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Novel mediators in phosphate homeostasis: noncoding RNAs and the microbiome
Get PDFPhD ThesisPhosphate is an essential nutrient and its level in the blood is tightly regulated by
well-studied hormonal and non-hormonal factors. The renal sodium phosphate
cotransporter (SLC34A1) is essential to maintaining Pi homeostasis. Recently two
novel factors have emerged that potentially modulate phosphate body levels; a non-coding SLC34A1-antisense transcript and the gut microbiome.
The first part of this study aimed to understand the coordination between SLC34A1-
sense/antisense transcripts in the human renal epithelial cell lines HEK293 and
HKC8. In both cell lines SLC34A1-sense/antisense RNAs are expressed at very low
levels. Transcription of SLC34A1 was stimulated using the epigenetic modifiers
Zebularine (Zeb) and dexamethasone (Dex) and its coordinated expression was
assessed by RT-qPCR. HKC8 cells treated with Zeb showed that SLC34A1-
sense/antisense transcripts are positively correlated, i.e. concordantly upregulated. A
similar expression pattern was recorded in HEK293 cells following Dex treatment.
The expression changes were paralleled by a reduction in DNA methylation of the
sense/antisense promoter regions. In addition a significant increase in histone
acetylation (H3K27Ac) at the sense promoter and a decrease in H3K4Me3 at the
antisense promoter were detected after 5 days of Dex treatment.
After establishing a system to induce SLC34A1-sense/antisense expression with the
aid of Zeb and Dex, we sought to experimentally manipulate SLC34A1 locus
expression by introducing polyadenylation signals using CRISPR/Cas9 to silence
sense or antisense transcription, respectively. Sense- antisense expression was
quantified by RT-qPCR using different primer sites up- and downstream of the
insertion site. Unexpectedly, termination was incomplete and read-through
transcripts were generated. Again, SLC34A1-sense/antisense transcripts were
concordantly upregulated regardless of the orientation of the read-through transcript.
From a functional perspective, both strategies -hormonal induction and read-through
transcription- led to an increase in SLC34A1 protein expression as determined by
western blot and 32Pi uptake experiments.
The second part of the thesis aimed to determine the impact of a high/low Pi diet on
the human gut microbiome. The experimental strategy included a dietary intervention
in two healthy groups of volunteers followed by stool sampling, DNA extraction and
sequencing. Alpha and beta diversity examination indicated that both high and low Pi
regimens resulted in only minor alterations in bacterial compositions. However, a
focus on the relative abundance of bacterial phyla and species demonstrated a
reduction in Bacteroidetes among probands with reduced Pi intake suggesting
potential involvement of this bacterial species in Pi homeostasis.
To summarise, this PhD investigated two novel aspects in the field of microbiology of
Pi homeostasis; noncoding RNAs and the microbiome. The concordant expression
of SLC34A1-sense/antisense transcripts confirms the impact and biological
importance of the antisense transcript on SLC34A1-sense expression, potentially
affecting renal Pi reabsorption. On the other hand, consuming a high or low Pi diet
may have an impact on the abundance of certain bacterial species, but only
insignificant effects on the overall composition of the microbiome. A potential link
between the affected bacterial groups and Pi homeostasis remains to be
investigated in depth
Mitochondrial DNA methylation ; cardiovascular diseases risk and response to diet
Get PDFPh. D. Thesis.Background: Cardiovascular diseases (CVD) are the leading cause of death worldwide.
CVD are complex, multifactorial disorders caused by both genetic and environmental factors.
Approximately 80% of CVD burden is attributable to modifiable risk factors, including poor
diet, smoking, lack of physical activity, and air pollution.
Higher body mass index (BMI) is considered an intermediate risk factor for the development
of CVD. Currently, 66% of men and 58% of women in the UK have overweight or obesity.
Although excessive adiposity is a risk factor for CVD, not everyone with overweight or
obesity will develop CVD. As yet, there is no established biomarker that distinguishes those
adults with overweight and obesity who will develop CVD from those adults who will remain
CVD-free.
This project was designed to test the hypothesis that participants with overweight/obesity
who will develop CVDs show different mitochondrial DNA methylation pattern compared to
those who remain CVD-free.
