Biology subjects

Allu, S. R.

Publications and source records attributed to Allu, S. R..

4 recordsLinked to original sources

bioRxiv2025

Global hypoperfusion leads to a mismatch in oxygen delivery and consumption in the cerebral watershed area

Despite the pivotal role of pial collaterals in maintaining cerebral blood flow during focal brain ischemia, it is largely unexplored how the microvascular blood flow and oxygenation in the watershed "pial-collateral territory" differ from those in the territory supplied by the major arteries during chronic global hypoperfusion. To answer this question, we applied 2-photon microscopy and Doppler optical coherence tomography to investigate the changes in cerebral microvascular blood flow and partial pressure of oxygen (PO2), induced by bilateral common carotid artery stenosis (BCAS). The measurements were performed in the somatosensory cortex that is supplied by the middle cerebral artery (MCA), and in the adjacent watershed area in the awake, head-restrained C57BL/6 mice, via the chronic cranial window. The results showed that the BCAS induced a larger decrease in capillary red blood cell (RBC) flux in the watershed area than in the MCA territory, especially in the subcortical white matter. Besides, PO2 in the pial collaterals was significantly lower than that in the upstream MCA segments under control conditions. However, the PO2 changes in the arteries and veins under global hypoperfusion displayed different trends in the two interrogated regions, resulting in a significant increase in oxygen extraction fraction in the watershed area. These findings suggest a mismatch between oxygen supply and demand in the watershed area due to global hypoperfusion and increased subcortical white matter vulnerability. We have also observed dilation of the pial collaterals after BCAS, which might suggest a compensatory mechanism to improve the blood flow in the watershed under hypoperfusion.

neuroscience↗

bioRxiv2025

ECgo: All-Optical Induction of Single Endothelial Cell Injury and Capillary Occlusion in the Brain

The ability to induce endothelial cell (EC) damage in the mouse brain with high spatial precision is invaluable for mechanistic studies of brain capillary injury and repair. Here, we introduce an optical method, termed ECgo, that utilizes a new two-photon-excitable porphyrin-based photosensitizer (Ps2P) to selectively obliterate single ECs within the brain microvascular network. Using the developed approach, we were able to induce occlusions of single capillaries with high spatiotemporal control, while preserving the surrounding tissue. Combined with longitudinal two-photon imaging, ECgo enables studies of morphological and functional consequences of targeted single capillary EC injury in vivo under healthy and diseased conditions. SIGNIFICANCE STATEMENTBrain capillary injury is a common feature of aging and many neurological disorders. While a single capillary lesion may appear inconsequential, the cumulative effect of repeated and spatially dispersed capillary insults can lead to substantial brain dysfunction. Understanding how single capillary injuries contribute cumulatively to long-term brain damage requires tools that can precisely target individual capillaries in the living brain. Here, we introduce an optical method that uses a new light-activatable compound to selectively injure single brain capillaries with high spatial accuracy. Our method enables detailed, longitudinal studies of capillary repair, blood flow recovery, local oxygen dynamics, and glial responses following microvascular injury.

neuroscience↗

bioRxiv2023

Aerobic exercise reverses aging-induced depth-dependent decline in cerebral microcirculation

Aging is a major risk factor for cognitive impairment. Aerobic exercise benefits brain function and may promote cognitive health in older adults. However, underlying biological mechanisms across cerebral gray and white matter are poorly understood. Selective vulnerability of the white matter to small vessel disease and a link between white matter health and cognitive function suggests a potential role for responses in deep cerebral microcirculation. Here, we tested whether aerobic exercise modulates cerebral microcirculatory changes induced by aging. To this end, we carried out a comprehensive quantitative examination of changes in cerebral microvascular physiology in cortical gray and subcortical white matter in mice (3-6 vs. 19-21 months old), and asked whether and how exercise may rescue age-induced deficits. In the sedentary group, aging caused a more severe decline in cerebral microvascular perfusion and oxygenation in deep (infragranular) cortical layers and subcortical white matter compared with superficial (supragranular) cortical layers. Five months of voluntary aerobic exercise partly renormalized microvascular perfusion and oxygenation in aged mice in a depth-dependent manner, and brought these spatial distributions closer to those of young adult sedentary mice. These microcirculatory effects were accompanied by an improvement in cognitive function. Our work demonstrates the selective vulnerability of the deep cortex and subcortical white matter to aging-induced decline in microcirculation, as well as the responsiveness of these regions to aerobic exercise.

neuroscience↗

bioRxiv2020

Identification of herboxidiene structural features that mediate conformation-dependent SF3B1 interactions to inhibit splicing.

Small molecules that target the spliceosome SF3B complex are potent inhibitors of cancer cell growth. The compounds affect an early stage of spliceosome assembly when U2 snRNP first engages the branch point sequence of an intron. Recent cryo-EM models of U2 snRNP before and after intron recognition suggest several large-scale rearrangements of RNA and protein interactions involving SF3B. Employing an inactive herboxidiene analog as a competitor with SF3B inhibitors, we present evidence for multiple conformations of SF3B in the U2 snRNP, only some of which are available for productive inhibitor interactions. We propose that both thermodynamics and an ATP-binding event promote the conformation conducive to SF3B inhibitor interactions. However, SF3B inhibitors do not impact an ATP-dependent rearrangement in U2 snRNP that exposes the branch binding sequence for base pairing. We also report extended structure activity relationship analysis of herboxidiene, which identified features of the tetrahydropyran ring that mediate its interactions with SF3B and its ability to interfere with splicing. In combination with structural models of SF3B interactions with inhibitors, our data leads us to extend the model for early spliceosome assembly and inhibitor mechanism. We postulate that interactions between a carboxylic acid substituent of herboxidiene and positively charged SF3B1 sidechains in the inhibitor binding channel are required to maintain inhibitor occupancy and counteract the SF3B transition to a closed state that is promoted by stable U2 snRNA interactions with the intron.

molecular biology↗