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Article ; Online: Conformational flexibility in carbapenem hydrolysis drives substrate specificity of the class D carbapenemase OXA-24/40.

Mitchell, Joshua M / June, Cynthia M / Baggett, Vincent L / Lowe, Beth C / Ruble, James F / Bonomo, Robert A / Leonard, David A / Powers, Rachel A

The Journal of biological chemistry

2022 Volume 298, Issue 7, Page(s) 102127

Abstract: The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D β-lactamase subfamily present in Acinetobacter spp. is ... ...

Abstract	The evolution of multidrug resistance in Acinetobacter spp. increases the risk of our best antibiotics losing their efficacy. From a clinical perspective, the carbapenem-hydrolyzing class D β-lactamase subfamily present in Acinetobacter spp. is particularly concerning because of its ability to confer resistance to carbapenems. The kinetic profiles of class D β-lactamases exhibit variability in carbapenem hydrolysis, suggesting functional differences. To better understand the structure-function relationship between the carbapenem-hydrolyzing class D β-lactamase OXA-24/40 found in Acinetobacter baumannii and carbapenem substrates, we analyzed steady-state kinetics with the carbapenem antibiotics meropenem and ertapenem and determined the structures of complexes of OXA-24/40 bound to imipenem, meropenem, doripenem, and ertapenem, as well as the expanded-spectrum cephalosporin cefotaxime, using X-ray crystallography. We show that OXA-24/40 exhibits a preference for ertapenem compared with meropenem, imipenem, and doripenem, with an increase in catalytic efficiency of up to fourfold. We suggest that superposition of the nine OXA-24/40 complexes will better inform future inhibitor design efforts by providing insight into the complicated and varying ways in which carbapenems are selected and bound by class D β-lactamases.
MeSH term(s)	Acinetobacter baumannii/enzymology ; Anti-Bacterial Agents/chemistry ; Anti-Bacterial Agents/metabolism ; Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Carbapenems/chemistry ; Carbapenems/metabolism ; Hydrolysis ; Microbial Sensitivity Tests ; Protein Conformation ; Substrate Specificity ; beta-Lactamases/chemistry ; beta-Lactamases/metabolism
Chemical Substances	Anti-Bacterial Agents ; Bacterial Proteins ; Carbapenems ; beta-Lactamases (EC 3.5.2.6) ; beta-lactamase OXA-24 (EC 3.5.2.6) ; beta-lactamase OXA-40, Acinetobacter baumannii (EC 3.5.2.6)
Language	English
Publishing date	2022-06-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1016/j.jbc.2022.102127
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Article ; Online: Immunogenicity and efficacy of vaccine boosters against SARS-CoV-2 Omicron subvariant BA.5 in male Syrian hamsters.

Machado, Rafael R G / Walker, Jordyn L / Scharton, Dionna / Rafael, Grace H / Mitchell, Brooke M / Reyna, Rachel A / de Souza, William M / Liu, Jianying / Walker, David H / Plante, Jessica A / Plante, Kenneth S / Weaver, Scott C

Nature communications

2023 Volume 14, Issue 1, Page(s) 4260

Abstract: The SARS-CoV-2 Omicron subvariant BA.5 rapidly spread worldwide and replaced BA.1/BA.2 in many countries, becoming globally dominant. BA.5 has unique amino acid substitutions in the spike protein that both mediate immune escape from neutralizing ... ...

Abstract	The SARS-CoV-2 Omicron subvariant BA.5 rapidly spread worldwide and replaced BA.1/BA.2 in many countries, becoming globally dominant. BA.5 has unique amino acid substitutions in the spike protein that both mediate immune escape from neutralizing antibodies produced by immunizations and increase ACE2 receptor binding affinity. In a comprehensive, long-term (up to 9 months post primary vaccination), experimental vaccination study using male Syrian hamsters, we evaluate neutralizing antibody responses and efficacy against BA.5 challenge after primary vaccination with Ad26.COV2.S (Janssen) or BNT162b2 (Pfizer/BioNTech) followed by a homologous or heterologous booster with mRNA-1273 (Moderna) or NVX-CoV2373 (Novavax). Notably, one high or low dose of Ad26.COV2.S provides more durable immunity than two primary doses of BNT162b2, and the NVX-CoV2373 booster provides the strongest augmentation of immunity, reduction in BA.5 viral replication, and disease. Our data demonstrate the immunogenicity and efficacy of different prime/boost vaccine regimens against BA.5 infection in an immune-competent model and provide new insights regarding COVID-19 vaccine strategies.
MeSH term(s)	Animals ; Cricetinae ; Male ; Humans ; COVID-19 Vaccines ; Ad26COVS1 ; BNT162 Vaccine ; Mesocricetus ; SARS-CoV-2 ; COVID-19/prevention & control ; Vaccines ; Antibodies, Neutralizing ; Antibodies, Viral
Chemical Substances	COVID-19 Vaccines ; Ad26COVS1 (JT2NS6183B) ; BNT162 Vaccine ; Vaccines ; Antibodies, Neutralizing ; Antibodies, Viral
Language	English
Publishing date	2023-07-17
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40033-2
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Article ; Online: Further characterisation of the functional neuroanatomy associated with prosodic emotion decoding.

