

Neuromorphic sensing of biomolecules covalently immobilised on polydimethyl glutarimide.

Polydimethyl glutarimide (PMGI) layers with sub-micron thicknesses have been modified in a 2.5 kV Ar plasma immersion ion implantation (PIII) process to introduce free radical covalent binding sites. The surface roughness of the PMGI increased after the PIII treatment but no through-layer defects were observed. When applied to the treated PMGI, horseradish peroxidase (HRP) enzyme remained bound to the surface after extended immersion in sodium dodecyl sulfate solution (SDS). Hence, covalent binding between the activated surface and enzyme was confirmed. This covalent binding was achieved up to 24-h after the PIII process. The treated PMGI was then incorporated as a gate dielectric layer within a lateral three-terminal electrolyte-gated device. The device output characteristics resembled those of post-synaptic outputs; as successive (pre-synaptic) voltage pulses were applied to the gate, paired pulse depression and spike rate dependent plasticity were observed in the source-drain (post-synaptic) current. These characteristics were altered by the presence of HRP immobilised on the plasma-modified PMGI gate dielectric layer thus providing readout detection. These results and preliminary device characteristics show the potential for the plasma functionalized PMGI as a sensitive and reproducible biosensing technology.

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates axon guidance genes in Drosophila.

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases and catalyze the transition of 5mC to 5hmC in DNA. These enzymes have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila as Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by mapping one, Tet DNA-binding sites throughout the genome and two, the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC modifications are distributed along the entire transcript, while Tet DNA-binding sites are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are preferentially involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs primarily in cells of the nervous system.

Tet-dependent 5-hydroxymethyl-Cytosine modification of mRNA regulates the axon guidance genes robo2 and slit in Drosophila.

Modifications of mRNA, especially methylation of adenosine, have recently drawn much attention. The much rarer modification, 5-hydroxymethylation of cytosine (5hmC), is not well understood and is the subject of this study. Vertebrate Tet proteins are 5-methylcytosine (5mC) hydroxylases enzymes catalyzing the transition of 5mC to 5hmC in DNA and have recently been shown to have the same function in messenger RNAs in both vertebrates and in Drosophila. The Tet gene is essential in Drosophila because Tet knock-out animals do not reach adulthood. We describe the identification of Tet-target genes in the embryo and larval brain by determining Tet DNA-binding sites throughout the genome and by mapping the Tet-dependent 5hmrC modifications transcriptome-wide. 5hmrC-modified sites can be found along the entire transcript and are preferentially located at the promoter where they overlap with histone H3K4me3 peaks. The identified mRNAs are frequently involved in neuron and axon development and Tet knock-out led to a reduction of 5hmrC marks on specific mRNAs. Among the Tet-target genes were the robo2 receptor and its slit ligand that function in axon guidance in Drosophila and in vertebrates. Tet knock-out embryos show overlapping phenotypes with robo2 and are sensitized to reduced levels of slit. Both Robo2 and Slit protein levels were markedly reduced in Tet KO larval brains. Our results establish a role for Tet-dependent 5hmrC in facilitating the translation of modified mRNAs, primarily in developing nerve cells.

Skin-inspired, sensory robots for electronic implants.

Living organisms with motor and sensor units integrated seamlessly demonstrate effective adaptation to dynamically changing environments. Drawing inspiration from cohesive integration of skeletal muscles and sensory skins in these organisms, we present a design strategy of soft robots, primarily consisting of an electronic skin (e-skin) and an artificial muscle, that naturally couples multifunctional sensing and on-demand actuation in a biocompatible platform. We introduce an in situ solution-based method to create an e-skin layer with diverse sensing materials (e.g., silver nanowires, reduced graphene oxide, MXene, and conductive polymers) incorporated within a polymer matrix (e.g., polyimide), imitating complex skin receptors to perceive various stimuli. Biomimicry designs (e.g., starfish and chiral seedpods) of the robots enable various motions (e.g., bending, expanding, and twisting) on demand and realize good fixation and stress-free contact with tissues. Furthermore, integration of a battery-free wireless module into these robots enables operation and communication without tethering, thus enhancing the safety and biocompatibility as minimally invasive implants. Demonstrations range from a robotic cuff encircling a blood vessel for detecting blood pressure, to a robotic gripper holding onto a bladder for tracking bladder volume, an ingestible robot residing inside stomach for pH sensing and on-site drug delivery, and a robotic patch wrapping onto a beating heart for quantifying cardiac contractility, temperature and applying cardiac pacing, highlighting the application versatilities and potentials of the nature-inspired soft robots. Our designs establish a universal strategy with a broad range of sensing and responsive materials, to form integrated soft robots for medical technology and beyond.

