Biology subjects

Zeiss, C. J.

Publications and source records attributed to Zeiss, C. J..

9 recordsLinked to original sources

bioRxiv2026

Loss of calbindin and rise in pT217-tau in aging monkey prefrontal cortical dendrites

INTRODUCTION: Tau pathology in Alzheimers disease preferentially afflicts excitatory neurons in the limbic and association cortices that utilize high levels of calcium signaling to perform cognitive operations. This includes the layer III pyramidal cells in the dorsolateral prefrontal cortex (dlPFC) that subserve higher cognition, which express the calcium-binding protein, calbindin, when young and healthy, but lose calbindin and develop tangles and degenerate in Alzheimers disease (AD). These data suggest that loss of calbindin may be associated with the emergence of tau pathology. However, the relationship between calbindin and early-stage, soluble tau pathology is challenging to study in human brains, as soluble pTau dephosphorylates within 15min postmortem. In contrast, the relationship between calbindin and soluble pT217-tau expression can be studied in aging macaques with naturally-occurring tau pathology, where perfusion fixation is possible to capture phosphorylation state in situ. METHODS: The current study used multiple-label-immunofluorescence to label MAP2-positive dlPFC layer III pyramidal cells for calbindin and pT217-tau in macaque brains across the adult age span (8-34.5yrs). The study employed a semi-automated CellProfiler workflow to identify labeled pyramidal cell dendrites the cellular compartment where tau pathology begins in AD. RESULTS: Calbindin expression decreased with age, while pT217Tau increased with age. Specifically, the ratio of calbindin/pT217-tau within a dendrite decreased with age, and was especially prominent in the aged macaques with long-term inflammatory disorders. DISCUSSION: These data suggest that the loss of calbindin in dendrites with advancing age, and especially with inflammation, contributes to the rise of tau pathology and the risk of AD.

neuroscience↗

bioRxiv2025

Defect in hematopoiesis and embryonic lethality at midgestation of Vps13a/Vps13c double knockout mice

VPS13 is the founding member of a family of proteins that mediate lipid transfer at intracellular membrane contact sites by a bridge-like mechanism. Mammalian genomes comprise 4 VPS13 genes encoding proteins with distinct localizations and function. The gene duplication resulting in VPS13A and VPS13C is the most recent in evolution and, accordingly, these two proteins are the most similar to each other. However, they have distinct subcellular localizations and their loss of function mutations in humans are compatible with life but result in two different age-dependent neurodegenerative diseases, chorea-acanthocytosis and Parkinsons disease, respectively. Thus, it remains unclear whether these two proteins have overlapping functions. Here, we show that while Vps13a KO and Vps13c KO mice are viable, embryonic development of Vps13a/Vps13c double knockout (DKO) mice is arrested at midgestation. Prior to death, DKO embryos were smaller than controls, were anemic and had a smaller liver, the key erythropoietic site at this developmental stage. Further analyses of erythroid precursor cells showed that their differentiation was impaired and that this defect was accompanied by activation of innate immunity as revealed by upregulation of interferon stimulated genes (ISGs). Additionally, the RIG-I and MDA5 components of dsRNA triggered innate immunity were found upregulated in the DKO fetal liver. Activation of innate immunity may result from loss of integrity of the membranes of intracellular organelles, such as mitochondria and autophagic lysosomes, due to the absence of these lipid transport proteins. The surprising and striking synthetic effect resulting for the combined loss of VPS13A and VPS13C suggests that despite of the different localization of these two proteins, the lipid fluxes that they mediate are partially redundant.

cell biology↗

bioRxiv2024

OST Catalytic Subunit Redundancy Enables Therapeutic Targeting of N-Glycosylation

Protein asparagine (N)-glycosylation, which promotes folding and trafficking of cell surface receptors such as the EGFR, has not been considered a viable target in oncology due to the essential and non-redundant enzymatic activities required for glycan synthesis and transfer. In mammals an exception to this rule is the presence of the oligosaccharyltransferase (OST) catalytic subunit paralogs, STT3A and STT3B. Here we delineate the chemical biology of OST inhibitors and develop an approach for limited inhibition of N-glycosylation optimized for downstream effects on EGFR. Small molecules with enhanced pharmacokinetic properties and preferences for STT3A or STT3B were synthesized, characterized in vitro, and advanced to in vivo testing. The lead from this series, NGI-189, causes tumor regression or growth delay of patient derived and TKI resistant EGFR-mutant lung cancer xenografts without toxicity. Together these results suggest that bioavailable OST inhibitors can be developed as therapeutic agents for oncology. SUMMARYA mechanistic approach for partial inhibition of N-glycosylation delivers small molecules with anti-tumor activity in EGFR mutant NSCLC.

