Molecular and behavioral mechanisms mediating paclitaxel-induced changes in affect-like behavior in mice

The antineoplastic paclitaxel is associated with negative affective outcomes, such as depression, anxiety, and decreased quality of life during treatment and convalescence. With the Baby Boomer population approaching peak cancer age, it is dire that the mechanisms behind paclitaxel-induced changes in mood are uncovered. Cancer-free male and female C57BL/6J mice were treated with one set of four injections of vehicle or paclitaxel (32mg/kg cumulative), or two sets of four injections of vehicle or paclitaxel (64mg/kg cumulative), and periodically assessed for depression-like behaviors. Paclitaxel caused significant, time-dependent deficits in sucrose preference and operant responding for palatable food. Because there is growing evidence to support the role of kappa opioid receptors (KORs) in stress-mediated depression and reward dysfunction, we investigated KOR signaling as a putative mechanism of paclitaxel-induced depression-like behaviors. The selective KOR antagonist norbinaltorphimine (norBNI) reversed paclitaxel-induced attenuation of sucrose preference. At the molecular level, paclitaxel time-dependently induced an increase in the expression of Prodynorphin mRNA, the precursor for endogenous KOR agonists, in the nucleus accumbens (NAc). Using the [35S]GTPγS assay, we discovered that a history of paclitaxel time-dependently attenuated activation of dopamine D2 receptors (D2R) and KORs in the NAc but not caudate putamen. These data suggest that paclitaxel-induced changes in affect-like behavior may be due to time- and region-dependent dysregulation of KOR and D2R signaling. These observations help to establish the roles of KOR and D2R systems in paclitaxel-induced disruption of behavioral reward, thus revealing potential neurochemical targets for therapeutic intervention in cancer survivors with treatment-resistant depression.https://scholarscompass.vcu.edu/gradposters/1038/thumbnail.jp

La proteína AOX como terapia génica para enfermedades mitocondriales

La proteína AOX como terapia génica para enfermedades mitocondriales. Las enfermedades mitocondriales constituyen un amplio grupo de patologías que se caracterizan por presentar alteraciones en la cadena de transporte de electrones, con la consiguiente disminución de la producción de energía en forma de ATP. El tratamiento de las enfermedades mitocondriales presenta una serie de dificultades y, de hecho, no existe una terapia efectiva para tratarlas. Actualmente, las medidas terapéuticas se limitan a ser de soporte en la gran mayoría de los pacientes. Una de las terapias que se está investigando en la actualidad consiste en la xenoexpresión de la oxidasa alternativa AOX, enzima procedente del hongo Emericella nidulans. En concreto, en el presente trabajo de fin de máster se ha continuado con la caracterización de dicha proteína, realizando ensayos de inmunodetección de AOX en distintos tejidos de ratón knock-in, y ensayos de viabilidad para estudiar la funcionalidad de la proteína. Los ensayos de inmunodetección revelaron que AOX se expresa en todos los tejidos de ratón analizados y que su expresión es mayor en ratones machos. Sin embargo, no se pudo concluir el origen de las tres bandas correspondientes a AOX. Además, los ensayos de viabilidad demostraron que no ejerce ningún efecto cuando se produce un fallo en la cadena a nivel del complejo I, al contrario de lo que sucedía con los complejos III y IV, validando la relevancia funcional de dicha proteína

Startup-yritysten kasvun ajurit ja pullonkaulat

Uusien ja kasvuhakuisten yritysten (tässä ”startup-yritysten”) merkitys elinkeinoelämän uudistumiselle on keskeinen. Tämän hankkeen päätavoitteena on ollut selvittää, miten julkista politiikkaa tulisi kehittää, jotta se edistäisi mahdollisimman hyvin startup-yritysten kasvua. Tässä raportissa tarkastellaan kansallista startup-yrityksiä, yrittäjyyttä ja startup-yritysten toimintaympäristöä useasta eri näkökulmasta. Raportissa on luotu tilannekuvaa startup-yritysten nykytilasta ja niiden merkityksestä elinkeinoelämälle, vertailtu kansallista startup-yritysten toimintaympäristöä kansainvälisiin verrokkimaihin sekä analysoitu startup-ekosysteemien ja startup-yrityspalvelujen nykytilaa. Tehty selvitys tukee näkemystä siitä, että kansallinen startup-toimintaympäristö on kehittynyt paljon viimeisen kymmenen vuoden aikana. Tästä huolimatta olemme kuitenkin kansainvälisestä kehityksestä jäljessä. Startup-toimintaympäristön kehittäminen edellyttää julkiselta sektorilta entistä vahvempaa ja fokusoidumpaa startup-yrityspolitiikkaa. Kansainvälisten esimerkkien viitoittamana peräänkuulutamme erityisesti poikkihallinnollista startup-politiikkaa. Näkemyksemme mukaan Suomi tarvitsee poikkihallinnollisen startup-strategian, joka on laadittu eri start-up –kentän toimijoiden ja hallinnonalojen tiiviillä yhteistyöll

