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Article: Repurposing Normal Chromosomal Microarray Data to Harbor Genetic Insights into Congenital Heart Disease.

Walton, Nephi A / Nguyen, Hoang H / Procknow, Sara S / Johnson, Darren / Anzelmi, Alexander / Jay, Patrick Y

2023 Volume 12, Issue 10

Abstract: About 15% of congenital heart disease (CHD) patients have a known pathogenic copy number variant. The majority of their chromosomal microarray (CMA) tests are deemed normal. Diagnostic interpretation typically ignores microdeletions smaller than 100 kb. ... ...

Abstract	About 15% of congenital heart disease (CHD) patients have a known pathogenic copy number variant. The majority of their chromosomal microarray (CMA) tests are deemed normal. Diagnostic interpretation typically ignores microdeletions smaller than 100 kb. We hypothesized that unreported microdeletions are enriched for CHD genes. We analyzed "normal" CMAs of 1762 patients who were evaluated at a pediatric referral center, of which 319 (18%) had CHD. Using CMAs from monozygotic twins or replicates from the same individual, we established a size threshold based on probe count for the reproducible detection of small microdeletions. Genes in the microdeletions were sequentially filtered by their nominal association with a CHD diagnosis, the expression level in the fetal heart, and the deleteriousness of a loss-of-function mutation. The subsequent enrichment for CHD genes was assessed using the presence of known or potentially novel genes implicated by a large whole-exome sequencing study of CHD. The unreported microdeletions were modestly enriched for both known CHD genes and those of unknown significance identified using their de novo mutation in CHD patients. Our results show that readily available "normal" CMA data can be a fruitful resource for genetic discovery and that smaller deletions should receive more attention in clinical evaluation.
Language	English
Publishing date	2023-09-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2661517-4
ISSN	2079-7737
ISSN	2079-7737
DOI	10.3390/biology12101290
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Article ; Online: Metal-Organic Frameworks for Drug Delivery: A Design Perspective.

Lawson, Harrison D / Walton, S Patrick / Chan, Christina

ACS applied materials & interfaces

2021 Volume 13, Issue 6, Page(s) 7004–7020

Abstract: The use of metal-organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide ... ...

Abstract	The use of metal-organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide variety of drug delivery applications. Initially, MOFs were used for delivery of small-molecule pharmaceuticals; however, more recent work has focused on macromolecular cargos, such as proteins and nucleic acids. Here, we review the historical application of MOFs for drug delivery, with a specific focus on the available options for designing MOFs for specific drug delivery applications. These options include choices of MOF structure, synthetic method, and drug loading. Further considerations include tuning, modifications, biocompatibility, cellular targeting, and uptake. Altogether, this Review aims to guide MOF design for novel biomedical applications.
MeSH term(s)	Biomedical Research ; Drug Delivery Systems ; Drug Design ; Metal-Organic Frameworks/chemical synthesis ; Metal-Organic Frameworks/chemistry
Chemical Substances	Metal-Organic Frameworks
Language	English
Publishing date	2021-02-07
Publishing country	United States
Document type	Journal Article ; Review
ISSN	1944-8252
ISSN (online)	1944-8252
DOI	10.1021/acsami.1c01089
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Article ; Online: Lifetime non-fatal overdose experiences among at-risk adolescents and young adults in the emergency department with past-year opioid use in the USA.

Seewald, Laura / Bonar, Erin / Bohnert, Amy S B / Carter, Patrick M / King, Cheryl A / Losman, Eve D / Bacon, Linnea / Wheeler, Tiffany / Walton, Maureen

Injury prevention : journal of the International Society for Child and Adolescent Injury Prevention

2024

Abstract: ... on substance(s) used during the worst overdose experience.: Results: Among 771 participants (27.9% male), 40 ... those with prior overdose experience(s) were less likely to be heterosexual, and more likely to report a prior ... suicide attempt and greater peer substance misuse. Regarding the worst overdose experience, substance(s) included ...

Abstract	Background: Adolescents and young adults with risk factors for opioid misuse and opioid use disorder are at elevated risk for overdose. We examined prior non-fatal overdose experiences among at-risk adolescents/young adults to inform prevention efforts. Methods: Adolescents/young adults (ages 16-30) in two US emergency departments self-reporting past year opioid misuse or opioid use plus a misuse risk factor completed a baseline survey as part of an ongoing randomised controlled trial. We describe baseline factors associated with (a) overall non-fatal overdose experiences and (b) groups based on substance(s) used during the worst overdose experience. Results: Among 771 participants (27.9% male), 40.7% reported a non-fatal overdose experience. Compared with those without a prior overdose experience, those with prior overdose experience(s) were less likely to be heterosexual, and more likely to report a prior suicide attempt and greater peer substance misuse. Regarding the worst overdose experience, substance(s) included: 36.6% alcohol only, 28.0% alcohol and cannabis, 22.6% alcohol with other substance(s) and 12.7% other substance(s) only (eg, opioids). Compared with the alcohol only group, the alcohol and cannabis group were younger and less likely to be heterosexual; the alcohol with other substance(s) group were older and had greater peer substance misuse; and the other substance(s) only group were more likely to be male, receive public assistance, screen positive for anxiety and less likely to be heterosexual. Conclusions: Among at-risk adolescents/young adults, findings support the need for tailored overdose prevention efforts based on substance(s) used, with consideration of sexuality, mental health and peer substance use. Trial registration number: NCT04550715.
Language	English
Publishing date	2024-02-08
Publishing country	England
Document type	Journal Article
ZDB-ID	1433667-4
ISSN	1475-5785 ; 1353-8047
ISSN (online)	1475-5785
ISSN	1353-8047
DOI	10.1136/ip-2023-045072
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Article: Metal–Organic Frameworks for Drug Delivery: A Design Perspective

Lawson, Harrison D. / Walton, S. Patrick / Chan, Christina

ACS applied materials & interfaces. 2021 Feb. 07, v. 13, no. 6

2021

Abstract: The use of metal–organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide ... ...

Abstract	The use of metal–organic frameworks (MOFs) in biomedical applications has greatly expanded over the past decade due to the precision tunability, high surface areas, and high loading capacities of MOFs. Specifically, MOFs are being explored for a wide variety of drug delivery applications. Initially, MOFs were used for delivery of small-molecule pharmaceuticals; however, more recent work has focused on macromolecular cargos, such as proteins and nucleic acids. Here, we review the historical application of MOFs for drug delivery, with a specific focus on the available options for designing MOFs for specific drug delivery applications. These options include choices of MOF structure, synthetic method, and drug loading. Further considerations include tuning, modifications, biocompatibility, cellular targeting, and uptake. Altogether, this Review aims to guide MOF design for novel biomedical applications.
Keywords	biocompatibility ; coordination polymers ; design ; drug delivery systems ; drug design ; drugs ; nucleic acids ; proteins ; surface area
Language	English
Dates of publication	2021-0207
Size	p. 7004-7020.
Publishing place	American Chemical Society
Document type	Article
ISSN	1944-8252
DOI	10.1021/acsami.1c01089
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Article ; Online: Severe meningoencephalitis secondary to calvarial invasion of

Shmalberg, Justin / Moyle, Patrick S / Craft, William F / Walton, Stuart A

Open veterinary journal

2020 Volume 10, Issue 1, Page(s) 31–38

Abstract: Background: The oomycete : Case description: A 6-year-old spayed female mixed-breed dog was evaluated at a referral institution with a 2-month history of suspected fungal infection in the region of the right mandibular lymph node that was refractory ... ...

Abstract	Background: The oomycete Case description: A 6-year-old spayed female mixed-breed dog was evaluated at a referral institution with a 2-month history of suspected fungal infection in the region of the right mandibular lymph node that was refractory to surgical resection and empiric medical therapy. Physical examination identified a 6-cm fluctuant subcutaneous mass caudoventral to the ramus of the right mandible and a second firm mass in the region of the right caudal maxilla. Lesional punch biopsies were submitted for fungal culture and polymerase chain reaction (PCR), which subsequently identified Conclusion: This is the first reported case of intracranial lagenidiosis in the dog. PCR distinguished this species from other
MeSH term(s)	Animals ; Dog Diseases/diagnosis ; Dogs ; Fatal Outcome ; Female ; Infections/complications ; Infections/diagnosis ; Infections/veterinary ; Lagenidium/genetics ; Lagenidium/isolation & purification ; Magnetic Resonance Imaging/veterinary ; Meningoencephalitis/complications ; Meningoencephalitis/diagnosis ; Meningoencephalitis/veterinary ; Polymerase Chain Reaction/veterinary
Language	English
Publishing date	2020-02-19
Publishing country	Libya
Document type	Case Reports
ZDB-ID	2651664-0
ISSN	2218-6050 ; 2226-4485
ISSN (online)	2218-6050
ISSN	2226-4485
DOI	10.4314/ovj.v10i1.6
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Article ; Online: Endocytosis Controls siRNA Efficiency: Implications for siRNA Delivery Vehicle Design and Cell-Specific Targeting.

Vocelle, Daniel / Chan, Christina / Walton, S Patrick

Nucleic acid therapeutics

2019 Volume 30, Issue 1, Page(s) 22–32

Abstract: While small interfering RNAs (siRNAs) are commonly used for laboratory studies, development of siRNA therapeutics has been slower than expected, due, in part, to a still limited understanding of the endocytosis and intracellular trafficking of siRNA- ... ...

Abstract	While small interfering RNAs (siRNAs) are commonly used for laboratory studies, development of siRNA therapeutics has been slower than expected, due, in part, to a still limited understanding of the endocytosis and intracellular trafficking of siRNA-containing complexes. With the recent characterization of multiple clathrin-/caveolin-independent endocytic pathways, that is, those mediated by Graf1, Arf6, and flotillin, it has become clear that the endocytic mechanism influences subsequent intracellular processing of the internalized cargo. To explore siRNA delivery in light of these findings, we developed a novel assay that differentiates uptake by each of the endocytic pathways and can be used to determine whether endocytosis by a pathway leads to the initiation of RNA interference (RNAi). Using Lipofectamine 2000 (LF2K), we determined the endocytosis pathway leading to active silencing (whether by clathrin, caveolin, Arf6, Graf1, flotillin, or macropinocytosis) across multiple cell types (HeLa, H1299, HEK293, and HepG2). We showed that LF2K is internalized by Graf1-, Arf6-, or flotillin-mediated endocytosis for the initiation of RNAi, depending on cell type. In addition, we found that a portion of siRNA-containing complexes is internalized by pathways that do not lead to initiation of silencing. Inhibition of these pathways enhanced intracellular levels of siRNAs with concomitant enhancement of silencing.
MeSH term(s)	ADP-Ribosylation Factors/genetics ; Caveolins/genetics ; Clathrin/genetics ; Endocytosis/drug effects ; Endocytosis/genetics ; GTPase-Activating Proteins/genetics ; Gene Silencing/drug effects ; Gene Transfer Techniques ; HEK293 Cells ; HeLa Cells ; Humans ; Membrane Proteins/genetics ; RNA Interference/drug effects ; RNA Transport/drug effects ; RNA Transport/genetics ; RNA, Small Interfering/genetics ; RNA, Small Interfering/pharmacology ; Signal Transduction/drug effects
Chemical Substances	ARHGAP26 protein, human ; Caveolins ; Clathrin ; GTPase-Activating Proteins ; Membrane Proteins ; RNA, Small Interfering ; flotillins ; ADP-Ribosylation Factors (EC 3.6.5.2) ; ADP-ribosylation factor 6 (EC 3.6.5.2)
Language	English
Publishing date	2019-11-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2639888-6
ISSN	2159-3345 ; 2159-3337
ISSN (online)	2159-3345
ISSN	2159-3337
DOI	10.1089/nat.2019.0804
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Article ; Online: Engineering active siRNA therapeutics.

Walton, S Patrick

The FEBS journal

2010 Volume 277, Issue 23, Page(s) 4805

MeSH term(s)	Animals ; Genetic Engineering ; Humans ; RNA Interference ; RNA, Small Interfering/genetics ; RNA, Small Interfering/therapeutic use
Chemical Substances	RNA, Small Interfering
Language	English
Publishing date	2010-11-16
Publishing country	England
Document type	Introductory Journal Article
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/j.1742-4658.2010.07902.x
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Article ; Online: Kinetic analysis of the intracellular processing of siRNAs by confocal microscopy.

Vocelle, Daniel / Chesniak, Olivia M / Smith, Milton R / Chan, Christina / Walton, S Patrick

Microscopy (Oxford, England)

2020 Volume 69, Issue 6, Page(s) 401–407

Abstract: Here, we describe a method for tracking intracellular processing of small interfering RNA (siRNA) containing complexes using automated microscopy controls and image acquisition to minimize user effort and time. This technique uses fluorescence ... ...

Abstract	Here, we describe a method for tracking intracellular processing of small interfering RNA (siRNA) containing complexes using automated microscopy controls and image acquisition to minimize user effort and time. This technique uses fluorescence colocalization to monitor dual-labeled fluorescent siRNAs delivered by silica nanoparticles in different intracellular locations, including the early/late endosomes, fast/slow recycling endosomes, lysosomes and the endoplasmic reticulum. Combining the temporal association of siRNAs with each intracellular location, we reconstructed the intracellular pathways used in siRNA processing, and demonstrate how these pathways vary based on the chemical composition of the delivery vehicle.
MeSH term(s)	Endoplasmic Reticulum/metabolism ; Endosomes/metabolism ; HeLa Cells ; Humans ; Kinetics ; Lysosomes/metabolism ; Microscopy, Confocal ; RNA, Small Interfering/metabolism
Chemical Substances	RNA, Small Interfering
Language	English
Publishing date	2020-06-10
Publishing country	England
Document type	Journal Article
ZDB-ID	2707496-1
ISSN	2050-5701 ; 2050-5698
ISSN (online)	2050-5701
ISSN	2050-5698
DOI	10.1093/jmicro/dfaa031
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Article ; Online: Use of Brevibacillus choshinensis for the production of biologically active brain-derived neurotrophic factor (BDNF).

Angart, Phillip A / Carlson, Rebecca J / Thorwall, Sarah / Patrick Walton, S

Applied microbiology and biotechnology

2017 Volume 101, Issue 14, Page(s) 5645–5652

Abstract: Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family critical for neuronal cell survival and differentiation, with therapeutic potential for the treatment of neurological disorders and spinal cord injuries. The production of ... ...

Abstract	Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family critical for neuronal cell survival and differentiation, with therapeutic potential for the treatment of neurological disorders and spinal cord injuries. The production of recombinant, bioactive BDNF is not practical in most traditional microbial expression systems because of the inability of the host to correctly form the characteristic cystine-knot fold of BDNF. Here, we investigated Brevibacillus choshinensis as a suitable expression host for bioactive BDNF expression, evaluating the effects of medium type (2SY and TM), temperature (25 and 30 °C), and culture time (48-120 h). Maximal BDNF bioactivity (per unit mass) was observed in cultures grown in 2SY medium at extended times (96 h at 30 °C or >72 h at 25 °C), with resulting bioactivity comparable to that of a commercially available BDNF. For cultures grown in 2SY medium at 25 °C for 72 h, the condition that led to the greatest quantity of biologically active protein in the shortest culture time, we recovered 264 μg/L of BDNF. As with other microbial expression systems, BDNF aggregates did form in all culture conditions, indicating that while we were able to recover biologically active BDNF, further optimization of the expression system could yield still greater quantities of bioactive protein. This study provides confirmation that B. choshinensis is capable of producing biologically active BDNF and that further optimization of culture conditions could prove valuable in increasing BDNF yields.
Language	English
Publishing date	2017-07
Publishing country	Germany
Document type	Journal Article
ZDB-ID	392453-1
ISSN	1432-0614 ; 0171-1741 ; 0175-7598
ISSN (online)	1432-0614
ISSN	0171-1741 ; 0175-7598
DOI	10.1007/s00253-017-8273-x
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Article ; Online: Effectiveness and cost-effectiveness of 4 supplementary foods for treating moderate acute malnutrition: results from a cluster-randomized intervention trial in Sierra Leone.

Griswold, Stacy P / Langlois, Breanne K / Shen, Ye / Cliffer, Ilana R / Suri, Devika J / Walton, Shelley / Chui, Ken / Rosenberg, Irwin H / Koroma, Aminata S / Wegner, Donna / Hassan, Amir / Manary, Mark J / Vosti, Stephen A / Webb, Patrick / Rogers, Beatrice L

The American journal of clinical nutrition

2023 Volume 114, Issue 3, Page(s) 973–985

Abstract: Background: Moderate acute malnutrition (MAM) affects 33 million children annually. Investments in formulations of corn-soy blended flours and lipid-based nutrient supplements have effectively improved MAM recovery rates. Information costs and cost- ... ...

Abstract	Background: Moderate acute malnutrition (MAM) affects 33 million children annually. Investments in formulations of corn-soy blended flours and lipid-based nutrient supplements have effectively improved MAM recovery rates. Information costs and cost-effectiveness differences are still needed. Objectives: We assessed recovery and sustained recovery rates of MAM children receiving a supplementary food: ready-to-use supplementary food (RUSF), corn soy whey blend with fortified vegetable oil (CSWB w/oil), or Super Cereal Plus with amylase (SC + A) compared to Corn Soy Blend Plus with fortified vegetable oil (CSB+ w/oil). We also estimated differences in costs and cost effectiveness of each supplement. Methods: In Sierra Leone, we randomly assigned 29 health centers to provide a supplement containing 550 kcal/d for ∼12 wk to 2691 children with MAM aged 6-59 mo. We calculated cost per enrollee, cost per child who recovered, and cost per child who sustained recovery each from 2 perspectives: program perspective and caregiver perspective, combined. Results: Of 2653 MAM children (98.6%) with complete data, 1676 children (63%) recovered. There were no significant differences in the odds of recovery compared to CSB+ w/oil [0.83 (95% CI: 0.64-1.08) for CSWB w/oil, 1.01 (95% CI: 0.78-1.3) for SC + A, 1.05 (95% CI: 0.82-1.34) for RUSF]. The odds of sustaining recovery were significantly lower for RUSF (0.7; 95% CI 0.49-0.99) but not CSWB w/oil or SC + A [1.08 (95% CI: 0.73-1.6) and 0.96 (95% CI: 0.67-1.4), respectively] when compared to CSB+ w/oil. Costs per enrollee [US dollars (USD)/child] ranged from $105/child in RUSF to $112/child in SC + A and costs per recovered child (USD/child) ranged from $163/child in RUSF to $179/child in CSWB w/oil, with overlapping uncertainty ranges. Costs were highest per sustained recovery (USD/child), ranging from $214/child with the CSB+ w/oil to $226/child with the SC + A, with overlapping uncertainty ranges. Conclusions: The 4 supplements performed similarly across recovery (but not sustained recovery) and costed measures. Analyses of posttreatment outcomes are necessary to estimate the full cost of MAM treatment. This trial was registered at clinicaltrials.gov as NCT03146897.
MeSH term(s)	Child Nutrition Disorders/diet therapy ; Child Nutrition Disorders/epidemiology ; Child, Preschool ; Cluster Analysis ; Cost-Benefit Analysis ; Dietary Supplements ; Female ; Food, Formulated/analysis ; Food, Formulated/economics ; Humans ; Infant ; Male ; Sierra Leone/epidemiology
Language	English
Publishing date	2023-01-10
Publishing country	United States
Document type	Journal Article ; Randomized Controlled Trial ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	280048-2
ISSN	1938-3207 ; 0002-9165
ISSN (online)	1938-3207
ISSN	0002-9165
DOI	10.1093/ajcn/nqab140
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