cancer biology↗

bioRxiv2024

Comparative lifespan and healthspan of nonhuman primate species common to biomedical research

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Sex-specific Kaplan-Meier survival curves were computed in 12 translational aging models: baboon, bonnet macaque, chimpanzee, common marmoset, coppery titi monkey, cotton-top tamarin, cynomolgus macaque, Japanese macaque, pigtail macaque, rhesus macaque, squirrel monkey, and vervet/African green. After employing strict inclusion criteria, primary results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. Results show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan since research NHP are typically euthanized for humane welfare reasons before their natural end of life. This resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. These results clarify relationships among NHP ages and provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of expected survival rates, providing a metric for comparisons in future studies, and contributing to understanding of factors driving lifespan differences within and among species.

physiology↗

bioRxiv2024

Medial amygdalar tau is associated with anxiety symptoms in preclinical Alzheimer's disease

BACKGROUNDWhile the amygdala receives early tau deposition in Alzheimers disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODSWe examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTSAmyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala (F(4, 442)=14.61, p=0.00045; F(4, 442)=5.83, p=0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (rs=-0.103, p=0.015). CONCLUSIONSOur findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms.

neuroscience↗

bioRxiv2022

SARS-CoV-2 exposure in Norwegian rats (Rattus norvegicus) from New York City

Millions of Norway rats (Rattus norvegicus)inhabit New York City (NYC), presenting the potential for transmission of SARS-CoV-2 from humans to rats and other wildlife. We evaluated SARS-CoV-2 exposure among 79 rats captured from NYC during the fall of 2021. Results showed that 13 of 79 rats (16.5%) tested IgG or IgM positive, and partial genomes of SARS-CoV-2 were recovered from four rats that were qRT-PCR positive. Using a virus challenge study, we also showed that Alpha, Delta, and Omicron variants can cause robust infections in wild-type Sprague Dawley (SD) rats, including high level replications in the upper and lower respiratory tracts and induction of both innate and adaptive immune responses. Additionally, the Delta variant resulted in the highest infectivity. In summary, our results indicated that rats are susceptible to infection with Alpha, Delta, and Omicron variants, and rats in the NYC municipal sewer systems have been exposed to SARS-CoV-2. Our findings highlight the potential risk of secondary zoonotic transmission from urban rats and the need for further monitoring of SARS-CoV-2 in those populations. ImportanceSince its emergence causing the COVID-19 pandemic, the host tropism expansion of SARS-CoV-2 raises a potential risk for reverse-zoonotic transmission of emerging variants into rodent species, including wild rat species. In this study, we presented both genetic and serological evidence for SARS-CoV-2 exposure in wild rat population from New York City, and these viruses are potentially linked to the viruses during the early stages of the pandemic. We also demonstrated that rats are susceptible to additional variants (i.e., Alpha, Delta, and Omicron) predominant in humans and that the susceptibility to different variants vary. Our findings highlight the potential risk of secondary zoonotic transmission from urban rats and the need for further monitoring of SARS-CoV-2 in those populations.

microbiology↗

bioRxiv2021

Viral shedding and transmission after natural infection and vaccination in an animal model of SARS-CoV-2 propagation

