Biology subjects

Rowe, M.

Publications and source records attributed to Rowe, M..

18 recordsLinked to original sources

bioRxiv2026

Fetal sex shapes placental inflammatory responses to extracellular mitochondrial DNA

Aberrant changes in circulating cell-free mitochondrial DNA (ccf-mtDNA) across gestation are associated with adverse pregnancy outcomes. Given the inflammatory properties of ccf-mtDNA via pattern recognition receptors such as Toll-like receptor 9 (TLR9), we hypothesized that extracellular mtDNA induces placental inflammation via TLR9 signaling and that this response differs by fetal sex. Pregnant Sprague-Dawley rats were treated intravenously with purified mtDNA (300 g/kg), nuclear DNA (nDNA), saline, and/or the TLR9 antagonist ODN2088 across five studies. Placental responses were evaluated 4 h (Studies 1-3) and 24 h (Study 4) post-treatment; pregnancy and neonatal outcomes were assessed at delivery (Study 5). Exposure to mtDNA, but not nDNA, increased placental il1{beta}, tnf, and il10 mRNA (p < 0.05), establishing response specificity. mtDNA-induced placental inflammation was fetal sex-dependent: mtDNA increased il6 and il1{beta} mRNA in male placentas (p [≤] 0.0004) but not female placentas, whereas ifn{gamma} was selectively induced in female placentas (p = 0.0004). TLR9 and MyD88 abundance increased in female but not male placentas, and TLR9 antagonism modified selected inflammatory responses with sex-specific patterns. The 4 h inflammatory transcriptional signature resolved by 24 h, whereas mtDNA exposure was associated with a sex-specific shift in antioxidant enzyme expression persisting to 24 h. Despite no effects on gestational length or neonatal biometrics, mtDNA exposure was associated with a higher estimated stillbirth count per litter (IRR = 4.23, 95% CI [0.89, 20.1], p = 0.069). These findings establish extracellular mtDNA as an acute, sex-differentiated placental inflammatory stimulus with partial TLR9 dependence and a potential impact on fetal viability. New & NoteworthyThis study demonstrates that acute exposure to extracellular mtDNA induces placental inflammatory responses in vivo. This response is specific to mtDNA, fetal-sex dependent, and partially mediated by TLR9, with male and female placentas engaging distinct inflammatory signals within hours of exposure. The biological effects extend beyond the initial inflammatory window, with mtDNA exposure producing lasting, sex-specific changes in antioxidant enzyme expression. mtDNA-exposed dams had higher expected stillbirth counts, suggesting extracellular mtDNA may affect fetal viability.

physiology↗

bioRxiv2026

Gut microbiota promote early-life digestive function in songbirds

The vertebrate digestive tract harbors complex microbial communities whose influences on phenotypes and fitness in non-model organisms remain poorly understood. Here, we show that colonization with gut microbiota is critical for digestive development and function in a non-model songbird, the House sparrow (Passer domesticus). We raised nestlings under sterile (axenic) conditions and compared them to nestlings reconstituted (conventionalized) with microbiota from adult sparrows. Conventionalization drove significant increases in villus length, crypt depth, goblet cell density, and mucosal thickness in the small intestine. Conventionalized nestlings also exhibited increased growth of several digestive organs and elevated circulating bile acid levels, including bacterial metabolites known to promote growth and lipid metabolism in vertebrates. These results reveal functions of songbird microbiota and establish axenic methods for non-model oviparous vertebrates.

microbiology↗

bioRxiv2026

Bifidobacterium pseudocatenulatum extracellular vesicles promote Ly6G+ granulocyte infiltration to inhibit melanoma tumour progression

