Biology subjects

Alexander, K.

Publications and source records attributed to Alexander, K..

8 recordsLinked to original sources

bioRxiv2026

Splenic tropism of Plasmodium vivax in acute infection and spleen-attenuated systemic inflammation

BackgroundIn chronic asymptomatic Plasmodium vivax infections, the spleen accounts for more than 98% of total-body parasite biomass. Whether this splenic tropism also exists in acute infection and how the spleen influences pathogenesis have not been systematically explored. Materials and MethodsIn Papua, Indonesia, we compared plasma levels of P. vivax lactate dehydrogenase [PvLDH]) and circulating parasitemia in 24 spleen-intact and 25 previously splenectomized patients with acute uncomplicated vivax malaria. Clinical and hematology data were collected and plasma markers of intravascular hemolysis (cell-free hemoglobin [CFHb]), endothelial activation (angiopoietin-2), inflammation (interleukin [IL]-1 beta, IL-6, IL-18, IL-10, tumor necrosis factor-alpha) and neutrophil activation (elastase) were measured by ELISA. Giemsa-based histology in one spleen from an untreated patient splenectomized for trauma during an episode of acute vivax malaria enabled direct assessment of splenic and circulating parasitemia and biomass microscopically. ResultsCirculating parasitemia was 4-times higher in splenectomized compared to spleen-intact patients (median 21,100 vs 4,820 parasites/{micro}L, p=0.0002) but total-body P. vivax biomass (PvLDH) was 3-times lower in patients without a spleen (median 721 vs 2,140 ng/mL, p=0.026). Parasite staging and greater organ-specific symptoms suggest redistribution of parasites in the absence of a spleen. Linear regression modeling, adjusting for circulating parasitemia, patient age, sex and duration of fever, demonstrated an 8.1-fold higher PvLDH concentration in spleen-intact patients (95% confidence interval [CI]: 3.4-19.5-fold, p<0.0001), indicating a splenic biomass accounting for 89% (95%CI: 77.3-95.1%) of total-body parasites. Histopathology revealed a spleen-to-blood biomass ratio of 10.7, in-line with the PvLDH-based estimate. In spleen-intact patients, splenic P. vivax biomass correlated strongly with markers of disease intensity, endothelial activation and systemic inflammation, whereas circulating parasitemia correlated weakly or not at all. Compared to spleen-intact patients, CFHb, endothelial activation and systemic inflammation were higher in splenectomized patients while inflammasome-dependent responses were lower. ConclusionsP. vivax is predominantly an infection of the spleen, even in acute clinical vivax malaria. We conservatively estimate that 89% of total-body parasite biomass in acute infection is splenic. While the size of this hidden population correlates with disease intensity, the spleen likely regulates inflammatory pathways and heme-associated pathology.

pathology↗

bioRxiv2024

Treading lightly: Quantitative estimates of seafloor contact for longline trap and hook fishing gear

Despite increasing calls for sustainability and ecosystem objectives to manage fishing gear interactions with bottom habitats there are few quantitative approaches for assessing risks from bottom contact fishing. Risk assessments for bottom longline fisheries are particularly challenging due to a lack of information for estimating bottom contact areas from longline gear. In this paper, we demonstrate how data sensors and video cameras deployed on fishing gear can be used to quantify the bottom contact area for longline trap and hook fishing gear from the British Columbia Sablefish fishery. Our bottom contact estimates indicate that Sablefish fishing risks to bottom habitat are low in the majority of fishing areas, since 91.8% of the area fished is expected to have had zero bottom contact over the last 17 years. For the other 8.2% of Sablefish fishing areas that experience some contact from fishing gear, the majority are only contacted once. This indicates that most habitats contacted by Sablefish gear can be expected to have a minimum of 17 years to recover between subsequent bottom contact events. We demonstrate an approach for estimating fisheries bottom contact that can be widely implemented across longline fisheries. Our findings address key data gaps in bottom impacts research for longline gear fisheries, allowing fishing risks to be quantified over fine spatial scales. Such quantitative approaches for habitat risk assessment can provide essential information for management decisions aimed at determining acceptable trade-offs between habitat preservation and fishery benefits.

ecology↗

bioRxiv2023

Targeting phosphoRab-RILPL Interactions as a Strategy to Downregulate Pathogenic LRRK2 in Parkinson's Disease