Mitochondria have a central role in ageing and in the development of age-related diseases,
including CVD, which is linked with dysregulated reactive oxygen species (ROS) production,
and mitochondrial DNA (mtDNA) instability. Platelets, anucleated cells that contain only
mtDNA, have a greater reactivity in adults with overweight and obesity, and are an indicator
of CVD risk. Additionally, platelet number and reactivity have been shown to be ameliorated
by the Mediterranean diet and by plant extracts. Furthermore, platelets derive from
megakaryocytes, which are affected negatively by inflammation, dysregulated adipocytes,
and obesity.
Experimental studies: First, I investigated the effects of selected polyphenolic compounds
on mtDNA methylation in megakaryocytes in vitro. This experiment was devised to test the
effects of treatment with specific polyphenols on patterns of mtDNA methylation in the
megakaryocyte, MEG-01 cell.
Secondly, I conducted a nested case-control study within the SPHERE cohort of Italian adults
with overweight and obesity who were otherwise healthy at Baseline. In a prospective study
design, I used a targeted approach to investigate mtDNA methylation at Baseline in those
who developed CVD over the following 5 years compared with those who remained diseasefree. I identified three specific genomic loci within mtDNA i.e. MT-CO1 nt6807, MT-CO3
nt9444, and MT-TL1 nt3254, that predicted future CVD risk. MtDNA methylation level at
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these loci was independent of conventional adiposity-related CVD risk factors and so may
represent an environment-related predictor of future CVD in adults with overweight/obesity.
In addition, I investigated the associations between mtDNA methylation in platelets and
adherence to the Mediterranean diet. Higher adherence to the Mediterranean diet, as
evaluated with the MeDiet Score, was associated with lower methylation at the D-loop
nt16383 and higher methylation at MT-CO2 nt8113.However, the MeDiet Score and the
methylation level at these two genes are not associated with future CVD outcome.
In summary, this is the first study investigating patterns of platelet mtDNA methylation in
relation to future risk of CVD. I observed that higher mtDNA methylation of MT-CO1
nt6807, MT-CO3 nt9444, and MT-TL1 nt3254 in platelets was associated with a higher risk of
developing CVD within five years. In addition, this appeared to be a dose-dependent
relationship so that participants with Score 2 (high methylation at two or three loci) were
more likely to develop CVD than the participants with Score 1 (higher methylation at one
locus) and Score 0 (no loci with high methylation).Santander scholarshi
Numerical modelling of fluid flow through a powered air-purifying respirator filter
Get PDFPh. D. Thesis.Powered Air-Purifying Respirators (PAPRs), in which air is forced through a filter by means of an integrated motor and blower can provide a significantly higher level of protection than other types of respirator. There is considerable scope for improvement over existing designs, particularly with regards to breath-responsive PAPRs, which provide air only in response to the wearer’s inhalation. Understanding the flow of air through such respirators presents a challenging fluid dynamics problem.
In this thesis, the state-of-the-art of respiratory protection is reviewed in order to identify shortcomings and potential areas of improvement. A system-level model has also been developed, which considers each of the key components of a PAPR and presents a simplified depiction of various PAPR parameters under a range of operating conditions. This tool has been designed to integrate more in-depth models of the various PAPR components as they are developed.
The area with the greatest scope for development was found to be the filter. A series of computational fluid dynamics (CFD) simulations using the finite volume method to solve the discretised Reynolds-averaged Navier-Stokes (RANS) equations were conducted based on a typical Chemical Biological Radiological and Nuclear (CNRN) filter canister.
An initial analysis has been conducted to measure the impact of canister geometry on performance metrics such as the pressure drop and the residence time distribution throughout the adsorbent bed by performing a parametric analysis of steady-state axisymmetric simulations. A selection of these geometries were then investigated under transient flow conditions.
A full 3D model of an existing canister geometry has then been developed and simulations are conducted to investigate the extent to which canister performance under steady flow conditions can be used to predict flow behaviour when under a range of real human breathing patterns.
A model to predict adsorption performance of volatile organic compounds on activated carbon has been developed in conjunction with experimental adsorption data, with the intention of relating adsorption behaviour to flow.
The distribution of porosity throughout the adsorbent bed has been shown to have a considerable impact on the distribution of flow. A new method has been developed to better represent the porosity profile by subdividing the bed into discrete sections and assigning a local porosity based on a longitudinally-averaged porosity profile which has been pseudo-randomly perturbed. This porosity model has then been implemented within a 3D CBRN canister model to investigate how different parameters of the porosity model will affect flow.
