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Artikel ; Online: Nanobody-Mediated Dualsteric Engagement of the Angiotensin Receptor Broadens Biased Ligand Pharmacology.

Braga Emidio, Nayara / Small, Brandi M / Keller, Amanda R / Cheloha, Ross W / Wingler, Laura M

2024 Band 105, Heft 3, Seite(n) 260–271

Abstract: Dualsteric G protein-coupled receptor (GPCR) ligands are a class of bitopic ligands that consist of an orthosteric pharmacophore, which binds to the pocket occupied by the receptor's endogenous agonist, and an allosteric pharmacophore, which binds to a ... ...

Abstract	Dualsteric G protein-coupled receptor (GPCR) ligands are a class of bitopic ligands that consist of an orthosteric pharmacophore, which binds to the pocket occupied by the receptor's endogenous agonist, and an allosteric pharmacophore, which binds to a distinct site. These ligands have the potential to display characteristics of both orthosteric and allosteric ligands. To explore the signaling profiles that dualsteric ligands of the angiotensin II type 1 receptor (AT1R) can access, we ligated a 6e epitope tag-specific nanobody (single-domain antibody fragment) to angiotensin II (AngII) and analogs that show preferential allosteric coupling to Gq (TRV055, TRV056) or
Mesh-Begriff(e)	Receptor, Angiotensin, Type 1/agonists ; Receptor, Angiotensin, Type 1/metabolism ; Angiotensin II/chemistry ; Ligands ; beta-Arrestins/metabolism ; Epitopes ; Allosteric Regulation
Chemische Substanzen	Receptor, Angiotensin, Type 1 ; Angiotensin II (11128-99-7) ; Ligands ; beta-Arrestins ; Epitopes
Sprache	Englisch
Erscheinungsdatum	2024-02-15
Erscheinungsland	United States
Dokumenttyp	Journal Article
ZDB-ID	124034-1
ISSN	1521-0111 ; 0026-895X
ISSN (online)	1521-0111
ISSN	0026-895X
DOI	10.1124/molpharm.123.000797
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Increased Actin Binding Is a Shared Molecular Consequence of Numerous SCA5 Mutations in β-III-Spectrin.

Atang, Alexandra E / Keller, Amanda R / Denha, Sarah A / Avery, Adam W

Cells

2023 Band 12, Heft 16

Abstract: Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in ... ...

Abstract	Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the
Mesh-Begriff(e)	Humans ; Actins/genetics ; Spectrin/genetics ; Mutation/genetics ; Mutation, Missense ; Spinocerebellar Ataxias/genetics
Chemische Substanzen	Actins ; Spectrin (12634-43-4)
Sprache	Englisch
Erscheinungsdatum	2023-08-19
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12162100
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Increased actin binding is a shared molecular consequence of numerous spinocerebellar ataxia mutations in β-III-spectrin.

Atang, Alexandra E / Keller, Amanda R / Denha, Sarah A / Avery, Adam W

bioRxiv : the preprint server for biology

2023

Abstract: Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the SPTBN2 gene encoding the cytoskeletal protein β-III-spectrin. Previously, we demonstrated that a L253P missense mutation, localizing to the β-III-spectrin ... ...

