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Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

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bioRxiv2018

Central sensitization increases the pupil dilation elicited by mechanical pinprick stimulation

High frequency electrical stimulation (HFS) of skin nociceptors triggers central sensitization, manifested as increased pinprick sensitivity of the skin surrounding the site at which HFS was applied. The aim of the present study was to compare the effects of HFS on pupil dilation and brain responses elicited by pinprick stimulation delivered in the area of increased pinprick sensitivity. In fourteen healthy volunteers HFS was applied to one of the two forearms. Before and twenty minutes after applying HFS, mechanical pinprick stimuli (64 mN and 96 mN) were delivered to the area surrounding the site at which HFS was applied as well as the contralateral control arm. During pinprick stimulation both the pupil size and electroencephalogram were recorded. HFS induced a clear and comparable increase in pinprick sensitivity for both the 64 and 96 mN stimulation intensity. Both pinprick stimulation intensities elicited a greater pupil dilation response when delivered to the area of increased pinprick sensitivity. However, this greater pupil dilation response was larger for the 64 mN compared to the 96 mN stimulation intensity. A similar pattern was observed for the negative wave of the pinprick-evoked brain potentials (PEPs), however, the increase was not significant for the 96 mN and showed only a trend towards significance for the 64 mN. These results show that there is a correspondence between the increase in pupil dilation and the increase in PEPs, but that pupil size is a more sensitive measure for detecting the effects of central sensitization than PEPs.

neuroscience↗

bioRxiv2018

ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo

Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in the basic neuronal process of axonal transport have been identified in several ALS models. However, in vivo evidence of early/pre-symptomatic deficiencies in neuronal cargo trafficking remains limited, thus the pathogenic importance of axonal transport to the ALS disease spectrum remains to be fully resolved. We therefore analysed the in vivo dynamics of retrogradely transported, neurotrophin-containing signalling endosomes in motor neuron axons of two new mouse models of ALS that have mutations in different RNA processing genes (Tardbp and Fus). TDP-43M337V mice, which show neuromuscular pathology but no overt motor neuron loss, displayed in vivo perturbations in axonal transport that manifested between 1.5 and 3 months and preceded motor symptom onset. In contrast, signalling endosome transport remained largely unaffected in mutant Fus{Delta}14/+ mice, despite 20% motor neuron loss. These findings indicate that deficiencies in retrograde neurotrophin signalling and axonal transport are not common to all ALS-linked genes, and that there are inherent and mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.

neuroscience↗

bioRxiv2018

Antiviral adaptive immunity and tolerance in the mosquito Aedes aegyti

Mosquitoes spread pathogenic arboviruses while themselves tolerate infection. We here characterize an immunity pathway providing long-term antiviral protection and define how this pathway discriminates between self and non-self. Mosquitoes use viral RNAs to create viral derived cDNAs (vDNAs) central to the antiviral response. vDNA molecules are acquired through a process of reverse-transcription and recombination directed by endogenous retrotransposons. These vDNAs are thought to integrate in the host genome as endogenous viral elements (EVEs). Sequencing of pre-integrated vDNA revealed that the acquisition process exquisitely distinguishes viral from host RNA, providing one layer of self-nonself discrimination. Importantly, we show EVE-derived piRNAs have antiviral activity and are loaded onto Piwi4 to inhibit virus replication. In a second layer of self-non-self discrimination, Piwi4 preferentially loads EVE-derived piRNAs, discriminating against transposon-targeting piRNAs. Our findings define a fundamental virus-specific immunity pathway in mosquitoes that uses EVEs as a potent and specific antiviral transgenerational mechanism.

immunology↗

bioRxiv2018

Effect of Dietary Fat on the Metabolism of Energy and Nitrogen, Serum Parameters, Rumen Fermentation, and Microbiota in twin Hu Male Lambs

