Biology subjects

Johnson, K.

Publications and source records attributed to Johnson, K..

88 records · Page 5Linked to original sources

bioRxiv2020

Natural infection with Giardia is associated with altered community structure of the human and canine gut microbiome.

Enteric parasitic infections are among the most prevalent infections in lower- and middle-income countries (LMICs), and have a profound impact on global public health. While the microbiome is increasingly recognized as a key determinant of gut health and human development, the impact of naturally-acquired parasite infections on microbial community structure in the gut, and the extent to which parasite-induced changes in the microbiome may contribute to gastrointestinal symptoms, is poorly understood. Enteric parasites are routinely identified in companion animals in the United States, presenting a unique opportunity to leverage this animal model to investigate the impact of naturally-acquired parasite infections on the microbiome. Clinical, parasitological, and microbiome profiling of a cohort of 258 dogs revealed a significant correlation between parasite infection and composition of the bacterial community in the gut. Relative to other enteric pathogens, Giardia was associated with a more pronounced perturbation of the microbiome. Using a database mining approach that allowed us to compare our findings to a large-scale epidemiological study of enteric diseases in humans, we also observed a substantial alteration to microbiome structure in Giardia-infected children. Importantly, infection was associated with a reduction in the relative abundance of potential pathobionts, including Gammaproteobacteria, and an increase in Prevotella - a profile often associated with gut health. Taken together, our data show that widespread Giardia infection in young animals and humans is associated with significant remodeling of the gut microbiome, and provide a possible explanation for the high prevalence of asymptomatic Giardia infections observed across host species. ImportanceWhile enteric parasitic infections are among the most important infections in lower- and middle-income countries, their impact on gut microbiota is poorly understood. We reasoned that clinical symptoms associated with these infections may be influenced by alterations of the microbiome that occur during infection. To explore this notion, we took a two-pronged approach. First, we studied a cohort of dogs naturally infected with various enteric parasites and found a strong association between parasite infection and altered gut microbiota composition. Giardia, one of the most prevalent parasite infections globally, had a particularly large impact on the microbiome. Second, we took a database-driven strategy to integrate microbiome data with clinical data from large human field studies and found that Giardia infection is also associated with marked alteration of the gut microbiome of children, suggesting a possible explanation for why Giardia has been reported to be associated with protection from moderate-to-severe diarrhea.

microbiology↗

bioRxiv2019

von Willebrand Factor D and EGF Domains is an evolutionarily conserved and required feature of blastemas capable of multi-tissue appendage regeneration

Regenerative ability varies tremendously across species. A common feature of regeneration of appendages such as limbs, fins, antlers, and tails is the formation of a blastema--a transient structure that houses a pool of progenitor cells that regenerate the missing tissue. We have identified the expression of von Willebrand Factor D and EGF Domains (vwde) as a common feature of blastemas capable of regenerating limbs and fins in a variety of highly regenerative species. Further, vwde expression is tightly linked to the ability to regenerate appendages. Functional experiments demonstrate a requirement for vwde in regeneration and indicate that Vwde is a potent mitogen in the blastema. These data identify a key role for vwde in regenerating blastemas and underscore the power of an evolutionarily-informed approach for identifying conserved genetic components of regeneration.

developmental biology↗

bioRxiv2019

Artifact-free whole-slide imaging with structured illumination microscopy and Bayesian image reconstruction

BackgroundStructured illumination microscopy (SIM) is a method which can be used to image biological samples and can achieve both optical sectioning and super-resolution effects. Optimization of the imaging setup and data processing methods results in high quality images without artifacts due to mosaicking or due to the use of SIM methods. Reconstruction methods based on Bayesian estimation can be used to produce images with a resolution beyond that dictated by the optical system.\n\nFindingsFive complete datasets are presented including large panoramic SIM images of human tissues in pathophysiological conditions. Cancers of the prostate, skin, ovary, and breast, as well as tuberculosis of the lung, were imaged using SIM. The samples are available commercially and are standard histological preparations stained with hematoxylin and eosin.\n\nConclusionThe use of fluorescence microscopy is increasing in histopathology. There is a need for methods which reduce artifacts when employing image stitching methods or optical sectioning methods such as SIM. Stitched SIM images produce results which may be useful for intraoperative histology. Releasing high quality, full slide images and related data will aid researchers in furthering the field of fluorescent histopathology.

bioengineering↗

bioRxiv2019

Disrupting the leukemia niche in the central nervous system attenuates leukemia chemoresistance

