Miracle-dz/UniFAR-FTUs huggingface dataset:
Role of Tripeptidyl peptidase II in cell cycle regulation and tumor progression

page 5 ABREVIATIONS 6 PUBLICATIONS AND MANUSCRIPTS 8 1. GENERAL INTRODUCTION 9 1.1 The ubiquitinproteasome system (UPS) 9 1.2 The Epstein-Barr virus 11 1.3 The Burkitt’s lymphoma 12 1.4 The c-myc proto-oncogene 13 1.5 Tripeptidyl peptidase II 15 2. THE CELL CYCLE 17 2.1 The cell cycle phases 17 2.2 Regulation of the cell cycle 17 2.2.1 Cdks and cyclins 17 2.2.2 The UPS in cell cycle regulation 19 2.3 Cell cycle checkpoints 20 2.3.1 The spindle assembly checkpoint 21 2.3.2 The mitotic catastrophe 22 3. APOPTOSIS 23 3.1 General apoptotic pathways 23 3.2 The caspases 23 3.3 The intrinsic pathway of apoptosis 23 3.3.1 The Bcl-2 family 24 3.4 The inhibitors of apoptosis (IAPs) 24 3.5 Apoptosis and cancer 25 4. THE CENTROSOME 26 4.1 The centrosome structure and function 26 4.2 The centrosome cycle 27 4.3 Centrosome defects and genetic instability 29 5. THE GOLGI APPARATUS 30 5.1 The Golgi structure and function 30 5.2 The Golgi apparatus and cell cycle 31 5.3 The Golgi interactions with the cytoskeleton 32 6. AIMS OF THE THESIS 33 7. RESULTS AND DISCUSSION 34 7.1 Paper I 34 7.2 Paper II 36 7.3 Paper III 38 8. FUTURE PERSPECTIVES 42 9. CONCLUDING REMARKS 42 10. ACKNOWLEDGMENTS 43 REFERENCES 44
Chloroplast DNA phylogeography of Alnus glutinosa (L.) Gaertn.

Traditionally, information on the postglacial history of plant species has been gained from the analysis of fossil pollen data. More recently, surveys of present patterns of genetic variation have given valuable insights into species phylogeography. The genus Alnus, based on fossil data, is known to have had at least four glacial refugia. A survey of chloroplast DNA (cpDNA) diversity in populations of black alder (A. glutinosa) was undertaken in order to gain more insight into its postglacial history. This revealed a high degree of structuring of 13 cpDNA haplotypes on a European scale which indicated that most of northern and central Europe was colonized from a refuge in the Carpathian Mountains. Based on the distribution of two common cpDNA haplotypes, colonization routes from this refuge can be determined. The locations of other previously identified refugia are confirmed and two formerly unconfirmed refugial areas for alder (southern Spain and Turkey) are proposed.
Phylogenetic Relationships of the Shafted Bonefish Albula Nemoptera (Albuliformes: Albulidae) from the Eastern Pacific Based on Cytochrome B Sequence Analyses

