Letter to Ed Edmonds regarding SEAALL State Practice Materials series, July 28, 1981

A letter from Judith Purcell to Ed Edmonds regarding a potential North Carolina article for the SEAALL State Practice Materials series in the Southeastern Law Librarian

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

Huntington’s disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ

An International Comparative Public Health Analysis of Sex Trafficking of Women and Girls in Eight Cities: Achieving a More Effective Health Sector Response

Sex trafficking, trafficking for the purpose of forced sexual exploitation, is a widespread form of human trafficking that occurs in all regions of the world, affects mostly women and girls, and has far-reaching health implications. Studies suggest that up to 50 % of sex trafficking victims in the USA seek medical attention while in their trafficking situation, yet it is unclear how the healthcare system responds to the needs of victims of sex trafficking. To understand the intersection of sex trafficking and public health, we performed in-depth qualitative interviews among 277 antitrafficking stakeholders across eight metropolitan areas in five countries to examine the local context of sex trafficking. We sought to gain a new perspective on this form of gender-based violence from those who have a unique vantage point and intimate knowledge of push-and-pull factors, victim health needs, current available resources and practices in the health system, and barriers to care. Through comparative analysis across these contexts, we found that multiple sociocultural and economic factors facilitate sex trafficking, including child sexual abuse, the objectification of women and girls, and lack of income. Although there are numerous physical and psychological health problems associated with sex trafficking, health services for victims are patchy and poorly coordinated, particularly in the realm of mental health. Various factors function as barriers to a greater health response, including low awareness of sex trafficking and attitudinal biases among health workers. A more comprehensive and coordinated health system response to sex trafficking may help alleviate its devastating effects on vulnerable women and girls. There are numerous opportunities for local health systems to engage in antitrafficking efforts while partnering across sectors with relevant stakeholders

Effects of flanking sequences and cellular context on subcellular behavior and pathology of mutant HTT

Huntington’s disease (HD) is caused by an expansion of a poly glutamine (polyQ) stretch in the huntingtin protein (HTT) that is necessary to cause pathology and formation of HTT aggregates. Here we ask whether expanded polyQ is sufficient to cause pathology and aggregate formation. By addressing the sufficiency question, one can identify cellular processes and structural parameters that influence HD pathology and HTT subcellular behavior (i.e. aggregation state and subcellular location). Using Drosophila, we compare the effects of expressing mutant full-length human HTT (fl-mHTT) to the effects of mutant human HTTexon1 and to two commonly used synthetic fragments, HTT171 and shortstop (HTT118). Expanded polyQ alone is not sufficient to cause inclusion formation since full-length HTT and HTTex1 with expanded polyQ are both toxic although full-length HTT remains diffuse while HTTex1 forms inclusions. Further, inclusions are not sufficient to cause pathology since HTT171-120Q forms inclusions but is benign and co-expression of HTT171-120Q with non-aggregating pathogenic fl-mHTT recruits fl-mHTT to aggregates and rescues its pathogenicity. Additionally, the influence of sequences outside the expanded polyQ domain is revealed by finding that small modifications to the HTT118 or HTT171 fragments can dramatically alter their subcellular behavior and pathogenicity. Finally, mutant HTT subcellular behavior is strongly modified by different cell and tissue environments (e.g. fl-mHTT appears as diffuse nuclear in one tissue and diffuse cytoplasmic in another but toxic in both). These observations underscore the importance of cellular and structural context for the interpretation and comparison of experiments using different fragments and tissues to report the effects of expanded polyQ

Miles to go (mtgo) encodes FNDC3 proteins that interact with the chaperonin subunit CCT3 and are required for NMJ branching and growth in Drosophila.