Protection from acute lymphoblastic leukemia (ALL) relapse in the central nervous system (CNS) is crucial to survival and quality of life for ALL patients. Current CNS-directed therapies cause significant toxicities and are only partially effective. Moreover, the impact of the CNS microenvironment on leukemia biology is poorly understood. Herein, we showed that leukemia cells associated with the meninges of xenotransplanted mice, or co-cultured with meningeal cells, exhibit enhanced chemoresistance due to effects on both apoptosis balance and quiescence. From a mechanistic standpoint, we identified that leukemia chemoresistance is primarily mediated by direct leukemia-meningeal cell interactions and overcome by detaching the leukemia cells from the meninges. Next, we used a co-culture adhesion assay to identify drugs that disrupted leukemia-meningeal adhesion. In addition to identifying several drugs that inhibit canonical cell adhesion targets we found that Me6TREN, a novel hematopoietic stem cell (HSC) mobilizing compound, also disrupts leukemia-meningeal adhesion in vitro and in vivo. Finally, Me6TREN enhanced the efficacy of cytarabine in treating CNS leukemia in xenotransplanted mice. This work demonstrates that the meninges exert a critical influence on leukemia chemoresistance, elucidates mechanisms of CNS relapse beyond the well-described role of the blood-brain barrier, and identifies novel therapeutic approaches for overcoming chemoresistance.

cancer biology↗

bioRxiv2019

The meninges enhance leukemia survival in cerebral spinal fluid

Central nervous system (CNS) relapse is a common cause of treatment failure in patients with acute lymphoblastic leukemia (ALL) despite current CNS-directed therapies that are also associated with significant short and long-term toxicities. Herein, we showed that leukemia cells exhibit decreased proliferation, elevated reactive oxygen species (ROS), and increased cell death in CSF both in vitro and in vivo. However, interactions between leukemia and meningeal cells mitigated these adverse effects. This work expands our understanding of the pathophysiology of CNS leukemia and suggests novel therapeutic approaches for more effectively targeting leukemia cells in the CNS.

cancer biology↗

bioRxiv2019

Impact of Ferumoxytol Magnetic Resonance Imaging on the Rhesus Macaque Maternal-Fetal Interface

Ferumoxytol is a superparamagnetic iron oxide nanoparticle (SPION) used off-label as an intravascular magnetic resonance imaging (MRI) contrast agent. Additionally, ferumoxytol-uptake by macrophages facilitates detection of inflammatory sites by MRI through ferumoxytol-induced image contrast changes. Therefore, ferumoxytol-enhanced MRI holds great potential for assessing vascular function and inflammatory response, critical to determine placental health in pregnancy. This study sought to assess the fetoplacental unit and selected maternal tissues, pregnancy outcomes, and fetal well-being after ferumoxytol administration. In initial developmental studies, pregnant rhesus macaques were imaged with and without ferumoxytol administration. Pregnancies went to term with vaginal delivery and infants showed normal growth rates compared to control animals born the same year that did not undergo MRI. To determine the impact of ferumoxytol on the maternal-fetal interface, fetal well-being, and pregnancy outcome, four pregnant rhesus macaques at [~]100 gd (gestational day) underwent MRI before and after ferumoxytol administration. Collection of the fetoplacental unit and selected maternal tissues was performed 3-4 days following ferumoxytol administration. A control group that did not receive ferumoxytol or MRI was used for comparison. Iron levels in fetal and maternal-fetal interface tissues did not vary between groups. There was no significant difference in tissue histopathology with or without exposure to ferumoxytol, and no effect on placental hormone secretion. Together, these results suggest that the use of ferumoxytol and MRI in pregnant rhesus macaques will not introduce a detectable risk to the mother or fetus at the time of imaging or up to one year following normal vaginal delivery.\n\nSummary SentenceFerumoxytol magnetic resonance imaging for non-invasive pregnancy monitoring of the rhesus macaque does not impact histopathology or iron content of the maternal-fetal interface.

physiology↗

bioRxiv2019

Deep transcriptome sequencing of subgenual anterior cingulate cortex reveals disorder-specific expression changes in major psychiatric disorders

How do differences in onset, symptoms, and treatment response arise between various mental illnesses despite substantial overlap of genetic risk factors? To address this question, we carried out deep RNA sequencing of human postmortem subgenual anterior cingulate cortex, a key component of limbic circuits linked to mental illness. Samples were obtained from 200 individuals diagnosed with bipolar disorder, schizophrenia, or major depression, and controls. Differential expression analysis in cases versus controls detected modest differences that were similar across disorders, although transcript-level differences were more pronounced. Case-case comparisons revealed greater expression differences between disorders, including many genes and transcripts that were expressed in opposite directions in each diagnostic group, compared to controls. Relative transcript abundances were associated with common genetic variants that accounted for disproportionate fractions of diagnosis-specific heritability. Inherited genetic risk factors shape the brain transcriptome and contribute to diagnostic differences between broad classes of mental illness.