At present, global immunity to SARS-CoV-2 resides within a heterogeneous combination of susceptible, naturally infected and vaccinated individuals. The extent to which viral shedding and transmission occurs on re-exposure to SARS-CoV-2 after prior natural exposure or vaccination is an emerging area of understanding. We used Sialodacryoadenitis Virus (SDAV) in rats to model the extent to which immune protection afforded by prior natural infection via high risk (inoculation; direct contact) or low risk (fomite) exposure, or by vaccination, influenced viral shedding and transmission on re-exposure. On initial infection, we confirmed that amount, duration and consistency of viral shedding were correlated with exposure risk. Animals were reinfected after 3.7-5.5 months using the same exposure paradigm. Amount and duration of viral shedding were correlated with re-exposure type and serologic status. 59% of seropositive animals shed virus. Previously exposed seropositive reinfected animals were able to transmit virus to 25% of naive recipient rats after 24-hour exposure by direct contact. Rats vaccinated intranasally with a related virus (Parkers Rat Coronavirus) were able to transmit SDAV to only 4.7% of naive animals after a 7-day direct contact exposure, despite comparable viral shedding. Observed cycle threshold values associated with transmission in both groups ranged from 29-36 cycles, however observed shedding was not a prerequisite for transmission. Results indicate that low-level shedding in both naturally infected and vaccinated seropositive animals can propagate infection in susceptible individuals. Extrapolated to COVID-19, our results suggest that continued propagation of SARS-CoV-2 by seropositive previously infected or vaccinated individuals is possible.

microbiology↗

bioRxiv2021

Salted roads lead to edema and reduced locomotor function in wood frogs

Human activities have caused massive losses of natural populations across the globe. Like many groups, amphibians have experienced substantial declines worldwide, driven by environmental changes such as habitat conversion, pollution, and disease emergence. Each of these drivers is often found in close association with the presence of roads. Here we report a novel consequence of roads affecting an amphibian native to much of North America, the wood frog (Rana sylvatica). Across 38 populations distributed from southern to central New England, we found that adult wood frogs living adjacent to roads had higher incidence and severity of edema (bloating caused by fluid accumulation) during the breeding season than frogs living away from the influence of roads. This effect was best explained by increased conductivity of breeding ponds, caused by runoff pollution from road salt used for de-icing. Edema severity was negatively correlated with locomotor performance in more northerly populations. Interestingly, northern populations experience more intense winters, which tends to result in more de-icing salt runoff and increased energetic demands associated with overwintering cryoprotection needs. Thus, this emerging consequence of roads appears to impose potential fitness costs associated with locomotion, and these effects might be most impactful on populations living in regions where de-icing is most intense.

ecology↗

bioRxiv2018

An ABCA4 loss-of-function mutation causes a canine form of Stargardt disease

Autosomal recessive retinal degenerative diseases cause visual impairment and blindness in humans and dogs. Currently, no standard treatment is available but pioneering gene therapy-based canine models have been instrumental for clinical trials in humans. To study a novel form of retinal degeneration in Labrador retriever dogs with clinical signs indicating cone and rod degeneration, we used whole-genome sequencing of an affected sib-pair and their unaffected parents. A frameshift insertion in the ATP binding cassette subfamily A member 4 (ABCA4) gene (c.4176insC), leading to a premature stop codon in exon 28 (p.F1393Lfs1395) was identified. In contrast to unaffected dogs, no full-length ABCA4 protein was detected in the retina of an affected dog. The ABCA4 gene encodes a membrane transporter protein localized in the outer segments of rod and cone photoreceptors. In humans, the ABCA4 gene is associated with Stargardt disease (STGD), an autosomal recessive retinal degeneration leading to central visual impairment. A hallmark of STGD is the accumulation of lipofuscin deposits in the retinal pigment epithelium. The discovery of a canine homozygous ABCA4 loss-of-function mutation may advance the development of dog as a large animal model for human STGD.\n\nAuthor summaryStargardt disease (STGD) is the most common inherited retinal disease causing visual impairment and blindness in children and young adults, affecting 1 in 8-10 thousand people. For other inherited retinal diseases, the dog has become an established comparative animal model, both for identifying the underlying genetic causes and for developing new treatment methods.\n\nTo date, there is no standard treatment for STGD and the mouse model is the only available animal model to study the disease. As a nocturnal animal, the morphology of the mouse eye differs from humans and therefore the mouse model is not ideal for developing methods for treatment. We have studied a novel form of retinal degeneration in Labrador retrievers showing clinical signs similar to human STGD. To investigate the genetic cause of the disease, we used whole-genome sequencing of a family quartet including two affected offspring and their unaffected parents. This led to the identification of a loss-of-function mutation in the ABCA4 gene. The findings of this study may enable the development of a canine model for human STGD.

genetics↗