Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacogenomics of Primary Blood Cancer Cells

Current developments of multi-omics technologies greatly accelerate advancements in the field of cancer research. They not only allow us to unravel the complex biology of tumors, but are also a huge step towards precision oncology, where a personalized treatment is proposed based on the tumor’s unique combination of molecular features. Heterogeneity present both within a single tumor and between patients with the same disease pose serious challenges to treatment success and trial design, as many factors influencing drug response in cancer remain unknown. The work presented here investigated the diversity of drug response profiles and their associations with the underlying molecular features of 273 primary cancer samples. The analysis combined data from high-throughput drug profiling of 90 compounds with multi-omics comprising exome sequencing, RNA sequencing and methylation profiling. The analysis of various hematological malignancies uncovered a rich landscape of phenotype genotype relationships. Targeted inhibition of, for example, CHK, SERCA, BCL2 and survivin revealed disease-specific pathway dependencies within B- and T-cell lymphomas. Moreover, the observed similarity of drug response profiles identified unexpected activity of compounds including CHK inhibitors, which implied to act through B-cell receptor (BCR) signaling pathway. By focusing specifically on chronic lymphocytic leukemia, dissection of the molecular fundamentals of known biomarkers was possible. Drug response measured ex vivo confirmed the biological relevance of major predictors of patient clinical outcome: the sensitivity of IGHV unmutated samples to BCR inhibition and the resistance of TP53 mutated samples to chemotherapy and nutlin-3. Susceptibility of trisomy 12 cases to SYK, BTK, PI3K and MEK inhibitors suggested a mode of action through amplification of BCR pathway signaling. Additionally, the study proposed possible targeting options for recurrently mutated genes, such as BRAF, CREBBP and PRPF8. Multivariate analysis estimated the contributions of mutations, RNA expression and DNA methylation to our power to predict drug response. Finally, drug response was shown to be valuable and frequently superior to established biomarkers in predicting patient clinical endpoints. In summary, the combination of viability screening with multi-omics profiling is a powerful tool for studying disregulated signaling pathways in cells. Ex vivo drug profiling performed on primary cancer samples has proved to be a proxy of true biology. Together with faithful reproducibility of measurements this shows great promise in directly advancing precision oncology.
Coordinated morphogenesis through tension-induced planar polarity

Tissues from different developmental origins must interact to achieve coordinated morphogenesis at the level of a whole organism. C. elegans embryonic elongation is controlled by actomyosin dynamics which trigger cell shape changes in the epidermis and by muscle contractions, but how the two processes are coordinated is not known. We found that a tissue-wide tension generated by muscle contractions and relayed by tendon-like hemidesmosomes in the dorso-ventral epidermis is required to establish a planar polarity of the apical PAR module in the lateral epidermis. This planar polarized PAR module then controls actin planar organization, thus determining the orientation of cell shape changes and the elongation axis of the whole embryo. This trans-tissular mechanotransduction pathway thus contributes to coordinate the morphogenesis of three embryonic tissues.
Inhibition of PPAR Gamma, Adipogenesis, and Insulin Sensitivity by MAGED1

Adipocytes serve as critical integrators of energy balance and glucose homeostasis by storing excess energy to prevent ectopic fat accumulation in non-adipose tissues and by secreting various adipokines to modulate whole-body metabolism. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipogenesis and a target of the thiazolidinedione (TZD) class of antidiabetic drugs; therefore, identifying novel regulators of PPARγ action in adipocytes is essential for the future development of therapeutics for diabetes. MAGE Family Member D1 (MAGED1), by acting as an adaptor for ubiquitin-dependent degradation pathways and a co-factor for transcription, plays an important role in neural development, cell differentiation, and circadian rhythm. Here, we showed that MAGED1 expression was downregulated during adipogenesis and MAGED1 inhibited preadipocyte proliferation and adipogenesis in vitro. Mechanistically, MAGED1 bound to PPARγ and suppressed the stability and transcriptional activity of PPARγ. Compared to wild type littermates, MAGED1-deficient mice showed increased levels of PPARγ protein and its target genes, more CD29+CD34+Sca-1+ adipocyte precursors, and hyperplasia of white adipose tissues (WATs) at young ages. Moreover, MAGED1-deficient mice developed late-onset obesity as a result of decreased energy expenditure and physical activity. However, these mice were metabolically healthy as shown by improved glucose clearance and insulin sensitivity. Lipid profiling showed that obesity in MAGED1 knockout (KO) mice did not cause increased levels of serum lipids. On the other hand, expression and secretion of adipokines such as leptin and adiponectin were upregulated in KO mice. Taken together, our data identify MAGED1 as a novel negative regulator of PPARγ activity, adipogenesis, and insulin sensitivity in mice. MAGED1 might therefore serve as a novel pharmaceutical target to treat obesity-associated insulin resistance. Disclosure Q. Wang: None. J. Tang: None. X. Gao: None. H. Ruan: None.
Erythrocytes’ Microrheological Features of Piglets during the Phase of Dairy-vegetable Nutrition after Damage or Common Supercooling

