Biology subjects

Ng, K.

Publications and source records attributed to Ng, K..

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bioRxiv2021

Genetic Analysis of Right Heart Structure and Function in 40,000 People

The heart evolved hundreds of millions of years ago. During mammalian evolution, the cardiovascular system developed with complete separation between pulmonary and systemic circulations incorporated into a single pump with chambers dedicated to each circulation. A lower pressure right heart chamber supplies deoxygenated blood to the lungs, while a high pressure left heart chamber supplies oxygenated blood to the rest of the body. Due to the complexity of morphogenic cardiac looping and septation required to form these two chambers, congenital heart diseases often involve maldevelopment of the evolutionarily recent right heart chamber. Additionally, some diseases predominantly affect structures of the right heart, including arrhythmogenic right ventricular cardiomyopathy (ARVC) and pulmonary hypertension. To gain insight into right heart structure and function, we fine-tuned deep learning models to recognize the right atrium, the right ventricle, and the pulmonary artery, and then used those models to measure right heart structures in over 40,000 individuals from the UK Biobank with magnetic resonance imaging. We found associations between these measurements and clinical disease including pulmonary hypertension and dilated cardiomyopathy. We then conducted genome-wide association studies, identifying 104 distinct loci associated with at least one right heart measurement. Several of these loci were found near genes previously linked with congenital heart disease, such as NKX2-5, TBX3, WNT9B, and GATA4. We also observed interesting commonalities and differences in association patterns at genetic loci linked with both right and left ventricular measurements. Finally, we found that a polygenic predictor of right ventricular end systolic volume was associated with incident dilated cardiomyopathy (HR 1.28 per standard deviation; P = 2.4E-10), and remained a significant predictor of disease even after accounting for a left ventricular polygenic score. Harnessing deep learning to perform large-scale cardiac phenotyping, our results yield insights into the genetic and clinical determinants of right heart structure and function.

genetics↗

bioRxiv2020

Disease Network Delineates the Disease Progression Profile of Cardiovascular Diseases

As Electronic Health Records (EHR) data accumulated explosively in recent years, the tremendous amount of patient clinical data provided opportunities to discover real world evidence. In this study, a graphical disease network, named progressive cardiovascular disease network (progCDN), was built based on EHR data from 14.3 million patients 1 to delineate the progression profiles of cardiovascular diseases (CVD). The network depicted the dominant diseases in CVD development, such as the heart failure and coronary arteriosclerosis. Novel progression relationships were also discovered, such as the progression path from long QT syndrome to major depression. In addition, three age-group progCDNs identified a series of age-associated disease progression paths and important successor diseases with age bias. Furthermore, we extracted a list of salient features to build a series of disease risk models based on the progression pairs in the disease network. The progCDN network can be further used to validate or explore novel disease relationships in real world data. Features with sufficient abundance and high correlation can be widely applied to train disease risk models when using EHR data.

bioinformatics↗

bioRxiv2020

Transcriptional subtype-specific microenvironmental crosstalk and tumor cell plasticity in metastatic pancreatic cancer

Bulk transcriptomic studies have defined classical and basal-like gene expression subtypes in pancreatic ductal adenocarcinoma (PDAC) that correlate with survival and response to chemotherapy; however, the underlying mechanisms that govern these subtypes and their heterogeneity remain elusive. Here, we performed single-cell RNA-sequencing of 23 metastatic PDAC needle biopsies and matched organoid models to understand how tumor cell-intrinsic features and extrinsic factors in the tumor microenvironment (TME) shape PDAC cancer cell phenotypes. We identify a novel cancer cell state that co-expresses basal-like and classical signatures, demonstrates upregulation of developmental and KRAS-driven gene expression programs, and represents a transitional intermediate between the basal-like and classical poles. Further, we observe structure to the metastatic TME supporting a model whereby reciprocal intercellular signaling shapes the local microenvironment and influences cancer cell transcriptional subtypes. In organoid culture, we find that transcriptional phenotypes are plastic and strongly skew toward the classical expression state, irrespective of genotype. Moreover, we show that patient-relevant transcriptional heterogeneity can be rescued by supplementing organoid media with factors found in the TME in a subtype-specific manner. Collectively, our study demonstrates that distinct microenvironmental signals are critical regulators of clinically relevant PDAC transcriptional states and their plasticity, identifies the necessity for considering the TME in cancer modeling efforts, and provides a generalizable approach for delineating the cell-intrinsic versus -extrinsic factors that govern tumor cell phenotypes.

cancer biology↗

bioRxiv2020

Tissue-specific and interferon-inducible expression of non-functional ACE2 through endogenous retrovirus co-option

