Phytosulfokine peptide optimizes plant growth and defense via glutamine synthetase GS2 phosphorylation in tomato.

Phytosulfokine (PSK) is a plant pentapeptide hormone that fulfills a wide range of functions. Although PSK has frequently been reported to function in the inverse regulation of growth and defense in response to (hemi)biotrophic pathogens, the mechanisms involved remain largely unknown. Using the tomato (Solanum lycopersicum) and Pseudomonas syringae pv. tomato (Pst) DC3000 pathogen system, we present compelling evidence that the PSK receptor PSKR1 interacts with the calcium-dependent protein kinase CPK28, which in turn phosphorylates the key enzyme of nitrogen assimilation glutamine synthetase GS2 at two sites (Serine-334 and Serine-360). GS2 phosphorylation at S334 specifically regulates plant defense, whereas S360 regulates growth, uncoupling the PSK-induced effects on defense responses and growth regulation. The discovery of these sites will inform breeding strategies designed to optimize the growth-defense balance in a compatible manner.

Rechargeable Na/Cl2 and Li/Cl2 batteries.

Lithium-ion batteries (LIBs) are widely used in applications ranging from electric vehicles to wearable devices. Before the invention of secondary LIBs, the primary lithium-thionyl chloride (Li-SOCl2) battery was developed in the 1970s using SOCl2 as the catholyte, lithium metal as the anode and amorphous carbon as the cathode1-7. This battery discharges by lithium oxidation and catholyte reduction to sulfur, sulfur dioxide and lithium chloride, is well known for its high energy density and is widely used in real-world applications; however, it has not been made rechargeable since its invention8-13. Here we show that with a highly microporous carbon positive electrode, a starting electrolyte composed of aluminium chloride in SOCl2 with fluoride-based additives, and either sodium or lithium as the negative electrode, we can produce a rechargeable Na/Cl2 or Li/Cl2 battery operating via redox between mainly Cl2/Cl- in the micropores of carbon and Na/Na+ or Li/Li+ redox on the sodium or lithium metal. The reversible Cl2/NaCl or Cl2/LiCl redox in the microporous carbon affords rechargeability at the positive electrode side and the thin alkali-fluoride-doped alkali-chloride solid electrolyte interface stabilizes the negative electrode, both are critical to secondary alkali-metal/Cl2 batteries.

HY5 functions as a systemic signal by integrating BRC1-dependent hormone signaling in tomato bud outgrowth.

Light plays an important role in determining plant architecture, which greatly influences crop yield. However, the precise mechanisms by which light signaling regulates bud outgrowth remain to be identified. Here, we show that light regulates bud outgrowth via both HY5 and brassinosteroid (BR)-dependent pathways in tomato. Inactivation of the red-light photoreceptor PHYB, or deficiencies in PHYB or the blue-light photoreceptor CRY1a, inhibits bud outgrowth and leads to decreased accumulation of HY5 protein and increased transcript level of BRANCHED1 (BRC1), a central integrator of branching signals. HY5, functioning as a mobile systemic signal from leaves, promotes bud outgrowth by directly suppressing BRC1 transcript and activating the transcript of BR biosynthesis genes within the lateral buds in tomato. Furthermore, BRC1 prevents the accumulation of cytokinin (CK) and gibberellin (GA) by directly inhibiting the transcript of CK synthesis gene LOG4, while increasing the transcript levels of CK and GA degradation genes (CKX7, GA2ox4, and GA2ox5), leading to an arrest of bud outgrowth. Moreover, bud outgrowth occurs predominantly in the day due to the suppression of BRC1 transcript by HY5. These findings demonstrate that light-inducible HY5 acts as a systemic signaling factor in fine-tuning the bud outgrowth of tomato.

Shedding light on rechargeable Na/Cl2 battery.

