Biology subjects

Henderson, M.

Publications and source records attributed to Henderson, M..

18 recordsLinked to original sources

bioRxiv2025

Lewy pathology accumulates in swollen corticostriatal synapses in α-synucleinopathies

Lewy body diseases (LBD), including Parkinsons disease (PD), Parkinsons disease dementia (PDD), and dementia with Lewy bodies (DLB), are neurodegenerative disorders characterized by the accumulation of misfolded -synuclein in the form of Lewy pathology. A hallmark of these diseases is degeneration of the nigrostriatal pathway, resulting in loss of dopaminergic input to the striatum and consequent motor dysfunction. Lewy pathology is present in many regions outside the substantia nigra, and cortical Lewy pathology is the best correlate of cognitive decline in individuals that develop dementia. In addition, there is a high burden of neuritic Lewy pathology in the putamen, though the neuronal origin of this pathology is unclear. In the current study, we quantified the burden of Lewy pathology in the putamen across the spectrum of LBDs. Immunohistochemistry was used to quantify the Lewy burden in the putamen, cingulate and frontal cortices of 9 controls and 24 LBD cases. Even in PD cases without dementia, we observed a nearly complete striatal dopaminergic denervation among LBDs. Consistent with this denervation, most -synuclein pathology did not co-localize with dopaminergic terminals, but was instead enriched in excitatory, VGLUT1-positive terminals. This enrichment in glutamatergic terminals was associated with swollen axons, but not with overall loss of VGLUT1 terminals. These findings suggest that Lewy pathology accumulates at excitatory corticostriatal synapses prior to overt synaptic degeneration and could contribute to cognitive decline in LBDs.

neuroscience↗

bioRxiv2025

Predicting interactions between the SARS-CoV-2 spike glycoprotein and the human proteome using AphaFold and molecular dynamics simulations

AbstractSince the COVID-19 pandemic began, the SARS-CoV-2 virus has caused over 775 million cases and more than 7 million deaths worldwide. Despite progress in treatments and vaccines, we still need better ways to prevent and treat the disease. To do this, a clearer understanding of how SARS-CoV-2 interacts with human proteins is needed. We developed a new computational tool to predict and study these protein-protein interactions. Our method uses two stages of AlphaFold, an AI tool, to predict how SARS-CoV-2 proteins bind to human proteins, followed by molecular dynamics simulation to refine these predictions. We tested this method in a small study focusing on the S1 subunit of the SARS-CoV-2 spike protein interacting with human cell junction and synaptic proteins, and in a larger study screening the spike S1 N- terminal domain against the entire human proteome. We validated the method using experimental virus-human protein interactions. The results provide valuable insights into how SARS-CoV-2 interacts with human proteins, guiding future experiments to better understand COVID-19s short- and long-term effects. This developed method could be utilized to study protein-protein interactions in other biological systems.

biochemistry↗

bioRxiv2025

Hepatic ADMA/PRMT1 axis regulation is associated with NO-dependent endothelial dysfunction in MASH