Familial Parkinsons disease (PD) is frequently linked to multiple disease-causing mutations within Leucine-Rich Repeat Protein Kinase 2 (LRRK2), leading to aberrant kinase activity. Multiple pathogenic effects of enhanced LRRK2 activity have been identified including loss of cilia and centrosomal cohesion defects. When phosphorylated by LRRK2, Rab8a and Rab10 bind to phospho-specific RILPL effector proteins. RILPL-mediated accumulation of pRabs proximal to the mother centriole is critical for initiating deficits in ciliogenesis and centrosome cohesion mediated by LRRK2. We hypothesized that Rab-derived phospho-mimics may serve to block phosphorylated Rab proteins from docking with RILPL in the context of hyperactive LRRK2 mutants. This would serve as an alternative strategy to downregulate pathogenic signaling mediated by LRRK2, rather than targeting LRRK2 kinase activity itself. To test this theory, we designed a series of constrained peptides mimicking phosphorylated Switch II derived from Rab8. These RILPL interacting peptides, termed RIP, were further shown to permeate cells. Further, several peptides were found to bind RILPL2 and restore ciliogenesis and centrosomal cohesion defects in cells expressing PD-associated mutant LRRK2. This research demonstrates the utility of constrained peptides as downstream inhibitors to target pathogenic LRRK2 activity and may provide an alternative approach to target specific pathways activated by LRRK2.

biochemistry↗

bioRxiv2023

CTCF/cohesin organize the ground state of chromatin-nuclear speckle association

The interchromatin space in the cell nucleus contains various membrane-less nuclear bodies. Recent findings indicate that nuclear speckles, comprising a distinct nuclear body, exhibit interactions with certain chromatin regions in a ground state. Key questions are how this ground state of chromatin-nuclear speckle association is established and what are the gene regulatory roles of this layer of nuclear organization. We report here that chromatin structural factors CTCF and cohesin are required for full ground state association between DNA and nuclear speckles. Disruption of ground state DNA-speckle contacts via either CTCF depletion or cohesin depletion had minor effects on basal level expression of speckle-associated genes, however we show strong negative effects on stimulus-dependent induction of speckle-associated genes. We identified a putative speckle targeting motif (STM) within cohesin subunit RAD21 and demonstrated that the STM is required for chromatin-nuclear speckle association. In contrast to reduction of CTCF or RAD21, depletion of the cohesin releasing factor WAPL stabilized cohesin on chromatin and DNA-speckle contacts, resulting in enhanced inducibility of speckle-associated genes. In addition, we observed disruption of chromatin-nuclear speckle association in patient derived cells with Cornelia de Lange syndrome (CdLS), a congenital neurodevelopmental diagnosis involving defective cohesin pathways, thus revealing nuclear speckles as an avenue for therapeutic inquiry. In summary, our findings reveal a mechanism to establish the ground organizational state of chromatin-speckle association, to promote gene inducibility, and with relevance to human disease.

genetics↗

bioRxiv2021

Spinal cord injury reprograms muscle fibro-adipogenic progenitors to formheterotopic bones within muscles

The cells-of-origin of neurogenic heterotopic ossifications (NHO), which develop frequently in the periarticular muscles following spinal cord injuries (SCI) and traumatic brain injuries, remain unclear because the skeletal muscle harbors two progenitor cell populations: satellite cells (SCs) which are myogenic, and fibro-adipogenic progenitors (FAPs) which are mesenchymal. Lineage-tracing experiments using the Cre recombinase /LoxP system were performed in two mouse strains with the fluorescent protein ZsGreen specifically expressed in either SCs or FAPs in the skeletal muscles under the control of the Pax7 or Prrx1 gene promotors respectively. These experiments demonstrate that following a muscle injury, SCI causes the upregulation of PDGFR on FAPs but not SCs and the failure of SCs to regenerate myofibers in the injured muscle, with instead reduced apoptosis and continued proliferation of muscle resident FAPs enabling their osteogenic differentiation into NHO. No cells expressing ZsGreen under the Prrx1 promoter were detected in the blood after injury suggesting that the cells-of-origin of NHO are locally derived from the injured muscle. We validated these findings in the human pathology using human NHO biopsies. PDGFR+ mesenchymal cells isolated from the muscle surrounding NHO biopsies could develop ectopic human bones when transplanted into immunocompromised mice whereas CD56+ myogenic cells had a much lower potential. Therefore, NHO is a pathology of the injured muscle in which SCI reprograms FAPs to uncontrolled proliferation and differentiation into osteoblasts.

pathology↗

bioRxiv2021

Interleukin-1 is overexpressed in injured muscles following spinal cord injury and promotes neurogenic heterotopic ossification