Advancing new ideas of rechargeable batteries represents an important path to meeting the ever-increasing energy storage needs. Recently, we showed rechargeable sodium/chlorine (Na/Cl2) (or lithium/chlorine Li/Cl2) batteries that used a Na (or Li) metal negative electrode, a microporous amorphous carbon nanosphere (aCNS) positive electrode, and an electrolyte containing dissolved aluminum chloride and fluoride additives in thionyl chloride [G. Zhu et al., Nature 596, 525-530 (2021) and G. Zhu et al., J. Am. Chem. Soc. 144, 22505-22513 (2022)]. The main battery redox reaction involved conversion between NaCl and Cl2 trapped in the carbon positive electrode, delivering a cyclable capacity of up to 1,200 mAh g-1 (based on positive electrode mass) at a ~3.5 V discharge voltage [G. Zhu et al., Nature 596, 525-530 (2021) and G. Zhu et al., J. Am. Chem. Soc. 144, 22505-22513 (2022)]. Here, we identified by X-ray photoelectron spectroscopy (XPS) that upon charging a Na/Cl2 battery, chlorination of carbon in the positive electrode occurred to form carbon-chlorine (C-Cl) accompanied by molecular Cl2 infiltrating the porous aCNS, consistent with Cl2 probed by mass spectrometry. Synchrotron X-ray diffraction observed the development of graphitic ordering in the initially amorphous aCNS under battery charging when the carbon matrix was oxidized/chlorinated and infiltrated with Cl2. The C-Cl, Cl2 species and graphitic ordering were reversible upon discharge, accompanied by NaCl formation. The results revealed redox conversion between NaCl and Cl2, reversible graphitic ordering/amorphourization of carbon through battery charge/discharge, and probed trapped Cl2 in porous carbon by XPS.

Phytosulfokine promotes fruit ripening and quality via phosphorylation of transcription factor DREB2F in tomato.

Phytosulfokine (PSK), a plant peptide hormone with a wide range of biological functions, is recognized by its receptor PHYTOSULFOKINE RECEPTOR 1 (PSKR1). Previous studies have reported that PSK plays important roles in plant growth, development, and stress responses. However, the involvement of PSK in fruit development and quality formation remains largely unknown. Here, using tomato (Solanum lycopersicum) as a research model, we show that exogenous application of PSK promotes the initiation of fruit ripening and quality formation, while these processes are delayed in pskr1 mutant fruits. Transcriptomic profiling revealed that molecular events and metabolic pathways associated with fruit ripening and quality formation are affected in pskr1 mutant lines and transcription factors are involved in PSKR1-mediated ripening. Yeast screening further identified that DEHYDRATION-RESPONSIVE ELEMENT BINDING PROTEIN 2F (DREB2F) interacts with PSKR1. Silencing of DREB2F delayed the initiation of fruit ripening and inhibited the promoting effect of PSK on fruit ripening. Moreover, the interaction between PSKR1 and DREB2F led to phosphorylation of DREB2F. PSK improved the efficiency of DREB2F phosphorylation by PSKR1 at the tyrosine-30 site, and the phosphorylation of this site increased the transcription level of potential target genes related to the ripening process and functioned in promoting fruit ripening and quality formation. These findings shed light on the involvement of PSK and its downstream signaling molecule DREB2F in controlling climacteric fruit ripening, offering insights into the regulatory mechanisms governing ripening processes in fleshy fruits.

Glucose-G protein signaling plays a crucial role in tomato resilience to high temperature and elevated CO2.

Global climate change is accompanied by carbon dioxide (CO2) enrichment and high temperature (HT) stress; however, how plants adapt to the combined environments and the underlying mechanisms remain largely unclear. In this study, we show that elevated CO2 alleviated plant sensitivity to HT stress, with significantly increased apoplastic glucose (Glc) levels in tomato (Solanum lycopersicum) leaves. Exogenous Glc treatment enhanced tomato resilience to HT stress under ambient CO2 conditions. Cell-based biolayer interferometry, subcellular localization, and Split-luciferase assays revealed that Glc bound to the tomato regulator of G protein signaling 1 (RGS1) and induced RGS1 endocytosis and thereby RGS1-G protein α subunit (GPA1) dissociation in a concentration-dependent manner. Using rgs1 and gpa1 mutants, we found that RGS1 negatively regulated thermotolerance and was required for elevated CO2-Glc-induced thermotolerance. GPA1 positively regulated the elevated CO2-Glc-induced thermotolerance. A combined transcriptome and chlorophyll fluorescence parameter analysis further revealed that GPA1 integrated photosynthesis- and photoprotection-related mechanisms to regulate thermotolerance. These results demonstrate that Glc-RGS1-GPA1 signaling plays a crucial role in the elevated CO2-induced thermotolerance in tomato. This information enhances our understanding of the Glc-G protein signaling function in stress resilience in response to global climate change and will be helpful for genetic engineering approaches to improve plant resilience.

