3,315 results match your criteria potential off-target


Smart Strategies for Precise Delivery of CRISPR/Cas9 in Genome Editing.

ACS Appl Bio Mater 2022 Jan 18. Epub 2022 Jan 18.

Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa.

The emergence of CRISPR/Cas technology has enabled scientists to precisely edit genomic DNA sequences. This approach can be used to modulate gene expression for the treatment of genetic disorders and incurable diseases such as cancer. This potent genome-editing tool is based on a single guide RNA (sgRNA) strand that recognizes the targeted DNA, plus a Cas nuclease protein for binding and processing the target. Read More

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January 2022

Lipid metabolism in autoimmune rheumatic disease: implications for modern and conventional therapies.

J Clin Invest 2022 Jan;132(2)

Centre for Rheumatology Research.

Suppressing inflammation has been the primary focus of therapies in autoimmune rheumatic diseases (AIRDs), including rheumatoid arthritis and systemic lupus erythematosus. However, conventional therapies with low target specificity can have effects on cell metabolism that are less predictable. A key example is lipid metabolism; current therapies can improve or exacerbate dyslipidemia. Read More

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January 2022

UdgX-Mediated Uracil Sequencing at Single-Nucleotide Resolution.

J Am Chem Soc 2022 Jan 16. Epub 2022 Jan 16.

Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China.

As an aberrant base in DNA, uracil is generated by either deoxyuridine (dU) misincorporation or cytosine deamination, and involved in multiple physiological and pathological processes. Genome-wide profiles of uracil are important for study of these processes. Current methods for whole-genome mapping of uracil all rely on uracil-DNA N-glycosylase (UNG) and are limited in resolution, specificity, and/or sensitivity. Read More

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January 2022

T-cell-receptor cross-recognition and strategies to select safe T-cell receptors for clinical translation.

Immunooncol Technol 2019 Sep;2:1-10

Section for Experimental and Translational Immunology, Department of Health Technology, The Technical University of Denmark, Kongens Lyngby, Denmark.

Adoptive transfer of T-cell-receptor (TCR)-transduced T cells has shown promising results for cancer treatment, but has also produced severe immunotoxicities caused by on-target as well as off-target TCR recognition. Off-target toxicities are related to the ability of a single T cell to cross-recognize and respond to several different peptide-major histocompatibility complex (pMHC) antigens; a property that is essential for providing broad antigenic coverage despite a confined number of unique TCRs in the human body. However, this degeneracy makes it incredibly difficult to account for the range of targets that any TCR might recognize, which represents a major challenge for the clinical development of therapeutic TCRs. Read More

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September 2019

Tissue Culture Models of Acute Kidney Injury: From Tubule Cells to Human Kidney Organoids.

J Am Soc Nephrol 2022 Jan 14. Epub 2022 Jan 14.

L Woodard, Department of Medicine, Division of Nephrology and Hypertension, Vanderbilt University Medical Center, Nashville, United States.

Acute kidney injury (AKI) affects approximately 13.3 million people around the world each year, causing chronic kidney disease and/or mortality. The mammalian kidney cannot generate new nephrons after postnatal renal damage and regenerative therapies for AKI are not available. Read More

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January 2022

Delivery of CRISPR-Cas tools for in vivo genome editing therapy: Trends and challenges.

J Control Release 2022 Jan 10. Epub 2022 Jan 10.

Center for iPS cell Research and Application, Kyoto University, Kyoto 606-8507, Japan; Takeda-CiRA Joint Program (T-CiRA), Fujisawa, Kanagawa 251-8555, Japan. Electronic address:

The discovery of clustered regularly interspaced short palindromic repeats (CRISPR) genome editing technology opened the door to provide a versatile approach for treating multiple diseases. Promising results have been shown in numerous pre-clinical studies and clinical trials. However, a safe and effective method to deliver genome-editing components is still a key challenge for in vivo genome editing therapy. Read More

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January 2022

ΔFOSB: A Potentially Druggable Master Orchestrator of Activity-Dependent Gene Expression.

ACS Chem Neurosci 2022 Jan 12. Epub 2022 Jan 12.

Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, United States.

ΔFOSB is a uniquely stable member of the FOS family of immediate early gene AP1 transcription factors. Its accumulation in specific cell types and tissues in response to a range of chronic stimuli is associated with biological phenomena as diverse as memory formation, drug addiction, stress resilience, and immune cell activity. Causal connections between ΔFOSB expression and the physiological and behavioral sequelae of chronic stimuli have been established in rodent and, in some cases, primate models for numerous healthy and pathological states with such preclinical observations often supported by human data demonstrating tissue-specific ΔFOSB expression associated with several specific syndromes. Read More

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January 2022

Comprehensive analysis of prime editing outcomes in human embryonic stem cells.

Nucleic Acids Res 2022 Jan 8. Epub 2022 Jan 8.

Department of Chemistry and Research Institute for Convergence of Basic Sciences, Hanyang University, Seoul 08826, South Korea.

Prime editing is a versatile and precise genome editing technique that can directly copy desired genetic modifications into target DNA sites without the need for donor DNA. This technique holds great promise for the analysis of gene function, disease modeling, and the correction of pathogenic mutations in clinically relevant cells such as human pluripotent stem cells (hPSCs). Here, we comprehensively tested prime editing in hPSCs by generating a doxycycline-inducible prime editing platform. Read More

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January 2022

Nanoparticulate strategies for the delivery of miRNA mimics and inhibitors in anticancer therapy and its potential utility in oral submucous fibrosis.

Nanomedicine (Lond) 2022 Jan 11. Epub 2022 Jan 11.

Department of Oral Pathology, Manipal College of Dental Sciences, Manipal Academy of Higher Education, Manipal, 576104, Karnataka, India.

MicroRNAs (miRNAs) are naturally occurring noncoding RNAs with multiple functionalities. They are dysregulated in several conditions and can serve as disease biomarkers, therapeutic targets and therapeutic agents. Translation of miRNA therapeutics to the clinic poses several challenges related to the safe and effective delivery of these agents to the site of action. Read More

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January 2022

The sphingosine 1-phosphate receptor 2/4 antagonist JTE-013 elicits off-target effects on sphingolipid metabolism.

Sci Rep 2022 Jan 10;12(1):454. Epub 2022 Jan 10.

Molecular Therapeutics Laboratory, Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.

Sphingosine 1-phosphate (S1P) is a signaling lipid that has broad roles, working either intracellularly through various protein targets, or extracellularly via a family of five G-protein coupled receptors Agents that selectively and specifically target each of the S1P receptors have been sought as both biological tools and potential therapeutics. JTE-013, a small molecule antagonist of S1P receptors 2 and 4 (S1P and S1P) has been widely used in defining the roles of these receptors in various biological processes. Indeed, our previous studies showed that JTE-013 had anti-acute myeloid leukaemia (AML) activity, supporting a role for S1P in the biology and therapeutic targeting of AML. Read More

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January 2022

An in-silico approach to design potential siRNAs against the ORF57 of Kaposi's sarcoma-associated herpesvirus.

Genomics Inform 2021 Dec 31;19(4):e47. Epub 2021 Dec 31.

Department of Biotechnology and Genetic Engineering, Faculty of Science, Noakhali Science and Technology University, Noakhali 3814, Bangladesh.

Kaposi's sarcoma-associated herpesvirus (KSHV) is one of the few human oncogenic viruses, which causes a variety of malignancies, including Kaposi's sarcoma, multicentric Castleman disease, and primary effusion lymphoma, particularly in human immunodeficiency virus patients. The currently available treatment options cannot always prevent the invasion and dissemination of this virus. In recent times, siRNA-based therapeutics are gaining prominence over conventional medications as siRNA can be designed to target almost any gene of interest. Read More

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December 2021

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α.

Nanomaterials (Basel) 2022 Jan 3;12(1). Epub 2022 Jan 3.

Institute of Chemistry, Academia Sinica, Taipei 11529, Taiwan.

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. Read More

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January 2022

Nanomaterials with changeable physicochemical property for boosting cancer immunotherapy.

