Biology subjects

Cheema, A.

Publications and source records attributed to Cheema, A..

4 recordsLinked to original sources

bioRxiv2025

Strigolactone effects on Sorghum bicolor ecophysiology and symbioses

Strigolactones are ecologically, developmentally, and physiologically important hormones, but much remains unknown about their evolution and role in non-model species. Sorghum is a globally important C4 cereal and exhibits natural variation in root-exuded strigolactones. Differences in sorghum strigolactone stereochemistry are associated with resistance to parasitic plants, but with evidence for potential trade-offs. We studied sorghum mutants of loci in the strigolactone biosynthetic pathway, CAROTENOID CLEAVAGE DIOXYGENASE 8 (SbCCD8b) and LOW GERMINATION STIMULANT 1 (LGS1), previously shown to be Striga resistant by stimulating little germination of the parasite. SbCCD8b CRISPR-Cas9 deletions changed the accumulation of low abundance metabolites, reduced net carbon assimilation rate, altered root architecture and anatomy, and diminished the establishment and benefit of mycorrhizal symbionts. For Striga-resistant LGS1 CRISPR-Cas9 deletions, differentially expressed genes were enriched with promoter motifs for stress response and growth pathways, net carbon assimilation rate was reduced, and the colonization of mycorrhizal symbionts was delayed. We additionally restored functional LGS1 into the RTx430 genetic background, which normally has the lgs1-2 natural deletion allele. While root exudates from LGS1 insertion mutants rescued Striga susceptibility, we did not see consistent rescue of other traits impacted in LGS1 loss-of-function mutants. We hypothesize that epistasis with a neighboring strigolactone synthesis gene, which is rarely lost without concomitant loss of LGS1, may alter the phenotypic effects of LGS1 variation. Our study gives context to potential trade-offs associated with host resistance to parasitic plants and, more broadly, builds on the contribution of strigolactones in shaping sorghum physiological processes, growth, and development.

plant biology↗

bioRxiv2023

Loss of the mitochondrial citrate carrier, SLC25A1/CIC disrupts embryogenesis via 2-Hydroxyglutarate

Germline inactivating mutations of the SLC25A1 gene contribute to various human developmental disorders, including combined D/L-2-hydroxyglutaric aciduria (D/L-2HGA), a severe systemic syndrome characterized by the accumulation of both enantiomers of 2-hydroxyglutaric acid (2HG). The mechanisms by which SLC25A1 deficiency leads to this disease and the role of 2HG are unclear and no therapies exist. We now show that mice lacking both Slc25a1 alleles display a spectrum of alterations that resemble human D/L-2HGA. Mechanistically, SLC25A1 loss results in a proliferation defect and activates two distinct senescence pathways, oncogene-induced senescence (OIS) and mitochondrial dysfunction-induced senescence (MiDAS), both involving the p53 tumor suppressor and driven by two discernible signals: the accumulation of 2HG, inducing OIS, and mitochondrial dysfunction, triggering MiDAS. Inhibiting these senescence programs or blocking p53 activity reverses the growth defect caused by SLC25A1 dysfunction and restores proliferation. These findings reveal novel pathogenic roles of senescence in human disorders and suggest potential strategies to correct the molecular alterations caused by SLC25A1 loss.

developmental biology↗

bioRxiv2021

NAD metabolism modulates mitochondrial function and inflammation and prevents progression of diabetic kidney disease

Diabetes mellitus is the leading cause of cardiovascular and renal disease in the United States. In spite of the beneficial interventions available for patients with diabetes, there remains a need for additional therapeutic targets and therapies in diabetic kidney disease (DKD). Inflammation and oxidative stress are increasingly recognized as important causes of renal diseases. Inflammation is closely associated with mitochondrial damage. The molecular connection between inflammation and mitochondrial metabolism remains to be elucidated. Recently, nicotinamide adenine nucleotide (NAD+) metabolism has been found to regulate immune function and inflammation. In the present studies we tested the hypothesis that enhancing NAD metabolism could prevent inflammation in and progression of DKD. We found that treatment of db/db mice with type 2 diabetes with nicotinamide riboside (NR) prevented several manifestations of kidney dysfunction (i.e., albuminuria, increased urinary kidney injury marker-1 (KIM1) excretion and pathologic changes). These effects were associated with decreased inflammation, at least in part via inhibiting the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. An antagonist of the serum stimulator of interferon genes (STING) and whole-body STING deletion in diabetic mice showed similar renoprotection. Further analysis found that NR increased SIRT3 activity and improved mitochondrial function, which led to decreased mitochondrial DNA damage, a trigger for mitochondrial DNA leakage which activates the cGAS-STING pathway. Overall, these data show that NR supplementation boosted NAD metabolism to augment mitochondrial function, reducing inflammation and thereby preventing progression of diabetic kidney disease.

pathology↗

bioRxiv2021

Identification of multi-omics molecular signature of acute radiation injury using nonhuman primate model

The availability of validated biomarkers to assess radiation exposure and to assist in developing medical countermeasures remains an unmet need. We used a cobalt-60 gamma-irradiated nonhuman primate (NHP) model to delineate a multi-omics-based serum probability index of radiation exposure. Both male and female NHPs were irradiated with different doses ranging from 6.0 to 8.5 Gy, with 0.5 Gy increments between doses. We leveraged high resolution mass spectrometry for analysis of metabolites, lipids, and proteins at 1,2, and 6 days post-irradiation in NHP serum. A logistic regression model was implemented to develop a 4-analyte panel to stratify irradiated NHPs from unirradiated with high accuracy that was agnostic for all doses of {gamma}-rays tested in the study, up to six days after exposure. This panel was comprised of Serpin Family A9, acetylcarnitine, PC (16:0/22:6), and suberylglycine, which showed 2 - 4-fold elevation in serum abundance upon irradiation in NHPs, and can potentially be translated for human use following larger validation studies. Taken together, this study, for the first time, demonstrates the utility of a combinatorial molecular characterization approach using an NHP model for developing minimally invasive assays from small volumes of blood that can be effectively used for radiation exposure assessments.

biochemistry↗