Harnessing the immunomodulatory capacity of commensal bacteria is an emerging avenue in cancer therapy. Bacterial extracellular vesicles (BEVs) provide a non-replicating, nanoscale alternative to live microbes with the potential for safer systemic delivery. Here, we investigated BEVs from a novel Gram-positive strain of Bifidobacterium pseudocatenulatum (Bif-210). Intravenous administration of Bif-210 BEVs reduced B16-F10 melanoma growth in C57BL/6J mice. Mechanistically, BEVs increased tumour-infiltrating Ly6G+ granulocytes in vivo, increased CD11b+Ly6G+ and ICAM-1+Ly6G+ bone marrow populations, and induced production of the neutrophil-attracting chemokines KC/CXCL1 (mouse) and IL-8 (human). Although Ly6G+ depletion independently inhibited tumour growth, it did not combine additively with BEVs, supporting a model in which Bif-210 BEVs alter Ly6G+ granulocyte function rather than simply expanding a conventional pro-tumour granulocyte pool. BEVs activated TLR2, did not activate TLR4, and upregulated TLR2 on Ly6G+ cells, while proxy assays provided no evidence of NETosis-associated activation. Repeated intravenous BEV administration produced no overt toxicity by tissue histology, body temperature, or body weight monitoring. These findings position B. pseudocatenulatum BEVs as a promising systemic immunotherapy that recruits and re-educates granulocytes via a TLR2-centred pathway to restrain melanoma progression. HIGHLIGHTSO_LIIntravenous Bif-210 BEVs reduce established B16-F10 melanoma growth in mice. C_LIO_LIBif-210 BEVs selectively increase tumour-associated Ly6G+ granulocytes. C_LIO_LIBEV treatment and Ly6G depletion are non-additive, linking BEV activity to granulocyte biology. C_LIO_LIBif-210 BEVs expand Ly6G+ bone marrow populations and induce granulocyte-recruiting chemokines. C_LIO_LIBif-210 BEVs engage TLR2 and enhance granulocyte fitness without NETosis-associated activation. C_LI

cancer biology↗

bioRxiv2026

Acute exposure to cell-free mitochondrial DNA induces pregnancy-specific aortic endothelial dysfunction and organ-selective inflammation in rats

Pregnancy complications such as preeclampsia are associated with circulating cell-free mitochondrial DNA (mtDNA), a damage-associated molecular pattern capable of activating Toll-like receptor 9 (TLR9). We hypothesized that acute mtDNA exposure induces maternal inflammation and endothelial dysfunction during pregnancy via TLR9 activation. Non-pregnant and pregnant rats (gestational days 14-15) were treated intravenously with saline or purified mtDNA and euthanized 4 h after treatment. mtDNA increased cytokine mRNA expression in lung and liver of non-pregnant and pregnant rats, with magnitude varying by pregnancy status and organ. Aortas from pregnant, but not non-pregnant, rats exhibited reduced acetylcholine (ACh)-induced relaxation following mtDNA treatment (Emax, saline: 90.1 {+/-} 3.9 % vs. mtDNA: 62.1 {+/-} 20.7 % KClmax, p<0.05), while uterine artery function was preserved, indicating vascular bed-specific effects. Ex vivo incubation of aortic rings with mtDNA {+/-} white blood cells did not replicate in vivo findings, implicating systemic rather than direct vascular mechanisms. Nuclear DNA did not affect ACh-induced relaxation (p>0.05), confirming that the vascular effects were mtDNA-specific. Pharmacological antagonism of TLR9 with ODN2088 partially attenuated mtDNA-induced maternal endothelial dysfunction. Although overt vascular ROS increases were not detected, aortas from pregnant rats had reduced sod-1 expression (p<0.05) and increased eNOS protein abundance (p<0.05). Acute mtDNA exposure during pregnancy induces maternal organ inflammation and impairs endothelium-dependent vasodilation, with partial TLR9 involvement. In conclusion, aortic transcriptional changes in antioxidant pathways and increased eNOS abundance were also observed, though their functional significance remains to be determined. New & NoteworthyTo our knowledge, this is the first study to demonstrate that acute exposure to circulating mtDNA induces pregnancy-specific maternal endothelial dysfunction and organ-selective inflammatory responses. Our findings reveal pregnancy- and vascular-bed specific responses of the maternal vasculature to mitochondrial danger signals, with partial TLR9 involvement. Aortic transcriptional changes in antioxidant pathways and increased nitric oxide synthase abundance were identified as molecular correlates of this dysfunction.

physiology↗

bioRxiv2025

Human length telomeres restrict the regenerative potential of hematopoietic stem cells in mice

