Biology subjects

Kimball, A.

Publications and source records attributed to Kimball, A..

6 recordsLinked to original sources

bioRxiv2026

Postpartum Systemic Inflammation is Reflected in Early Distinct Fecal Microbiome Differences in Dairy Cows

A tightly regulated inflammatory response occurs during and following parturition; however, excessive or prolonged inflammation negatively affects herd health and productivity. The gut microbiota plays an important role in host immunity and metabolism and undergoes substantial changes during the transition period. However, the relationship between systemic inflammation, measured by serum acute-phase proteins, and gut microbial dynamics during early lactation remains poorly understood. We investigated fecal microbiota dynamics in relation to systemic inflammation in early postpartum dairy cows. Fecal and blood samples were collected from 71 Holstein cows on days 1 and 3 in milk (DIM). The V3-V4 region of the 16S rRNA gene was sequenced and microbial diversity, differential abundance, and microbial interaction networks were evaluated. Inflammatory status, defined by fibrinogen, haptoglobin, and their combined classification, was associated with significant alterations in fecal microbial composition during the immediate postpartum period, independent of body condition score, parity, DIM, and DNA extraction parameters. Differential abundance analyses revealed extensive taxonomic restructuring, while network analyses identified increased modularity, altered keystone taxa distribution, and greater compartmentalization of microbial interactions in animals with elevated inflammatory markers. Several taxa were consistently associated with inflammatory status across analytical approaches. Notably, Ruminococcaceae UCG-002 and Dielma were associated with inflammatory states, whereas Xylanibacter, Marvinbryantia, Akkermansia, and Oscillibacter were associated with non-inflammatory status. This study identifies an association between systemic inflammation and fecal microbiota composition in early transition dairy cows, providing a foundation for future microbiome-based biomarkers of inflammatory status. IMPORTANCESubclinical systemic inflammation during early postpartum can negatively affect dairy cow health and productivity, yet current monitoring relies on repeated blood sampling and transient inflammatory biomarkers. For the first time association of systemic inflammation, assessed using fibrinogen, haptoglobin, and their combined classification, with alterations in fecal microbial composition, microbial interaction networks, and keystone taxa distribution during the early postpartum period was established. Several bacterial taxa were consistently associated with either elevated or normal inflammatory states across differential abundance, network, and odds ratio analyses. Many of these taxa remain poorly characterized in dairy cattle, highlighting the need for future mechanistic studies. This study demonstrates that systemic inflammation during early postpartum is associated with measurable alterations in the fecal microbiota. This work provides a foundation for developing microbiome-based biomarkers for detecting and monitoring subclinical systemic inflammation in dairy cattle.

microbiology↗

bioRxiv2025

Independent evolution of holocentric centromeres in an early branching apicomplexan parasite

During its asexual cycle, Cryptosporidium parvum (C. parvum) amplifies through three rounds of nuclear division before undergoing cytokinesis to form infectious merozoites. However, chromosome organization and segregation during nuclear division remain unstudied. Here, we visualized H3-histones, including the centromeric histone H3 (CENH3), telomeres, and centrosomes during mitosis. Nuclear division was accompanied by centrosome duplication and elongated microtubules that spanned the dividing nuclei. Surprisingly, C. parvum centromeres detected by CENH3 showed diffuse staining throughout nuclear division, that overlapped with telomeres in the apical nucleus. Analysis of centromeres based on CENH3 capture and DNA sequencing revealed numerous distinct binding sites scattered across all eight chromosomes, including both coding regions and intergenic regions, that were typified by GA rich repeat sequences. The unique holocentric chromosome structure of C. parvum is unlike the single regional centromeres found in related apicomplexans, suggesting it arose independently from other known examples in plants, insects and worms.

microbiology↗

bioRxiv2025

Intrarenal Generation of Aldosterone Contributes to Ischemia-Induced Hypertension and Nephropathy in Mice

BackgroundThe past few years have witnessed a significant advancement in aldosterone (Aldo)-targeted therapies for the management of treatment-resistant hypertension and chronic kidney disease, which often exist in tandem. While Aldo is believed to predominantly originate from the adrenal glands, this study provides evidence to support the involvement of intrarenal Aldo biosynthesis in the pathogenesis of ischemic nephropathy and hypertension in a two-kidney, one-clip (2K1C) model. MethodsWe generated inducible renal tubule-specific deletion of C11B2 (RT C11B2 KO) and characterized the phenotype during the 2K1C procedure. We investigated the underlying mechanisms involving the use of mice with collecting duct-specific (pro)renin receptor (CD PRR KO) or renin (CD renin KO). ResultsRT C11B2 KO induced a partial blockade of the hypertensive response but a much greater improvement in renal fibrosis and inflammation four weeks post-2K1C. This phenotype was associated with an effective blockade of intrarenal generation of Aldo contrasting to unchanged circulating Aldo concentrations. Furthermore, clipping-induced acute kidney injury was also attenuated 24 hours post-2K1C, at which point blood pressure (BP) did not increase. Similarly, sodium nitroprusside effectively lowered BP in C57BL/6j/2K1C mice but failed to improve renal injury. Additionally, we identified CD) PRR and renin as key upstream regulators of intrarenal Aldo biosynthesis following the 2K1C procedure. ConclusionsTogether, these results support the idea that CD PRR/renin-dependent generation of intrarenal Aldo may play a primary role in the pathogenesis of ischemic nephropathy and a secondary role in hypertension development during renovascular constriction. Therefore, targeting intrarenal Aldo biosynthesis may represent a more effective and safer intervention than existing Aldo-targeted therapy to manage ischemic nephropathy as well as hypertension.

