Miracle-dz/UniFAR-FTUs huggingface dataset:
Customizing Scoring Functions in Molecular Docking

Author(s): Pham, Tuan | Advisor(s): Jain, Ajay N | Abstract: In drug discovery, where a model of the protein structure is known, molecular docking is a well-established approach for predictive modeling. Docking algorithms utilize a search strategy for exploring ligand poses within an active site and a scoring function for evaluating the poses. This dissertation explores improvements to both aspects of docking, emphasizing the use of machine learning methods for improving scoring functions. The work is built upon an extensible software platform for modeling molecular interactions, called Surflex.Performance evaluation has been carried out on benchmarks that have been made publicly available, some of which were constructed in the course of this work. The novel tool pdbgrind, developed as part of the infrastructure for this work, was used to generate the large amount of data necessary to create adequate training and test sets. While the dissertation focuses most strongly on the scoring function problem in docking, some effort was also spent on the tightly coupled problem of search, and modest improvements were shown by enhancing Surflex's representation of protein active sites.The bulk of the work describes improvements to empirical scoring functions for protein-ligand interactions. This dissertation demonstrates a robust method for tuning scoring function parameters to improve modeling of known binding phenomena. Penalties for inter-atomic overlap and same-charge repulsion were learned using synthetic negative data. The new function was shown to be equivalent or better than the original function in terms of screening utility on a large and diverse benchmark. This approach was generalized for the entire scoring function to support the use of multiple constraints in refining scoring function parameters. Using the constraint-based optimization procedure, users can exploit multiple types of data to customize functions to suit a particular task or a particular protein target or family of targets. Significant improvement to screening utility was shown using data typical of applications in docking.The main contributions of this dissertation are generalizable methods for generating and exploiting multiple types of data in refining scoring functions for docking. The approaches can be extended to other areas, including quantitative structure activity prediction or protein folding.
Grandpaternal effects are lineage- and sex-specific in threespined sticklebacks

Transgenerational plasticity (TGP) occurs when the environment encountered by one generation (F0) alters the phenotypes of one or more future generations (e.g. F1 and F2). Selective inheritance of ancestral environments, via specific lineages or to only male or female descendants, may be adaptive if it allows past generations to fine-tune the phenotypes of future generations in response to sex-specific life history strategies. Here, we reared F1 offspring of unexposed and predator-exposed threespined stickleback (Gasterosteus aculeatus) fathers under ‘control’ conditions and generated F2s with a predator-exposed maternal and/or paternal grandfather. Grandpaternal effects were both sex and lineage-specific: female F2s were heavier and reacted less strongly to a simulated predator attack when their paternal grandfather was exposed to predation risk while male F2s were bolder when their maternal grandfather was exposed to predation risk. Therefore, grandpaternal effects were mediated across sexes, from F1 males to F2 females and from F1 females to F2 males. However, these patterns were only evident when one grandfather, but not both grandfathers, were exposed to predation risk. This selective inheritance may mean that grandparental effects are underestimated in the literature and raises new questions about the proximate and ultimate causes of selective transmission across generations.
Advances in newborn screening for Pompe disease and resulting clinical outcomes

Introduction:Pompe disease is a lysosomal storage disorder caused by a deficiency in acid α-glucosidase, which is responsible for the degradation of lysosomal glycogen. Enzyme replacement therapy (ERT) is now the standard treatment for Pompe disease and as such newborn screening to diagnose patients early is advantageous for the best therapy outcomes. Areas covered:This review is based on personal experience and the currently available literature; it provides an overview of the advances in newborn screening for Pompe disease and of the efficacy and limitations of ERT for newborns after identification by screening. Expert opinion: Newborn screening coupled immediately with ERT provides the best outcome for Pompe disease, but residual muscle weakness and other morbidity promotes development of second-generation therapies for improvements in both the muscular and neurologic aspects. Drawbacks of newborn screening for Pompe disease, such as false positives due to pseudodeficiency, have been largely eliminated and interference by anti-drug antibodies in certain individuals may be resolved by preventive immune modulation therapy. However, uncertainty regarding newly discovered genotypes and the onset age in later-onset individuals burden the clinicians, parents and babies and need to be further addressed carefully.
Hypertriglyceridemia and the Related Factors in Middle-aged Adults in Taiwan

