From nature to man in Vergil

Thesis (M.A.)--Boston Universit

Rural Community Development as a Teaching Environment for Cross-Professional Training in Macro Social Work and Community and Regional Planning

A rural community development project combined faculty and students from two courses (community and regional planning, and social work practice in groups, communities, and organizations) housed in different colleges (Arts and Sciences, and Health Sciences, respectively) at a medium-sized public university in a small Appalachian community. The project required students from two different courses to cooperate on data collection, and collaborate on analysis and recommendations, in an exploratory effort at cross-professional training focusing on social work and community development in a rural region

Dynamics of vitamin D in patients with mild or inactive inflammatory bowel disease and their families

BACKGROUND: 25(OH) vitamin D levels may be low in patients with moderately or severely active inflammatory bowel diseases (IBD: Crohn’s disease and Idiopathic Ulcerative Colitis) but this is less clear in patients with mild or inactive IBD. Furthermore there is limited information of any family influence on 25(OH) vitamin D levels in IBD. As a possible risk factor we hypothesize that vitamin D levels may also be low in families of IBD patients. OBJECTIVES: To evaluate 25[OH] vitamin D levels in patients with IBD in remission or with mild activity. A second objective is to evaluate whether there are relationships within IBD family units of 25[OH] vitamin D and what are the influences associated with these levels. METHODS: Participants underwent medical history, physical examination and a 114 item diet questionnaire. Serum 25[OH] vitamin D was measured, using a radioimmunoassay kit, (replete ≥ 75, insufficient 50–74, deficient < 25–50, or severely deficient < 25 nmol/L). Associations between 25[OH] vitamin D and twenty variables were evaluated using univariate regression. Multivariable analysis was also applied and intrafamilial dynamics were assessed. RESULTS: 55 patients and 48 controls with their respective families participated (N206). 25[OH] vitamin D levels between patients and controls were similar (71.2 ± 32.8 vs. 68.3 ±26.2 nmol/L). Vitamin D supplements significantly increased intake but correlation with serum 25[OH] vitamin D was significant only during non sunny months among patients. Within family units, patients’ families had mean replete levels (82.3 ± 34.2 nmol/L) and a modest correlation emerged during sunny months between patients and family (r(2) =0.209 p = 0.032). These relationships were less robust and non significant in controls and their families. CONCLUSIONS: In patients with mild or inactive IBD 25[OH] vitamin D levels are less than ideal but are similar to controls. Taken together collectively, the results of this study suggest that patient family dynamics may be different in IBD units from that in control family units. However contrary to the hypothesis, intra familial vitamin D dynamics do not pose additional risks for development of IBD

Intolerance of uncertainty and threat generalization: a replication and extension

Intolerance of uncertainty (IU) is a transdiagnostic risk factor for internalizing disorders. Prior work has found that IU may be associated with either increased reactivity to threat or, alternatively, with decreased differential responding between threat and nonthreat/safety cues (i.e., threat generalization). For example, work by Morriss, Macdonald, & van Reekum (2016) found that higher IU was associated with increased threat generalization during acquisition (using skin conductance response (SCR)), as well as less differentiation between acquisition and extinction (using subjective uneasiness ratings). Here, three labs attempted direct and conceptual replications of Morriss, Macdonald, et al. (2016). Results showed that the direct replication failed, despite being conducted at the same lab site as the original study; moreover, in contrast to Morriss, Macdonald, et al. (2016), the direct replication found that higher IU was associated with greater SCR discrimination between threat and safety cues (across acquisition and extinction), as well as greater differences in uneasiness ratings between acquisition and extinction. Nonetheless, in the conceptual replications, higher IU was associated with greater threat generalization, as well as less discrimination between acquisition and extinction, as measured using SCR. Higher IU was also associated with larger late positive potentials to threat versus safety cues during extinction—results that mirror those observed by Morriss, Macdonald, et al. (2016) using SCR. Results are discussed with regards to the challenge involved in defining a successful replication attempt, the benefits of collaborative replication and the use and reliability of multiple measures