BackgroundFat is the main substance that provides energy to animals. However, the use of fat in twin Hu lambs has not been investigated. Thirty pairs of male twin lambs were examined to investigate the effects of dietary fat on the metabolism of energy and nitrogen, ruminal fermentation, and microbial communities. The twins are randomly allotted to two groups (high fat: HF, normal fat: NF). Two diets of equal protein and different fat levels. The metabolism test was made at 50-60 days of age. Nine pairs of twin lambs are slaughtered randomly, and the rumen fluid is collected at 60 days of age.\n\nResultsThe initial body weight (BW) in the HF group did not differ from that of NF group (P > 0.05), but the final BW was tended to higher than that of NF group (0.05 < P < 0.1). The digestive energy (DE), metabolism energy (ME), DE/ME in the HF group tend to be higher than those in the NF group (0.05 < P < 0.1). Ruminal ammonia nitrogen (NH3-N) and the proportion of total volatile fatty acids (TVFA) are higher than that in the NF group (P < 0.05). A high throughput sequencing analysis reveals that there were no differences between the two groups in terms of the richness estimates and diversity indices (P > 0.05). The Proteobacteria and Fibrobacteres phyla were higher than that in NF group (P<0.05).\n\nConclusionsThis study demonstrated that high fat diet before weaning can affect the abundance of several groups of rumen bacteria in rumen, such as significantly increasing phyla Proteobacteria and Fibrobacteres, and genera of Succinivibrio, Alloprevotella, and Saccharofermentans, but significantly decreasing genera of Clostridium IV, Dialister, Roseburia, and Butyrivibrio. And high fat diet improved the performance of lambs at weight gain, energy utilization, and had effect on VFA composition but no effects on serum enzymes and serum hormone.

microbiology↗

bioRxiv2018

Building gene regulatory networks from single-cell ATAC-seq and RNA-seq using Linked Self-Organizing Maps

Rapid advances in single-cell assays have outpaced methods for analysis of those data types. Different single-cell assays show extensive variation in sensitivity and signal to noise levels. In particular, scATAC-seq generates extremely sparse and noisy datasets. Existing methods developed to analyze this data require cells amenable to pseudo-time analysis or require datasets with drastically different cell-types. We describe a novel approach using self-organizing maps (SOM) to link scATAC-seq and scRNA-seq data that overcomes these challenges and can generate draft regulatory networks. Our SOMatic package generates chromatin and gene expression SOMs separately and combines them using a linking function. We applied SOMatic on a mouse pre-B cell differentiation time-course using controlled Ikaros over-expression to recover gene ontology enrichments, identify motifs in genomic regions showing similar single-cell profiles, and generate a gene regulatory network that both recovers known interactions and predicts new Ikaros targets during the differentiation process. The ability of linked SOMs to detect emergent properties from multiple types of highly-dimensional genomic data with very different signal properties opens new avenues for integrative analysis of single-cells.

genomics↗

bioRxiv2018

Histologically derived fiber response functions for diffusion MRI vary across white matter fibers - an ex vivo validation study in the squirrel monkey brain

Understanding the relationship between the diffusion-weighted MRI signal and the arrangement of white matter fibers is fundamental for accurate voxel-wise reconstruction of the fiber orientation distribution (FOD) and subsequent fiber tractography. Spherical deconvolution reconstruction techniques model the diffusion signal as the convolution of the FOD with a response function which represents the signal profile of a single fiber orientation. Thus, given the signal and a fiber response function, the FOD can be estimated in every imaging voxel by deconvolution. However, the selection of the appropriate response function remains relatively un-studied, and requires further validation. In this work, using 3D histologically-defined FODs and the corresponding diffusion signal from three ex vivo squirrel monkey brains, we derive the ground truth response functions. We find that the histologically-derived response functions differ from those conventionally used. Next, we find that response functions statistically vary across brain regions, which suggests that the practice of using the same kernel throughout the brain is not optimal. Additionally, response functions vary significantly across subjects. We show that different kernels lead to different FOD reconstructions, which in turn can lead to different tractography results depending on algorithmic parameters, with large variations in the accuracy of resulting reconstructions. Together, this suggests that there is room for improvement in estimating and understanding the relationship between the diffusion signal and the underlying FOD.

neuroscience↗

bioRxiv2018

Accurate characterization of expanded tandem repeat length and sequence through whole genome long-read sequencing on PromethION.

