Biology subjects

Knudsen, S.

Publications and source records attributed to Knudsen, S..

5 recordsLinked to original sources

bioRxiv2025

Point mutation in sensor triples zinc levels in Sorghum bicolor

Zinc (Zn) deficiency is widespread in agricultural soils and it is also a common nutritional problem in humans. We previously discovered a Zn Sensor Motif (ZSM) in the Arabidopsis F-bZIP transcription factors, bZIP19 and bZIP23, which impacts the concentration of Zn in Arabidopsis plants. Sorghum (Sorghum bicolor (L.) Moench) is one of the most important cereals crops worldwide and here, using a large-scale sorghum mutant library, we report the identification of variants with a ZSM point mutation. We show that a cysteine substitution in the ZSM of the sorghum bZIP19/23 homolog causes a three-fold increase in Zn levels in sorghum seeds with no visible developmental penalty. Our work provides the first evidence that modulating the F-bZIP ZSM is a promising strategy for Zn biofortification in crops. This discovery paves the way to generate Zn biofortified crops and alleviate the global problems of Zn deficient soils and Zn malnutrition.

plant biology↗

bioRxiv2021

Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerases (PARPs), blocks in vitro replication of SARS-CoV-2 variants

We recently published a preliminary assessment of the activity of a poly (ADP-ribose) polymerase (PARP) inhibitor, stenoparib, also known as 2X-121, which inhibits viral replication by affecting pathways of the host. Here we show that stenoparib effectively inhibits a SARS-CoV-2 wt (BavPat1/2020) strain and four additional variant strains; alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 M, 8.5 M, 24.1 M, 8.2 M and 13.6 M, respectively. A separate experiment focusing on a combination of 10 M stenoparib and 0.5 M remdesivir, an antiviral drug, resulted in over 80% inhibition of the alpha (B.1.1.7) variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.

microbiology↗

bioRxiv2021

FIND-IT: Ultrafast mining of genome diversity

Novel crop improvement methodologies, including the exploitation of natural genetic variation, are urgently required to feed our rapidly growing human population in the context of global climate change. Here we describe a Fast Identification of Nucleotide variants by DigITal PCR (FIND-IT) method for the rapid identification of pre-targeted genetic variants or rare alleles in large genomic populations. Libraries of 500,000 individuals can be screened and desired variants isolated within two weeks. FIND-IT is widely applicable for mining valuable diversity in any genomic population, including elite breeding and wild germplasm collections. The method provides single nucleotide resolution that has been validated by identifying and isolating knockout lines, non-synonymous codon changes and variants of miRNA and transcription factor binding sites in the agronomically important crop barley. In contrast to existing methods, FIND-IT does not require transformation, cloning or enzymatic steps, and is exempt from GMO regulations. Thus, FIND-IT can be applied immediately to elite crop cultivars and can be tailored to minimize or eliminate time-consuming backcrossing requirements.

genetics↗

bioRxiv2018

Narcolepsy type 1 patients have abnormal brain activation to neutral-rated movies in humor-paradigm

