Biology subjects

Gutierrez, A.

Publications and source records attributed to Gutierrez, A..

53 records · Page 3Linked to original sources

bioRxiv2021

Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer's disease.

Alzheimers disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-{beta} (A{beta}) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between A{beta} and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that A{beta} pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of A{beta}o correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by A{beta}o in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of A{beta}o-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from A{beta}o-stimulated microglia elicited necroptosis in neurons through activation of TNF- signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that A{beta}o-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD.

cell biology↗

bioRxiv2021

Induced ligno-suberin vascular coating and tyramine-derived hydroxycinnamic acid amides restrict Ralstonia solanacearum colonization in resistant tomato roots

The soil borne pathogen Ralstonia solanacearum is the causing agent of bacterial wilt, a devastating disease affecting major agricultural crops. R. solanacearum enters plants through the roots and reaches the vasculature, causing rapid wilting. We recently showed that tomato varieties resistant to bacterial wilt restrict bacterial movement in the plant. In the present work we go a step forward by identifying the physico-chemical nature of the barriers induced in resistant tomato roots in response to R. solanacearum. We describe that resistant tomato specifically responds to infection by assembling de novo a structural barrier at the vasculature formed by a ligno-suberin coating and tyramine-derived hydroxycinnamic acid amides (HCAAs). On the contrary, susceptible tomato does not form these reinforcements in response to the pathogen but instead displays lignin structural changes compatible with its degradation. Further, we show that overexpressing genes of the ligno-suberin pathway in a commercial susceptible variety of tomato restricts R. solanacearum movement inside the plant and slows disease progression, enhancing resistance to the pathogen. We thus propose that the induced barrier in resistant plants does not only restrict the movement of the pathogen, but may also prevent cell wall degradation by the pathogen and confer anti-microbial properties.

plant biology↗

bioRxiv2021

Behavioral effects of ethanol in the Red Swamp Crayfish(Procambarus clarkii)

Alcohol abuse and dependence remains one of the primary preventable sources of human mortality in the United States. Model laboratory species can be used to evaluate behavioral, neuropharmacological and other biological changes associated with alcohol exposure and to identify novel treatment modalities. This report describes methods for evaluating the behavioral effects of ethyl alcohol (ethanol; EtOH) in a crayfish model. Crayfish (Procambarus clarkii) were immersed in ethanol baths with concentrations ranging from 0.1 to 1.0 molar, and for durations of 10-30 minutes. Studies evaluated hemolymph alcohol concentration, locomotor behavior in an open field and anxiety-like behavior using a Light/Dark transfer approach. EtOH immersion produced dose dependent increases in hemolymph EtOH concentration (up to 249 mg/dL) and reductions in open field locomotor behavior that depended on EtOH concentration or exposure duration. Under baseline conditions, crayfish exhibit avoidance of the open parts of the locomotor arena and a preference for the covered portion, when available. Acute EtOH immersion decreased time spent in the covered portion of the Light/Dark arena, consistent with a decrease in anxiety-like behavior. EtOH immersion once per day for 5 days did not alter the acute locomotor behavioral response, however increased activity was observed 3 days after the repeated EtOH regimen. Overall, this study shows that this inexpensive, easily maintained species can be used for behavioral pharmacological experiments designed to assess the acute and repeated effects of EtOH.

pharmacology and toxicology↗

bioRxiv2021

Effects of vapor exposure to Δ9-tetrahydrocannabinol (THC) in the Maine Lobster (Homarus americanus)

RationaleDespite a long history of use in synaptic physiology, the lobster has been a neglected model for behavioral pharmacology. A restaurateur proposed that exposing lobster to cannabis smoke reduces anxiety and pain during the cooking process. It is unknown if lobster gill respiration in air would result in significant {Delta}9-tetrahydrocannabinol (THC) uptake and whether this would have any detectable behavioral effects. ObjectiveThe primary goal was to determine tissue THC levels in the lobster after exposure to THC vapor. Secondary goals were to determine if THC vapor altered locomotor behavior or nociception. MethodsTissue samples were collected (including muscle, brain and hemolymph) from Homarus americanus (N=3 per group) following 30 or 60 minutes of exposure to vapor generated by an e-cigarette device using THC (100 mg/mL in a propylene glycol vehicle). Separate experiments assessed locomotor behavior and hot water nociceptive responses following THC vapor exposure. ResultsTHC vapor produced duration-related THC levels in all tissues examined. Locomotor activity was decreased (distance, speed, time-mobile) by 30 min inhalation of THC. Lobsters exhibit a temperature-dependent withdrawal response to immersion of tail, antennae or claws in warm water; this is novel evidence of thermal nociception for this species. THC exposure for 60 minutes had only marginal effect on nociception under the conditions assessed. ConclusionsVapor exposure of lobsters, using an e-cigarette based model, produces dose-dependent THC levels in all tissues and reduces locomotor activity. Hot water nociception was temperature dependent, but only minimal anti-nociceptive effect of THC exposure was confirmed.