genomics↗

bioRxiv2019

Artificial Intelligence for Bioinformatics: Applications in Protein Folding Prediction

AI recently shows great promise in the field of bioinformatics, such as protein structure prediction. The Critical Assessment of protein Structure Prediction (CASP) is a nationwide experiment that takes place biannually, which centered around analyzing the best current systems for predicting protein tertiary structures. In this paper, we research on available AI methods and features, and then explore novel methods based on reinforcement learning. Such method will have profound implications for R&D in bioinformatics and add an additional platform to the management of innovation in biotechnology.

bioinformatics↗

bioRxiv2019

Parasite dispersal influences introgression rate

Organisms vary in their dispersal abilities, and these differences can have important biological consequences, such as impacting the likelihood of hybridization events. However, there is still much to learn about the factors influencing hybridization, and specifically how dispersal ability affects the opportunities for hybridization. Here, using the ecological replicate system of dove wing and body lice (Insecta: Phthiraptera), we show that species with higher dispersal abilities exhibited increased genomic signatures of introgression. Specifically, we found a higher proportion of introgressed genomic reads and more reticulated phylogenetic networks in wing lice, the louse group with higher dispersal abilities. Our results are consistent with the hypothesis that differences in dispersal ability might drive the extent of introgression through hybridization.

evolutionary biology↗

bioRxiv2019

Prevention of heart failure in hypertension: disentangling the role of evolving left ventricular hypertrophy and blood pressure lowering: the ALLHAT study

BackgroundHypertension (HTN) is a known risk factor for heart failure (HF), possibly via the mechanism of cardiac remodeling and left ventricular hypertrophy (LVH). We studied how much blood pressure (BP) change and evolving LVH contribute to the effect that lisinopril, doxazosin, amlodipine have on HF compared to chlorthalidone.\n\nMethodsWe conducted causal mediation analysis of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) data. ALLHAT participants with available serial ECGs and BP measurements were included (n=29,892; mean age 67{+/-}4 y; 32% black; 56% men): 11,008 were randomized to chlorthalidone, 5,967 - to doxazosin, 6,593 - to amlodipine, and 6,324 - to lisinopril. Evolving ECG-LVH, and BP-lowering served as mediators. Incident symptomatic HF was the primary outcome. Linear regression (for mediator) and logistic regression (for outcome) models were adjusted for mediator-outcome confounders (demographic and clinical characteristics known to be associated both with both LVH/HTN and HF).\n\nResultsA large majority of participants (96%) had ECG-LVH status unchanged; 4% developed evolving ECG-LVH. On average, BP decreased by 11/7 mmHg. In adjusted Cox regression analyses, progressing ECG-LVH [HR 1.78(1.43-2.22)], resolving ECG-LVH [HR 1.33(1.03-1.70)], and baseline ECG-LVH [1.17(1.04-1.31)] carried risk of incident HF. After full adjustment, evolving ECG-LVH mediated 4% of the effect of doxazosin on HF. Systolic BP-lowering mediated 12% of the effect of doxazosin, and diastolic BP-lowering mediated 10% effect of doxazosin, 7% effect of amlodipine, and borderline 9% effect of lisinopril on HF.\n\nConclusionsEvolving ECG-LVH and BP change account for 4-13% of the mechanism by which antihypertensive medications prevent HF.

clinical trials↗

bioRxiv2018

Speaker-normalized vowel representations in the human auditory cortex

Humans identify speech sounds, the fundamental building blocks of spoken language, using the same cues, or acoustic dimensions, as those that differentiate the voices of different speakers. The correct interpretation of speech cues is hence uncertain, and requires normalizing to the specific speaker. Here we assess how the human brain uses speaker-related contextual information to constrain the processing of speech cues. Using high-density electrocorticography, we recorded local neural activity from the cortical surface of participants who were engaged in a speech sound identification task. The speech sounds were preceded by speech from different speakers whose voices differed along the same acoustic dimension that differentiated the target speech sounds (the first formant; the lowest resonance frequency of the vocal tract). We found that the same acoustic speech sound tokens were perceived differently, and evoked different neural responses in auditory cortex, when they were heard in the context of different speakers. Such normalization involved the rescaling of acoustic-phonetic representations of speech, demonstrating a form of recoding before the signal is mapped onto phonemes or higher level linguistic units. This process is the result of auditory cortex sensitivity to the contrast between the dominant frequencies in speech sounds and those in their just preceding context. These findings provide important insights into the mechanistic implementation of normalization in human listeners. Moreover, they provide the first direct evidence of speaker-normalized speech sound representations in human parabelt auditory cortex, highlighting its critical role in resolving variability in sensory signals.

