Biology subjects

Jordan, P.

Publications and source records attributed to Jordan, P..

8 recordsLinked to original sources

bioRxiv2026

ZDHHC17–Mediated Palmitoylation of Hepatitis E Virus ORF3 Protein Regulates Vectorial Trafficking in Polarized Epithelial Cells

The hepatitis E virus (HEV) is a leading cause of acute hepatitis worldwide and is transmitted enterically along the gut-liver axis. Epithelial cell polarity in the gut and liver plays a critical role in HEV transmission. In intestinal epithelial cells, HEV enters through the apical membrane and is released basolaterally to access the bloodstream, whereas in hepatocytes, the virus enters basolaterally and is secreted apically into the bile duct. In this study, we sought to identify the viral and host determinants governing directional HEV secretion in both tissue types. Using polarized intestinal and hepatocyte models, we found that the small phosphoprotein ORF3, which is essential for progeny secretion, localizes predominantly to the apical membrane, in contrast to the ORF2 capsid protein. We further identified the palmitoyltransferase ZDHHC17 as a specific ORF3 interactor that mediates its apical localization and promotes HEV progeny release. Using automated cell segmentation and quantitative image analysis, we screened a panel of ORF3 mutants and found that positively charged residues within the N-terminus regulate membrane association. In addition, we identified a conserved PIFIQP motif that mediates the critical interaction with the ankyrin repeat domain (ARD) of ZDHHC17. Leveraging this interaction, we generated high-confidence structural models of ORF3 in complex with the ZDHHC17 ARD using AlphaFold. These models, further validated by molecular dynamics simulations, revealed additional ORF3 residues involved in the interaction. Collectively, our findings define key mechanisms underlying directional HEV release and provide broader insights into trafficking processes in polarized epithelial cells.

Cell Biology↗

bioRxiv2026

A framework for quantifying the mechanics of dexterous grasp

AO_SCPLOWBSTRACTC_SCPLOWA hallmark of primate behavior is the exceptional ability to dexterously grasp and manipulate objects, yet the investigation of the neural mechanisms that support manual dexterity has been hindered by technical challenges. Optical hand tracking is complicated by frequent occlusions, and contact forces are hard to measure with sufficient precision. Furthermore, while monitoring the kinematics during reaching phase, and the contact forces during object manipulation phase is difficult, joint torques are impossible to measure directly. While challenging, the ability to estimate joint torques in the complex primate hand could provide an invaluable continuous mechanical description spanning both phases. With this in mind, we have developed an experimental apparatus and data processing pipeline for quantifying these variables describing prehension. The apparatus presented objects of various sizes and orientations throughout the workspace, evoking different grasping strategies. Object surfaces were instrumented with thousands of pressure-sensitive elements, enabling high-resolution measurement of distributed contact forces. Simultaneously, eight high-speed cameras were used to reconstruct hand and arm movements with markerless tracking, triangulating 3D landmarks, and mapping them onto a musculoskeletal model, enabling estimation of time-varying joint angles. This posture quantification allowed contact forces to be automatically assigned to specific hand segments, in close agreement with manual human annotations. We used the reconstructed movements and contact forces with the musculoskeletal model of the hand to compute inverse dynamics, yielding joint torques throughout behavior, unifying the hand kinematics and grasp forces into a single physical description. Throughout the processing, we identified individual neurons in the motor cortex of monkeys that were related to grasp force, kinematics, and torques. Together, this framework enabled a comprehensive and precise physical characterization of primate manual behavior, providing a foundation for investigating the neural mechanisms of manual dexterity.

neuroscience↗

bioRxiv2025

The nucleotide analog bemnifosbuvir inhibits hepatitis E virus replication in preclinical models

BackgroundHepatitis E virus infections remain a global health concern. Immunocompromised patients are at an increased risk to develop chronic HEV infection and thereby severe liver disease. Current off-label regimens are suboptimal with treatment failure being reported. Therefore, there is an urgent need for an effective anti-HEV treatment. ObjectiveIn this study, we aimed to identify potent inhibitors of HEV replication. DesignWe developed a rapid, image-based screening platform based on a full-length HEV fluorescence reporter virus and screened a nucleotide/nucleoside analog library. The identified lead candidate was validated in authentic hepatocyte culture systems, as well as in a gerbil infection model. ResultsBemnifosbuvir (BEM), previously characterized as a nucleotide analog with activity against other RNA viruses, efficiently suppressed HEV replication in vitro and in vivo in a dose-dependent manner, with minimal cytotoxicity at effective concentrations. Combining BEM with ribavirin, the off-label drug given to chronic HEV patients, resulted in an additive antiviral effect against HEV. We found that HEV-3 remains susceptible to inhibition by BEM over an extended treatment period, reducing concerns about the rapid development of viral resistance. Importantly, BEM significantly reduced HEV viral loads and liver inflammation in a gerbil infection model. ConclusionsGiven BEMs favorable safety profile in preclinical and clinical settings, our results suggest investigating its efficacy in patients with chronic HEV infection.

