Biology subjects

Martin, A. M.

Publications and source records attributed to Martin, A. M..

9 recordsLinked to original sources

bioRxiv2026

DNA catenation is essential for Sister Chromatid Cohesion

From S phase until anaphase, sister chromatids remain physically linked to ensure accurate chromosome segregation. This linkage, called sister chromatid cohesion, must withstand the pulling forces generated by the mitotic spindle and is thought to require entrapment of sister DNAs inside the ring-shaped cohesin complex. DNA catenations that arise naturally during replication could also tether sister chromatids, but whether they contribute to cohesion has remained unresolved. Here, using budding yeast, we show that cohesin-mediated sister DNA entrapment alone cannot withstand spindle-generated pulling forces and that robust sister chromatid cohesion requires DNA catenation. Selective removal of DNA catenations causes catastrophic cohesion loss, delays chromosome biorientation and increases chromosome mis-segregation, even when cohesin rings remain intact. Importantly, DNA catenation similarly underpins force-resistant cohesion in metazoan chromosomes. Our findings fundamentally redefine the physical basis of sister chromatid cohesion by establishing DNA catenation as an evolutionarily conserved component of the force-resistant linkage between sister chromatids that enables accurate chromosome segregation.

molecular biology↗

bioRxiv2026

Decoupling Fabrication from Encoding: DNA-Addressable Template Microparticles for Large, User-Defined Optical Barcode Libraries

Optical barcodes for pooled high-throughput screening must support large libraries while remaining decodable in a single imaging step. Existing approaches often trade design control for manufacturability: deterministic barcodes often require per-code redesign of particle fabrication, whereas stochastic combinatorial barcodes are difficult to generate as predefined batches. Here we introduce a chemically programmable barcoding architecture that decouples particle fabrication from barcode assignment. Using a contact-free multilaminar flow lithography platform with all-around three-dimensional sheathing, we continuously fabricate a universal hydrogel scaffold containing five spatially segregated DNA-addressable domains at rates >106 particles/h. Chosen barcode identities are subsequently written on demand onto the same template batch by domain-selective DNA hybridization. Single-domain measurements resolved 64 candidate optical states, indicating an experimentally informed theoretical upper bound of 645 {approx} 1.1 x 109 barcodes. We further implemented a predefined 59,049-code library by split-pool labeling, achieving an 88% recovery of decoded beads at a stringent posterior threshold (>0.95). After 11 days, >7,800 beads were correctly re-identified at >0.95 accuracy in matched fields of view. This strategy provides a highly scalable, chemically programmable route to build large, user-defined optical barcode libraries with single-image optical readout and longitudinal traceability.

bioengineering↗

bioRxiv2026

The mood stabilizer lithium alters behaviour and physiology via the gut brain axis.

Lithium, introduced 75 years ago by John Cade1, remains the most effective mood stabilizer for bipolar disorder2. Lithium is proposed to modulate an array of cellular pathways, many ubiquitous to all cells, with pleiotropic roles unlinked to bipolar disorder or lithium responsiveness in genome-wide association studies3,4. These mechanisms cannot explain lithiums specific effects on mood and behaviour. We demonstrate that lithiums primary action is in the periphery, not in the brain itself. Lithium acts in the gut to trigger behavioural and physiological changes, akin to those associated with a torpor-like state, that protect individuals from ingested toxins. Lithium activates gastrointestinal enterochromaffin (EC) cells via their Trpm2 cation channels to modulate afferent vagal and area postrema inputs to the brain. Eliminating these inputs by focal brain lesions eliminates lithiums effects, as does ablation of EC cells or their Trpm2 expression. Lithiums Trpm2-dependent activation of EC cells also occurs in human gut tissue, providing translational relevance for our discovery. These findings challenge the prevailing perception that lithium acts directly on the brain. Via a previously unsuspected gut-brain pathway, lithium engages brain circuitry that reduces arousal and interaction with the external world, therapeutic goals in the manic phase of bipolar disorder.

neuroscience↗

bioRxiv2025

Alternative probe chemistries for single-molecule analysis of long non-coding RNA

