Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting comorbid diseases via network endopharmacology

The traditional drug discovery paradigm has shaped around the idea of “one target, one disease”. Recently, it has become clear that not only it is hard to achieve single target specificity but also it is often more desirable to tinker the complex cellular network by targeting multiple proteins, causing a paradigm shift towards polypharmacology (multiple targets, one disease). Given the lack of clear-cut boundaries across disease (endo)phenotypes and genetic heterogeneity across patients, a natural extension to the current polypharmacology paradigm is targeting common biological pathways involved in diseases, giving rise to “endopharmacology” (multiple targets, multiple diseases). In this study, leveraging powerful network medicine tools, we describe a recipe for first, identifying common pathways pertaining to diseases and then, prioritizing drugs that target these pathways towards endopharmacology. We present proximal pathway enrichment analysis (PxEA) that uses the topology information of the network of interactions between disease genes, pathway genes, drug targets and other proteins to rank drugs for their interactome-based proximity to pathways shared across multiple diseases, providing unprecedented drug repurposing opportunities. As a proof of principle, we focus on nine autoimmune disorders and using PxEA, we show that many drugs indicated for these conditions are not necessarily specific to the condition of interest, but rather target the common biological pathways across these diseases. Finally, we provide the high scoring drug repurposing candidates that can target common mechanisms involved in type 2 diabetes and Alzheimer’s disease, two phenotypes that have recently gained attention due to the increased comorbidity among patients.
Estimating variance components in population scale family trees

The rapid digitization of genealogical and medical records enables the assembly of extremely large pedigree records spanning millions of individuals and trillions of pairs of relatives. Such pedigrees provide the opportunity to investigate the sociological and epidemiological history of human populations in scales much larger than previously possible. Linear mixed models (LMMs) are routinely used to analyze extremely large animal and plant pedigrees for the purposes of selective breeding. However, LMMs have not been previously applied to analyze population-scale human family trees. Here, we present Sparse Cholesky factorIzation LMM (Sci-LMM), a modeling framework for studying population-scale family trees that combines techniques from the animal and plant breeding literature and from human genetics literature. The proposed framework can construct a matrix of relationships between trillions of pairs of individuals and fit the corresponding LMM in several hours. We demonstrate the capabilities of Sci-LMM via simulation studies and by estimating the heritability of longevity and of reproductive fitness (quantified via number of children) in a large pedigree spanning millions of individuals and over five centuries of human history. Sci-LMM provides a unified framework for investigating the epidemiological history of human populations via genealogical records.
Langerhans cell histiocytosis : a reactive or neoplastic disease?

Although Langerhans cell histiocytosis (LCH) was first described a century ago, the aetiology is still not understood. Recent studies on the role of cytokines, chemokines, immunologic dysfunction, cell surface antigen expression, clonality and cell cycle regulation have provided new insights into the pathogenesis of LCH. Much of the data from these studies points to the Langerhans cell (LC) being intrinsically abnormal in LCH. Studies have shown that there is a proliferation of clonal LCs in the lesions of LCH. Furthermore, these LCH cells not only have differences in cytoplasmic and surface markers compared to the normal LC but also show abnormalities in cytokine production and antigen presentation. The recent progress in LCH research has provoked much discussion on whether LCH is a reactive disease resulting from environmental triggers, or a neoplastic process. The main goal of this thesis was to gain insight into the immunological and genetic aspects of LCH. We set out to address several previously unanswered questions in LCH, namely, why are the lesional CD1a+ LCs in LCH aberrantly present in many body sites; what is the origin – whether via recruitment or in situ formation – of the many cells characteristic of the lesion composition and finally, the ultimate question of what is the cause behind this disease, a reactive trigger or a neoplastic defect.
Investigation of 2-oxoacid oxidoreductases in Methanococcus maripaludis and large scale growth of M. maripaludis