Deep crustal earthquakes in North Tanzania, East Africa: Interplay between tectonic and magmatic processes in an incipient rift

International audienceIn this study, we explore the origin of lower crustal seismicity and the factors controlling rift propagation using seismological data recorded within the youngest part of the East African Rift System, the North Tanzanian Divergence (NTD). Most earthquakes below Lake Manyara occur at depth ranging between 20 and 40 km and have a swarm-like distribution. Focal mechanisms of 26 events indicate a combination of strike-slip and normal faulting involving Archaean basement structures and forming a relay zone. The derived local stress regime is transtensive and the minimum principal stress is oriented N110°E. Crustal seismic tomography reveals low-velocity anomalies below the rifted basins in the NTD, interpreted as localized thermomechanical perturbations promoting fluid release and subsequent seismicity in the lower crust. SKS splitting analysis in the NTD indicates seismic anisotropy beneath 17 stations most likely due to aligned magma lenses and/or dikes beneath the rift and to the lithospheric fabrics. Our results favor a strain pattern intermediate between purely mechanical and purely magmatic. We suggest that melt products arising from a large asthenospheric thermal anomaly enhance lithospheric weakening and facilitate faulting and creeping on critically oriented inherited structures of the Precambrian lower crust. Although the crust is unlikely weakened at a point comparable to other parts of the East African Rift System, this deep-seated thermomechanical process is efficient enough to allow slow rift propagation within the eastern Tanzanian cratonic edge

Design of a peptide-based vector, PepFect6, for efficient delivery of siRNA in cell culture and systemically in vivo

While small interfering RNAs (siRNAs) have been rapidly appreciated to silence genes, efficient and non-toxic vectors for primary cells and for systemic in vivo delivery are lacking. Several siRNA-delivery vehicles, including cell-penetrating peptides (CPPs), have been developed but their utility is often restricted by entrapment following endocytosis. Hence, developing CPPs that promote endosomal escape is a prerequisite for successful siRNA implementation. We here present a novel CPP, PepFect 6 (PF6), comprising the previously reported stearyl-TP10 peptide, having pH titratable trifluoromethylquinoline moieties covalently incorporated to facilitate endosomal release. Stable PF6/siRNA nanoparticles enter entire cell populations and rapidly promote endosomal escape, resulting in robust RNAi responses in various cell types (including primary cells), with minimal associated transcriptomic or proteomic changes. Furthermore, PF6-mediated delivery is independent of cell confluence and, in most cases, not significantly hampered by serum proteins. Finally, these nanoparticles promote strong RNAi responses in different organs following systemic delivery in mice without any associated toxicity. Strikingly, similar knockdown in liver is achieved by PF6/siRNA nanoparticles and siRNA injected by hydrodynamic infusion, a golden standard technique for liver transfection. These results imply that the peptide, in addition to having utility for RNAi screens in vitro, displays therapeutic potential

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P \u3c 3.53 × 10 CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations

Whole-genome sequencing of pharmacogenetic drug response in racially diverse children with asthma

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P \u3c 3.53 × 10-7) and suggestive (P \u3c 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and β-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations

Extensive Genetic Diversity, Unique Population Structure and Evidence of Genetic Exchange in the Sexually Transmitted Parasite Trichomonas vaginalis

The human parasite Trichomonas vaginalis causes trichomoniasis, the world's most common non-viral sexually transmitted infection. Research on T. vaginalis genetic diversity has been limited by a lack of appropriate genotyping tools. To address this problem, we recently published a panel of T. vaginalis-specific genetic markers; here we use these markers to genotype isolates collected from ten regions around the globe. We detect high levels of genetic diversity, infer a two-type population structure, identify clinically relevant differences between the two types, and uncover evidence of genetic exchange in what was believed to be a clonal organism. Together, these results greatly improve our understanding of the population genetics of T. vaginalis and provide insights into the possibility of genetic exchange in the parasite, with implications for the epidemiology and control of the disease. By taking into account the existence of different types and their unique characteristics, we can improve understanding of the wide range of symptoms that patients manifest and better implement appropriate drug treatment. In addition, by recognizing the possibility of genetic exchange, we are more equipped to address the growing concern of drug resistance and the mechanisms by which it may spread within parasite populations