Ubiquitylation of PHYTOSULFOKINE RECEPTOR 1 modulates the defense response in tomato.

Phytosulfokine (PSK) is a danger-associated molecular pattern recognized by PHYTOSULFOKINE RECEPTOR 1 (PSKR1) and initiates intercellular signaling to coordinate different physiological processes, especially in the defense response to the necrotrophic fungus Botrytis cinerea. The activity of peptide receptors is largely influenced by different posttranslational modifications, which determine intercellular peptide signal outputs. To date, the posttranslational modification to PHYTOSULFOKINE RECEPTOR 1 (PSKR1) remains largely unknown. Here, we show that tomato (Solanum lycopersicum) PSKR1 is regulated by the ubiquitin/proteasome degradation pathway. Using multiple protein-protein interactions and ubiquitylation analyses, we identified that plant U-box E3 ligases PUB12 and PUB13 interacted with PSKR1, among which PUB13 caused PSKR1 ubiquitylation at Lys-748 and Lys-905 sites to control PSKR1 abundance. However, this posttranslational modification was attenuated upon addition of PSK. Moreover, the disease symptoms observed in PUB13 knock-down and overexpression lines demonstrated that PUB13 significantly suppressed the PSK-initiated defense response. This highlights an important regulatory function for the turnover of a peptide receptor by E3 ligase-mediated ubiquitylation in the plant defense response.

Time Dependence of the Graphene Surface Adhesion Force of the Sphere-Plane Contact at Different Relative Humidities.

Graphene has a promising application prospect in integrated circuits and microelectromechanical systems, and sphere-plane contacts are their common contact types. At present, it is difficult to explain the time dependence of the adhesion force of the sphere-plane contact by conventional theory. Therefore, a single rough peak of sphere-plane contact adhesion force model based on variable water contact angle theory and Bradley contact theory was established; the aim is to reveal the changing law of graphene adhesion force. Then, the time dependence of the graphene surface adhesion force at different humidity levels was investigated by using an atomic force microscopy spherical probe. Finally, a quantitative comparative analysis of the theory and experiment was performed. The results show that the theoretical adhesion force was in good agreement with the experimental measurement results. The time dependence of graphene surface adhesion was not obvious within a relative humidity of 45-55%. When the relative humidity was greater than 65%, the graphene surface adhesion first increased and then decreased with dwell time and finally tended to be stable. Because of the increase in relative humidity, the capillary condensation effect increases, and then the adhesion force increases with the development of the meniscus. When the water film was generated on the sample surface, the adhesion force decreased until the meniscus achieved equilibrium.

Palladium-Catalyzed Annulative π-Extension of Bay-Iodinated Triphenylenes to Access Polycyclic Aromatic Compounds.

A palladium-catalyzed annulative π-extension reaction of bay-iodinated triphenylenes with aryl iodides/o-chloroaromatic carboxylic acids was developed. This approach enabled the synthesis of diverse polycyclic aromatic compounds, including dibenzo[fg,op]tetracenes, azadibenzo[fg,op]tetracenes, and tribenzo[a,g,m]coronenes. Initial studies indicate that the resulting product, 2,3,8,9,14,15-hexakis(decyloxy)tribenzo[a,g,m]coronene, exhibits good liquid-crystalline properties.

Discovery andsynthesis of novel benzoylhydrazone neuraminidase inhibitors.