Abstract	Spinocerebellar ataxia type 5 (SCA5) is a neurodegenerative disease caused by mutations in the SPTBN2 gene encoding the cytoskeletal protein β-III-spectrin. Previously, we demonstrated that a L253P missense mutation, localizing to the β-III-spectrin actin-binding domain (ABD), causes increased actin-binding affinity. Here we investigate the molecular consequences of nine additional ABD-localized, SCA5 missense mutations: V58M, K61E, T62I, K65E, F160C, D255G, T271I, Y272H, and H278R. We show that all of the mutations, similar to L253P, are positioned at or near the interface of the two calponin homology subdomains (CH1 and CH2) comprising the ABD. Using biochemical and biophysical approaches, we demonstrate that the mutant ABD proteins can attain a well-folded state. However, thermal denaturation studies show that all nine mutations are destabilizing, suggesting a structural disruption at the CH1-CH2 interface. Importantly, all nine mutations cause increased actin binding. The mutant actin-binding affinities vary greatly, and none of the nine mutations increase actin-binding affinity as much as L253P. ABD mutations causing high-affinity actin binding, with the notable exception of L253P, appear to be associated with early age of symptom onset. Altogether, the data indicate increased actin-binding affinity is a shared molecular consequence of numerous SCA5 mutations, which has important therapeutic implications.
Sprache	Englisch
Erscheinungsdatum	2023-04-10
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2023.02.20.529285
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Harsh parenting among veterans: parents' military-related PTSD, mentalization, and pre-military trauma.

Wang, Xiafei / Liu, Qingyang / Merrin, Gabriel J / Keller, Amanda / Yoon, Dalhee / Henderson, Ava

Frontiers in psychology

2023 Band 14, Seite(n) 1283801

Abstract: Objectives: Veteran parents experiencing posttraumatic stress disorder (PTSD) may resort to harsh parenting. The indirect pathway from parental military-related PTSD to harsh parenting, and the moderating role of parents' pre-military trauma histories, ... ...

Abstract	Objectives: Veteran parents experiencing posttraumatic stress disorder (PTSD) may resort to harsh parenting. The indirect pathway from parental military-related PTSD to harsh parenting, and the moderating role of parents' pre-military trauma histories, has been less explored. Informed by mentalization theory, as well as trauma-sensitive and posttraumatic growth perspectives, we aim to explore the associations between veteran parents' military-related PTSD, mentalization, harsh parenting, and prior trauma before military service. Methods: Data were collected from an online research panel of 509 veteran parents with children under 10. We employed Structural Equation Models to test indirect and moderating effects. Results: We identified an indirect effect of parental pre-mentalization from military PTSD to harsh parenting [corporal punishment: Conclusion: Modifying parents' interpretation of their child's mental states can potentially counteract the effects of veterans' military PTSD on harsh parenting. Family-based programs should be created considering veteran parents' pre-military trauma histories.
Sprache	Englisch
Erscheinungsdatum	2023-12-19
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2563826-9
ISSN	1664-1078
ISSN	1664-1078
DOI	10.3389/fpsyg.2023.1283801
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Religion, politics and COVID-19 risk perception among urban residents in Malawi.

Chilanga, Emmanuel / Dzimbiri, Mastano / Mwanjawala, Patrick / Keller, Amanda / Mbeya, Ruth Agather

BMC public health

2022 Band 22, Heft 1, Seite(n) 1430

Abstract: Introduction: Majority of Malawians have not yet adopted COVID-19 mitigation measures despite having knowledge about its infectivity, morbidity, and fatality. Understanding drivers of hesitancy to adoption of COVID-19 mitigation measures is critical as ... ...

Abstract	Introduction: Majority of Malawians have not yet adopted COVID-19 mitigation measures despite having knowledge about its infectivity, morbidity, and fatality. Understanding drivers of hesitancy to adoption of COVID-19 mitigation measures is critical as it can inform prevention programs. This study explores Malawians' COVID-19 risk perception, and the associated constraints in the adoption of mitigation efforts. A Health Belief Model (HBM) approach was used to understand perceived factors that undermine public health COVID-19 messages to reduce the spread of the pandemic in Malawi. Methods: The study applied rapid appraisal and photovoice qualitative inquiry to comprehend risk perception regarding COVID-19. We purposively selected 52 participants from three major cities in Malawi. Audio and video interviews were transcribed verbatim, and transcripts were coded manually to derive key themes and concepts. Results: The study identified that social factors particularly religious and political beliefs influenced COVID-19 risk perception. Specific religious beliefs pertaining to individuals recognizing signs of the 'Christian apocalypse' were particularly associated with lower risk perceptions. Politically, participants believed COVID-19 lockdown measures were a ploy by the then-ruling party to remain in power. Conclusion: The study suggests that religious beliefs and political environment undermine self -perceived risk of contracting COVID-19 among urban dwellers in Malawi. We recommend that diverse actors in Malawi should collaborate to promote the dissemination of accurate COVID-19 discourses and reduce the severity of the pandemic's impact in Malawi.
Mesh-Begriff(e)	COVID-19/epidemiology ; COVID-19/prevention & control ; Communicable Disease Control ; Humans ; Malawi/epidemiology ; Perception ; Politics ; Religion ; Urban Population
Sprache	Englisch
Erscheinungsdatum	2022-07-27
Erscheinungsland	England
Dokumenttyp	Journal Article
ZDB-ID	2041338-5
ISSN	1471-2458 ; 1471-2458
ISSN (online)	1471-2458
ISSN	1471-2458
DOI	10.1186/s12889-022-13858-7
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Expanding the Trauma-Informed Care Measurement Toolkit: An Evaluation of the Attitudes Related to Trauma-Informed Care (ARTIC-45) Scale with SUD Workers in PIMH.

Mendez, Alicia / Bosk, Emily A / Keller, Amanda / Williams-Butler, Abigail / Hardan, Tareq / Ruisard, Debra J / MacKenzie, Michael J

Behavioral sciences (Basel, Switzerland)

2023 Band 13, Heft 6

Abstract: Human service organizations (HSO) have increasingly recognized the value of employing trauma-informed care (TIC) in a variety of practice settings. Evidence suggests that effectively adopting TIC has shown client improvements. Organizational barriers to ... ...

Abstract	Human service organizations (HSO) have increasingly recognized the value of employing trauma-informed care (TIC) in a variety of practice settings. Evidence suggests that effectively adopting TIC has shown client improvements. Organizational barriers to TIC implementation, however, exist. To improve TIC practice, the attitudes related to trauma-informed care (ARTIC) scale was developed to measure staff attitudes and beliefs towards TIC. The ARTIC has been widely adopted by researchers without evaluating its psychometric performance in diverse practice settings. The purpose of this study was to independently validate the ARTIC scale drawn from a sample of staff (n = 373) who provide services to substance-using parents. Psychometric tests were conducted to evaluate how the ARTIC performs with our HSO population. Results from a confirmatory factor analysis showed poor fit (
Sprache	Englisch
Erscheinungsdatum	2023-06-05
Erscheinungsland	Switzerland
Dokumenttyp	Journal Article
ZDB-ID	2651997-5
ISSN	2076-328X
ISSN	2076-328X
DOI	10.3390/bs13060471
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Early-phase drug discovery of β-III-spectrin actin-binding modulators for treatment of spinocerebellar ataxia type 5.

Guhathakurta, Piyali / Rebbeck, Robyn T / Denha, Sarah A / Keller, Amanda R / Carter, Anna L / Atang, Alexandra E / Svensson, Bengt / Thomas, David D / Hays, Thomas S / Avery, Adam W

The Journal of biological chemistry

2023 Band 299, Heft 3, Seite(n) 102956

Abstract: β-III-Spectrin is a key cytoskeletal protein that localizes to the soma and dendrites of cerebellar Purkinje cells and is required for dendritic arborization and signaling. A spinocerebellar ataxia type 5 L253P mutation in the cytoskeletal protein β-III- ... ...