With the emergence of Methanococcus maripaludis as a genetic model for methanogens, it becomes imperative to devise inexpensive yet effective ways to grow large numbers of cells for protein studies. Chapter 2 details methods that were used to cut costs of growing M. maripaludis in large scale. Also, large scale growth under different conditions was explored in order to find the conditions that yield the most cells. Chapter 3 details the phylogenetic analysis of 2-oxoacid oxidoreductase (OR) homologs from M. maripaludis. ORs are enzymes that catalyze the oxidative decarboxylation of 2-oxoacids to their acyl-CoA derivatives in many prokaryotes. Also in chapter 3, a specific OR homolog in M. maripaludis, an indolepyruvate oxidoreductase (IOR), was mutagenized, and the mutant was characterized. PCR and Southern hybridization analysis showed gene replacement. A no-growth phenotype on media containing aromatic amino acid derivatives was found.
Development of a Novel, Peptide-based Vaccine for Lyme Disease

ii DEDICATION . iii ACKNOWLEDGEMENTS . iv CONTRIBUTORS AND FUNDING SOURCES . vi NOMENCLATURE . viii TABLE OF CONTENTS . x LIST OF FIGURES . xii LIST OF TABLES . xiv CHAPTER
Influence of root growth of two pioneering plant species on soil development during the initial stage of ecosystem genesis in the Lusatian post mining landscape

Boldt, K. , Schneider, B. U. , Fritsch, S. and Hüttl, R. F. 2012. Influence of root growth of two pioneering plant species on soil development during the initial stage of ecosystem genesis in the Lusatian post mining landscape. Can. J. Soil Sci. 92: 67-76. To characterize the role of root growth of Lotus corniculatus L. (bird's-foot trefoil) and Calamagrostis epigeios L. Roth (chee reed grass) in soil development during the initial stage of ecosystem genesis, the root systems of these plant species growing in soils from quaternary calcareous sediments were studied. The spatial distribution pattern of root systems varied considerably. Both plant species contributed to the accumulation of organic carbon in the bulk soil, although the highest concentrations were from the legume L. corniculatus. Total nitrogen concentration in the bulk soil was not affected, but increased in the rhizosphere soil of both plant species. There were clear indications that both plant species contributed to homogenizing phosphorus distribution, resulting in phosphorus depletion of those soil compartments where root proliferation was highest. Pronounced differences were detected between plant species, which led to the conclusion that the homogenizing effect caused by one species on a plot level may be overridden by the heterogeneity of patches composed of different plant species at the ecosystem level. All considered components suggest that the development of root systems of herbaceous pioneer plant species provides significant contributions to land reclamation in a natural way.
Interactions between ectomycorrhizal fungi and chestnut blight (Cryphonectria parasitica) on American chestnut (Castanea dentata) used in coal mine restoration

Plant and fungal interactions drive successional trajectories within reforestation offering both mutualisms (ectomycorrhizal fungi [ECM]) and fungal pathogens. Appalachian forest and mine reclamation projects re-introducing American chestnut and chestnut hybrids will inevitably document the return of chestnut blight, resulting in cankers causing branch dieback and loss of photosynthetic tissue. Similar to herbivory, the loss of photosynthetic tissue may reduce ECM root colonization and cause changes in fungal species composition. To test this, 75 six-year-old established chestnut trees were selected to represent the following: (1) Healthy trees free of chestnut blight; (2) trees with cankers and 50% branch dieback; (3) trees that died prior to the fifth growing season. Each tree had a chestnut seed planted 24 cm from the base. ECM colonization of both the established parent trees (n = 50) and five-month-old seedlings (n = 64) were quantified and genera determined by fungal DNA sequencing of the internal transcribed (ITS) region. Healthier seven-year-old chestnuts trees had significantly more ECM roots than those trees infected with chestnut blight cankers. However, disease die-back on chestnut did not have an influence on community composition among the parent trees or the neighboring five month seedlings. Results also demonstrated that five-month-old seedlings neighboring healthy parent trees had greater ECM on roots (P = 0.002), were larger in size (P = 0.04), and had greater survival (P = 0.01). ECM genera such as Cortinarius, Russula and Scleroderma provided tree to seedling inoculation. ECM colonization by Cortinarius spp. resulted in larger chestnut plants and increased nitrogen foliar concentrations on the five month seedlings. It can be hypothesized that blight will aid in diversifying forest stand composition and these early ECM networks will help facilitate the survival of other native hardwoods that recruit into these sites over time.
Roles of the Mother Centriole Appendage Protein Cenexin in Microtubule Organization during Cell Migration and Cell Division: A Dissertation

