Biology subjects

Stark, C.

Publications and source records attributed to Stark, C..

6 recordsLinked to original sources

bioRxiv2025

Harmonized Protocol for Subfield Segmentation in the Hippocampal Body on High-Resolution in vivo MRI from the Hippocampal Subfields Group (HSG)

Hippocampal subfields differentially develop and age, and they vary in vulnerability to neurodegenerative diseases. Innovation in high-resolution imaging has accelerated clinical research on human hippocampal subfields, but substantial differences in segmentation protocols impede comparisons of results across laboratories. The Hippocampal Subfields Group (HSG) is an international organization seeking to address this issue by developing a histologically-valid, reliable, and freely available segmentation protocol for high-resolution T2-weighted 3 tesla MRI (http://www.hippocampalsubfields.com). Here, we report the first portion of the protocol focused on subfields in the hippocampal body; protocols for the head and tail are in development. The body protocol includes definitions of the internal boundaries between subiculum, Cornu Ammonis (CA) 1-3 subfields, and dentate gyrus, in addition to the external boundaries of the hippocampus apart from surrounding white matter and cerebrospinal fluid. The segmentation protocol is based on a novel histological reference data set labeled by multiple expert neuroanatomists. With broad participation of the research community, we voted on the segmentation protocol via online survey, which included detailed protocol information, feasibility testing, demonstration videos, example segmentations, and labeled histology. All boundary definitions were rated as having high clarity and reached consensus agreement by Delphi procedure. The harmonized body protocol yielded high inter- and intra-rater reliability. In the present paper we report the procedures to develop and test the protocol, as well as the detailed procedures for manual segmentation using the harmonized protocol. The harmonized protocol will significantly facilitate cross-study comparisons and provide increased insight into the structure and function of hippocampal subfields across the lifespan and in neurodegenerative diseases.

neuroscience↗

bioRxiv2025

Differentiating unirradiated mice from those exposed to conventional or FLASH radiotherapy using MRI

Background and purposeThe FLASH effect expands the therapeutic ratio of tumor control to normal tissue toxicity observed after delivery of ultra-high (>100 Gy/s FLASH-RT) vs. conventional dose rate radiation (CONV-RT). In this first exploratory study, we assessed whether ex-vivo Magnetic Resonance Imaging (MRI) could reveal long-term differences after FLASH-RT and CONV-RT whole-brain irradiation. Materials and methodsFemale C57BL/6 mice were divided into three groups: control (non-irradiated), conventional (CONV-RT 0.1 Gy/s), and ultra-high dose rates (FLASH-RT 1 pulse, 5.5 x 106 Gy/s), and received 10 Gy of whole-brain irradiation in a single fraction at 10 weeks of age. Mice were evaluated by Novel Object Recognition cognitive testing at 10 months post-irradiation and were sampled at 13 months post-irradiation. Ex-vivo brains were imaged with a 14.1 Tesla/26 cm magnet with a multimodal MRI protocol, including T2-weighted TurboRare (T2W) and diffusion-weighted imaging (DWI) sequences. ResultsIn accordance with previous results, cognitive tests indicated that animals receiving CONV-RT exhibited a decline in cognitive function, while FLASH-RT performed similarly to the controls. MRI showed decreased hippocampal mean intensity in the CONV-RT mice compared to controls but not in the FLASH-RT group. Comparing CONV-RT to control, we found significant changes in multiple whole-brain diffusion metrics, including the mean Apparent Diffusion Coefficient (ADC) and Mean Apparent Propagator (MAP) metrics. By contrast, no significant diffusion changes were found between the FLASH-RT and control groups. In an exploratory analysis compared to controls, regional diffusion metrics were primarily altered in the basal forebrain and the insular cortex after CONV-RT, and after FLASH-RT, a trend reduction was also observed. ConclusionThis study presents initial evidence that MRI can uncover clear changes in the brain after CONV-RT but not after FLASH-RT. The MRI results aligned with the observed cognitive protection after FLASH-RT, indicating the potential use of MRI to analyze the FLASH response.

neuroscience↗

bioRxiv2025

Improving American chestnut resistance to two invasive pathogens through genome-enabled breeding