Neuraminidase (NA) serves as a promising target for the exploration and development of anti-influenza drugs. In this work, lead compound 5 was discovered through pharmacophore-based virtual screening and molecular dynamics simulation, and 14 new compounds were obtained by modifying the lead compound 5 based on pharmacophore features. The biological activity test shows that 5n (IC50 = 0.13 µM) has a better inhibitory effect on wild-type NA (H5N1), while 5i (IC50 = 0.44 µM) has a prominent inhibitory effect on mutant NA (H5N1-H274Y), both of them are better than the positive control oseltamivir carboxylate (OSC). The analysis of docking results indicate that the good activities of compounds 5n and 5i may be attributed to the thiophene ring in 5n can stretch into the 150-cavity of NA, whereas the thiophene moiety in 5i can extend to the 430-cavity of NA. The findings of this study may be helpful for the discovery of new NA inhibitors.

Catalyst-free visible light-promoted defunctionalization of alkyl isocyanides with a hydrosilane through C-N bond cleavage.

A radical initiator-free defunctionalization reaction of alkyl isocyanides with a hydrosilane has been established through C-N bond cleavage under catalyst-free visible light irradiation. Various alkyl isocyanides participated in the defunctionalization with tris(trimethylsilyl)silane under blue light irradiation at room temperature, delivering the reduced products in good yields with high chemoselectivity.

Theoretical and experimental investigation of Al3+ ion-suppressed phase-separation structures in rare-earth-doped high-phosphorus silica glasses.

Rare-earth-doped silica-based composite glasses (Re-SCGs) are widely used as high-quality laser gain media in defense, aerospace, energy, power, and medical applications. The variable regional chemical environments of Re-SCGs can induce new photoluminescence properties of rare-earth ions but can cause the selective aggregation of rare-earth ions, limiting the application of Re-SCGs in the field of high-power lasers. Here, topological engineering is proposed to adjust the degree of cross-linking of phase-separation network chains in Re-SCGs. A combination of experimental and theoretical characterization techniques suggested that the selective aggregation of rare-earth ions originates from the formation of phase-separated structures in glasses. The decomposition of nanoscale phase separation structures to the sub-nanometer scale, enabled by incorporating Al3+ ions, not only maintains the high luminescence efficiency of rare earth ions but also increases light transmittance and reduces light scattering. Furthermore, our investigation encompassed the exploration of the inhibitory mechanism of Al3+ ions on phase-separation structures, as well as their influence on the spectral characteristics of Re-SCGs. This work provides a new design concept for composite glass materials doped with rare-earth ions and could broaden their application in the field of high-power lasers.

Integrated Single-cell and Transcriptome Sequencing Analyses Identified PREX1 as an Immune-related Prognostic Biomarker for Liver Hepatocellular Carcinoma.

Background: PtdIns (3,4,5) P3-dependent Rac exchanger 1 (PREX1), also known as PREX1, a member of the Rac guanine nucleotide exchange factors (Rac-GEF) family. Studies have suggested that PREX1 plays a role in mediating oncogenic pathway activation and controlling various biological mechanisms in different types of cancer, including liver hepatocellular carcinoma (LIHC). However, the function of PREX1 in the pathogenesis of LIHC and its potential role on immunological regulation is not clearly elucidated. Methods: The expression level and the clinical role of PREX1 in LIHC was analyzed based on database from the Cancer Genome Atlas (TCGA), TNM plotter and University of Alabama Cancer Database (UALCAN). We investigated the relationship between PREX1 and immunity in LIHC by TISIDB, CIBERSORT and single cell analysis. Immunotherapy responses were assessed by the immunophenoscores (IPS). Moreover, biological functional assays were performed to further investigate the roles of PREX1 in liver cancer cell lines. Results: Higher expression of PREX1 in LIHC tissues than in normal liver tissues was found based on public datasets. Further analysis revealed that PREX1 was associated with worse clinical characteristics and dismal prognosis. Pathway enrichment analysis indicated that PREX1 participated in immune-related pathways. Through CIBERSORT and single cell analysis, we found a remarkable correlation between the expression of PREX1 and various immune cells, especially macrophages. In addition, high PREX1 expression was found to be associated with a stronger response to immunotherapy. Furthermore, in vitro assays indicated that depletion of PREX1 can suppress invasion and proliferation of LIHC cells. Conclusion: Elevated expression of PREX1 indicates poor prognosis, influences immune modulation and predicts sensitivity of immunosuppression therapy in LIHC. Our results suggested that PREX1 may be a prognostic biomarker and therapeutic target, offering new treatment options for LIHC.