pharmacology and toxicology↗

bioRxiv2021

THC modifies the impact of heroin delivered by vapor inhalation in rats

Opioids are effective medications, but they have several key limitations including the development of tolerance, establishment of dependence, diversion for non-medical use and the development of addiction. Therefore, any drugs which act in an additive or synergistic fashion with opioids to address medical applications have the potential to reduce opioid-related harms. This study was conducted to determine if heroin and {Delta}9-tetrahydrocannabinol (THC) interact in an additive or independent manner to alter nociception, body temperature and spontaneous locomotor activity when inhaled or injected. Groups of male and female rats implanted with radiotelemetry transmitters were exposed to vapor for assessment of effects on temperature and activity. Heroin (50 mg/mL in the propylene glycol; PG) inhalation increased temperature and activity whereas THC (50 mg/mL) inhalation decreased temperature and activity. Effects of combined inhalation were in opposition, and additional experiments found the same outcome for the injection of heroin (0.5 mg/kg, s.c.) and THC (10 mg/kg, i.p.) alone and in combination. In contrast, the co-administration of Heroin and THC by either inhalation or injection produced additive effects on thermal nociception assessed with a warm water tail-withdrawal assay in male and female Sprague-Dawley and Wistar rats. The conclusion of this study is that additive effects of THC with heroin on a medical endpoint such as analgesia may not generalize to other behavioral or physiological effects, which may be a positive outcome for unwanted side effects.

pharmacology and toxicology↗

bioRxiv2020

A vapor inhalation method for delivering heroin alters nociception, body temperature and spontaneous activity in female and male rats

BackgroundThe ongoing crisis related to non-medical use of opioids makes it of continued importance to understand the risk factors for opioid addiction, the behavioral and neurobiological consequences of opioid exposure and to seek potential avenues for therapy. Pre-clinical rodent models have been critical to advancing understanding of opioid consequences for decades, but have been mostly limited to drug delivery by injection or by oral dosing. Inhalation, a significant route for many human users, has not been as well-established. MethodWe adapted an e-cigarette based exposure system, previously shown efficacious for delivery of other drugs to rats, to deliver heroin vapor. Effects in vivo were assessed in male and female Sprague-Dawley rats using a warm-water assay for anti-nociception and an implanted radiotelemetry system for evaluating changes in body temperature and spontaneous activity rate. ResultsInhalation of vapor created by heroin 100 mg/mL in the propylene glycol (PG) vehicle significantly slowed tail-withdrawal from a 52{degrees}C water bath, bi-phasically altered activity, and increased temperature in male and female rats. Inhalation of heroin 50 mg/mL for 15 minutes produced significant effects, as the lower bound on efficacy, whereas inhalation of heroin 100 mg/mL for 30 minutes produced robust effects across all endpoints and groups. ConclusionsThis work shows that e-cigarette devices deliver psychoactive doses of heroin to rats, using concentrations of [~]50-100 mg/mL and inhalation durations of 15-30 minutes. This technique may be useful to assess the health consequences of inhaled heroin and other opioid drugs.