Analysis of mutants that affect formation and function of the Drosophila larval neuromuscular junction (NMJ) has provided valuable insight into genes required for neuronal branching and synaptic growth. We report that NMJ development in Drosophila requires both the Drosophila ortholog of FNDC3 genes; CG42389 (herein referred to as miles to go; mtgo), and CCT3, which encodes a chaperonin complex subunit. Loss of mtgo function causes late pupal lethality with most animals unable to escape the pupal case, while rare escapers exhibit an ataxic gait and reduced lifespan. NMJs in mtgo mutant larvae have dramatically reduced branching and growth and fewer synaptic boutons compared with control animals. Mutant larvae show normal locomotion but display an abnormal self-righting response and chemosensory deficits that suggest additional functions of mtgo within the nervous system. The pharate lethality in mtgo mutants can be rescued by both low-level pan- and neuronal-, but not muscle-specific expression of a mtgo transgene, supporting a neuronal-intrinsic requirement for mtgo in NMJ development. Mtgo encodes three similar proteins whose domain structure is most closely related to the vertebrate intracellular cytosolic membrane-anchored fibronectin type-III domain-containing protein 3 (FNDC3) protein family. Mtgo physically and genetically interacts with Drosophila CCT3, which encodes a subunit of the TRiC/CCT chaperonin complex required for maturation of actin, tubulin and other substrates. Drosophila larvae heterozygous for a mutation in CCT3 that reduces binding between CCT3 and MTGO also show abnormal NMJ development similar to that observed in mtgo null mutants. Hence, the intracellular FNDC3-ortholog MTGO and CCT3 can form a macromolecular complex, and are both required for NMJ development in Drosophila

Two chemically similar stellar overdensities on opposite sides of the plane of the Galaxy

Our Galaxy is thought to have undergone an active evolutionary history dominated by star formation, the accretion of cold gas, and, in particular, mergers up to 10 gigayear ago. The stellar halo reveals rich fossil evidence of these interactions in the form of stellar streams, substructures, and chemically distinct stellar components. The impact of dwarf galaxy mergers on the content and morphology of the Galactic disk is still being explored. Recent studies have identified kinematically distinct stellar substructures and moving groups, which may have extragalactic origin. However, there is mounting evidence that stellar overdensities at the outer disk/halo interface could have been caused by the interaction of a dwarf galaxy with the disk. Here we report detailed spectroscopic analysis of 14 stars drawn from two stellar overdensities, each lying about 5 kiloparsecs above and below the Galactic plane - locations suggestive of association with the stellar halo. However, we find that the chemical compositions of these stars are almost identical, both within and between these groups, and closely match the abundance patterns of the Milky Way disk stars. This study hence provides compelling evidence that these stars originate from the disk and the overdensities they are part of were created by tidal interactions of the disk with passing or merging dwarf galaxies.Comment: accepted for publication in Natur

Pharmacogenetics of telatinib, a VEGFR-2 and VEGFR-3 tyrosine kinase inhibitor, used in patients with solid tumors

Purpose Telatinib is an orally active small-molecule tyrosine kinase inhibitor of kinase insert domain receptor (KDR; VEGFR-2) and fms-related tyrosine kinase 4 (FLT4; VEGFR-3). This study aims at the identification of relationships between single nucleotide polymorphisms (SNPs) in genes encoding for transporter proteins and pharmacokinetic parameters in order to clarify the significant interpatient variability in drug exposure. In addition, the potential relationship between target receptor polymorphisms and toxicity of telatinib is explored. Methods Blood samples from 33 patients enrolled in a phase I dose-escalation study of telatinib were analyzed. For correlation with dose normalized AUC(0–12), ATP-binding cassette (ABC) B1 (ABCB1), ABCC1, and ABCG2 were the genes selected. For correlation with telatinib toxicity, selected genes were the drug target genes KDR and FLT4. Results No association between dose normalized AUC(0–12) and drug transporter protein polymorphisms was observed. In addition, no association between toxicity and KDR or FLT4 genotype or haplotype was seen. Conclusions Our pharmacogenetic analysis could not reveal a correlation between relevant gene polymorphisms and clinical and pharmacokinetic observations of telatinib