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1.
Biochemistry ; 61(15): 1625-1632, 2022 08 02.
Article in English | MEDLINE | ID: mdl-35802500

ABSTRACT

Structured RNAs bind ligands and are attractive targets for small-molecule drugs. A wide variety of analytical methods have been used to characterize RNA-ligand interactions, but our experience is that most have significant limitations in terms of material requirements and applicability to complex RNAs. Surface plasmon resonance (SPR) potentially overcomes these limitations, but we find that the standard experimental framework measures notable nonspecific electrostatic-mediated interactions, frustrating analysis of weak RNA binders. SPR measurements are typically quantified relative to a non-target reference channel. Here, we show that referencing to a channel containing a non-binding control RNA enables subtraction of nonspecific binding contributions, allowing measurements of accurate and specific binding affinities. We validated this approach for small-molecule binders of two riboswitch RNAs with affinities ranging from nanomolar to millimolar, including low-molecular-mass fragment ligands. SPR implemented with reference subtraction reliably discriminates specific from nonspecific binding, uses RNA and ligand material efficiently, and enables rapid exploration of the ligand-binding landscape for RNA targets.


Subject(s)
RNA , Surface Plasmon Resonance , Ligands , Surface Plasmon Resonance/methods
2.
Mol Cell ; 82(9): 1708-1723.e10, 2022 05 05.
Article in English | MEDLINE | ID: mdl-35320755

ABSTRACT

7SK is a conserved noncoding RNA that regulates transcription by sequestering the transcription factor P-TEFb. 7SK function entails complex changes in RNA structure, but characterizing RNA dynamics in cells remains an unsolved challenge. We developed a single-molecule chemical probing strategy, DANCE-MaP (deconvolution and annotation of ribonucleic conformational ensembles), that defines per-nucleotide reactivity, direct base pairing interactions, tertiary interactions, and thermodynamic populations for each state in RNA structural ensembles from a single experiment. DANCE-MaP reveals that 7SK RNA encodes a large-scale structural switch that couples dissolution of the P-TEFb binding site to structural remodeling at distal release factor binding sites. The 7SK structural equilibrium shifts in response to cell growth and stress and can be targeted to modulate expression of P-TEFbresponsive genes. Our study reveals that RNA structural dynamics underlie 7SK function as an integrator of diverse cellular signals to control transcription and establishes the power of DANCE-MaP to define RNA dynamics in cells.


Subject(s)
Positive Transcriptional Elongation Factor B , RNA-Binding Proteins , Binding Sites/genetics , HeLa Cells , Humans , Positive Transcriptional Elongation Factor B/genetics , RNA, Small Nuclear/genetics , RNA, Untranslated , RNA-Binding Proteins/genetics
3.
Diabet Med ; 37(5): 805-813, 2020 05.
Article in English | MEDLINE | ID: mdl-31872457

ABSTRACT

AIM: To examine the value of peer support in the self-management of diabetes among veterans in an integrated health care system. METHODS: We conducted semi-structured in-depth interviews with veterans and clinicians 6 months after their participation in Empowering Patients in Chronic Care (EPIC), a group-based diabetes intervention with a peer-support component. Interviews elicited clinicians' narratives of how peer support unfolded in the groups and veterans' experiences of giving and receiving support from their peers. Data analysis was guided by principles of framework analysis using Heisler's peer-support model. RESULTS: Findings support Heisler's peer-support model and provide evidence supporting professional-led group visits with peer exchange. Clinicians and veterans endorsed informational and emotional support received in EPIC groups. Clinicians often referred to EPIC as an open forum or a support group where veterans could both give and receive help. Veterans noted the benefits of shared problem-solving and the support they received. Clinicians and veterans perceived the peer-support component of EPIC as facilitating increased empowerment in terms of self-efficacy, increased perceived social support and increased understanding of self-care. Ultimately, many veterans acknowledged that their participation in EPIC facilitated improved health-related quality of life, improved health behaviours and improved chronic disease control. CONCLUSIONS: Findings emphasize the value of peer support in managing chronic illness. Peer-support programmes may address veterans' unique challenges and have the potential to improve physical and mental health.