Single-molecule microscopy has been widely used to study the structure and dynamics of RNA, but extension to larger systems such as long non-coding RNA (lncRNA) has proven challenging. Methods such as single-molecule kinetic analysis of RNA transient structure (SiM-KARTS), where the binding of a short, complementary oligonucleotide probe is used to determine accessibility of a specific region of the RNA, are promising. However, adapting SiM-KARTS to systems as complex as lncRNA requires careful optimization of experimental variables that have not been thoroughly explored. In this work, SiM-KARTS, thermal denaturation experiments, and circular dichroism spectroscopy were used to analyze the binding behaviors of probes with alternative backbone chemistries, specifically DNA with locked nucleic acid (LNA) residues incorporated and morpholinos. A segment of lncRNA that enabled control over the accessibility of the target sequence was used as a model. We show that optimizing probe backbone chemistry can allow for a more precise distinction between different structures of the target RNA, and for fine-tuning of probe binding stability without the structural impacts that other variables such as ionic concentration may have. Specifically, we demonstrate that LNA probes exhibit a high degree of structural sensitivity in both their binding and unbinding kinetics. We further show that when binding and unbinding rates are considered holistically, LNA probes allow traces arising from different target RNA structures to be individually classified with a high degree of accuracy. These results provide design principles for the application of SiM-KARTS to target RNAs of increased complexity such as lncRNA.

biophysics↗

bioRxiv2025

Two morphologically distinct formae speciales in Neonectria magnoliae differ in their virulence on Magnolia family hosts Liriodendron tulipifera and Magnolia fraseri

The family Nectriaceae includes numerous phytopathogenic fungal genera that cause canker diseases on both angiosperm and conifer hosts worldwide. Among these, Neonectria species are globally important canker pathogens of numerous hosts, but their roles in contributing to forest decline and mortality outside their role in beech bark disease and apple canker are largely understudied. In the U.S., Neonectria magnoliae causes perennial cankers on two native hosts in central Appalachia: Fraser magnolia (Magnolia fraseri) and tulip-poplar (Liriodendron tulipifera) and has been recently confirmed from non-native star magnolia (Magnolia stellata) in West Virginia. Both native hosts occur in the central Appalachian Mountains, but Fraser magnolia occurs mostly at higher elevations. Neonectria magnoliae was first described in 1943, yet its impact across the forested landscape remains unclear. To clarify host-specific differences across the contemporary range of Neonectria magnoliae, we used multi-locus phylogenetics, comparative pathogenicity / virulence assays, and morphological analyses to determine if N. magnoliae represents two cryptic species that specialize on tulip-poplar and magnolia, or if N. magnoliae has host-specific pathotypes. Our studies revealed two morphologically distinct formae speciales within N. magnoliae: 1) Neonectria magnoliae f. sp. liriodendri; strains originating from tulip-poplar with increased virulence on this host and lacking macroconidia production and 2) Neonectria magnoliae f. sp. magnoliae; strains originating from Fraser magnolia with increased virulence on this host and producing macroconidia readily in culture. Overall, the incidence of these two pathotypes indicates that neither pathogen alone poses serious risks to either host but adds to cumulative stresses that both tree species are experiencing in the face of global climate change.

microbiology↗

bioRxiv2022

Exponential magnetophoretic gradient for the direct isolation of basophils from whole blood in a microfluidic system

Despite their rarity in peripheral blood, basophils play important roles in allergic disorders and other diseases including sepsis and COVID-19. Existing basophil isolation methods require many manual steps and suffer from significant variability in purity and recovery. We report an integrated basophil isolation device (i-BID) in microfluidics for negative immunomagnetic selection of basophils directly from 100 L of whole blood within 10 minutes. We use a simulation-driven pipeline to design a magnetic separation module to apply an exponentially increasing magnetic force to capture magnetically tagged non-basophils flowing through a microtubing sandwiched between magnetic flux concentrators sweeping across a Halbach array. The exponential profile captures non-basophils effectively while preventing their excessive initial buildup causing clogging. The i-BID isolates basophils with a mean purity of 93.9%{+/-}3.6% and recovery of 95.6%{+/-}3.4% without causing basophil degradation or unintentional activation. Our i-BID has the potential to enable basophil-based point-of-care diagnostics such as rapid allergy assessment.

immunology↗

bioRxiv2021

Sarcoptic mange outbreak decimates South American camelid populations in San Guillermo National Park, Argentina