Transcriptome analysis reveals the effect of propyl gallate on kiwifruit callus formation.

KEY MESSAGE: Exploring the potential action mechanisms of reactive oxygen species during the callus inducing, they can activate specific metabolic pathways in explants to regulate callus development. Reactive oxygen species (ROS) play an important role in the regulation of plant growth and development, but the mechanism of their action on plant callus formation remains to be elucidated. To address this question, kiwifruit was selected as the explant for callus induction, and the influence of ROS on callus formation was investigated by introducing propyl gallate (PG) as an antioxidant into the medium used for inducing callus. The results have unveiled that the inclusion of PG in the medium has disturbed the equilibrium of ROS during the formation of the kiwifruit callus. We selected the callus that was induced by the addition of 0.05 mmol/L PG to the MS medium. The callus exhibited a significant difference in the amount compared to the control medium without PG. The callus induced by the MS medium without PG was used as the control for comparison. KEGG enrichment indicated that PG exposure resulted in significant differences in gene expression in related pathways, such as phytohormone signaling and glutathione in kiwifruit callus. Weighted gene co-expression analysis indicated that the pertinent regulatory networks of both ROS and phytohormone signaling were critical for the establishment of callus in kiwifruit leaves. In addition, during the process of callus establishment, the ROS level of the explants was also closely related to the genes for transmembrane transport of substances, cell wall formation, and plant organ establishment. This investigation expands the theory of ROS-regulated callus formation and presents a new concept for the expeditious propagation of callus in kiwifruit.

The immunoproteasome subunit ß2i ameliorates myocardial ischemia/reperfusion injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Mitochondrial dynamics are critical for maintaining mitochondrial morphology and function during cardiac ischemia and reperfusion (I/R). The immunoproteasome complex is an inducible isoform of the proteasome that plays a key role in modulating inflammation and some cardiovascular diseases, but the importance of immunoproteasome catalytic subunit ß2i (also known as LMP10 or MECL1) in regulating mitochondrial dynamics and cardiac I/R injury is largely unknown. Here, using ß2i-knockout (KO) mice and rAAV9-ß2i-injected mice, we discovered that ß2i expression and its trypsin-like activity were significantly attenuated in the mouse I/R myocardium and in patients with myocardial infarction (MI). Moreover, ß2i-KO mice exhibited greatly enhanced I/R-mediated cardiac dysfunction, infarct size, myocyte apoptosis and oxidative stress accompanied by excessive mitochondrial fission due to Mfn1/2 and Drp1 imbalance. Conversely, cardiac overexpression of ß2i in mice injected with recombinant adeno-associated virus 9 (rAAV9)-ß2i ameliorated cardiac I/R injury. Mechanistically, I/R injury reduced ß2i expression and activity, which increased the expression of the E3 ligase Parkin protein and promoted the degradation of mitofusin 1/2 (Mfn1/2), leading to excessive mitochondrial fission. In conclusion, our data suggest for the first time that ß2i exerts a protective role against cardiac I/R injury and that increasing ß2i expression may be a new therapeutic option for cardiac ischemic disease in clinical practice. Graphical abstract showing how the immunoproteasome subunit ß2i ameliorates myocardial I/R injury by regulating Parkin-Mfn1/2-mediated mitochondrial fusion.

Forests or trees? The effect of generating solutions to distant analogies on global-local processing.

The present research was designed to examine the effect of solving distant analogies on global-local processing. In two experiments, participants generated solutions to near analogies (near condition), or distant analogies (distant condition), and then they were required to either complete the Kimchi-Palmer task (Experiment 1) or the Navon letter task (Experiment 2). The experimental results showed that participants who generated solutions to distant analogies scored higher on the Kimchi-Palmer task and had faster reaction times to global letters. These findings indicated that solving distant analogies could promote global processing.

Brassinosteroid signaling integrates multiple pathways to release apical dominance in tomato.

