Biology subjects

Hekmatyar, K.

Publications and source records attributed to Hekmatyar, K..

5 recordsLinked to original sources

bioRxiv2025

Prevention and reversal of hypertension-induced coronary microvascular dysfunction by a plant-based diet

Background and aimsCoronary microvascular dysfunction (CMD) is associated with adverse cardiovascular outcomes. CMD is driven by endothelial and vascular smooth muscle cell (VSMC) dysfunction. We aimed to test whether CMD could be mitigated by a plant-based diet (PBD) in an animal model of hypertension. MethodsWe compared 28- and 40-week-old female normotensive Wistar-Kyoto and spontaneously hypertensive (SHR) rats, maintained, from age 4 weeks, on a control refined diet or a PBD, comprised of 28% fruits, vegetables, nuts and legumes. A subset of control SHRs were switched to the PBD at 28 weeks. CMD was assessed by coronary flow reserve via echocardiogram. Cardiac microvascular endothelial function was assessed via cMRI. Endothelial and VSMC function were assessed in the left ventricle (LV) or in isolated VSMCs. The role of gut microbiota was probed via 16S sequencing and antibiotics. Cardiac inflammation, oxidative stress, and fibrosis were also explored. ResultsSHRs exhibited endothelial dysfunction and likely VSMC dysfunction. PBD did not ameliorate their hypertension but, nonetheless, prevented and reversed CMD. PBDs mitigation of CMD was associated with improved endothelial nitric oxide synthase function and NO-mediated VSMC signaling, as well as reductions in LV oxidative stress, inflammatory signaling, and fibrosis. PBD altered the gut microbiota, although antibiotic studies failed to establish its importance in ameliorating CMD. ConclusionsA PBD prevented CMD development and reversed established CMD in SHRs. Such benefits of PBD, which occurred without alleviating hypertension, were possibly due to improved endothelial function and likely improved VSMC function. These results support clinical trials to test PBDs in human CMD. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/649660v2_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@1a87550org.highwire.dtl.DTLVardef@add809org.highwire.dtl.DTLVardef@1426561org.highwire.dtl.DTLVardef@de9e0_HPS_FORMAT_FIGEXP M_FIG C_FIG A plant-based diet prevented and reversed CMD without attenuating hypertension. Such amelioration of CMD was not negated by antibiotics and correlated with improved endothelial and VSMC function. Legend: ABX, antibiotics; BP, blood pressure; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PBD, plant-based diet; PKG, protein kinase G; PLN, phospholamban; SHR, spontaneously hypertensive rat; SR, sarcoplasmic reticulum; VSMC, vascular smooth muscle cell.

physiology↗

bioRxiv2024

From circuits to lifespan: translating mouse and human timelines with neuroimaging based tractography

Age is a major predictor of developmental processes and disease risk, but humans and model systems (e.g., mice) differ substantially in the pace of development and aging. The timeline of human developmental circuits is well known. It is unclear how such timelines compare to those in mice. We lack age alignments across the lifespan of mice and humans. Here, we build upon our Translating Time resource, which is a tool that equates corresponding ages during development. We collected 477 time points (n=1,132 observations) from age-related changes in body, bone, dental, and brain processes to equate corresponding ages across humans and mice. We acquired high-resolution diffusion MR scans of mouse brains (n=12) at sequential stages of postnatal development (postnatal day 3, 4, 12, 21, 60) to trace the timeline of brain circuit maturation (e.g., olfactory association pathway, corpus callosum). We found heterogeneity in white matter pathway growth. The corpus callosum largely ceases to grow days after birth while the olfactory association pathway grows through P60. We found that a P3 mouse equates to a human at roughly GW24, and a P60 mouse equates to a human in teenage years. Therefore, white matter pathway maturation is extended in mice as it is in humans, but there are species-specific adaptations. For example, olfactory-related wiring is protracted in mice, which is linked to their reliance on olfaction. Our findings underscore the importance of translational tools to map common and species-specific biological processes from model systems to humans. Significance statementMice are essential models of human brain development, but we currently lack precise age alignments across their lifespan. Here, we equate corresponding ages across mice and humans. We utilize high-resolution diffusion mouse brain scans to track the growth of brain white matter pathways, and we use our cross-species age alignments to map the timeline of these growth patterns from mouse to humans. In mice, olfactory association pathway growth continues well into the equivalent of human teenage years. The protracted development of olfactory association pathways in mice aligns with their specialized sense of smell. The generation of translational tools bridges the gap between animal models and human biology while enhancing our understanding of developmental processes generating variation across species.

neuroscience↗

bioRxiv2023

Therapeutic mitigation of measles-like immune amnesia and exacerbated disease after prior respiratory virus infections in ferrets