Notwithstanding the great successes of biology and veterinary science, possible changes of cytoarchitecture and erythrocytes’ aggregation in piglets during the phase of dairy-vegetable nutrition after unfavorable environmental impacts haven’t been studied yet. The aim of the research: to find out peculiarities of erythrocytes’ microrheological features in piglets during the phase of dairy-vegetable nutrition after damage or common supercooling. We observed piglets during the phase of dairy-vegetable nutrition after casual unfavorable environmental impact: 28 animals with arthritis after some joint damage and 23 piglets with bronchitis after common supercooling. Control group was composed of 39 healthy piglets of the same age. We estimated the activity of lipids’ peroxidation, indices of plasma and erythrocytes’ antioxidant protection, condition of cytoarchitecture and erythrocytes’ aggregation. Statistical processing was conducted by Student’s t-criterion. We found similar intensity increase of lipids’ peroxidation in blood plasma and erythrocytes of observed piglets after unfavorable impacts (about 66.7% for arthritis and about 68.9% for bronchitis) against the background of comparable weakening of their antioxidant protectability (in both groups for catalase on approximately 25.0%, for superoxide dismutase on approximately 11.0%). There was quantity increase of erythrocytes’ changed forms (reversibly changed forms on approximately 50.0%, irreversibly changed forms approximately in 2 times) in these piglets and strengthening of their spontaneous aggregation (number increase of erythrocytes’ aggregates in blood of animals in both states on more than 20.0%). In our research it was shown that piglets during the phase of dairy-vegetable nutrition after negative environmental impacts experienced worsening of erythrocytes’ microrheological features. Its evidence didn’t depend on the character of the influencing factor.
The Major Transitions in Evolution

List of Tables Preface 1. Introduction 2. What is Life? 3. Chemical evolution 4. The evolution of templates 5. The chicken and egg problem 6. The origin of translation and the genetic code 7. The origin of protocells 8. The origin of eukaryotes 9. The origin of sex and the nature of species 10. Intragenomic conflict 11. Symbiosis 12. Development in simple organisms 13. Gene regulation and cell heredity 14. The development of spatial patterns 15. Development and evolution 16. The origins of societies 17. The origins of language References Index
Structural plasticity of CENP-A regulated by H4 influences cellular levels and kinetochore assembly

The Histone variant CENP-ACse4 is a core component of the specialized nucleosome at the centromere in budding yeast. The level of Cse4 in cells is tightly regulated, primarily by ubiquitin-mediated proteolysis. However, the structural transitions in Cse4 that regulate centromere localization and interaction with regulatory components are poorly understood. Using time resolved fluorescence, NMR and molecular dynamics we show for the first time that soluble Cse4 can exist in a ‘closed’ conformation, inaccessible to various regulatory components. We further determined that binding of its obligate partner H4, alters the inter-domain interaction within Cse4, ensuring an ‘open’ state that will lend itself to proteolysis. This dynamic model allows kinetochore formation only in presence of H4, as the N-terminus, which is required for interaction with centromeric components will be unavailable in absence of H4. The specific requirement of H4 binding for the conformational regulation of Cse4 suggests a unique structure-based regulatory mechanism for Cse4 localization and prevention of premature kinetochore assembly.
Predation of common wall lizards: experiences from a study using scentless plasticine lizards

The potential influence of predators on lacertid lizards has been studied by using models made of plasticine which shows the attack marks of predators and as such allows their identification and estimation of predation pressure. The general aim was to study predation on plasticine models of lizards and to improve methods, since the results depend on the number of plasticine models used, their spatial pattern and the duration of experiments. We estimated the density of the common wall lizard Podarcis muralis population on stone walls of a vineyard in the city of Pecs (Hungary) in August 2015 in order to imitate the real density in our experiment with plasticine models. The density of common wall lizards was 8.2 ind. /100 m 2 and accordingly we placed 25 scentless plasticine lizards on the stone walls on the first transect with 10 m distance between them, which imitates the real pattern. In the second transect 25 lizard models were placed more sparsely, the distance between them being 20 m. During four weeks the predation rate was 24% in densely spaced plasticine lizards and 40% in sparsely spaced plasticine lizards, but the difference was not significant. The daily survival rate of densely spaced lizards was 0.99 (=99.1%) and that of sparsely spaced lizard models was 0.98 (=98.25%), but this difference was not significant either. On the basis of marks left on plasticine lizards, mammal predators (e.g. beech marten) dominated, while the impact of bird predators was smaller than expected. Predators attacked the head of plasticine lizards more frequently than their trunk, tail or limbs, but a significant preference of body parts was not detected. From our experience it is important to study the distribution and density of real animals, to imitate their real pattern, instead of an arbitrarily designed experiment with models. The typical scent of plasticine also could influence the results, which can be avoided by using scentless plasticine models coated with liquid rubber. We suggest the calculation of daily survival rates in order to produce results that allow the comparison of different studies.
Antimicrobial activity of extracts from exotic fruits and vegetables