Mitchell, Rachel L C

Cortex; a journal devoted to the study of the nervous system and behavior

2013 Volume 49, Issue 6, Page(s) 1722–1732

Abstract: Introduction: Current models of prosodic emotion comprehension propose a three stage cognition mediated by temporal lobe auditory regions through to inferior and orbitofrontal regions. Cumulative evidence suggests that its mediation may be more flexible ...

Abstract	Introduction: Current models of prosodic emotion comprehension propose a three stage cognition mediated by temporal lobe auditory regions through to inferior and orbitofrontal regions. Cumulative evidence suggests that its mediation may be more flexible though, with a facility to respond in a graded manner based on the need for executive control. The location of this fine-tuning system is unclear, as is its similarity to the cognitive control system. Methods: In the current study, need for executive control was manipulated in a block-design functional MRI study by systematically altering the proportion of incongruent trials across time, i.e., trials for which participants identified prosodic emotions in the face of conflicting lexico-semantic emotion cues. Resultant Blood Oxygenation Level Dependent contrast data were analysed according to standard procedures using Statistical Parametric Mapping v8 (Ashburner et al., 2009). Results: In the parametric analyses, superior (medial) frontal gyrus activity increased linearly with increased need for executive control. In the separate analyses of each level of incongruity, results suggested that the baseline prosodic emotion comprehension system was sufficient to deal with low proportions of incongruent trials, whereas a more widespread frontal lobe network was required for higher proportions. Conclusions: These results suggest an executive control system for prosodic emotion comprehension exists which has the capability to recruit superior (medial) frontal gyrus in a graded manner and other frontal regions once demand exceeds a certain threshold. The need to revise current models of prosodic emotion comprehension and add a fourth processing stage are discussed.
MeSH term(s)	Acoustic Stimulation ; Analysis of Variance ; Brain/anatomy & histology ; Brain/physiology ; Brain Mapping ; Cognition/physiology ; Comprehension ; Conflict (Psychology) ; Data Interpretation, Statistical ; Emotions/physiology ; Executive Function ; Facial Expression ; Female ; Frontal Lobe/physiology ; Humans ; Image Processing, Computer-Assisted ; Magnetic Resonance Imaging ; Male ; Models, Neurological ; Psychomotor Performance/physiology ; Social Perception ; Stereotaxic Techniques ; Temporal Lobe/physiology ; Young Adult
Language	English
Publishing date	2013-06
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	280622-8
ISSN	1973-8102 ; 0010-9452
ISSN (online)	1973-8102
ISSN	0010-9452
DOI	10.1016/j.cortex.2012.07.010
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Article: What is the Value of Embedding Artificial Emotional Prosody in Human-Computer Interactions? Implications for Theory and Design in Psychological Science.

Mitchell, Rachel L C / Xu, Yi

Frontiers in psychology

2015 Volume 6, Page(s) 1750

Abstract: In computerized technology, artificial speech is becoming increasingly important, and is already used in ATMs, online gaming and healthcare contexts. However, today's artificial speech typically sounds monotonous, a main reason for this being the lack of ...

Abstract	In computerized technology, artificial speech is becoming increasingly important, and is already used in ATMs, online gaming and healthcare contexts. However, today's artificial speech typically sounds monotonous, a main reason for this being the lack of meaningful prosody. One particularly important function of prosody is to convey different emotions. This is because successful encoding and decoding of emotions is vital for effective social cognition, which is increasingly recognized in human-computer interaction contexts. Current attempts to artificially synthesize emotional prosody are much improved relative to early attempts, but there remains much work to be done due to methodological problems, lack of agreed acoustic correlates, and lack of theoretical grounding. If the addition of synthetic emotional prosody is not of sufficient quality, it may risk alienating users instead of enhancing their experience. So the value of embedding emotion cues in artificial speech may ultimately depend on the quality of the synthetic emotional prosody. However, early evidence on reactions to synthesized non-verbal cues in the facial modality bodes well. Attempts to implement the recognition of emotional prosody into artificial applications and interfaces have perhaps been met with greater success, but the ultimate test of synthetic emotional prosody will be to critically compare how people react to synthetic emotional prosody vs. natural emotional prosody, at the behavioral, socio-cognitive and neural levels.
Language	English
Publishing date	2015-11-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2563826-9
ISSN	1664-1078
ISSN	1664-1078
DOI	10.3389/fpsyg.2015.01750
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Article ; Online: Complex sensory environments alter mate choice outcomes.