Metabolic dysfunction-associated steatohepatitis (MASH) is a severe form of fatty liver disease and a recognized cardiovascular risk factor, yet the mechanisms linking hepatic pathology to vascular dysfunction remain poorly understood. We aimed to investigate whether MASH impairs endothelial function via nitric oxide (NO)-dependent mechanisms and to identify potential liver-derived mediators involved in this process. Endothelial function was assessed in two murine MASH models, Foz mice fed a high-fat diet and C57BL/6JRj mice fed a western diet with fructose, by using wire myography, while blood pressure was monitored via telemetry. NO pathway was further investigated through eNOS expression and activation and Hb-NO measurements. ADMA metabolism was analyzed in both liver tissue and plasma by LC-MS and gene expressions. Additionally, bovine aortic endothelial cells (BAECs) were treated with mouse plasma to measure the circulating factors effects on eNOS activation and the role of oxidative stress. Both models exhibited impaired NO-dependent vasorelaxation without evidence of atherosclerosis. In Foz mice, this impairment was associated with reduced eNOS expression and activation. Surprisingly, plasma Hb-NO levels did not reflect vascular NO deficiency, likely due to elevated hepatic iNOS expression. In both models, hepatic and plasma ADMA levels were increased, concomitant with hepatic upregulation of Prmt1. BAECs exposed to plasma from MASH mice showed reduced eNOS activation independent of oxidative stress. Our findings reveal that MASH is consistently associated with NO-dependent endothelial dysfunction, with ADMA emerging as a key liver-derived mediator. The PRMT1/ADMA/NO axis may represent a mechanistic link between liver pathology and vascular impairment, positioning ADMA as a potential biomarker and therapeutic target for cardiovascular risk associated with MASH. HighlightsO_LIMASH is associated with impaired NO-dependent endothelial function in two distinct MASH models. C_LIO_LICirculating factors disrupt the NOS/NO pathway independently of oxidative stress C_LIO_LIReduced plasma Hb-NO levels do not accurately reflect NO-dependent endothelial dysfunction in a context of MASH. C_LIO_LIElevated plasma and hepatic ADMA levels associated with hepatic prmt1 upregulation are consistently observed in both MASH models. C_LIO_LIThe PRMT1/ADMA/NO axis emerges as a key liver-mediated mechanism driving endothelial dysfunction in MASH C_LI

physiology↗

bioRxiv2024

Pathological α-synuclein elicits granulovacuolar degeneration independent of tau

BackgroundPathologic heterogeneity is a hallmark of Lewy body dementia (LBD), yet the impact of Lewy pathology on co-pathologies is poorly understood. Lewy pathology, containing -synuclein, is often associated with regional tau pathology burden in LBD. Similarly, granulovacuolar degeneration bodies (GVBs) have been associated with tau pathology in Alzheimers disease. Interestingly, GVBs have been detected in a broad range of neurodegenerative conditions including both -synucleinopathies and tauopathies. Despite the frequent co-occurrence, little is known about the relationship between -synuclein, tau, and granulovacuolar degeneration. MethodsWe developed a mouse model of limbic-predominant -synucleinopathy by stereotactic injection of -synuclein pre-formed fibrils (PFFs) into the basal forebrain. This model was used to investigate the relationship of -synuclein pathology with tau and GVB formation. ResultsOur model displayed widespread -synuclein pathology with a limbic predominant distribution. Aberrantly phosphorylated tau accumulated in a subset of -synuclein inclusion-bearing neurons, often colocalized with lysosomes. Many of these same neurons also contained CHMP2b- and CK1{delta}-positive granules, established markers of GVBs, which suggests a link between tau accumulation and GVB formation. Despite this observation, GVBs were also detected in tau-deficient mice following PFF-injection, suggesting that pathological -synuclein alone is sufficient to elicit GVB formation. ConclusionsOur findings support that -synuclein pathology can independently elicit granulovacuolar degeneration. The frequent co-accumulation of tau and GVBs suggests a parallel mechanism of cellular dysfunction. The ability of -synuclein pathology to drive GVB formation in the absence of tau highlights the broader relevance of this process to neurodegeneration with relevance to the pathobiology of LBD.

neuroscience↗

bioRxiv2024

Predict metal-binding proteins and structuresthrough integration of evolutionary-scale andphysics-based modeling

Metals are essential elements in all living organisms, binding to approximately 50% of proteins. They serve to stabilize proteins, catalyze reactions, regulate activities, and fulfill various physiological and pathological functions. While there have been many advancements in determining the structures of protein-metal complexes, numerous metal-binding proteins still need to be identified through computational methods and validated through experiments. To address this need, we have developed the ESMBind workflow, which combines evolutionary scale modeling (ESM) for metal-binding prediction and physics-based protein-metal modeling. Our approach utilizes the ESM-2 and ESM-IF models to predict metal-binding probability at the residue level. In addition, we have designed a metal-placement method and energy minimization technique to generate detailed 3D structures of protein-metal complexes. Our workflow outperforms other models in terms of residue and 3D-level predictions. To demonstrate its effectiveness, we applied the workflow to 142 uncharacterized fungal pathogen proteins and predicted metal-binding proteins involved in fungal infection and virulence.