Novel sources of antimicrobial agents need to be identified to address the looming crisis of antimicrobial resistance. The overall goal of the described experiments was to determine whether extracts of exotic vegetables, mushrooms, and herbs have antimicrobial properties. Vegetable and herbal extracts were purchased from online supplier. Fresh vegetable roots and mushrooms were run through a commercially available juicer to obtain aqueous extracts. Extracts were spotted onto filter paper disks and activity assessed by measuring the zone of inhibition for both E. coli K-12 and B. subtilis as representative Gram-negative and Gram-positive organisms, respectively. Synergy testing was also performed by placing disks spotted with extracts in close proximity to one another. Amongst commercial extracts, prominent Gram-positive activity was found for Echinacea, grapefruit seed, olive leaf, and golden seal extracts; and prominent mixed Gram-negative and Gram-positive activity was found for clove extract. Amongst fresh vegetable and mushroom juicing extracts, Gram-positive activity was detected for celery root.
Chapter 8:Biological Lignin Degradation

In nature, white-rot fungi and some bacteria secrete powerful oxidative enzymes such as peroxidases and laccases to break down lignin and lignin products. These enzymes, together with different chemical mediators, form a chemo-enzymatic system for delignifying biomass so that the microbes can gain access to the polysaccharides. Ligninolytic oxidoreductases have been widely studied in terms of their unique reaction mechanisms and industrial applicability (largely related to production and stability issues). In the context of an integrated biorefinery, both ligninolytic organisms and ligninolytic enzymes may have a role to play for delignification and lignin valorization. This chapter reviews microbial degradation of lignin from an enzymatic perspective, discusses the recent discoveries and advances in a global context including genomic and structure/function information, and provides a perspective on the potential for its utilization in different green chemistry transformations.
Interindividual variability in HRV reactivity: autonomic flexibility or regression to the mean?

Objective There is now a substantial body of evidence linking the baseline level of heart rate variability (HRV) with the magnitude of stress-induced reduction in respiratory sinus arrhythmia. However, it remains to be proved to what extent these interindividual differences in stress responses may be attributed to the statistical phenomenon of regression to the mean (RTM). We sought to test the hypothesis that the statistical artifact RTM explains part of the baseline effect. Approach Heart rate recording was carried out in 1,156 volunteers. To obtain an estimate of the stress response, 148 persons were randomly selected. Participants were monitored on a rest day and just before an academic examination for state anxiety and HRV. Participants were divided into quartiles according to baseline HRV levels and were compared for response to academic stress. Main results We observed a significant reduction in HRV in subjects with a high baseline HRV (> 75th percentile), while a significant increase was found in the group with low baseline HRV. Regression analysis demonstrated that the value of baseline HRV correlated with the magnitude of stress reaction consistent with the RTM model. Baseline-adjusted ANCOVA does not reveal significant intergroup differences in the changes in heart rate (HR) and HRV from rest to exam. RTM-adjusted estimates confirmed an exam effect for HR and HRV. Significance The results of our study strongly support RTM as the source of variability of stress-related changes in HRV.
The giant cryptic amphipod species of the subterranean genus Niphargus (Crustacea, Amphipoda)

