Abstract
Motivation
Sequence-based protein–protein interaction (PPI) prediction represents a fundamental computational biology problem. To address this problem, extensive research efforts have been ...made to extract predefined features from the sequences. Based on these features, statistical algorithms are learned to classify the PPIs. However, such explicit features are usually costly to extract, and typically have limited coverage on the PPI information.
Results
We present an end-to-end framework, PIPR (Protein–Protein Interaction Prediction Based on Siamese Residual RCNN), for PPI predictions using only the protein sequences. PIPR incorporates a deep residual recurrent convolutional neural network in the Siamese architecture, which leverages both robust local features and contextualized information, which are significant for capturing the mutual influence of proteins sequences. PIPR relieves the data pre-processing efforts that are required by other systems, and generalizes well to different application scenarios. Experimental evaluations show that PIPR outperforms various state-of-the-art systems on the binary PPI prediction problem. Moreover, it shows a promising performance on more challenging problems of interaction type prediction and binding affinity estimation, where existing approaches fall short.
Availability and implementation
The implementation is available at https://github.com/muhaochen/seq_ppi.git.
Supplementary information
Supplementary data are available at Bioinformatics online.
•The human microbiome plays a critical role in human health and disease.•Predicting disease status from metagenomic data is increasingly important.•We review new methods for this task, focusing ...mostly on deep learning.•We perform an in-depth analysis of challenging type 2 diabetes and obesity datasets.•We offer perspectives on study design concerns and potential future directions.
The human microbiome plays a number of critical roles, impacting almost every aspect of human health and well-being. Conditions in the microbiome have been linked to a number of significant diseases. Additionally, revolutions in sequencing technology have led to a rapid increase in publicly-available sequencing data. Consequently, there have been growing efforts to predict disease status from metagenomic sequencing data, with a proliferation of new approaches in the last few years. Some of these efforts have explored utilizing a powerful form of machine learning called deep learning, which has been applied successfully in several biological domains. Here, we review some of these methods and the algorithms that they are based on, with a particular focus on deep learning methods. We also perform a deeper analysis of Type 2 Diabetes and obesity datasets that have eluded improved results, using a variety of machine learning and feature extraction methods. We conclude by offering perspectives on study design considerations that may impact results and future directions the field can take to improve results and offer more valuable conclusions. The scripts and extracted features for the analyses conducted in this paper are available via GitHub:https://github.com/nlapier2/metapheno.
There is increasing evidence that many risk loci found using genome-wide association studies are molecular quantitative trait loci (QTLs). Here we introduce a new set of functional annotations based ...on causal posterior probabilities of fine-mapped molecular cis-QTLs, using data from the Genotype-Tissue Expression (GTEx) and BLUEPRINT consortia. We show that these annotations are more strongly enriched for heritability (5.84× for eQTLs; P = 1.19 × 10
) across 41 diseases and complex traits than annotations containing all significant molecular QTLs (1.80× for expression (e)QTLs). eQTL annotations obtained by meta-analyzing all GTEx tissues generally performed best, whereas tissue-specific eQTL annotations produced stronger enrichments for blood- and brain-related diseases and traits. eQTL annotations restricted to loss-of-function intolerant genes were even more enriched for heritability (17.06×; P = 1.20 × 10
). All molecular QTLs except splicing QTLs remained significantly enriched in joint analysis, indicating that each of these annotations is uniquely informative for disease and complex trait architectures.
Medial axis (MA) is a classical shape descriptor in graphics and vision. The practical utility of MA, however, is hampered by its sensitivity to boundary noise. To prune unwanted branches from MA, ...many definitions of significance measures over MA have been proposed. However, pruning MA using these measures often comes at the cost of shrinking desirable MA branches and losing shape features at fine scales. We propose a novel significance measure that addresses these shortcomings. Our measure is derived from a variational pruning process, where the goal is to find a connected subset of MA that includes as many points that are as parallel to the shape boundary as possible. We formulate our measure both in the continuous and discrete settings, and present an efficient algorithm on a discrete MA. We demonstrate on many examples that our measure is not only resistant to boundary noise but also excels over existing measures in preventing MA shrinking and recovering features across scales.
The Specker theorem is considered, stating that if for some cardinal m there is no strictly intermediate cardinal between m and 2m (briefly CH(m)), and also between 2m and 22m (briefly CH(2m)), then ...the cardinal 2m is an aleph (briefly WO(2m)).