Extremely short telomeres cause bone marrow failure in telomere biology disorder (TBDs) patients. Here, we employed the recently developed Telomouse with human-length telomeres resulting from a single amino acid substitution in the helicase Rtel1 (Rtel1M492K/M492K) to determine the effects of the short telomeres on the bone marrow and hematopoiesis. Under homeostatic conditions, Telomice have notably short telomeres but normal hematopoiesis. However, when forced to repopulate following repeated treatment with 5-fluoro-uracil or upon bone marrow transplantation into lethally irradiated mice, bone marrow progenitor cells are significantly depleted in Telomice compared to wild-type controls. This effect is associated with increased frequency of telomere repeat arrays too short to be detected by fluorescence in situ hybridization in the bone marrow of Telomice.

genetics↗

bioRxiv2024

Independent evolution of atypical sperm morphology in a passerine bird, the red-browed finch (Neochmia temporalis temporalis)

Spermatozoa exhibit striking morphological variation across the animal kingdom. In passerine birds, sperm exhibit considerable variation in size, yet the basic sperm phenotype is highly conserved; sperm are filiform, the head is corkscrew-shaped, and the midpiece is elongated and twisted around the flagellum. A significant departure from this typical sperm morphology has been reported in the sister species, the Eurasian bullfinch (Pyrrhula pyrrhula) and Azores bullfinch (P. murina). Here, we report a second evolutionary shift in passerine sperm phenotype in the nominate subspecies of the red-browed finch (Neochmia temporalis temporalis); sperm are non-filiform, with an ellipsoid head, and an extremely short midpiece restricted to the nuclear-axoneme junction. Additionally, we show that the sperm phenotype of the red-browed finch is similar to the putatively neotenous sperm described in the two bullfinch species. Using whole-genome data, we found no evidence that the unusual sperm phenotype of the red-browed finch is associated with reduced genetic variation or a population bottleneck. In contrast, we find some support for the hypothesis that relaxed post-copulatory sexual selection may, at least in part, explain the unusual sperm of the red-browed finch. We also discuss the possible roles of mutation, genetic drift, and genetic hitchhiking, in the evolutionary origins and maintenance of neotenous sperm phenotypes. Finally, we suggest that these dramatic evolutionary shifts in sperm phenotype warrant further investigation and highlight the need for a greater understanding of the developmental and genomic basis of sperm phenotype.

evolutionary biology↗

bioRxiv2024

Bifidobacterium pseudocatenulatum capsular exopolysaccharide enhances systemic anti-tumour immunity in pre-clinical breast cancer

Gut microbes have merged as powerful regulators of cancer responses, with Bifidobacterium species and strains playing a key role in promoting anti-tumour immunity. While they represent promising candidates for cancer therapeutics, the specific underlying microbial mechanisms driving their efficacy remains poorly understood. In this study, we demonstrate the broad potential of Bifidobacterium species to inhibit breast cancer progression across multiple pre-clinical mouse models. We identify a novel strain, Bifidobacterium pseudocatenulatum 210, which induces systemic anti-tumour immunity and enhances responses to standard-of-care therapies via its cell surface capsular exopolysaccharide (EPS). B. pseudocatenulatum 210 EPS promotes dendritic cell activation and increases systemic cDC1 infiltration, leading to robust CD8+ T cell-mediated anti-tumour activity. Our findings position Bifidobacterium EPS as a novel class of therapeutic compounds with significant potential for cancer treatment.

cancer biology↗

bioRxiv2024

The Enterococcal Polysaccharide Antigen: from structure to biosynthesis and function

L-Rhamnose-containing polysaccharides are produced by Streptococci and Enterococci. They define Lancefield serotypes and represent promising candidates for the design of glycoconjugate vaccines. The Enterococcal Polysaccharide Antigen produced by the opportunistic pathogen Enterococcus faecalis plays a critical role in normal growth, division, biofilm formation, antimicrobial resistance, phage susceptibility, and innate immune evasion. Despite the critical role of this polymer for E. faecalis physiology and host-pathogen interactions, little information is available on its structure and biosynthesis. Here, we elucidate the structure of the intact EPA produced by E. faecalis OG1RF. We report the structure of the linkage unit, revealing an unprecedented complexity of the rhamnose backbone and decorations. Finally, we explore the impact of several EPA structural modifications on innate immune evasion and recognition by bacteriophages. This work represents a first step towards the functional characterisation of EPA for the rational design of therapeutic strategies against a group of important pathogens.