Tandem repeats (TRs) can cause disease through their length, sequence motif interruptions, and nucleotide modifications. For many TRs, however, these features are very difficult - if not impossible - to assess, requiring low-throughput and labor-intensive assays. One example is a VNTR in ABCA7 for which we recently discovered that expanded alleles strongly increase risk of Alzheimers disease. Here, we investigated the potential of long-read whole genome sequencing to surmount these challenges, using the high-throughput PromethION platform from Oxford Nanopore Technologies. To overcome the limitations of conventional base calling and alignment, we developed an algorithm to study the TR size and sequence directly on raw PromethION current data.\n\nWe report the long-read sequencing of multiple human genomes (n = 11) using only a single sequencing run and flow cell per individual. With the use of fresh DNA extractions, DNA shearing to approximately 20kb and size selection, we obtained an average output of 70 gigabases (Gb) per flow cell, corresponding to a 21x genome coverage, and a maximum yield of 98 Gb (30x genome coverage). All ABCA7 VNTR alleles, including expansions up to 10,000 bases, were spanned by long sequencing reads, validated by Southern blotting. Classical approaches of TR length estimation suffered from low accuracy, low precision, DNA strand effects and/or inability to call pathogenic repeat expansions. In contrast, our novel NanoSatellite algorithm, which circumvents base calling by using dynamic time warping on raw PromethION current data, achieved more than 90% accuracy and high precision (5.6% relative standard deviation) of TR length estimation, and detected all clinically relevant repeat expansions. In addition, we identified alternative TR sequence motifs with high consistency, allowing determination of TR sequence and distinction of VNTR alleles with homozygous length.\n\nIn conclusion, we validated the robustness of single-experiment whole genome long-read sequencing on PromethION, a prerequisite for application of long-read sequencing in the clinic. In addition, we outperformed Southern blotting, enabling improved characterization of the role of expanded ABCA7 VNTR alleles in Alzheimers disease, and opening new opportunities for TR research.

genomics↗

bioRxiv2018

Isolating syntax in natural language: MEG evidence for an early contribution of left posterior temporal cortex

Syntax is the engine that allows us to create an infinitude of linguistic expressions, and the construction of syntactic structures, such as noun phrases and verb phrases, is considered a fundamental component of language processing. Nevertheless, insights concerning the neurobiological basis of syntax have remained elusive, in part because it is difficult to isolate syntax from semantic composition. Consequently, many studies of syntax have relied on meaningless artificial stimuli, such as jabberwocky expressions or artificial grammars. However, while pure manipulations of syntax are challenging to design, natural language grammars do have a sparse set of constructions presenting this possibility. Here we examined one such case, English post-nominal adjectives (mountain TALL enough for a strenuous hike), which were contrasted with semantically parallel but structurally simpler noun-adjective sequences in an MEG experiment. We observed a sharp activity increase in the left posterior temporal lobe (PTL) when syntactic composition was more straightforward, approximately 200 ms after adjective onset. The semantic fit between the noun and adjective was also varied, but this affected anterior temporal cortex, consistent with prior work. These findings offer a unique demonstration of the relevance of posterior temporal cortex for syntactic processing in natural language. We also present connectivity evidence that the syntax-related PTL responses were relayed to ipsilateral inferior frontal and anterior temporal regions. The combined results draw an initial picture of the rapid spatio-temporal dynamics of the syntactic and semantic composition network in sentence processing.

neuroscience↗

bioRxiv2018

The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

Currently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

cancer biology↗

bioRxiv2018

Cell type-specific differences in protein complex stoichiometry and transcriptional regulation affect the timing of stem cell division

Stem cells divide and differentiate to form all the specialized cell types in a multicellular organism. In the Arabidopsis root, stem cells are maintained in an undifferentiated state by a less mitotically active population of cells called the Quiescent Center (QC). Determining how the QC regulates the surrounding stem cell initials, or what makes the QC fundamentally different from the actively dividing initials, is important for understanding how stem cell divisions are maintained. Here, we gained insight into the differences between the QC and the Cortex Endodermis Initials (CEI) by studying the mobile transcription factor SHORTROOT (SHR) and its binding partner SCARECROW (SCR). We constructed an Ordinary Differential Equation (ODE) model of SHR and SCR in the QC and CEI which incorporated the stoichiometry of the SHR-SCR complex as well as upstream transcriptional regulation of SHR and SCR. Our model prediction coupled with experimental validation showed that high levels of the SHR-SCR complex is associated with more CEI division but less QC division. Further, our model prediction allowed us to establish the timing of QC and CEI division and propose that SHR repression of QC division depends on the formation of SHR homodimer. Thus, our results support that SHR-SCR protein complex stoichiometry and regulation of SHR transcription modulate the division timing of two different specialized cell types in the root stem cell niche.

plant biology↗

bioRxiv2018

Reorganization in cerebral and cerebellar cortices is not restricted by proximity between body-part representations