Sarcoptic mange epidemics can devastate wildlife populations. In 2014, mange was first detected in vicuna (Vicugna vicugna) and guanaco (Lama guanicoe) in San Guillermo National Park (SGNP), Argentina. This study characterized the potential source and the impacts of the outbreak in 2017-2019. Transect surveys indicated a sharp decrease in the density of live vicuna and guanaco by 68% and 77%, respectively, from May 2017 to June 2018. By April 2019 no vicuna or guanaco were recorded on transect surveys, suggesting a near-extinction at the local level. Clinical signs consistent with mange (e.g. intense pruritus, hyperkeratosis, alopecia) were observed in 24% of live vicuna (n = 478) and 33% of live guanaco (n = 12) during surveys, as well as in 94% of vicuna carcasses (n = 124) and 85% of guanaco carcasses (n = 20) opportunistically examined during the study period. Histological examination (n = 15) confirmed sarcoptic mange as the cause of the cutaneous lesions. Genetic characterization revealed that Sarcoptes scabiei recovered from seven vicuna (n = 13) and three guanaco (n = 11) shared the same genotype, which is consistent with a single source and recent origin of the epidemic. A governmental livestock incentive program introduced llama (Lama glama) in areas adjacent to SGNP in 2009, some of which reportedly had alopecic scaling consistent with sarcoptic mange. We hypothesize that the introduction of mange-infected llama may have triggered the outbreak in wild camelids which has now put them at a high risk of local extinction. This unprecedented event highlights that the accidental introduction of disease may be underestimated at the onset yet can have devastating effects on native ungulate populations with potentially profound effects at the community and ecosystem levels.

zoology↗

bioRxiv2020

Endoderm Nitric Oxide Signals to Regulate Nascent Development of Cardiac Progenitors in Chicken Embryos

Heart development in the chicken embryo is regulated by a concert of cardiogenic morphogens and signaling molecules, but the physiological signal molecule nitric oxide(NO) has not been studied in the context of heart formation. A dynamic investigation of endoderm NO formation demonstrates for the first time a correlation with the established development events of the cardiac heart fields and heart tube. Manipulation of endoderm NO signaling demonstrate a role of NO signaling in the differentiation and proliferation of cardiac progenitors for heart tube formation and cardiac heart field development. To investigate NO in the proliferation of myocardial cells in the heart tube embryos, a computer vision based artificial intelligence approach is followed to automate the long and tedious job of counting cells in a large image dataset. We document NO as an important signaling molecule in the regulation of nascent embryonic cardiogenesis whose effects on other early cardiogenic morphogens is unknown.

developmental biology↗

bioRxiv2020

The low-density lipoprotein receptor-related protein-1 is essential for Dengue virus infection

Dengue virus (DENV) causes the most prevalent and rapidly spreading arboviral disease of humans. It enters human cells by receptor-mediated endocytosis. Numerous cell surface proteins have been proposed as DENV entry factors. Among these, the phosphatidylserine receptor TIM-1 is the only one known to mediate virus internalization. However, several cellular models lacking TIM-1 are permissive to DENV infection, suggesting that other receptors exist. Here we show that the Low-density lipoprotein receptor-related protein-1 (LRP1) binds DENV virions by interacting with the DIII of the viral envelope glycoprotein. DENV infection is effectively inhibited by the purified receptor at 5x10-8 mol/L and the interaction of the envelope protein with LRP1 is also blocked by a natural ligand of LRP1. Depletion of LRP1 causes 100-fold lower production of infectious virus than controls. Our results indicate that LRP1 is another DENV receptor thus, becoming an attractive target to evaluate for the development of effective antiviral drugs against DENV. Author summaryDengue virus (DENV) is a complex of four related viruses, recognized as serotypes, designated as DENV1-4. Any of the four DENV serotypes can cause a self-limited disease of mild flu-like symptoms known as dengue or its life threatening form, severe dengue, with hemorrhagic manifestations, organ impairment and shock. This disease is widely spread in tropical and sub-tropical areas worldwide, where the incidence of severe dengue has been increasing steadily. So far, efforts that target components of the viral replication machinery in order to develop a specific antiviral drug for dengue disease patients have failed. Thus, identifying the cell surface receptors used by DENV to enter host cells would provide a new molecular target to develop inhibitory drugs. Here, we evaluate the Low density lipoprotein receptor-related protein-1 (LRP1) as a putative DENV receptor. We present evidence demonstrating that LRP1 binds DENV through the viral envelope protein. We show that the production of infective virus is impaired on cells lacking LRP1, and that purified LRP1 is a potent blocker of DENV infection. These results are consistent with LRP1 playing an important role on DENV entry, making this receptor a molecule of interest on the investigation for medical treatments of dengue/severe dengue disease.

biochemistry↗