bioinformatics↗

bioRxiv2024

Tet2 loss suppress α-synuclein pathology by stimulating ciliogenesis

There are no approved treatments that slow Parkinsons disease (PD) progression and therefore it is important to identify novel pathogenic mechanisms that can be targeted. Loss of the epigenetic marker, Tet2 appears to have some beneficial effects in PD models, but the underlying mechanism of action is not well understood. We performed an unbiased transcriptomic analysis of cortical neurons isolated from patients with PD to identify dysregulated pathways and determine their potential contributions to the disease process. We discovered that genes associated with primary cilia, non-synaptic sensory and signaling organelles, are upregulated in both early and late PD patients. Enhancing ciliogenesis in primary cortical neurons via sonic hedgehog signaling suppressed the accumulation of -synuclein pathology in vitro. Interestingly, deletion of Tet2 in mice also enhanced the expression of primary cilia and sonic hedgehog signaling genes and rescued the accumulation of -synuclein pathology and dopamine neuron degeneration in vivo. Our findings demonstrate the crucial role of Tet2 loss in regulating ciliogenesis and potentially affecting the progression of PD pathology.

neuroscience↗

bioRxiv2024

Method and timing of rhizobacteria inoculation to plant roots alters success and strength of aphid suppression

Insect pests cause substantial yield losses globally, necessitating novel pest control approaches beyond chemical pesticides. Rhizobacteria, beneficial root-associated bacteria, present a promising alternative by enhancing plant growth and defences against pests. This study explores the use of sodium alginate encapsulation for precise inoculation of two rhizobacteria, Acidovorax radicis and Bacillus subtilis, to suppress aphid populations on barley (Hordeum vulgare). We optimized a method using 4mm diameter wet-matrix alginate beads for controlled bacterial delivery directly to plant roots. Two experiments evaluated the impact of inoculation methods and timing on aphid suppression. Results indicated that rhizobacteria inoculation via alginate beads at root emergence significantly reduced aphid reproductive output, outperforming seed soaking methods. This suggests that more consistent bacterial establishment and prolonged release from alginate beads enhances plant defence priming. Additionally, alginate bead inoculation demonstrated effective long-term bacterial viability following storage at 4{degrees} C for eight months, supporting potential field application. Our findings highlight the potential of alginate bead-encapsulated rhizobacteria for aphid suppression on barley, but emphasizing the need for precise inoculation timing and placement. This approach offers a robust method for empirical research and practical agricultural application, paving the way for sustainable pest management strategies. Future work should focus on optimizing formulations and understanding plant-microbe interactions to enhance field efficacy.

ecology↗

bioRxiv2024

Cortical synaptic vulnerabilities revealed in a α-synuclein aggregation model of Parkinson's disease

-Synuclein aggregates characterize -synucleinopathies, including Parkinsons disease and Dementia with Lewy bodies. A majority of people with these disorders experience cognitive decline, and its extent correlates with cortical -synuclein pathology. Mechanisms by which pathology targets cortical circuits remain to be understood so that the debilitating non-motor impairments can be addressed. Overt neuronal loss is not a major feature of cortical pathology, but a reduction of presynaptic sites has been reported at late stages of PD. We here define excitatory synapses as neuronal loci affected by -synuclein aggregation, showing that they are progressively lost, and identify temporal and spatial patterns of synaptic vulnerability. Results were obtained in a mouse model using intrastriatal injection of pre-formed -synuclein fibrils to template the aggregation of endogenous -synuclein in cortical neurons. Lewy neurite-like aggregates were predominantly observed in axons. Super-resolved imaging showed -synuclein aggregation within cortical synapses and revealed that synaptic aggregation is most severe proximal to Lewy neurite-like structures and linked to the earliest detectable loss of excitatory synapses. Excitatory synapses also exhibited ultrastructural aberrations, including a redistribution of pre- and post-synaptic protein clusters away from contact sites and reduced synaptic vesicle size. As pathology advanced, VGLUT1-positive intracortical synapses, enriched in -synuclein, were progressively vulnerable in this striatal seeding model, while VGLUT2-positive long-range synapses with minimal -synuclein were spared. Inhibitory synapses were not affected. In agreement with a disruptive role of synaptic -synuclein aggregation, super-resolved mesoscale imaging determined that synaptic but not non-synaptic -synuclein pathology is correlated with excitatory synapse loss. Physiological recordings confirmed impaired excitatory neurotransmission. Pathology propagation tracked cortical connectivity, with intra-column synapse loss correlated between interconnected layers V and II/III. Contralateral areas receiving projections from pathologic layer V also exhibited synapse loss. These findings reveal synapses as principal cellular loci of -synuclein pathology and define how molecular and circuit-based mechanisms underlie the cortical progression of synaptic pathology in -synucleinopathies.

