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Article ; Online: Regulation of 1 and 24 hydroxylation of vitamin D metabolites in the proximal tubule.

Young, Kennedi / Beggs, Megan R / Grimbly, Chelsey / Alexander, R Todd

Experimental biology and medicine (Maywood, N.J.)

2022 Volume 247, Issue 13, Page(s) 1103–1111

Abstract: ... concentration of these ions are tightly regulated. Calcitriol, the active form of vitamin D, is a positive ... hydroxyitamin D. The next hydroxylation step occurs in the renal proximal tubule via the 1-αhydroxylase enzyme ...

Abstract	Calcium and phosphate are critical for numerous physiological processes. Consequently, the plasma concentration of these ions are tightly regulated. Calcitriol, the active form of vitamin D, is a positive modulator of mineralization as well as calcium and phosphate metabolism. The molecular and physiological effects of calcitriol are well documented. Calcitriol increases blood calcium and phosphate levels by increasing absorption from the intestine, and resorption of bone. Calcitriol synthesis is a multistep process. A precursor is first made via skin exposure to UV, it is then 25-hydroxylated in the liver to form 25-hydroxyitamin D. The next hydroxylation step occurs in the renal proximal tubule via the 1-αhydroxylase enzyme (encoded by
MeSH term(s)	25-Hydroxyvitamin D3 1-alpha-Hydroxylase/metabolism ; Calcitriol/pharmacology ; Calcium/metabolism ; Hydroxylation ; Parathyroid Hormone ; Phosphates ; Receptors, Calcitriol/metabolism ; Vitamin D ; Vitamin D3 24-Hydroxylase/metabolism
Chemical Substances	Parathyroid Hormone ; Phosphates ; Receptors, Calcitriol ; Vitamin D (1406-16-2) ; Vitamin D3 24-Hydroxylase (EC 1.14.15.16) ; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase (EC 1.14.15.18) ; Calcitriol (FXC9231JVH) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2022-04-28
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	4015-0
ISSN	1535-3699 ; 1525-1373 ; 0037-9727
ISSN (online)	1535-3699 ; 1525-1373
ISSN	0037-9727
DOI	10.1177/15353702221091982
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Article ; Online: The Gut Microbiome, Microsatellite Status and the Response to Immunotherapy in Colorectal Cancer.

Sillo, Toritseju O / Beggs, Andrew D / Middleton, Gary / Akingboye, Akinfemi

International journal of molecular sciences

2023 Volume 24, Issue 6

Abstract: There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with ... ...

Abstract	There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field.
MeSH term(s)	Humans ; Gastrointestinal Microbiome/genetics ; Colorectal Neoplasms/therapy ; Colorectal Neoplasms/drug therapy ; Immunotherapy ; Microsatellite Repeats ; DNA Mismatch Repair ; Microsatellite Instability
Language	English
Publishing date	2023-03-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24065767
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Article: Measuring Energy Requirements of Traumatic Brain Injury Patients in Pediatric Intensive Care With Indirect Calorimetry: A Comparison With Empiric Methods.

Beggs, Megan R / Ashkin, Allison / Larsen, Bodil M K / Garros, Daniel

Pediatric critical care medicine : a journal of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies

2023 Volume 24, Issue 10, Page(s) e468–e475

Abstract: Objectives: Energy requirements following moderate or severe pediatric traumatic brain injury (TBI) have not been fully elucidated. Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure (MREE) in PICU. However, ... ...