A fundamental organizing principle in the somatosensory and motor systems is somatotopy, where specific body parts are represented separately and adjacently to other body parts, resulting in a body map. Different terminals of the sensorimotor network show varied somatotopic layouts, in which the relative position, distance and overlap between body-part representations differ. Since somatotopy is best characterized in the primary somatosensory (S1) and motor (M1) cortices, these terminals have been the main focus of research on somatotopic remapping following loss of sensory input (e.g. arm amputation). Cortical remapping is generally considered to be driven by the layout of the underlying somatotopy, such that neighboring body-part representations tend to activate the deprived brain region. Here, we challenge the assumption that somatotopic layout restricts remapping, by comparing patterns of remapping in humans born without one hand (hereafter, one-handers, n=26) across multiple terminals of the sensorimotor pathway. We first report that in the cerebellum of one-handers, the deprived hand region represents multiple body parts. Importantly, the representations of some of these body parts do not neighbor the deprived hand region. We further replicate our previous finding, showing a similar pattern of remapping in the deprived hand region of the cerebral cortex in one-handers. Finally, we report preliminary results of a similar remapping pattern in the putamen of one-handers. Since these three sensorimotor terminals (cerebellum, cerebrum, putamen) contain different somatotopic layouts, the parallel remapping they undergo demonstrates that the mere spatial layout of body-part representations may not exclusively dictate remapping in the sensorimotor systems.\n\nSignificance StatementWhen a hand is missing, the brain region that typically processes information from that hand may instead process information from other body-parts, a phenomenon termed remapping. It is commonly thought that only body-parts whose information is processed in regions neighboring the hand region could \"take up\" the resources of this now deprived region. Here we demonstrate that information from multiple body-parts is processed in the hand regions of both the cerebral cortex and cerebellum. The native brain regions of these body-parts have varying levels of overlap with the hand region across multiple terminals in the sensorimotor hierarchy, and do not necessarily neighbor the hand region. We therefore propose that proximity between brain regions does not limit brain remapping.

neuroscience↗

bioRxiv2018

Selective D2 and D3 receptor antagonists oppositely modulate cocaine responses in mice via distinct postsynaptic mechanisms in nucleus accumbens

BackgroundThe D3 receptor (D3R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinsons disease, and substance use disorders. However, studies investigating the modulatory impact of D3R antagonism on dopamine neurotransmission or the effects drugs of abuse have produced mixed results, in part because D3R-targeted compounds often also interact with D2 receptors (D2R). The purpose of this study was to compare the consequences of selective D2R or D3R antagonism on the behavioral effects of cocaine in mice, and to identify the neurobiological mechanisms underlying their modulatory effects.\n\nMethodsWe characterized the effects of selective D2R or D3R antagonism in mice on 1) basal and cocaine-induced locomotor activity, 2) presynaptic dopamine release and clearance in the nucleus accumbens using ex vivo fast scan cyclic voltammetry, and 3) dopamine-mediated signaling in D1-expressing and D2-expressing medium spiny neurons using ex vivo electrophysiology.\n\nResultsPretreatment with the selective D2R antagonist L-741,626 attenuated, while pretreatment with the selective D3R antagonist PG01037 enhanced, the locomotor-activating effects of acute and repeated cocaine administration. While both antagonists potentiated cocaine-induced increases in presynaptic DA release, D3R blockade uniquely facilitated DA-mediated excitation of D1-expressing medium spiny neurons in the nucleus accumbens.\n\nConclusionsSelective D3R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D2R antagonism or nonselective D2-like receptor antagonists, likely by facilitating D1-mediated excitation in the nucleus accumbens. These findings provide important insights into the neuropharmacological actions of D3R antagonists on mesolimbic dopamine neurotransmission.

neuroscience↗

bioRxiv2018

To Overwrite or to Recall? Individual Differences in Motor Adaptation

The central nervous system predicts the consequences of motor commands by leaning multiple internal models of external perturbations and of the body. It is not well understood, however, how new internal models are created. Here, we propose a novel computational model of motor adaptation in which a stochastic Bayesian decision-making process determines whether i) a previously updated expert perturbation model is recalled and updated, ii) a novice model is selected and is updated into a new expert, or iii) the \"body\" model is updated. Results from computer simulations provide insights into various and contradictory experimental data on savings and error-clamp, and predicts qualitative individual differences in adaptation. We verified these predictions in a visuomotor adaptation experiment in which we varied the perturbation amplitudes as well as the amount of noise added to perturbation, and added \"trigger\" trials in the error-clamp condition. Single trigger trials led to largely qualitatively different behavior and can therefore be used to probe individual differences in memory updates between \"one-model\" and \"two-model\" learners. \"One-model\" learners continuously update the body model, showing no savings during re-adaptation to the perturbation, and gradual decay during error clamp. In contrast, \"two-model\" learners switch between an updated expert model and the body model, showing large savings during re-adaptation and stochastic lags during error clamp. Our results thus support the view that motor adaptation belongs to the general class of human learning according to which new memories are created when no existing memories can account for discontinuities in sensory data.\n\nShort summary/significanceWhen movements are followed by unexpected outcomes, such as following the introduction of a visuomotor or force field perturbation, or the sudden removal of such perturbations, it is unclear whether the central nervous system updates existing memories or creates new memories. Here, we propose a novel model of adaptation, and investigate, via simulation and behavioral experiments, how the amplitude and schedule of the perturbation, as well as the characteristics of the learner, lead to updates of existing memories or creation of new memories. Our results provide insights into a number of puzzling and contradictory experimental data on savings and error-clamp, as well as large qualitative individual differences in adaptation.