Abstract	β-III-Spectrin is a key cytoskeletal protein that localizes to the soma and dendrites of cerebellar Purkinje cells and is required for dendritic arborization and signaling. A spinocerebellar ataxia type 5 L253P mutation in the cytoskeletal protein β-III-spectrin causes high-affinity actin binding. Previously we reported a cell-based fluorescence assay for identification of small-molecule actin-binding modulators of the L253P mutant β-III-spectrin. Here we describe a complementary, in vitro, fluorescence resonance energy transfer (FRET) assay that uses purified L253P β-III-spectrin actin-binding domain (ABD) and F-actin. To validate the assay for high-throughput compatibility, we first confirmed that our 50% FRET signal was responsive to swinholide A, an actin-severing compound, and that this yielded excellent assay quality with a Z' value > 0.77. Second, we screened a 2684-compound library of US Food and Drug Administration-approved drugs. Importantly, the screening identified numerous compounds that decreased FRET between fluorescently labeled L253P ABD and F-actin. The activity and target of multiple Hit compounds were confirmed in orthologous cosedimentation actin-binding assays. Through future medicinal chemistry, the Hit compounds can potentially be developed into a spinocerebellar ataxia type 5-specific therapeutic. Furthermore, our validated FRET-based in vitro high-throughput screening platform is poised for screening large compound libraries for β-III-spectrin ABD modulators.
Mesh-Begriff(e)	Humans ; Actins/genetics ; Actins/metabolism ; Drug Discovery ; Neurons/metabolism ; Spectrin/metabolism ; Spinocerebellar Ataxias/drug therapy ; Spinocerebellar Ataxias/genetics ; Spinocerebellar Ataxias/metabolism
Chemische Substanzen	Actins ; Spectrin (12634-43-4) ; SPTBN2 protein, human
Sprache	Englisch
Erscheinungsdatum	2023-01-31
Erscheinungsland	United States
Dokumenttyp	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2023.102956
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Robotic RNA extraction for SARS-CoV-2 surveillance using saliva samples.

PloS one

2021 Band 16, Heft 8, Seite(n) e0255690

Abstract: Saliva is an attractive specimen type for asymptomatic surveillance of COVID-19 in large populations due to its ease of collection and its demonstrated utility for detecting RNA from SARS-CoV-2. Multiple saliva-based viral detection protocols use a ... ...

Abstract	Saliva is an attractive specimen type for asymptomatic surveillance of COVID-19 in large populations due to its ease of collection and its demonstrated utility for detecting RNA from SARS-CoV-2. Multiple saliva-based viral detection protocols use a direct-to-RT-qPCR approach that eliminates nucleic acid extraction but can reduce viral RNA detection sensitivity. To improve test sensitivity while maintaining speed, we developed a robotic nucleic acid extraction method for detecting SARS-CoV-2 RNA in saliva samples with high throughput. Using this assay, the Free Asymptomatic Saliva Testing (IGI FAST) research study on the UC Berkeley campus conducted 11,971 tests on supervised self-collected saliva samples and identified rare positive specimens containing SARS-CoV-2 RNA during a time of low infection prevalence. In an attempt to increase testing capacity, we further adapted our robotic extraction assay to process pooled saliva samples. We also benchmarked our assay against nasopharyngeal swab specimens and found saliva methods require further optimization to match this gold standard. Finally, we designed and validated a RT-qPCR test suitable for saliva self-collection. These results establish a robotic extraction-based procedure for rapid PCR-based saliva testing that is suitable for samples from both symptomatic and asymptomatic individuals.
Mesh-Begriff(e)	Adult ; COVID-19/diagnosis ; COVID-19 Testing/methods ; Female ; Humans ; Male ; Mass Screening/methods ; RNA/genetics ; RNA/isolation & purification ; RNA, Viral/genetics ; RNA, Viral/isolation & purification ; Real-Time Polymerase Chain Reaction/methods ; Robotics/methods ; SARS-CoV-2/genetics ; Saliva/chemistry ; Specimen Handling/methods
Chemische Substanzen	RNA, Viral ; RNA (63231-63-0)
Sprache	Englisch
Erscheinungsdatum	2021-08-05
Erscheinungsland	United States
Dokumenttyp	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	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0255690
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel: Robotic RNA extraction for SARS-CoV-2 surveillance using saliva samples.

