The Lantern Vol. 60, No. 1, December 1992

• Bacon and Incense • The Rubix Cube • Recovery • Untitled • Star Six Nine • Breakfast Talk • Life as a Worker Bee • Cabal • One Cold Sunday Morning With Eggs • By the End of February • Eight Years and Five Minutes Away • Distance • Stuart\u27s Gift • Solitary Remembrance • The Gene Thing • Addictionhttps://digitalcommons.ursinus.edu/lantern/1139/thumbnail.jp

Severe neurocognitive and growth disorders due to variation in THOC2, an essential component of nuclear mRNA export machinery

Highly conserved TREX-mediated mRNA export is emerging as a key pathway in neuronal development and differentiation. TREX subunit variants cause neurodevelopmental disorders (NDDs) by interfering with mRNA export from the cell nucleus to the cytoplasm. Previously we implicated four missense variants in the X-linked THOC2 gene in intellectual disability (ID). We now report an additional six affected individuals from five unrelated families with two de novo and threematernally inherited pathogenic or likely pathogenic variants in THOC2 extending the genotypic and phenotypic spectrum. These comprise three rare missense THOC2 variants that affect evolutionarily conserved amino acid residues and reduce protein stability and two with canonical splice-site THOC2 variants that result in C-terminally truncated THOC2 proteins.We present detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. Severe neurocognitive features, including movement and seizure disorders, were observed in this cohort. Taken together our data show that even subtle alterations to the canonical molecular pathways such asmRNAexport, otherwise essential for cellular life, can be compatible with life, but lead to NDDs in human

The Crystal Structure of the SV40 T-Antigen Origin Binding Domain in Complex with DNA

DNA replication is initiated upon binding of “initiators” to origins of replication. In simian virus 40 (SV40), the core origin contains four pentanucleotide binding sites organized as pairs of inverted repeats. Here we describe the crystal structures of the origin binding domain (obd) of the SV40 large T-antigen (T-ag) both with and without a subfragment of origin-containing DNA. In the co-structure, two T-ag obds are oriented in a head-to-head fashion on the same face of the DNA, and each T-ag obd engages the major groove. Although the obds are very close to each other when bound to this DNA target, they do not contact one another. These data provide a high-resolution structural model that explains site-specific binding to the origin and suggests how these interactions help direct the oligomerization events that culminate in assembly of the helicase-active dodecameric complex of T-ag

Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder

PURPOSE: We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). METHODS: Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers. RESULTS: We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined. CONCLUSION: Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals

For

In memory of Tarik Nadim Rawdah, A remarkable brother and an amazing friend iv ACKNOWLEDGEMENTS For my sons

Unmet Support Service Needs and Health-Related Quality of Life among Adolescents and Young Adults with Cancer: The AYA HOPE Study

Introduction: Cancer for adolescents and young adults (AYA) differs from younger and older patients; AYA face medical challenges while navigating social and developmental transitions. Research suggests that these patients are under- or inadequately served by current support services, which may affect health-related quality of life (HRQOL).Methods: We examined unmet service needs and HRQOL in the National Cancer Institute’s Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) study, a population-based cohort (n=484), age 15-39, diagnosed with cancer 6-14 months prior, in 2007-2009. Unmet service needs were psychosocial, physical, spiritual, and financial services where respondents endorsed that they needed, but did not receive, a listed service. Linear regression models tested associations between any or specific unmet service needs and HRQOL, adjusting for demographic, medical and health insurance variables.Results: Over one-third of respondents reported at least one unmet service need. The most common were financial (16%), mental health (15%), and support group (14%) services. Adjusted models showed that having any unmet service need was associated with worse overall HRQOL, fatigue, physical, emotional, social, and school/work functioning, and mental health (p’s<0.0001). Specific unmet services were related to particular outcomes (e.g., needing pain management was associated with worse overall HRQOL, physical and social functioning (p’s<0.001)). Needing mental health services had the strongest associations with worse HRQOL outcomes; needing physical/occupational therapy was most consistently associated with poorer functioning across domains.Discussion: Unmet service needs in AYAs recently diagnosed with cancer are associated with worse HRQOL. Research should examine developmentally appropriate, relevant practices to improve access to services demonstrated to adversely impact HRQOL, particularly physical therapy and mental health services