pharmacology and toxicology↗

bioRxiv2020

In Situ Unzipping of Long, High Molecular Weight DNA in Solid State Nanopores

Nanopores are an established paradigm in genome sequencing technology, with remarkable advances still being made today. All efforts continually address the challenges associated with rapid, accurate, high-throughput, and low cost detection, particularly with long-read length DNA. We report on the in situ melting and unzipping of long, high molecular weight DNA. At varying salt concentration, we directly compare the translocation conductance and speeds between SiN and graphene nanopores at sub-10 nm pore diameters. We observe the force-induced unzipping of dsDNA at higher salt concentrations than previously reported in literature. We observe free running translocation without secondary structures of ssDNA that is an order of magnitude longer than reported before. We hypothesize that the frayed single strands at the molecules end get captured with a higher likelihood than both ends together. In understanding this phenomena for long-read lengths, we continue to address the challenges revolving around future generations of sequencing technology. Statement of SignificanceGenome sequencing is an advancing field with applications in clinical diagnostics. However, the challenges of providing accurate identification of longer DNA molecules at low cost are still developing. While detection of long DNA molecules is established, the identification of its individual nucleotides presents its own set of challenges. By separating the hydrogen bonds between the two strands, individual nucleotides are made directly measurable. However, identification is hindered from the formation of secondary structures, where the single-stranded DNA sticks to itself. Previous studies only included short DNA molecules. We report in situ force-induced unzipping and translocation of long DNA without secondary structures almost an order of magnitude longer than reported before. Our findings present new experimental conditions and insights that progress the field towards high accuracy sequencing of individual long molecules.

biophysics↗

bioRxiv2020

Self-administration of heroin by vapor inhalation in female Wistar rats

Over the last two decades the United States has experienced a significant increase in the medical and non-medical use of opioid drugs, resulting in record numbers of opioid-related overdoses and deaths. There was an initial increase in non-medical use of prescription opioids around 2002, followed later by increased heroin use and then most recently fentanyl. Inhalation is a common route of administration for opioids, with a documented history spanning back to Mediterranean antiquity and up through modern use with e-cigarette devices. Unfortunately, preclinical studies using inhalation as the route of administration remain relatively few. This study was conducted to determine the efficacy of e-cigarette vapor inhalation of heroin in rats. Non-contingent exposure to heroin or methadone vapor produced anti-nociceptive efficacy in male and female rats. Female rats were trained to self-administer heroin vapor; the most-preferring half of the distribution obtained more vapor reinforcers when the concentration of heroin was reduced in the vapor vehicle and when pre-treated with the opioid receptor antagonist naloxone. The anti-nociceptive effect of heroin self-administered by vapor was identical in magnitude to that produced by intravenous self-administration. Finally, anxiety-like behavior increased 24-48 hours after last heroin vapor access, consistent with withdrawal signs observed after intravenous self-administration. In sum, these studies show that rewarding and anti-nociceptive effects of heroin are produced in rats by vapor inhalation using e-cigarette technology. Importantly, self-administration models by this route can be deployed to determine health effects of inhaled heroin or other opioids.

pharmacology and toxicology↗

bioRxiv2019

Characterising the mechanisms underlying genetic resistance to amoebic gill disease in Atlantic salmon using RNA sequencing

BackgroundGill health is one of the main concerns for Atlantic salmon aquaculture, and Amoebic Gill Disease (AGD), attributable to infection by the amoeba Neoparamoeba perurans, is a frequent cause of morbidity. In the absence of preventive measures, increasing genetic resistance of salmon to AGD via selective breeding can reduce the incidence of the disease and mitigate gill damage. Understanding the mechanisms leading to AGD resistance and the underlying causative genomic features can aid in this effort, while also providing critical information for the development of other control strategies. AGD resistance is considered to be moderately heritable, and several putative QTL have been identified. The aim of the current study was to improve understanding of the mechanisms underlying AGD resistance, and to identify putative causative genomic factors underlying the QTL. To achieve this, RNA was extracted from the gill and head kidney of AGD resistant and susceptible animals following a challenge with N. perurans, and sequenced.\n\nResultsComparison between resistant and susceptible animals pointed to differences mainly in the local immune response in the gill, involving red blood cell genes and genes related to immune function and cell adhesion. Differentially expressed immune genes highlighted differences in the Th2 and Th17 responses, which are consistent with the increased heritability observed after successive challenges with the amoeba. Five QTL-region candidate genes showed differential expression, including a gene connected to interferon responses (GVINP1), a gene involved in systemic inflammation (MAP4K4), and a positive regulator of apoptosis (TRIM39). Analyses of allele-specific expression highlighted a gene in the QTL region on chromosome 17, cellular repressor of E1A-stimulated genes 1 (CREG1), showing allelic differential expression suggestive of a cis-acting regulatory variant.\n\nConclusionsIn summary, this study provides new insights into the mechanisms of resistance to AGD in Atlantic salmon, and highlights candidate genes for further functional studies that can further elucidate the genomic mechanisms leading to resistance and contribute to enhancing salmon health via improved genomic selection.