Neurogenic heterotopic ossifications (NHOs) form in periarticular muscles following severe spinal cord (SCI) and traumatic brain injuries. The pathogenesis of NHO is poorly understood with no effective preventive treatment. The only curative treatment remains surgical resection of pathological NHOs. In a mouse model of SCI-induced NHO that involves a transection of the spinal cord combined with a muscle injury, a differential gene expression analysis revealed that genes involved in inflammation such as interleukin-1{beta} (IL-1{beta}) were overexpressed in muscles developing NHO. Using mice knocked-out for the gene encoding IL-1 receptor (IL1R1) and neutralizing antibodies for IL-1 and IL-1{beta}, we show that IL-1 signaling contributes to NHO development following SCI in mice. Interestingly, other proteins involved in inflammation that were also overexpressed in muscles developing NHO, such as colony-stimulating factor-1, tumor necrosis factor or C-C chemokine ligand-2 did not promote NHO development. Finally using NHO biopsies from SCI and TBI patients, we show that IL-1{beta} is expressed by CD68+ macrophages. IL-1 and IL-1{beta} produced by activated human monocytes promote calcium mineralization of fibro-adipogenic progenitors isolated from muscles surrounding NHOs. Altogether these data suggest that interleukin-1 promotes NHO development in both humans and mice.

physiology↗

bioRxiv2018

Relationship between epicardial and perivascular fatty tissue and adipokine-cytokine level in coronary artery disease patients

The aim of this study was to determine the relationship between the thickness of EAT and PVAT and the adipokine-cytokine profile of patients with coronary heart disease, which can be of significant importance for predicting the course of CVD. 84 patients with CVD, were assessed and divided into two groups based on the presence of visceral obesity (VO). In VO patients, the thickness of the epicardial deposits of the left and right ventricles were 1.75 and 1.43 times greater, respectively, than in patients without VO. For patients with VO, the prevalence of the volume of the left anterior descending artery was 10% higher, and the middle third of the envelope artery was 28% higher, when compared to patients without VO. When evaluating inflammatory status, it was established that the concentration of TNF- and IL-1{beta}, leptin in the blood serum of patients with VO exceeded the values of patients without VO. Level of proinflammatory IL-10 was 2-times lower in patients with VO. The findings of this study show that the increase of EAT and PVAT are independent risk factors of CVD, as well as a possible model for the assessment of drug effectiveness for CVD.

biochemistry↗

bioRxiv2018

The global distribution of Bacillus anthracis and associated anthrax risk to humans, livestock, and wildlife

Bacillus anthracis is a spore-forming, Gram-positive bacterium responsible for anthrax, an acute and commonly lethal infection that most significantly affects grazing livestock, wild ungulates and other herbivorous mammals, but also poses a serious threat to human health1, 2. The geographic extent of B. anthracis endemism is still poorly understood, despite multi-decade research on anthrax epizootic and epidemic dynamics around the world3, 4. Several biogeographic studies have focused on modeling environmental suitability for anthrax at local or national scales5-9, but many countries have limited or inadequate surveillance systems, even within known endemic regions. Here we compile an extensive global occurrence dataset for B. anthracis, drawing on confirmed human, livestock, and wildlife anthrax outbreaks. With these records, we use boosted regression trees10, 11 to produce the first map of the global distribution of B. anthracis as a proxy for anthrax risk. Variable contributions to the model support pre-existing hypotheses that environmental suitability for B. anthracis depends most strongly on soil characteristics such as pH that affect spore persistence, and the extent of seasonal fluctuations in vegetation, which plays a key role in transmission for herbivores12, 13. We apply the global model to estimate that 1.83 billion people (95% credible interval: 0.59--4.16 billion) live within regions of anthrax risk, but most of that population faces little occupational exposure to anthrax. More informatively, a global total of 63.8 million rural poor livestock keepers (95% CI: 17.5--168.6 million) and 1.1 billion livestock (95% CI: 0.4--2.3 billion) live within vulnerable regions. Human risk is concentrated in rural areas, and human and livestock vulnerability are both concentrated in rainfed systems throughout arid and temperate land across Eurasia, Africa, and North America. We conclude by mapping where anthrax risk overlaps with vulnerable wild ungulate populations, and therefore could disrupt sensitive conservation efforts for species like bison, pronghorn, and saiga that coincide with anthrax-prone, mixed-agricultural landscapes. Anthrax is a zoonotic disease caused by the Gram-positive bacterium Bacillus anthracis, a generalist soil-transmitted pathogen found on every inhabited continent14, and several islands including Haiti and parts of the Philippines and Indonesia. Worldwide, an estimated 20,000 to 100,000 cases of anthrax occur annually, mostly in poor rural areas15. In clinical presentations of anthrax, case fatality rates are a function of exposure pathway. Respiratory exposure from spore inhalation is important the context of bioterrorism, but is highly uncommon, and accounts for a negligible fraction of the global burden of anthrax cases. Cutaneous exposure to B. anthracis accounts for the majority of human cases worldwide, and typically presents with low mortality; gastrointestinal exposure accounts for the remainder and presents with intermediate to high fatality rates. Cutaneous and gastrointestinal cases of anthrax are most commonly caused by handling and slaughtering infected livestock, or butchering and eating contaminated meat; untreated gastrointestinal cases likely account for most human mortality from anthrax.14-16

epidemiology↗