neuroscience↗

bioRxiv2023

Human Endogenous Retrovirus Expression is Dynamically Regulated in Parkinson's Disease

Parkinsons disease (PD) is a progressive, debilitating neurodegenerative disease that afflicts approximately every 1000th individual. Recently, activation of genomic transposable elements (TE) has been suggested as a potential driver of PD onset. However, it is unclear where, when, and to what extent TEs are dysregulated in PD. Here, we performed a multi-tissue transcriptional analysis of multiple patient cohorts and identified TE transcriptional activation as a hallmark of PD. We find that PD patients exhibit up-regulation primarily of human endogenous retrovirus (HERV) transcripts in prefrontal cortex tissue, prefrontal neurons as well as in blood, and we demonstrate that TE activation in the blood is highest at the time of PD diagnosis. Supporting a potentially causal association between ERV dysregulation and PD heterogeneity, reduced gene dosage of the TE repressor Trim28 triggers transcriptional changes highly correlated to those measured in animal models of synucleinopathy (PFF-injection), and importantly, to those exhibited by patients themselves. These data identify ERV up-regulation as a common feature of central and peripheral PD etiology, and highlight potential roles for Trim28-dependent TEs in stratifying and monitoring PD and treatment compliance.

neuroscience↗

bioRxiv2023

Tumor- and Nerve-Derived Axon Guidance Molecule Promotes Pancreatic Ductal Adenocarcinoma Progression and Metastasis through Macrophage Reprogramming

Axon guidance molecules were found to be the gene family most frequently altered in pancreatic ductal adenocarcinoma (PDA) through mutations and copy number changes. However, the exact molecular mechanism regarding PDA development remained unclear. Using genetically engineered mouse models to examine one of the axon guidance molecules, semaphorin 3D (SEMA3D), we found a dual role for tumor-derived SEMA3D in malignant transformation of pancreatic epithelial cells and a role for nerve-derived SEMA3D in PDA development. This was demonstrated by the pancreatic-specific knockout of the SEMA3D gene from the KRASG12D and TP53R172H mutation knock-in, PDX1-Cre (KPC) mouse model which demonstrated a delayed tumor initiation and growth comparing to the original KPC mouse model. Our results showed that SEMA3D knockout skews the macrophages in the pancreas away from M2 polarization, providing a potential mechanistic role of tumor-derived SEMA3D in PDA development. The KPC mice with the SEMA3D knockout remained metastasis-free, however, died from primary tumor growth. We then tested the hypothesis that a potential compensation mechanism could result from SEMA3D which is naturally expressed by the intratumoral nerves. Our study further revealed that nerve-derived SEMA3D does not reprogram macrophages directly, but reprograms macrophages indirectly through ARF6 signaling and lactate production in PDA tumor cells. SEMA3D increases tumor-secreted lactate which is sensed by GPCR132 on macrophages and subsequently stimulates pro-tumorigenic M2 polarization in vivo. Tumor intrinsic- and extrinsic-SEMA3D induced ARF6 signaling through its receptor Plexin D1 in a mutant KRAS-dependent manner. Consistently, RNA sequencing database analysis revealed an association of higher KRASMUT expression with an increase in SEMA3D and ARF6 expression in human PDAs. Moreover, multiplex immunohistochemistry analysis showed an increased number of M2-polarized macrophages proximal to nerves in human PDA tissue expressing SEMA3D. Thus, this study suggests altered expression of SEMA3D in tumor cells lead to acquisition of cancer-promoting functions and the axon guidance signaling originating from nerves is "hijacked" by tumor cells to support their growth. Other axon guidance and neuronal development molecules may play a similar dual role which is worth further investigation. One sentence summaryTumor- and nerve-derived SEMA3D promotes tumor progression and metastasis through macrophage reprogramming in the tumor microenvironment. STATEMENT OF SIGNIFICANCEThis study established the dual role of axon guidance molecule, SEMA3D, in the malignant transformation of pancreatic epithelial cells and of nerve-derived SEMA3D in PDA progression and metastasis. It revealed macrophage reprogramming as the mechanism underlying bothroles. Together, this research elucidated how inflammatory responses promote invasive PDA progression and metastasis through an oncogenic process.