genomics↗

bioRxiv2019

Engineering gene overlaps to sustain genetic constructs in vivo

Evolution is often an obstacle to the engineering of stable biological systems due to the selection of mutations inactivating costly gene circuits. Gene overlaps induce important constraints on sequences and their evolution. We show that these constraints can be harnessed to increase the stability of synthetic circuits by purging loss-of-function mutations. We combine computational and synthetic biology approaches to rationally design an overlapping reading frame expressing an essential gene within an existing gene to protect. Our algorithm succeeded in creating overlapping reading frames in 80% of E. coli genes. Experimentally, scoring mutations in both genes of such overlapping construct, we found that a significant fraction of mutations impacting the gene to protect have a deleterious effect on the essential gene. Such an overlap thus protects a costly gene from removal by natural selection by associating the benefit of this removal with a larger or even lethal cost. In our synthetic constructs, the overlap converts many of the possible mutants into evolutionary dead-ends, effectively changing the fitness landscape and reducing the evolutionary potential of the system.

synthetic biology↗

bioRxiv2019

Creatine transporter knockout mice (Slc6a8) show increases in serotonin-related proteins and are resilient to learned helplessness

Approximately 20% of adults in the U.S. will experience an affective disorder during their life. While it is well established that serotonin (5-HT) is a crucial factor in mood, impaired cellular bioenergetics are also implicated. Creatine (Cr), through the Cr/Phospho-Cr (PCr) shuttle, maintains high ATP concentrations in the neuron. This system may be implicated in the etiology of affective disorders, as reduced Cr, PCr, and ATP are often seen in the brains of affected patients. To address this issue, Cr transporter (Crt) deficient male mice (Slc6a8-/y) and female mice heterozygous for Crt expression (Slc6a8+/-) were used to evaluate how a Cr deficient system would alter affective-like behaviors. Slc6a8-/y and Slc6a8+/- mice had more escapes and faster escape latencies in learned helplessness, indicating a potential resilience to behavioral despair. Elevated zero maze and tail-suspension test performance matched that of wildtype mice, however. Slc6a8-/y mice have increased 5-hydroxyindoleacetic acid content in the hippocampus and striatum and increased monoamine oxidase protein and tryptophan hydroxylase-2 protein content in the hippocampus, while serotonin levels are unchanged. This indicates an increase in 5-HT turnover. Our results indicate that Cr plays a complex role in affective disorders and 5-HT neurotransmission, warranting further investigation.

animal behavior and cognition↗

bioRxiv2018

Galectin-3, A Novel Endogenous Trem2 Ligand, Regulates Inflammatory Response and Aβ Fibrilation in Alzheimer’s Disease

Alzheimers disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (A{beta}) peptide, intraneuronal tau neurofibrillary tangles and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimers disease) mice, and found specifically expressed in microglia associated with A{beta} plaques. Single nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated to an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data demonstrated the requirement of gal3 to fully activate microglia in response to fibrillar A{beta}. Gal3 deletion decreased the A{beta} burden in 5xFAD mice and improved cognitive behavior. Electron microscopy of gal3 in AD mice demonstrated i) a preferential expression of gal3 by plaque-associated microglia, ii) its presence in the extracellular space and iii) its association to A{beta} plaques. Low concentrations (1 nM) of pure gal3 promoted cross-seeding fibrilization of pure A{beta}. Importantly, a single intrahippocampal injection of gal3 along with A{beta} monomers in WT mice was sufficient to induce the formation of insoluble A{beta} aggregates that were absent when gal3 was lacking. High-resolution microscopy (STORM) demonstrated close co-localization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 CRD domain. Furthermore, gal3 stimulated the TREM2-DAP12 signaling pathway. In conclusion, we provide evidence that gal3 is a central regulator of microglial immune response in AD. It drives proinflammatory activation and A{beta} aggregation, as well as acting as an endogenous ligand to TREM2, a key receptor driving microglial response under disease conditions. Gal3 inhibition may, hence, be a potential pharmacological approach to counteract AD.