Abstract	Objectives: Energy requirements following moderate or severe pediatric traumatic brain injury (TBI) have not been fully elucidated. Indirect calorimetry (IC) is the gold standard for measuring resting energy expenditure (MREE) in PICU. However, technical complexity limits its use. We aimed to determine whether MREE differs from standard of care energy estimation and delivery in a cohort of pediatric patients following moderate to severe TBI during PICU admission. Design: Retrospective case series study. Setting: Single-center, 16-bed general PICU in Canada between May 2011 and January 2019. Patients: Children (0-18 yr) admitted to a PICU for moderate (Glasgow Coma Scale [GCS] 9-12) to severe TBI (GCS < 9) and had an IC study performed while mechanically ventilated. Interventions: None. Measurements and main results: During the study period, 245 patients were admitted with the diagnosis of trauma with TBI. The study includes a convenience sample of 26 patients with severe ( n = 23) and moderate ( n = 3) TBI who underwent a total of 34 IC measurements. MREE varied considerably from 29% to 144% of predicted energy expenditure. Using Bland-Altman comparative analysis, neither Schofield nor World Health Organization predictive equations were in agreement with MREE. Only one measurement revealed that the patient was appropriately fed (energy provided in nutrition support was within 10% of MREE); 10 (38%) measurements revealed overfeeding and 15 (58%) underfeeding at the time of testing. Conclusions: The present study adds to the small body of literature highlighting the limitations of predictive equations to evaluate energy requirements following moderate to severe pediatric TBI. IC, when feasible, should be used as the preferred method to orient PICU teams to feed such vulnerable patients.
MeSH term(s)	Humans ; Child ; Calorimetry, Indirect ; Retrospective Studies ; Basal Metabolism ; Energy Metabolism ; Brain Injuries, Traumatic/therapy ; Critical Care
Language	English
Publishing date	2023-05-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2052349-X
ISSN	1947-3893 ; 1529-7535
ISSN (online)	1947-3893
ISSN	1529-7535
DOI	10.1097/PCC.0000000000003266
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Zs.MO 472: Show issues

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Article ; Online: Conditional depletion of transcriptional kinases Ctk1 and Bur1 and effects on co-transcriptional spliceosome assembly and pre-mRNA splicing.

Maudlin, Isabella E / Beggs, Jean D

RNA biology

2021 Volume 18, Issue sup2, Page(s) 782–793

Abstract: From yeast to humans, pre-mRNA splicing occurs mainly co-transcriptionally, with splicing and transcription functionally coupled such that they influence one another. The recruitment model of co-transcriptional splicing proposes that core members of the ... ...

Abstract	From yeast to humans, pre-mRNA splicing occurs mainly co-transcriptionally, with splicing and transcription functionally coupled such that they influence one another. The recruitment model of co-transcriptional splicing proposes that core members of the transcription elongation machinery have the potential to influence co-transcriptional spliceosome assembly and pre-mRNA splicing. Here, we tested whether the transcription elongation kinases Bur1 and Ctk1 affect co-transcriptional spliceosome assembly and pre-mRNA splicing in the budding yeast
MeSH term(s)	Chromosomal Proteins, Non-Histone/metabolism ; Cyclin-Dependent Kinases/metabolism ; Gene Expression Regulation, Fungal ; Phosphorylation ; Protein Kinases/metabolism ; RNA Precursors/genetics ; RNA Splicing ; Saccharomyces cerevisiae Proteins/metabolism ; Spliceosomes/metabolism ; Transcriptional Elongation Factors/metabolism
Chemical Substances	CTDK-I protein complex, S cerevisiae ; Chromosomal Proteins, Non-Histone ; RNA Precursors ; Saccharomyces cerevisiae Proteins ; Transcriptional Elongation Factors ; SPT5 transcriptional elongation factor (138673-72-0) ; Protein Kinases (EC 2.7.-) ; Cyclin-Dependent Kinases (EC 2.7.11.22) ; SGV1 protein, S cerevisiae (EC 2.7.11.22)
Language	English
Publishing date	2021-10-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2159587-2
ISSN	1555-8584 ; 1555-8584
ISSN (online)	1555-8584
ISSN	1555-8584
DOI	10.1080/15476286.2021.1991673
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Article ; Online: Mutagenesis of Snu114 domain IV identifies a developmental role in meiotic splicing.

Gautam, Amit / Beggs, Jean D

RNA biology

2019 Volume 16, Issue 2, Page(s) 185–195

Abstract: Snu114, a component of the U5 snRNP, plays a key role in activation of the spliceosome. It controls the action of Brr2, an RNA-stimulated ATPase/RNA helicase that disrupts U4/U6 snRNA base-pairing prior to formation of the spliceosome's catalytic centre. ...

Abstract	Snu114, a component of the U5 snRNP, plays a key role in activation of the spliceosome. It controls the action of Brr2, an RNA-stimulated ATPase/RNA helicase that disrupts U4/U6 snRNA base-pairing prior to formation of the spliceosome's catalytic centre. Snu114 has a highly conserved domain structure that resembles that of the GTPase EF-2/EF-G in the ribosome. It has been suggested that the regulatory function of Snu114 in activation of the spliceosome is mediated by its C-terminal region, however, there has been only limited characterisation of the interactions of the C-terminal domains. We show a direct interaction between protein phosphatase PP1 and Snu114 domain 'IVa' and identify sequence 'YGVQYK' as a PP1 binding motif. Interestingly, this motif is also required for Cwc21 binding. We provide evidence for mutually exclusive interaction of Cwc21 and PP1 with Snu114 and show that the affinity of Cwc21 and PP1 for Snu114 is influenced by the different nucleotide-bound states of Snu114. Moreover, we identify a novel mutation in domain IVa that, while not affecting vegetative growth of yeast cells, causes a defect in splicing transcripts of the meiotic genes, SPO22, AMA1 and MER2, thereby inhibiting an early stage of meiosis.
MeSH term(s)	Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; Carrier Proteins/genetics ; Carrier Proteins/metabolism ; Cell Cycle/genetics ; Epistasis, Genetic ; Gene Expression Regulation ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Miosis/genetics ; Miosis/metabolism ; Mutagenesis ; Mutation ; Protein Binding ; Protein Interaction Domains and Motifs/genetics ; RNA Splicing ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Ribonucleoprotein, U5 Small Nuclear/chemistry ; Ribonucleoprotein, U5 Small Nuclear/genetics ; Ribonucleoprotein, U5 Small Nuclear/metabolism
Chemical Substances	Carrier Proteins ; RNA-Binding Proteins ; Ribonucleoprotein, U5 Small Nuclear ; Guanosine Diphosphate (146-91-8) ; Guanosine Triphosphate (86-01-1)
Language	English
Publishing date	2019-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2159587-2
ISSN	1555-8584 ; 1555-8584
ISSN (online)	1555-8584
ISSN	1555-8584
DOI	10.1080/15476286.2018.1561145
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Article ; Online: Mutation Frequencies in Patients With Early-Onset Colorectal Cancer.

Beggs, Andrew D

JAMA oncology

2017 Volume 3, Issue 11, Page(s) 1585

MeSH term(s)	Colorectal Neoplasms/epidemiology ; Germ Cells ; Germ-Line Mutation ; Humans ; Mutation Rate ; Prevalence
Language	English
Publishing date	2017-07-04
Publishing country	United States
Document type	Journal Article ; Comment
ISSN	2374-2445
ISSN (online)	2374-2445
DOI	10.1001/jamaoncol.2016.7089
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Book ; Online: The dynamics of belief

Beggs, Edwin J. / Tucker, John V.

continuously monitoring and visualising complex systems

2022

Abstract: The rise of AI in human contexts places new demands on automated systems to be transparent and explainable. We examine some anthropomorphic ideas and principles relevant to such accountablity in order to develop a theoretical framework for thinking about ...

Abstract	The rise of AI in human contexts places new demands on automated systems to be transparent and explainable. We examine some anthropomorphic ideas and principles relevant to such accountablity in order to develop a theoretical framework for thinking about digital systems in complex human contexts and the problem of explaining their behaviour. Structurally, systems are made of modular and hierachical components, which we abstract in a new system model using notions of modes and mode transitions. A mode is an independent component of the system with its own objectives, monitoring data, and algorithms. The behaviour of a mode, including its transitions to other modes, is determined by functions that interpret each mode's monitoring data in the light of its objectives and algorithms. We show how these belief functions can help explain system behaviour by visualising their evaluation as trajectories in higher-dimensional geometric spaces. These ideas are formalised mathematically by abstract and concrete simplicial complexes. We offer three techniques: a framework for design heuristics, a general system theory based on modes, and a geometric visualisation, and apply them in three types of human-centred systems. Comment: Comments welcome
Keywords	Computer Science - Artificial Intelligence ; Electrical Engineering and Systems Science - Systems and Control ; I.6.5 ; D.2.2 ; I.2.0
Subject code	006
Publishing date	2022-08-11
Publishing country	us
Document type	Book ; Online
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Article ; Online: Revisiting the window of opportunity for cotranscriptional splicing in budding yeast.

Aslanzadeh, Vahid / Beggs, Jean D

RNA (New York, N.Y.)