Axisymmetric simulations have been carried out on a simplified carbon bed geometry using both of these novel adsorption and porosity models in order to gain a better understanding of how the residence time distribution can be related to adsorption.DSTL and EPSR
Prediction of in-hospital mortality in exacerbations of chronic obstructive pulmonary disease requiring assisted ventilation, and patient-centred outcomes over the subsequent year
Get PDFPh. D. Thesis.Background: COPD exacerbations account for over 141,000 hospitalisations annually in
the UK, and 20% are complicated by respiratory acidaemia. In such cases non-invasive
ventilation (NIV) substantially reduces mortality, but only 50% of patients receive NIV
and delivery is often suboptimal. Prognostic pessimism may partially explain underuse.
Little is known about the quality of life (QoL) of patients following ventilation.
Aims and Methods: The NIV Outcomes (NIVO) study aimed to validate a simple
prognostic tool for inpatient mortality in this population and assess patient-centred
outcomes over one year among those surviving to discharge. Prospective recruitment of
patients occurred in 10 trusts. Model performance was assessed. QoL and mortality
were tracked for one year following discharge.
Results: 733 patients were included. The NIVO score comprised eMRCD, acidaemia
occurring >12 hours after admission, atrial fibrillation, chest x-ray consolidation,
Glasgow coma scale ≤14 and pH <7.25. Stepwise increase in inpatient mortality was
observed, with a c-statistic of 0.79. The NIVO score significantly outperformed preidentified comparator scores. 586 patients survived to discharge; QoL was assessed in
272 patients over one year. Symptom burden was substantial. QoL peaked 2-months
after discharge and overall was well maintained subsequently. Most patients would
accept NIV again. Poor outcome, defined as death within six months or poor QoL with a
clinically significant deterioration, could be accurately predicted (c-statistic 0.81) using:
LTOT, admission haemoglobin, left ventricular systolic dysfunction, diaphragm height,
confusion, plus measures of depression and independence.
Discussion: Using six simple indices strong prediction of inpatient mortality was
achieved. In most survivors, QoL remained stable over one year post-discharge.
Predictors of patients likely to have poor outcome were identified. Clinical applications
include facilitating informed discussions with patients and shared decisions about
escalation to ventilation, challenging pessimism, comparing risk-adjusted outcomes
between units (national audit), advance care planning and referral to specialist services
Understanding Charles Bonnet syndrome: mechanisms and intervention
Get PDFPh. D. Thesis.Background: Charles Bonnet Syndrome (CBS) is defined by the occurrence of vivid,
recurring visual hallucinations (VH) secondary to visual impairment in the absence of
psychiatric illness or cognitive impairment. Previous research has proposed that
deafferentation, due to loss of sensory input from the eyes, leads to spontaneous
hyperexcitability in the visual cortex resulting in VH. Approximately one-third of people
with CBS report distress and disruption to daily functioning as a consequence of VH,
however there are currently no effective treatments and a lack of research into the aetiology
of VH has hindered their development.
Aims: 1) To investigate the role of visual cortical activity in the production of VH in CBS,
compared to non-hallucinating controls, to better understand why VH occur in some patients
but not others. 2) To investigate whether inhibitory non-invasive transcranial direct current
stimulation (tDCS) could be used to remediate VH by reducing cortical excitability in CBS.
Methods: Study 1: A comparison study consisting of people with CBS (n=19) and nonhallucinating sight-matched controls (n=18) was performed utilising transcranial magnetic
stimulation, functional magnetic resonance imaging, and magnetic resonance spectroscopy to
compare differences in visual cortical activity between groups. Study 2: Informed by a pilot
study in continuous CBS hallucinators, sixteen members of the CBS group received 4-
consecutive days of active and sham inhibitory tDCS over the primary visual cortex,
comparing visual cortical activity and VH ratings before and after stimulation between active
and sham weeks.
Results: Study 1: Comparable visual cortical excitability was observed in both groups,
although greater excitability was associated with more severe VH in the CBS group.
Functional activation of the visual cortex was observed to be lower in the CBS group than
controls during an eye movement task, with greater functional activation associated with
lower visual cortical excitability. Study 2: Active cathodal tDCS of the primary visual cortex
resulted in a significant decrease to VH frequency and intrusiveness compared to sham
stimulation. No significant changes to cortical activity were observed following stimulation.