Narcolepsy type 1 is a neurological sleep disorder mainly characterized by excessive daytime sleepiness, fragmented night sleep, and cataplexy (muscle atonia triggered by emotions). To characterize brain activation patterns in response to neutral-rated and fun-rated movies in narcolepsy type 1 we performed functional magnetic resonance imaging during a paradigm consisting of 30 short movies (25/30 with a humorous punchline; 5/30 without a humorous punchline (but with similar build-up/anticipation)) that the participants rated based on their humor experience. We included 41 narcolepsy type 1 patients (31 females, mean age 23.6 years, 38/41 H1N1-vaccinated, 41/41 HLA-DQB1*06:02-positive, 40/40 hypocretin-deficient) and 44 first-degree relatives (24 females, mean age 19.6 years, 30/44 H1N1-vaccinated, 27/44 HLA-DQB1*06:02-positive) as controls. Group-level inferences were made using permutation testing.\n\nPermutation testing revealed no significant differences in the average ratings of patients and controls. Functional magnetic resonance imaging analysis revealed that both groups showed higher activations in response to fun-rated movies in several brain regions associated with humor processing, with no significant group differences. In contrast, patients showed significantly higher activation compared to controls during neutral-rated movies; including bilaterally in the thalamus, pallidum, putamen, amygdala, hippocampus, middle temporal gyrus, cerebellum, brainstem and in the left precuneus, supramarginal gyrus and caudate.\n\nThe presence of a humorous punchline in a neutral-rated movie is important since we found no brain overactivation for narcolepsy type 1 patients for movies without a humorous punchline (89.0% neutral-rated) compared with controls.\n\nFurther, a comparison between fun-rated and neutral-rated movies revealed a pattern of higher activation during fun-rated movies in controls, patients showed no significant differentiation between these states. Group analyses revealed significantly stronger differentiation between fun-rated and neutral-rated movies in controls compared with patients, including bilaterally in the inferior frontal gyrus, thalamus, putamen, precentral gyrus, lingual gyrus, supramarginal gyrus, occipital areas, temporal areas, cerebellum and in the right hippocampus, postcentral gyrus, pallidum and insula.\n\nIn conclusion, during neutral-rated movies, narcolepsy type 1 patients showed significantly higher activation in several cortical and subcortical regions previously implicated in humor and REM sleep, including the thalamus and basal ganglia. The relative lack of differentiation between neutral-rated and fun-rated movies in narcolepsy type 1 patients might represent insight into the mechanisms associated with cataplexy, in which a long-lasting hypervigilant state could represent risk (hypersensitivity to potential humorous stimuli) for the narcolepsy type 1 patients, which seem to have a lower threshold for activating the humor response, even during neutral-rated movies.

neuroscience↗

bioRxiv2018

Narcolepsy risk loci are enriched in immune cells and suggest autoimmune modulation of the T cell receptor repertoire

Type 1 narcolepsy (T1N) is a neurological condition, in which the death of hypocretin-producing neurons in the lateral hypothalamus leads to excessive daytime sleepiness and symptoms of abnormal Rapid Eye Movement (REM) sleep. Known triggers for narcolepsy are influenza-A infection and associated immunization during the 2009 H1N1 influenza pandemic. Here, we genotyped all remaining consented narcolepsy cases worldwide and assembled this with the existing genotyped individuals. We used this multi-ethnic sample in genome wide association study (GWAS) to dissect disease mechanisms and interactions with environmental triggers (5,339 cases and 20,518 controls). Overall, we found significant associations with HLA (2 GWA significant subloci) and 11 other loci. Six of these other loci have been previously reported (TRA, TRB, CTSH, IFNAR1, ZNF365 and P2RY11) and five are new (PRF1, CD207, SIRPG, IL27 and ZFAND2A). Strikingly, in vaccination-related cases GWA significant effects were found in HLA, TRA, and in a novel variant near SIRPB1. Furthermore, IFNAR1 associated polymorphisms regulated dendritic cell response to influenza-A infection in vitro (p-value =1.92*10-25). A partitioned heritability analysis indicated specific enrichment of functional elements active in cytotoxic and helper T cells. Furthermore, functional analysis showed the genetic variants in TRA and TRB loci act as remarkable strong chain usage QTLs for TRAJ*24 (p-value = 0.0017), TRAJ*28 (p-value = 1.36*10-10) and TRBV*4-2 (p-value = 3.71*10-117). This was further validated in TCR sequencing of 60 narcolepsy cases and 60 DQB1*06:02 positive controls, where chain usage effects were further accentuated. Together these findings show that the autoimmune component in narcolepsy is defined by antigen presentation, mediated through specific T cell receptor chains, and modulated by influenza-A as a critical trigger.

genetics↗