Epithelial cells are necessary building blocks of the organs they line. Their apicalbasolateral polarity, characterized by an asymmetric distribution of cell components along their apical-basal axis, is a requirement for normal organ function. Although the centrosome, also known as the microtubule organizing center, is important in establishing cell polarity the mechanisms through which it achieves this remain unclear. It has been suggested that the centrosome influences cell polarity through microtubule cytoskeleton organization and endosome trafficking. In the first chapter of this thesis, I summarize the current understanding of the mechanisms regulating cell polarity and review evidence for the role of centrosomes in this process. In the second chapter, I examine the roles of the mother centriole appendages in cell polarity during cell migration and cell division. Interestingly, the subdistal appendages, but not the distal appendages, are essential in both processes, a role they achieve through organizing centrosomal microtubules. Depletion of subdistal appendages disrupts microtubule organization at the centrosome and hence, affects microtubule stability. These microtubule defects affect centrosome reorientation and spindle orientation during cell migration and division, respectively. In addition, depletion of subdistal appendages affects the localization and dynamics of apical polarity proteins in relation to microtubule stability and endosome recycling. Taken together, our results suggest the mother centriole subdistal appendages play an essential role in regulating cell polarity. A discussion of the significance of these results is included in chapter three.
Responses of growing‐season soil respiration to water and nitrogen addition as affected by grazing intensity

1. Most grasslands in the world, including the semi-arid steppe in China, are threat ened by nitrogen deposition, precipitation change and livestock grazing, which greatly affect soil carbon processes (e.g. soil respiration). Although the individual effects of nitrogen deposition and precipitation change on soil respiration are well understood, how their effects on soil respiration are altered by different grazing intensities is unclear. 2. To determine how the effects of nitrogen deposition and precipitation change on soil respiration are affected by grazing intensity, we conducted an experiment in a semi-arid steppe involving areas that experienced 10 years of no, light, moderate or heavy grazing. These areas were treated with water addition (110 mm, 30% of the mean annual precipitation) and nitrogen addition (10.5 g m −2 year −1 ).
Thiol-stabilized atomically precise, superatomic silver nanoparticles for catalysing cycloisomerization of alkynyl amines

Both the electronic and surface structures of metal nanomaterials play critical roles in determining their chemical properties. However, the non-molecular nature of conventional nanoparticles makes it extremely challenging to understand the molecular mechanism behind many of their unique electronic and surface properties. In this work, we report the synthesis, molecular and electronic structures of an atomically precise nanoparticle, [Ag 206 L 72 ] q (L = thiolate, halide; q = charge). With a four-shell Ag 7 @Ag 32 @Ag 77 @Ag 90 Ino-decahedral structure having a nearly perfect D 5h symmetry, the metal core of the nanoparticle is co-stabilized by 68 thiolate and 4 halide ligands. Both electrochemistry and plasmonic absorption reveal the metallic nature of the nanoparticles, which is explained by density functional theory calculations. Electronically, the nanoparticle can be considered as a superatom, just short of a major electron shell closing of 138 electrons ( q = -4). More importantly, many of ligands capping on the nanoparticle are labile due to their low-coordination modes, leading to high surface reactivity for catalysing the synthesis of indoles from 2-ethynylaniline derivatives. The results exemplify the power of the atomic-precision nanocluster approach to catalysis in probing reaction mechanisms and in revealing the interplay of heterogeneous reactivities, electronic and surface structural dynamics, thereby providing ways for optimization.
Recruitment drives successional changes in the community‐level leaf mass per area in a winter‐deciduous broad‐leaf forest

Areas of oldgrowth forest are decreasing due to logging and changes in human land use, while secondary forests are increasing due to wood harvesting, cropland and pastureland abandonment, and reforestation efforts (Hurtt et al., 2006; Yang, Richardson, & Jain, 2010). Therefore, secondary forests are important for maintaining the multiple functions of forest ecosystems. Without anthropogenic management, secondary forests will keep growing, and succession will progress. How species and communities respond to Received: 22 February 2018 | Revised: 23 May 2018 | Accepted: 24 May 2018 DOI: 10.1111/jvs.12660
Recruitment of occipital cortex by arithmetic processing follows computational bias in early blind