neuroscience↗

bioRxiv2018

Synthetic Lethality of Wnt Pathway Activation and Asparaginase in Drug-Resistant Acute Leukemias

Resistance to asparaginase, an antileukemic enzyme that depletes asparagine, is a common clinical problem. Using a genome-wide CRISPR/Cas9 screen, we found a synthetic lethal interaction between Wnt pathway activation and asparaginase in acute leukemias resistant to this enzyme. Wnt pathway activation induced asparaginase sensitivity in distinct treatment-resistant subtypes of acute leukemia, including T-lymphoblastic, hypodiploid B-lymphoblastic, and acute myeloid leukemias, but not in normal hematopoietic progenitors. Sensitization to asparaginase was mediated by Wnt-dependent stabilization of proteins (Wnt/STOP), which inhibits GSK3-dependent protein ubiquitination and degradation. Inhibiting the alpha isoform of GSK3 phenocopied this effect, and pharmacologic GSK3 inhibition profoundly sensitized drug-resistant leukemias to asparaginase. Our findings provide a molecular rationale for activation of Wnt/STOP signaling to improve the therapeutic index of asparaginase.\n\nSIGNIFICANCEThe intensification of asparaginase-based therapy has improved outcomes for several subtypes of acute leukemia, but the development of treatment resistance has a poor prognosis. We hypothesized, from the concept of synthetic lethality, that gain-of-fitness alterations in drug-resistant cells had conferred a survival advantage that could be exploited therapeutically. We found a synthetic lethal interaction between activation of Wnt-dependent stabilization of proteins (Wnt/STOP) and asparaginase in acute leukemias resistant to this enzyme. Inhibition of the alpha isoform of GSK3 was sufficient to phenocopy this effect, and the combination of GSK3-selective inhibitors and asparaginase had marked therapeutic activity against leukemias resistant to monotherapy with either agent. These data indicate that drug-drug synthetic lethal interactions can improve the therapeutic index of cancer therapy.

cancer biology↗

bioRxiv2018

Comparative analysis of IgG Responses to recombinant Qβ phage displayed MSP3 and UB05 in Dual HIV-malaria infected adults living in areas differing in Malaria transmission intensities

Immunoglobulin G specific responses against Plasmodium falciparum merozoite antigens such as the merozoite surface protein 3 (MSP3) and UB05 are known to play critical roles in parasitemia control and protection from symptomatic illness. However when there is intense perennial malaria transmission coupled with concurrent infection with the human immunodeficiency virus type 1 (HIV), knowledge of IgG antibody response profiles is limited. In this study we assessed the impact of dual HIV-Malaria infections on IgG subclass responses to MSP3 (Q{beta}MSP3) and UB05 (Q{beta}UB05) in individuals living in two areas of Cameroon differing in transmission intensity. We observed differences in antigen specific IgG and IgG subclass responses which was dependent upon the antigen type, malaria transmission intensity, HIV infection, malaria infection and dual HIV-malaria infections. Individuals living in high malaria transmission areas irrespective of HIV or malaria status had significantly higher IgG responses to both antigens (P=0.0001 for Q{beta}MSP3, P=0.0001 for Q{beta}UB05) than their counterpart from low transmission areas. When dual HIV-Malaria infection is considered significantly higher Q{beta}MSP3 specific IgG1 (P=0.0001) and IgG3 (P=0.04) responses in double negative individuals was associated with protection against malaria in low transmission areas. Superior Q{beta}UBO5 specific IgG1 responses (P=0.0001) in double negative individuals were associated with protection in high transmission areas in contrast to significantly higher IgG3 responses to Q{beta}UB05 (P=0.0001) which were more relevant to protection in low malaria transmission areas in the same population. Thus, understanding immune responses to Q{beta}UB05 and Q{beta}MSP3 could facilitate the development of immunotherapeutic strategies suitable for areas differing in malaria transmission intensity.

immunology↗

bioRxiv2017

The transcriptional dynamics of two filmy ferns from Hymenophyllaceae with different niche preferences unravel key aspects of their desiccation tolerance and vertical distribution along host trees