The control of apical dominance involves auxin, strigolactones (SLs), cytokinins (CKs), and sugars, but the mechanistic controls of this regulatory network are not fully understood. Here, we show that brassinosteroid (BR) promotes bud outgrowth in tomato through the direct transcriptional regulation of BRANCHED1 (BRC1) by the BR signaling component BRASSINAZOLE-RESISTANT1 (BZR1). Attenuated responses to the removal of the apical bud, the inhibition of auxin, SLs or gibberellin synthesis, or treatment with CK and sucrose, were observed in bud outgrowth and the levels of BRC1 transcripts in the BR-deficient or bzr1 mutants. Furthermore, the accumulation of BR and the dephosphorylated form of BZR1 were increased by apical bud removal, inhibition of auxin, and SLs synthesis or treatment with CK and sucrose. These responses were decreased in the DELLA-deficient mutant. In addition, CK accumulation was inhibited by auxin and SLs, and decreased in the DELLA-deficient mutant, but it was increased in response to sucrose treatment. CK promoted BR synthesis in axillary buds through the action of the type-B response regulator, RR10. Our results demonstrate that BR signaling integrates multiple pathways that control shoot branching. Local BR signaling in axillary buds is therefore a potential target for shaping plant architecture.

Chemical Composition and Phytotoxic Activity of Mentha vagans Boriss. Essential Oil.

This study explored the composition of essential oil (EO) and the first phytotoxic screening of EO obtained from the stems and leaves of Mentha vagans Boriss (MVEO) via hydro-distillation technique. The EO ingredients were detected through Gas Chromatography-Mass Spectrometry (GC-MS). GC-MS analysis revealed that MVEO contained 49 constituents, constituting 93.95 % of the total oil. Among MVEO constituents, dihydrocarvone was observed as the dominant constituent (24.14%), followed by D-carvone (16.28%) and piperitone (18.14%). The phytotoxic effects of MVEO and its dominant compounds were examined against Amaranthus retroflexus, Lolium perenne, and Poa annua. Significant inhibition was observed by MVEO in comparison with the major constituents and their mixture, suppressing the seedling growth of tested species at the lowest dosage (0.01 mg/mL); in general, seedling growth of all tested species was markedly inhibited when applied concentration of the EO and its constituents reached 0.05 mg/mL. Our results also indicated that constituents other than the dominant compounds of MVEO possessed considerable phytotoxic effects because the EO's activity was stronger than its major constituents and their mixture. Thus, additional studies are required to investigate MVEO and its constituents and commercialize them as environment-friendly bio-herbicides.

Relationships between bilateral auditory brainstem activity and inter-implant interval in children with cochlear implants.

PURPOSE: To investigate the effect of the interval between bilateral cochlear implantation on the development of bilateral peripheral auditory pathways as revealed by the electrically evoked auditory brainstem response (EABR). METHODS: Fifty-eight children with profound bilateral sensorineural hearing loss were recruited. Among them, 33 children received sequential bilateral cochlear implants (CIs), and 25 children received simultaneous bilateral CIs. The bilateral EABRs evoked by electrical stimulation from the CI electrode were recorded on the day of second-side CI activation. RESULTS: The latencies of wave III (eIII) and wave V (eV) were significantly shorter on the first CI side than on the second CI side in children with sequential bilateral CIs but were similar between the two sides in children with simultaneous bilateral CIs. Furthermore, the latencies were prolonged from apical to basal channels along the cochlea in the two groups. In children with sequential CIs, the inter-implant interval was negatively correlated with the eV latency on the first CI side and was positively correlated with bilateral differences in the eIII and eV latencies. CONCLUSIONS: Unilateral CI use promotes the maturation of ipsilateral auditory conduction function. However, a longer inter-implant interval results in more unbalanced development of bilateral auditory brainstem pathways. Bilateral cochlear implantation with no or a short interval is recommended.

The Abca7V1613M variant reduces Aß generation, plaque load, and neuronal damage.

BACKGROUND: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD). METHODS: CRISPR-Cas9 was used to generate an Abca7V1613M variant in mice, modeling the homologous human ABCA7V1599M variant, and extensive characterization was performed. RESULTS: Abca7V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aß) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aß-associated inflammation, gliosis, and neuronal damage. DISCUSSION: Overall, homozygosity for the Abca7V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aß pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology. HIGHLIGHTS: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice.