Biology subjects

Williams, M. S.

Publications and source records attributed to Williams, M. S..

4 recordsLinked to original sources

bioRxiv2025

Larp1 supports brain growth and spatial memory via post-transcriptional control of the translation machinery

In the brain, tight regulation of the translation of mRNAs is essential for development and plasticity. The translation machinery itself is largely encoded by mRNAs with terminal oligopyrimidine (TOP) motifs, which can be post-transcriptionally controlled by the mTOR signaling pathway. In neurons, these mRNAs are selectively enriched in axons, dendrites and synapses, suggesting local functions for their regulation. Here, we use a brain-specific knockout of the mTOR effector and TOP mRNA binding protein, Larp1, to uncover its role in brain development and behavior. Loss of Larp1 significantly decreases brain mass and reduces the density of neurons. We find that TOP mRNAs levels are depleted by more than 50% and selectively lost from synapses, reversing the enrichment that occurs when Larp1 is present. In behavior tests, Larp1-deficient mice are severely impaired in spatial learning and memory. These results demonstrate a critical role for Larp1 in maintaining the levels of essential mRNAs necessary for brain growth and highlight the importance of post-transcriptional regulation by mTOR for normal learning and memory.

neuroscience↗

bioRxiv2019

Clinical and Cost Effectiveness of Two New Lynch Syndrome Case Finding Protocols in Endometrial Cancer Population Contrasted with the IHC-based Protocol

PurposeTo investigate the effectiveness and costs of two Lynch syndrome screening protocols among endometrial cancer (EC) patients and compare to an immunohistochemistry (IHC)-based protocol.\n\nMethodsAnalytic models were developed to represent the two protocols: a brief cancer family history questionnaire (bFHQ) and direct-to-sequencing of the germline. Data from reviews of published literature, augmented by local data and expert opinion were used to populate the model representing the number of women diagnosed in the U.S. in 2018. Multiple analyses employing simulation modeling were performed to estimate a variety of clinical and economic outcomes.\n\nResultsUnder conditions considered here to be plausible, the bFHQ is expected to miss 58% (min./max. = 24 to 80%) of LS index cases, a direct-to-sequencing protocol to miss 30% (min./max. = 6% to 53%), and the IHC-based protocol based on previous analysis 58% (min./max. = 33 to 80%). When direct costs of testing and genetic counseling are added to the models, the total screening program costs for the bFHQ protocol are substantially lower at all sequencing price points than the other protocols. For example, at the low end of the sequencing price point (ie, $250), the total cost of screening programs for IHC, bFHQ, and sequencing are $22.9 million, $5.3 million, and $13.8 million, respectively. The best estimate of the break-even price of sequencing, when the cost of the program is equivalent between the IHC and sequencing protocols, is about $635.\n\nConclusionThe bFHQ and direct-to-sequencing LS screening protocols are more effective and cost effective at identifying LS index cases than the standard IHC-based protocol under the conditions represented in our models. These estimates of various outcome metrics of the three LS index case finding protocols may help stakeholders make decisions of the use of limited healthcare dollars.

genetics↗

bioRxiv2019

GSTM1 copy number is not associated with risk of kidney failure in a large cohort

Deletion of glutathione S-transferase {micro}1 (GSTM1) is common in populations and has been asserted to associate with chronic kidney disease progression in some research studies. The association needs to be validated. We estimated GSTM1 copy number using whole exome sequencing data in the DiscovEHR cohort. Kidney failure was defined as requiring dialysis or receiving kidney transplant using data from the electronic health record and linkage to the United States Renal Data System, or the most recent eGFR < 15 ml/min/1.73m2. In a cohort of 46,983 unrelated participants, 28.8% of blacks and 52.1% of whites had 0 copies of GSTM1. Over a mean of 9.2 years follow-up, 645 kidney failure events were observed in 46,187 white participants, and 28 in 796 black participants. No significant association was observed between GSTM1 copy number and kidney failure in Cox regression adjusting for age, sex, BMI, smoking status, genetic principal components, or co-morbid conditions (hypertension, diabetes, heart failure, coronary artery disease, and stroke), whether using a genotypic, dominant, or recessive model. In sensitivity analyses, GSTM1 copy number was not associated with kidney failure in participants that were 45 years or older at baseline, had baseline eGFR < 60 ml/min per 1.73 m2, or with baseline year between 1996-2002. In conclusion, we found no association between GSTM1 copy number and kidney failure in a large cohort study.\n\nTranslational StatementDeletion of GSTM1 has been shown to be associated with higher risk of kidney failure. However, inconsistent results have been reported. We used electronic health record and whole exome sequencing data of a large cohort from a single healthcare system to evaluate the association between GSTM1 copy number and risk of kidney failure. We found no significant association between GSTM1 copy number and risk of kidney failure overall, or in multiple sensitivity and subgroup analyses.

genetics↗

bioRxiv2017

A Model for Genome-First Care: Returning Secondary Genomic Findings to Participants and Their Healthcare Providers in a Large Research Cohort

BackgroundResearch cohorts with linked genomic data exist, or are being developed, at many research centers. Within any such \"sequenced cohort\" of more than 100 participants, it is likely that there are participants with previously undisclosed risk for life-threatening monogenic diseases that could be identified with targeted analysis of their existing data. Identification of such disease-associated findings are not usually primary to the enrollment research goals. At Geisinger Health System, MyCode(R) Community Health Initiative (MyCode) participants represent one such large sequenced cohort. Since 2013, MyCode participants in discovery research have been consented for secondary analysis of their existing research genomic sequences to allow delivery of medically actionable findings to them and their healthcare providers. This return of genomic results program was developed to manage an anticipated 3.5% of MyCode participants who will receive clinically confirmed genomic variants from an approved gene list out of more than 150,000 total participants. Risk-associated DNA sequences alone without any clinical parameter, prompt \"genome-first\" follow-up encounters.\n\nMethodsThis article describes our process for generating clinical grade results from research-based genomic sequencing data, delivering results to patients and their providers, facilitating targeted clinical evaluations of patients and promoting cascade testing of at-risk relatives. We also summarize our early data about the results generated during this process and our ability to contact patients and their providers to disclose the information.\n\nResultsThis process has been used to generate 343 results on 339 patients. 93% of patients with a result have been successfully contacted about their results as evidenced by direct interaction about their result with the research team or a healthcare provider. 222 healthcare providers have been notified of a result on one or more patient through this result delivery process.\n\nConclusionsHere we describe the existing GHS model to deliver genomic data into the electronic medical record and the clinical interactions that are prompted and supported. Elements of this genome-first care model can be applied in other healthcare settings and in national efforts, such as \"All of Us\", that wish to establish programs for returning genomic results to research participants.

genomics↗