microbiology↗

bioRxiv2024

Persistent Activation of Chronic Inflammatory Pathways in Long Covid

Long Covid, or Post-Acute Sequelae of COVID-19 (PASC), involves a spectrum of chronic symptoms following resolution of acute SARS-CoV-2 infection. Current hypotheses for the pathogenesis of Long Covid include persistent SARS-CoV-2, activation of other viruses, tissue damage, autoimmunity, endocrine insufficiency, immune dysfunction, and complement activation. We evaluated 142 participants, including uninfected controls (N=35), acutely infected individuals (N=54), convalescent controls (N=25), and Long Covid patients (N=28), by comprehensive immunologic, virologic, transcriptomic, and proteomic analyses. Long Covid was characterized by persistent inflammatory pathways compared with convalescent controls and uninfected controls, including upregulation of IL-6 and JAK-STAT pathways as well as activation of coagulation, complement, metabolism, and T cell exhaustion pathways. Moreover, robust activation of these pathways during acute COVID-19 infection correlated with the subsequent development of Long Covid. In an independent validation cohort (N=47), Long Covid patients had higher levels of plasma IL-6R compared with convalescent controls and uninfected controls. These data demonstrate that Long Covid is characterized by persistent activation of chronic inflammatory pathways, suggesting novel therapeutic targets and biomarkers of disease.

immunology↗

bioRxiv2023

Neutralization Escape by SARS-CoV-2 Omicron Subvariant BA.2.86

The continued evolution of SARS-CoV-2 may lead to evasion of vaccine immunity and natural immunity. A highly mutated Omicron variant BA.2.86 has recently been identified with over 30 amino acid changes in Spike compared with BA.2 and XBB.1.5. As of September 4, 2023, BA.2.86 has been identified in 37 sequences from 10 countries, which is likely an underestimate due to limited surveillance. The ability of BA.2.86 to evade NAbs compared with other currently circulating Omicron variants remains unknown. Our data show that NAb responses to BA.2.86 were lower than to BA.2 but were comparable or slightly higher than to the current circulating recombinant variants XBB.1.5, XBB.1.16, EG.5, EG.5.1, and FL.1.5.1.

microbiology↗

bioRxiv2023

Waning Immunity Against XBB.1.5 Following Bivalent mRNA Boosters

The SARS-CoV-2 Omicron variant has continued to evolve. XBB is a recombinant between two BA.2 sublineages, XBB.1 includes the G252V mutation, and XBB.1.5 includes the G252V and F486P mutations. XBB.1.5 has rapidly increased in frequency and has become the dominant virus in New England. The bivalent mRNA vaccine boosters have been shown to increase neutralizing antibody (NAb) titers to multiple variants, but the durability of these responses remains to be determined. We assessed humoral and cellular immune responses in 30 participants who received the bivalent mRNA boosters and performed assays at baseline prior to boosting, at week 3 after boosting, and at month 3 after boosting. Our data demonstrate that XBB.1.5 substantially escapes NAb responses but not T cell responses after bivalent mRNA boosting. NAb titers to XBB.1 and XBB.1.5 were similar, suggesting that the F486P mutation confers greater transmissibility but not increased immune escape. By month 3, NAb titers to XBB.1 and XBB.1.5 declined essentially to baseline levels prior to boosting, while NAb titers to other variants declined less strikingly.