Ferns from the Hymenophyllaceae family are one of the main components of the epiphytic species diversity in the Chilean temperate rain forest. Having membranous fronds of a single layer of cells, they show a poikilohydric strategy most typical from bryophytes. Although Hymenophyllaceae species shows the ability to tolerate desiccation, there are interspecific differences in their water loss kinetic. Counter-intuitively, those species that have rapid desiccation kinetic are able to reach higher host height and tolerate higher light exposure and vapor pressure deficit. Therefore, what are the mechanisms (constitutive and/or induced) responsible of the desiccation tolerance in this fern family? As this primitive fern family is closely related with mosses, it can be hypothesized that desiccation tolerance in this particular group would be associated with constitutive features rather than induced responses during dehydration. However, the inter-specific differences in water loss and vertical distribution would be associated to different degrees of induction either within the dehydration or rehydration phases. We applied an ecophysiological transcriptomic approach to study the dynamic of gene expression in two species of filmy ferns with contrasting desiccation kinetics and vertical distribution on the host tree. Our analysis identified commonalities and differences in gene regulation, and key genes correlated with the fronds hydration state, providing the patterns of gene expression responding to microenvironmental signals and behind the physiology of their resurrection strategy

plant biology↗

bioRxiv2017

A genome-wide association study for host resistance to Ostreid Herpesvirus in Pacific oysters (Crassostrea gigas)

Ostreid herpesvirus (OsHV) can cause mass mortality events in Pacific oyster aquaculture. While various factors impact on the severity of outbreaks, it is clear that genetic resistance of the host is an important determinant of mortality levels. This raises the possibility of selective breeding strategies to improve the genetic resistance of farmed oyster stocks, thereby contributing to disease control. Traditional selective breeding can be augmented by use of genetic markers, either via marker-assisted or genomic selection. The aim of the current study was to investigate the genetic architecture of resistance to OsHV in Pacific oyster, to identify genomic regions containing putative resistance genes, and to inform the use of genomics to enhance efforts to breed for resistance. To achieve this, a population of ~1,000 juvenile oysters were experimentally challenged with a virulent form of OsHV, with samples taken from mortalities and survivors for genotyping and qPCR measurement of viral load. The samples were genotyped using a recently-developed SNP array, and the genotype data were used to reconstruct the pedigree. Using these pedigree and genotype data, the first high density linkage map was constructed for Pacific oyster, containing 20,353 SNPs mapped to the ten pairs of chromosomes. Genetic parameters for resistance to OsHV were estimated, indicating a significant but low heritability for the binary trait of survival and also for viral load measures (h2 0.12 - 0.25). A genome-wide association study highlighted a region of linkage group 6 containing a significant QTL affecting host resistance. These results are an important step towards identification of genes underlying resistance to OsHV in oyster, and a step towards applying genomic data to enhance selective breeding for disease resistance in oyster aquaculture.

genomics↗

bioRxiv2017

Acute myeloid/T-lymphoblastic leukemia (AMTL): A distinct category of acute leukemias with common pathogenesis in need of improved therapy

Advances in the immunophenotypic and cytogenetic classification of acute leukemias have led to improved clinical outcomes for a substantial fraction of patients. However, resistance to chemotherapy remains a major barrier to cure for patients with specific subsets of acute myeloid and lymphoblastic leukemias. Here, we propose that a molecularly distinct subtype of acute leukemia with shared myeloid and T-cell lymphoblastic features, which we term acute myeloid/T-lymphoblastic leukemia (AMTL), and has been divided between 3 diagnostic categories owing to variable expression of markers deemed to be defining of myeloid and T-cell lymphoid lineages. This new diagnostic group is supported by the i) shared hematopoietic ontogeny in which myeloid differentiation potential is specifically retained during early T-cell lymphoid development, ii) recognition of cases of AML with hallmarks of T-cell development such as clonal rearrangements of the T-cell receptor genes, and iii) identification of common gene mutations in subsets of AML and T-ALL cases. This proposed diagnostic entity overlaps with early T-cell precursor (ETP) T-ALL and T-cell/myeloid mixed phenotype acute leukemias (MPAL), and also includes a subset of leukemias currently classified as AML with hallmarks of T-lymphoblastic development. AMTLs express variable levels of both T-cell and myeloid-specific markers, such as CD3 and myeloperoxidase, and additionally have shared gene mutations including WT1, PHF6, RUNX1 and BCL11B. The proposed classification of AMTL as a distinct entity should enable prospective diagnosis and development of improved therapies for patients whose treatment is inadequate with current approaches.

cancer biology↗