Biology subjects

Hoseini, M.

Publications and source records attributed to Hoseini, M..

3 recordsLinked to original sources

bioRxiv2026

Modeled Oxidative Lesions Remodel the ABCB1 Linker: A Hypothesis for Transporter Regulation

Multidrug resistance mediated by P-glycoprotein (P-gp; ABCB1) remains a major barrier to chemotherapy. Cold atmospheric plasma (CAP) has increased drug responsiveness in resistant cancer models, but the molecular link between plasma-derived oxidative chemistry and ABCB1 regulation remains unresolved. We investigated whether site-specific oxidative lesions remodel the intrinsically disordered linker connecting nucleotide-binding domain 1 to transmembrane domain 2. Native-ensemble exposure analysis identified contrasting oxidation candidates: dynamically exposed Met653 and persistently exposed Trp698. Met653 oxidation to methionine sulfoxide and Trp698 oxidation to kynurenine were examined individually and together using a balanced 2 by 2 molecular-dynamics design with a mechanically tethered linker construct. Analyses integrated global descriptors, residue-resolved mobility, backbone order, native-state occupancies, projected breadth, and conformational switching. Trp698[->]KYN produced the dominant response: all seven global descriptors shifted toward restriction, accompanied by distributed mobility changes, compaction, and increased intramolecular hydrogen bonding. In the radius-of-gyration/end-to-end-distance projection, compact-state occupancy increased from 46.9% to 99.7%, switching decreased from 6.50 to 0.07 transitions per 10 ns, and projected breadth contracted. Met653[->]SME produced weaker, heterogeneous effects, while the double-modified linker remained restricted but showed greater projected exchange than Trp698[->]KYN alone. In this model, Trp698[->]KYN generated a compact, low-exchange projected ensemble in the tethered ABCB1 linker. These findings identify oxidation-site-specific linker remodeling as a candidate molecular intermediate that could influence linker-mediated domain coordination, while requiring experimental validation of lesion formation, transporter activity, and multidrug resistance outcomes.

biophysics↗

bioRxiv2022

Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability in the world and the strongest environmental risk factor for the development of dementia. Even mild TBI (resulting from concussive injuries) is associated with a >2-fold increase in the risk of dementia onset. Little is known about the cellular mechanisms responsible for the progression of long lasting cognitive deficits. The integrated stress response (ISR), a phylogenetically conserved pathway involved in the cellular response to stress, is activated after TBI, axsnd inhibition of the ISR -- even weeks after injury -- can reverse behavioral and cognitive deficits. However, the cellular mechanisms by which ISR inhibition restores cognition are unknown. Here we used longitudinal two-photon imaging in vivo after concussive injury in mice to study dendritic spine dynamics in the parietal cortex, a brain region involved in working memory. Concussive injury profoundly altered spine dynamics measured up to a month after injury. Strikingly, brief pharmacological treatment with the drug-like small-molecule ISR inhibitor ISRIB entirely reversed the structural changes measured in the parietal cortex and the associated working memory deficits. Thus, both neural and cognitive consequences of concussive injury are mediated in part by activation of the ISR and can be corrected by its inhibition. These findings suggest that targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after TBI. Significance StatementAfter traumatic brain injury, temporary pharmacological inhibition of the integrated stress response (ISR), with a small-molecule inhibitor (ISRIB), rescued long lasting trauma-induced cognitive deficits. Here, we found that ISRIB treatment rapidly and persistently reversed the aberrant changes in cortical spine dynamics in the parietal cortex while rescuing working memory deficits. These data suggests that the link between the ISR and memory function involves, at least in part, changes in neuronal structure. Targeting ISR activation could serve as a promising approach for the clinical treatment of chronic cognitive deficits after brain injuries.

neuroscience↗

bioRxiv2019

Transplanted cells are essential for the induction but not the expression of cortical plasticity

Transplantation of even a small number of embryonic inhibitory neurons from the medial ganglionic eminence (MGE) into postnatal visual cortex makes it lose responsiveness to an eye deprived of vision when the transplanted neurons reach the age of the normal critical period of activity-dependent ocular dominance (OD) plasticity. The transplant might induce OD plasticity in the host circuitry or might instead construct a parallel circuit of its own to suppress cortical responses to the deprived-eye. We transplanted MGE neurons expressing archaerhodopsin, closed one eyelid for 4-5 days, and, as expected, observed transplant-induced OD plasticity. This plasticity was evident even when the activity of the transplanted cells was suppressed optogenetically, demonstrating that the plasticity was produced by changes in the host visual cortex.\n\nSignificance StatementInterneuron transplantation into mouse V1 creates a window of heightened plasticity which is quantitatively and qualitatively similar to the normal critical period, i.e. short-term occlusion of either eye markedly changes ocular dominance. The underlying mechanism of this process is not known. Transplanted interneurons might either form a separate circuit to maintain the ocular dominance shift or might instead trigger changes in the host circuity. We designed experiments to distinguish the two hypotheses. Our findings suggest that while inhibition produced by the transplanted cells triggers this form of plasticity, the host circuity is entirely responsible for maintaining the ocular dominance shift.\n\nOne Sentence SummaryNeuronal transplants do not just grow and connect--they induce plasticity in the adult brain.

neuroscience↗