2020 Volume 26, Issue 9, Page(s) 1081–1085

Abstract: We reported previously that, in budding yeast, transcription rate affects both the efficiency and fidelity of pre-mRNA splicing, especially of ribosomal protein transcripts. Here, we report that the majority of ribosomal protein transcripts with non- ... ...

Abstract	We reported previously that, in budding yeast, transcription rate affects both the efficiency and fidelity of pre-mRNA splicing, especially of ribosomal protein transcripts. Here, we report that the majority of ribosomal protein transcripts with non-consensus 5' splice sites are spliced less efficiently when transcription is faster, and more efficiently with slower transcription. These results support the "window of opportunity" model, and we suggest a possible mechanism to explain these findings.
MeSH term(s)	RNA Precursors/genetics ; RNA Splicing/genetics ; Ribosomes/genetics ; Saccharomycetales/genetics ; Transcription, Genetic/genetics
Chemical Substances	RNA Precursors
Language	English
Publishing date	2020-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.075895.120
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Zs.A 4777: Show issues

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Article: The impact of stress and anesthesia on animal models of infectious disease.

Layton, Rachel / Layton, Daniel / Beggs, David / Fisher, Andrew / Mansell, Peter / Stanger, Kelly J

Frontiers in veterinary science

2023 Volume 10, Page(s) 1086003

Abstract: Stress and general anesthesia have an impact on the functional response of the organism due to the detrimental effects on cardiovascular, immunological, and metabolic function, which could limit the organism's response to an infectious event. Animal ... ...

Abstract	Stress and general anesthesia have an impact on the functional response of the organism due to the detrimental effects on cardiovascular, immunological, and metabolic function, which could limit the organism's response to an infectious event. Animal studies have formed an essential step in understanding and mitigating infectious diseases, as the complexities of physiology and immunity cannot yet be replicated
Language	English
Publishing date	2023-02-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2834243-4
ISSN	2297-1769
ISSN	2297-1769
DOI	10.3389/fvets.2023.1086003
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Article ; Online: Impact of supplementary air filtration on aerosols and particulate matter in a UK hospital ward: a case study.

Butler, M J / Sloof, D / Peters, C / Conway Morris, A / Gouliouris, T / Thaxter, R / Keevil, V L / Beggs, C B

The Journal of hospital infection

2023 Volume 135, Page(s) 81–89

Abstract: Background: Aerosol spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a major problem in hospitals, leading to an increase in supplementary high-efficiency particulate air filtration aimed at reducing nosocomial transmission. ... ...

Abstract	Background: Aerosol spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is a major problem in hospitals, leading to an increase in supplementary high-efficiency particulate air filtration aimed at reducing nosocomial transmission. This article reports a natural experiment that occurred when an air cleaning unit (ACU) on a medicine for older people ward was switched off accidentally while being commissioned. Aim: To assess aerosol transport within the ward and determine whether the ACU reduced airborne particulate matter (PM) levels. Methods: An ACU was placed in a ward comprising two six-bedded bays plus three single-bed isolation rooms which had previously experienced several outbreaks of coronavirus disease 2019. During commissioning, real-time measurements of key indoor air quality parameters (PM1-10, CO Findings: The ACU reduced the PM counts considerably (e.g. PM1 65.5-78.2%) throughout the ward (P<0.001 all sizes), with positive correlation found for all PM fractions and CO Conclusion: Aerosols migrated rapidly between the various ward subcompartments, suggesting that social distancing alone cannot prevent nosocomial transmission of SARS-CoV-2 as this fails to mitigate longer-range (>2 m) transmission. The ACU reduced PM levels considerably throughout the ward space, indicating its potential as an effective intervention to reduce the risk posed by infectious airborne particles.
MeSH term(s)	Humans ; Aged ; Particulate Matter/analysis ; COVID-19/prevention & control ; SARS-CoV-2 ; Carbon Dioxide ; Respiratory Aerosols and Droplets ; Air Pollution, Indoor/analysis ; Hospitals ; Cross Infection/prevention & control ; United Kingdom
Chemical Substances	Particulate Matter ; Carbon Dioxide (142M471B3J)
Language	English
Publishing date	2023-02-24
Publishing country	England
Document type	Journal Article
ZDB-ID	779366-2
ISSN	1532-2939 ; 0195-6701
ISSN (online)	1532-2939
ISSN	0195-6701
DOI	10.1016/j.jhin.2023.02.006
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