Characteristics of polycyclic aromatic hydrocarbons in ambient air of a tropical mega-area, Ho Chi Minh City, Vietnam: concentration, distribution, gas/particle partitioning, potential sources and cancer risk assessment.

This is the first investigation on overall characteristics of 25 polycyclic aromatic hydrocarbons (PAHs) (15 PAHs regulated by US-EPA (excluding naphthalene) and 16 PAHs recommended by the European Union) in ambient air of Ho Chi Minh City, Vietnam. Their levels, congener profiles, gas/particle partitioning, potential sources of atmospheric PAHs (gas and particulate phases), and lung cancer risks in the dry and rainy seasons were examined. The ∑25 PAH concentration in the dry and rainy seasons ranged from 8.79 to 33.2 ng m-3 and 26.0 to 60.0 ng m-3, respectively. Phenanthrene and Indeno[123-cd]pyrene were major contributors to gaseous and particulate PAHs, respectively, while benzo[c]fluorene was dominant component of the total BaP-TEQ. The ∑16 EU-PAH concentration contributed to 13 ± 2.7% of the total ∑ 25 PAH concentration; however, they composed over 99% of the total ∑ 25 PAH toxic concentration. Adsorption mainly governed the phase partitioning of PAHs because the slope of correlation between logKp and logP0L was steeper than - 1. Vehicular emission was the primary source of PAHs in two seasons; however, PAHs in the dry season were also originated from biomass burning. Assessment of lung cancer risk showed that children possibly exposed to potential lung cancer risk via inhalation.

EEG Peak Detection in Cognitive Conflict Processing Using Summit Navigator and Clustering-Based Ranking.

Correct detection of peaks in electroencephalogram (EEG) signals is of essence due to the significant correlation of those potentials with cognitive performance and disorders. This paper proposes a novel and non-parametric approach to detect prediction error negativity (PEN) in cognitive conflict processing. The PEN candidates are first located from the input signal via an adaptation of a recent effective method for local maxima extraction, processed in a multi-scale manner. The found candidates are then fused and ranked based on their shape and location-based features. False positives caused by candidates' magnitude are eliminated by rotating the sorted candidate list where the one with the second-best ranking score will be identified as PEN. The EEG data collected from a 3D object selection task have been used to verify the efficacy of the proposed approach. Compared with the state-of-the-art peak detection techniques, the proposed method shows an improvement of at least 2.67% in accuracy and 6.27% in sensitivity while requires only about 4 ms to process an epoch. The accuracy and computational efficiency of the proposed technique in the detection of PEN in cognitive conflict processing would lead to promising applications in performance improvement of brain-computer interfaces (BCIs).

Summit Navigator: A Novel Approach for Local Maxima Extraction.

This paper presents a novel method, called the Summit Navigator, to effectively extract local maxima of an image histogram for multi-object segmentation of images. After smoothing with a moving average filter, the obtained histogram is analyzed, based on the data density and distribution to find the best observing location. An observability index for each initial peak is proposed to evaluate if it can be considered as dominant by using the calculated observing location. Recursive algorithms are then developed for peak searching and merging to remove any false detection of peaks that are located on one side of each mode. Experimental results demonstrated the advantages of the proposed approach in terms of accuracy and consistency in different reputable datasets.

Tet protein function during Drosophila development.

The TET (Ten-eleven translocation) 1, 2 and 3 proteins have been shown to function as DNA hydroxymethylases in vertebrates and their requirements have been documented extensively. Recently, the Tet proteins have been shown to also hydroxylate 5-methylcytosine in RNA. 5-hydroxymethylcytosine (5hmrC) is enriched in messenger RNA but the function of this modification has yet to be elucidated. Because Cytosine methylation in DNA is barely detectable in Drosophila, it serves as an ideal model to study the biological function of 5hmrC. Here, we characterized the temporal and spatial expression and requirement of Tet throughout Drosophila development. We show that Tet is essential for viability as Tet complete loss-of-function animals die at the late pupal stage. Tet is highly expressed in neuronal tissues and at more moderate levels in somatic muscle precursors in embryos and larvae. Depletion of Tet in muscle precursors at early embryonic stages leads to defects in larval locomotion and late pupal lethality. Although Tet knock-down in neuronal tissue does not cause lethality, it is essential for neuronal function during development through its affects upon locomotion in larvae and the circadian rhythm of adult flies. Further, we report the function of Tet in ovarian morphogenesis. Together, our findings provide basic insights into the biological function of Tet in Drosophila, and may illuminate observed neuronal and muscle phenotypes observed in vertebrates.