microbiology↗

bioRxiv2024

Cell-cycle and Age-Related Modulations in Mouse Chromosome Stiffness

Chromosome structure is complex, and many aspects of chromosome organization are still not understood. Measuring the stiffness of chromosomes offers valuable insight into their structural properties. In this study, we analyzed the stiffness of chromosomes from metaphase I (MI) and metaphase II (MII) oocytes. Our results revealed a ten-fold increase in stiffness (Youngs modulus) of MI chromosomes compared to somatic chromosomes. Furthermore, the stiffness of MII chromosomes was found to be lower than that of MI chromosomes. We examined the role of meiosis-specific cohesin complexes in regulating chromosome stiffness. Surprisingly, the stiffness of chromosomes from three meiosis-specific cohesin mutants did not significantly differ from that of wild-type chromosomes, indicating that these cohesins may not be primary determinants of chromosome stiffness. Additionally, our findings revealed an age-related increase of chromosome stiffness for MI oocytes. Since aging is associated with elevated levels of DNA damage, we investigated the impact of etoposide-induced DNA damage on chromosome stiffness and found that it led to a reduction in stiffness in MI oocytes. Overall, our study underscores the dynamic and cyclical nature of chromosome stiffness, modulated by both the cell cycle, and by age-related factors.

biophysics↗

bioRxiv2023

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands

AO_SCPLOWBSTRACTC_SCPLOWManual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participants ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

neuroscience↗

bioRxiv2019

Aurora B and C kinases regulate prophase exit and chromosome segregation during spermatogenesis

Precise control of chromosome dynamics during meiosis is critical for fertility. A gametocyte undergoing meiosis coordinates formation of the synaptonemal complex (SC) to promote efficient homologous chromosome recombination. Subsequent disassembly of the SC is required prior to meiotic divisions to ensure accurate segregation of chromosomes. We examined the requirements of the mammalian Aurora kinases (AURKA, B, and C) during SC disassembly and chromosome segregation using a combination of chemical inhibition and gene deletion approaches. We find that both mouse and human spermatocytes fail to disassemble SC lateral elements when AURKB and AURKC are inhibited. Interestingly, both Aurkb conditional knockout and Aurkc knockout spermatocytes successfully progress through meiosis and mice are fertile. In contrast, Aurkb, Aurkc double knockout spermatocytes failed to coordinate disassembly of SC lateral elements with chromosome segregation, resulting in delayed meiotic progression, spindle assembly checkpoint failure, chromosome missegregation, and abnormal spermatids. Collectively, our data demonstrates that AURKB and AURKC functionally compensate for one another ensuring successful mammalian spermatogenesis. SUMMARYChemical inhibition and gene deletion approaches show that Aurora B and Aurora C have overlapping functions that ensure timely disassembly of lateral element components of the synaptonemal complex in mouse and human spermatocytes and ensure accurate chromosome segregation during meiosis.

cell biology↗

bioRxiv2019

Sex identification of ancient pinnipeds using the dog genome

Determining the male and female representation in zooarchaeological material from hunted animal species is essential, to fully investigate the effects and means of prehistoric hunting practices, and may further provide valuable biological information on past animal life-history, behaviour and demography. However, the fragmented nature of the zooarchaeological record and a lack of clear diagnostic skeletal markers, often prevents such inference. Here, we test the usability of the dog nuclear genome (CanFam3.1) for sex identification of pinnipeds. First, a contemporary sample set (n=72) of ringed seals (Pusa hispida), with known sex was used to test the genetic sex identification method. By quantifying the proportion of X chromosome reads, as the chrX/chr1 ratio, the ratios clustered in two clearly distinguishable sex groups. Of the 72 individuals, 69 were identified to the accurate sex, which proves a high reliability of the genetic method. Second, random down sampling of a subset of the ringed seal samples to different read number, suggests at least 5000 DNA sequence reads mapped to the reference genome as the lower limit for which this method is applicable. Finally, applying this standard, sex identification was successfully carried out on a broad set of ancient pinniped samples, including walruses (Odobenus rosmarus), grey seals (Halichoerus grypus) and harp seals (Pagophilus groenlandicus), which all showed clearly distinct male and female chrX/chr1 ratio groups.

genomics↗

bioRxiv2019

Cariogenic Streptococcus mutans produces strain-specific antibiotics that impair commensal colonization

Streptococcus mutans is a common constituent of dental plaque and an etiologic agent of dental caries (tooth decay). Here we elucidate a biosynthetic pathway, encoded by globally distributed strains of S. mutans, which produces a series of bioactive small molecules including reutericyclin and two N-acyl tetramic acid analogues active against oral commensal bacteria. This pathway may provide S. mutans with a competitive advantage, promoting dysbiosis and caries pathogenesis.

microbiology↗