Over a century after two introduced pathogens decimated American chestnut populations, breeding programs continue to incorporate resistance from Chinese chestnut to recover self-sustaining populations. Due to complex genetics of chestnut blight resistance, it is challenging to obtain trees with sufficient resistance and competitive growth. We developed high quality reference genomes for Chinese and American chestnut and leveraged large disease phenotype and genotype datasets to develop accurate genomic selection. Inoculation and simulation results indicate that resistance may be substantially increased in trees that inherited 70% to 100% of their genome from American chestnut. To facilitate gene editing, we integrated multiple lines of evidence to discover candidate alleles for blight resistance and susceptibility. These genomic resources provide a strong foundation to accelerate restoration of this iconic tree.

genomics↗

bioRxiv2024

Myo-inositol and total NAA in the hippocampus are linked to CSF tau pathology in cognitively normal older adults

INTRODUCTIONUnderstanding relationships between in vivo neurometabolic changes and Alzheimers disease (AD) pathology in the hippocampus, a region vulnerable to early changes in AD, will support early diagnosis. METHODSTwo studies using 1H-MRS examined concentrations of myo-inositol (MI), total creatine (tCr) and total NAA (tNAA) in the hippocampus. The first study compared hippocampal metabolite concentrations in healthy young and older adults and the second study assessed relationships between hippocampal metabolites and cerebrospinal fluid (CSF) measurements of A{beta}42, phosphotau 181 (pTau181), and total tau (t-Tau) while adjusting for demographic covariates and spectral characteristics (linewidth, signal- to-noise ratio) in a separate group of older adults ranging from cognitively normal (CN) to AD-dementia. RESULTSHippocampal MI, but not tCr or tNAA, was increased in cognitively normal older versus young adults. Within the second older adult group, MI and tNAA, but not tCr, were linked to increases in CSF pTau181 and t-Tau, but not A{beta}42. DISCUSSIONTau deposition in cognitively normal individuals is associated with biochemical changes related to glial reactivity and neural integrity in the hippocampus.

neuroscience↗

bioRxiv2024

Cognitive modeling of the Mnemonic Similarity Task as a digital biomarker for Alzheimer's Disease

AD related pathologies, such as beta-amyloid (A{beta}) and phosphorylated tau (pTau), are evident decades before any noticeable decline in memory occurs. Identifying individuals during this asymptomatic phase is crucial for timely intervention. The Mnemonic Similarity Task (MST), a modified recognition memory task, is especially relevant for early AD screening, as it assesses hippocampal integrity, a region affected (both directly and indirectly) early in the progression of the disease. Further, strong inferences on the underlying cognitive mechanisms that support performance on this task can be made using Bayesian cognitive modeling. We assessed whether analyzing MST performance using a cognitive model could detect subtle changes in cognitive function and AD biomarker status prior to overt cognitive decline. We analyzed MST data from >200 individuals (young, cognitively healthy older adults, and individuals with MCI), a subset of which also had existing CSF A{beta} and pTau data. Traditional performance scores and cognitive modeling using multinomial processing trees was applied to each participants MST data using Bayesian approaches. We assessed how well each could predict age group, memory ability, MCI status, A{beta}/pTau status using ROC analyses. Both approaches predicted age group membership equally, but cognitive modeling approaches exceeded traditional metrics in all other comparisons. This work establishes that cognitive modeling of the MST can detect individuals with AD prior to cognitive decline, making it a potentially useful tool for both screening and monitoring older adults during the asymptomatic phase of AD.

neuroscience↗

bioRxiv2021

Systematic investigation of the link between enzyme catalysis and cold adaptation

Cold temperature is prevalent across the biosphere and slows the rates of chemical reactions. Increased catalysis has been predicted to be a general adaptive trait of enzymes to reduced temperature, and this expectation has informed physical models for enzyme catalysis and influenced bioprospecting strategies. To broadly test rate as an adaptive trait to cold, we paired kinetic constants of 2223 enzyme reactions with their organisms optimal growth temperature (TGrowth) and analyzed trends of rate as a function of TGrowth. These data do not support a prevalent increase in rate in cold adaptation. In the model enzyme ketosteroid isomerase (KSI), there was prior evidence for temperature adaptation from a change in an active site residue that results in a tradeoff between activity and stability. Here, we found that little of the overall rate variation for 20 KSI variants was accounted for by TGrowth. In contrast, and consistent with prior expectations, we observed a correlation between stability and TGrowth across 433 proteins. These results suggest that temperature exerts a weaker selection pressure on enzyme rate than stability and that evolutionary forces other than temperature are responsible for the majority of enzymatic rate variation.

biochemistry↗