Abstract Nucleotide and amino acid sequence data from a 544-bp segment of the mitochondrial cytochrome B (Cytb) gene were used to examine phylogenetic relationships of the Shafted Bonefish, Albula ( = Dixonina) nemoptera, a morphologically distinct bonefish limited to the coastal waters of the eastern Pacific and western Atlantic, among members of the widely distributed and cryptic A. vulpes species complex of Albula (Albuliformes: Albulidae). Phylogenetic trees based on Bayesian and parsimony methods indicated that A. nemoptera from the tropical eastern Pacific (Colima, México) nested within the A. vulpes complex, supporting the placement of the genus Dixonina Fowler, 1911 into the synonymy of Albula Scopoli, 1777. Phylogenetic analyses also showed that A. nemoptera is the sister taxon to the undescribed Albula sp. E from the western Atlantic (Bahia, Brazil), previously placed in the A. vulpes complex. This evidence, together with the presence of a diagnostic amino acid substitution in the translated Cytb segment in both species, suggested that Albula sp. E, identified solely from molecular data with no adult voucher available, should be provisionally assigned to A. nemoptera. Secuencias de nucleótidos y aminoácidos que provinieron de un segmento de 544 bp del gen citocromo B (Cytb) de las mitocondrias fueron utilizadas para analizar las relaciones filogenéticas del macabí de hebra Albula ( = Dixonina) nemoptera, un macabí morfológicamente distinto que habita las aguas costeras del océano Pacifico Oriental y el Atlántico Occidental, con las especies crípticas del complejo A. vulpes del género Albula (Albuliformes: Albulidae) que tienen una amplia distribución. Dos clases de árboles filogenéticos estaban de acuerdo y demostraron que el A. nemoptera del Pacifico Oriental Tropical (Colima, México) se agruparon con las especies del complejo A. vulpes, apoyando la conclusión de que el género Dixonina Fowler, 1911 debería ser considerado un sinónimo del género Albula Scopoli, 1777. Los análisis filogenéticos también demostraron que la especie hermana a la A. nemoptera es la especie no identificada Albula sp. E del Atlántico Occidental (Bahía, Brasil) que previamente fue colocada en el complejo A. vulpes. Esta evidencia, así como la presencia de una sustitución diagnóstica de un aminoácido en la proteina de citocromo B en ambas especies, sugirieron que el Albula sp. E, que fue descrito utilizando solamente datos moleculares sin especimenes completos, debería ser asignado provisionalmente a la especie A. nemoptera.
The effects of work and two planes of nutrition on trypanotolerant draught cattle infected with Trypanosoma congolense

Thirty-two N'Dama bulls aged 3 to 4 years were used to study the interactions between work, tl"ypanosomosis and nutrition. The bulls were randomly allocated to two treatments, working (W) and non-working (N). Half in each treatment were placed on an andropogon hay basal diet (B), the other half on a better quality groundnut hay diet (H). Five days a week, four pairs ~f animals in the BW group and and four pairs in the HW group pulled weighted sledges four times around a 2056-m track. Loads ! L1ere set to ensure energy expenditure u'as equil'alent to 1.4 times maintenance. After 4 weeks all 32 bulls were injected intradermally with 104 Trypanosoma congolense organisms. The trial continued for a further 8 weeks. Trypanosome infection caused a significant (P < 0.001) decline in packed cell volume (PC V), and the anaemia was more severe (P < 0.05) in working animals; three pairs in the HW group and two pairs in the BW group u'ere withdrawn because PCV fell below 17%. Diet had no effect on PCV or parasitaemia. Infection caused a decline in food intake (P < 0.001) but u1ith significant interactions between diet and work. Intake patterns were similar in the BN and BW groups whilst the HW animals consumed significantly more groundnut hay compared with the HN group (P < 0.01). However, nutrition had no significant effect on lap times or the team's ability to work under trypanosomosis challenge. Post-infection, diet was the dominant factor determining weight change, HN and HW animals weighed sign~ficantly more than BN and BW animals (P < 0.01) and the interaction between period, diet and work demonstrated that BW had the lowest weights in the latter stages of the trial (P < 0.05). The results suggest that supplementation with better quality forages confers no benefit to an animal infected with trypanosomes. Nor can trypanotolerant cattle sustain long periods of work if subiected to a primary challenge of
PKC-θ-Deficient Mice Are Protected from Th1-Dependent Antigen-Induced Arthritis

T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-θ transduces the signal from the TCR through activation of transcription factors NF-κB, AP-1, and NFAT. We examined the effects of PKC-θ deficiency on two Th1-dependent models of Ag-induced arthritis and found that PKC-θ-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In the methylated BSA model, cellular infiltrates and articular cartilage damage were mild in the PKC-θ-deficient mice as compared with wild-type mice. Quantitation of histopathology reveals 63 and 77% reduction in overall joint destruction in two independent experiments. In the type II collagen-induced arthritis model, we observed a significant reduction in clinical scores (p < 0.01) in three independent experiments and diminished joint pathology (p < 0.005) in PKC-θ-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-θ deficiency also protects from bone destruction. PKC-θ-deficient CD4+ T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-γ, IL-2, and IL-4, and significantly diminished cell surface expression of the activation markers CD25, CD69, and CD134/OX40 on memory T cells. We demonstrate decreased T-bet expression and significantly reduced IgG1 and IgG2a anti-collagen II Ab levels in PKC-θ-deficient mice. Collectively, our results demonstrate that PKC-θ deficiency results in an attenuated response to Ag-induced arthritis, which is likely mediated by the reduced T cell proliferation, Th1/Th2 cell differentiation and T cell activation before and during disease peak.
Dynamic properties of the advertisement calls of gray tree frogs: patterns of variability and female choice