immunology↗

bioRxiv2022

The neurophysiology of closed-loop auditory stimulation in sleep: a MEG study

Closed-loop auditory stimulation (CLAS) is a brain modulation technique in which sounds are timed to enhance or disrupt endoge-nous neurophysiological events. CLAS of slow oscillation up-states in sleep is becoming a popular tool to study and enhance sleeps functions, as it increases slow oscillations, evokes sleep spindles, and enhances memory consolidation of certain tasks. However, few studies have examined the specific neurophysiological mechanisms involved in CLAS, in part because of practical limitations to available tools. To evaluate evidence for possible models of how sound stimulation during brain up-states alters brain activity, we simultaneously recorded electro- and magnetoencephalography in human participants who received auditory stimulation across sleep stages. We conducted a series of analyses that test different models of pathways through which CLAS of slow oscillations may affect widespread neural activity that have been suggested in literature, using spatial information, timing, and phase relationships in the source-localized magnetoencephalography data. The results suggest that auditory information reaches ventral frontal lobe areas via non-lemniscal pathways. From there, a slow oscillation is created and propagated. We demonstrate that while the state of excitability of tissue in auditory cortex and frontal ventral regions shows some synchrony with the EEG-recorded up-states that are commonly used for CLAS, it is the state of ventral frontal regions that is most critical for slow oscillation generation. Our findings advance models of how CLAS leads to enhancement of slow oscillations, sleep spindles, and associated cognitive benefits, and offer insight into how the effectiveness of brain stimulation techniques can be improved.

neuroscience↗

bioRxiv2022

Immunogenicity of the BA.5 Bivalent mRNA Vaccine Boosters

Waning immunity following mRNA vaccination and the emergence of SARS-CoV-2 variants has led to reduced mRNA vaccine efficacy against both symptomatic infection and severe disease. Bivalent mRNA boosters expressing the Omicron BA.5 and ancestral WA1/2020 Spike proteins have been developed and approved, because BA.5 is currently the dominant SARS-CoV-2 variant and substantially evades neutralizing antibodies (NAbs). Our data show that BA.5 NAb titers were comparable following monovalent and bivalent mRNA boosters.

immunology↗

bioRxiv2021

The NK receptor NKp46 recognizes ecto-calreticulin on ER-stressed cells

Natural killer cells (NK) are a first line of immune defense to eliminate infected, transformed and stressed cells by releasing cytotoxic granules1. NK activation is controlled by the balance of signals transmitted by activating and inhibitory receptors but activating receptor engagement is required to trigger cytotoxicity. The activating receptor NKp46, encoded by the NCR1 gene, is expressed by virtually all NK cells and is the most evolutionarily ancient NK receptor. NKp46 plays a major role in NK recognition of cancer cells, since NKp46 blocking antibodies potently inhibit NK killing of many cancer targets2,3. Although a few viral, fungal and soluble host ligands4 have been identified, the endogenous cell-surface ligand of this important activating NK receptor is unknown. Here we show that NKp46 recognizes and is activated by the P-domain of externalized calreticulin (ecto-CRT). CRT, normally localized to the ER, translocates to the cell surface during ER stress and is a hallmark of chemotherapy-treated dying cancer cells that induce an immune response (immunogenic cell death, ICD)5. NKp46 caps with ecto-CRT in NK immune synapses formed with ecto-CRT-bearing target cells. ER stress, induced by ZIKV infection, ICD-causing chemotherapy drugs and some senescence activators, externalizes CRT and triggers NKp46 signaling. NKp46-mediated killing is inhibited by CRT knockout or knockdown or anti-CRT antibodies and is enhanced by ectopic expression of GPI-anchored CRT. NCR1/Ncr1-deficient human and mouse NK are impaired in killing ZIKV-infected, ER-stressed, and senescent cells and cancer cells that endogenously or ectopically express ecto-CRT. Importantly, NKp46 recognition of ecto-CRT controls the growth of B16 melanoma and RAS-driven lung cancer in mouse models and enhances tumor-infiltrating NK degranulation and cytokine secretion. Thus, ecto-CRT is a danger-associated molecular pattern (DAMP) that is an endogenous NKp46 ligand that promotes innate immune elimination of ER-stressed cells.

