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Article ; Online: Evolutionary changes in the predatory attack of carnivorous rodents: A comparative analysis emphasizing grasshopper mice (Onychomys spp.).

Langley, William M

Journal of comparative psychology (Washington, D.C. : 1983)

2021 Volume 135, Issue 1, Page(s) 114–126

Abstract: The predatory attack itself may differ between that of a carnivorous and omnivorous species, given the shift in lifestyles. I reviewed the information on 63 carnivorous rodent species. The approach here is to compare the predatory attack of carnivorous ... ...

Abstract	The predatory attack itself may differ between that of a carnivorous and omnivorous species, given the shift in lifestyles. I reviewed the information on 63 carnivorous rodent species. The approach here is to compare the predatory attack of carnivorous grasshopper mice (
MeSH term(s)	Animals ; Arvicolinae/psychology ; Predatory Behavior
Language	English
Publishing date	2021-02-08
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	3130-6
ISSN	1939-2087 ; 0735-7036 ; 0093-4127
ISSN (online)	1939-2087
ISSN	0735-7036 ; 0093-4127
DOI	10.1037/com0000257
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Article: LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.

Peters, Colin H / Singh, Rohit K / Langley, Avery A / Nichols, William G / Ferris, Hannah R / Jeffrey, Danielle A / Proenza, Catherine / Bankston, John R

bioRxiv : the preprint server for biology

2024

Abstract: Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4 but the interaction domains, mechanisms of ... ...

Abstract	Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4 but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here we identify the domains of LRMP essential for regulation. We show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating. And we demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we showed that the initial 227 residues of LRMP and the N-terminus of HCN4 are necessary for LRMP to interact with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. And we demonstrate that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of 5 residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.
Language	English
Publishing date	2024-01-24
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.08.29.555242
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Article ; Online: LRMP inhibits cAMP potentiation of HCN4 channels by disrupting intramolecular signal transduction.

Peters, Colin H / Singh, Rohit K / Langley, Avery A / Nichols, William G / Ferris, Hannah R / Jeffrey, Danielle A / Proenza, Catherine / Bankston, John R

eLife

2024 Volume 12

Abstract: Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4, but the interaction domains, mechanisms of ... ...

Abstract	Lymphoid restricted membrane protein (LRMP) is a specific regulator of the hyperpolarization-activated cyclic nucleotide-sensitive isoform 4 (HCN4) channel. LRMP prevents cAMP-dependent potentiation of HCN4, but the interaction domains, mechanisms of action, and basis for isoform-specificity remain unknown. Here, we identify the domains of LRMP essential for this regulation, show that LRMP acts by disrupting the intramolecular signal transduction between cyclic nucleotide binding and gating, and demonstrate that multiple unique regions in HCN4 are required for LRMP isoform-specificity. Using patch clamp electrophysiology and Förster resonance energy transfer (FRET), we identified the initial 227 residues of LRMP and the N-terminus of HCN4 as necessary for LRMP to associate with HCN4. We found that the HCN4 N-terminus and HCN4-specific residues in the C-linker are necessary for regulation of HCN4 by LRMP. Finally, we demonstrated that LRMP-regulation can be conferred to HCN2 by addition of the HCN4 N-terminus along with mutation of five residues in the S5 region and C-linker to the cognate HCN4 residues. Taken together, these results suggest that LRMP inhibits HCN4 through an isoform-specific interaction involving the N-terminals of both proteins that prevents the transduction of cAMP binding into a change in channel gating, most likely via an HCN4-specific orientation of the N-terminus, C-linker, and S4-S5 linker.
MeSH term(s)	Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/genetics ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/chemistry ; Cyclic AMP/metabolism ; Signal Transduction ; Humans ; Membrane Proteins/metabolism ; Membrane Proteins/genetics ; Animals ; Protein Binding ; HEK293 Cells ; Potassium Channels/metabolism ; Potassium Channels/genetics ; Potassium Channels/chemistry ; Patch-Clamp Techniques ; Fluorescence Resonance Energy Transfer ; Protein Isoforms/metabolism ; Protein Isoforms/genetics ; Muscle Proteins ; Receptors, Cytoplasmic and Nuclear
Chemical Substances	Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Cyclic AMP (E0399OZS9N) ; Membrane Proteins ; PEX5L protein, human ; HCN4 protein, human ; Potassium Channels ; Protein Isoforms ; Muscle Proteins ; Receptors, Cytoplasmic and Nuclear
Language	English
Publishing date	2024-04-23
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.92411
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Article ; Online: RNA sequencing reveals a complete picture of a homozygous missense variant in a patient with VPS13D movement disorder: a case report and review of the literature.

Baker, Elizabeth K / Han, Jingfen / Langley, William A / Reott, Michael A / Hallinan, Barbara E / Hopkin, Robert J / Zhang, Wenying

Molecular genetics and genomics : MGG

2023 Volume 298, Issue 5, Page(s) 1185–1199

Abstract: RNA sequencing (RNA-seq) is a complementary diagnostic tool to exome sequencing (ES), only recently clinically available to undiagnosed patients post-ES, that provides functional information on variants of unknown significance (VUS) by evaluating its ... ...

Abstract	RNA sequencing (RNA-seq) is a complementary diagnostic tool to exome sequencing (ES), only recently clinically available to undiagnosed patients post-ES, that provides functional information on variants of unknown significance (VUS) by evaluating its effect on RNA transcription. ES became clinically available in the early 2010s and promised an agnostic platform for patients with a neurological disease, especially for those who believed to have a genetic etiology. However, the massive data generated by ES pose challenges in variant interpretation, especially for rare missense, synonymous, and deep intronic variants that may have a splicing effect. Without functional study and/or family segregation analysis, these rare variants would be likely interpreted as VUS which is difficult for clinicians to use in clinical care. Clinicians are able to assess the VUS for phenotypic overlap, but this additional information alone is usually not enough to re-classify a variant. Here, we report a case of a 14-month-old male who presented to clinic with a history of seizures, nystagmus, cerebral palsy, oral aversion, global developmental delay, and poor weight gain requiring gastric tube placement. ES revealed a previously unreported homozygous missense VUS, c.7406A > G p.(Asn2469Ser), in VPS13D. This variant has not been previously reported in genome aggregation database (gnomAD), ClinVar, or in any peer-reviewed published literature. By RNA-seq, we demonstrated that this variant mainly impacts splicing and results in a frameshift and early termination. It is expected to generate either a truncated protein, p.(Val2468fs*19), or no protein from this transcript due to nonsense-mediated mRNA decay leading to VPS13D deficiency. To our knowledge, this is the first case utilizing RNA-seq to further functionally characterize a homozygous novel missense VUS in VPS13D and confirm its impact on splicing. This confirmed pathogenicity gave the diagnosis of VPS13D movement disorder to this patient. Therefore, clinicians should consider utilizing RNA-seq to clarify VUS by evaluating its effect on RNA transcription.
MeSH term(s)	Humans ; Male ; Infant ; Exome Sequencing ; Mutation ; RNA ; Movement Disorders ; Sequence Analysis, RNA ; Proteins
Chemical Substances	RNA (63231-63-0) ; VPS13D protein, human ; Proteins
Language	English
Publishing date	2023-06-20
Publishing country	Germany
Document type	Review ; Case Reports ; Journal Article
ZDB-ID	2044817-X
ISSN	1617-4623 ; 1617-4615
ISSN (online)	1617-4623
ISSN	1617-4615
DOI	10.1007/s00438-023-02044-y
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Zs.A 1198: Show issues

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Book: Pancreatitis research advances

Langley, William C.

(Nova biomedical)

2007

Author's details	William C. Langley, ed
Series title	Nova biomedical
Keywords	Pancreatitis ; Pancreatitis / diagnosis ; Pancreatic Neoplasms / diagnosis
Subject code	616.37
Language	English
Size	XVI, 382 S. : Ill.
Publisher	Nova Biomed. Books
Publishing place	New York
Publishing country	United States
Document type	Book
HBZ-ID	HT015961114
ISBN	978-1-600-21883-5 ; 978-1-60021-883-5 ; 1-60021-883-0 ; 1-600-21883-0
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Alternative Facts and the ICER Proposed Policy on Access to Imaginary Pharmacoeconomic Worlds.

Langley, Paul C

Innovations in pharmacy

2018 Volume 9, Issue 2, Page(s) 1–5

Abstract: ... to which ICER is willing to commit to transparency in the creation of modeled claims. While a commitment ...

Abstract	The Institute for Clinical and Economic Review (ICER) announced at the end of March 2018 that it proposed to share executable draft economic models with relevant drug manufacturers during ICER evidence reviews. Taken at face value, ICER is offering manufacturers and other interested parties the possibility of a greater involvement in the assessment of modeled claims for product pricing. The purpose of this commentary is to point to the obvious limitations to this policy and to raise questions as to the extent to which ICER is willing to commit to transparency in the creation of modeled claims. While a commitment to greater transparency is to be welcomed, the fact remains that the ICER methodology does not meet the standards of normal science. ICER modeled claims not only lack credibility but are impossible to evaluate or replicate in treating environments. In proposing greater transparency ICER runs the risk of undermining its own credibility. If manufacturers have the opportunity to generate alternative models which create alternative claims, then ICER runs the risk of its pole position in health technology assessment being questioned. Rather than focused on non-evaluable lifetime modeled claims, there is the opportunity for ICER to reject its current business model, accepting instead a modelling paradigm that is consistent with the standards of normal science.
Language	English
Publishing date	2018-04-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2689516-X
ISSN	2155-0417 ; 2155-0417
ISSN (online)	2155-0417
ISSN	2155-0417
DOI	10.24926/iip.v9i2.1300
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Article ; Online: Routine saliva testing for the identification of silent coronavirus disease 2019 (COVID-19) in healthcare workers.

Zhang, Kevin / Shoukat, Affan / Crystal, William / Langley, Joanne M / Galvani, Alison P / Moghadas, Seyed M

Infection control and hospital epidemiology

2021 Volume 42, Issue 10, Page(s) 1189–1193

Abstract: Objective: Current COVID-19 guidelines recommend symptom-based screening and regular nasopharyngeal (NP) testing for healthcare personnel in high-risk settings. We sought to estimate case detection percentages with various routine NP and saliva testing ... ...

Abstract	Objective: Current COVID-19 guidelines recommend symptom-based screening and regular nasopharyngeal (NP) testing for healthcare personnel in high-risk settings. We sought to estimate case detection percentages with various routine NP and saliva testing frequencies. Design: Simulation modeling study. Methods: We constructed a sensitivity function based on the average infectiousness profile of symptomatic coronavirus disease 2019 (COVID-19) cases to determine the probability of being identified at the time of testing. This function was fitted to reported data on the percent positivity of symptomatic COVID-19 patients using NP testing. We then simulated a routine testing program with different NP and saliva testing frequencies to determine case detection percentages during the infectious period, as well as the presymptomatic stage. Results: Routine biweekly NP testing, once every 2 weeks, identified an average of 90.7% (SD, 0.18) of cases during the infectious period and 19.7% (SD, 0.98) during the presymptomatic stage. With a weekly NP testing frequency, the corresponding case detection percentages were 95.9% (SD, 0.18) and 32.9% (SD, 1.23), respectively. A 5-day saliva testing schedule had a similar case detection percentage as weekly NP testing during the infectious period, but identified ~10% more cases (mean, 42.5%; SD, 1.10) during the presymptomatic stage. Conclusion: Our findings highlight the utility of routine noninvasive saliva testing for frontline healthcare workers to protect vulnerable patient populations. A 5-day saliva testing schedule should be considered to help identify silent infections and prevent outbreaks in nursing homes and healthcare facilities.
MeSH term(s)	COVID-19 ; COVID-19 Testing ; Clinical Laboratory Techniques ; Health Personnel ; Humans ; SARS-CoV-2 ; Saliva
Language	English
Publishing date	2021-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	639378-0
ISSN	1559-6834 ; 0195-9417 ; 0899-823X
ISSN (online)	1559-6834
ISSN	0195-9417 ; 0899-823X
DOI	10.1017/ice.2020.1413
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Article ; Online: Phage therapy: Awareness and demand among clinicians in the United Kingdom.

Simpson, Emily A / Stacey, Helen J / Langley, Ross J / Jones, Joshua D

PloS one

2023 Volume 18, Issue 11, Page(s) e0294190

Abstract: ... per clinician). Most respondents (71.1%, n = 90) were already willing to consider using phage therapy ...

Abstract	Bacterial resistance or tolerance to antibiotics is costly to patients and healthcare providers. With the impact of antibiotic resistance forecast to grow, alternative antimicrobial approaches are needed to help treat patients with antibiotic refractory infections and reduce reliance upon existing antibiotics. There is renewed interest in bacteriophage (phage) therapy as a promising antimicrobial strategy. We therefore performed the first multi-specialty survey about phage therapy and the first such survey among clinicians in the United Kingdom. An anonymous 10-question survey of clinicians from medical and surgical specialties in two Scottish Health Boards was performed. The 90 respondents spanned 26 specialties and were predominantly consultants (73.3%). The respondents were concerned about antibiotic resistance in their clinical practice; 83 respondents estimated having seen 711 patients in the last 12 months whose infections were refractory to antibiotics (delaying or preventing resolution). Over half (58.8%) of the respondents had previously heard of phage therapy. Staphylococci, Pseudomonas and E. coli were identified as the highest cross-specialty priorities for the development of phage therapy. Together, 77 respondents estimated seeing 300 patients in the last 12 months for whom phage therapy may have been appropriate (an average of 3.9 patients per clinician). Most respondents (71.1%, n = 90) were already willing to consider using phage therapy in appropriate cases. Additional comments from the respondents affirmed the potential utility of phage therapy and highlighted a need for more information. The results of this survey demonstrate substantial demand for and willingness to use phage therapy in appropriate cases, both from individual clinicians and across specialties. Demand from a wide range of specialties illustrates the broad clinical utility of phage therapy and potential scope of impact. Widening access to phage therapy could deliver substantial clinical and financial benefits for patients and health authorities alike.
MeSH term(s)	Humans ; Escherichia coli ; Phage Therapy ; Bacteriophages ; Bacterial Infections/drug therapy ; Anti-Bacterial Agents/therapeutic use
Chemical Substances	Anti-Bacterial Agents
Language	English
Publishing date	2023-11-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0294190
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Article ; Online: National case series of group A streptococcus pleural empyema in children: clinical and microbiological features.

Holdstock, Victoria / Twynam-Perkins, Jonathan / Bradnock, Timothy / Dickson, Elizabeth M / Harvey-Wood, Kathleen / Kalima, Pota / King, Jill / Olver, William J / Osman, Mustafa / Sabharwal, Atul / Smith, Andrew / Unger, Stefan / Pollock, Louisa / Langley, Ross / Davies, Philip / Williams, Thomas C

The Lancet. Infectious diseases

2023 Volume 23, Issue 2, Page(s) 154–156

MeSH term(s)	Child ; Humans ; Empyema, Pleural/microbiology ; Streptococcus pneumoniae ; Streptococcus pyogenes
Language	English
Publishing date	2023-01-09
Publishing country	United States
Document type	Letter
ZDB-ID	2061641-7
ISSN	1474-4457 ; 1473-3099
ISSN (online)	1474-4457
ISSN	1473-3099
DOI	10.1016/S1473-3099(23)00008-7
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Zs.A 5743: Show issues

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Article: Automated detection and delineation of lymph nodes in haematoxylin & eosin stained digitised slides.

Beuque, Manon / Magee, Derek R / Chatterjee, Avishek / Woodruff, Henry C / Langley, Ruth E / Allum, William / Nankivell, Matthew G / Cunningham, David / Lambin, Philippe / Grabsch, Heike I

Journal of pathology informatics

2023 Volume 14, Page(s) 100192

Abstract: Treatment of patients with oesophageal and gastric cancer (OeGC) is guided by disease stage, patient performance status and preferences. Lymph node (LN) status is one of the strongest prognostic factors for OeGC patients. However, survival varies between ...

Abstract	Treatment of patients with oesophageal and gastric cancer (OeGC) is guided by disease stage, patient performance status and preferences. Lymph node (LN) status is one of the strongest prognostic factors for OeGC patients. However, survival varies between patients with the same disease stage and LN status. We recently showed that LN size from patients with OeGC might also have prognostic value, thus making delineations of LNs essential for size estimation and the extraction of other imaging biomarkers. We hypothesized that a machine learning workflow is able to: (1) find digital H&E stained slides containing LNs, (2) create a scoring system providing degrees of certainty for the results, and (3) delineate LNs in those images. To train and validate the pipeline, we used 1695 H&E slides from the OE02 trial. The dataset was divided into training (80%) and validation (20%). The model was tested on an external dataset of 826 H&E slides from the OE05 trial. U-Net architecture was used to generate prediction maps from which predefined features were extracted. These features were subsequently used to train an XGBoost model to determine if a region truly contained a LN. With our innovative method, the balanced accuracies of the LN detection were 0.93 on the validation dataset (0.83 on the test dataset) compared to 0.81 (0.81) on the validation (test) datasets when using the standard method of thresholding U-Net predictions to arrive at a binary mask. Our method allowed for the creation of an "uncertain" category, and partly limited false-positive predictions on the external dataset. The mean Dice score was 0.73 (0.60) per-image and 0.66 (0.48) per-LN for the validation (test) datasets. Our pipeline detects images with LNs more accurately than conventional methods, and high-throughput delineation of LNs can facilitate future LN content analyses of large datasets.
Language	English
Publishing date	2023-01-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2579241-6
ISSN	2153-3539 ; 2229-5089
ISSN (online)	2153-3539
ISSN	2229-5089
DOI	10.1016/j.jpi.2023.100192
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