We assessed the potential for several acoustic properties of the advertisement calls of male gray tree frogs to affect relative mating success by relating patterns of variation in these properties to minimum differences required to elicit female choice. Dynamic properties (pulse number, PN; call rate, CR; and duty cycle, DC, the ratio of call duration to call period) varied much more within bouts of calling than a static property (dominant frequency, DF) but nevertheless exhibited significant between male variation in three of four breeding seasons. Many multiply recorded males consistently produced calls with values substantially above or below mean values of males recorded on the same nights. Nightly ranges of variation in PN and CR were often greater than the minimum differences required to elicit female preferences in the laboratory. In most experiments, females chose high-PN or fast-CR calls over low-PN or slow-CR alternatives, respectively, even if the preferred stimuli were farther away or 6-10 dB lower in sound pressure level (SPL), provided that differences in PN or CR were 100%. Consistent with these results, females did not always choose the closer of two calling males in the field. Nightly ranges of variation in DF rarely equaled the minimum difference required to elicit SPL independent preferences. Females preferred a stimulus of high-PN and slow-CR over an alternative of low-PN or fast-CR with the same acoustic on-time; in two experiments, females chose calls of high-PN over low-PN alternatives even though the playback of the high-PN call was interrupted and the low-PN call was broadcast continuously. Thus, female preferences were not merely based on the total time of acoustic stimulation. Responses of females tested twice in the same experiment suggest that phenotypic variation in preference was limited in our study populations.
Characterization of cowpea mottle virus on cowpea (Vigna unguiculata) in the Ivory Coast and the identification of a new vector.

In Ivory Coast, a mechanically transmissible virus, with isometric particles 30 nm in diameter, was isolated from cowpea (Vigna unguiculata) that showed stunt and severe mosaic. This paper describes the characterization of the virus as an isolate of cowpea mottle virus, previously known only from Nigeria, and reports a new chrysomelid beetle vector, Monolepta tenuicornis Jacoby
Mitochondrial DNA diversity and population structure of a forest-dependent rodent, Praomys taitae (Rodentia: Muridae) Heller 1911, in the fragmented forest patches of Taita Hills, Kenya

The population genetic structure of the forest-dependent rodent, Praomys taitae, sampled from nine indigenous forest fragments distributed over three ranges of the Taita Hills in Kenya, was deter- mined using mitochondrial DNA (mtDNA) control region sequence variation. Thirty-three unique haplotypes were observed in a total sample of 132 individuals, whereas the number of different haplotypes per population ranged from two to 10. An overall low nucleotide diversity of 0.9% was observed in the total sample but varied widely between populations (0.2-1.3%). Significant genetic differentiation was observed in 30 of the 36 possible pair-wise comparisons between populations, while a hierarchical AMOVA revealed signifi- cant genetic subdivision between groups of populations on the three hill ranges of Dabida, Mbololo and Kyulu (FCT = 0.404, P < 0.01), among populations on each of the hill ranges (FSC = 0.112, P < 0.01) and among populations in the total sample (FST = 0.471, P < 0.001). Demographic history analyses based on pair-wise nucleotide sequence mismatch distributions revealed that all the populations were in mutation-drift disequilibrium except the popu- lations of the Kyulu and Ronge forest fragments.
Neuronal electrical activity induced by optical trapping of neurotransmitter receptors on neuron

AMPA-type glutamate receptor (AMPAR) is one of neurotransmitter receptors at excitatory synapses in neuronal cell. For realizing the artificial control of synaptic transmission, we have applied optical trapping of quantum-dot (QD) conjugated AMPARs on neuronal cells. Here, we demonstrate simultaneous measurement combined with optical trapping and patch-clamp recordings to evaluate the neuronal electrical activity. The relationship between optical trapping dynamics of QD-AMPARs located on neuronal cells and the neuronal electrical activity was discussed.
Pathways for phosphatidylcholine biosynthesis: targets and strategies for antimalarial drugs