cancer biology↗

bioRxiv2023

A topographical atlas of alpha-Synuclein dosage and cell-type expression in the mouse brain and periphery

Parkinsons disease (PD) is the second most common neurodegenerative disease worldwide and presents pathologically with Lewy pathology and dopaminergic neuron loss. Lewy pathology contains aggregated Synuclein (Syn), a protein encoded by the SNCA gene which is also mutated or duplicated in a subset of familial PD cases. Due to its predominant presynaptic localization, immunostaining for the protein results in diffuse signal, providing little insight into the types of cells expressing Syn. As a result, insight into Syn expression-driven cellular vulnerability has been difficult to ascertain. Using a combination of knock-in mice that target Syn to the nucleus of cells (SncaNLS) and in situ hybridization of Snca in wild-type mice, we systematically map the topography and cell types expressing Syn in the mouse brain, spinal cord, retina, and gut. We find a high degree of correlation between Syn protein and RNA levels across multiple brain regions and further identify cell types with low and high Syn. We found that Syn is highly expressed in neurons, particularly those involved in PD and to a lower extent in non-neuronal cell types, notably those of oligodendrocyte lineage. We also find that Syn is devoid in certain neuron types (e.g. ChAT-positive motor neurons), and that all enteric neurons express Syn to a certain degree. Taken together, this atlas provides much-needed insight into the cellular topography of Syn, and provides a quantitative map to test assumptions about the role of Syn in network vulnerability in PD and other Synucleinopathies.

neuroscience↗

bioRxiv2022

A novel automated morphological analysis of microglia activation using a deep learning assisted model

There is growing evidence for the key role of microglial activation in brain pathophysiology. Consequently, there is a need for efficient automated methods to measure the morphological changes distinctive of microglia functional states in research settings. Currently, many commonly used automated methods can be subject to sample representation bias, time consuming imaging, specific hardware requirements, and difficulty in maintaining an accurate comparison across research environments. To overcome these issues, we use commercially available deep learning tools (Aiforia(R) Cloud (Aifoira Inc., Cambridge, United States) to quantify microglial morphology and cell counts from histopathological slides of Iba1 stained tissue sections. We provide evidence for the effective application of this method across a range of independently collected datasets in mouse models of viral infection and Parkinsons disease. Additionally, we provide a comprehensive workflow with training details and annotation strategies by feature layer that can be used as a guide to generate new models. In addition, all models described in this work are shared within the Aiforia(R) platform and are available for study-specific adaptation and validation.

neuroscience↗

bioRxiv2022

Synaptic Location Is a Determinant of the Detrimental Effects of α-Synuclein Pathology to Glutamatergic Transmission in the Basolateral Amygdala