Background. Our purpose was to evaluate the relationship between hypertriglyceridemia and the related factors in middle-aged adults. Methods. We used data collected from the Provincial Government in Chung-Hsing Village in Taiwan during May 1998. All officers included in the study were between 40 and 64 years old. Totally, 709 volunteers underwent blood tests. To study the significant correlates of hypertrigl yceridemia, the t-test, chi-squared analysis, and multivariate logistic regression were used. Results. Our results showed that the participants included 40% men and 60% women. The mean age was 50.5± 6.8 years. The mean triglyceride values were 1.74± 1.17 mmol/L in the men and 1.43 ± 0.85 mmol/L in the women, respectively (p ＜ 0.000. The proportions of hypertriglyceridemia were 20.1% in the men and 12.7% in the women (p ＜ 0.01). After controlling the other covariates, the multivariate logistic regression analysis showed that the significant related factors of hypertriglyceridemia were abnormal glutamic pyruvic transaminase, hypercholesterolemia, hyperglycemia, and hyperuricemia. Conclusions. Hypertriglyceridemia is more common in middle-aged men than in middle-aged women. It is recommended that serum triglyceride levels should be tested if high serum glutamic pyruvic transaminase value, hypercholesterolemia, hyperglycemia, or hyperuricemia is found in middle-aged adults.
Erosion of the Epigenetic Landscape and Loss of Cellular Identity as a Cause of Aging in Mammals

All living things experience entropy, manifested as a loss of inherited genetic and epigenetic information over time. As budding yeast cells age, epigenetic changes result in a loss of cell identity and sterility, both hallmarks of yeast aging. In mammals, epigenetic information is also lost over time, but what causes it to be lost and whether it is a cause or a consequence of aging is not known. Here we show that the transient induction of genomic instability, in the form of a low number of non-mutagenic DNA breaks, accelerates many of the chromatin and tissue changes seen during aging, including the erosion of the epigenetic landscape, a loss of cellular identity, advancement of the DNA methylation clock and cellular senescence. These data support a model in which a loss of epigenetic information is a cause of aging in mammals. One Sentence Summary The act of repairing DNA breaks induces chromatin reorganization and a loss of cell identity that may contribute to mammalian aging
Effect of foliar application of moringa (Moringa oleifera) leaf extract with recommended fertilizer on growth and yield of okra (Abelmoschus esculentus)

A field experiment was carried out at the Crop farm of Eastern University, Sri Lanka during the period June 2018 to September 2018 to study the effects of different concentrations and frequencies of Moringa (Moringa oleifera) Leaf Extract (MLE) as a foliar application on growth and yield of okra (Abelmoschus esculentus) plants. This experiment was laid out in a Randomized Complete Block Design (RCBD) with three replicates with the following treatments; T0 – control (Distilled water), T1 – 10% MLE at once a week interval, T2 – 10% MLE at once in two weeks interval, T3 – 20% MLE at once a week interval, T4 – 20% MLE at once in two weeks interval, T5 – 30% MLE at once a week interval and T6 – 30% MLE at once in two weeks interval. Foliar application of MLE was initiated at two weeks after germination and each plant is sprayed with 25 ml of MLE and the growth performance was recorded at 4, 6 and 7 WAP. The results showed that foliar application of MLE had a significant (p < 0.05) effects on tested parameters of okra over the control at all growth stages. MLE with 10% of the foliar application at once a week interval increased plant height, number of branches/plant, number of leaves/plant, leaf area index, dry weight of leaves, stems, roots, total biomass, number of pods/ha and dry weight of pods. The results suggest that under the conditions in the experiment, yield could be increased by three-fold using MLE at 10%. The use of Moringa leaf extract as a plant growth booster is inexpensive, environmentally safe and low-cost technology to improve the yields by the small farmers.
Social Games and Genic Selection Drive Mammalian Mating System Evolution and Speciation

