Predicting Affinity Through Homology (PATH): Interpretable Binding Affinity Prediction with Persistent Homology.

Accurate binding affinity prediction is crucial to structure-based drug design. Recent work used computational topology to obtain an effective representation of protein-ligand interactions. Although persistent homology encodes geometric features, previous works on binding affinity prediction using persistent homology employed uninterpretable machine learning models and failed to explain the underlying geometric and topological features that drive accurate binding affinity prediction. In this work, we propose a novel, interpretable algorithm for protein-ligand binding affinity prediction. Our algorithm achieves interpretability through an effective embedding of distances across bipartite matchings of the protein and ligand atoms into real-valued functions by summing Gaussians centered at features constructed by persistent homology. We name these functions internuclear persistent contours (IPCs) . Next, we introduce persistence fingerprints , a vector with 10 components that sketches the distances of different bipartite matching between protein and ligand atoms, refined from IPCs. Let the number of protein atoms in the protein-ligand complex be n , number of ligand atoms be m , and ω ≈ 2.4 be the matrix multiplication exponent. We show that for any 0 < ε < 1, after an 𝒪 ( mn log( mn )) preprocessing procedure, we can compute an ε -accurate approximation to the persistence fingerprint in 𝒪 ( m log 6 ω ( m/" )) time, independent of protein size. This is an improvement in time complexity by a factor of 𝒪 (( m + n ) 3 ) over any previous binding affinity prediction that uses persistent homology. We show that the representational power of persistence fingerprint generalizes to protein-ligand binding datasets beyond the training dataset. Then, we introduce PATH , Predicting Affinity Through Homology, an interpretable, small ensemble of shallow regression trees for binding affinity prediction from persistence fingerprints. We show that despite using 1,400-fold fewer features, PATH has comparable performance to a previous state-of-the-art binding affinity prediction algorithm that uses persistent homology features. Moreover, PATH has the advantage of being interpretable. Finally, we visualize the features captured by persistence fingerprint for variant HIV-1 protease complexes and show that persistence fingerprint captures binding-relevant structural mutations. The source code for PATH is released open-source as part of the osprey protein design software package.

Hierarchical hollow zeolite fiber in catalytic applications: A critical review.

Zeolites have widely been studied because of the better performance as catalysts and supports. However, the zeolites with only micropores have drawbacks in reactivity and selectivity due to limitation of diffusivity. The hollow zeolite fibers (HZF) with hierarchical porosity however can overcome the problem. The HZF can be synthesized by such methods as incorporated substrate removal method, solid-solid transformation method, co-axial electrospinning technology, dry-wet spinning technology, and hollow fiber incorporation method. The unique hierarchical porous structure leads to the great improvement in the diffusion efficiency of reactants. The catalytic zeolite membrane fibers are the most commonly used as they have stronger catalyst stability and higher catalytic selectivity. The HZFs are suitable in catalytic applications such as selective catalysis, CO preferential oxidation, air purification and wastewater treatment. In order that the HZFs can be applied to industrial operations, more research work should be carried out, such as developments of self-assembly pure HZFs, catalytic substrate incorporated HZFs, HZFs with gradient multicomponent zeolites and HZFs with nanoscale diameters.

Different Phenotypes Represent Advancing Stages of ABCA4-Associated Retinopathy: A Longitudinal Study of 212 Chinese Families From a Tertiary Center.

Purpose: To evaluate the nature and association of different phenotypes associated with ABCA4 mutations in Chinese. Methods: All patients were recruited from our pediatric and genetic eye clinic. Detailed ocular phenotypes were characterized. The disease course was evaluated by long-term follow-up observation, with a focus on fundus changes. Cox regression was used to identify the factors associated with disease progression. Results: A systematic review of genetic and clinical data for 228 patients and follow-up data for 42 patients indicated specific features in patients with two ABCA4 variants. Of 185 patients with available fundus images, 107 (57.8%) showed focal lesions restricted to the central macula without flecks. Among these 107 patients, 30 patients (28.0%) initially presented with relatively preserved visual acuity and inconspicuous performance on routine fundus screening. A pigmentary change in the posterior pole was observed in 22 of 185 patients (11.9%), and this change mimicked retinitis pigmentosa in 10 cases (45.5%). Follow-up visits and sibling comparisons demonstrated disease progression from cone-rod dystrophy, Stargardt disease, to retinitis pigmentosa. An earlier age of onset was associated with a more rapid decrease in visual acuity (P = 0.03). Patients with two truncation variants had an earlier age of onset. Conclusion: Phenotypic variation in ABCA4-associated retinopathy may represent sequential changes in a single disease: early-stage Stargardt disease may resemble cone-rod dystrophy, whereas the presence of diffuse pigmentation in the late stage may mimic retinitis pigmentosa. Recognizing the natural progression of fundus changes, especially those visualized by wide-field fundus autofluorescence, is valuable for diagnostics and therapeutic decision-making.