neuroscience↗

bioRxiv2018

Aquaporin-4 facilitator TGN-073 demonstrates novel analgesic activity

During pre-clinical development, we tested the novel, internally developed AQP-4 facilitator TGN-073 for its effect in a rodent pain model. Therein, TGN-073 was found to exert a strong analgesic effect. Following a single 200 mg/kg (i.p.) administration of TGN-073, a virtually complete block in the acetic acid writhing test was observed. Subsequent in vitro tests demonstrated that TGN-073 had no binding affinity for the -opioid or NK-1 receptors. Accordingly, we suspect TGN-073 or other AQP-4 facilitators may be developed into potent non-opioid analgesic agents. Given the potential significance of this discovery, we feel it should be openly shared with the scientific community.

pharmacology and toxicology↗

bioRxiv2018

Virus infection might cause cells producing black swimming dots

Black swimming dots (BSDs) are nanoscale dot-like contaminants in the dishes of cultured cells. Until now, the identity of BSDs has not yet been determined. In our recent study, we proposed that BSDs per se are nonliving inorganic nanoparticles yet should derive from the cells infected with an unidentified airborne pathogen. We showed the pathogen possessed the characteristics including airborne transmitted, cell-dependent, insensitive to antibiotics, filterable through 0.1 m membrane. These properties prompt us to speculate that the pathogen of BSDs might be one kind of unidentified virus-like organism. However, the imperfection is that we have not isolated this putative pathogen from BSD+ samples [1]. Here, we report a further investigation of finding the virus-like pathogen in the serum and tissue extracts from BSD+ mice. Most importantly, this virus-like pathogen can be reisolated from the BSD+ extracts-inoculated, diseased BSD- cells.\n\nTo de ...

cell biology↗

bioRxiv2018

Type I Interferon regulates IgE-mediated enhancement of rhinovirus-induced Th2 priming by primary human monocytes

Rhinovirus infections are linked to the development and exacerbation of allergic diseases including allergic asthma. IgE, another contributor to atopic disease pathogenesis, has been shown to regulate dendritic cell antiviral functions and influence T cell priming by monocytes. We previously demonstrated that IgE-mediated stimulation of monocytes alters multiple cellular functions including cytokine secretion, phagocytosis, and influenza-induced Th1 priming. In this study, we investigate the effects of IgE-mediated allergic stimulation on monocyte-driven, RV-induced T cell priming utilizing primary human monocyte-T cell co-cultures. We demonstrate that IgE crosslinking of RV-exposed monocytes enhances monocyte-driven Th2 priming. This increase in RV-induced Th2 differentiation was regulated by IgE-mediated inhibition of type I interferon and induction of IL-10. These findings suggest an additional mechanism by which two clinically significant risk factors for allergic disease exacerbations - IgE-mediated stimulation and rhinovirus infection, may synergistically promote Th2 differentiation and allergic inflammation.

immunology↗

bioRxiv2018

Genetic And Epigenetic Fine Mapping Of Complex Trait Associated Loci In The Human Liver

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory regions of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the impacts of genetic variation that direct histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 77 GWAS loci that have been associated with at least one complex phenotype. Our results contribute to the repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

genetics↗

bioRxiv2018

Network-aware mutation clustering of cancer

The grouping of cancers across tissue boundaries is central to precision oncology, but remains a difficult problem. Here we present EPICC (Experimental Protein Interaction Clustering of Cancer), a novel technique to cluster cancer patients based on DNA mutation profile, that leverages knowledge of protein-protein interactions to reduce noise and amplify biological signal. We applied EPICC to data from The Cancer Genome Atlas (TCGA), and both recapitulated known cancer clusterings, and identified new cross-tissue cancer groups that may indicate novel cancer molecular subtypes. Investigation of EPICC clusters revealed new protein modules which were recurrently mutated across cancers, and indicate new avenues for research into cancer biology. EPICC leveraged the Vodafone DreamLab citizen science platform, and we provide our results as a resource for researchers to investigate the role of protein modules in cancer.

bioinformatics↗