Arithmetic reasoning activates the occipital cortex of early blind people (EB). This activation of visual areas may reflect functional flexibility or the intrinsic computational role of specific occipital regions. We contrasted these competing hypotheses by characterizing the brain activity of EB and sighted participants while performing subtraction, multiplication and a control verbal task. In both groups, subtraction selectively activated a bilateral dorsal network commonly activated during spatial processing. Multiplication triggered more activity in temporal regions thought to participate in memory retrieval. No between-group difference was observed for the multiplication task whereas subtraction induced enhanced activity in the right dorsal occipital cortex of the blind individuals only. As this area overlaps and exhibits increased functional connectivity with regions showing selective tuning to auditory spatial processing, our results suggest that the recruitment of occipital regions during high-level cognition in the blind actually relates to the intrinsic computational role of the reorganized regions.
Earthworm avoidance behavior to antimicrobial sulfadiazine on tropical artificial soil

Veterinary pharmaceuticals can reach the soil via animal excretions and cause impacts on aquatic and terrestrial ecosystems. In this work, we employed a standardized avoidance behavior test to assess the sublethal effects of antimicrobial sulfadiazine on the earthworm Eisenia andrei. Cultivation of red worms was based on an alternative substrate made of mostly household vegetable wastes and dry leaves. The bioassays were performed with tropical artificial soil spiked with the tests substance at five different concentrations ranging from 0.01 to 100 mg sulfadiazine kg-1. The outcome resulted in avoidance response of 30% (maximum) and a nonlinear concentration-response curve, differing from classical pollutant responses and correlating with those asymmetric responses over the environment caused by some rare xenobiotics. Avoidance tests were validated with reference substance, resulting in an EC50-48h of 819 mg boric acid kg-1 (628-1066 mg boric acid kg-1 95% confidence interval). We concluded that the avoidance test with E. andrei is useful as a standardized tool for a rapid ecotoxicological screening of soil.
Hybrid necroptosis inhibitors

The present invention, heterocyclic compounds (e.g., compounds were Formula (I)) and to their pharmaceutically acceptable salts. The present invention relates to pharmaceutical compositions comprising these compounds, and necroptosis also their use in therapy for treatment of a condition where there is substantial potential role characterized. Heterocyclic compounds described herein, can be realized improvements in activity and selectivity to RIP1 and / or RIP 3. [Formula 1] . BACKGROUND
Identification and characterisation of new potential antigens involved in GAP-mediated immunity

Stage-specific sterile protection against malaria can be achieved in rodents and human volunteers by administration of Plasmodium parasites that attenuate during liver-stage development by either radiation (RAS) or genetic modification (GAP). In this study we focussed on the identification and characterisation of potential antigens involved in GAP-mediated immunity. We identified within this study novel potential antigens involved in GAP-mediated immunity. We compared the transcript repertoire expressed of Plasmodium liver-stage parasites from GAP and RAS versus wild-type in an attempt to detect antigens that are uniquely or differentially expressed in GAP. One of the most abundant transcript up-regulated in RAS and GAP coded for a P. berghei C2-containing protein (C2CP). C2 domains are generally involved in Ca2+-sensing and -signalling and characteristic domains of the ferlin protein family. Database search revealed beside the Pb C2CP one annotated Pb ferlin (FER) and a ferlin-like protein (FLP). The cellular functions of Plasmodial ferlins, however, are unknown. We therefore also aimed at the cellbiological characterisation of the identified protein family. Targeted gene disruption experiments revealed an essential role of Pb C2CP and Pb FER during blood-stage development. The main objective of this study, however, focussed on the investigation of the antigenic potential of this novel pre-erythrocytic antigen. Interestingly epitope prediction identified several high-binding Pb C2CP-specific H2b-restricted CD8+ T-cell epitopes. Indeed, we could show that Pb C2CP-specific cells are recognised and lysed in immunised C57BL/6 mice. Moreover, we were able to specifically restimulate T cells in the livers of immunised animals with the Pb C2CP-derived peptide T9L. Altogether, both the dissection of novel antigens from the protection-inducing attenuated parasites and the immunogenic capacity as shown by a selected critical target antigen Pb C2CP for the first time allows specific restimulation of T cells in the experimental GAP vaccination model. Therefore this work clears the way for studying effector mechanisms underlying GAP-induced immunity. This work is of fundamental importance to understanding the mechanisms of pre-erythrocytic immunity to malaria and may further pave the way for the composition of an anti-infective multi-component subunit malarial vaccine.
Effect of two drying methods on antioxidant activity and hypoglycemic action of polysaccharides in three cultivars of lychee pulp