Mating system theory based on economics of resource defense has been applied to describe social system diversity across taxa. Such models are generally successful but fail to account for stable mating systems across different environments or shifts in mating system without a change in ecological conditions. We propose an alternative approach to resource defense theory based on frequency-dependent competition among genetically determined alternative behavioral strategies characterizing many social systems (polygyny, monogamy, sneak). We modeled payoffs for competition, neighborhood choice, and paternal care to determine evolutionary transitions among mating systems. Our model predicts four stable outcomes driven by the balance between cooperative and agonistic behaviors: promiscuity (two or three strategies), polygyny, and monogamy. Phylogenetic analysis of 288 rodent species supports assumptions of our model and is consistent with patterns of evolutionarily stable states and mating system transitions. Support for model assumptions include that monogamy and polygyny evolve from promiscuity and that paternal care and monogamy are coadapted in rodents. As predicted by our model, monogamy and polygyny occur in sister taxa among rodents more often than by chance. Transitions to monogamy also favor higher speciation rates in subsequent lineages, relative to polygynous sister lineages. Taken together, our results suggest that genetically based neighborhood choice behavior and paternal care can drive transitions in mating system evolution. While our genic mating system theory could complement resource-based theory, it can explain mating system transitions regardless of resource distribution and provides alternative explanations, such as evolutionary inertia, when resource ecology and mating systems do not match.
Genomic signature of ongoing alkaline adaptation in a Schizothoracine fish (Cyprinidae) inhabiting soda lake on the Tibetan Plateau

Comparative genomics has elucidate the molecular footprints of adaptations to extreme environments at high altitude including hypoxia, but insight into the genomic basis of saline and alkaline adaptation in highland fish has rarely been provided. The increasing of water salinization is a growing threat to Tibetan endemic fish species. Here we performed one of the first comparative genomics studies and began to characterize genomic signature of alkaline adaptation in a Schizothoracine fish inhabiting soda lake on the Tibetan Plateau. We found that expansions of lineage-specific genes associated with ion transport and transmembrane functions, genome-wide elevated rate of molecular evolution in Schizothoracine fishes relative to other lowland teleost fish species. In addition, we found specific changes in the rate of molecular evolution between G. p. kelukehuensis and other teleost fishes for ion transport-related genes. Furthermore, we identified a set of genes associated with ion transport and energy metabolism underwent positive selection. Using tissue-transcriptomics, we found that most REGs and PSGs in G. p. kelukehuensis were broadly expressed across three tissues and significantly enriched for ion transport functions. Finally, we identified a set of ion transport-related genes with evidences for both selection and co-expressed which contributed to alkaline tolerance in G. p. kelukehuensis. Altogether, our study identified putative genomic signature and potential candidate genes contributed to ongoing alkaline adaptation in Schizothoracine fish.
A Novel COL4A5 Splicing Mutation Causes Skipping of Exon 14 in a Chinese Family with Alport Syndrome

Background: Alport syndrome (AS) is an inherited progressive renal disease caused by mutations in COL4A3, COL4A4, and COL4A5. Although mutation screening in the genes responsible for AS is typically performed, only a small proportion of patients receive genetic testing in China, and the functional consequences of multiple splicing variants in AS patients have not been investigated. Methods: A family with X-linked AS was diagnosed based on family history and pathological findings from a kidney biopsy. Targeted next-generation sequencing was used to identify the causative mutation, and a minigene assay was performed to test the influence of the mutation on splicing. Results: A c.834+2T>G in COL4A5 was identified and shown to co-segregate with AS in the family. The variant is located in the canonical splicing site and is predicted to induce aberrant splicing. Minigene assay using HEK 293T cells indicated the skipping of exon 14 in COL4A5. Conclusions: The novel COL4A5 splicing mutation identified in the current study broadened the genetic spectrum of X-linked AS and further deepened our insight of the disease’s molecular mechanism.
Effect of periods of hydro-priming and seed weights on the germination of Vitex doniana sweet seeds