J Control Release 2022 Jan 6;342:210-227. Epub 2022 Jan 6.

Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

The past decade has witnessed a great progress in cancer immunotherapy with the sequential approvals of therapeutic cancer vaccine, immune checkpoint inhibitor and chimeric antigen receptor (CAR) T cell therapy. However, some hurdles still remain to the wide implementation of cancer immunotherapy, including low immune response, complex tumor heterogeneity, off-target immunotoxicity, poor solid tumor infiltration, and immune evasion-induced treatment tolerance. Owing to changeable physicochemical properties in response to endogenous or exogenous stimuli, nanomaterials hold the remarkable potential in incorporation of multiple agents, efficient biological barrier penetration, precise immunomodulator delivery, and controllable content release for boosting cancer immunotherapy. Read More

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January 2022

Circadian disruption and cisplatin chronotherapy for mammary carcinoma.

Toxicol Appl Pharmacol 2022 Jan 5;436:115863. Epub 2022 Jan 5.

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA; Sleep and Performance Research Center, Washington State University, Spokane, WA, USA. Electronic address:

Solid tumors are commonly treated with cisplatin, which can cause off-target side effects in cancer patients. Chronotherapy is a potential strategy to reduce drug toxicity. To determine the effectiveness of timed-cisplatin treatment in mammals, we compared two conditions: clock disrupted jet-lag and control conditions. Read More

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January 2022

VCP/p97 inhibitor CB-5083 modulates muscle pathology in a mouse model of VCP inclusion body myopathy.

J Transl Med 2022 Jan 8;20(1):21. Epub 2022 Jan 8.

Division of Genetics and Genomic Medicine, Dept. of Pediatrics, UC Irvine, Irvine, CA, USA.

Background: Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency. Read More

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January 2022

CRISPR/Cas9-mediated gene knockout and interallelic gene conversion in human induced pluripotent stem cells using non-integrative bacteriophage-chimeric retrovirus-like particles.

BMC Biol 2022 Jan 7;20(1). Epub 2022 Jan 7.

IRMB, Univ Montpellier, INSERM, CHU Montpellier, Hôpital St Eloi, 80 avenue Augustin Fliche, 34295, Montpellier, France.

Background: The application of CRISPR/Cas9 technology in human induced pluripotent stem cells (hiPSC) holds tremendous potential for basic research and cell-based gene therapy. However, the fulfillment of these promises relies on the capacity to efficiently deliver exogenous nucleic acids and harness the repair mechanisms induced by the nuclease activity in order to knock-out or repair targeted genes. Moreover, transient delivery should be preferred to avoid persistent nuclease activity and to decrease the risk of off-target events. Read More

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January 2022

Reduction of Off-Target Effects of Gapmer Antisense Oligonucleotides by Oligonucleotide Extension.

Mol Diagn Ther 2022 Jan 7;26(1):117-127. Epub 2022 Jan 7.

Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, Japan.

Aim: Antisense oligonucleotide (ASO) has the potential to induce off-target effects by inadvertent binding of ASOs to unintended RNAs that have a sequence similar to the target RNA. In the present study, we focused on the association between oligonucleotide length and off-target effects. Oligonucleotide extension is assumed to have bilateral effects on hybridization-dependent changes in gene expression, i. Read More

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January 2022

Differential associations of statin treatment and polymorphism in genes coding for HMGCR and PCSK9 to risk for insomnia.

Front Biosci (Landmark Ed) 2021 12;26(12):1453-1463

Department of Neuroscience, Functional Pharmacology Unit, Uppsala Biomedical Centre (BMC), Uppsala University, 75124 Uppsala, Sweden.

Importance: Statins have been linked to an increased risk for insomnia, but the literature is controversial. Moreover, it is unknown, if the potential effects are directly related to the inhibition of the statin target HMGCR, the subsequently lowered cholesterol levels, or other off-target effects of statins.

Aims: To investigate the association of statin treatment and genetic proxies of cholesterol lowering drugs with the risk for insomnia and chronotype in a large population-based cohort. Read More

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December 2021

CRISPR/Cas9 delivery by NIR-responsive biomimetic nanoparticles for targeted HBV therapy.

