Biology subjects

Hekmatyar, K.

Publications and source records attributed to Hekmatyar, K..

3 recordsLinked to original sources

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↗