Angiotensin-converting enzyme 2 (ACE2) is an entry receptor for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), as well as a regulator of several physiological processes. ACE2 has recently been proposed to be interferon-inducible, suggesting that SARS-CoV-2 may exploit this phenomenon to enhance viral spread and questioning the efficacy of interferon treatment in Coronavirus disease 2019 (COVID-19). Using a recent de novo transcript assembly that captured previously unannotated transcripts, we describe a novel isoform of ACE2, generated by co-option of an intronic long terminal repeat (LTR) retroelement promoter. The novel transcript, termed LTR16A1-ACE2, exhibits specific expression patterns across the aerodigestive and gastrointestinal tracts and, importantly, is highly responsive to interferon stimulation. In stark contrast, expression of canonical ACE2 is completely unresponsive to interferon stimulation. Moreover, the LTR16A1-ACE2 translation product is a truncated, unstable ACE2 form, lacking domains required for SARS-CoV-2 binding and therefore unlikely to contribute to or enhance viral infection.

genomics↗

bioRxiv2020

High-throughput cultivation of stable, diverse, fecal-derived microbial communities to model the intestinal microbiota

SummaryMechanistic understanding of the impacts of the gut microbiota on human health has been hampered by limited throughput in animal models. To enable systematic interrogation of gut-relevant microbial communities, here we generated hundreds of in vitro communities cultured from diverse stool samples in various media. Species composition revealed stool-derived communities that are phylogenetically complex, diverse, stable, and highly reproducible. Community membership depended on both medium and initial inoculum, with certain media preserving inoculum compositions. Different inocula yielded different community compositions, indicating their potential for personalized therapeutics. Communities were robust to freezing and large-volume culturing, enabling future translational applications. Defined communities were generated from isolates and reconstituted growth and composition similar to those of communities derived from stool inocula. Finally, in vitro experiments probing the response to ciprofloxacin successfully predicted many changes observed in vivo, including the resilience and sensitivity of each Bacteroides species. Thus, stool-derived in vitro communities constitute a powerful resource for microbiota research.Competing Interest StatementThe authors have declared no competing interest.View Full Text

microbiology↗

bioRxiv2020

Pre-existing and de novo humoral immunity to SARS-CoV-2 in humans

Several related human coronaviruses (HCoVs) are endemic in the human population, causing mild respiratory infections1. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiologic agent of Coronavirus disease 2019 (COVID-19), is a recent zoonotic infection that has quickly reached pandemic proportions2,3. Zoonotic introduction of novel coronaviruses is thought to occur in the absence of pre-existing immunity in the target human population. Using diverse assays for detection of antibodies reactive with the SARS-CoV-2 spike (S) glycoprotein, we demonstrate the presence of pre-existing humoral immunity in uninfected and unexposed humans to the new coronavirus. SARS-CoV-2 S-reactive antibodies were readily detectable by a sensitive flow cytometry-based method in SARS-CoV-2-uninfected individuals and were particularly prevalent in children and adolescents. These were predominantly of the IgG class and targeted the S2 subunit. In contrast, SARS-CoV-2 infection induced higher titres of SARS-CoV-2 S-reactive IgG antibodies, targeting both the S1 and S2 subunits, as well as concomitant IgM and IgA antibodies, lasting throughout the observation period of 6 weeks since symptoms onset. SARS-CoV-2-uninfected donor sera also variably reacted with SARS-CoV-2 S and nucleoprotein (N), but not with the S1 subunit or the receptor binding domain (RBD) of S on standard enzyme immunoassays. Notably, SARS-CoV-2-uninfected donor sera exhibited specific neutralising activity against SARS-CoV-2 and SARS-CoV-2 S pseudotypes, according to levels of SARS-CoV-2 S-binding IgG and with efficiencies comparable to those of COVID-19 patient sera. Distinguishing pre-existing and de novo antibody responses to SARS-CoV-2 will be critical for our understanding of susceptibility to and the natural course of SARS-CoV-2 infection.

immunology↗

bioRxiv2019

Diotic and dichotic frequency discrimination thresholds in musicians and non-musicians: relationships between perception, musical ability and self-evaluated competence.