Circ_0020123 plays an oncogenic role in non-small cell lung cancer depending on the regulation of miR-512-3p/CORO1C.

BACKGROUND: Non-small cell lung cancer (NSCLC) is one of the leading causes responsible for cancer-associated death globally. The aim of this study was to illustrate the function of circular RNA_0020123 (circ_0020123) in NSCLC progression and its associated mechanism. METHODS: RNA and protein expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot assay. Cell proliferation, migration, invasion, angiogenesis, apoptosis and autophagy were analyzed to assess the role of circ_0020123/microRNA-512-3p (miR-512-3p)/coronin 1C (CORO1C) axis in NSCLC cells. Tumorigenesis in nude mice was analyzed to determine the in vivo role of circ_0020123. The intermolecular target relation was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. RESULTS: Circ_0020123 expression was aberrantly upregulated in NSCLC tissues and cell lines. Circ_0020123 interference markedly restrained cell proliferation, migration, invasion, angiogenesis and autophagy and induced cell apoptosis of NSCLC cells. Circ_0020123 knockdown suppressed xenograft tumor growth in vivo. Circ_0020123 acted as a molecular sponge for miR-512-3p. Circ_0020123 silencing-induced effects in NSCLC cells were largely reversed by the knockdown of miR-512-3p. miR-512-3p interacted with the 3' untranslated region (3'UTR) of CORO1C. CORO1C overexpression largely reversed miR-512-3p accumulation-induced influences in NSCLC cells. Circ_0020123 positively regulated CORO1C expression by sponging miR-512-3p in NSCLC cells. CONCLUSION: Circ_0020123 aggravated NSCLC progression by binding to miR-512-3p to induce CORO1C expression, which provided new potential targets for the treatment of NSCLC.

An Early Diagnostic Clue for COL18A1- and LAMA1-Associated Diseases: High Myopia With Alopecia Areata in the Cranial Midline.

BACKGROUND: High myopia with alopecia areata in the occipital region has been observed in patients with Knobloch syndrome caused by COL18A1 mutations. This study investigated other possible genetic causes of high myopia in patients with alopecia areata in the cranial midline. METHODS: Six patients with early onset high myopia and alopecia areata in the cranial midline were recruited. Targeted high-throughput sequencing was performed on the proband's DNA to detect potential pathogenic variants. Cosegregation analysis was performed for available family members. Minigene assay and RNA Sequencing were used to validate the abnormality of possible splicing change and gross deletion. Ophthalmological and neuroimaging examinations were performed. RESULTS: Eight novel and one known loss-of-function mutants were detected in all six patients, including a gross deletion detected by RNA sequencing. Four COL18A1 mutants in three patients with scalp leisure in the occipital region; and five LAMA1 mutations in three patients with scalp leisure in the parietal region. Further assessments indicated that patients with COL18A1 mutations had Knobloch syndrome, and the patients with LAMA1 mutations had Poretti-Boltshauser syndrome. CONCLUSION: Our study found that early onset high myopia with midline alopecia areata could be caused not only by mutations of the COL18A1 gene but also by mutations in the LAMA1 gene. To our knowledge, we are the first to observe scalp defects in patients with LAMA1 mutations. High myopia with alopecia areata in the cranial midline could be treated as an early diagnostic clue for ophthalmologists to consider the two kinds of rare diseases.

An Ophthalmic Targeted Exome Sequencing Panel as a Powerful Tool to Identify Causative Mutations in Patients Suspected of Hereditary Eye Diseases.

PURPOSE: We evaluate the power of a next-generation sequencing-based ophthalmic targeted sequencing panel (NGS-based OTSP) as a genetics-testing tool for patients suspected of a wide range of hereditary eye diseases. METHODS: NGS-based OTSP encompasses 126 genes with identified mutations that account for the majority of Chinese families with hereditary eye diseases. A total of 568 probands suspected of having hereditary eye diseases underwent genetic testing by OTSP with targeted phenotype-driven analysis. RESULTS: NGS-based OTSP detected 329 potential pathogenic variants in 62 genes. These mutations might represent the genetic cause in 52% (293/568) of probands suspected of having hereditary eye diseases. Within the disease subgroups, the detection rates were 61% (124/202) for retinal degeneration disease, 53% (35/66) for eye tumors, 49% (53/108) for retinal vessel disease, 46% (13/28) for retinal detachment, 33% (19/58) for significant refractive error, 35% (16/46) for optic atrophy, 48% (11/23) for anterior segment dysgenesis, and 59% (22/37) for other hereditary eye diseases. These detection rates are comparable to those obtained in our previous study performed with whole exome sequencing. Mutations in the same gene were detected in different forms of hereditary eye diseases. The average turnaround time for OTSP is 30 days, and the average cost is 139 USD per patient. CONCLUSIONS: NGS-based OTSP is a powerful tool for routine clinical genetic diagnostic testing in patients suspected of having hereditary eye diseases. TRANSLATIONAL RELEVANCE: NGS-based OTSP can be used as a routine clinical test to improve the genetic counseling and medical care of patients suspected of having hereditary eye diseases.