The presynaptic protein -synuclein (Syn) has been suggested to be involved in the pathogenesis of Parkinsons disease (PD). In PD, the amygdala is prone to develop insoluble Syn aggregates, and it has been suggested that circuit dysfunction involving the amygdala contributes to the psychiatric symptoms. Yet, how Syn aggregates affect amygdala function is unknown. In this study, we examined Syn in glutamatergic axon terminals and the impact of its aggregation on glutamatergic transmission in the basolateral amygdala (BLA). We found that Syn is primarily present in the vesicular glutamate transporter 1-expressing (vGluT1+) terminals in mouse BLA, which is consistent with higher levels of Syn expression in vGluT1+ glutamatergic neurons in the cerebral cortex relative to the vGluT2+ glutamatergic neurons in the thalamus. We found that Syn aggregation selectively decreased the cortico-BLA, but not the thalamo-BLA, transmission; and that cortico-BLA synapses displayed enhanced short-term depression upon repetitive stimulation. In addition, using confocal microscopy, we found that vGluT1+ axon terminals exhibited decreased levels of soluble Syn, which suggests that lower levels of soluble Syn might underlie the enhanced short-term depression of cortico-BLA synapses. In agreement with this idea, we found that cortico-BLA synaptic depression was also enhanced in Syn knockout mice. In conclusion, both basal and dynamic cortico-BLA transmission were disrupted by abnormal aggregation of Syn and these changes might be relevant to the perturbed cortical control of the amygdala that has been suggested to play a role in psychiatric symptoms in PD.

neuroscience↗

bioRxiv2021

Genotype-phenotype correlation analysis and therapeutic development using a patient stem cell-derived disease model of Wolfram syndrome

Wolfram syndrome is a rare genetic disorder largely caused by pathogenic variants in the WFS1 gene and manifested by diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Recent genetic and clinical findings have revealed Wolfram syndrome as a spectrum disorder. Therefore, a genotype-phenotype correlation analysis is needed for diagnosis and therapeutic development. Here, we focus on the WFS1 c.1672C>T, p.R558C variant which is highly prevalent in the Ashkenazi-Jewish population. Clinical investigation indicates that subjects carrying the homozygous WFS1 c.1672C>T, p.R558C variant show mild forms of Wolfram syndrome phenotypes. Expression of WFS1 p.R558C is more stable compared to the other known recessive pathogenic variants associated with Wolfram syndrome. Stem cell-derived islets (SC-islets) homozygous for WFS1 c.1672C>T variant recapitulates genotype-related Wolfram phenotypes, which are milder than those of SC-islets with compound heterozygous WFS1 c.1672C>T (p.R558C), c.2654C>T (p.P885L). Enhancing residual WFS1 function by a combination treatment of chemical chaperones, sodium 4-phenylbutyrate (4-PBA) and tauroursodeoxycholic acid (TUDCA), mitigates detrimental effects caused by the WFS1 c.1672C>T, p.R558C variant and restored SC-islet function. Thus, the WFS1 c.1672C>T, p.R558C variant causes a mild form of Wolfram syndrome phenotypes, which can be remitted with a combination treatment of chemical chaperones. We demonstrate that our patient stem cell-derived disease model provides a valuable platform for further genotype-phenotype analysis and therapeutic development for Wolfram syndrome. One sentence summaryDevelopment of personalized therapy for Wolfram syndrome using genetics and iPSC model.

genetics↗

bioRxiv2020

Tau pathology spreads between anatomically-connected regions of the brain and is modulated by a LRRK2 mutation

Tau pathology is a diagnostic feature of Alzheimers disease (AD) but is also a prominent feature of Parkinsons disease (PD), including genetic forms of PD with mutations in leucine-rich repeat kinase 2 (LRRK2). In both diseases, tau pathology is progressive and correlates with cognitive decline. Neuropathological staging studies in humans and mouse models have suggested that tau spreads through the brain, but it is unclear how neuroanatomical connections, spatial proximity, and regional vulnerability contribute to pathology spread. Further, it is unknown how mutations in the LRRK2 gene may modulate susceptibility to tau pathologys initiation or spread. In this study, we used seed-based models of tauopathy to capture spatiotemporal patterns of pathology in mice. Following the injection of AD brain-derived tau into the brains of non-transgenic mice, tau pathology spreads progressively through the brain in a spatiotemporal pattern that is well-explained by anatomical connectivity. We validated and compared network models based on diffusion along anatomical connections to predict tau spread, estimate regional vulnerability to tau pathology, and investigate gene expression patterns related to regional vulnerability. We further investigated tau pathology spread in mice harboring a mutation in LRRK2 and found that while tau pathology spread is still constrained by anatomical connectivity, it spreads preferentially in a retrograde direction to regions that are otherwise resilient in wildtype mice. This study provides a quantitative demonstration that tau pathology spreads along anatomical connections, explores the kinetics of this spread, and provides a platform for investigating the effect of genetic risk factors and treatments on the progression of tauopathies.