There is paucity of information on breaking the dormancy of Vitex doniana through hydro-priming. Hydropriming is the method of ensuring uniform and high germination percentage, by soaking seeds in water and follow by drying of seeds, while the emergence of radicle is prevented. There is need to determine the appropriate periods of hydropriming to prevent over or under hydro-priming of seeds. In light of this, investigation was conducted on the effect of periods of hydro-priming and seed weights on the germination of V.doniana seeds. To assess the effect of periods of hydropriming (0, 6, 12, 18, 24 and 36hrs) and three seed weights (1.2, 1.4 and 3.3g) on the germination of V.doniana seeds, a split-plot experimental design with five replications was employed. Result revealed that periods of hydropriming significantly (P<0.05) enhanced the germination of V.doniana . A significant germination percentage value of 50% was recorded in seeds hydroprimed for 36hours. Germination percentage of seeds increased with the increasing periods of hydropriming. Highest germination percentage value of 40% was recorded in average seed size of 1.4g A significant germination percentage of 100% was recorded in 1.4g seeds hydro-primed for 36hours. Least mean germination time of 8days was recorded for 1.4 and 3.3g seeds. Hydro-priming of 1.4g for 36hours enhances the germination percentage of V.doniana seeds. The study therefore recommends hydro-primng of 1.4g seeds for 36hours for mass production of its seedlings for agro-forestry systems. Keywords: Dormancy, Soaking and drying of seeds, Pre-sowing treatment, Germination, Agro-forestry species
Re-Examine The Use Of The Student's First Language In The English As A Foreign Language Classrooms: A Cross-Case Analysis From Undergraduate Engineering Students In Bangkok, Thailand

The purpose of this study was to examine how the use of the student‟s first language (L1) by a non-native English-speaking EFL teacher affects the students‟ experiences in learning English compared to those in the classrooms where only English is used as a means of teaching. This study also investigates the role of the teacher in providing comprehensible inputs to her EFL learners. A total of four groups participated in this study (approximately 25 students per group). Two groups were randomly assigned to be taught by using both Thai and English languages while the other two groups were taught with English only. Two qualitative data collection methods employed included focus group interviews and classroom observations. A Comprehensible Inputs Checklist was developed to code the classroom observation data and the results were analyzed using a cross case analysis technique. From the cross-case analysis, it was revealed that the students‟ English competency level and their attitudes toward English played the most important role in the students‟ learning of English. The teacher‟s use and non use of the L1 would have a significant effect only when it came to difficult topics or topics that are not related to the students‟ backgrounds and interests. The results from the checklist showed that the teacher supported and provided „enough‟ comprehensible inputs during her teaching. Surprisingly, instead of benefiting more on the students‟ learning, the use of the L1 was found to help facilitate the teaching of the non-native EFL teacher. Furthermore, classroom atmosphere, as well as students‟ interactions in the participating classrooms, were analyzed and discussed.
Screening of differential expressed genes from gene chip and sequencing data and evaluate its prognostic values in males with digestive system neoplasms

Background Digestive system neoplasm is a common cancer in males worldwide. This study aimed to explore the commonalities in males with digestive system neoplasms (MDSN) and its clinical relevance. Methods A total of 46 differential expressed genes (DEGs) in MDSN were identified shared in TCGA and GEO databases. Results These DEGs significantly affected a variety of cell function and signaling pathways. Of which, a hub of 7 genes (CCNB1, MAD2L1, BUB1, CHEK1, MCM2, CCNA2 and CDC25B) were interacted with each other in protein level and significantly enriched in cell cycle pathway. Further methylation analysis, we found that BUB1, MAD2L1 and MCM2 were hypomethylation via m6A modification. Besides, BUB1, MAD2L1 and MCM2 were co-expressed in mRNA level and up-regulation of them led to worse prognostic in hepatocellular carcinoma, while caused a better prognostic in stomach adenocarcinoma (STAD), and had a race difference between white and Asian people in STAD. Medicine molecules, I-threonine (ID: PA451673) and enzymes (ID: PA164712734) might be efficient medicines in BUB1, MAD2L1 and MCM2 up-regulated MDSN patients. Conclusions Taken together, hypomethylation via m6A modification might cause BUB1, MAD2L1 and MCM2 up-regulation in MDSN. Dysregulation of BUB1, MAD2L1 and MCM2 function as contrast prognostic in liver hepatocellular carcinoma and STAD. Our study provides more accurate therapeutic targets and prognostic biomarkers for specific cancer types.
Variation in host home range decreases rabies vaccination effectiveness by increasing the spatial spread of rabies