Conclusions: This thesis constitutes the largest neurophysiological comparison and treatment
study performed in CBS to date. These data support the role of changes to visual cortical
activity in the production of VH following sight loss, providing a basis for further study.
Furthermore, tDCS was observed to present a potential effective new treatment option for
CBS, however further study is needed to understand underlying mechanisms.The Macular Society, Esme’s Umbrella, Fight for Sight, the
National Eye Research Centre, and the Thomas Pocklington Trus
Accounting for social value: exploring local perspectives and annual reporting by local third sector infrastructure organisations in England
Get PDFPh. D. Thesis.The Public Services (Social Value) Act 2012 led to increased interest in social value among
public service and third sector organisations, due to its perceived potential for securing greater
economic, social or environmental benefits. The non-prescriptive nature of the legislation
offers flexibility for interpreting and communicating social value. Utilising multiple
constituency theory (MCT), institutional reality theory (IRT) and accountability concepts, the
study explores interpretations of social value from local authority, community foundation and
local third sector infrastructure organisation (LTSIO) perspectives, and their influence on
LTSIO annual reporting.
A qualitative multi-methods research design supported exploration of local perspectives and
reporting practice. Thematic analysis of local authority documents, LTSIO annual reports and
interviews with local authority, community foundation and LTSIO managers contributed to
the study’s findings.
Multiple interpretations of social value were found to co-exist within an overarching theme of
economic, social and environmental benefits. Although resource providers presented as
dominant constituencies influencing definitions, the study adds to knowledge and theory in
developing a more nuanced version of MCT power perspectives by recognising power ceded
to service providers where major changes in resource interdependency are evident.
Additionally, the findings contribute to social accounting literature by highlighting
perceptions of monetised metrics as epistemologically subjective, unstable representations of
social and economic reality. Conversely, alternative reporting methods incorporating
epistemologically objective non-monetised metrics and illustrative examples offer more stable
and transparent representations of social value.
The findings also contribute to policy and practice by demonstrating that organisational social
responsibilities (OSR) constitute the basis of LTSIO reporting on social value. Extending
charity accounting guidance to encourage reporting on ethical and citizenship dimensions of
OSR alongside social mission would further a more holistic accountability.
The use of MCT and IRT alongside accountability concepts provides a highly applicable lens
for understanding accounts of social value from differing constituency perspectives.Economic and Social Research Counci
Blend formation tendencies, from English to Arabic : a comparative study
Get PDFPhD ThesisBlending in English is a widely recognized means for forming new lexemes by joining two or more existing words in a way where at least one of them is shortened (Algeo 1991: 10). Familiar examples are brunch from breakfast and lunch, slanguage from slang and language, and chortle from chuckle and snort (Algeo 1977: 49). Linguistic studies of English blends – which are numerous – have focused in particular on the three following features of blends: the cut-off point in the source words, the proportional contributions from the source words to the blend, and the stress pattern of the blend.
The main aim of the present research is to examine Arabic blends in the light of the blend formation tendencies that have been identified with respect to these features in English.
Blends in Classical Arabic are generally formed by joining the first two root consonants of each source word and imposing the prosodic pattern CaCCaC on them. Typical examples of Classical Arabic blends are /ʕabdar(ij)/ 'someone from the family of Abdul Dār' < /ʕabd/ 'slave' and /da:r/ 'house', /ʕabqas(ij)/ 'someone from the family of Abdul Qays' < /ʕabd/ 'slave' and /qajs/ 'a male name', and /ʕabʃam(ij)/ 'someone from the family of Abdi Shams' < /ʕabd/ 'slave' and /ʃams/ 'sun'– all names for Arab tribes in the 6th Century AD. However, such Classical blends are few in number. The more numerous blends that have been formed in Arabic in recent times do not appear to follow this root-and-pattern template. Examples are /fawsʕawt(ij)/ 'supersonic' < /fawq/ 'above' and /sʕawt(ij)/ 'sound', and /qabħarb/ 'pre-war' < /qabl/ 'before' and /ħarb/ 'war'.
Since no linguistic study has investigated in depth the structure of modern Arabic blends, the main aim of this thesis is to uncover the regularities that are found in these modern formations and in that way contribute to understanding the structure of Arabic words in general and blends in particular.