J Nanobiotechnology 2022 Jan 6;20(1):27. Epub 2022 Jan 6.

Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016, China.

Background: Currently, there are no curative drugs for hepatitis B virus (HBV). Complete elimination of HBV covalently closed circular DNA (cccDNA) is key to the complete cure of hepatitis B virus infection. The CRISPR/Cas9 system can directly destroy HBV cccDNA. Read More

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January 2022

Potential Applications for Targeted Gene Therapy to Protect Against Anthracycline Cardiotoxicity: Primer.

JACC CardioOncol 2021 Dec 21;3(5):650-662. Epub 2021 Dec 21.

Centre for Heart Research, The Westmead Institute for Medical Research, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.

Anthracyclines are associated with risk of significant dose-dependent cardiotoxicity. Conventional heart failure therapies have neither ameliorated declining cardiac function nor addressed the underlying cause. Gene therapy may confer long-term cardioprotection by rendering the heart resistant to anthracyclines after 1 treatment, although the optimal therapeutic target remains to be elucidated. Read More

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December 2021

Augmented Transcutaneous Stimulation Using an Injectable Electrode: A Computational Study.

Front Bioeng Biotechnol 2021 20;9:796042. Epub 2021 Dec 20.

Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, United States.

Minimally invasive neuromodulation technologies seek to marry the neural selectivity of implantable devices with the low-cost and non-invasive nature of transcutaneous electrical stimulation (TES). The Injectrode is a needle-delivered electrode that is injected onto neural structures under image guidance. Power is then transcutaneously delivered to the Injectrode using surface electrodes. Read More

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December 2021

Sonobiopsy for minimally invasive, spatiotemporally-controlled, and sensitive detection of glioblastoma-derived circulating tumor DNA.

Theranostics 2022 1;12(1):362-378. Epub 2022 Jan 1.

Department of Biomedical Engineering, Washington University in St. Louis, Saint Louis, MO 63130, USA.

Though surgical biopsies provide direct access to tissue for genomic characterization of brain cancer, they are invasive and pose significant clinical risks. Brain cancer management via blood-based liquid biopsies is a minimally invasive alternative; however, the blood-brain barrier (BBB) restricts the release of brain tumor-derived molecular biomarkers necessary for sensitive diagnosis. A mouse glioblastoma multiforme (GBM) model was used to demonstrate the capability of focused ultrasound (FUS)-enabled liquid biopsy (sonobiopsy) to improve the diagnostic sensitivity of brain tumor-specific genetic mutations compared with conventional blood-based liquid biopsy. Read More

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January 2022

Genetic Ablation of the Mitochondrial Calcium Uniporter (MCU) Does not Impair T Cell-Mediated Immunity .

Front Pharmacol 2021 20;12:734078. Epub 2021 Dec 20.

Würzburg Institute of Systems Immunology, Max Planck Research Group at the Julius-Maximilians-Universität Würzburg, Würzburg, Germany.

T cell activation and differentiation is associated with metabolic reprogramming to cope with the increased bioenergetic demand and to provide metabolic intermediates for the biosynthesis of building blocks. Antigen receptor stimulation not only promotes the metabolic switch of lymphocytes but also triggers the uptake of calcium (Ca) from the cytosol into the mitochondrial matrix. Whether mitochondrial Ca influx through the mitochondrial Ca uniporter (MCU) controls T cell metabolism and effector function remained, however, enigmatic. Read More

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December 2021

Evaluation of CRISPR gene-editing tools in zebrafish.

BMC Genomics 2022 Jan 6;23(1):12. Epub 2022 Jan 6.

Genome Center, MIND Institute, and Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Davis, CA, USA.

Background: Zebrafish have practical features that make them a useful model for higher-throughput tests of gene function using CRISPR/Cas9 editing to create 'knockout' models. In particular, the use of G mosaic mutants has potential to increase throughput of functional studies significantly but may suffer from transient effects of introducing Cas9 via microinjection. Further, a large number of computational and empirical tools exist to design CRISPR assays but often produce varied predictions across methods leaving uncertainty in choosing an optimal approach for zebrafish studies. Read More

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January 2022

Pathways Toward a Functional HIV-1 Cure: Balancing Promise and Perils of CRISPR Therapy.