Animal movement influences the spatial spread of wildlife infectious diseases through host-host contact structure and hence pathogen transmission. Wildlife disease hosts vary in characteristics related to pathogen transmission, which can increase the spread and intensity of disease outbreaks. The consequences of home range size variation on wildlife disease dynamics are poorly understood, but could help to predict disease spread and determine more effective disease management strategies. We developed a spatially-explicit individual-based model to examine the effect of variation in host home range size on the spatial spread rate, persistence, and incidence of rabies virus (RABV) in raccoons (Procyon lotor). We tested the hypothesis that host home range area variation decreases vaccination effectiveness in wildlife host populations following pathogen invasion into a vaccination zone. We simulated raccoon demography and RABV dynamics across a range of magnitudes and variances in weekly home range radius distributions for raccoons, and compared results to conditions that assumed a fixed host home range area. We examined how variable host home range radius distributions influenced the relative effectiveness of three components of orally-baited raccoon RABV vaccination (ORV) programs—timing and frequency of bait delivery, width of the zone where ORV baits were delivered, and proportion of hosts immunized. Variability in home range radius distributions increased RABV spread rates by 1.2 - 5.2-fold compared to simulations with fixed radii. More variable host home range radius distributions decreased relative vaccination effectiveness by 71% compared to less variable host home range radius distributions under conventional vaccination conditions. We found that vaccination timing was more influential for vaccination effectiveness than vaccination frequency or vaccination zone width. Our results suggest that variation in wildlife home range exploration increases the spatial spread and incidence of wildlife disease. Our vaccination results underscore the importance of prioritizing individual-level space use data collection to understand the dynamics of wildlife diseases and plan their effective control and elimination.
Binding of the motor protein SecA to the bacterial protein translocation channel SecYEG in the absence of ATP

Translocation of many secretory proteins through the bacterial plasma membrane is facilitated by a complex of the protein translocase SecYEG with the motor protein SecA. The ATP-free complex is unstable in detergent, raising the question how SecA may perform several rounds of ATP hydrolysis without being released. Here we show that dual recognition of (i) SecYEG and (ii) acidic lipids in its immediate vicinity confers an apparent nanomolar affinity. As a result the complex between SecA and reconstituted SecYEG may be stable for tens of seconds as visualized by high-speed atomic force microscopy. These long lasting events and complementary shorter ones both give rise to single ion channel openings of equal duration. The existence of two different conformations of the complex was confirmed by luminescence resonance energy transfer. The deep protrusion of SecA’s two-helix finger into the aqueous channel is in line with the power stroke mechanism of translocation.
The complete mitochondrial genome of Aporia crataegi L. (Lepidoptera: Pieridae)

Abstract The complete mitochondrial genome of Aporia crataegi is 15,147 bp long, and consists of 13 protein-coding genes (PCGs), 2 ribosomal RNA genes, 22 transfer RNA (tRNA) genes, and a putative control region (GenBank accession No. MN371463). The nucleotide composition is significantly biased (A, G, C, and T is 39.66%, 7.30%, 11.41%, and 41.63%, respectively) with A + T contents of 81.29%. All PCGs are initiated by ATG, ATT, and ATC codons. Seven PCGs use a common stop codon of TAA, whereas the remaining six terminated with a single T. The phylogenetic relationships based on maximum-likelihood phylogenetic tree method showed that A. crataegi is closely related to Aporia bieti, Mesapia peloria, and Aporia martineti.