The main research question in this study is: To what extent do the blend formation tendencies identified in English apply to blend formation in Arabic?
The data for Arabic come from published resources as well as a survey and an experiment, both designed to collect some novel blends by asking native speakers of Arabic to form blends from a list of word pairs. These data were examined in light of the main features and tendencies related to blend-formation in English. The overall result of the investigation is that there is a high degree of resemblance between modern Arabic blends and English blends. This is the case for both the established Modern Arabic blends and the novel invented blends. In this respect, they differ notably from the established blends of Classical Arabic.
The main tendencies for forming Arabic blends that have been identified in this study are:
(1) There is a general tendency for the cut-off points in source words to occur at syllabic joints with the greatest preference for them to occur between syllabic constituents.
(2) There is a general tendency for the greater proportional contribution to come from the shorter source word, and for source words of equal phonemic lengths to contribute equal proportions to the blend.
(3) There is a general tendency for the stress pattern of the blend to be identical to that of the source word that has identical syllabic size as that of the blend.the Directorate of Scholarships and Cultural Relations of the Iraqi Ministry of Higher Education and Scientific Researc
Impact of ageing on mitochondrial complex expression and islet cell composition in mtDNA mutator mice and human pancreas
Get PDFPh. D. Thesis.Age-related cumulative mitochondrial mutations can cause mitochondrial dysfunction. The
mitochondrial DNA mutator mouse (PolgAmut/mut) is a model of premature ageing and has been
previously shown to develop impaired insulin secretion with age. Normal human ageing has been
associated with islet β-cell dysfunction and the change of islet cell composition. The overall aim was
to explore the impact of ageing on mitochondrial complex expression and islet cell composition in
PolgAmut/mut mice and human pancreas.
Immunofluorescence was used to study mitochondrial respiratory chain protein expression (complex
I and IV) by normalizing to mitochondrial mass marker (Tomm20). This technique was also applied to
the study of islet cell composition with proliferation marker Ki67. Experiments were conducted on
pancreas tissue from PolgAmut/mut mice and age-matched wild type (WT) mice at two ages: 3 months
(young) and 11 months(old). Some of the PolgAmut/mut mice underwent exercise training from 4 months
of age. Non-diabetic normal human pancreas tissue from two age groups: 20~40 years (young) and
60~80 years (old) were also studied for mitochondrial complex expression and islet cell composition.
The findings of the first three result chapters described the impact of ageing in mtDNA mutator mice
model. Complex I expression was decreased in islets from young PolgAmut/mut mice, and it persisted
with age in comparison with the WT mice. Investigation of islet cell composition identified an increase
in absolute α-cell number with age in the PolgAmut/mut mice that contributed to a decreased β:α ratio
in islets from the old PolgAmut/mut mice versus the age-matched WT mice. Ki67 examination showed
that increased α-cell proliferation contributed to the increase in α-cell mass. Islet cell subtype analysis
in old PolgAmut/mut mice revealed that the complex I deficiency was greater in the α-cells compared
with the β-cells, suggesting that the increased α-cell proliferation observed in old PolgAmut/mut mouse
islets maybe a direct response to complex I deficiency. Although none of these mice developed
diabetes with age, decreased insulin expression was discovered in the pancreatic islets of the old
PolgAmut/mut mice. Endurance exercise did not have significant impact on mitochondrial complex
expression nor islet cell composition in old PolgAmut/mut mice. The last result chapter explored the
impact of ageing in human pancreatic tissues from non-diabetic donors. Tomm20 expression was
higher in pancreatic islets from old versus young donors, but there was no difference in complex I and
IV expression. Whole islet cell number and absolute β-cell number were lower in the old versus young
islets, but there was no significant difference in the β:α ratio. Taken together, my findings show that
mitochondrial dysfunction alters pancreatic islet cell composition in response to ageing in the
PolgAmut/mut mice. In non-diabetic human islets, there is no evidence of altered mitochondrial subunit
expression but Tomm20 expression was increased in the islets from old donors appears to reflect a
compensatory increase in mitochondrial mass
The Role of Fractalkine and CX3CR1-expressing lymphocytes during myocardial ischaemia/reperfusion injury
Get PDFPhD ThesisIntroduction: Ischaemia/reperfusion (I/R) injury contributes up to 50% of the final infarct size following myocardial infarction (MI). Lymphocytes expressing the fractalkine receptor (CX3CR1) are associated with poor long-term survival. This project aims to investigate the role of fractalkine in lymphocyte-mediated myocardial I/R injury and evaluate whether this damage can be reduced by inhibiting fractalkine/receptor (CX3CL1/CX3CR1) interaction.