Pitch perception provides important information for musical and vocal communication. Numerous studies have shown that musical training and expertise are associated with better pitch processing, however, it is unclear what types of pitch percepts are plastic with music training. The current study addresses this issue by measuring discrimination thresholds of Musicians (n=20) and Non-musicians (n=18) to diotic (same sound to both ears) and dichotic (different sounds to each ear) stimuli created from four types of acoustic computations:1) pure sinusoidal tones, PT; 2) four-harmonic complex tones, CT; 3) iterated rippled noise, IRN; and 4) interaurally correlated broadband noise, called \"Huggins\" or \"dichotic\" pitch sounds, DP. Frequency Difference Limens (DLF) in each condition were obtained via a 3-alternative-forced-choice adaptive task requiring selection of the interval with the highest pitch, yielding the smallest perceptible fundamental frequency (F0) distance (in Hz) between two sounds. Music skill was measured by an online test of musical Pitch, Melody and Timing (International Laboratory for Brain Music and Sound Research, https://www.brams.org/en/onlinetest/). Musicianship, length of music experience and self-evaluation of musical skill were assessed by questionnaire. Results showed musicians had smaller DLFs in all four conditions and that thresholds were related to subjective and objective musical ability. In addition, self-report of musical ability was shown to be a significant variable in group classification, suggesting that the neurobehavioral profile of musicians includes self-evaluation of musical competence.

neuroscience↗

bioRxiv2019

Does rehearsal benefit visual memory? The role of semantic associations in the maintenance of intact and phase scrambled scenes.

Rehearsal during working memory (WM) maintenance facilitates retrieval. Less is known about how rehearsal modulates WM delay activity. In the present study, 44 participants completed a Sternberg Task with either intact novel scenes or phase-scrambled scenes, which had similar color and spatial frequency but lacked semantic content. During each condition participants generated a descriptive label and covertly rehearsed or suppressed (repeated "the") during the delay. This was easy in the former but more difficult in the later condition where scenes lacked semantic content. Behavioral performance and EEG delay activity was analyzed as a function of maintenance strategy. Performance during WM revealed a benefit of rehearsal for phase-scrambled but not intact scenes. Examination of the absolute amplitude revealed three underlying sources of activity for rehearsal, including the left anterior temporal (TAL), left and midline parietal regions. Increases in alpha and theta activity in TAL were correlated with improvement in performance on WM with rehearsal only when labeling was not automatic (i.e. phase-scrambled scenes), which may reflect differences in labeling and rehearsal (i.e. semantic associations vs. shallow labels). We conclude that rehearsal only benefits memory for visual stimuli that lack semantic information, and that this is correlated with changes in alpha and theta rhythms.

neuroscience↗

bioRxiv2018

Emergence of enteroaggregative Escherichia coli within the ST131 lineage as a cause of extraintestinal infections

Escherichia coli sequence type 131 (ST131) is a major cause of urinary and bloodstream infections and its association with extended-spectrum {beta}-lactamases (ESBL) significantly complicates treatment. Most notorious is its rapidly expanding H30-Rx clade (named for containing allele 30 of the type-1 fimbrial adhesin gene fimH and extensive antimicrobial resistance), which appears to have emerged in the United States due in part due to the acquisition of the ESBL-encoding blaCTX-M-15 gene and resistance to fluoroquinolones. However, non-H30 ST131 lineages with acquired CTX-M-type resistance genes also are emerging. Based on whole-genome analyses, we describe here the presence of an (fimH) H27 E. coli ST131 lineage that currently is causing an outbreak of community-acquired bacteremia and recurrent urinary tract infections (UTIs) in Denmark. This lineage has acquired both a virulence plasmid (pAA) that defines the enteroaggregative E. coli (EAEC) diarrheagenic pathotype and multiple genes associated with extraintestinal E. coli (ExPEC) that combined has made this particular ST131 lineage highly successful at colonizing its human host and cause recurrent UTI. Moreover, using a historic World Health Organization E. coli collection and publically available genome sequences, we identify a global H27 EAEC ST131 lineage dating back as far as 1998. Most H27 EAEC ST131 isolates harbor pAA or pAA-like plasmids, which analysis strongly imply was caused by a single ancestral acquisition. These findings illustrate the profound plasticity of this important pathogenic E. coli H27 lineage in general, and the genetic acquisitions of EAEC-specific virulence traits that likely confer an enhanced ability to cause intestinal colonization.\n\nImportanceThe E. coli ST131 lineage is a notorious extraintestinal pathogen. A signature characteristic of ST131 is its ability to asymptomatically colonize the gastrointestinal tract and then opportunistically cause extraintestinal infections, such as cystitis, pyelonephritis and urosepsis. In this study, we report a novel ST131 sublineage that has acquired the enteroaggregative diarrheagenic phenotype, spread across multiple continents and has been associated with multiple outbreaks of community-acquired bloodstream infections in Denmark. The strains ability to both cause diarrhea and colonize the human gastrointestinal tract may facilitate its dissemination and establishment in the community, whereas the strains clonal nature may facilitate targeted control strategies, such as vaccination.