After years of the COVID-19 pandemic, over 40 million children worldwide are at risk of measles due to delayed vaccination1 and temporary SARS-CoV-2 viral dominance2. Acute measles has a case-fatality rate of [~]1%, but most morbidity and mortality arise post-measles due to destruction of pre-existing immune memory by lymphotropic measles virus (MeV)3,4, a paramyxovirus of the Morbillivirus genus. MeV-induced immune amnesia is not mitigated by post-exposure vaccination and the impact of unrelated respiratory virus disease history on measles severity has not been defined. We used a lethal canine distemper virus (CDV)-ferret model as surrogate for human morbillivirus disease5 and employed the orally efficacious broad-spectrum paramyxovirus polymerase inhibitor GHP-883096 to establish measles treatment paradigms. Applying a receptor tropism-intact recombinant CDV with low lethality, we provide in vivo confirmation of the morbillivirus immune amnesia hypothesis and reveal an 8-day advantage of antiviral treatment versus therapeutic vaccination in preserving immune memory. Infection of ferrets with non-lethal influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks prior to CDV caused exacerbated CDV disease that rapidly advanced to fatal hemorrhagic pneumonia associated with lung onslaught by commensal bacteria. RNAseq of BAL samples and lung tissue identified CDV-induced expression of trefoil factor (TFF) peptides, which was absent in animals pre-infected with IAV, thus highlighting that immune priming by unrelated respiratory viruses influences morbillivirus infection outcome. Non-invasive pulmonary ferret MRI revealed that severe outcomes of consecutive IAV/CDV infections were prevented by oral GHP-88309 treatment even when initiated after peak clinical signs of CDV. These findings validate the morbillivirus immune amnesia hypothesis, define treatment paradigms for measles, identify prior disease history as risk factor for exacerbated morbillivirus disease, and demonstrate that treating morbillivirus infection with direct-acting oral antivirals provides therapeutic benefit regardless of whether the time window to mitigate primary clinical signs of infection has closed.

microbiology↗

bioRxiv2022

Evaluating Quantitative and Functional MRI As Potential Techniques to Identify the Subdivisions in the Human Lateral Geniculate Nucleus

Segmenting the magnocellular (M) and parvocellular (P) divisions of the human lateral geniculate nucleus (LGN) has been challenging yet remains an important goal because the LGN is the only place in the brain where these two information streams are spatially disjoint and can be studied independently. Previous research used the amplitude of responses to different types of stimuli to separate M and P regions (Denison et al., 2014; Zhang et al., 2015). However, this method is confounded because the hilum region of the LGN exhibits greater response amplitudes to all stimuli and can be mistaken for the M subdivision (DeSimone & Schneider, 2019). Therefore, we have employed two independent methodologies that do not rely upon the functional response properties of the M and P neurons to segment the M and P regions: 1) structural quantitative MRI (qMRI) at 3T to measure the T1 relaxation time, and 2) monocular and dichoptic functional MRI (fMRI) procedures to measure eye-specific responses. Our qMRI results agreed with the anatomical expectations, identifying M regions on the ventromedial surface of the LGN. The monocular fMRI procedure was better than the dichoptic condition to identify the eye-dominance signals. Both procedures revealed significant right eye bias, and neither could reliably identify the first M layer of the LGN. These findings indicated that the qMRI methods are promising whereas the functional identification of contralateral layers requires further refinement. HighlightsO_LIT1 parameter in qMRI segregates M and P regions of LGN in individual subjects at 3T. C_LIO_LIEye-specific voxels in LGN respond more strongly to monocular than dichoptic viewing. C_LIO_LIClusters of eye-specific regions but not layers can be separated at 1.5 mm resolution. C_LI

neuroscience↗

bioRxiv2021

Tracing cortical circuits in humans and non-human primates from high resolution connectomic, transcriptomic, and temporal dimensions

The neural circuits that support human cognition are a topic of enduring interest. Yet, the lack of tools available to map human brain circuits has precluded our ability to trace the human and non-human primate connectome. We harnessed high-resolution connectomic, anatomic, and transcriptomic data to investigate the evolution and development of frontal cortex circuitry. We applied machine learning to RNA sequencing data to find corresponding ages between humans and macaques and to compare the development of circuits across species. We transcriptionally defined neural circuits by testing for associations between gene expression and white matter maturation. We then considered transcriptional and structural growth to test whether frontal cortex circuit maturation is unusually extended in humans relative to other species. We also considered gene expression and high-resolution diffusion MR tractography of adult brains to test for cross-species variation in frontal cortex circuits. We found that frontal cortex circuitry development is extended in primates, and concomitant with an expansion in cortico-cortical pathways compared with mice in adulthood. Importantly, we found that these parameters varied relatively little across humans and studied primates. These data identify a surprising collection of conserved features in frontal cortex circuits across humans and Old World monkeys. Our work demonstrates that integrating transcriptional and connectomic data across temporal dimensions is a robust approach to trace the evolution of brain connectomics in primates. Significance StatementWe lack appropriate tools to visualize the human brain connectome. We develop new approaches to study connections in the human and non-human primate brains. The integration of transcription with structure offers an unprecedented opportunity to study circuitry evolution. Our integrative approach finds corresponding ages across species and transcriptionally defines neural circuits. We used this information to test for variation in circuit maturation across species and found a surprising constellation of similar features in frontal cortex neural circuits across humans and primates. Integrating across scales of biological organization expands the repertoire of tools available to study connections in primates, which opens new avenues to study connections in health and diseases of the human brain.

neuroscience↗