Subject(s)
Diabetes Mellitus, Type 2/therapy , Peer Group , Self Care , Self-Management , Social Support , Veterans , Aged , Humans , Male , Patient Participation , Problem Solving , Qualitative Research , Self Efficacy
5.
J Org Chem ; 83(12): 6541-6555, 2018 06 15.
Article in English | MEDLINE | ID: mdl-29751727

ABSTRACT

The piperazine heterocycle is broadly exploited in FDA-approved drugs and biologically active compounds, but its chemical diversity is usually limited to ring nitrogen substitutions, leaving the four carbon atoms underutilized. Using an efficient four-step synthesis, chiral amino acids were transformed into 6-substituted piperazine-2-acetic acid esters as diastereomeric mixtures whose cis and trans products could be chromatographically separated. From six amino acids (both antipodes), a complete matrix of 24 monoprotected chiral 2,6-disubstituted piperazines was obtained, each as a single absolute stereoisomer in multigram quantities. These diverse and versatile piperazines can be functionalized on either nitrogen atom, allowing them to be used as scaffolds for parallel library synthesis or intermediates for the production of novel piperazine compounds.

6.
Dis Esophagus ; 26(7): 682-9, 2013.
Article in English | MEDLINE | ID: mdl-23383987

ABSTRACT

Adherence to practice guidelines for endoscopic surveillance of Barrett's esophagus is equivocal with evidence of underutilization and overutilization. While physicians report strong agreement with and adherence to recommended surveillance endoscopy (esophagogastroduodenoscopy [EGD]) guidelines, less is known about modifiable barriers and facilitators shaping patients' adherence behaviors. The aim of this study is to conduct a structured literature review of studies exploring patients' perspectives regarding surveillance EGD and to place these results within a conceptual framework. A structured literature review of PubMed, Cochrane, and Google Scholar databases with qualitative thematic analysis was performed. Six studies met eligibility criteria. Analysis of results identified five distinct themes. First, patients' objective cancer risk estimates are consistent with subjective risk perceptions, but neither is associated with EGD surveillance. Second, patients have strong beliefs in the benefits of cancer screening and surveillance and trust in their doctors. Third, anxiety and depression symptoms are related to risk perceptions and outcome expectancies of surveillance. Fourth, endoscopic surveillance itself has affective and physical consequences. Finally, health services and system variables are related to risk perception and EGD surveillance. These themes coherently fit within an integrated model of intuitive decision-making and health behaviors. Studies meeting eligibility criteria were heterogeneous in terms of their study objectives and findings. Quantitative meta-analyses of study findings could not be performed. To improve adherence, endoscopic surveillance programs should consider how patients intuitively frame risks and benefits and patients' emotional reactions to the endoscopy procedure, and focus on how physicians communicate recommendations.


Subject(s)
Barrett Esophagus/psychology , Decision Making , Endoscopy, Digestive System/psychology , Esophagoscopy/psychology , Intuition , Precancerous Conditions/psychology , Adenocarcinoma/diagnosis , Adenocarcinoma/psychology , Early Detection of Cancer/psychology , Early Detection of Cancer/statistics & numerical data , Endoscopy, Digestive System/statistics & numerical data , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/psychology , Humans , Models, Psychological , Patient Acceptance of Health Care/psychology , Patient Acceptance of Health Care/statistics & numerical data , Patient Compliance/psychology , Patient Compliance/statistics & numerical data
7.
Dev Med Child Neurol ; 38(3): 226-37, 1996 Mar.
Article in English | MEDLINE | ID: mdl-8631519

ABSTRACT

Forty-four children aged 3 to 11 years with quadriplegic cerebral palsy were prospectively stratified and randomised into four treatment groups. The acquisition of motor skills was assessed in a 2 x 2 factorial design using the Gross Motor Function Measure. The two factors were conventional amounts of physiotherapy vs intensive amounts of physiotherapy, and the use of broad, generalised aims vs the use of specific measurable goals directed at motor skill acquisition. 82% of the children improved. Over the two-week period, intensive physiotherapy produced a slightly greater effect than conventional physiotherapy but the factor more strongly associated with increased motor skill acquisition was the use of specific measurable goals.


Subject(s)
Cerebral Palsy/therapy , Goals , Physical Therapy Modalities , Adolescent , Child , Child, Preschool , Humans , Motor Skills , Prospective Studies , Severity of Illness Index
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