Amphipods from the genus Niphargus represent an important part of the Western Palearctic subterranean fauna. The genus is morphologically diverse, comprising several distinct ecomorphs bound to microhabitats in the subterranean environment. The most impressive among them are “lake giants,” a series of massive, large‐bodied species. These range from morphologically distinct to morphologically cryptic taxa. We analysed the taxonomic structure of the Niphargus arbiter–Niphargus salonitanus species complex, belonging to “lake giants” from the Dinaric Karst (West Balkans), and assessed their phylogenetic, morphological and ecological diversity. Multilocus phylogeny suggested that the complex is monophyletic and nested within other cave lake ecomorphs. Unilocus and multilocus coalescence species delimitations indicated that the complex totals nine species. These species substantially overlap in morphology and cannot be unambiguously told apart without the use of molecular markers. An analysis of splitting events within a palaeogeological context, and modelling of environmental characteristics on the phylogeny unveiled a complex history of diversification. Part of this diversification might have been influenced by ecological divergence along the altitudinal gradient reaching from the Adriatic coast to inland Dinaric mountain chains and Poljes. Other splits coincide with the marine regression–transgression cycles during Pliocene. We describe Niphargus alpheus sp. n. , Niphargus anchialinus sp. n. , Niphargus antipodes sp. n. , Niphargus arethusa sp. n. , Niphargus doli sp. n. , Niphargus fjakae sp. n. and Niphargus pincinovae sp. n. , and by doing so hope to prompt their further research.
Physiological Analysis of Desulfovibrio vulgaris Hildenborough Under Conditions Relevant to the Subsurface Environment: Carbon and Energy Limitation and Biofilm Formation

Physiological Analysis of Desulfovibrio vulgaris Hildenborough Under Conditions Relevant to the Subsurface Environment: Carbon and Energy Limitation and Biofilm Formation By Melinda Erin Clark Desulfovibrio vulgaris Hildenborough is a member of the sulfate-reducing bacteria (SRB) and is considered a model microorganism. SRB are beneficial because of their potential for bioremediation applications and detrimental due to their ability to corrode metals. Therefore, not only is it important to understand the metabolic capacity of SRB but also understand the mechanisms of survival and the physiology of SRB as they thrive in the subsurface. In order to elucidate the metabolic capacity and survival of SRB, one organism was analyzed under conditions relevant to the subsurface environment. In this study, D. vulgaris was analyzed under two environmentally relevant conditions, carbon and energy limitation and biofilm growth. D. vulgaris was studied throughout growth and into stasis by transcriptomic analysis which provided the responses this organism has during electron and carbon depletion. This resulted in increased expression of iron acquisition systems, phage genes, carbon starvation genes, and transcripts involved with cell division and growth. The expression of genes involved with translation, ATP synthesis, and substrate transport was reduced. Since fluxes in carbon and energy sources are common within the subsurface, responses such as these should be considered when examining ways to stimulate or hinder D. vulgaris growth. Biofilms developed by D. vulgaris were analyzed in terms of content as well as physiology. Biofilms formed upon glass slides within a defined medium by D. vulgaris were dependent upon proteins for biofilm formation and stability and did not have an extensive exopolysaccharide matrix. Flagella also appear to play an important role in biofilm formation and stabilization and a knock-out mutant made in a particular flagellin was biofilm deficient even though the cells remained motile. Physiologically, the biofilm appeared to utilize carbon and energy sources differently, had increased iron sequestration systems and stress responses, and may be nitrogen-limited. Cells within the biofilm were active, with metabolic rates similar to those of exponential phase cells. These results indicate that biofilm cells are responding to their environment and actively maintaining cell integrity. Overall, our results contribute to the understanding of D. vulgaris survival within the subsurface and provide a basis for other physiological studies. Physiological Analysis of Desulfovibrio vulgaris Hildenborough Under Conditions Relevant to the Subsurface Environment: Carbon and Energy Limitation and Biofilm Formation
Recherches morphologiques et expérimentales sur le Trichomonas felis Da Cunha et Muniz, 1922, parasite du chat et du chien

Au cours d’études sur l’immunité dans les infections à protozoaires et en particulier dans celles provoquées par les coccidies du chat, j ’ai eu l'occasion de rencontrer, à deux reprises, chez des animaux âgés respectivement de trois et de deux mois environ (N° 374, VII) et (402, VII) le Trichomonas felis d’Aristides Marques da Cunha et Julio Muniz de l’Institut Oswaldo Cruz. Ce flagellé n’a été signalé qu’une seule fois jusqu’à ce jour, en 1922, dans le gros intestin d’un chat du Brésil, malade et atteint de diarrhée, autopsié par les deux auteurs précités. Le contenu intestinal montrait de nombreux Trichomonas (1), souvent en voie de division simple ou multiple, parfois phagocytés par des leucocytes (2). Ces auteurs n’ont malheureusement pu faire de bonnes prépara­ tions colorées des parasites intestinaux Vus par jeux à l’état frais et leur description est basée sur des préparations de Trichomonas de cultures obtenues sur divers milieux. Le Trichomonas du chat doit être rare, ce qui tient probablement à la brièveté des infections qu’il produit parfois, comme nous le verrons plus loin (chat 389). Personne (3), parmi les nombreux auteurs ayant étudié le contenu intestinal des chats au cours de la dysenterie amibienne expérimentale, n’avait signalé sa présence avant A. -M. da Cunha et J. Muniz. Personnellement je ne l’avais