neuroscience↗

bioRxiv2019

PTPN2 deletion in T cells promotes anti-tumour immunity and CAR T cell efficacy in solid tumours

Although adoptive T cell therapy has shown remarkable clinical efficacy in hematological malignancies, its success in combating solid tumours has been limited. Here we report that PTPN2 deletion in T cells enhances cancer immunosurveillance and the efficacy of adoptively transferred tumour-specific T cells. T cell-specific PTPN2 deficiency prevented tumours forming in aged mice heterozygous for the tumour suppressor p53. Adoptive transfer of PTPN2-deficient CD8+ T cells markedly repressed tumour formation in mice bearing mammary tumours. Moreover, PTPN2 deletion in T cells expressing a chimeric antigen receptor (CAR) specific for the oncoprotein HER-2 increased the activation of the Src family kinase LCK and cytokine-induced STAT-5 signalling thereby enhancing both CAR T cell activation and homing to CXCL9/10 expressing tumours to eradicate HER-2+ mammary tumours in vivo. Our findings define PTPN2 as a target for bolstering T-cell mediated anti-tumour immunity and CAR T cell therapy against solid tumours.

immunology↗

bioRxiv2018

A phylogeography of the second plague pandemic revealed through the analysis of historical Y. pestis genomes

The second plague pandemic (14th - 18th century AD), caused by the bacterium Yersinia pestis, is infamous for its initial wave, the Black Death (1346-1353 AD), and its repeated scourges in Europe and the vicinity until the Early Modern Era. Here, we report 32 ancient Y. pestis genomes spanning the 14th to 17th century AD through the analysis of human remains from nine European archaeological sites. Our data support an initial entry of the bacterium from Eastern Europe and the absence of genetic diversity during the Black Death as well as low diversity during local outbreaks thereafter. Moreover, analysis of post-Black Death genomes shows the diversification of a Y. pestis lineage into multiple genetically distinct clades that may have given rise to more than one disease reservoir in, or close to, Europe. Finally, we show the loss of a genomic region that includes virulence-associated genes in strains associated with late stages of the second plague pandemic (17th - 18th century AD). This deletion could not be detected in extant strains within our modern dataset, though it was identified in a today-extinct lineage associated with the first plague pandemic (6th - 8th century AD), suggesting convergent evolution during both pandemic events.

evolutionary biology↗

bioRxiv2018

The Healthy Nevada Project: rapid recruitment for population health study

BackgroundNevada ranks in the bottom half of overall health rankings in the United States. The majority of residents of Northern Nevada live in Washoe County, which is confounded with high age-adjusted death rates for heart disease, cancer and chronic lower respiratory disease.\n\nMethodsSaliva as a source of DNA was collected from adults in Northern Nevada as the first phase of a much larger (100,000 participants) effort to contribute to comprehensive population health studies in Nevada. The personal genetics company 23andMe was used to genotype the first 10,250 participants and deliver their custom ancestry, traits, wellness, and carrier status reports.\n\nResultsThe study was announced by Governor Brian Sandoval on September 15, 2016 and within two days the registration of 9,700 volunteers for an appointment was complete. Processing of 9,344 participants was achieved in 3 months, with a no-show rate of just over 11%. The participant population was skewed to female and was less racially diverse than the population.\n\nConclusionDNA genotyping was administered free-of-charge and the patient population was representative of the socio-economic diversity in northern Nevada - indicating that free genetic testing is of interest to a broad swath of the population and a powerful motivator for comprehensive population health study research.

scientific communication and education↗