The ethanol extract of Involcucrum castaneae ameliorated ovalbumin-induced airway inflammation and smooth muscle thickening in guinea pigs.

ETHNOPHARMACOLOGICAL RELEVANCE: Involucrum castaneae(IC)is used in Chinese folk medicine to treat various lung diseases, as well as for its reducing phlegm and anti-inflammatory properties. AIM OF THE STUDY: The purpose of this experiment is to verify the effect of IC on airway inflammation, responsiveness in ovalbumin (OVA)-induced asthmatic guinea pigs. The main chemical components of IC were also analyzed. MATERIALS AND METHODS: The potential of the ethanol extract of Involucrum castaneae (EEIC) to protect against OVA-induced allergic airway response in guinea pigs was investigated. The latency of asthma in guinea pigs were recorded after the allergic asthma induced. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of immunoglobulin E (IgE), interleukin-5 (IL-5), nerve growth factor (NGF) and interferon-γ (IFN-γ) in asthma allergy. Reverse transcription-PCR (RT-PCR) was used to detect the expression of IL-5 mRNA in asthmatic guinea pig lungs. Paraffin sections of lung tissue were used to analyze pathological changes. The total flavonoid content was determined and the chemical components were analyzed by LC-MS/MS. RESULTS: It was found that EEIC was able to reduce the number of eosinophil (EOS) in bronchoalveolar lavage fluid (BALF) and peripheral blood (PB) in the guinea pig model of OVA -induced asthma. Meanwhile, it also significantly reduced the levels of inflammation-related factors IgE and IL-5, decreased the expression of IL-5 mRNA in lung tissue, and increased the level of IFN-γ. Pathological examination of paraffin section of lung tissue showed that EEIC can reduce the thickening of bronchial smooth muscle and reduce the infiltration damage of tissues by various inflammatory cells. The presence of flavonoids, terpenoids and phenolic compounds in EEIC might be responsible for these activities. CONCLUSION: IC alleviated airway inflammation and smooth muscle thickening in guinea pigs with OVA-sensitized allergic asthma. The paper explains the traditional efficacy and material basis of IC and lays a foundation for further development.

Predicting binary, discrete and continued lncRNA-disease associations via a unified framework based on graph regression.

BACKGROUND: In human genomes, long non-coding RNAs (lncRNAs) have attracted more and more attention because their dysfunctions are involved in many diseases. However, the associations between lncRNAs and diseases (LDA) still remain unknown in most cases. While identifying disease-related lncRNAs in vivo is costly, computational approaches are promising to not only accelerate the possible identification of associations but also provide clues on the underlying mechanism of various lncRNA-caused diseases. Former computational approaches usually only focus on predicting new associations between lncRNAs having known associations with diseases and other lncRNA-associated diseases. They also only work on binary lncRNA-disease associations (whether the pair has an association or not), which cannot reflect and reveal other biological facts, such as the number of proteins involved in LDA or how strong the association is (i.e., the intensity of LDA). RESULTS: To address abovementioned issues, we propose a graph regression-based unified framework (GRUF). In particular, our method can work on lncRNAs, which have no previously known disease association and diseases that have no known association with any lncRNAs. Also, instead of only a binary answer for the association, our method tries to uncover more biological relationship between a pair of lncRNA and disease, which may provide better clues for researchers. We compared GRUF with three state-of-the-art approaches and demonstrated the superiority of GRUF, which achieves 5%~16% improvement in terms of the area under the receiver operating characteristic curve (AUC). GRUF also provides a predicted confidence score for the predicted LDA, which reveals the significant correlation between the score and the number of RNA-Binding Proteins involved in LDAs. Lastly, three out of top-5 LDA candidates generated by GRUF in novel prediction are verified indirectly by medical literature and known biological facts. CONCLUSIONS: The proposed GRUF has two advantages over existing approaches. Firstly, it can be used to work on lncRNAs that have no known disease association and diseases that have no known association with any lncRNAs. Secondly, instead of providing a binary answer (with or without association), GRUF works for both discrete and continued LDA, which help revealing the pathological implications between lncRNAs and diseases.