Rejecting the second condition CH(2m) in Specker's theorem, a different condition of local bounded selection of elements from the family of bijections of the set X, |X|=m, to sets X⊔0,α), 0<α<ℵ(m) (briefly AC2m(ℵ(m))) is specified, which is not only a sufficient condition for 2m=ℵ(m), which strengthens Specker's theorem, but also a necessary condition for it. More precisely, if m is an infinite cardinal, then the formula 2m=ℵ(m) holds if and only if the following formula CH(m)∧AC2m(ℵ(m)) is true. Here ℵ(m) is a Hartogs number.
The following generalized Specker theorems are also proved:(CH(m+ℵ(m))∧CH(2m))⇒WO(2m),(CH(m)∧CH(m+ℵ)∧ℵ≥ℵ(m))⇒WO(2m) and(CH(m+ℵ)∧CH(2m)∧ℵ(m)<ℵ≤2m)⇒WO(2m).
The following nontrivial theorem is proved: Let m be a cardinal such that the formula CH(2m) is true and Hartogs number ℵ(2m) is a regular cardinal. Then formula WO(m) is true if and only if m2=m and for every two alephs ℵ and ℵ′ such that 2m<2ℵ and 2ℵ′<2m the following inequalities m<ℵ and ℵ′<m are valid, respectively.
An unsolved problem is still being discussed: is the formula CH(m)⇒WO(m) true?
Solving this problem boils down to solving the question of the consistency of the formula CH(m)∧¬WO(m) with the axioms of Zermelo-Fraenkel set theory without the axioms of choice and regularity (briefly ZF).
The problem of consistency and independence of formulas CH(m)∧¬WO(m) and CH(m)∧¬WO(2m) with the axioms of set theory ZF is also discussed. Their independence from these axioms ZF is proved. The consistency of the last formula is known and the question of the consistency of the first formula with axioms ZF remains unresolved yet.
Scalp dysesthesia: a neuropathic phenomenon Ju, T.; Vander Does, A.; Yosipovitch, G.
Journal of the European Academy of Dermatology and Venereology,
June 2022, Letnik:
36, Številka:
6
Journal Article
Recenzirano
Scalp dysesthesia is an abnormal sensation of the scalp in the absence of cutaneous disease. It is characterized by a burning and/or itching sensation and can be related to a variety of neurogenic or ...psychogenic causes. This condition is extremely bothersome and is also common‐ especially among the geriatric population, in women, in patients with diabetes mellitus, and patients with psychiatric history. However, despite its prevalence in many populations, there are limited data about its causes and characteristics. Given its limited cutaneous manifestations, it is also easily misdiagnosed and an underrecognized cause of scalp pruritus in the dermatological community. Therefore, education on scalp dysesthesia is paramount to helping physicians identify and provide appropriate treatment for these patients. This review focuses predominantly on the neurogenic causes (with a brief review of psychogenic itch) of scalp dysesthesia and the therapeutics that have been found to be effective for this condition. Neurogenic causes of scalp dysesthesia occur with damage to the central or peripheral pathways of itch sensation, resulting in modification and heightened sensitivity of nerves that result in abnormal sensations in the absence of or out of proportion to external stimuli. A comprehensive review of etiologies is provided here, ranging from lesions to the central nervous system caused by cervical spine disease, trigeminal trophic syndrome, tumor, stroke, and multiple sclerosis, to small‐fiber neuropathies caused by diabetes, brow lifts, keloid, and burn scarring. Recently, there have also been reports of scalp dysesthesias associated with post‐infectious COVID‐19. Treatment options tailored toward disease severity and different causes of disease will also be discussed. By elucidating the different mechanisms and therapeutic treatments of scalp dysesthesia, we hope to provide clinicians with the tools to identify and treat this condition as well as encourage further research into its etiologies and therapeutics.
Background
Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. ...Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer.
Methods
The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography–mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice.
Results
GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1.
Conclusions
Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.