microbiology↗

bioRxiv2018

Saccades and Handedness Interact to Affect Scene Memory

Repetitive saccades benefit memory when executed before retrieval, with greatest effects for episodic memory in consistent-handers. Questions remain including how saccades affect scene memory, an important visual component of episodic memory. The present study tested how repetitive saccades affect working and recognition memory for novel scenes. Handedness direction (left-right) and degree (strong/consistent vs. mixed/inconsistent) was measured by raw and absolute laterality quotients respectively from an 8-question handedness inventory completed by 111 adults. Each then performed either 30 seconds of repetitive horizontal saccades or fixation before or after tasks of scene working memory and scene recognition. Regression with criterion variables of overall percent correct accuracy and d-prime sensitivity showed that when saccades were made before working memory, there was better overall accuracy as a function of increased direction but not degree of handedness. Subjects who made saccades before working memory also performed worse during subsequent recognition memory, while subjects who fixated or made saccades after the working memory task performed better. Saccades made before recognition resulted in recognition accuracy that was better (Cohens d=0.3729), but not significantly different from fixation before recognition. The results demonstrate saccades and handedness interact to affect scene memory with larger effects on encoding than recognition. Saccades before scene encoding in working memory are detrimental to short- and long-term memory, especially for those who are not consistently right-handed, while saccade execution before scene recognition does not appear to benefit recognition accuracy. The findings are discussed with respect to theories of interhemispheric interaction and control of visuospatial attention.

neuroscience↗

bioRxiv2018

Gut microbiome transition across a lifestyle gradient in Himalaya

The composition of the gut microbiome in industrialized populations differs from those living traditional lifestyles. However, it has been difficult to separate the contributions of human genetic and geographic factors from lifestyle/modernization. Here, we characterize the stool bacterial composition of four Himalayan populations to investigate how the gut community changes in response to shifts in human lifestyles. These groups led seminomadic hunting-gathering lifestyles until transitioning to varying dependence upon farming. The Tharu began farming 250-300 years ago, the Raute and Raji transitioned 30-40 years ago, and the Chepang retain many aspects of a foraging lifestyle. We assess the contributions of dietary and environmental factors on their gut microbiota and find that the gut microbiome composition is significantly associated with lifestyle. The Chepang foragers harbor elevated abundance of taxa associated with foragers around the world. Conversely, the gut microbiomes of populations that have transitioned to farming are more similar to those of Americans, with agricultural dependence and several associated lifestyle and environmental factors correlating with the extent of microbiome divergence from the foraging population. For example, our results show that drinking water source and solid cooking fuel are significantly associated with the gut microbiome. Despite the pronounced differences in gut bacterial composition across populations, we found little differences in alpha diversity across populations. These findings in genetically similar populations living in the same geographical region establish the key role of lifestyle in determining human gut microbiome composition and point to the next challenging steps of isolating dietary effects from other factors that change during modernization.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC=\"FIGDIR/small/253450_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (108K):\norg.highwire.dtl.DTLVardef@68f595org.highwire.dtl.DTLVardef@d33792org.highwire.dtl.DTLVardef@e56314org.highwire.dtl.DTLVardef@1cbbba2_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2018

Toxoplasma gondii infection triggers chronic cachexia and sustained commensal dysbiosis in mice

Toxoplasma gondii is a protozoan parasite with a predation-mediated transmission cycle between rodents and felines. Intermediate hosts acquire Toxoplasma by eating parasite cysts which invade the small intestine, disseminate systemically and finally establish host life-long chronic infection in brain and muscles. Here we show that Toxoplasma infection can trigger a severe form of sustained cachexia: a disease of progressive weight loss that is a causal predictor of mortality in cancer, chronic disease and many infections. Toxoplasma cachexia is characterized by acute anorexia, systemic inflammation and loss of 20% body mass. Although mice recover from symptoms of peak sickness they fail to regain muscle mass or visceral adipose depots. We asked whether the damage to the intestinal microenvironment observed at acute time points was sustained in chronic infection and could thereby play a role the sustaining cachexia. We found that parasites replicate in the same region of the distal jejunum/proximal ileum throughout acute infection, inducing the development of secondary lymphoid structures and severe, regional inflammation. Small intestine pathology was resolved by 5 weeks post-infection. However, changes in the commensal populations, notably an outgrowth of Clostridia spp., were sustained in chronic infection. Importantly, uninfected animals co-housed with infected mice display similar changes in commensal microflora but never display symptoms of cachexia, indicating that altered commensals are not sufficient to explain the cachexia phenotype alone. These studies indicate that Toxoplasma infection is a novel and robust model to study the immune-metabolic interactions that contribute chronic cachexia development, pathology and potential reversal.