immunology↗

bioRxiv2021

Extensive transgressive gene expression in a homoploid hybrid species

Hybridization can result in novel allelic combinations which can impact the hybrid phenotype through changes in gene expression. While mis-expression in F1 hybrids is well documented, how gene expression evolves in stabilized hybrid taxa remains an open question. As gene expression evolves in a stabilizing manner, break-up of co-evolved cis- and trans-regulatory elements could lead to transgressive patterns of gene expression in hybrids. Here, we address to what extent gonad gene expression has evolved in an established and stable homoploid hybrid, the Italian sparrow (Passer italiae). Through comparison of gene expression in gonads from individuals of the two parental species (i.e., house and Spanish sparrow) to that of Italian sparrows, we find evidence for strongly transgressive expression in male Italian sparrows - 22% of testis genes exhibit expression patterns outside the range of both parent species. In contrast, Italian sparrow ovary expression was similar to that of one of the parent species, the house sparrow (Passer domesticus). Moreover, the Italian sparrow testis transcriptome is 26 times as diverged from those of the parent species as the parental transcriptomes are from each other, despite being genetically intermediate. This highlights the potential for regulation of gene expression to produce novel variation following hybridization. Genes involved in mitochondrial respiratory chain complexes and protein synthesis are enriched in the subset that is over-dominantly expressed in Italian sparrow testis, suggesting that selection on key functions have molded the hybrid Italian sparrow transcriptome.

evolutionary biology↗

bioRxiv2019

A Plant-Specific Polarity Module Establishes Cell Fate Asymmetry in the Arabidopsis Stomatal Lineage

Generating cell polarity in anticipation of asymmetric cell division is required in many developmental contexts across a diverse range of species. Physical and genetic diversity among major multicellular taxa, however, demand different molecular solutions to this problem. The Arabidopsis stomatal lineage displays asymmetric, stem cell-like and oriented cell divisions, which require the activity of the polarly localized protein, BASL. Here we identify the plant-specific BREVIS RADIX (BRX) family as localization and activity partners of BASL. We show that members of the BRX family are polarly localized to peripheral domains in stomatal lineage cells and that their collective activity is required for asymmetric cell divisions. We further demonstrate a mechanism for these behaviors by uncovering mutual, yet unequal dependencies of BASL and the BRX family for each others localization and segregation at the periphery of stomatal lineage cells.

plant biology↗

bioRxiv2018

Tractography Reproducibility Challenge with Empirical Data (TraCED): The 2017 ISMRM Diffusion Study Group Challenge

PurposeFiber tracking with diffusion weighted magnetic resonance imaging has become an essential tool for estimating in vivo brain white matter architecture. Fiber tracking results are sensitive to the choice of processing method and tracking criteria. Phantom studies provide concrete quantitative comparisons of methods relative to absolute ground truths, yet do not capture variabilities because of in vivo physiological factors.\n\nMethodsTo date, a large-scale reproducibility analysis has not been performed for the assessment of the newest generation of tractography algorithms with in vivo data. Reproducibility does not assess the validity of a brain connection however it is still of critical importance because it describes the variability for an algorithm in group studies. The ISMRM 2017 TraCED challenge was created to fulfill the gap. The TraCED dataset consists of a single healthy volunteer scanned on two different scanners of the same manufacturer. The multi-shell acquisition included b-values of 1000, 2000 and 3000 s/mm2 with 20, 45 and 64 diffusion gradient directions per shell, respectively.\n\nResultsNine international groups submitted 46 tractography algorithm entries. The top five submissions had high ICC > 0.88. Reproducibility is high within these top 5 submissions when assessed across sessions or across scanners. However, it can be directly attributed to containment of smaller volume tracts in larger volume tracts. This holds true for the top five submissions where they are contained in a specific order. While most algorithms are contained in an ordering there are some outliers.\n\nConclusionThe different methods clearly result in fundamentally different tract structures at the more conservative specificity choices (i.e., volumetrically smaller tractograms). The data and challenge infrastructure remain available for continued analysis and provide a platform for comparison.

neuroscience↗

bioRxiv2018

A florigen paralog is required for short-day vernalization in a pooid grass

Perception of seasonal cues is critical for reproductive success in many plants. Exposure to winter cold is a cue that can confer competence to flower in the spring via a process known as vernalization. In certain grasses, exposure to short days is another winter cue that can lead to a vernalized state. In Brachypodium distachyon, we find that natural variation for the ability of short days to confer competence to flower is due to allelic variation of the florigen paralog FT-like9 (FTL9). An active FTL9 allele is required for the acquisition of floral competence, demonstrating a novel role for a member of the florigen family of genes. Loss of the short-day vernalization response appears to have arisen once in B. distachyon and spread through diverse lineages indicating that this loss has adaptive value, perhaps by delaying spring flowering until the danger of cold damage to flowers has subsided.

plant biology↗