Taylor, Ryan C / Wilhite, Kyle O / Ludovici, Rosalind J / Mitchell, Kelsey M / Halfwerk, Wouter / Page, Rachel A / Ryan, Michael J / Hunter, Kimberly L

The Journal of experimental biology

2021 Volume 224, Issue Pt 1

Abstract: Noise is a common problem in animal communication. We know little, however, about how animals communicate in the presence of noise using multimodal signals. Multimodal signals are hypothesised to be favoured by evolution because they increase the ... ...

Abstract	Noise is a common problem in animal communication. We know little, however, about how animals communicate in the presence of noise using multimodal signals. Multimodal signals are hypothesised to be favoured by evolution because they increase the efficacy of detection and discrimination in noisy environments. We tested the hypothesis that female túngara frogs' responses to attractive male advertisement calls are improved in noise when a visual signal component is added to the available choices. We tested this at two levels of decision complexity (two and three choices). In a two-choice test, the presence of noise did not reduce female preferences for attractive calls. The visual component of a calling male, associated with an unattractive call, also did not reduce preference for attractive calls in the absence of noise. In the presence of noise, however, females were more likely to choose an unattractive call coupled with the visual component. In three-choice tests, the presence of noise alone reduced female responses to attractive calls and this was not strongly affected by the presence or absence of visual components. The responses in these experiments fail to support the multimodal signal efficacy hypothesis. Instead, the data suggest that audio-visual perception and cognitive processing, related to mate choice decisions, are dependent on the complexity of the sensory scene.
MeSH term(s)	Animal Communication ; Animals ; Anura ; Female ; Male ; Noise ; Sexual Behavior, Animal ; Visual Perception ; Vocalization, Animal
Language	English
Publishing date	2021-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	218085-6
ISSN	1477-9145 ; 0022-0949
ISSN (online)	1477-9145
ISSN	0022-0949
DOI	10.1242/jeb.233288
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Zs.A 2629: Show issues

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Article ; Online: Age-related decline in emotional prosody discrimination: acoustic correlates.

Mitchell, Rachel L C / Kingston, Rachel A

Experimental psychology

2014 Volume 61, Issue 3, Page(s) 215–223

Abstract: It is now accepted that older adults have difficulty recognizing prosodic emotion cues, but it is not clear at what processing stage this ability breaks down. We manipulated the acoustic characteristics of tones in pitch, amplitude, and duration ... ...

Abstract	It is now accepted that older adults have difficulty recognizing prosodic emotion cues, but it is not clear at what processing stage this ability breaks down. We manipulated the acoustic characteristics of tones in pitch, amplitude, and duration discrimination tasks to assess whether impaired basic auditory perception coexisted with our previously demonstrated age-related prosodic emotion perception impairment. It was found that pitch perception was particularly impaired in older adults, and that it displayed the strongest correlation with prosodic emotion discrimination. We conclude that an important cause of age-related impairment in prosodic emotion comprehension exists at the fundamental sensory level of processing.
MeSH term(s)	Aged ; Aged, 80 and over ; Aging/physiology ; Auditory Perception/physiology ; Comprehension ; Cues ; Discrimination (Psychology)/physiology ; Emotions ; Face ; Female ; Humans ; Male ; Middle Aged ; Recognition (Psychology)/physiology ; Social Perception
Language	English
Publishing date	2014
Publishing country	Germany
Document type	Clinical Trial ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2071412-9
ISSN	2190-5142 ; 1618-3169
ISSN (online)	2190-5142
ISSN	1618-3169
DOI	10.1027/1618-3169/a000241
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Zs.B 1461: Show issues

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Article ; Online: Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population.

Humphries, Elizabeth M / Ahn, Kwangmi / Kember, Rachel L / Lopes, Fabiana L / Mocci, Evelina / Peralta, Juan M / Blangero, John / Glahn, David C / Goes, Fernando S / Zandi, Peter P / Kochunov, Peter / Van Hout, Cristopher / Shuldiner, Alan R / Pollin, Toni I / Mitchell, Braxton D / Bucan, Maja / Hong, L Elliot / McMahon, Francis J / Ament, Seth A

Molecular psychiatry

2023 Volume 28, Issue 12, Page(s) 5262–5271

Abstract: Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover ...

Abstract	Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.
MeSH term(s)	Humans ; Genome-Wide Association Study/methods ; Male ; Female ; Genetic Predisposition to Disease/genetics ; Mood Disorders/genetics ; Middle Aged ; Polymorphism, Single Nucleotide/genetics ; Amish/genetics ; Adult ; Case-Control Studies ; Transcription Factors/genetics ; Risk Factors ; Genetic Loci ; Repressor Proteins/genetics ; Aged ; Homeodomain Proteins/genetics ; Founder Effect ; Nuclear Proteins/genetics
Chemical Substances	Transcription Factors ; Repressor Proteins ; Homeodomain Proteins ; Nuclear Proteins
Language	English
Publishing date	2023-03-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1330655-8
ISSN	1476-5578 ; 1359-4184
ISSN (online)	1476-5578
ISSN	1359-4184
DOI	10.1038/s41380-023-02014-1
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Zs.A 4812: Show issues

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Article ; Online: High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer.

Cell reports

2023 Volume 42, Issue 8, Page(s) 112821

Abstract: Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor- ... ...

Abstract	Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.
Language	English
Publishing date	2023-07-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112821
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Article ; Online: Equity and bias in electronic health records data.

Boyd, Andrew D / Gonzalez-Guarda, Rosa / Lawrence, Katharine / Patil, Crystal L / Ezenwa, Miriam O / O'Brien, Emily C / Paek, Hyung / Braciszewski, Jordan M / Adeyemi, Oluwaseun / Cuthel, Allison M / Darby, Juanita E / Zigler, Christina K / Ho, P Michael / Faurot, Keturah R / Staman, Karen / Leigh, Jonathan W / Dailey, Dana L / Cheville, Andrea / Del Fiol, Guilherme /

Knisely, Mitchell R / Marsolo, Keith / Richesson, Rachel L / Schlaeger, Judith M

Contemporary clinical trials

2023 Volume 130, Page(s) 107238

Abstract: Embedded pragmatic clinical trials (ePCTs) are conducted during routine clinical care and have the potential to increase knowledge about the effectiveness of interventions under real world conditions. However, many pragmatic trials rely on data from the ... ...

Abstract	Embedded pragmatic clinical trials (ePCTs) are conducted during routine clinical care and have the potential to increase knowledge about the effectiveness of interventions under real world conditions. However, many pragmatic trials rely on data from the electronic health record (EHR) data, which are subject to bias from incomplete data, poor data quality, lack of representation from people who are medically underserved, and implicit bias in EHR design. This commentary examines how the use of EHR data might exacerbate bias and potentially increase health inequities. We offer recommendations for how to increase generalizability of ePCT results and begin to mitigate bias to promote health equity.
MeSH term(s)	Humans ; Electronic Health Records ; Health Promotion ; Bias ; Data Accuracy ; Health Equity
Language	English
Publishing date	2023-05-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2182176-8
ISSN	1559-2030 ; 1551-7144
ISSN (online)	1559-2030
ISSN	1551-7144
DOI	10.1016/j.cct.2023.107238
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Zs.A 1581: Show issues

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Article: Theory of Mind in Bipolar Disorder, with Comparison to the Impairments Observed in Schizophrenia.

Mitchell, Rachel L C / Young, Allan H

Frontiers in psychiatry

2016 Volume 6, Page(s) 188

Abstract: Our ability to make sense of information on the potential intentions and dispositions of others is of paramount importance for understanding their communicative intent, and for judging what an appropriate reaction might be. Thus, anything that impinges ... ...

Abstract	Our ability to make sense of information on the potential intentions and dispositions of others is of paramount importance for understanding their communicative intent, and for judging what an appropriate reaction might be. Thus, anything that impinges on this ability has the potential to cause significant social impairment, and compromise an individual's level of functioning. Both bipolar disorder and schizophrenia are known to feature theory of mind impairment. We conducted a theoretical review to determine the extent and types of theory of mind impairment in bipolar disorder, and evaluate their relationship to medication and symptoms. We also considered possible mediatory mechanisms, and set out to discover what else could be learnt about the impairment in bipolar disorder by comparison to the profile of impairment in schizophrenia. The literature established that in bipolar disorder (i) some form of theory of mind impairment has been observed in all mood states, including euthymia, (ii) the form of theory of mind assessed and task used to make the assessment influence the impairment observed, and (iii) there might be some relationship to cognitive impairment, although a relationship to standard clinical variables was harder to establish. What also became clear in the literature on bipolar disorder itself was the possible relationship of theory of mind impairment to history of psychotic symptoms. Direct comparative studies, including patients with schizophrenia, were thus examined, and provided several important directions for future research on the bases of impairment in bipolar disorder. Particularly prominent was the issue of whether theory of mind impairment could be considered a candidate endophenotype for the psychoses, although current evidence suggests that this may be premature. The differences in impairment across schizophrenia and bipolar disorder may, however, have genuine differential effects on social functioning and the likely success of remediation.
Language	English
Publishing date	2016-01-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2564218-2
ISSN	1664-0640
ISSN	1664-0640
DOI	10.3389/fpsyt.2015.00188
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