Methods: Flow cytometry, microscopy, qPCR, mass cytometry and MRI are used to study lymphocyte infiltration following MI in a surgical mouse model of I/R injury.
Results: CX3CR1 knockout leads to over 30% reduction in leukocyte infiltration at the MI site 2h after reperfusion, both in heterozygous (p≤0.01) and knockout (p≤0.001) mice. This returns to WT levels by 24h I/R. Despite the 20% increase in leukocyte infiltration at 24h, CX3CR1 knockout mice show a 2-fold decrease in T cell infiltrate, compared to WT (p≤0.01) and heterozygous animals (p≤0.001). Knockout mice show 30% reduction in the number of CX3CR1-expressing T cells and 50% in total CX3CR1+ cells (p≤0.01) that infiltrate the injured myocardium. MRI shows a trend towards more detrimental cardiac function in CX3CR1 heterozygous and knockout mice. Moreover, RAG2 knockout mice show non-significant 35% increase (p=0.067) in leukocyte infiltrate. Finally, significant T cell maturation and increase in CX3CR1 expression is detected in mouse models of ageing and infection.
Conclusions: These findings suggest that knockout of CX3CR1 leads to delayed recruitment of leukocytes following cardiac I/R. This results in an altered immune cell infiltrate including reduced number of T cells. In addition, the role for CX3CR1-expressing T cells in myocardial I/R is supported by results showing that the number of CX3CR1+ CD3+ cells is significantly reduced from heterozygous to knockout animals following injury. However, more clinically representative mouse models may be required in order to elucidate the role of CX3CR1+ T cells in myocardial I/R
Family business in Saudi Arabia
Get PDFPhD ThesisThis thesis constitutes the first comprehensive study of family business in Saudi Arabia. Others have focused on aspects of the topic such as succession and strategy, but no prior author has conducted a multi-faceted investigation of the type presented here. Yet family business is an institution of fundamental importance to the economy and society in the country, accounting for a large proportion of employment in the private sector in firms large and small. In what follows, family business is located within the context of national economic policy (chapter 4), its social foundations are analysed (chapter 5), a typology is presented revealing profound differences between firms with respect to age, size and decision making (chapter 6), and issues relating to power, governance, succession and conflict are revealed and interpreted (chapter 7). Comparisons are made between family businesses in Saudi Arabia and in western countries, mainly the UK and USA, to highlight what is truly distinctive about custom and practice in Saudi Arabia.
The approach taken in this thesis is primarily qualitative. Semi-structured interviews were conducted at 30 companies with 60 family members of differing status, including CEOs, chairmen and executives, of whom 10 were women and 50 were men. Additionally, documents were gathered from publicly available sources for each case relating to strategy, management and organization. The data were then coded thematically and analysed using the Gioia methodology to identify aggregate themes. Each theme was then examined, discussed and interpreted in detail, drawing on appropriate theory. Especially important to this exercise in sensemaking were the theoretical ideas and constructs of Pierre Bourdieu, enabling fresh insights to be garnered concerning power and the social organization of family business in Saudi Arabia.
Little is known or published concerning the role of family members and their daily interactions in family business in Saudi Arabia. My research aims to fill this gap in the literature. A focus on capturing Islamic cultural identity from a Saudi perspective and reflecting upon Saudi nationals’ views and lifestyles are fundamental to understanding family businesses in the country. My research has led to three original and substantive findings. First, while many other authors have identified the importance of culture in shaping family business, I find Saudi Arabia to be distinguished by its stringent approach to the application of Islamic law and societal norms, resulting in distinctive practices such as gender segregation and men inheriting twice as much as women. Second, I find that firm strategies vary considerably depending on company size, age and the practices of family members, leading to four predominant types of strategic decision making. Third, I find that the nature of succession problems varies depending on firm size. In small and medium-sized firms, succession is conceived in classical terms of management succession, with the older generation typically micromanaging the future, whereas in large firms what matters is ownership succession since managerial authority has already been delegated to professional managers.Taibah Universit