ABSTRACT Effect of air drying and freeze drying on polysaccharides of lychee with three cultivars was determined in terms of polysaccharides yield, antioxidant capacity and hypoglycemic action. The results show that Guiwei lychee pulp had the highest crude polysaccharide yield among three lychees. However, Feizixiao lychee had the lowest EC50 concentration and the highest FRAP (Ferric reducing antioxidant power) value. Moreover, Guiwei lychees dried by air drying had the best effect for improving glucose tolerance of normal mice and diabetic mice. Three freeze dried lychees had no significant effect. The effect of air dried Guiwei samples on decreasing TG was the best and it was even better than dapagliflozin group. Only freeze-dried Guiwei lychee could significant decrease the TC content in blood among all lychee samples. In a word, Feizixiao lychees had the best antioxidant capacity and Guiwei lychees had the best hypoglycemic effect. Air drying was better drying method for lychee polysaccharides than freeze drying in this study.
Weed Management, Folic Acid and Seaweed Extract Effects on Faba Bean Plants and Associated Weeds under Sandy Soil Conditions

Two field experiments were conducted during the winter seasons of 2014/2015 and 2015/2016 at the agricultural experimental station of the National Research Centre, Nubaria, Egypt. Field evaluation of the efficiency of weed-control treatments (unweeded, oxadiargyl, metribuzin and two hand hoeing) and bio-stimulants levels (folic acid at the rate of 10, 20 and 30 mg/L, and seaweed extract 100, 200 and 300 mg/L) and their interactive effects on faba bean growth, yield, yield attributes and chemical composition of seeds. Two hand hoeing achieved the highest weed depression expressed in the lowest dry matter of broadleaved, narrow-leaved and total weeds. Also, two hand hoeing was the most superior treatment in increasing plant height, shoot dry weight, leaf area index and SPAD value at 60 and 90 days from sowing as well as yield, yield attributes and chemical composition of faba bean seeds followed by that of oxadiargyl and metribuzin treatments. Folic acid at the rate of 30 mg L -1 or seaweed extract at the rate of 300 mg L -1 enhanced growth, yield and chemical composition of faba bean seeds. Two hand hoeing or oxadiargyl herbicide integrated with folic acid at the rate of 30 mg L -1 or seaweed extract at the rate of 300 mg L -1 application produced the maximum values of leaf area index, seed yield and total carbohydrate percentage. It could be concluded that two hand hoeing or herbicide oxadiargyl combined with folic acid application up to 30 mg L -1 or seaweed extract at the rate of 300 mg L -1 could effectively improve growth and productivity of faba bean under sandy soil conditions.
Otolith increments in European plaice (Pleuronectes platessa) reveal temperature and density-dependent effects on growth

Otolith increments in European plaice (Pleuronectes platessa) reveal temperature and density-dependent effects on growth Peter van der Sleen*, Christoph Stransky, John R. Morrongiello, Holger Haslob, Melita Peharda, and Bryan A. Black Marine Science Institute, University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX 78373, USA Department of Wetland Ecology, Karlsruhe Institute of Technology, Josefstrasse 1, Rastatt 76437, Germany Thünen Institute of Sea Fisheries, Palmaille 9, Hamburg 22767, Germany School of BioSciences, University of Melbourne, Parkville, VIC 3010, Australia Institute of Oceanography and Fisheries, Setali ste Ivana Me strovi ca 63, Split 21000, Croatia *Corresponding author: tel: þ49 7222 3807-11; e-mail: j.p.vandersleen@gmail.com.