medRxiv : the preprint server for health sciences

2021

Abstract	Saliva is an attractive specimen type for asymptomatic surveillance of COVID-19 in large populations due to its ease of collection and its demonstrated utility for detecting RNA from SARS-CoV-2. Multiple saliva-based viral detection protocols use a direct-to-RT-qPCR approach that eliminates nucleic acid extraction but can reduce viral RNA detection sensitivity. To improve test sensitivity while maintaining speed, we developed a robotic nucleic acid extraction method for detecting SARS-CoV-2 RNA in saliva samples with high throughput. Using this assay, the Free Asymptomatic Saliva Testing (IGI-FAST) research study on the UC Berkeley campus conducted 11,971 tests on supervised self-collected saliva samples and identified rare positive specimens containing SARS-CoV-2 RNA during a time of low infection prevalence. In an attempt to increase testing capacity, we further adapted our robotic extraction assay to process pooled saliva samples. We also benchmarked our assay against the gold standard, nasopharyngeal swab specimens. Finally, we designed and validated a RT-qPCR test suitable for saliva self-collection. These results establish a robotic extraction-based procedure for rapid PCR-based saliva testing that is suitable for samples from both symptomatic and asymptomatic individuals.
Sprache	Englisch
Erscheinungsdatum	2021-01-29
Erscheinungsland	United States
Dokumenttyp	Preprint
DOI	10.1101/2021.01.10.21249151
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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Artikel ; Online: Current issues and trends in the diagnosis and treatment of adults with ADHD.

Cumyn, Lucy / Kolar, Dusan / Keller, Amanda / Hechtman, Lily

Expert review of neurotherapeutics

2007 Band 7, Heft 10, Seite(n) 1375–1390

Abstract: Attention-deficit/hyperactivity disorder (ADHD) has been commonly thought of as a childhood disorder that diminished over time. It is one of the most common developmental disorders and it is estimated that ADHD affects 5-10% of children. Two-thirds of ... ...

Abstract	Attention-deficit/hyperactivity disorder (ADHD) has been commonly thought of as a childhood disorder that diminished over time. It is one of the most common developmental disorders and it is estimated that ADHD affects 5-10% of children. Two-thirds of children with ADHD will continue to have symptoms of ADHD that persist throughout adolescence. Longitudinal studies have demonstrated that symptoms of ADHD can also remain in adulthood, affecting 4.4% of the adult population. However, diagnosing adults with ADHD can prove difficult because they often find that their symptoms are egosyntonic. In addition, the development of comorbid conditions, such as anxiety, depression, personality disorders or substance abuse, can often overshadow underlying ADHD symptoms. Nonetheless, treatments such as stimulant and nonstimulant medication (e.g., atomoxetine), and cognitive-behavior therapy have been effective in treating adults with ADHD. This article reviews the prevalence of adults with ADHD, followed by a discussion of the neurobiological and genetic underpinnings of the disorder. Issues regarding the diagnosis and treatment of ADHD are also addressed.
Mesh-Begriff(e)	Adult ; Age Factors ; Attention Deficit Disorder with Hyperactivity/diagnosis ; Attention Deficit Disorder with Hyperactivity/psychology ; Attention Deficit Disorder with Hyperactivity/therapy ; Child ; Diagnosis, Differential ; Humans ; Mental Disorders/diagnosis ; Mental Disorders/psychology ; Mental Disorders/therapy ; Psychiatric Status Rating Scales ; Treatment Outcome
Sprache	Englisch
Erscheinungsdatum	2007-10
Erscheinungsland	England
Dokumenttyp	Journal Article
ZDB-ID	2112534-X
ISSN	1744-8360 ; 1473-7175
ISSN (online)	1744-8360
ISSN	1473-7175
DOI	10.1586/14737175.7.10.1375
Datenquelle	MEDical Literature Analysis and Retrieval System OnLINE

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