Human immunoglobulin A1 (IgA1), which carries four to six mucin-type O-glycans (O-glycans) on its hinge region (HR), is the most abundant O-glycoprotein in plasma or serum. While normal O-glycans ...from hematopoietic-originated cells are core 1-based complex structures, many reports showed that the IgA1 from patients with IgA nephropathy (IgAN) carries undergalactosylated or truncated O-glycans such as the Tn antigen and its sialylated version the SialylTn (STn) antigen on the HR. Yet, there is still a debate whether Tn/STn on the HR of IgA1 is specific to the IgA1 from patients with IgAN since these antigens have also been seen in serum IgA1 of healthy individuals. An additional question is whether the O-glycans at all sites on the two HRs of one IgA1 molecule are homogeneous (either all normal or all Tn/STn) or heterogeneous (both normal and Tn/STn O-glycans). To address these questions, we conducted a systematic study on the O-glycans of plasma IgA1 from both IgAN patients and healthy controls using serial HPA and PNA lectin chromatography followed by western blotting and further analysis of O-glycans from HPA-bound and PNA-bound IgA1 fractions by mass spectrometry. Unexpectedly, we found that a variable minor fraction of IgA1 from both IgAN patients and healthy controls had Tn/STn antigens, and that the O-glycoprotein IgA1 molecules from most samples had only two distinct O-glycoforms: one major glycoform with homogeneous normal core 1-based O-glycans and one minor glycoform with homogeneous Tn/STn antigens. These results raised a serious question about the role of Tn/STn antigens on IgA1 in pathogenesis of IgAN, and there is a demand for a practical methodology that any laboratory can utilize to analyze the O-glycans of IgA1. Herein, we describe the methodology we developed in more detail. The method could also be applied to the analysis of any other O-glycosylated proteins.
Human epidermal growth factor receptor 2 (HER2) overexpression is not only closely associated with the tumor growth, but is also related to tumor invasion. We here aimed to investigate the mechanism ...of HER2 mediation in the pathogenesis of gastric cancer. The human gastric cancer cell lines SGC-7901, MKN-45, AGS, the immortalized cell line GES-1 derived from normal gastric mucosa. Cell transfection and selection of stable cell lines and the gene and protein levels of HER2 and Matrix metalloproteinase-9 (MMP-9) were examined to determine the molecular relationship between them in the pathogenesis of gastric cancer. The human gastric cancer cell lines SGC-7901, MKN-45, AGS, the immortalized cell line GES-1 derived from normal gastric mucosa. Cell transfection and selection of stable cell lines and the gene and protein levels of HER2 and MMP-9 were examined to determine the molecular relationship between them in the pathogenesis of gastric cancer. We demonstrated that vector-based shRNA significantly knocked down the expression of HER2 and considerably inhibited both the migration and invasion of gastric cancer cells. HER2 knockdown resulted in the downregulation of the expression of MMP-9, whereas HER2 overexpression improved the transcription of MMP-9 through the activation of an MMP-9 promoter. The promoter region of MMP-9 between -2500 and -2000 bp was found to be crucial for the upregulation of HER2-mediated transcription. Furthermore, a truncated promoter (-70 to +63) did not display any transcriptional activity. Cell invasion activity was almost completely inhibited when MMP-9 was knocked down. Conversely, the overexpression of MMP-9 partly rescued the invasion ability of cell strains with knockdown HER2. These findings help further understanding of the molecular mechanisms through which HER2 promotes malignancy, and suggest that targeting both HER2 and MMP-9 may be required to effectively block HER2 signaling in gastric cancer therapy.
Itch is the most common skin symptom among tropical parasitic diseases (TPD), but there are limited data about its characteristics in these conditions. In dermatology practices and travellers' health ...clinics in the developed world, itch is a common complaint among travellers returning from endemic areas, as well among migrants arriving from endemic areas, where they may have been exposed to TPD. Studying aspects of pruritus among TPD may lead to improvements in prompt, accurate diagnosis and management of these conditions. This review examines the major itch‐inducing TPDs, including schistosomiasis, echinococcosis, onchocerciasis, scabies, cutaneous larva migrans, larva currens, African trypanosomiasis, dracunculiasis and other causes of travel associated pruritus. We focus on the link between pruritus and other symptoms, aetiology, clinical staging and therapeutic options for these parasitic illnesses. Because some tropical parasitic diseases can present with significant pruritus, we attempt to identify aspects of the pruritus that are characteristic of—or unique to—specific conditions. These diagnostic insights may help clinicians create a rational and focused differential diagnosis and help determine optimal disease management pathways. In this sense, management involves treating the individual, seeking epidemiologically linked cases, preventing recurrences or relapses, and reducing spread of the disease.
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