Decision heuristics in contexts integrating action selection and execution

Heuristics can inform human decision making in complex environments through a reduction of computational requirements (accuracy-resource trade-off) and a robustness to overparameterisation (less-is-more). However, tasks capturing the efficiency of heuristics typically ignore action proficiency in determining rewards. The requisite movement parameterisation in sensorimotor control questions whether heuristics preserve efficiency when actions are nontrivial. We developed a novel action selection-execution task requiring joint optimisation of action selection and spatio-temporal skillful execution. State-appropriate choices could be determined by a simple spatial heuristic, or by more complex planning. Computational models of action selection parsimoniously distinguished human participants who adopted the heuristic from those using a more complex planning strategy. Broader comparative analyses then revealed that participants using the heuristic showed combined decisional (selection) and skill (execution) advantages, consistent with a less-is-more framework. In addition, the skill advantage of the heuristic group was predominantly in the core spatial features that also shaped their decision policy, evidence that the dimensions of information guiding action selection might be yoked to salient features in skill learning

Heterozygous MAP3K20 Variants Cause Ectodermal Dysplasia, Craniosynostosis, Sensorineural Hearing Loss, and Limb Anomalies

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. These individuals exhibit both shared and unique clinical manifestations, highlighting the complexity and variability of the disorder. We propose that the involvement of MAP3K20 in endothelial-mesenchymal transition provides a plausible etiology of these features. Together, these findings characterize a disorder that both expands the phenotypic spectrum associated with MAP3K20 and highlights the need for further studies on its role in early human development

The Comprehensive Assessment of Neurodegeneration and Dementia: Canadian Cohort Study.

BackgroundThe Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) cohort study of the Canadian Consortium on Neurodegeneration in Aging (CCNA) is a national initiative to catalyze research on dementia, set up to support the research agendas of CCNA teams. This cross-country longitudinal cohort of 2310 deeply phenotyped subjects with various forms of dementia and mild memory loss or concerns, along with cognitively intact elderly subjects, will test hypotheses generated by these teams.MethodsThe COMPASS-ND protocol, initial grant proposal for funding, fifth semi-annual CCNA Progress Report submitted to the Canadian Institutes of Health Research December 2017, and other documents supplemented by modifications made and lessons learned after implementation were used by the authors to create the description of the study provided here.ResultsThe CCNA COMPASS-ND cohort includes participants from across Canada with various cognitive conditions associated with or at risk of neurodegenerative diseases. They will undergo a wide range of experimental, clinical, imaging, and genetic investigation to specifically address the causes, diagnosis, treatment, and prevention of these conditions in the aging population. Data derived from clinical and cognitive assessments, biospecimens, brain imaging, genetics, and brain donations will be used to test hypotheses generated by CCNA research teams and other Canadian researchers. The study is the most comprehensive and ambitious Canadian study of dementia. Initial data posting occurred in 2018, with the full cohort to be accrued by 2020.ConclusionAvailability of data from the COMPASS-ND study will provide a major stimulus for dementia research in Canada in the coming years

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems

Macrocephaly and developmental delay caused by missense variants in RAB5C

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical studies revealed that all four variants were damaging, resulting in increased nucleotide exchange rate, attenuated responsivity to guanine exchange factors and heterogeneous effects on interactions with effector proteins. Studies in C. elegans confirmed that all four variants were damaging in vivo and showed defects in endocytic pathway function. The variant heterozygotes displayed phenotypes that were not observed in null heterozygotes, with two shown to be through a dominant negative mechanism. Expression of the human RAB5C variants in zebrafish embryos resulted in defective development, further underscoring the damaging effects of the RAB5C variants. Our combined bioinformatic, in vitro and in vivo experimental studies and clinical data support the association of RAB5C missense variants with a neurodevelopmental disorder characterized by macrocephaly and mild-to-moderate developmental delay through disruption of the endocytic pathway