neuroscience↗

bioRxiv2018

Wolbachia-infected Drosophila prefer cooler temperatures

O_LITemperature plays a fundamental role in the dynamics of host-pathogen interactions.\nC_LIO_LIWolbachia is an endosymbiotic bacteria that infects about 40% of arthropod species, which can affect host behaviour and reproduction. Yet, the effect of Wolbachia on host thermoregulatory behaviour is largely unknown, despite its use in disease vector control programs in thermally variable environments.\nC_LIO_LIHere, we used a thermal gradient to test whether Drosophila melanogaster infected with Wolbachia strain wMelCS exhibit different temperature preferences (Tp) to uninfected flies.\nC_LIO_LIWe found that Wolbachia-infected flies preferred a cooler mean temperature (Tp = 25.06{+/-}0.25{degrees}C) than uninfected flies (Tp = 25.78{+/-}0.24{degrees}C).\nC_LIO_LIThis finding suggests that Wolbachia-infected hosts might seek out cooler microclimates to reduce exposure to and lessen the consequences of high temperatures. This finding has generated hypotheses that will be fruitful in areas of research for exploring the mechanisms by which the change in Tp occurs in this complex and significant host-pathogen-environment interaction.\nC_LI

pathology↗

bioRxiv2018

Prioritizing Small Molecule as Candidates for Drug Repositioning using Machine Learning

Drug repositioning, i.e. identifying new uses for existing drugs and research compounds, is a cost-effective drug discovery strategy that is continuing to grow in popularity. Prioritizing and identifying drugs capable of being repositioned may improve the productivity and success rate of the drug discovery cycle, especially if the drug has already proven to be safe in humans. In previous work, we have shown that drugs that have been successfully repositioned have different chemical properties than those that have not. Hence, there is an opportunity to use machine learning to prioritize drug-like molecules as candidates for future repositioning studies. We have developed a feature engineering and machine learning that leverages data from publicly available drug discovery resources: RepurposeDB and DrugBank. ChemVec is the chemoinformatics-based feature engineering strategy designed to compile molecular features representing the chemical space of all drug molecules in the study. ChemVec was trained through a variety of supervised classification algorithms (Naive Bayes, Random Forest, Support Vector Machines and an ensemble model combining the three algorithms). Models were created using various combinations of datasets as Connectivity Map based model, DrugBank Approved compounds based model, and DrugBank full set of compounds; of which RandomForest trained using Connectivity Map based data performed the best (AUC=0.674). Briefly, our study represents a novel approach to evaluate a small molecule for drug repositioning opportunity and may further improve discovery of pleiotropic drugs, or those to treat multiple indications.

bioinformatics↗

bioRxiv2017

B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage

B-1a cells are long-lived, self-renewing innate like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells they have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver (FL) versus bone marrow (BM) environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa (Igk) recombination at the early pro-B cell stage. As a result, B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain (SLC). This alternate pathway of development enables the production of B cells with self reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing models of B-1a cell development and explain how these cells acquire their unique properties.

immunology↗

bioRxiv2017

Autosomal recessive coding variants explain only a small proportion of undiagnosed developmental disorders in the British Isles

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.

genetics↗

bioRxiv2017

Local processing of visual information in neurites of VGluT3-expressing amacrine cells

Synaptic inputs to neurons are distributed across extensive neurite arborizations. To what extent arbors process inputs locally or integrate them globally is, for most neurons, unknown. This question is particularly relevant for amacrine cells, a diverse class of retinal interneurons, which receive input and provide output through the same neurites. Here, we used two-photon Ca2+ imaging to analyze visual processing in VGluT3-expressing amacrine cells (VG3-ACs), an important component of object motion sensitive circuits in the retina. VG3-AC neurites differed in their preferred stimulus contrast (ON vs. OFF); and ON and OFF responses varied in transience and preferred stimulus size. Contrast preference changed predictably with the laminar position of neurites in the inner plexiform layer. Yet, neurites at all depths were strongly activated by local but not by global image motion. Thus, VG3-AC neurites process visual information locally, exhibiting diverse responses to contrast steps, but uniform object motion selectivity.

neuroscience↗