Phospholipids play an important role in the intra-erythrocytic life cycle of Plasmodium falciparum, the agent of the severe form of human malaria, both as essential structural components of parasite membranes and as regulatory molecules that modulate diverse essential enzymatic and cell biological functions. These molecules are therefore critical for parasite development and are required for their rapid multiplication inside human erythrocytes. Following invasion of erythrocytes, the relative levels of phospholipids increases up to sixfold, with phosphatidylcholine as the major constituent. Malaria parasites synthesize phosphatidylcholine de novo using choline as a precursor. The importance of this de novo pathway in parasite development and survival has been inferred by the fact that structural mimics of choline cause a strong inhibition of choline transport into the parasite, blockage of phosphatidylcholine biosynthesis from choline and inhibition of parasite growth. P. falciparum uses a second pathway .
Outcrossing rates of barley landraces from Syria.

Diversity levels in populations of barley landraces may be influenced by varying levels of natural outcrossing caused by environmental conditions. Outcrossing was studied in 10 accessions of the barley landrace Arabi Aswad from different environments in Syria. Electrophoretic variation at two codominant isoenzymes (Est1 and Est2) in six seeds of 50 families per population were analysed and multilocus outcrossing rates calculated. Results were correlated with interpolated environmental conditions. Outcrossing was, on average, 1.7% and not significantly different from the outcrossing rate of wild barley. A significant increase of outcrossing was observed with increasing inter-annual variation in rainfall and decreasing minimum temperatures of the coldest month.
The Canadian Productivity Stagnation, 2002–2014

Total Factor Productivity (TFP) growth in Canada between 2002 and 2014 has been only 0.16% per year. Although many developed countries have experienced a productivity slowdown since the beginning of the century, this figure is still substantially smaller than that of the U.S. We perform multiple counterfactual exercises to show that this difference in TFP growth cannot be accounted for by several compositional effects and/or mismeasurements of factors of production. We identify two key sectors (Mining and Manufacturing) that drive all of the TFP growth difference with the U.S. Despite the lack of TFP growth, Canada has experienced sustained income growth due to a prolonged period of appreciation of the terms of trade (while terms of trade in the U.S. have deteriorated), making real income in the two countries grow at similar rates.
Combining an Ecological Experiment and a Genome Scan Show Idiosyncratic Responses to Salinity Stress in Local Populations of a Seaweed

Climate change-related effects threaten species worldwide; within-species populations may react differently to climate-induced stress due to local adaptation and partial isolation, particularly in areas with steep environmental gradients. Populations of the marine foundation seaweed Fucus vesiculosus are established over a steep salinity gradient at the entrance of the brackish water in the Baltic Sea (NE Atlantic). First, we analyzed the genetic differentiation among populations using thousands of genetic markers. Second, we measured the physiological tolerance to reduced salinity, a predicted effect of climate change in the study area, by measuring growth, phlorotannin (defense compounds) content, and maximum photochemical yield in tissue of the same individuals exposed to both current and projected future salinities. Our results show that despite short geographic distances (max 100 km), most populations were genetically well separated. Furthermore, populations responded very differently to a salinity decrease of four practical salinity units (psu) corresponding to projected future salinity. At the high salinity end of the gradient, some populations maintained growth at the cost of reduced phlorotannin production. However, at the low salinity end, mortality increased and growth was strongly reduced in one population, while a second population from similar salinity instead maintained growth and phlorotannin production. Among genetic markers that appeared as outliers (showing more genetic differentiation than the majority of loci), we found that four were associated with genes that were potential candidates for being under selection. One of these, a calcium-binding protein gene, also showed a significant genotype–phenotype relationship in the population where this genetic marker was variable. We concluded that local selection pressure, genetic affinity, and possibly also population history could explain the very different responses to reduced salinity among these populations, despite being from the same geographic area. Our results highlight the importance of local perspective in the management of species.
Impacts of the 2010 Droughts and Floods on Community Welfare in Rural Thailand: Differential Effects of Village Educational Attainment