physiology↗

bioRxiv2024

Mendelian segregation and high recombination rates facilitate genetic analyses in Cryptosporidium parvum

Very little is known about the process of meiosis in the apicomplexan parasite Cryptosporidium despite the essentiality of sex in its life cycle. Most cell lines only support asexual growth of Cryptosporidium parvum (C. parvum), but stem cell derived intestinal epithelial cells grown under air-liquid interface (ALI) conditions support the sexual cycle. To examine chromosomal dynamics during meiosis in C. parvum, we generated two transgenic lines of parasites that were fluorescently tagged with mCherry or GFP on chromosomes 1 or 5, respectively. Infection of ALI cultures or Ifngr1-/- mice with mCherry and GFP parasites produced "yellow" oocysts generated by cross-fertilization. Outcrossed oocysts from the F1 generation were purified and used to infect HCT-8 cultures, and phenotypes of the progeny were observed by microscopy. All possible phenotypes predicted by independent segregation were represented equally ([~]25%) in the population, indicating that C. parvum chromosomes exhibit a Mendelian inheritance pattern. Unexpectedly, the most common pattern observed from the outgrowth of single oocysts included all possible parental and recombinant phenotypes derived from a single meiotic event, suggesting a high rate of crossover. To estimate the frequency of crossover, additional loci on chromosomes 1 and 5 were tagged and used to monitor intrachromosomal crosses in Ifngr1-/- mice. Both chromosomes showed a high frequency of crossover compared to other apicomplexans with map distances (i.e., 1% recombination) of 3-12 kb. Overall, a high recombination rate may explain many unique characteristics observed in Cryptosporidium spp. such as high rates of speciation, wide variation in host range, and rapid evolution of host-specific virulence factors. AUTHOR SUMMARYAlthough sex is essential for the transmission and maintenance of infection of Cryptosporidium, it has been historically challenging to study the process of meiosis in this medically relevant protist. We utilize recent methodological advances such as a specialized in vitro culture system, cell sorting, and the generation of transgenic parasites to cross identical strains of parasites in the absence of selection pressure to identify intrinsic chromosome behavior during meiosis. By specifically examining the phenotypes from the first generation of parasites, we reveal that cross-fertilization frequently occurs in parasite populations, chromosomes segregate in a Mendelian manner, and the rate of crossover is high on Chromosomes 1 and 5. Understanding these baseline meiotic mechanisms is essential for planning and interpreting future genetic studies of Cryptosporidium seeking to identify genes associated with phenotypes of interest.

microbiology↗

bioRxiv2022

Inflammaging in human photoexposed skin: Early onset of senescence and imbalanced epidermal homeostasis across the decades.

Inflammaging is a theory of aging which purports that low-level chronic inflammation leads to cellular dysfunction and premature aging of surrounding tissue. Skin is susceptible to inflammaging because it is the first line of defense from the environment, particularly solar radiation. To better understand the impact of aging and photoexposure on epidermal biology we performed a systems biology-based analysis of photoexposed face and arm and photoprotected buttock sites from women between the ages of 20s to 70s. Biopsies were analyzed by histology, transcriptomics, and proteomics and skin surface biomarkers collected from tape strips. We identified morphological changes with age of epidermal thinning, rete ridge pathlength loss, and stratum corneum thickening. The SASP biomarkers IL-8 and IL-1RA/IL1- were consistently elevated in face across age and cis/trans-urocanic acid were elevated in arms and face with age. In older arms, the DNA damage response biomarker 53BP1 showed higher puncti numbers in basal layers and epigenetic aging was accelerated. Genes associated with differentiation and senescence show increasing expression in the 30s whereas genes associated with hypoxia and glycolysis increase in the 50s. Proteomics comparing 60s vs 20s confirmed elevated levels of differentiation and glycolytic related proteins. Representative immunostaining for proteins of differentiation, senescence, and oxygen sensing/hypoxia shows similar relationships. This systems biology-based analysis provides a body of evidence that young photoexposed skin is undergoing inflammaging. We propose the presence of chronic inflammation in young skin contributes to an imbalance of epidermal homeostasis that leads to a prematurely aged appearance during later life.

systems biology↗

bioRxiv2018

Pathogenic DDX3X mutations impair RNA metabolism and neurogenesis during fetal cortical development

De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

genetics↗