Methods Mol Biol 2022 ;2407:429-445

Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.

First identified as a viral defense mechanism, clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (Cas) has been transformed into a gene-editing tool. It now affords promise in the treatment and potential eradication of a range of divergent genetic, cancer, infectious, and degenerative diseases. Adapting CRISPR-Cas into a programmable endonuclease directed guide RNA (gRNA) has attracted international attention. Read More

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January 2022

Targeted Gene Knockouts by Protoplast Transformation in the Moss .

Authors:
Lei Zhu

Front Genome Ed 2021 17;3:719087. Epub 2021 Dec 17.

Department of Botany and Plant Sciences, University of California, Riverside, CA, United States.

Targeted gene knockout is particularly useful for analyzing gene functions in plant growth, signaling, and development. By transforming knockout cassettes consisting of homologous sequences of the target gene into protoplasts, the classical gene targeting method aims to obtain targeted gene replacement, allowing for the characterization of gene functions . The moss is a known model organism for a high frequency of homologous recombination and thus harbors a remarkable rate of gene targeting. Read More

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December 2021

Time-controlled and muscle-specific CRISPR/Cas9-mediated deletion of CTG-repeat expansion in the gene.

Mol Ther Nucleic Acids 2022 Mar 29;27:184-199. Epub 2021 Nov 29.

Institute of Biochemistry and Cell Biology, National Research Council, Monterotondo, 00015 Rome, Italy.

CRISPR/Cas9-mediated therapeutic gene editing is a promising technology for durable treatment of incurable monogenic diseases such as myotonic dystrophies. Gene-editing approaches have been recently applied to and models of myotonic dystrophy type 1 (DM1) to delete the pathogenic CTG-repeat expansion located in the 3' untranslated region of the gene. In DM1-patient-derived cells removal of the expanded repeats induced beneficial effects on major hallmarks of the disease with reduction in transcript-containing ribonuclear foci and reversal of aberrant splicing patterns. Read More

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Bone-targeted Bortezomib Inhibits Bortezomib-Resistant Multiple Myeloma in Mice by Providing Higher Levels of Bortezomib in Bone.

J Bone Miner Res 2021 Dec 30. Epub 2021 Dec 30.

Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.

Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone-residing cancer, especially drug-resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off-target effects. To this end, bone-targeted conjugate (BP-Btz) was generated by linking Bortezomib (Btz, an anticancer, bone-stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled delivery of Btz to bone under acidic conditions for treating multiple myeloma (MM). Read More

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December 2021

Lipid Nanocarriers for Neurotherapeutics: Introduction, Challenges, Blood-brain Barrier, and Promises of Delivery Approaches.

CNS Neurol Disord Drug Targets 2021 Jul 6. Epub 2021 Jul 6.

University School of Biotechnology, Guru Gobind Singh Indraprastha University, New Delhi,India.

Significant efforts have been made in research to discover newer neurotherapeutics, however, the rate of reported neurological disorders has been increasing at an alarming speed. Neurotherapeutics delivery in the brain is still posing a significant challenge, owing to the blood-brain barrier and blood-cerebrospinal fluid barrier. These physiological barriers restrict the passage of systemically available fractions of neurotherapeutics into the brain, owing to low permeability and drug localization factors. Read More

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Spray drift potential of dicamba plus S-metolachlor formulations.

Pest Manag Sci 2021 Dec 29. Epub 2021 Dec 29.

University of Nebraska-Lincoln, West Central Research and Extension Center, North Platte, NE, USA.

Background: Early-postemergence herbicide applications in the US often include residual herbicides such as S-metolachlor to suppress late late-emerging Amaranthus spp. Although this practice benefits weed control, herbicide tankmixes can influence spray droplet size and drift potential during applications. The addition of S-metolachlor products to dicamba spray solutions generally decreases spray droplet size and increases spray drift potential. Read More

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December 2021