Climatic events can have disastrous consequences on rural livelihoods, which rely mainly on agriculture and natural resources. The way households and communities respond to climatic shocks depends on their available resources. We formulated that education is a human capital asset that can increase coping abilities in difficult times because education improves access to both social and economic resources. Based on the Thai government surveys of the living conditions and life quality of 68,343 rural villages for the years 2009 and 2011, we investigated the impacts of floods and droughts in 2010 on community welfare, i.e., consumption and income in 2011 at the village level. Using difference-in-difference methods, we analyzed how differential demographic composition and education could reduce or increase economic vulnerability to natural disasters. We found that floods and droughts do not produce a negative effect either on food and nonfood consumption, investment in agriculture and education, or on income. However, this applies mainly to communities with higher educational attainment partly because these communities can better secure government financial aid for flood and drought affected areas. Education thus may have an important role in reducing economic vulnerability. <br>
Evaluation of the Anti-Tumor Activity of the Humanized Monoclonal Antibody NEO-201 in Preclinical Models of Ovarian Cancer

Purpose: Despite high initial response rates with cytoreductive surgery, conventional chemotherapy and the incorporation of biologic agents, ovarian cancer patients often relapse and die from their disease. New approaches are needed to improve patient outcomes. This study was designed to evaluate the antitumor activity of NEO-201 monoclonal antibody (mAb) in preclinical models of ovarian cancer where the NEO-201 target is highly expressed. Experimental Design: Functional analysis of NEO-201 against tumor cell lines was performed by antibody-dependent cellular cytotoxicity (ADCC) assays. Binding of NEO-201 to tumor tissues and cell lines were determined by immunohistochemistry (IHC) and flow cytometry, respectively. Further characterization of the antigen recognized by NEO-201 was performed by mass spectrometry. Ovarian cancer models were used to evaluate the anti-tumor activity of NEO-201 in vivo. NEO-201 at a concentration of 250 g/mouse was injected intraperitoneally (IP) on days 1, 4, and 8. Human PBMCs were injected IP simultaneously as effector cells. Results: Both IHC and flow cytometry revealed that NEO-201 binds prominently to the colon, pancreatic, and mucinous ovarian cancer tissues and cell lines. Immunoprecipitation of the antigen recognized by NEO-201 was performed in human ovarian, colon, and pancreatic cancer cell lines. From these screening, carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and CEACAM6 were identified as the most likely targets of NEO-201. Our results confirmed that NEO-201 binds different types of cancers; the binding is highly selective for the tumor cells without cross reactivity with the surrounding healthy tissue. Functional analysis revealed that NEO-201 mediates ADCC killing against human ovarian and colorectal carcinoma cell lines in vitro. In addition, NEO-201 inhibited tumor growth in the presence of activated human PBMCs in orthotopic mouse models of both primary and metastatic ovarian cancer. Importantly, NEO-201 prolonged survival of tumor-bearing mice. Conclusions: These data suggested that NEO-201 has an antitumor activity against tumor cells expressing its antigen. Targeting an antigen expressed in tumors, but not in normal tissues, allows patient selection for optimal treatment. These findings strongly indicate that NEO-201 warrants clinical testing as both a novel therapeutic and diagnostic agent for treatment of ovarian carcinomas. A first in human clinical trial evaluating NEO-201 in adults with chemo-resistant solid tumors is ongoing at the NIH clinical Center.
An Extensive Survey of CK2 α and β Subunits in Arabidopsis: Multiple Isoforms Exhibit Differential Subcellular Localization

Casein kinase 2 (CK2) is a ubiquitous enzyme essential for the viability of eukaryotic cells. In the present work we analyzed the Arabidopsis thaliana genome in a search for the genes coding for all CK2 a and b subunits. We found four a subunit and four b subunit genes. Expression analysis showed that all CK2 subunit genes are expressed in inflorescences, stems, leaves and roots. The level of expression of these genes is very similar, except for the one that codes for an a subunit harboring a putative chloroplastic destination peptide (acp), which shows a slightly higher expression level in all tissues. Using transgenic plants and agroinfiltration, we have also characterized the subcellular localization of all proteins encoded by CK2 genes. Our results show that all a subunits are localized in the nucleus, with the exception of acp, which is only found in the chloroplasts. On the other hand, b subunits have a more diverse distribution, with some of them localizing both to the nucleus and to the cytosol, while others are exclusively located in one of these compartments. Remarkably, no CK2b subunit was found in the chloroplasts. Finally, by directly measuring its activity, we have demonstrated that purified Arabidopsis chloroplasts have active CK2 that can be regulated by external addition of CK2b. This study represents a complete survey of the CK2 gene family in Arabidopsis and the first step for future studies on CK2 cellular function in this species.