Drosophila Ubiquitin C-Terminal Hydrolase Knockdown Model of Parkinson's Disease.

Parkinson's disease (PD) is the second most common neurodegenerative disorder worldwide. Many factors have been shown to contribute to its pathogenesis including genetic and environmental factors. Ubiquitin C-terminal hydrolase L1 (UCHL1) is also known to be involved in the pathogenesis of PD. We herein modeled the study of UCHL1 in Drosophila melanogaster and investigated its functions in PD. The specific knockdown of the Drosophila ortholog of UCHL1 (dUCH) in dopaminergic neurons (DA neurons) led to the underdevelopment and/or degeneration of these neurons, specifically in DL1 DA neuron cluster in the larval brain lobe and PPM2, PPM3, PPL2ab, and VUM DA neuron clusters in the adult brain. These defects were followed by a shortage of dopamine in the brain, which subsequently resulted in locomotor dysfunction. The degeneration of DA neurons in dUCH knockdown adult brain, which occurred progressively and severely during the course of aging, mimics the epidemiology of PD. DA neuron and locomotor defects were rescued when dUCH knockdown flies were treated with vitamin C, a well-known antioxidant. These results suggest that dUCH knockdown fly is a promising model for studying the pathogenesis and epidemiology of PD as well as the screening of potential antioxidants for PD therapeutics.

Determinants of early atherosclerosis in obese children and adolescents.

CONTEXT: Obesity in childhood is associated with an increased mortality due to cardiovascular (CV) diseases in adulthood, independent of adult weight. Recent studies in children indicate that the atherosclerosis process starts at an early age and is linked to obesity. OBJECTIVE: The aim of the study was to investigate determinants of increased carotid intima-media thickness (IMT), an early marker of atherosclerosis, in obese children. DESIGN: A total of 104 obese children [age, 12.7 +/- 0.2 yr; body mass index (BMI)-z-score, 2.8 +/- 0.7] underwent an oral glucose tolerance test. Fasting levels of glucose, insulin, C-reactive protein and adhesion molecules (sICAM, sVCAM, sE-selectin), lipid profile, adiponectin, and resistin were determined. IMT was measured by ultrasound. Insulin resistance was estimated by the homeostatic model assessment index. Baseline measurements of blood parameters were obtained from 93 nonobese children (age, 13.0 +/- 0.2 yr; BMI-z-score, -0.2 +/- 0.9), and IMT was measured in 23 other control children with similar characteristics. RESULTS: Univariate analysis showed a significant positive correlation between IMT and relative BMI, the degree of systolic hypertension, fasting insulin levels, homeostatic model assessment-R index, and resistin concentrations, whereas an inverse correlation with adiponectin levels was found. No correlation was obtained between IMT and classical CV risk factors such as positive familial history of type 2 diabetes or precocious CV disease, visceral obesity, or the lipid profile. C-reactive protein and adhesion molecule levels were not associated with IMT in our obese population. When controlled for sex, Tanner stage, and relative BMI, only adiponectin levels remained an independent determinant of IMT. CONCLUSION: Adiponectin more than conventional CV risk factors and inflammation status may be related to early atherosclerosis in obese children.

Degree of Tissue Differentiation Dictates Susceptibility to BRAF-Driven Colorectal Cancer.

Oncogenic mutations in BRAF are believed to initiate serrated colorectal cancers; however, the mechanisms of BRAF-driven colon cancer are unclear. We find that oncogenic BRAF paradoxically suppresses stem cell renewal and instead promotes differentiation. Correspondingly, tumor formation is inefficient in BRAF-driven mouse models of colon cancer. By reducing levels of differentiation via genetic manipulation of either of two distinct differentiation-promoting factors (Smad4 or Cdx2), stem cell activity is restored in BRAFV600E intestines, and the oncogenic capacity of BRAFV600E is amplified. In human patients, we observe that reduced levels of differentiation in normal tissue is associated with increased susceptibility to serrated colon tumors. Together, these findings help resolve the conditions necessary for BRAF-driven colon cancer initiation. Additionally, our results predict that genetic and/or environmental factors that reduce tissue differentiation will increase susceptibility to serrated colon cancer. These findings offer an opportunity to identify susceptible individuals by assessing their tissue-differentiation status.