microbiology↗

bioRxiv2017

Visual Continuous Recognition Reveals Widespread Cortical Contributions to Scene Memory

Humans have a remarkably high capacity and long duration memory for complex scenes. Previous research documents the neural substrates that allow for efficient categorization of scenes from other complex stimuli like objects and faces, but the spatiotemporal neural dynamics underlying scene memory are less well understood. In the present study, we used high density EEG during a visual continuous recognition task in which new, old, and scrambled scenes consisting of color outdoor photographs were presented at an average rate 0.26 Hz. Old scenes were single repeated presentations occurring within either a short-term ([≤] 20 seconds) or longer-term intervals of between 30 sec and 3 minutes or 4 and 10 minutes. Overall recognition was far above chance, with better performance at short- than longer-term intervals. A group ANOVA found parietal and frontal ERPs discriminated the three scene types as early as 59 ms after stimulus onset. Parietal ERPs were greater for old compared to new scenes by 189 ms, while fronto-temporal ERPs were greater for new compared to old scenes by 194 ms. For old scenes presented within longer-term intervals, parieto-temporal and centro-frontal ERPs were greater by 228 and 355 ms respectively compared to old scenes presented within a short-term interval. Supervised machine learning exhibited above-chance decoding of scene type by 275 ms. Single-subject BOLD-fMRI showed greater activity for old scenes across frontal, parietal, and temporal cortex. These converging findings show that a widespread network including parietal, frontal, and temporal regions supports short- and long-term scene memory.\n\nSignificance StatementThe ability to recognize a scene as novel or familiar is critical for basic cognition. Scene recognition plays an important role in episodic memory because it helps us quickly establish place, a first step in recalling where previous events occurred. Short-term recognition supports our ability to detect changes in the immediate environment, an ability critical to survival. Scene recognition after a longer-term interval is often the essential cue for retrieving autobiographical memories. Previous behavioral studies demonstrate high capacity and long duration scene memory. Neural studies have identified the brain regions that support scene-specific processing. The present study extends this research by filling a gap in understanding how distributed spatiotemporal patterns of neural activity support short- and long-term scene memory.

neuroscience↗

bioRxiv2017

Complex rearrangements and oncogene amplifications revealed by long-read DNA and RNA sequencing of a breast cancer cell line

The SK-BR-3 cell line is one of the most important models for HER2+ breast cancers, which affect one in five breast cancer patients. SK-BR-3 is known to be highly rearranged although much of the variation is in complex and repetitive regions that may be underreported. Addressing this, we sequenced SK-BR-3 using long-read single molecule sequencing from Pacific Biosciences, and develop one of the most detailed maps of structural variations (SVs) in a cancer genome available with nearly 20,000 variants present, most of which were missed by prior efforts. Surrounding the important HER2 locus, we discover a complex sequence of nested duplications and translocations, suggesting a punctuated progression. Full-length transcriptome sequencing further revealed several novel gene fusions within the nested genomic variants. Combining long-read genome and transcriptome sequencing enables an in-depth analysis of how SVs disrupt the transcriptome and sheds new light on the complexity of cancer progression.

genomics↗

bioRxiv2017

Early And Late Components Of EEG Delay Activity Correlate Differently With Scene Working Memory Performance

Sustained and elevated activity during the working memory delay period has long been considered the primary neural correlate for maintaining information over short time intervals. This idea has recently been reinterpreted in light of findings generated from multiple neural recording modalities and levels of analysis. To further investigate the sustained or transient nature of activity, the temporal-spectral evolution (TSE) of delay period activity was examined in humans with high density EEG during performance of a Sternberg working memory paradigm with a relatively long six second delay and with novel scenes as stimuli. Multiple analyses were conducted using different trial window durations and different baseline periods for TSE computation. Sensor level analyses revealed transient rather than sustained activity during delay periods. Specifically, the consistent finding among the analyses was that high amplitude activity encompassing the theta range was found early in the first three seconds of the delay period. These increases in activity early in the delay period correlated positively with subsequent ability to distinguish new from old probe scenes. Source level signal estimation implicated a right parietal region of transient early delay activity that correlated positively with working memory ability. This pattern of results adds to recent evidence that transient rather than sustained delay period activity supports visual working memory performance. The findings are discussed in relation to synchronous and desynchronous intra- and inter-regional neural transmission, and choosing an optimal baseline for expressing temporal-spectral delay activity change.

neuroscience↗